In a lecture he delivered in 1906, the German physician Paul Ehrlich coined the term Zauberkugel, or "magic bullet," as shorthand for a highly targeted medical treatment.
Magic bullets, also called silver bullets, because of the folkloric belief that only silver bullets can kill supernatural creatures, remain the goal of drug development efforts today.
A team of scientists at Washington University in St. Louis is currently working on a magic bullet for cancer, a disease whose treatments are notoriously indiscriminate and nonspecific. But their bullets are gold rather than silver. Literally.
The gold bullets are gold nanocages that, when injected, selectively accumulate in tumors. When the tumors are later bathed in laser light, the surrounding tissue is barely warmed, but the nanocages convert light to heat, killing the malignant cells.
In an article just published in the journal Small, the team describes the successful photothermal treatment of tumors in mice.
The team includes Younan Xia, Ph.D., the James M. McKelvey Professor of Biomedical Engineering in the School of Engineering and Applied Science, Michael J. Welch, Ph.D., professor of radiology and developmental biology in the School of Medicine, Jingyi Chen, Ph.D., research assistant professor of biomedical engineering and Charles Glaus, Ph.D., a postdoctoral research associate in the Department of Radiology.
"We saw significant changes in tumor metabolism and histology," says Welch, "which is remarkable given that the work was exploratory, the laser 'dose' had not been maximized, and the tumors were 'passively' rather than 'actively' targeted."
Why the nanocages get hot
The nanocages themselves are harmless. "Gold salts and gold colloids have been used to treat arthritis for more than 100 years," says Welch. "People know what gold does in the body and it's inert, so we hope this is going to be a nontoxic approach."
"The key to photothermal therapy," says Xia, "is the cages' ability to efficiently absorb light and convert it to heat. "
Suspensions of the gold nanocages, which are roughly the same size as a virus particle, are not always yellow, as one would expect, but instead can be any color in the rainbow.
They are colored by something called a surface plasmon resonance. Some of the electrons in the gold are not anchored to individual atoms but instead form a free-floating electron gas, Xia explains. Light falling on these electrons can drive them to oscillate as one. This collective oscillation, the surface plasmon, picks a particular wavelength, or color, out of the incident light, and this determines the color we see.
Medieval artisans made ruby-red stained glass by mixing gold chloride into molten glass, a process that left tiny gold particles suspended in the glass, says Xia.
The resonance - and the color - can be tuned over a wide range of wavelengths by altering the thickness of the cages' walls. For biomedical applications, Xia's lab tunes the cages to 800 nanometers, a wavelength that falls in a window of tissue transparency that lies between 750 and 900 nanometers, in the near-infrared part of the spectrum.
Light in this sweet spot can penetrate as deep as several inches in the body (either from the skin or the interior of the gastrointestinal tract or other organ systems).
The conversion of light to heat arises from the same physical effect as the color. The resonance has two parts. At the resonant frequency, light is typically both scattered off the cages and absorbed by them.
By controlling the cages' size, Xia's lab tailors them to achieve maximum absorption.
Passive targeting
"If we put bare nanoparticles into your body," says Xia, "proteins would deposit on the particles, and they would be captured by the immune system and dragged out of the bloodstream into the liver or spleen."
To prevent this, the lab coated the nanocages with a layer of PEG, a nontoxic chemical most people have encountered in the form of the laxatives GoLyTELY or MiraLAX. PEG resists the adsorption of proteins, in effect disguising the nanoparticles so that the immune system cannot recognize them.
Instead of being swept from the bloodstream, the disguised particles circulate long enough to accumulate in tumors.
A growing tumor must develop its own blood supply to prevent its core from being starved of oxygen and nutrients. But tumor vessels are as aberrant as tumor cells. They have irregular diameters and abnormal branching patterns, but most importantly, they have thin, leaky walls.
The cells that line a tumor's blood vessel, normally packed so tightly they form a waterproof barrier, are disorganized and irregularly shaped, and there are gaps between them.
The nanocages infiltrate through those gaps efficiently enough that they turn the surface of the normally pinkish tumor black.
A trial run
In Welch's lab, mice bearing tumors on both flanks were randomly divided into two groups. The mice in one group were injected with the PEG-coated nanocages and those in the other with buffer solution. Several days later the right tumor of each animal was exposed to a diode laser for 10 minutes.
The team employed several different noninvasive imaging techniques to follow the effects of the therapy. (Welch is head of the oncologic imaging research program at the Siteman Cancer Center of Washington University School of Medicine and Barnes-Jewish Hospital and has worked on imaging agents and techniques for many years.)
During irradiation, thermal images of the mice were made with an infrared camera. As is true of cells in other animals that automatically regulate their body temperature, mouse cells function optimally only if the mouse's body temperature remains between 36.5 and 37.5 degrees Celsius (98 to 101 degrees Fahrenheit).
At temperatures above 42 degrees Celsius (107 degrees Fahrenheit) the cells begin to die as the proteins whose proper functioning maintains them begin to unfold.
In the nanocage-injected mice, the skin surface temperature increased rapidly from 32 degrees Celsius to 54 degrees C (129 degrees F).
In the buffer-injected mice, however, the surface temperature remained below 37 degrees Celsius (98.6 degrees Fahrenheit).
To see what effect this heating had on the tumors, the mice were injected with a radioactive tracer incorporated in a molecule similar to glucose, the main energy source in the body. Positron emission and computerized tomography (PET and CT) scans were used to record the concentration of the glucose lookalike in body tissues; the higher the glucose uptake, the greater the metabolic activity.
The tumors of nanocage-injected mice were significantly fainter on the PET scans than those of buffer-injected mice, indicating that many tumor cells were no longer functioning.
The tumors in the nanocage-treated mice were later found to have marked histological signs of cellular damage.
Active targeting
The scientists have just received a five-year, $2,129,873 grant from the National Cancer Institute to continue their work with photothermal therapy.
Despite their results, Xia is dissatisfied with passive targeting. Although the tumors took up enough gold nanocages to give them a black cast, only 6 percent of the injected particles accumulated at the tumor site.
Xia would like that number to be closer to 40 percent so that fewer particles would have to be injected. He plans to attach tailor-made ligands to the nanocages that recognize and lock onto receptors on the surface of the tumor cells.
In addition to designing nanocages that actively target the tumor cells, the team is considering loading the hollow particles with a cancer-fighting drug, so that the tumor would be attacked on two fronts.
But the important achievement, from the point of view of cancer patients, is that any nanocage treatment would be narrowly targeted and thus avoid the side effects patients dread.
The TV and radio character the Lone Ranger used only silver bullets, allegedly to remind himself that life was precious and not to be lightly thrown away. If he still rode today, he might consider swapping silver for gold.
Source:
Diana Lutz
Washington University in St. Louis
понедельник, 6 июня 2011 г.
Having An Older Brother Raises A Male's Chances Of Being Gay
A male is more likely to be gay if he has an older brother, the likelihood grows the more older brothers he has. The percentage of gay males is estimated to be around 3%, this probability can go up to 5% for males with several older brothers, say researchers from Brock University, St. Catharines, Canada.
The researchers are certain there is a biological basis for sexual orientation - in other words, there is a prenatal effect. It is not a case of older brothers having a psychological effect on the male baby after it is born. Males with older stepbrothers, or adopted brothers, are not more likely to be gay, only males with blood brothers. The scientists say the effect has to be through the mother, the only link between them.
You can read about this study in the Proceedings of the National Academy of Sciences.
Previous studies have shown a link between male homosexuality and the number of older brothers. This study is the first one to factor out social and environmental effects.
Study leader, Anthony Bogaert, and team examined four groups of men - 944 males. They looked at how many male and female siblings they had, whether they were blood related and lived in the same house when they grew up. The also looked at whether the men had been adopted.
They found that males with one older blood brother were more likely to be gay than males with no older brother(s). The more older brothers a male had the higher his chances of being gay. They said the likelihood had the same increase when blood brothers were raised in different households.
The team stressed that even with several older brothers, the chances of a male being heterosexual is 95%. 97% of all males are heterosexual.
Only males who had an older brother from the same mother had a higher chance of being gay, said the researchers.
The researchers said the environment the male was brought up in makes no difference at all. The only link is that the older brother(s) shared the same womb.
Proceedings of the National Academy of Sciences
pnas
The Social Sciences and Humanities Research Council of Canada funded the research
sshrc.ca/web/home_e.asp
Written by:
The researchers are certain there is a biological basis for sexual orientation - in other words, there is a prenatal effect. It is not a case of older brothers having a psychological effect on the male baby after it is born. Males with older stepbrothers, or adopted brothers, are not more likely to be gay, only males with blood brothers. The scientists say the effect has to be through the mother, the only link between them.
You can read about this study in the Proceedings of the National Academy of Sciences.
Previous studies have shown a link between male homosexuality and the number of older brothers. This study is the first one to factor out social and environmental effects.
Study leader, Anthony Bogaert, and team examined four groups of men - 944 males. They looked at how many male and female siblings they had, whether they were blood related and lived in the same house when they grew up. The also looked at whether the men had been adopted.
They found that males with one older blood brother were more likely to be gay than males with no older brother(s). The more older brothers a male had the higher his chances of being gay. They said the likelihood had the same increase when blood brothers were raised in different households.
The team stressed that even with several older brothers, the chances of a male being heterosexual is 95%. 97% of all males are heterosexual.
Only males who had an older brother from the same mother had a higher chance of being gay, said the researchers.
The researchers said the environment the male was brought up in makes no difference at all. The only link is that the older brother(s) shared the same womb.
Proceedings of the National Academy of Sciences
pnas
The Social Sciences and Humanities Research Council of Canada funded the research
sshrc.ca/web/home_e.asp
Written by:
New Biological Models Of Homeopathy Published In Special Issues
The journal Homeopathy has published a two part special issue focusing on biological models of homeopathy. The special issue highlights experiments on homeopathic treatments in biological models, ranging from whole animals and plants to cell cultures and enzymes, showing a remarkable range of findings.
Homeopathy is a form of complementary medicine which is controversial because of its use of extremely dilute medicines. Although there is considerable clinical research, homeopathy remains the subject of a heated debate. The special issue makes an important contribution to this debate, by reviewing laboratory experiments with high dilutions. It includes reviews and new findings in biosystems, ranging from whole animal behavioral, intoxication and inflammation models through diseased and healthy plant models, to test tube experiments using isolated cells, cell cultures or enzymes.
Featured articles include one on the basophil degranulation test, a test tube model of allergy, developed by Jean Sainte Laudy. These results have now been confirmed in multi-centre and independent experiments. Other articles include systematic reviews of healthy and diseased plant models and experimental work on the effect of homeopathic arsenic on wheat seedlings. There are reviews of mouse and rat models of homeopathic responses and a review, including original results of animal models of homeopathic treatment of anxiety-like behaviours.
Other articles focus on the basic concept of homeopathy 'like cures like': in a series of cell-culture experiments Fred Wiegant's team at the University of Utrecht demonstrated the importance of similarity. Christian Endler and his multinational team conclude that seven different biological models of high dilution response with positive results have been reproduced in multi-centre and/or independent experiments.
Editor-in-Chief Dr Peter Fisher commented: 'Throughout its 200 year history claims that homeopathy has 'real' (as opposed to placebo) effects have been hotly contested. Our special issue brings together a wide range of scientific work in biological systems, where there can be no placebo effect, showing that there are now several biological experiments which yield consistently positive results with homeopathic dilutions'.
Source: Fiona Macnab
Elsevier
Homeopathy is a form of complementary medicine which is controversial because of its use of extremely dilute medicines. Although there is considerable clinical research, homeopathy remains the subject of a heated debate. The special issue makes an important contribution to this debate, by reviewing laboratory experiments with high dilutions. It includes reviews and new findings in biosystems, ranging from whole animal behavioral, intoxication and inflammation models through diseased and healthy plant models, to test tube experiments using isolated cells, cell cultures or enzymes.
Featured articles include one on the basophil degranulation test, a test tube model of allergy, developed by Jean Sainte Laudy. These results have now been confirmed in multi-centre and independent experiments. Other articles include systematic reviews of healthy and diseased plant models and experimental work on the effect of homeopathic arsenic on wheat seedlings. There are reviews of mouse and rat models of homeopathic responses and a review, including original results of animal models of homeopathic treatment of anxiety-like behaviours.
Other articles focus on the basic concept of homeopathy 'like cures like': in a series of cell-culture experiments Fred Wiegant's team at the University of Utrecht demonstrated the importance of similarity. Christian Endler and his multinational team conclude that seven different biological models of high dilution response with positive results have been reproduced in multi-centre and/or independent experiments.
Editor-in-Chief Dr Peter Fisher commented: 'Throughout its 200 year history claims that homeopathy has 'real' (as opposed to placebo) effects have been hotly contested. Our special issue brings together a wide range of scientific work in biological systems, where there can be no placebo effect, showing that there are now several biological experiments which yield consistently positive results with homeopathic dilutions'.
Source: Fiona Macnab
Elsevier
Advanced BioHealing Enrolls First Patient In Celaderm(TM) Pilot Venous Leg Ulcer Clinical Trial
Advanced BioHealing, Inc. (ABH)
announced today that it has enrolled the first patient in its initial
Celaderm(TM) pilot study. The study, whose primary purpose is to evaluate
the safety of Celaderm in humans, will also assess the potential for
Celaderm to accelerate healing of venous leg ulcers compared with optimal
standard therapy. The study is designed to enroll 55 patients who will be
evaluated throughout a 12-week healing period and then be observed for an
additional three months to assess the safety of the product. Separately,
ABH announced that it has requested permission from the U.S. Food and Drug
Administration (FDA) to add two more clinical sites to facilitate
enrollment, bringing the number of clinical sites to eight.
"We are very pleased to officially begin evaluating the safety of
Celaderm, our next-generation bioengineered tissue product, in humans,"
said David Eisenbud, M.D., Executive Vice President and Chief Medical
Officers of Advanced BioHealing. "This marks the first clinical trial with
our own internally-developed product, allowing us to expand on our existing
product portfolio that currently includes two FDA approved wound healing
products. Celaderm utilizes a proprietary cryopreservation technology which
we believe will provide doctors and patients with advancement over earlier
bioengineered products."
"When first-generation bioengineered tissue products were introduced,
physicians who treat wounds were provided a tremendous option that changed
our approach to wound care," said William Marston, MD, Associate Professor
of Surgery, Division of Vascular Surgery at the University of North
Carolina at Chapel Hill. "As an investigator in the Celaderm study, I am
thrilled to test this next-generation product that could significantly
expand the market for advanced wound therapy by being both highly effective
and immediately available at the point-of-care."
Success in this clinical study would allow Celaderm, which is regulated
as a medical device, to move directly into a pivotal trial of clinical
efficacy and this would culminate in a subsequent PreMarket Approval (PMA)
submission. If approved for sale, Celaderm would complement ABH's current
portfolio of approved products: Dermagraft(R) (Dermagraft,) which
is approved for diabetic foot ulcers and TransCyte(R) for the treatment of
full and partial- thickness burns.
About Advanced BioHealing, Inc.
Advanced BioHealing is a leader in regenerative medicine. The company
is focused on the development and marketing of cell-based and
tissue-engineered products. Privately held, ABH has two approved products:
Dermagraft and TransCyte. The company's development pipeline also includes
a next-generation bioengineered wound therapy for which two Investigational
Device Exemption (IDE) exemptions have been approved by the FDA. The
company's manufacturing and corporate offices are located in La Jolla, CA
with research and development offices in New York, NY.
For more information visit AdvancedBioHealing.
Advanced BioHealing, Inc.
AdvancedBioHealing
announced today that it has enrolled the first patient in its initial
Celaderm(TM) pilot study. The study, whose primary purpose is to evaluate
the safety of Celaderm in humans, will also assess the potential for
Celaderm to accelerate healing of venous leg ulcers compared with optimal
standard therapy. The study is designed to enroll 55 patients who will be
evaluated throughout a 12-week healing period and then be observed for an
additional three months to assess the safety of the product. Separately,
ABH announced that it has requested permission from the U.S. Food and Drug
Administration (FDA) to add two more clinical sites to facilitate
enrollment, bringing the number of clinical sites to eight.
"We are very pleased to officially begin evaluating the safety of
Celaderm, our next-generation bioengineered tissue product, in humans,"
said David Eisenbud, M.D., Executive Vice President and Chief Medical
Officers of Advanced BioHealing. "This marks the first clinical trial with
our own internally-developed product, allowing us to expand on our existing
product portfolio that currently includes two FDA approved wound healing
products. Celaderm utilizes a proprietary cryopreservation technology which
we believe will provide doctors and patients with advancement over earlier
bioengineered products."
"When first-generation bioengineered tissue products were introduced,
physicians who treat wounds were provided a tremendous option that changed
our approach to wound care," said William Marston, MD, Associate Professor
of Surgery, Division of Vascular Surgery at the University of North
Carolina at Chapel Hill. "As an investigator in the Celaderm study, I am
thrilled to test this next-generation product that could significantly
expand the market for advanced wound therapy by being both highly effective
and immediately available at the point-of-care."
