Complementary Medicine News

The glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) null genotypes have been linked to increased risk of developing cancer. The results regarding the association between GSTM1 and GSTT1 null genotypes and the risk of GC or CRC were contradictory. However, the majority of previous reports are limited by their small sample sizes. Therefore, the association of the GSTM1/GSTT1 null genotype with the risk of GC and CRC need to be confirmed in studies with larger numbers of samples.

A research article published in the World Journal of Gastroenterology addresses this question. The research team led by Dr. Shin from Chonnam National University Medical School conducted a population-based, large-scale case-control study, to evaluate the association of GSTM1 and GSTT1 null genotypes with the risk of gastric and colorectal cancer in a South Korean population.

This is the first investigation of the risk of GC and CRC according to the GSTM1 and GSTT1 null genotypes in a large Korean population, and in addition, this study aims to determine whether smoking, alcohol consumption, and age modify the association between these polymorphisms and GC or CRC risk.

They found that GSTM1 and GSTT1 null genotypes were not associated with increased risk of GC or CRC in Koreans. Smoking, alcohol consumption and age did not modify the association. No difference in the frequency of the combined GSTM1 and GSTT1 null genotype was observed between the two cancer groups and controls.

Although there is a profusion of reports on the association of polymorphisms with GC or CRC risk, few of these results have been convincingly replicated. Therefore, large sample size replication studies are required to confirm these associations in the future.

Reference: Piao JM, Shin MH, Kweon SS, Kim HN, Choi JS, Bae WK, Shim HJ, Kim HR, Park YK, Choi YD, Kim SH. Glutathione-S-transferase (GSTM1, GSTT1) and the risk of gastrointestinal cancer in a Korean population. World J Gastroenterol 2009; 15(45): 5716-5721 wjgnet/1007-9327/15/5716.asp

Source: Jin-Lei Wang

World Journal of Gastroenterology Continue reading →

Intracellular hypoxia has been linked to genetic instability, tumour progression and poor prognosis. Little is known about the effect of hypoxia on DNA-dsb sensing and repair. We tested whether the sensing of DNA-dsbs and chromatin biology is decreased in cells irradiated under continual hypoxic or anoxic conditions. To test this hypothesis, we used normal diploid fibroblast strains, GM05757, synchronised in G0-G1 to preclude DNA replication as a source of DNA repair foci.

The cells were pre-treated with 0.2% O2 (hypoxia), 0.0% O2 (anoxia) or 21% O2 (normoxia) for 16 hours and then irradiated and kept under hypoxic/ anoxic/ normoxic conditions for another 24 hours.

The biomarkers gammaH2AX, MRE11, 53BP1, ATMser1981 and the MRN complexes were tracked using quantitative immunofluorescent microscopy to score intranuclear foci. We observed an expected 2 to 3 fold decrease in initial number of gammaH2AX ATMser1981 and 53BP1 foci at 30 minutes following 2 or 5 Gy post-IR under hypoxia and anoxia consistent with the OER. However, we observed an increase in the relative ATM-dependent residual foci at times between 4 and 24 hours post-IR under continual hypoxia. These were residual DNA-dsbs based on neutral COMET assays and were not associated with increased cell kill following clongenic assays, suggesting misrepair or repair can occur in such cells when releases into S and G2Mphases. We conclude that hypoxic cells have an altered ability during NHEJ to sense and repair DNA-dsbs and could serve as a potential factor in genetic instability and tumour progression.

Supported by a Terry Fox Hypoxia Project Program Grant and CCS Career Award to RGB.

Bristow Robert et al. Princess Margaret Hospital and University of Toronto, Toronto, Canada

About ESTRO 27

ESTRO 27 (September 14th to 18th, 2008) offered an outstanding scientific programme combining lectures from eminent invited speakers, proffered papers and poster discussions, teaching lectures on a wide range of topics including clinical issues, brachytherapy, radiobiology, physics and technology as well as debates on controversial topics and clinical case discussions, a special poster reception, poster discussion sessions and electronic poster viewing.

ESTRO 27 hosted the largest European exhibition in Radiotherapy with participation from all the leading manufacturers.

ESTRO 27

ESTRO (European Society for Therapeutic Radiology and Oncology)
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Two are one too many – this is the motto used by cells of a female organism: These contain two X chromosomes, one of which always becomes inactivated. How does the cell recognize that it contains two of these sex chromosomes and how does it choose which one to turn off? Scientists of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), working together with French colleagues, have now been able to elucidate an early step in this complex process.

Forty-five years ago, British scientist Mary Lyon already described this chromosome inactivation typical of female cells. Lyon proposed a hypothesis: With two copies of the X chromosome, all X-linked genes are present in two copies. However, in a male organism, which is equipped with a set of one X and one Y chromosome, the X genes are present in only one copy in each cell. To restore genetic balance, a female cell inactivates one of its two X chromosomes.

During development of a female embryo, inactivation of either of the X chromosomes, the one inherited from the father or the one inherited from the mother, occurs at random. To coordinate inactivation, the cell first needs to determine whether it contains more than one X chromosome and then make a choice which of the two to switch off. Since the mid-1980s it has been known that a specific region of the X chromosome termed X inactivation center (Xic) is crucial for a correct inactivation process.