Success in this clinical study would allow Celaderm, which is regulated
as a medical device, to move directly into a pivotal trial of clinical
efficacy and this would culminate in a subsequent PreMarket Approval (PMA)
submission. If approved for sale, Celaderm would complement ABH's current
portfolio of approved products: Dermagraft(R) (Dermagraft,) which
is approved for diabetic foot ulcers and TransCyte(R) for the treatment of
full and partial- thickness burns.
About Advanced BioHealing, Inc.
Advanced BioHealing is a leader in regenerative medicine. The company
is focused on the development and marketing of cell-based and
tissue-engineered products. Privately held, ABH has two approved products:
Dermagraft and TransCyte. The company's development pipeline also includes
a next-generation bioengineered wound therapy for which two Investigational
Device Exemption (IDE) exemptions have been approved by the FDA. The
company's manufacturing and corporate offices are located in La Jolla, CA
with research and development offices in New York, NY.
For more information visit AdvancedBioHealing.
Advanced BioHealing, Inc.
AdvancedBioHealing
A Novel Approach For Treating Cognitive Impairments Identified By Animal Model For Schizophrenia
Researchers have been seeking a safe and effective way to treat cognitive impairments associated with schizophrenia by enhancing N-methyl-D-aspartate (NMDA) glutamate receptors. Functional deficits in NMDA receptors may contribute to the underlying neurobiology of this disorder. The first generation of studies trying to stimulate NMDA receptors administered large amounts of substances, like glycine or D-serine, which indirectly enhance NMDA receptor function. While there were some positive reports of efficacy, findings across studies were more inconsistent than was hoped.
New approaches following this line of research are just beginning to be tested in patients. For example, several pharmaceutical companies are studying drugs that block the glycine transporter (GlyT1) and thereby raise synaptic glycine levels. A new study in Biological Psychiatry, published by Elsevier, by Dr. Kenji Hashimoto and colleagues may represent a "next step," which is to prevent the inactivation of D-serine by the enzyme D-amino acid oxidase (DAAO). The authors found that this approach enhances the efficacy of D-serine in an animal model for deficits in NMDA glutamate receptor function.
To put it more simply, although D-serine is used as a treatment for schizophrenia, it is metabolized by DAAO, reducing its availability in the brain. So, using an animal model of schizophrenia, these scientists co-administered D-serine and a compound that blocks the effects of DAAO. This increased the levels of D-serine in the mice and therefore its effectiveness in treating the abnormal behaviors in this animal model that may be relevant to schizophrenia.
"We still do not have effective treatments that specifically target the cognitive and functional impairments associated with schizophrenia. These findings are very interesting because there is a continued sense that we have not yet captured the therapeutic promise associated with the glycine site of the NMDA receptor. GlyT1 blockers and DAAO inhibitors may be important new clinical research tools," comments John Krystal, M.D., Editor of Biological Psychiatry.
Further research is still needed to see whether these findings can be extended to humans, but it is hoped that this combination therapy proves to be a novel and effective treatment of schizophrenia.
Notes:
The article is "Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine" by Kenji Hashimoto, Yuko Fujita, Mao Horio, Shinsui Kunitachi, Masaomi Iyo, Dana Ferraris, and Takashi Tsukamoto. Authors Hashimoto, Fujita, Horio, and Kunitachi are affiliated with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Iyo is from the Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. Ferraris and Tsukamoto are with the Eisai Research Institute, Baltimore, Maryland. The article appears in Biological Psychiatry, Volume 65, Issue 12 (June 15, 2009), published by Elsevier. The authors' disclosures of financial and conflicts of interests are available in the article. John H. Krystal, M.D. is affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System and his disclosures of financial and conflicts of interests are available at journals.elsevierhealth/webfiles/images/journals/bps/Biological_Psychiatry_Editorial_Disclosures_08_01_08.pdf.
Source:
Jayne Dawkins
Elsevier
New approaches following this line of research are just beginning to be tested in patients. For example, several pharmaceutical companies are studying drugs that block the glycine transporter (GlyT1) and thereby raise synaptic glycine levels. A new study in Biological Psychiatry, published by Elsevier, by Dr. Kenji Hashimoto and colleagues may represent a "next step," which is to prevent the inactivation of D-serine by the enzyme D-amino acid oxidase (DAAO). The authors found that this approach enhances the efficacy of D-serine in an animal model for deficits in NMDA glutamate receptor function.
To put it more simply, although D-serine is used as a treatment for schizophrenia, it is metabolized by DAAO, reducing its availability in the brain. So, using an animal model of schizophrenia, these scientists co-administered D-serine and a compound that blocks the effects of DAAO. This increased the levels of D-serine in the mice and therefore its effectiveness in treating the abnormal behaviors in this animal model that may be relevant to schizophrenia.
"We still do not have effective treatments that specifically target the cognitive and functional impairments associated with schizophrenia. These findings are very interesting because there is a continued sense that we have not yet captured the therapeutic promise associated with the glycine site of the NMDA receptor. GlyT1 blockers and DAAO inhibitors may be important new clinical research tools," comments John Krystal, M.D., Editor of Biological Psychiatry.
Further research is still needed to see whether these findings can be extended to humans, but it is hoped that this combination therapy proves to be a novel and effective treatment of schizophrenia.
Notes:
The article is "Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine" by Kenji Hashimoto, Yuko Fujita, Mao Horio, Shinsui Kunitachi, Masaomi Iyo, Dana Ferraris, and Takashi Tsukamoto. Authors Hashimoto, Fujita, Horio, and Kunitachi are affiliated with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Iyo is from the Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. Ferraris and Tsukamoto are with the Eisai Research Institute, Baltimore, Maryland. The article appears in Biological Psychiatry, Volume 65, Issue 12 (June 15, 2009), published by Elsevier. The authors' disclosures of financial and conflicts of interests are available in the article. John H. Krystal, M.D. is affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System and his disclosures of financial and conflicts of interests are available at journals.elsevierhealth/webfiles/images/journals/bps/Biological_Psychiatry_Editorial_Disclosures_08_01_08.pdf.
Source:
Jayne Dawkins
Elsevier
Artificial Enzyme Removes Natural Poison
For the first time ever, a completely man-made chemical enzyme has been successfully used to neutralise a toxin found naturally in fruits and vegetables.
Proof of concept for artificial enzymes
Chemzymes are designed molecules emulating the targeting and efficiency of naturally occurring enzymes and the recently graduated Dr. Bjerre is pleased about her results.
"Showing that these molecules are capable of decomposing toxins required vast amounts of work and time. But it's been worth every minute because it proves the general point that it's possible to design artificial enzymes for this class of task", explains Bjerre.
Simple molecules performing complex tasks
Most people know enzymes as an ingredient in detergents. In our bodies enzymes are in charge of decomposing everything we eat, so that our bodies can absorb the nutrients. But they also decompose ingested toxins, ensuring that our bodies survive the encounter.
In several important aspects artificial enzymes function in the same way as naturally occurring ones. But where natural enzymes are big and complex, the artificial ones have been pared down to the basics.
The flat-nosed plier of the molecular world
One consequence of this simplicity is that designing chemzymes for targeted tasks ought to be easier. With fewer parts, there's less to go wrong when changing the structure of chemzymes. And for enzymes as well as for their artificial counterparts even small changes in structure will have massive consequences for functionality.
In this, enzymes are very much like hand-tools, where scissors and flat nosed pliers, though almost identical, have very different duties.
Hardwearing replacement enzymes
Even though naturally occurring enzymes are several orders of magnitude smaller than flat-nosed pliers, they are still unrivalled tools. Some of the fastest chemical reactions blast off when enzymes are added to the broth.
Several known enzymes in the body catalyze more than one million reactions per second when they decompose compounds. There's just one drawback to enzymes. They are extremely fragile.
If an enzyme in our body was to be warmed above sixtyfive degrees centigrade or subjected to organic solvents, they would immediately denature. They would unravel and stop functioning.
Taking the heat
So far no one has succeeded in designing chemzymes that are anywhere near as fast as their naturally occurring cousins. But they are far more resilient.
Manmade enzymes take on heat and solvents without batting a molecular eyelid. One of the consequences of this is that chemzymes can be mass-produced using industrial chemical processes. This is a huge advantage when you need a lot of product in a hurry.
Factory-made enzymes
Producing natural enzymes in industrial settings is considerably more time-consuming because they have to be grown. Rather like one grows apples or grain.
So the robust and designable compounds may turn out to be just what's needed for a wide variety of jobs. Not least in the pharmaceutical industries, where the need is massive for chemical compounds which can solve problems that no amount of designing could ever tweak the natural ones to work on, which are unaffected by industrial processes, and to top it of, cheap to produce.
Source:
Jes Andersen
University of Copenhagen
Proof of concept for artificial enzymes
Chemzymes are designed molecules emulating the targeting and efficiency of naturally occurring enzymes and the recently graduated Dr. Bjerre is pleased about her results.
"Showing that these molecules are capable of decomposing toxins required vast amounts of work and time. But it's been worth every minute because it proves the general point that it's possible to design artificial enzymes for this class of task", explains Bjerre.
Simple molecules performing complex tasks
Most people know enzymes as an ingredient in detergents. In our bodies enzymes are in charge of decomposing everything we eat, so that our bodies can absorb the nutrients. But they also decompose ingested toxins, ensuring that our bodies survive the encounter.
In several important aspects artificial enzymes function in the same way as naturally occurring ones. But where natural enzymes are big and complex, the artificial ones have been pared down to the basics.
The flat-nosed plier of the molecular world
One consequence of this simplicity is that designing chemzymes for targeted tasks ought to be easier. With fewer parts, there's less to go wrong when changing the structure of chemzymes. And for enzymes as well as for their artificial counterparts even small changes in structure will have massive consequences for functionality.
In this, enzymes are very much like hand-tools, where scissors and flat nosed pliers, though almost identical, have very different duties.
Hardwearing replacement enzymes
Even though naturally occurring enzymes are several orders of magnitude smaller than flat-nosed pliers, they are still unrivalled tools. Some of the fastest chemical reactions blast off when enzymes are added to the broth.
Several known enzymes in the body catalyze more than one million reactions per second when they decompose compounds. There's just one drawback to enzymes. They are extremely fragile.
If an enzyme in our body was to be warmed above sixtyfive degrees centigrade or subjected to organic solvents, they would immediately denature. They would unravel and stop functioning.
Taking the heat
So far no one has succeeded in designing chemzymes that are anywhere near as fast as their naturally occurring cousins. But they are far more resilient.
Manmade enzymes take on heat and solvents without batting a molecular eyelid. One of the consequences of this is that chemzymes can be mass-produced using industrial chemical processes. This is a huge advantage when you need a lot of product in a hurry.
Factory-made enzymes
Producing natural enzymes in industrial settings is considerably more time-consuming because they have to be grown. Rather like one grows apples or grain.
So the robust and designable compounds may turn out to be just what's needed for a wide variety of jobs. Not least in the pharmaceutical industries, where the need is massive for chemical compounds which can solve problems that no amount of designing could ever tweak the natural ones to work on, which are unaffected by industrial processes, and to top it of, cheap to produce.
Source:
Jes Andersen
University of Copenhagen
Key Fat And Cholesterol Cell Regulator Identified, Promising Target
Researchers at Harvard Medical School and Massachusetts General Hospital have identified how a molecular switch regulates fat and cholesterol production, a step that may help advance treatments for metabolic syndrome, the constellation of diseases that includes high cholesterol, obesity, type II diabetes, and high blood pressure. The study is now published in the online version of the scientific journal Nature and will appear in the August 10th print edition.
"We have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat (or lipid) production," says principal investigator Anders Naar, PhD, assistant professor of cell biology at Harvard Medical School and the Massachusetts General Hospital Cancer Center. "The identification of this protein interaction and the nature of the molecular interface may one day allow us to pursue a more comprehensive approach to the treatment of metabolic syndrome."
High levels of cholesterol and lipids are linked to a number of interrelated medical conditions and diseases, including obesity, type II diabetes, fatty liver, and high blood pressure. This set of conditions and diseases, known as metabolic syndrome, are afflicting a rapidly increasing portion of society and serve as a major risk factor for heart disease, the leading cause of death in the developed world.
Treatments for diseases associated with metabolic syndrome have focused primarily on individual elements, such as high LDL-cholesterol (targeted by the cholesterol-lowering statin drugs). However, more effective ways to treat all of the components of metabolic syndrome are needed. One attractive approach might be to target the genetic switches that promote cholesterol and lipid synthesis, but it would require a detailed understanding of the regulatory mechanisms before drug targets can be identified.
After eating a meal, a family of proteins act as switches to turn on cholesterol and fat (or lipid) production. This family of proteins is known as SREBPs, or sterol regulatory element binding proteins. Between meals, the production of cholesterol and lipids should be turned off, however, excess intake of foods, coupled with lack of exercise, appear to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.
In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein called ARC105, which binds to SREBPs, is essential in controlling the activity of the SREBP family of proteins. "ARC105 represents a lynchpin for SREBPs control of cholesterol and lipid biosynthesis genes, which may provide a potential molecular Achilles heel that could be targeted by drugs" says Dr. Nддr.
The researchers initially found that after removing ARC105 from human cells by a process called RNAi, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes. To validate these findings in a physiological setting, the researchers turned to the microscopic worm C. elegans, a favorite model organism among those studying evolutionarily conserved biological processes because of its rapid generation time and relative simplicity of genetics, and which had previously been used to study mechanisms of fat regulation.
Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center, the team demonstrated that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15, respectively, are necessary for production and storage of fat. The worms had regular fat production when SBP-1 and MDT-15 functioned normally, but when researchers used RNAi to knock out function of either SBP-1 or MDT-15, the worms lost their ability to properly store fat, lay eggs, and move normally.
"The striking effects of the RNAi knock downs in C. elegans suggest that the ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences, which partially supported the research. "This work highlights the value of model organisms in helping us understand cellular processes that impact human health."
The research team also showed that removal of ARC105 in human cells by RNAi also negatively affects the same key SREBP target gene as identified in C. elegans. This suggests that the molecular switch is evolutionarily conserved (and therefore likely physiologically important).
Exhaustive biochemical detective work performed by the Nддr group together with the group of Gerhard Wagner, PhD, HMS professor in the Department of Biological Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105 interact. They found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX.
The researchers analyzed the amino acid sequence of the ARC105 protein, testing many different sections using NMR spectroscopy to eventually find the KIX area--just one tenth the area of the larger ARC105 protein--that specifically binds to SREBP. This specific interaction between SREBP and ARC105 might be a target for small molecule drugs, according to Dr. Wagner.
"While RNAi completely knocks out a protein including its other functions, perhaps not related to fat metabolism, a small molecule is a more subtle tool that could eliminate one protein-to-protein interaction," says Dr. Wagner. Finding a molecule that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search for inhibitors to fit the grooved KIX site looks much more promising.
The team is already initiating high-throughput screening at Harvard Medical School's Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the KIX site.
"Of course there are numerous hurdles that would need to be overcome before finding specific and effective treatments based on these findings," says Dr. Naar. If small molecules that specifically interfere with the interaction of SREBPs and ARC105 could be identified, careful studies in human cells and in mice would be needed to verify the specificity and efficacy in repressing cholesterol and fat production. "Unforeseen side effects of such small molecules in mouse studies or in human clinical trials could also emerge, prohibiting further follow-up", cautions Dr. Naar.
The National Institutes of Health, the Damon Runyon Cancer Research Foundation, and the Milton Foundation of Harvard University supported the study.
HARVARD MEDICAL SCHOOL
hms.harvard/
Harvard Medical School has more than 7,000 full-time faculty working in 10 academic departments housed on the School's Boston quadrangle or in one of 48 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and the VA Boston Healthcare System.
MASSACHUSETTS GENERAL HOSPITAL
mgh.harvard/
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Contact: John Lacey
Harvard Medical School
"We have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat (or lipid) production," says principal investigator Anders Naar, PhD, assistant professor of cell biology at Harvard Medical School and the Massachusetts General Hospital Cancer Center. "The identification of this protein interaction and the nature of the molecular interface may one day allow us to pursue a more comprehensive approach to the treatment of metabolic syndrome."
High levels of cholesterol and lipids are linked to a number of interrelated medical conditions and diseases, including obesity, type II diabetes, fatty liver, and high blood pressure. This set of conditions and diseases, known as metabolic syndrome, are afflicting a rapidly increasing portion of society and serve as a major risk factor for heart disease, the leading cause of death in the developed world.
Treatments for diseases associated with metabolic syndrome have focused primarily on individual elements, such as high LDL-cholesterol (targeted by the cholesterol-lowering statin drugs). However, more effective ways to treat all of the components of metabolic syndrome are needed. One attractive approach might be to target the genetic switches that promote cholesterol and lipid synthesis, but it would require a detailed understanding of the regulatory mechanisms before drug targets can be identified.
After eating a meal, a family of proteins act as switches to turn on cholesterol and fat (or lipid) production. This family of proteins is known as SREBPs, or sterol regulatory element binding proteins. Between meals, the production of cholesterol and lipids should be turned off, however, excess intake of foods, coupled with lack of exercise, appear to disturb the normal checks and balances that control SREBPs, resulting in overproduction of cholesterol and lipids.
In the Nature paper, the HMS and MGH Cancer Center team has shown that a protein called ARC105, which binds to SREBPs, is essential in controlling the activity of the SREBP family of proteins. "ARC105 represents a lynchpin for SREBPs control of cholesterol and lipid biosynthesis genes, which may provide a potential molecular Achilles heel that could be targeted by drugs" says Dr. Nддr.
The researchers initially found that after removing ARC105 from human cells by a process called RNAi, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes. To validate these findings in a physiological setting, the researchers turned to the microscopic worm C. elegans, a favorite model organism among those studying evolutionarily conserved biological processes because of its rapid generation time and relative simplicity of genetics, and which had previously been used to study mechanisms of fat regulation.
Through a collaborative effort with the worm genetics group of Anne Hart, PhD, HMS associate professor of pathology at the MGH Cancer Center, the team demonstrated that the C. elegans homologues of SREBP and ARC105, known as SBP-1 and MDT-15, respectively, are necessary for production and storage of fat. The worms had regular fat production when SBP-1 and MDT-15 functioned normally, but when researchers used RNAi to knock out function of either SBP-1 or MDT-15, the worms lost their ability to properly store fat, lay eggs, and move normally.
"The striking effects of the RNAi knock downs in C. elegans suggest that the ARC105/SREBP pathway may play a key role in lipid production in humans," said Laurie Tompkins, PhD, of the National Institute of General Medical Sciences, which partially supported the research. "This work highlights the value of model organisms in helping us understand cellular processes that impact human health."
The research team also showed that removal of ARC105 in human cells by RNAi also negatively affects the same key SREBP target gene as identified in C. elegans. This suggests that the molecular switch is evolutionarily conserved (and therefore likely physiologically important).
Exhaustive biochemical detective work performed by the Nддr group together with the group of Gerhard Wagner, PhD, HMS professor in the Department of Biological Chemistry and Molecular Pharmacology, identified exactly how SREBP and ARC105 interact. They found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX.
The researchers analyzed the amino acid sequence of the ARC105 protein, testing many different sections using NMR spectroscopy to eventually find the KIX area--just one tenth the area of the larger ARC105 protein--that specifically binds to SREBP. This specific interaction between SREBP and ARC105 might be a target for small molecule drugs, according to Dr. Wagner.
"While RNAi completely knocks out a protein including its other functions, perhaps not related to fat metabolism, a small molecule is a more subtle tool that could eliminate one protein-to-protein interaction," says Dr. Wagner. Finding a molecule that attaches to and inhibits the flexible tail of SREBP is unlikely, but a search for inhibitors to fit the grooved KIX site looks much more promising.
The team is already initiating high-throughput screening at Harvard Medical School's Institute of Chemistry and Cell Biology to identify small molecule inhibitors of the KIX site.
"Of course there are numerous hurdles that would need to be overcome before finding specific and effective treatments based on these findings," says Dr. Naar. If small molecules that specifically interfere with the interaction of SREBPs and ARC105 could be identified, careful studies in human cells and in mice would be needed to verify the specificity and efficacy in repressing cholesterol and fat production. "Unforeseen side effects of such small molecules in mouse studies or in human clinical trials could also emerge, prohibiting further follow-up", cautions Dr. Naar.
The National Institutes of Health, the Damon Runyon Cancer Research Foundation, and the Milton Foundation of Harvard University supported the study.
HARVARD MEDICAL SCHOOL
hms.harvard/
Harvard Medical School has more than 7,000 full-time faculty working in 10 academic departments housed on the School's Boston quadrangle or in one of 48 academic departments at 18 Harvard teaching hospitals and research institutes. Those Harvard hospitals and research institutions include Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Cambridge Health Alliance, The CBR Institute for Biomedical Research, Children's Hospital Boston, Dana-Farber Cancer Institute, Forsyth Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, and the VA Boston Healthcare System.
MASSACHUSETTS GENERAL HOSPITAL
mgh.harvard/
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of nearly $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, transplantation biology and photomedicine. MGH and Brigham and Women's Hospital are founding members of Partners HealthCare HealthCare System, a Boston-based integrated health care delivery system.
Contact: John Lacey
Harvard Medical School
Replacing Absent MicroRNAs Could Make Tumors Less Invasive, More Treatable
One group of small, non-coding RNA molecules could serve as a marker to improve cancer staging and may also be able to convert some advanced tumors to more treatable stages, report a University of Chicago-based research team in the April 1, 2008, issue of the journal Genes & Development.
Carcinomas are cancers that develop from epithelial tissue, which lines internal and external body surfaces. When normal cells are transformed into cancer cells, this epithelial tissue can take on the characteristics of embryonic tissue, known as mesenchymal tissue, which is comprised of unspecialized cells that will develop, as the embryo matures, into more specialized tissues.
That process also goes in reverse. Epithelial to mesenchymal transition (EMT) occurs, for example, during wound healing. In cancer, however, this process can produce invasive and mobile cells that can pass through membranes and travel to distant sites, where they seed new tumors.
"There are a bewildering numbers of pathways or stimuli that can either trigger EMT or reverse that process," said study author Marcus E. Peter, PhD, professor in the Ben May Department for Cancer Research at the University of Chicago. "What we have identified is a master regulator of EMT that is probably controlled by many of these stimuli."
Peter and colleagues showed that this master regulator consists of a specific group of microRNAs, a family called miR-200. MicroRNAs are tiny RNA molecules that have very important roles in gene regulation. They have multiple targets and act mainly by attaching themselves to specific sites in messenger RNA to prevent the production of proteins.
The authors studied a standard panel of 60 established human tumor cell lines representing nine different human cancers, as well as several specimens of human primary ovarian cancer. They showed that miR-200 was always present in epithelial (less invasive) and not in mesenchymal (more invasive) types of tumors.
"The importance of this finding is, first, that miR-200 may represent a good marker to stage cancer," Peter said, and "second, that reintroducing miR-200 into late cancer cells could provide a new form of treatment, preventing these cells from going through EMT and becoming more invasive."
Physicians already have a set of fairly reliable markers for carcinoma. Tumors with high levels of E-cadherin tend to be tightly tethered to nearby cells and less likely to break free and travel to other sites. Those with high Vimentin levels represent mesenchymal cells able to pass though other tissues.
Peter and colleagues found that miR-200 added mechanistic depth to those markers. Every tumor cell line the researchers tested that had the epithelial marker E-cadherin and not the mesenchymal marker Vimentin, had high amounts of miR-200. Every cell line with high Vimentin and no E-cadherin had no detectable miR-200.
"So we were able to show a complete correlation between miR-200 and E-cadherin/Vimentin expression," Peter added.
The authors found that miR-200 microRNAs helped regulate EMT transition. They bind directly to non-coding regions in the RNA of ZEB1 and ZEB2, known blockers of E-cadherin transcription. Both ZEB proteins have previously been implicated in human malignancies, ZEB1 in aggressive colorectal and uterine cancers, and ZEB2 in advanced stages of ovarian, gastric and pancreatic tumors.
By inhibiting miR-200, Peter and his coworkers could induce EMT. More important, by introducing miR-200, they managed to activate production of E-cadherin protein and reverse tumors from a more-invasive mesenchymal into a less-invasive epithelial form.
"In a previous paper we found that another micro RNA, let-7, drives tumor progression at an earlier stage," Peter said. "Let-7 appears to be a key player in preventing a cancer from becoming more aggressive. Now we want to figure out how these two micro RNAs work together to regulate carcinogenesis."
Once they understand this process, they want to use these microRNAs to treat cancer. Both microRNA families have the connection to drug resistance as well as to cancer stem cells, sub-population of cancer cells that have self-renewal properties and the ability to give rise to new tumors that are more resistant to current therapy.
"Our aim is not only to make tumors less invasive by reintroducing let-7 and miR-200," explained Peter. "We hope that we'll make tumors more sensitive to drugs and be able to target the stem cell population, which gives tumors their renewal capacity."
"The idea is a two-hit strategy," Peter said, "hit them first with the microRNA and make those drug-resistant cells sensitive again, then hit them again with low levels of conventional chemotherapy."
The National Institutes of Health, the Ovarian Cancer Research Fund, and the University of Chicago Women's Board funded this study. Additional authors include Sun-Mi Park and Ernst Lengyel from the University of Chicago and Arti B. Gaur from Dartmouth Medical School, Lebanon, New Hampshire.
University of Chicago Medical Center
MC 6063, 5841 S. Maryland Ave.
Chicago, IL 60637
United States
uchospitals
Carcinomas are cancers that develop from epithelial tissue, which lines internal and external body surfaces. When normal cells are transformed into cancer cells, this epithelial tissue can take on the characteristics of embryonic tissue, known as mesenchymal tissue, which is comprised of unspecialized cells that will develop, as the embryo matures, into more specialized tissues.
That process also goes in reverse. Epithelial to mesenchymal transition (EMT) occurs, for example, during wound healing. In cancer, however, this process can produce invasive and mobile cells that can pass through membranes and travel to distant sites, where they seed new tumors.
"There are a bewildering numbers of pathways or stimuli that can either trigger EMT or reverse that process," said study author Marcus E. Peter, PhD, professor in the Ben May Department for Cancer Research at the University of Chicago. "What we have identified is a master regulator of EMT that is probably controlled by many of these stimuli."
Peter and colleagues showed that this master regulator consists of a specific group of microRNAs, a family called miR-200. MicroRNAs are tiny RNA molecules that have very important roles in gene regulation. They have multiple targets and act mainly by attaching themselves to specific sites in messenger RNA to prevent the production of proteins.
The authors studied a standard panel of 60 established human tumor cell lines representing nine different human cancers, as well as several specimens of human primary ovarian cancer. They showed that miR-200 was always present in epithelial (less invasive) and not in mesenchymal (more invasive) types of tumors.
"The importance of this finding is, first, that miR-200 may represent a good marker to stage cancer," Peter said, and "second, that reintroducing miR-200 into late cancer cells could provide a new form of treatment, preventing these cells from going through EMT and becoming more invasive."
Physicians already have a set of fairly reliable markers for carcinoma. Tumors with high levels of E-cadherin tend to be tightly tethered to nearby cells and less likely to break free and travel to other sites. Those with high Vimentin levels represent mesenchymal cells able to pass though other tissues.
Peter and colleagues found that miR-200 added mechanistic depth to those markers. Every tumor cell line the researchers tested that had the epithelial marker E-cadherin and not the mesenchymal marker Vimentin, had high amounts of miR-200. Every cell line with high Vimentin and no E-cadherin had no detectable miR-200.
"So we were able to show a complete correlation between miR-200 and E-cadherin/Vimentin expression," Peter added.
The authors found that miR-200 microRNAs helped regulate EMT transition. They bind directly to non-coding regions in the RNA of ZEB1 and ZEB2, known blockers of E-cadherin transcription. Both ZEB proteins have previously been implicated in human malignancies, ZEB1 in aggressive colorectal and uterine cancers, and ZEB2 in advanced stages of ovarian, gastric and pancreatic tumors.
By inhibiting miR-200, Peter and his coworkers could induce EMT. More important, by introducing miR-200, they managed to activate production of E-cadherin protein and reverse tumors from a more-invasive mesenchymal into a less-invasive epithelial form.
"In a previous paper we found that another micro RNA, let-7, drives tumor progression at an earlier stage," Peter said. "Let-7 appears to be a key player in preventing a cancer from becoming more aggressive. Now we want to figure out how these two micro RNAs work together to regulate carcinogenesis."
Once they understand this process, they want to use these microRNAs to treat cancer. Both microRNA families have the connection to drug resistance as well as to cancer stem cells, sub-population of cancer cells that have self-renewal properties and the ability to give rise to new tumors that are more resistant to current therapy.
"Our aim is not only to make tumors less invasive by reintroducing let-7 and miR-200," explained Peter. "We hope that we'll make tumors more sensitive to drugs and be able to target the stem cell population, which gives tumors their renewal capacity."
"The idea is a two-hit strategy," Peter said, "hit them first with the microRNA and make those drug-resistant cells sensitive again, then hit them again with low levels of conventional chemotherapy."
The National Institutes of Health, the Ovarian Cancer Research Fund, and the University of Chicago Women's Board funded this study. Additional authors include Sun-Mi Park and Ernst Lengyel from the University of Chicago and Arti B. Gaur from Dartmouth Medical School, Lebanon, New Hampshire.
University of Chicago Medical Center
MC 6063, 5841 S. Maryland Ave.
Chicago, IL 60637
United States
uchospitals
Several Deep-Sea Mussels And Their Associated Symbionts Are Able To Live Both On Wood And On Whale Falls
Original organisms occur at hydrothermal vents and cold seeps, deep-sea ecosystems where they thrive thanks to symbiotic associations with bacteria. Among those organisms, mussels have markedly closely related parents which are also associated with sunken woods and bones. These organic falls were suggested as potential evolutionary 'stepping-stones', allowing colonization processes toward vent and seeps. The current study provides evidences that some mussels are able to live both on sunken wood and on bones, thus providing new insights into this 'stepping-stones' hypothesis. Their symbiotic relationships were also studied to explain the abilities of host species to adapt to various substrates.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Echo-Location In Humans Developed By Spanish Scientists
A team of researchers from the University of AlcalГЎ de Henares (UAH) has shown scientifically that human beings can develop echolocation, the system of acoustic signals used by dolphins and bats to explore their surroundings. Producing certain kinds of tongue clicks helps people to identify objects around them without needing to see them, something which would be especially useful for the blind.
"In certain circumstances, we humans could rival bats in our echolocation or biosonar capacity", Juan Antonio MartГnez, lead author of the study and a researcher at the Superior Polytechnic School of the UAH, tells SINC. The team led by this scientist has started a series of tests, the first of their kind in the world, to make use of human beings' under-exploited echolocation skills.
In the first study, published in the journal Acta Acustica united with Acustica, the team analyses the physical properties of various sounds, and proposes the most effective of these for use in echolocation. "The almost ideal sound is the 'palate click, a click made by placing the tip of the tongue on the palate, just behind the teeth, and moving it quickly backwards, although it is often done downwards, which is wrong", MartГnez explains.
The researcher says that palate clicks "are very similar to the sounds made by dolphins, although on a different scale, as these animals have specially-adapted organs and can produce 200 clicks per second, while we can only produce three or four". By using echolocation, "which is three-dimensional, and makes it possible to 'see' through materials that are opaque to visible radiation" it is possible to measure the distance of an object based on the time that elapses between the emission of a sound wave and an echo being received of this wave as it is reflected from the object.
In order to learn how to emit, receive and interpret sounds, the scientists are developing a method that uses a series of protocols. This first step is for the individual to know how to make and identify his or her own sounds (they are different for each person), and later to know how to use them to distinguish between objects according to their geometrical properties "as is done by ships' sonar".
Some blind people had previously taught themselves how to use echolocation "by trial and error". The best-known cases of these are the Americans Daniel Kish, the only blind person to have been awarded a certificate to act as a guide for other blind people, and Ben Underwood, who was considered to be the world's best "echolocator" until he died at the start of 2009.
However, no special physical skills are required in order to develop this skill. "Two hours per day for a couple of weeks are enough to distinguish whether you have an object in front of you, and within another two weeks you can tell the difference between trees and a pavement", MartГnez tells SINC.
The scientist recommends trying with the typical "sh" sound used to make someone be quiet. Moving a pen in front of the mouth can be noticed straightaway. This is a similar phenomenon to that when travelling in a car with the windows down, which makes it possible to "hear" gaps in the verge of the road.
The next level is to learn how to master the "palate clicks". To make sure echoes from the tongue clicks are properly interpreted, the researchers are working with a laser pointer, which shows the part of an object at which the sound should be aimed.
A new way of seeing the world
MartГnez has told SINC that his team is now working to help deaf and blind people to use this method in the future, because echoes are not only perceived by their ear, but also through vibrations in the tongue and bones. "For these kinds of people in particular, and for all of us in general, this would be a new way of perceiving the world".
Another of the team's research areas involves establishing the biological limits of human echolocation ability, "and the first results indicate that detailed resolution using this method could even rival that of sight itself". In fact, the researchers started out by being able to tell if there was someone standing in front of them, but now can detect certain internal structures, such as bones, and even "certain objects inside a bag".
The scientists recognise that they are still at the very early stages, but the possibilities that would be opened up with the development of echolocation in humans are enormous. This technique will be very practical not only for the blind, but also for professionals such as firemen (enabling them to find exit points through smoke), and rescue teams, or simply people lost in fog.
A better understanding of the mental mechanisms used in echolocation could also help to design new medical imaging technologies or scanners, which make use of the great penetration capacity of clicks. MartГnez stresses that these sounds "are so penetrating that, even in environments as noisy as the metro, one can sense discontinuities in the platform or tunnels".
References:
Juan Antonio MartГnez Rojas, JesГєs Alpuente Hermosilla, Pablo Luis LГіpez EspГ y RocГo SГЎnchez Montero. "Physical Analysis of Several Organic Signals for Human Echolocation: Oral Vacuum Pulses". Acta Acustica united with Acustica 95 (2): 325-330, 2009.
Source:
SINC
FECYT - Spanish Foundation for Science and Technology
"In certain circumstances, we humans could rival bats in our echolocation or biosonar capacity", Juan Antonio MartГnez, lead author of the study and a researcher at the Superior Polytechnic School of the UAH, tells SINC. The team led by this scientist has started a series of tests, the first of their kind in the world, to make use of human beings' under-exploited echolocation skills.
In the first study, published in the journal Acta Acustica united with Acustica, the team analyses the physical properties of various sounds, and proposes the most effective of these for use in echolocation. "The almost ideal sound is the 'palate click, a click made by placing the tip of the tongue on the palate, just behind the teeth, and moving it quickly backwards, although it is often done downwards, which is wrong", MartГnez explains.
The researcher says that palate clicks "are very similar to the sounds made by dolphins, although on a different scale, as these animals have specially-adapted organs and can produce 200 clicks per second, while we can only produce three or four". By using echolocation, "which is three-dimensional, and makes it possible to 'see' through materials that are opaque to visible radiation" it is possible to measure the distance of an object based on the time that elapses between the emission of a sound wave and an echo being received of this wave as it is reflected from the object.
In order to learn how to emit, receive and interpret sounds, the scientists are developing a method that uses a series of protocols. This first step is for the individual to know how to make and identify his or her own sounds (they are different for each person), and later to know how to use them to distinguish between objects according to their geometrical properties "as is done by ships' sonar".
Some blind people had previously taught themselves how to use echolocation "by trial and error". The best-known cases of these are the Americans Daniel Kish, the only blind person to have been awarded a certificate to act as a guide for other blind people, and Ben Underwood, who was considered to be the world's best "echolocator" until he died at the start of 2009.
However, no special physical skills are required in order to develop this skill. "Two hours per day for a couple of weeks are enough to distinguish whether you have an object in front of you, and within another two weeks you can tell the difference between trees and a pavement", MartГnez tells SINC.
The scientist recommends trying with the typical "sh" sound used to make someone be quiet. Moving a pen in front of the mouth can be noticed straightaway. This is a similar phenomenon to that when travelling in a car with the windows down, which makes it possible to "hear" gaps in the verge of the road.
The next level is to learn how to master the "palate clicks". To make sure echoes from the tongue clicks are properly interpreted, the researchers are working with a laser pointer, which shows the part of an object at which the sound should be aimed.
A new way of seeing the world
MartГnez has told SINC that his team is now working to help deaf and blind people to use this method in the future, because echoes are not only perceived by their ear, but also through vibrations in the tongue and bones. "For these kinds of people in particular, and for all of us in general, this would be a new way of perceiving the world".
Another of the team's research areas involves establishing the biological limits of human echolocation ability, "and the first results indicate that detailed resolution using this method could even rival that of sight itself". In fact, the researchers started out by being able to tell if there was someone standing in front of them, but now can detect certain internal structures, such as bones, and even "certain objects inside a bag".
The scientists recognise that they are still at the very early stages, but the possibilities that would be opened up with the development of echolocation in humans are enormous. This technique will be very practical not only for the blind, but also for professionals such as firemen (enabling them to find exit points through smoke), and rescue teams, or simply people lost in fog.
A better understanding of the mental mechanisms used in echolocation could also help to design new medical imaging technologies or scanners, which make use of the great penetration capacity of clicks. MartГnez stresses that these sounds "are so penetrating that, even in environments as noisy as the metro, one can sense discontinuities in the platform or tunnels".
References:
Juan Antonio MartГnez Rojas, JesГєs Alpuente Hermosilla, Pablo Luis LГіpez EspГ y RocГo SГЎnchez Montero. "Physical Analysis of Several Organic Signals for Human Echolocation: Oral Vacuum Pulses". Acta Acustica united with Acustica 95 (2): 325-330, 2009.
Source:
SINC
FECYT - Spanish Foundation for Science and Technology
Studying The Earliest Brain Changes That Could Lead To Alzheimer's Disease
Five researchers receive grants to investigate biological, genetic, and environmental causes of AD
Five early-career scientists were awarded The Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Awards in Alzheimer's Disease. The $75,000 awards provide a broad array of funding in the biological, genetic, and environmental causes of AD. By studying the early changes suggesting Alzheimer's disease from different but complementary angles, the awards seek to accelerate development of diagnostic, preventative interventions, and treatments. The program, now in its third year, has provided more than $1 million to 16 scientists in the U.S. and Israel.
Award recipients include:
Ehud Cohen, PhD, Lecturer, The Hebrew University of Jerusalem: Roles of Peptidylprolyl Cis/Trans Isomerases in the Regulation of Aging and Countering Alzheimer's Disease
Dr. Cohen's research will focus on the possible roles of cyclophilins - a group of proteins that help other proteins fold properly - in preventing Alzheimer's disease (AD) from emerging early in life and will test how this activity is affected by the aging process. His research could answer the question of whether the maintenance of cyclophilin activity through late life could protect against developing AD and will help unearth the mechanisms underlying the onset of some types of familial AD.
Raquel L. Lieberman, PhD, Assistant Professor, Georgia Tech: Crystal Structure of an Intramembrane Asparyl Protease
Over-production of beta amyloid peptides contribute to the pathogenesis of Alzheimer's disease.
The objective of this research is to understand the crystal structure of signal peptide peptidase (SPP). This protein is closely related to gamma secretase, the enzyme that participates in the generation of beta amyloids, species that are known to play roles in the development of Alzheimer's disease. Insights into these crystal structures could significantly further the development of structure-based designs for potential therapeutic agents.
Gad A. Marshall, MD, Instructor in Neurology, Associate Neurologist, Brigham and Women's Hospital: Amyloid Deposition and Frontally Mediated Symptoms in MCI
Although memory loss is the hallmark of Alzheimer's disease (AD), behavioral changes and executive dysfunction often play a major role in disability. Dr. Marshall will use state of the art imaging techniques to better understand the biological underpinnings of apathy and executive dysfunction in relation to mild cognitive impairment (MCI) and mild AD. This may provide the opportunity to differentiate between patients whose MCI will progress to AD and intervene with disease-modifying agents, attacking the disease at its earliest stages.
Esther Oh, MD, Assistant Professor, Johns Hopkins University: Oral Glucose Tolerance Test For Alzheimer's Disease Biomarker Development
The goal of Dr. Oh's research is to modify an amyloid blood test so that it may be able to determine whether someone has early forms of Alzheimer's disease (AD) or predict who may develop the disease among individuals who have certain forms of mild cognitive impairment (MCI). Since many cases of AD are diagnosed at more advanced stages, the diagnostic blood test, which could predict the likelihood of a person developing AD years in advance, could allow clinicians greater opportunity to intervene when drug therapy is likelier to be more effective.
Lucia Pastorino, PhD, Instructor in Medicine, Beth Israel Deaconess Medical Center: Role of the Prolyl Isomerase Pin1 in the Modulation of PS1 Activity
Dr. Pastorino will investigate how the regulation of protein conformation may be crucial in the development of Alzheimer's disease. Specifically, Dr. Pastorino will investigate whether Pin1, a protein that regulates the spatial conformation of other protein substrates, modifies the functional activity of another protein, presenilin 1, key to the generation of amyloid peptides typically seen in patients with AD.
Read more about these grant recipients at afar/gilbert09.html
According to the Alzheimer's Association, 5.3 million Americans are living with Alzheimer's disease. By 2010, it is estimated that there will be nearly half a million new cases of Alzheimer's disease diagnosed each year with that number doubling by 2050. There are currently no treatments to prevent AD or reverse its effects.
"Aging is by far the biggest risk factor for Alzheimer's disease. Researching the fundamental mechanisms that set the stage for Alzheimer's disease will help us get at the root of how this disease develops and progresses that could lead to a viable program of prevention and therapy, our ultimate goal," said George M. Martin, MD, Director Emeritus, Alzheimer's Disease Research Center at the University of Washington School of Medicine and Scientific Director of the American Federation for Aging Research. "The Rosalinde and Arthur Gilbert Foundation and an anonymous donor who supplemented each award are to be commended for their continued commitment to supporting these promising young scientists with innovative approaches to tackling our most pressing public health problem."
"The Rosalinde and Arthur Gilbert Foundation has invested in an outstanding group of U.S. and Israeli researchers who have the potential to make important and lasting contributions to Alzheimer's disease and aging science," said Martin H. Blank, Jr., co-director and Chief Operating Officer of the Foundation.
Source:
Stacey Harris
American Federation for Aging Research
Five early-career scientists were awarded The Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Awards in Alzheimer's Disease. The $75,000 awards provide a broad array of funding in the biological, genetic, and environmental causes of AD. By studying the early changes suggesting Alzheimer's disease from different but complementary angles, the awards seek to accelerate development of diagnostic, preventative interventions, and treatments. The program, now in its third year, has provided more than $1 million to 16 scientists in the U.S. and Israel.
Award recipients include:
Ehud Cohen, PhD, Lecturer, The Hebrew University of Jerusalem: Roles of Peptidylprolyl Cis/Trans Isomerases in the Regulation of Aging and Countering Alzheimer's Disease
Dr. Cohen's research will focus on the possible roles of cyclophilins - a group of proteins that help other proteins fold properly - in preventing Alzheimer's disease (AD) from emerging early in life and will test how this activity is affected by the aging process. His research could answer the question of whether the maintenance of cyclophilin activity through late life could protect against developing AD and will help unearth the mechanisms underlying the onset of some types of familial AD.
Raquel L. Lieberman, PhD, Assistant Professor, Georgia Tech: Crystal Structure of an Intramembrane Asparyl Protease
Over-production of beta amyloid peptides contribute to the pathogenesis of Alzheimer's disease.
The objective of this research is to understand the crystal structure of signal peptide peptidase (SPP). This protein is closely related to gamma secretase, the enzyme that participates in the generation of beta amyloids, species that are known to play roles in the development of Alzheimer's disease. Insights into these crystal structures could significantly further the development of structure-based designs for potential therapeutic agents.
Gad A. Marshall, MD, Instructor in Neurology, Associate Neurologist, Brigham and Women's Hospital: Amyloid Deposition and Frontally Mediated Symptoms in MCI
Although memory loss is the hallmark of Alzheimer's disease (AD), behavioral changes and executive dysfunction often play a major role in disability. Dr. Marshall will use state of the art imaging techniques to better understand the biological underpinnings of apathy and executive dysfunction in relation to mild cognitive impairment (MCI) and mild AD. This may provide the opportunity to differentiate between patients whose MCI will progress to AD and intervene with disease-modifying agents, attacking the disease at its earliest stages.
Esther Oh, MD, Assistant Professor, Johns Hopkins University: Oral Glucose Tolerance Test For Alzheimer's Disease Biomarker Development
The goal of Dr. Oh's research is to modify an amyloid blood test so that it may be able to determine whether someone has early forms of Alzheimer's disease (AD) or predict who may develop the disease among individuals who have certain forms of mild cognitive impairment (MCI). Since many cases of AD are diagnosed at more advanced stages, the diagnostic blood test, which could predict the likelihood of a person developing AD years in advance, could allow clinicians greater opportunity to intervene when drug therapy is likelier to be more effective.
Lucia Pastorino, PhD, Instructor in Medicine, Beth Israel Deaconess Medical Center: Role of the Prolyl Isomerase Pin1 in the Modulation of PS1 Activity
Dr. Pastorino will investigate how the regulation of protein conformation may be crucial in the development of Alzheimer's disease. Specifically, Dr. Pastorino will investigate whether Pin1, a protein that regulates the spatial conformation of other protein substrates, modifies the functional activity of another protein, presenilin 1, key to the generation of amyloid peptides typically seen in patients with AD.
Read more about these grant recipients at afar/gilbert09.html
According to the Alzheimer's Association, 5.3 million Americans are living with Alzheimer's disease. By 2010, it is estimated that there will be nearly half a million new cases of Alzheimer's disease diagnosed each year with that number doubling by 2050. There are currently no treatments to prevent AD or reverse its effects.
"Aging is by far the biggest risk factor for Alzheimer's disease. Researching the fundamental mechanisms that set the stage for Alzheimer's disease will help us get at the root of how this disease develops and progresses that could lead to a viable program of prevention and therapy, our ultimate goal," said George M. Martin, MD, Director Emeritus, Alzheimer's Disease Research Center at the University of Washington School of Medicine and Scientific Director of the American Federation for Aging Research. "The Rosalinde and Arthur Gilbert Foundation and an anonymous donor who supplemented each award are to be commended for their continued commitment to supporting these promising young scientists with innovative approaches to tackling our most pressing public health problem."
"The Rosalinde and Arthur Gilbert Foundation has invested in an outstanding group of U.S. and Israeli researchers who have the potential to make important and lasting contributions to Alzheimer's disease and aging science," said Martin H. Blank, Jr., co-director and Chief Operating Officer of the Foundation.
Source:
Stacey Harris
American Federation for Aging Research
Advance In The Battle Against "gray Mold" - ACS Chemical Biology Journal
Scientists are reporting identification of the cluster of genes responsible for the toxins produced by "gray mold," a devastating plant disease that kills almost 200 different food and ornamental plants including tomatoes, strawberries and roses. Their findings could lead to genetically engineered crops or new fungicides to fight this disease, which frustrates backyard gardeners and commercial farmers alike, the researchers say. The study is in the current online issue issue of ACS Chemical Biology, a monthly journal.
David Cane, Isidro Collado, Muriel Viaud and colleagues note that gray mold is so-named because it covers infected plants with fuzzy gray spores that can ultimately kill plants. A fungus named Botrytis cinerea causes the disease. Studies show that the fungus kills by producing two main plant toxins, botrydial and botcinic acid. Conventional fungicides are largely ineffective in destroying the fungus, which can easily spread to other plants.
In the new study, the scientists describe the identification of five genes involved in producing the enzymes that are responsible for making the toxins produced by the fungus. In lab studies, the researchers showed that inactivating one of the genes, called BcBOT2, blocked the gene cluster's ability to make the botrydial toxin. The finding could help the development of new, more effective fungicides or other resistance strategies, that target the ability of B. cinerea to make botrydial, the researchers suggest.
"Sesquiterpene Synthase from the Botrydial Biosynthetic Gene Cluster of the Phytopathogen Botrytis cinerea"
DOWNLOAD FULL TEXT ARTICLE
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
American Chemical Society
David Cane, Isidro Collado, Muriel Viaud and colleagues note that gray mold is so-named because it covers infected plants with fuzzy gray spores that can ultimately kill plants. A fungus named Botrytis cinerea causes the disease. Studies show that the fungus kills by producing two main plant toxins, botrydial and botcinic acid. Conventional fungicides are largely ineffective in destroying the fungus, which can easily spread to other plants.
In the new study, the scientists describe the identification of five genes involved in producing the enzymes that are responsible for making the toxins produced by the fungus. In lab studies, the researchers showed that inactivating one of the genes, called BcBOT2, blocked the gene cluster's ability to make the botrydial toxin. The finding could help the development of new, more effective fungicides or other resistance strategies, that target the ability of B. cinerea to make botrydial, the researchers suggest.
"Sesquiterpene Synthase from the Botrydial Biosynthetic Gene Cluster of the Phytopathogen Botrytis cinerea"
DOWNLOAD FULL TEXT ARTICLE
The American Chemical Society - the world's largest scientific society - is a nonprofit organization chartered by the U.S. Congress and a global leader in providing access to chemistry-related research through its multiple databases, peer-reviewed journals and scientific conferences. Its main offices are in Washington, D.C., and Columbus, Ohio.
American Chemical Society
Inhibiting 2 Pathways Rather Than 1 Enhances Anti-Tumor Effects
Two independent research groups have found that simultaneous inhibition of two signaling pathways resulted in substantially enhanced antitumor effects in mouse models of prostate and breast cancer. In an accompany commentary, Steven Grant, at Virginia Commonwealth University Health Science Center, Richmond, discusses the clinical importance of these studies and highlights some of the questions that still need to be answered.
In the first study, Pier Paolo Pandolfi and colleagues, at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and Memorial Sloan-Kettering Cancer Center, New York, report that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with a drug that inhibits the mTOR signaling pathway showed increased activation of the MAPK signaling pathway. Similar results were observed in a mouse model of prostate cancer following treatment with the same drug. As inhibition of the MAPK signaling pathway enhanced the antitumoral effects of inhibition of the mTOR signaling pathway in mice transplanted with a human breast cancer cell line, the authors suggest that a combination therapy using drugs that target each pathway might improve the treatment of human cancers.
In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer. This was particularly true in a model of highly aggressive and frequently lethal forms of the disease, which do not respond to hormone deprivation therapy, leading the authors to suggest that this combination therapy might be particularly useful for treating patients with advanced, hormone-refractory prostate cancer.
TITLE: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
AUTHOR CONTACT:
Pier Paolo Pandolfi
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
View the PDF of this article at: https://the-jci/article.php?id=34739
RELATED MANUSCRIPT
TITLE: Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
AUTHOR CONTACT:
Cory Abate-Shen
Columbia University College of Physicians and Surgeons, New York, New York, USA.
View the PDF of this article at: https://the-jci/article.php?id=34764
ACCOMPANYING COMMENTARY
TITLE: Cotargeting survival signaling pathways in cancer
AUTHOR CONTACT:
Steven Grant
Virginia Commonwealth University Health Science Center, Richmond, Virginia, USA.
View the PDF of this article at: https://the-jci/article.php?id=36898
Source: Karen Honey
Journal of Clinical Investigation
In the first study, Pier Paolo Pandolfi and colleagues, at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, and Memorial Sloan-Kettering Cancer Center, New York, report that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with a drug that inhibits the mTOR signaling pathway showed increased activation of the MAPK signaling pathway. Similar results were observed in a mouse model of prostate cancer following treatment with the same drug. As inhibition of the MAPK signaling pathway enhanced the antitumoral effects of inhibition of the mTOR signaling pathway in mice transplanted with a human breast cancer cell line, the authors suggest that a combination therapy using drugs that target each pathway might improve the treatment of human cancers.
In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer. This was particularly true in a model of highly aggressive and frequently lethal forms of the disease, which do not respond to hormone deprivation therapy, leading the authors to suggest that this combination therapy might be particularly useful for treating patients with advanced, hormone-refractory prostate cancer.
TITLE: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
AUTHOR CONTACT:
Pier Paolo Pandolfi
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
View the PDF of this article at: https://the-jci/article.php?id=34739
RELATED MANUSCRIPT
TITLE: Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
AUTHOR CONTACT:
Cory Abate-Shen
Columbia University College of Physicians and Surgeons, New York, New York, USA.
View the PDF of this article at: https://the-jci/article.php?id=34764
ACCOMPANYING COMMENTARY
TITLE: Cotargeting survival signaling pathways in cancer
AUTHOR CONTACT:
Steven Grant
Virginia Commonwealth University Health Science Center, Richmond, Virginia, USA.
View the PDF of this article at: https://the-jci/article.php?id=36898
Source: Karen Honey
Journal of Clinical Investigation
Abnormal Protein Makes Huntington's Disease Patients Sick
An aggregating protein causes many of the symptoms of Huntington's disease, an incurable and frequently fatal brain disorder. Mosaic winner Ahmad Aziz discovered that the abnormal protein also aggregates in the hypothalamus, the part of the brain that regulates the autonomic nervous system and the endocrine system.
Ahmad Aziz investigated the severity and causes of a number of less well-known symptoms of Huntington's disease: weight loss, sleep disturbances and a poorly functioning autonomic nervous system. He established that many patients suffer from weight loss and sleeping problems. Abnormalities in the hypothalamus appear to account for some of these symptoms.
The hypothalamus was an obvious suspect for Aziz, as it regulates the autonomic nervous system and the endocrine system. Aziz established that certain nerve cells are lost in a part of the hypothalamus. In this part as well as in other parts of the hypothalamus abnormal protein aggregates were found. These hypothalamic nerve cells play an important role in the maintenance of body weight and a normal sleeping pattern.
Sleep and depression
Many of the patients investigated by Aziz get to sleep too late and wake up later in the morning than healthy people. Moreover, it appeared that the further the sleep rhythm is displaced, the more depressive the patients are. These patients also suffer from more cognitive abnormalities. The disruption of the sleeping rhythm could partly be due to a shift in the rhythm of the 'sleeping hormone' melatonin. That rhythm is regulated by the biological clock in the hypothalamus. Many Alzheimer's patients also have an abnormal sleep/wake rhythm. This can partially be corrected by light therapy and the administration of melatonin. Huntington patients might also benefit from such an approach.
Weight loss
Although the mutated Huntington's disease gene mainly causes damage in the brain, it is expressed in virtually all tissues, even though it does not cause damage everywhere. However, Aziz demonstrated that weight loss in the initial stages of Huntington's disease is not the consequence of other symptoms, such as hyperactivity, but is directly related to the mutation. This indicates that the cause must partly lie in the peripheral tissues, such as muscle and fat tissue. The defective gene probably causes damage there as well.
Influence of the normal gene
Huntington's disease is caused by a mutation in the huntingtin gene. In the mutated gene the DNA sequence C-A-G is repeated too often. Aziz's research reveals that weight loss and the number of CAG repeats are directly correlated: the greater the number of repeats, the greater the loss of weight.
The number of CAG repeats in the normal huntingtin gene can also influence the symptoms of the disease. This is because each person carries two copies of the huntingtin gene. In a normal gene there are 35 or less CAG repeats. Huntington patients have one normal gene and one defective gene with 36 or more repeats. Aziz discovered that the number of CAG repeats in both the normal gene and the defective gene is important for the rate at which the disease progresses. However, the effect of the normal gene is small and is mainly important for understanding how the disease develops and for a correct interpretation of future drug studies. It follows that such studies must take into account the differences in the number of CAG repeats in both genes.
Source: NWO (Netherlands Organization for Scientific Research)
Ahmad Aziz investigated the severity and causes of a number of less well-known symptoms of Huntington's disease: weight loss, sleep disturbances and a poorly functioning autonomic nervous system. He established that many patients suffer from weight loss and sleeping problems. Abnormalities in the hypothalamus appear to account for some of these symptoms.
The hypothalamus was an obvious suspect for Aziz, as it regulates the autonomic nervous system and the endocrine system. Aziz established that certain nerve cells are lost in a part of the hypothalamus. In this part as well as in other parts of the hypothalamus abnormal protein aggregates were found. These hypothalamic nerve cells play an important role in the maintenance of body weight and a normal sleeping pattern.
Sleep and depression
Many of the patients investigated by Aziz get to sleep too late and wake up later in the morning than healthy people. Moreover, it appeared that the further the sleep rhythm is displaced, the more depressive the patients are. These patients also suffer from more cognitive abnormalities. The disruption of the sleeping rhythm could partly be due to a shift in the rhythm of the 'sleeping hormone' melatonin. That rhythm is regulated by the biological clock in the hypothalamus. Many Alzheimer's patients also have an abnormal sleep/wake rhythm. This can partially be corrected by light therapy and the administration of melatonin. Huntington patients might also benefit from such an approach.
Weight loss
Although the mutated Huntington's disease gene mainly causes damage in the brain, it is expressed in virtually all tissues, even though it does not cause damage everywhere. However, Aziz demonstrated that weight loss in the initial stages of Huntington's disease is not the consequence of other symptoms, such as hyperactivity, but is directly related to the mutation. This indicates that the cause must partly lie in the peripheral tissues, such as muscle and fat tissue. The defective gene probably causes damage there as well.
Influence of the normal gene
Huntington's disease is caused by a mutation in the huntingtin gene. In the mutated gene the DNA sequence C-A-G is repeated too often. Aziz's research reveals that weight loss and the number of CAG repeats are directly correlated: the greater the number of repeats, the greater the loss of weight.
The number of CAG repeats in the normal huntingtin gene can also influence the symptoms of the disease. This is because each person carries two copies of the huntingtin gene. In a normal gene there are 35 or less CAG repeats. Huntington patients have one normal gene and one defective gene with 36 or more repeats. Aziz discovered that the number of CAG repeats in both the normal gene and the defective gene is important for the rate at which the disease progresses. However, the effect of the normal gene is small and is mainly important for understanding how the disease develops and for a correct interpretation of future drug studies. It follows that such studies must take into account the differences in the number of CAG repeats in both genes.
Source: NWO (Netherlands Organization for Scientific Research)
Insects Had It First: Surfactants As A Defence Against Predators
Surfactants are compounds that reduce the surface tension of water and thus have important functions in biological systems and in our daily lives.
A surprising new role has been found for surfactants by demonstrating their contribution to the self-defence of plant-feeding insects. Threatened caterpillars regurgitate gut fluid with very low surface tension enabling the fluid to spread over the strongly water-repellent cuticle of predatory insects.
The affected predator needs to engage in intensive cleansing, thus allowing the victim to escape.
This finding also shows that insects 'invented' defensive surfactants long before modern agriculture started applying them as insecticides.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
A surprising new role has been found for surfactants by demonstrating their contribution to the self-defence of plant-feeding insects. Threatened caterpillars regurgitate gut fluid with very low surface tension enabling the fluid to spread over the strongly water-repellent cuticle of predatory insects.
The affected predator needs to engage in intensive cleansing, thus allowing the victim to escape.
This finding also shows that insects 'invented' defensive surfactants long before modern agriculture started applying them as insecticides.
Proceedings of the Royal Society B: Biological Sciences
Proceedings B is the Royal Society's flagship biological research journal, dedicated to the rapid publication and broad dissemination of high-quality research papers, reviews and comment and reply papers. The scope of journal is diverse and is especially strong in organismal biology.
Proceedings of the Royal Society B: Biological Sciences
Sickle Cell Patients Treated Safely With Anticlotting Drug
An intravenous "blood thinner" widely used in patients with acute coronary syndromes and during coronary artery stent placement appears to be safe in patients with sickle cell disease and may have beneficial anti-inflammatory effects, a small study at the University of North Carolina at Chapel Hill School of Medicine has found.
"We have tested a potentially promising drug in sickle cell patients, and the drug appears to be well tolerated. This gives us the impetus to go ahead with further studies of eptifibatide in these patients," said Dr. Leslie V. Parise, department chair and professor of biochemistry and biophysics at the UNC-Chapel Hill School of Medicine.
The hallmark of sickle cell disease is malformed red blood cells that can cause sudden painful episodes when they block small blood vessels. However, sickle cell patients are also at increased risk of developing multiple other complications, including strokes, lung complications and pulmonary hypertension.
The most frequent manifestations of sickle cell disorders are anemia and pain episodes. The episodic exacerbation of pain, often called "crises," is unpredictable and may occur often in some patients.
The only drug presently approved for the treatment of sickle cell disease is hydroxyurea, which has been shown to reduce the frequency of painful episodes.
Parise emphasized the need for further study. "We did not test this drug in patients who are in crisis, and we cannot recommend that doctors prescribe this drug for sickle cell patients at this time," she said.
The results of the study were published online in the British Journal of Haematology.
The researchers gave intravenous infusions of eptifibatide (brand name Integrilin) to four patients with sickle cell anemia who were not experiencing pain episodes. "They did well clinically. They did not experience any deleterious changes in their blood tests or have a pain episode," said coauthor Dr. Kenneth I. Ataga, assistant professor of medicine at UNC-Chapel Hill.
In the current study, blood tests showed that while the patients' liver, kidney and other functions remained at baseline, several indicators of inflammation decreased, including levels of a protein called CD40L known to play a role in inflammation and in blood clotting.
Previous studies conducted by Sheritha Lee a graduate student in Parise's lab showed that patients with sickle cell disease have CD40L levels that are as much as 30 times higher than in patients without the disease. Eptifibatide's known ability to decrease CD40L led the researchers to study whether the drug might help sickle cell patients.
In addition to Lee, Parise, and Ataga, other UNC authors of the study are graduate student Mohamed Zayed of the department of pharmacology; and Dr. Eugene P. Orringer, professor of medicine. Authors from Millennium Pharmaceuticals at the time of the study are Drs. Jeanne M. Manganello and David R. Phillips.
The study was funded by the National Institutes of Health and the American Heart Association.
School of Medicine contact: Leslie Lang or Stephanie Crayton
Source: Les Lang
University of North Carolina at Chapel Hill
View drug information on Integrilin.
"We have tested a potentially promising drug in sickle cell patients, and the drug appears to be well tolerated. This gives us the impetus to go ahead with further studies of eptifibatide in these patients," said Dr. Leslie V. Parise, department chair and professor of biochemistry and biophysics at the UNC-Chapel Hill School of Medicine.
The hallmark of sickle cell disease is malformed red blood cells that can cause sudden painful episodes when they block small blood vessels. However, sickle cell patients are also at increased risk of developing multiple other complications, including strokes, lung complications and pulmonary hypertension.
The most frequent manifestations of sickle cell disorders are anemia and pain episodes. The episodic exacerbation of pain, often called "crises," is unpredictable and may occur often in some patients.
The only drug presently approved for the treatment of sickle cell disease is hydroxyurea, which has been shown to reduce the frequency of painful episodes.
Parise emphasized the need for further study. "We did not test this drug in patients who are in crisis, and we cannot recommend that doctors prescribe this drug for sickle cell patients at this time," she said.
The results of the study were published online in the British Journal of Haematology.
The researchers gave intravenous infusions of eptifibatide (brand name Integrilin) to four patients with sickle cell anemia who were not experiencing pain episodes. "They did well clinically. They did not experience any deleterious changes in their blood tests or have a pain episode," said coauthor Dr. Kenneth I. Ataga, assistant professor of medicine at UNC-Chapel Hill.
In the current study, blood tests showed that while the patients' liver, kidney and other functions remained at baseline, several indicators of inflammation decreased, including levels of a protein called CD40L known to play a role in inflammation and in blood clotting.
Previous studies conducted by Sheritha Lee a graduate student in Parise's lab showed that patients with sickle cell disease have CD40L levels that are as much as 30 times higher than in patients without the disease. Eptifibatide's known ability to decrease CD40L led the researchers to study whether the drug might help sickle cell patients.
In addition to Lee, Parise, and Ataga, other UNC authors of the study are graduate student Mohamed Zayed of the department of pharmacology; and Dr. Eugene P. Orringer, professor of medicine. Authors from Millennium Pharmaceuticals at the time of the study are Drs. Jeanne M. Manganello and David R. Phillips.
The study was funded by the National Institutes of Health and the American Heart Association.
School of Medicine contact: Leslie Lang or Stephanie Crayton
Source: Les Lang
University of North Carolina at Chapel Hill
View drug information on Integrilin.
Researchers Attack Stem Cells That Cause Colon Cancer
Many of the colon cancer cells that form tumors can be killed by genetically short-circuiting the cells' ability to absorb a key nutrient, a new study has found. While the findings are encouraging, the test tube study using human colon cancer cells also illustrates the difficulty of defeating these cells, known as cancer stem cells (CSCs).
"It is becoming more evident that only a small number of cells in the tumor are capable of forming the tumor, namely the cancer stem cells," said one of the study's authors Adhip P.N. Majumdar of the VA Medical Center and Karmanos Cancer Institute, Wayne State University in Detroit. "So the new strategy is to eliminate the cancer stem cells and thus lower the recurrence of cancer."
Colorectal cancer remains the third deadliest cancer in the U.S. There are 147,000 new cases of colorectal cancer each year, and 49,920 deaths, according to the American Cancer Society. About half of all cancers, including colon cancer, reoccur within five years of treatment, Majumdar said.
Majumdar will present the study, "IFG-1R regulation of colon cancer stem cells," on Wednesday, April 28 at the Experimental Biology 2010 conference. The presentation is part of the cancer stem cell track sponsored by the American Society for Investigative Pathology. The conference takes place April 24-28 at the Anaheim Convention Center. Majumdar carried out the study with Yingie Yu and Bhaumik B. Patel, who are also with Wayne State University.
Tumor factories
Unlike most cells in the body, which are programmed to die after dividing a number of times, normal adult stem cells have a remarkable ability to renew themselves by dividing almost without limit. In addition to this ability to replicate, they can also develop into many different types of cells, such as new heart muscle cells or intestinal cells. In the mature organism, stem cells play a critical role of renewal, replacing dead cells and repairing tissue.
CSCs are a type of stem cell discovered less than 15 years ago and are believed to be the result of mutations of normal stem cells. When CSCs divide, they can develop into new CSCs or into any type of cancer cell. While CSCs make up only 1% of a tumor's cells, they are believed to play a pivotal role in the recurrence of tumors following chemotherapy.
Traditional chemotherapy is good at killing most tumor cells, but not CSCs. Cell studies have found that chemotherapy kills only some of the tumor's CSCs. As a result, tumors may shrink or even disappear with chemotherapy, but the CSCs survive, replicating themselves and eventually producing new tumor cells.
Given the crucial role they play in cancer, it is no surprise that research has focused on destroying the CSCs. But there is a problem: these cells are so similar to normal stem cells that eradicating CSCs may also eradicate normal stem cells, an unacceptable outcome.
Starving them out
"Because CSCs have properties similar to normal stem cells, we have to find a way to attack them while keeping the adult stem cells alive," Majumdar said. To do that, the research team inactivated a receptor that is found in increased amounts in colon cancer cells: the insulin-like growth factor receptor (IGF-1R). The colon cancer CSCs seem to need a fair amount of IGF to live, more than other cells, and they can't function without the IGF receptor.
"We found that cells that survive chemotherapy show high activation of the IGF receptor and other receptors," Majumdar said. "We thought if we could inhibit or lower the receptor, we may have a treatment strategy."
Working with human colon cancer cells, the researchers manipulated the cellular genetics using small interfering RNA (siRNA) to prevent the synthesis of IGF-1R. In this way, they reduced the number of IGF receptors by half, and reduced the number of CSCs by 35%.
Questions about toxicity remain
Interestingly, Majumdar's laboratory has also had success disabling CSCs with curcumin, a principal constituent of turmeric, a spice commonly used in Indian cuisine. His studies have found that curcumin also can lower the number of IGF-1R and can reduce CSCs further when paired with the siRNA method he outlined in the current study.
The problem with combining the above mentioned anti-CSC strategies is that they can adversely affect normal adult stem cells which, if damaged, would only cause greater harm to the organism.
In addition, it is not yet clear whether reducing the number of CSCs can reduce the recurrence rate of colon cancer. However, Majumdar's laboratory has tried out the curcumin treatment with animals, with some encouraging results.
"Whether we can do this on humans without harming normal stem cells, that's the biggest challenge," Majumdar concluded.
The American Society for Investigative Pathology (ASIP) is a society of biomedical scientists who investigate mechanisms of disease. Investigative pathology is an integrative discipline that links the presentation of disease in the whole organism to its fundamental cellular and molecular mechanisms. It uses a variety of structural, functional, and genetic techniques and ultimately applies research findings to the diagnosis and treatment of diseases. ASIP advocates for the practice of investigative pathology and fosters the professional career development and education of its members.
Source: Federation of American Societies for Experimental Biology (FASEB)
"It is becoming more evident that only a small number of cells in the tumor are capable of forming the tumor, namely the cancer stem cells," said one of the study's authors Adhip P.N. Majumdar of the VA Medical Center and Karmanos Cancer Institute, Wayne State University in Detroit. "So the new strategy is to eliminate the cancer stem cells and thus lower the recurrence of cancer."
Colorectal cancer remains the third deadliest cancer in the U.S. There are 147,000 new cases of colorectal cancer each year, and 49,920 deaths, according to the American Cancer Society. About half of all cancers, including colon cancer, reoccur within five years of treatment, Majumdar said.
Majumdar will present the study, "IFG-1R regulation of colon cancer stem cells," on Wednesday, April 28 at the Experimental Biology 2010 conference. The presentation is part of the cancer stem cell track sponsored by the American Society for Investigative Pathology. The conference takes place April 24-28 at the Anaheim Convention Center. Majumdar carried out the study with Yingie Yu and Bhaumik B. Patel, who are also with Wayne State University.
Tumor factories
Unlike most cells in the body, which are programmed to die after dividing a number of times, normal adult stem cells have a remarkable ability to renew themselves by dividing almost without limit. In addition to this ability to replicate, they can also develop into many different types of cells, such as new heart muscle cells or intestinal cells. In the mature organism, stem cells play a critical role of renewal, replacing dead cells and repairing tissue.
CSCs are a type of stem cell discovered less than 15 years ago and are believed to be the result of mutations of normal stem cells. When CSCs divide, they can develop into new CSCs or into any type of cancer cell. While CSCs make up only 1% of a tumor's cells, they are believed to play a pivotal role in the recurrence of tumors following chemotherapy.
Traditional chemotherapy is good at killing most tumor cells, but not CSCs. Cell studies have found that chemotherapy kills only some of the tumor's CSCs. As a result, tumors may shrink or even disappear with chemotherapy, but the CSCs survive, replicating themselves and eventually producing new tumor cells.
Given the crucial role they play in cancer, it is no surprise that research has focused on destroying the CSCs. But there is a problem: these cells are so similar to normal stem cells that eradicating CSCs may also eradicate normal stem cells, an unacceptable outcome.
Starving them out
"Because CSCs have properties similar to normal stem cells, we have to find a way to attack them while keeping the adult stem cells alive," Majumdar said. To do that, the research team inactivated a receptor that is found in increased amounts in colon cancer cells: the insulin-like growth factor receptor (IGF-1R). The colon cancer CSCs seem to need a fair amount of IGF to live, more than other cells, and they can't function without the IGF receptor.
"We found that cells that survive chemotherapy show high activation of the IGF receptor and other receptors," Majumdar said. "We thought if we could inhibit or lower the receptor, we may have a treatment strategy."
Working with human colon cancer cells, the researchers manipulated the cellular genetics using small interfering RNA (siRNA) to prevent the synthesis of IGF-1R. In this way, they reduced the number of IGF receptors by half, and reduced the number of CSCs by 35%.
Questions about toxicity remain
Interestingly, Majumdar's laboratory has also had success disabling CSCs with curcumin, a principal constituent of turmeric, a spice commonly used in Indian cuisine. His studies have found that curcumin also can lower the number of IGF-1R and can reduce CSCs further when paired with the siRNA method he outlined in the current study.
The problem with combining the above mentioned anti-CSC strategies is that they can adversely affect normal adult stem cells which, if damaged, would only cause greater harm to the organism.
In addition, it is not yet clear whether reducing the number of CSCs can reduce the recurrence rate of colon cancer. However, Majumdar's laboratory has tried out the curcumin treatment with animals, with some encouraging results.
"Whether we can do this on humans without harming normal stem cells, that's the biggest challenge," Majumdar concluded.
The American Society for Investigative Pathology (ASIP) is a society of biomedical scientists who investigate mechanisms of disease. Investigative pathology is an integrative discipline that links the presentation of disease in the whole organism to its fundamental cellular and molecular mechanisms. It uses a variety of structural, functional, and genetic techniques and ultimately applies research findings to the diagnosis and treatment of diseases. ASIP advocates for the practice of investigative pathology and fosters the professional career development and education of its members.
Source: Federation of American Societies for Experimental Biology (FASEB)
Researchers Identify Protein That Regulates Magnesium And Can Restart Stem Cells
An international team led by researchers at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School has published new findings that demonstrate how a specific protein controls the body's ability to balance magnesium levels. Magnesium is an essential element for good health and is critical to more than 300 biochemical reactions that occur in the body.
"Currently more than half of the US population does not consume an adequate amount of magnesium in their diet," said Alexey G. Ryazanov, Ph.D., one of the study's authors and a professor of pharmacology and member of The Cancer Institute of New Jersey at UMDNJ-Robert Wood Johnson Medical School.
"Magnesium deficiency may be associated with many medical disorders including hypertension, atherosclerosis, anxiety, asthma and a host of other disorders."
The team of researchers from the United States, France and Poland demonstrated for the first time that a protein called TRPM7 plays a key role in the maintenance of magnesium homeostasis (balance within the body) and is essential for proliferation of embryonic stem cells. TRPM7, which was previously discovered by the researchers, is unusual in that it consists of an ion channel fused to a protein kinase, a type of enzyme that chemically modifies other proteins. It is one of just two such proteins known to exist in vertebrate organisms.
"This has significant medical relevance," Ryazanov said. "Even though maintaining magnesium balance appears vital to good health, the molecular mechanisms for controlling magnesium are not well understood. Our research not only provides important clues about magnesium homeostasis but we were also able to show that adding magnesium can restart mouse embryonic stem cells that have stopped replicating because of a malfunction of TRPM7."
The researchers' findings appear in the current issue of Nature Communications. The study was supported by a Program Project Grant from the National Institutes of Health.
Source: University of Medicine and Dentistry of New Jersey (UMDNJ)
"Currently more than half of the US population does not consume an adequate amount of magnesium in their diet," said Alexey G. Ryazanov, Ph.D., one of the study's authors and a professor of pharmacology and member of The Cancer Institute of New Jersey at UMDNJ-Robert Wood Johnson Medical School.
"Magnesium deficiency may be associated with many medical disorders including hypertension, atherosclerosis, anxiety, asthma and a host of other disorders."
The team of researchers from the United States, France and Poland demonstrated for the first time that a protein called TRPM7 plays a key role in the maintenance of magnesium homeostasis (balance within the body) and is essential for proliferation of embryonic stem cells. TRPM7, which was previously discovered by the researchers, is unusual in that it consists of an ion channel fused to a protein kinase, a type of enzyme that chemically modifies other proteins. It is one of just two such proteins known to exist in vertebrate organisms.
"This has significant medical relevance," Ryazanov said. "Even though maintaining magnesium balance appears vital to good health, the molecular mechanisms for controlling magnesium are not well understood. Our research not only provides important clues about magnesium homeostasis but we were also able to show that adding magnesium can restart mouse embryonic stem cells that have stopped replicating because of a malfunction of TRPM7."
The researchers' findings appear in the current issue of Nature Communications. The study was supported by a Program Project Grant from the National Institutes of Health.
Source: University of Medicine and Dentistry of New Jersey (UMDNJ)
News From The Journal Of Clinical Investigation, June 8, 2009
ONCOLOGY: Learning about antitumor immune responses from human patients
Insight into antitumor immune responses can be gained by studying the small number of individuals with small cell lung cancer (SCLC) that develop the neurologic disorder Hu paraneoplastic neurologic syndrome. SCLC cells express the protein HuD, which is normally only expressed by nerve cells, and the presence of an immune response against HuD correlates with improved prognosis for individuals with SCLC. However, in a small number of patients, the immune response against HuD on the cancer cells attacks nerve cells expressing HuD, leading to neurologic symptoms. It has been proposed for many years that immune cells known as CD8+ T cells contribute to disease in Hu patients, but no one has been able to detect these cells. However, Robert Darnell and colleagues, at The Rockefeller University, New York, have now identified, in Hu patients, HuD-specific CD8+ T cells and determined one potential explanation for why they have been so difficult to detect.
In the study, the HuD-specific CD8+ T cells detected in Hu patients were of two types: normal CD8+ T cells that produce the molecule IFN-gamma and kill cells expressing their target (in this case HuD); and atypical CD8+ T cells that produce the molecules IL-13 and IL-15 and cannot kill HuD-expressing cells. Further analysis revealed that SCLC cells produce factors that skew CD8+ T cells to the atypical type, leading the authors to suggest that SCLC might evade antitumor immune responses by skewing tumor-targeted CD8+ T cells to the nonkilling type.
TITLE: Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells https://the-jci/article.php?id=36131
AUTHOR CONTACT:
Robert B. Darnell
The Rockefeller University, New York, New York, USA.
OPHTHALMOLOGY: When development of the eye fails to give clear sight
Masaru Inatani and colleagues, at Kumamoto University Graduate School of Medical Sciences, Japan, have provided new insight into the development of the anterior chamber of the mouse eye, the fluid-filled space inside the eye that lies between the iris and the cornea. The clinical relevance of this information lies in the fact that failure of the anterior chamber to develop causes developmental glaucoma.
In the study, failure of the anterior chamber to develop was caused by a lack of the molecule HS in mouse neural crest cells. Specifically, the characteristics of the mice resembled the form of human developmental glaucoma known as Peters anomaly. Signaling induced by the molecule TGF-beta-2 was disturbed in the neural crest cells lacking HS; this altered expression of the proteins Foxc1 and Pitx2. Mutations in the genes responsible for generating these two proteins are known to cause developmental glaucoma. These data indicate that HS is required for proper formation of the anterior chamber of the mouse eye from neural crest cells and lead the authors to suggest that modulation of HS levels might cause developmental glaucoma.
TITLE: Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-beta-2 signaling https://the-jci/article.php?id=38519
AUTHOR CONTACT:
Masaru Inatani
Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
BACTERIOLOGY: Clearing pneumococcal bacteria from the upper airways
The bacterium Streptococcus pneumoniae can be found in the upper airways (the nose, mouth, and throat) of most children. When living in the upper airways, S. pneumoniae is harmless. However, if the bacteria are carried to other sites, they cause disease, for example ear infections and life-threatening pneumonia. Long-term studies have shown that the upper airways of children do not continuously harbor S. pneumoniae. Rather, it is a cycle of bacterial clearance followed by recolonization, with little known about how the bacteria are cleared. However, Jeffrey Weiser and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now identified a cellular immune mechanism by which mice clear S. pneumoniae from their upper airways.
In the study, they found that efficient clearance of S. pneumoniae from the upper airways of mice that had not been previously colonized by the bacteria required immune cells known as Th17 cells (CD4+ T cells that secrete the soluble factor IL-17). Further analysis indicated that these cells were required to sustain the recruitment of other immune cells known as monocyte/macrophages, which effectively cleared the pneumococcal bacteria. The authors suggest these data provide a new model for immune-mediated clearance of S. pneumoniae from the upper airways.
TITLE: Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice https://the-jci/article.php?id=36731
AUTHOR CONTACT:
Jeffrey N. Weiser
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
GENE THERAPY: Selecting genetically modified cells in rhesus macaques
Transplanting individuals with genetically modified hematopoietic stem cells has been considered a viable gene therapy approach to treat a number of diseases. One major limitation to this approach is the low efficiency of gene transfer into the target cells. Including a drug resistance gene in the viral vector containing the therapeutic gene has been suggested as a way to overcome this limitation. Andre Larochelle and colleagues, at the NIH, Bethesda, have now tested this hypothesis in rhesus macaques using the gene MGMT*, which confers resistance to the drugs O6-benzylguanine and temozolomide.
In the study, when rhesus macaques were transplanted with hematopoietic progenitor cells genetically modified to carry MGMT* and a fluorescent protein, there was a transient increase in cells expressing the fluorescent protein after treatment with O6-benzylguanine and temozolomide. However, there was no long-term selection of genetically modified cells. Despite the lack of long-term effects, these data should have clinical impact. For example, the observation that rhesus macaques transplanted with cells modified to express MGMT* were able to receive increasing doses of temozolomide without toxic consequences might provide benefit to individuals with malignant brain tumors that require temozolomide dose intensification.
TITLE: In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene https://the-jci/article.php?id=37506
AUTHOR CONTACT:
Andre Larochelle
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
DEVELOPMENT: 'Notch'ing up our understanding of embryonic heart development
Congenital heart disease can be caused by mutations in either the JAGGED or NOTCH genes. Jonathan Epstein and colleagues, at the University of Pennsylvania, Philadelphia, have now provided new insight into the role of Jagged-Notch signaling in heart development in mice, defining a potential cellular explanation for forms of congenital heart disease linked to JAGGED and NOTCH mutations.
In the study, genetic manipulation of the region of the developing mouse embryo that gives rise to the right ventricle of the heart (the second heart field) such that it either lacked Jagged1 (a molecule that binds Notch, initiating signaling) or expressed an inhibitor of the Notch signaling pathway led to abnormal development of the heart. Further, inhibition of Notch in the second heart field affected the development of neighboring tissues; for example, abnormal migration of cardiac neural crest cells was observed. Further analysis revealed a molecular explanation for the heart defects: decreased expression of the Fgf8 and Bmp4 genes. The authors therefore suggest that altered Notch-Jagged signaling within the second heart field might underlie forms of congenital heart disease linked to JAGGED and NOTCH mutations.
TITLE: Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development https://the-jci/article.php?id=38922
AUTHOR CONTACT:
Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Source:
Karen Honey
Journal of Clinical Investigation
Insight into antitumor immune responses can be gained by studying the small number of individuals with small cell lung cancer (SCLC) that develop the neurologic disorder Hu paraneoplastic neurologic syndrome. SCLC cells express the protein HuD, which is normally only expressed by nerve cells, and the presence of an immune response against HuD correlates with improved prognosis for individuals with SCLC. However, in a small number of patients, the immune response against HuD on the cancer cells attacks nerve cells expressing HuD, leading to neurologic symptoms. It has been proposed for many years that immune cells known as CD8+ T cells contribute to disease in Hu patients, but no one has been able to detect these cells. However, Robert Darnell and colleagues, at The Rockefeller University, New York, have now identified, in Hu patients, HuD-specific CD8+ T cells and determined one potential explanation for why they have been so difficult to detect.
In the study, the HuD-specific CD8+ T cells detected in Hu patients were of two types: normal CD8+ T cells that produce the molecule IFN-gamma and kill cells expressing their target (in this case HuD); and atypical CD8+ T cells that produce the molecules IL-13 and IL-15 and cannot kill HuD-expressing cells. Further analysis revealed that SCLC cells produce factors that skew CD8+ T cells to the atypical type, leading the authors to suggest that SCLC might evade antitumor immune responses by skewing tumor-targeted CD8+ T cells to the nonkilling type.
TITLE: Patients with lung cancer and paraneoplastic Hu syndrome harbor HuD-specific type 2 CD8+ T cells https://the-jci/article.php?id=36131
AUTHOR CONTACT:
Robert B. Darnell
The Rockefeller University, New York, New York, USA.
OPHTHALMOLOGY: When development of the eye fails to give clear sight
Masaru Inatani and colleagues, at Kumamoto University Graduate School of Medical Sciences, Japan, have provided new insight into the development of the anterior chamber of the mouse eye, the fluid-filled space inside the eye that lies between the iris and the cornea. The clinical relevance of this information lies in the fact that failure of the anterior chamber to develop causes developmental glaucoma.
In the study, failure of the anterior chamber to develop was caused by a lack of the molecule HS in mouse neural crest cells. Specifically, the characteristics of the mice resembled the form of human developmental glaucoma known as Peters anomaly. Signaling induced by the molecule TGF-beta-2 was disturbed in the neural crest cells lacking HS; this altered expression of the proteins Foxc1 and Pitx2. Mutations in the genes responsible for generating these two proteins are known to cause developmental glaucoma. These data indicate that HS is required for proper formation of the anterior chamber of the mouse eye from neural crest cells and lead the authors to suggest that modulation of HS levels might cause developmental glaucoma.
TITLE: Heparan sulfate deficiency leads to Peters anomaly in mice by disturbing neural crest TGF-beta-2 signaling https://the-jci/article.php?id=38519
AUTHOR CONTACT:
Masaru Inatani
Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.
BACTERIOLOGY: Clearing pneumococcal bacteria from the upper airways
The bacterium Streptococcus pneumoniae can be found in the upper airways (the nose, mouth, and throat) of most children. When living in the upper airways, S. pneumoniae is harmless. However, if the bacteria are carried to other sites, they cause disease, for example ear infections and life-threatening pneumonia. Long-term studies have shown that the upper airways of children do not continuously harbor S. pneumoniae. Rather, it is a cycle of bacterial clearance followed by recolonization, with little known about how the bacteria are cleared. However, Jeffrey Weiser and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now identified a cellular immune mechanism by which mice clear S. pneumoniae from their upper airways.
In the study, they found that efficient clearance of S. pneumoniae from the upper airways of mice that had not been previously colonized by the bacteria required immune cells known as Th17 cells (CD4+ T cells that secrete the soluble factor IL-17). Further analysis indicated that these cells were required to sustain the recruitment of other immune cells known as monocyte/macrophages, which effectively cleared the pneumococcal bacteria. The authors suggest these data provide a new model for immune-mediated clearance of S. pneumoniae from the upper airways.
TITLE: Cellular effectors mediating Th17-dependent clearance of pneumococcal colonization in mice https://the-jci/article.php?id=36731
AUTHOR CONTACT:
Jeffrey N. Weiser
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
GENE THERAPY: Selecting genetically modified cells in rhesus macaques
Transplanting individuals with genetically modified hematopoietic stem cells has been considered a viable gene therapy approach to treat a number of diseases. One major limitation to this approach is the low efficiency of gene transfer into the target cells. Including a drug resistance gene in the viral vector containing the therapeutic gene has been suggested as a way to overcome this limitation. Andre Larochelle and colleagues, at the NIH, Bethesda, have now tested this hypothesis in rhesus macaques using the gene MGMT*, which confers resistance to the drugs O6-benzylguanine and temozolomide.
In the study, when rhesus macaques were transplanted with hematopoietic progenitor cells genetically modified to carry MGMT* and a fluorescent protein, there was a transient increase in cells expressing the fluorescent protein after treatment with O6-benzylguanine and temozolomide. However, there was no long-term selection of genetically modified cells. Despite the lack of long-term effects, these data should have clinical impact. For example, the observation that rhesus macaques transplanted with cells modified to express MGMT* were able to receive increasing doses of temozolomide without toxic consequences might provide benefit to individuals with malignant brain tumors that require temozolomide dose intensification.
TITLE: In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene https://the-jci/article.php?id=37506
AUTHOR CONTACT:
Andre Larochelle
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
DEVELOPMENT: 'Notch'ing up our understanding of embryonic heart development
Congenital heart disease can be caused by mutations in either the JAGGED or NOTCH genes. Jonathan Epstein and colleagues, at the University of Pennsylvania, Philadelphia, have now provided new insight into the role of Jagged-Notch signaling in heart development in mice, defining a potential cellular explanation for forms of congenital heart disease linked to JAGGED and NOTCH mutations.
In the study, genetic manipulation of the region of the developing mouse embryo that gives rise to the right ventricle of the heart (the second heart field) such that it either lacked Jagged1 (a molecule that binds Notch, initiating signaling) or expressed an inhibitor of the Notch signaling pathway led to abnormal development of the heart. Further, inhibition of Notch in the second heart field affected the development of neighboring tissues; for example, abnormal migration of cardiac neural crest cells was observed. Further analysis revealed a molecular explanation for the heart defects: decreased expression of the Fgf8 and Bmp4 genes. The authors therefore suggest that altered Notch-Jagged signaling within the second heart field might underlie forms of congenital heart disease linked to JAGGED and NOTCH mutations.
TITLE: Murine Jagged1/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue-tissue interactions during outflow tract development https://the-jci/article.php?id=38922
AUTHOR CONTACT:
Jonathan A. Epstein
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Source:
Karen Honey
Journal of Clinical Investigation
Solving The Structure Of Proteins That Allow Bacteria To Gain Resistance To Multiple Antibiotics
A team of scientists from the University Paris Descartes has solved the structure of two proteins that allow bacteria to gain resistance to multiple types of antibiotics, according to a report in EMBO reports this month. This work provides new clues as to how bacteria adapt to resist antibiotics and how to design new drugs that counteract this defense mechanism.
FrГ©dГ©ric Dardel and colleagues crystallized both the narrow and broad-spectrum resistance forms of the antibiotic-modifying acetyltransferase enzyme. Their report reveals that the enzyme has a flexible active site that can evolve to accommodate new antibiotics, allowing the bacteria to break them down and render them useless. This explains why this type of enzyme is now carried by many bacteria struggling for survival in the antibiotic age.
More importantly, the research provides new insight for the design of new antibiotics that could evade this form of resistance, and new inhibitors that would extend the effectiveness of current antibiotics, both of which could help in the fight against the deadly infections becoming more frequent in hospitals.
Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance
FrГ©dГ©rique Maurice, Isabelle Broutin, Isabelle Podglajen, Philippe Benas, Ekkehard Collatz & FrГ©dГ©ric Dardel
nature/embor/journal/vaop/ncurrent/abs/embor20089.html
Author Contact
FrГ©dГ©ric Dardel
Source: Nonia Pariente
European Molecular Biology Organization
FrГ©dГ©ric Dardel and colleagues crystallized both the narrow and broad-spectrum resistance forms of the antibiotic-modifying acetyltransferase enzyme. Their report reveals that the enzyme has a flexible active site that can evolve to accommodate new antibiotics, allowing the bacteria to break them down and render them useless. This explains why this type of enzyme is now carried by many bacteria struggling for survival in the antibiotic age.
More importantly, the research provides new insight for the design of new antibiotics that could evade this form of resistance, and new inhibitors that would extend the effectiveness of current antibiotics, both of which could help in the fight against the deadly infections becoming more frequent in hospitals.
Enzyme structural plasticity and the emergence of broad-spectrum antibiotic resistance
FrГ©dГ©rique Maurice, Isabelle Broutin, Isabelle Podglajen, Philippe Benas, Ekkehard Collatz & FrГ©dГ©ric Dardel
nature/embor/journal/vaop/ncurrent/abs/embor20089.html
Author Contact
FrГ©dГ©ric Dardel
Source: Nonia Pariente
European Molecular Biology Organization
Novel Sulfide-Binding Mechanism Found in Deep-Sea Tubeworms
The discovery that zinc contained in the hemoglobin of deep-sea tubeworms is used to bind and transport nutrients to symbiotic bacteria will be published online in the Proceedings of the National Academy of Science during the week of 14 February 2005. Further research with the hemoglobin could lead to its use in a variety of ways, including as an artificial substitute for oxygen carriers in human blood.
Tubeworms living near hydrothermal vents and cold seeps in the world's oceans must adapt to sulfide levels that would prove lethal to most aquatic life while simultaneously providing hydrogen sulfide molecules to symbiotic bacteria within their bodies. A Penn State research team, in collaboration with researchers at the University of Massachusetts Medical School in Worcester and in the United Kingdom, reports a new mechanism for sulfide binding in the hemoglobins, the same molecules that carry oxygen to the worm's own cells. The research team reports that zinc ions in the hemoglobin bind hydrogen sulfide, the first example of any hemoglobin incorporating a metal specifically for that purpose.
"The worms need to bind free sulfide so that it doesn't react with oxygen, to reduce sulfide exposure in their tissues, and to provide the sulfide to the bacteria that, as far as we know, provide all of the worm's nutritional needs," says Charles Fisher, professor of biology at Penn State, whose research team includes Penn State graduate assistant Jason Flores, the lead author of the research paper, and William Royer, professor of biochemistry and molecular pharmacology at the University of Massachusetts. "Our discovery, which results from a very multi-disciplinary approach, replaces the current paradigm for the evolution of worm hemoglobin by demonstrating that hydrogen-sulfide molecules are bound by a metal ion rather than by an arrangement of amino acids."
In addition to a very large hexagonal hemoglobin, typical of many worm species, the deep-sea hydrothermal vent tubeworm, Riftia pachyptila, has a second, smaller hemoglobin. The research group characterized this second hemoglobin by X-ray crystallography, providing the first such detailed structural information of a protein from a hydrothermal-vent animal.
Hydrothermal-vent species must adapt to conditions of pressure and chemicals that are toxic to most other animals. While the worms are able to absorb the oxygen and sulfide through their gills, they have no organs for capturing or digesting food. Their only known source of nutrition comes from internal bacteria, which, in turn, rely on the worm's hemoglobin for both sulfide and oxygen. The unusual form of hemoglobin gives the worms an advantage over other organisms competing for space near the vents and may play a role in their ability to adapt to a wide temperature range.
"The hollow spherical structure in the hemoglobin of this species includes 12 zinc ions in depressions at the outer part of the molecule," explains Flores. "These ions form a reversible bond with the hydrogen sulfide molecules that could block the oxygen-carrying sites, allowing the molecule to simultaneously carry oxygen and sulfide."
Flores says that the hollow spherical structure is unique. "Human and other hemoglobins have a 'globular' form, but none have been discovered with this symmetrical sphere. This sphere is a very stable shape, which may be part of the adaptation for the extreme conditions in which these worms thrive."
Because zinc is the second most utilized transition metal (after iron) in biological systems, the characterization of this hemoglobin's structure, assembly, and function could provide a starting point for other studies into the incorporation of metal ions into biological functions. The structure also could prove a useful means of sulfide transport for chemical synthesis and detection systems. In addition, the hemoglobin itself could have medical applications. Recent medical studies have focused on the worm's large hexagonal hemoglobins as possible substitutes for oxygen carriers in human blood. "The newly characterized molecule is substantially smaller than the hexagonal hemoglobin, reducing problems of removal by kidney filtration, but still has six times as many active oxygen-carrying sites as human hemoglobin," Flores adds.
This research was supported by the Alfred P. Sloan Foundation, the National Oceanic and Atmospheric Administration National Undersea Research Program, the National Institutes of Health, and the National Science Foundation.
CONTACTS:
Charles Fisher: cfisherpsu
Jason Flores: jff133psu
Barbara Kennedy (PIO): sciencepsu
Tubeworms living near hydrothermal vents and cold seeps in the world's oceans must adapt to sulfide levels that would prove lethal to most aquatic life while simultaneously providing hydrogen sulfide molecules to symbiotic bacteria within their bodies. A Penn State research team, in collaboration with researchers at the University of Massachusetts Medical School in Worcester and in the United Kingdom, reports a new mechanism for sulfide binding in the hemoglobins, the same molecules that carry oxygen to the worm's own cells. The research team reports that zinc ions in the hemoglobin bind hydrogen sulfide, the first example of any hemoglobin incorporating a metal specifically for that purpose.
"The worms need to bind free sulfide so that it doesn't react with oxygen, to reduce sulfide exposure in their tissues, and to provide the sulfide to the bacteria that, as far as we know, provide all of the worm's nutritional needs," says Charles Fisher, professor of biology at Penn State, whose research team includes Penn State graduate assistant Jason Flores, the lead author of the research paper, and William Royer, professor of biochemistry and molecular pharmacology at the University of Massachusetts. "Our discovery, which results from a very multi-disciplinary approach, replaces the current paradigm for the evolution of worm hemoglobin by demonstrating that hydrogen-sulfide molecules are bound by a metal ion rather than by an arrangement of amino acids."
In addition to a very large hexagonal hemoglobin, typical of many worm species, the deep-sea hydrothermal vent tubeworm, Riftia pachyptila, has a second, smaller hemoglobin. The research group characterized this second hemoglobin by X-ray crystallography, providing the first such detailed structural information of a protein from a hydrothermal-vent animal.
Hydrothermal-vent species must adapt to conditions of pressure and chemicals that are toxic to most other animals. While the worms are able to absorb the oxygen and sulfide through their gills, they have no organs for capturing or digesting food. Their only known source of nutrition comes from internal bacteria, which, in turn, rely on the worm's hemoglobin for both sulfide and oxygen. The unusual form of hemoglobin gives the worms an advantage over other organisms competing for space near the vents and may play a role in their ability to adapt to a wide temperature range.
"The hollow spherical structure in the hemoglobin of this species includes 12 zinc ions in depressions at the outer part of the molecule," explains Flores. "These ions form a reversible bond with the hydrogen sulfide molecules that could block the oxygen-carrying sites, allowing the molecule to simultaneously carry oxygen and sulfide."
Flores says that the hollow spherical structure is unique. "Human and other hemoglobins have a 'globular' form, but none have been discovered with this symmetrical sphere. This sphere is a very stable shape, which may be part of the adaptation for the extreme conditions in which these worms thrive."
Because zinc is the second most utilized transition metal (after iron) in biological systems, the characterization of this hemoglobin's structure, assembly, and function could provide a starting point for other studies into the incorporation of metal ions into biological functions. The structure also could prove a useful means of sulfide transport for chemical synthesis and detection systems. In addition, the hemoglobin itself could have medical applications. Recent medical studies have focused on the worm's large hexagonal hemoglobins as possible substitutes for oxygen carriers in human blood. "The newly characterized molecule is substantially smaller than the hexagonal hemoglobin, reducing problems of removal by kidney filtration, but still has six times as many active oxygen-carrying sites as human hemoglobin," Flores adds.
This research was supported by the Alfred P. Sloan Foundation, the National Oceanic and Atmospheric Administration National Undersea Research Program, the National Institutes of Health, and the National Science Foundation.
CONTACTS:
Charles Fisher: cfisherpsu
Jason Flores: jff133psu
Barbara Kennedy (PIO): sciencepsu
SEBM European Best Poster Prize Awarded At Annual Conference Of The German Society For Gene Therapy
Frauke Koenig, a PhD student in Professor Christoph Brauchle'd group, in the Department of Physical Chemistry at the Ludwig Maximilians University (LMU) Munich, was awarded this year's Society for Experimental Biology and Medicine European Prize for her work on live cell imaging of EGFR receptor targeting with short synthetic peptides. This multidisciplinary study was performed in collaboration with Professor Christoph Brauchle, Professor Ernst Wagner and Dr Manfred Oris's groups in the departments of Physical chemistry and Pharmacy at LMU.
The work selected for oral presentation was described at the 2010 Annual Conference of the German society for Gene Therapy, held in October in Munich. In this study live-cell imaging experiments were used to examine cellular internalization and trafficking of artificial gene vectors carrying a short peptide ligand, GE11, for specific targeting of EGF receptor positive cells.
Frauke Koenig said "EGF receptor is a promising target for selective gene therapy of cancer cells as it is overexpressed in many human tumors. Previous studies have shown that full-length EGF can be coupled to artificial gene vectors, such as polyplexes, resulting in their fast endocytosis into cancer cells. However full-length EGF has limitations for clinical application, as it is expensive in production, has a high tendency to aggregate and most importantly is able to activate the EGFR mediated mitogenic signaling cascades in the target cells. In this study polyplexes displaying GE11, a short peptide ligand with high affinity for the EGF receptor, provided a potential alternative for targeted cancer therapy. Highly sensitive fluorescence microscopy with high spatial and temporal resolution was employed to follow the cellular internalization of single polyplexes in real time". The presented data demonstrated slower kinetics of internalization for GE11 polyplexes, compared to EGF polyplexes. However, GE11 polyplexes provided considerable advantages for clinical applications, including higher transduction efficiency, lower aggregation and reduced mitogenic activity."
Presenting the award on behalf of the Society for Experimental Biology and Medicine, Professor Farzin Farzaneh (European Editor of Experimental Biology and Medicine), pointed out the therapeutic potential of receptor targeting not just for the tumor specific delivery of genes but also other therapeutic applications. This study also demonstrates the tremendous potential of live cell imaging as a tool for screening of candidate molecules for detailed analysis of molecular interactions and the identification of new drugs. The panel of Judges commended Ms Koenig for her outstanding work, its clear presentation and the stimulating discussion of broader implications of this study.
Source:
Dr. Farzin Farzaneh
Society for Experimental Biology and Medicine
The work selected for oral presentation was described at the 2010 Annual Conference of the German society for Gene Therapy, held in October in Munich. In this study live-cell imaging experiments were used to examine cellular internalization and trafficking of artificial gene vectors carrying a short peptide ligand, GE11, for specific targeting of EGF receptor positive cells.
Frauke Koenig said "EGF receptor is a promising target for selective gene therapy of cancer cells as it is overexpressed in many human tumors. Previous studies have shown that full-length EGF can be coupled to artificial gene vectors, such as polyplexes, resulting in their fast endocytosis into cancer cells. However full-length EGF has limitations for clinical application, as it is expensive in production, has a high tendency to aggregate and most importantly is able to activate the EGFR mediated mitogenic signaling cascades in the target cells. In this study polyplexes displaying GE11, a short peptide ligand with high affinity for the EGF receptor, provided a potential alternative for targeted cancer therapy. Highly sensitive fluorescence microscopy with high spatial and temporal resolution was employed to follow the cellular internalization of single polyplexes in real time". The presented data demonstrated slower kinetics of internalization for GE11 polyplexes, compared to EGF polyplexes. However, GE11 polyplexes provided considerable advantages for clinical applications, including higher transduction efficiency, lower aggregation and reduced mitogenic activity."
Presenting the award on behalf of the Society for Experimental Biology and Medicine, Professor Farzin Farzaneh (European Editor of Experimental Biology and Medicine), pointed out the therapeutic potential of receptor targeting not just for the tumor specific delivery of genes but also other therapeutic applications. This study also demonstrates the tremendous potential of live cell imaging as a tool for screening of candidate molecules for detailed analysis of molecular interactions and the identification of new drugs. The panel of Judges commended Ms Koenig for her outstanding work, its clear presentation and the stimulating discussion of broader implications of this study.
Source:
Dr. Farzin Farzaneh
Society for Experimental Biology and Medicine
Much-Needed Kidney Failure Treatment May Result From Novel Discovery By Einstein Scientists
The unwanted activation of an important cell-signaling pathway may play a role in two kidney problems that are major causes of end-stage renal disease, scientists at the Albert Einstein College of Medicine of Yeshiva University have found. Their research, which opens up a novel approach for treating kidney failure, is described in the March issue of Nature Medicine. The study was led by Dr. Katalin Susztak, an assistant professor of medicine (nephrology) at Einstein.
The kidneys filter waste products from the blood and maintain the body's fluid balance by producing urine. The filtration is carried out by numerous capillary tufts within the kidney known as glomeruli. Kidney disease occurs when glomeruli become damaged and can no longer perform their filtering function. Kidney damage may ultimately progress to end-stage renal disease, in which patients need dialysis or a kidney transplant.
The Einstein scientists focused on cells known as podocytes that line the glomeruli. Since dysfunction of podocytes cells is important in progressive kidney disease, and since a cell-signaling pathway called Notch is crucial in podocyte development, the Einstein researchers reasoned that aberrant Notch signaling might play a role in causing kidney disease.
The Notch signaling pathway plays a key role in embryonic development of humans and most other multicellular organisms. The Notch pathway tells some cells to proliferate and others to undergo programmed cell death as it profoundly affects the way tissues are organized. Faulty Notch signaling has been found in several types of cancer and in many other diseases such as multiple sclerosis.
Collectively, the observations made in the Einstein study offer strong evidence that aberrant Notch signaling is also involved in diabetic nephropathy (DNP) and focal segmental glomerulosclerosis (FSGS) - two of the major causes of end-stage renal disease. For example:
* When comparing biopsy samples from healthy kidneys and kidneys from people with DNP and FSGS, the researchers found evidence that the Notch pathway was active in diseased but not in healthy kidneys.
* The researchers bred a strain of mice in which they could specifically activate the Notch pathway within podocytes. Examination revealed that the podocytes in these mice underwent programmed cell death, and the mice themselves died from end-stage renal failure.
* After inducing glomerular disease in mice by injecting them with a toxic chemical, the researchers were able to protect the rats from developing kidney disease by injecting them with a gamma secretase inhibitor - one of a class of compounds known to "shut off" the Notch pathway.
"An exciting aspect of this new work is the therapeutic implications," according to a Nature Medicine commentary on the Einstein study written by kidney experts from the University of Michigan Medical Center. The experts noted that gamma secretase inhibitors, like the one that protected the mice from kidney disease in this study, are already in phase 1 and 2 clinical trials for treating diseases including Alzheimer's and leukemia. The Einstein findings, they wrote, "provide some hope that researchers in the field of kidney disease can reverse the grim record of the last 20 years - during which no new therapeutic agent has been successfully implemented" for treating end-stage kidney disease.
Other Einstein researchers involved in the study were Thiruvur Niranjan, Bernhard Bielesz, Antje Gruenwald, Manish P. Ponda and David B. Thomas. Jeffrey B. Kopp of the National Institute of Diabetes and Digestive and Kidney Diseases also contributed to the research.
Source: Karen Gardner
Albert Einstein College of Medicine
The kidneys filter waste products from the blood and maintain the body's fluid balance by producing urine. The filtration is carried out by numerous capillary tufts within the kidney known as glomeruli. Kidney disease occurs when glomeruli become damaged and can no longer perform their filtering function. Kidney damage may ultimately progress to end-stage renal disease, in which patients need dialysis or a kidney transplant.
The Einstein scientists focused on cells known as podocytes that line the glomeruli. Since dysfunction of podocytes cells is important in progressive kidney disease, and since a cell-signaling pathway called Notch is crucial in podocyte development, the Einstein researchers reasoned that aberrant Notch signaling might play a role in causing kidney disease.
The Notch signaling pathway plays a key role in embryonic development of humans and most other multicellular organisms. The Notch pathway tells some cells to proliferate and others to undergo programmed cell death as it profoundly affects the way tissues are organized. Faulty Notch signaling has been found in several types of cancer and in many other diseases such as multiple sclerosis.
Collectively, the observations made in the Einstein study offer strong evidence that aberrant Notch signaling is also involved in diabetic nephropathy (DNP) and focal segmental glomerulosclerosis (FSGS) - two of the major causes of end-stage renal disease. For example:
* When comparing biopsy samples from healthy kidneys and kidneys from people with DNP and FSGS, the researchers found evidence that the Notch pathway was active in diseased but not in healthy kidneys.
* The researchers bred a strain of mice in which they could specifically activate the Notch pathway within podocytes. Examination revealed that the podocytes in these mice underwent programmed cell death, and the mice themselves died from end-stage renal failure.
* After inducing glomerular disease in mice by injecting them with a toxic chemical, the researchers were able to protect the rats from developing kidney disease by injecting them with a gamma secretase inhibitor - one of a class of compounds known to "shut off" the Notch pathway.
"An exciting aspect of this new work is the therapeutic implications," according to a Nature Medicine commentary on the Einstein study written by kidney experts from the University of Michigan Medical Center. The experts noted that gamma secretase inhibitors, like the one that protected the mice from kidney disease in this study, are already in phase 1 and 2 clinical trials for treating diseases including Alzheimer's and leukemia. The Einstein findings, they wrote, "provide some hope that researchers in the field of kidney disease can reverse the grim record of the last 20 years - during which no new therapeutic agent has been successfully implemented" for treating end-stage kidney disease.
Other Einstein researchers involved in the study were Thiruvur Niranjan, Bernhard Bielesz, Antje Gruenwald, Manish P. Ponda and David B. Thomas. Jeffrey B. Kopp of the National Institute of Diabetes and Digestive and Kidney Diseases also contributed to the research.
Source: Karen Gardner
Albert Einstein College of Medicine
On-the-Job Pesticide Exposure Associated With Parkinson's Disease
Individuals whose occupation involves contact with pesticides appear to have an increased risk of having Parkinson's disease, according to a report in the September issue of Archives of Neurology, one of the JAMA/Archives journals.
The development of Parkinson's disease related to chemical exposure was identified in the late 20th century, according to background information in the article. Since then, occupations such as farming, teaching and welding have all been proposed to increase the risk of Parkinson's disease. However, associations have been inconsistent and few previous studies have evaluated the direct relationship between occupational chemical exposure and disease risk.
Caroline M. Tanner, M.D., Ph.D., of the Parkinson's Institute, Sunnyvale, Calif., and colleagues studied 519 individuals with Parkinson's disease and 511 controls who were the same age and sex and lived in the same location. Participants were surveyed about their occupational history and exposure to toxins, including solvents and pesticides.
Working in agriculture, education, health care or welding was not associated with Parkinson's disease, nor was any other specific occupation studied after adjustment for other factors.
Among the patients with Parkinson's disease, 44 (8.5 percent) reported pesticide exposure compared with 27 (5.3 percent) of controls, such that occupational pesticide exposure was associated with an increased risk of the disease. "Growing evidence suggests a causal association between pesticide use and parkinsonism. However, the term 'pesticide' is broad and includes chemicals with varied mechanisms," the authors write. "Because few investigations have identified specific pesticides, we studied eight pesticides with high neurotoxic plausibility based on laboratory findings. Use of these pesticides was associated with higher risk of parkinsonism, more than double that in those not exposed."
Three individual compounds-an organochloride (2,4-dichlorophenoxyacetic acid), an herbicide (paraquat) and an insecticide (permethrin)-were associated with a more than three-fold increased risk of Parkinson's disease. All three have been shown to have effects on dopaminergic neurons-affected by Parkinson's disease-in the laboratory.
"This convergence of epidemiologic and laboratory data from experimental models of Parkinson's disease lends credence to a causative role of certain pesticides in the neurodegenerative process," the authors conclude. "Other pesticide exposures such as hobby gardening, residential exposure, wearing treated garments or dietary intake were not assessed. Because these exposures may affect many more subjects, future attention is warranted."
Arch Neurol. 2009;66[9]:1106-1113.
Source
Archives of Neurology
The development of Parkinson's disease related to chemical exposure was identified in the late 20th century, according to background information in the article. Since then, occupations such as farming, teaching and welding have all been proposed to increase the risk of Parkinson's disease. However, associations have been inconsistent and few previous studies have evaluated the direct relationship between occupational chemical exposure and disease risk.
Caroline M. Tanner, M.D., Ph.D., of the Parkinson's Institute, Sunnyvale, Calif., and colleagues studied 519 individuals with Parkinson's disease and 511 controls who were the same age and sex and lived in the same location. Participants were surveyed about their occupational history and exposure to toxins, including solvents and pesticides.
Working in agriculture, education, health care or welding was not associated with Parkinson's disease, nor was any other specific occupation studied after adjustment for other factors.
Among the patients with Parkinson's disease, 44 (8.5 percent) reported pesticide exposure compared with 27 (5.3 percent) of controls, such that occupational pesticide exposure was associated with an increased risk of the disease. "Growing evidence suggests a causal association between pesticide use and parkinsonism. However, the term 'pesticide' is broad and includes chemicals with varied mechanisms," the authors write. "Because few investigations have identified specific pesticides, we studied eight pesticides with high neurotoxic plausibility based on laboratory findings. Use of these pesticides was associated with higher risk of parkinsonism, more than double that in those not exposed."
Three individual compounds-an organochloride (2,4-dichlorophenoxyacetic acid), an herbicide (paraquat) and an insecticide (permethrin)-were associated with a more than three-fold increased risk of Parkinson's disease. All three have been shown to have effects on dopaminergic neurons-affected by Parkinson's disease-in the laboratory.
"This convergence of epidemiologic and laboratory data from experimental models of Parkinson's disease lends credence to a causative role of certain pesticides in the neurodegenerative process," the authors conclude. "Other pesticide exposures such as hobby gardening, residential exposure, wearing treated garments or dietary intake were not assessed. Because these exposures may affect many more subjects, future attention is warranted."
Arch Neurol. 2009;66[9]:1106-1113.
Source
Archives of Neurology
Penn Study Suggests New Model For Testing And Discovery Of Anti-HIV Drugs
Researchers at the University of Pennsylvania School of Medicine are the first to show that a mouse protein, whose human equivalent is related to defense against HIV-1, inhibits the infection and spread of a mouse tumor virus. The study, which appeared online in advance of its print publication in Nature, provides a new model for the discovery and evaluation of anti-HIV drugs. HIV-1, like the mouse tumor virus, is a retrovirus which infects immune system cells. However, unlike HIV-1, the mouse virus causes breast cancer in mice.
"Our study is the first to show that the mouse equivalent to the human protein, called APOBEC3, actually inhibits a retrovirus in a live animal," says lead author Susan R. Ross, PhD, Professor of Microbiology. The study is based on a mouse strain that does not have the gene for mouse APOBEC3, developed by co-author B. Matija Peterlin, PhD, University of California at San Francisco.
In this study, normal mice and mutant mice were injected with mouse mammary tumor virus (MMTV). Using a sensitive test for virus infection, the researchers found that lymph nodes from mutant mice were more infected than normal mice. At six days after injection, the lymph nodes near the injection site in mutant mice had four times more of the breast cancer-causing virus. By 18 days after infection, the virus had spread to other sites in the mice, and spleen cells from the mutant mice were seven-fold more infected by MMTV than spleen cells from normal mice. The research team is currently waiting to see if mutant mice develop breast cancer at a greater rate than normal mice.
"Although this study was performed with mice and used a mouse tumor virus for which there is no human counterpart, the mouse model of infection we have developed may be useful as a test system for evaluating drugs that augment the role of human APOBEC3 in defending against HIV," says Ross. Since its discovery in 2002, the human equivalent to mouse APOBEC3 has been shown to defend some cell types against HIV-1 infection.
Some unanswered questions remain about APOBEC3 and how it can prevent virus replication and spread. Some cells cannot be infected with a retrovirus unless the virus has viral infectivity factor (Vif). Vif is a protein made by viruses like HIV that binds to APOBEC3 and marks it for destruction.
On the other hand, if APOBEC3 is not degraded by binding with Vif, it gets packaged into new virus particles. When these virus particles infect new cells, APOBEC3 causes mutations in virus RNA and DNA by a process called deamination. The mutations are so extensive that the new viruses cannot infect more cells, thus stopping the spread of the virus.
However, in the Nature study, no mutated MMTV virus was detected in the normal mice. "Thus, APOBEC3 must not use the deamination activity to mutate and limit the spread of MMTV," says Ross. "We plan to study the mechanism of the antiviral activity in our model system."
This study was funded by the National Cancer Institute and the Slovenian Research Agency.
Co-authors in addition to Ross and Peterlin are Chioma M. Okeoma, from Penn, and Nika Lovsin, University of Ljublijana (Slovenia).
This release can be viewed at pennhealth/news.
PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice
Contact: Karen Kreeger
University of Pennsylvania School of Medicine
"Our study is the first to show that the mouse equivalent to the human protein, called APOBEC3, actually inhibits a retrovirus in a live animal," says lead author Susan R. Ross, PhD, Professor of Microbiology. The study is based on a mouse strain that does not have the gene for mouse APOBEC3, developed by co-author B. Matija Peterlin, PhD, University of California at San Francisco.
In this study, normal mice and mutant mice were injected with mouse mammary tumor virus (MMTV). Using a sensitive test for virus infection, the researchers found that lymph nodes from mutant mice were more infected than normal mice. At six days after injection, the lymph nodes near the injection site in mutant mice had four times more of the breast cancer-causing virus. By 18 days after infection, the virus had spread to other sites in the mice, and spleen cells from the mutant mice were seven-fold more infected by MMTV than spleen cells from normal mice. The research team is currently waiting to see if mutant mice develop breast cancer at a greater rate than normal mice.
"Although this study was performed with mice and used a mouse tumor virus for which there is no human counterpart, the mouse model of infection we have developed may be useful as a test system for evaluating drugs that augment the role of human APOBEC3 in defending against HIV," says Ross. Since its discovery in 2002, the human equivalent to mouse APOBEC3 has been shown to defend some cell types against HIV-1 infection.
Some unanswered questions remain about APOBEC3 and how it can prevent virus replication and spread. Some cells cannot be infected with a retrovirus unless the virus has viral infectivity factor (Vif). Vif is a protein made by viruses like HIV that binds to APOBEC3 and marks it for destruction.
On the other hand, if APOBEC3 is not degraded by binding with Vif, it gets packaged into new virus particles. When these virus particles infect new cells, APOBEC3 causes mutations in virus RNA and DNA by a process called deamination. The mutations are so extensive that the new viruses cannot infect more cells, thus stopping the spread of the virus.
However, in the Nature study, no mutated MMTV virus was detected in the normal mice. "Thus, APOBEC3 must not use the deamination activity to mutate and limit the spread of MMTV," says Ross. "We plan to study the mechanism of the antiviral activity in our model system."
This study was funded by the National Cancer Institute and the Slovenian Research Agency.
Co-authors in addition to Ross and Peterlin are Chioma M. Okeoma, from Penn, and Nika Lovsin, University of Ljublijana (Slovenia).
This release can be viewed at pennhealth/news.
PENN Medicine is a $2.9 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.
Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.
The University of Pennsylvania Health System includes three hospitals, all of which have received numerous national patient-care honors [Hospital of the University of Pennsylvania; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice
Contact: Karen Kreeger
University of Pennsylvania School of Medicine
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