Professor Dr. Roland Eils, who leads the bioinformatics departments at the German Cancer Research Center and at the Institute of Pharmacy and Molecular Biotechnology of Heidelberg University, suspected that the spatial arrangement of the Xics within the nucleus is key to inactivation. Working together with colleagues of the Curie Institute, Paris, he searched different cells for distinctive features in the distribution of Xic regions. The scientists compared developing female embryonic stem cells of mice just before X inactivation, with mouse cells in which X inactivation had already taken place. Using a 3-dimensional visualization of fluorescent labels of the Xic regions, they observed that the Xics of both X chromosomes in the developing stem cells were located very close to each other in up to 15 percent of cells. In the comparative cell line, this was found in only about three percent of cells, which constitutes a random result. The formation of pairs (co-localization) was particularly noticeable in the stem cells after about one and a half days of development, i.e. shortly before X inactivation.

A specific loss of DNA (deletion) in the Xic region of one of the two X chromosomes prevents the pairing of Xics. In addition, cells that have forgotten how to count show no pairing at all. The scientist postulate that the pairing of Xic regions is a necessary prerequisite for correct chromosome counting, but they cannot give any information yet as to what kind of interaction there is between the two Xic regions during transient co-localization.

The task of the Deutsches Krebsforschungszentrum in Heidelberg (German Cancer Research Center, DKFZ) is to systematically investigate the mechanisms of cancer development and to identify cancer risk factors. The results of this basic research are expected to lead to new approaches in the prevention, diagnosis and treatment of cancer. The Center is financed to 90 percent by the Federal Ministry of Education and Research and to 10 percent by the State of Baden-Wuerttemberg. It is a member of the Helmholtz Association of National Research Centers (Helmholtz-Gemeinschaft Deutscher Forschungszentren e.V., HGF).

dkfz.de Continue reading →

CD200 stifles antitumor immunity

The prognosis for individuals with metastatic melanoma (MM) is not good. Therapeutic strategies to enhance the immune response have some clinical benefit; however, most patients eventually succumb to progressive disease, in part because their immune cells known as dendritic cells (DCs) fail to sustain an effective antitumor T cell immune response. New data generated in vitro using human melanoma cell lines and resected tumors by Norman Sharpless and colleagues at the University of North Carolina School of Medicine, Chapel Hill, has identified one mechanism that represses DC function in MM.

Expression of CD200 mRNA and protein was found to be higher in resected human melanomas than in other solid tumors. Further analysis revealed that expression of CD200 was regulated by the N-RAS/B-RAF/MEK/ERK MAP kinase signaling pathway, which is aberrantly activated in approximately 80% of individuals with MM. In vitro analysis indicated the potential functional significance of high levels of CD200 expression — it enabled melanoma cell lines to repress activation of antitumor T cell immune responses by DCs. The authors therefore suggested that targeting the interaction between CD200 and its receptor might provide a new strategy for the treatment of MM.

Title: CD200 is induced by ERK and is a potential therapeutic target in melanoma

Author:
Norman E. Sharpless
University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.

ClC-1 helps mice get a move on

In addition to the progressive muscle weakness and degeneration common to all forms of muscular dystrophy, patients with the most common form of muscular dystrophy affecting adults, myotonic dystrophy type 1 (DM1), also experience an inability to voluntarily relax the muscles (a problem known as myotonia). DM1 originates from complex genetic mutations that result in abnormalities of the muscle proteins, including the muscle-specific chloride channel ClC-1.

Working under the theory that abnormal inclusion of a region of the ClC-1 gene known as exon 7a in the ClC-1 mRNA (the intermediate between gene and protein) may play a role in the development of DM1, Charles Thornton and his colleagues at the University of Rochester, Rochester, discovered a powerful method of correcting this aberrant exon 7a inclusion and reversing myotonia in mouse models of DM1. A nucleic acid compound known as a morpholino antisense oligonucleotide was generated that would allow the muscle cells to “skip” over the erroneously included exon7a. When this compound was injected into mice with DM1-like disease, exclusion of the extra genetic segment in the ClC-1 mRNA restored the function of ClC-1 protein and eliminated myotonia in the mice. The authors therefore suggested that it might be possible to use this approach to treat myotonia in individuals with DM1.

Title: Correction of ClC-1 splicing eliminates chloride channelopathy and myotonia in mouse models of myotonic dystrophy

Author:
Charles A. Thornton
University of Rochester, Rochester, New York, USA.

A gut reaction to infection

To ensure that the gut absorbs as many as possible of the nutrients that we consume tiny finger-like structures known as villi protrude from the lining of the gut to increase its absorptive surface area. Continuous turnover of the cells lining the gut is required for it to function optimally. As cells at the tips of the villi naturally die off they are replaced by cells that have migrated to their new home from the base of the villi. Similarly, repair of intestinal injury, which often accompanies traumatic stress, occurs through migration of healthy intestinal cells to the site of injury from the base of the villi. MFG-E8 is a component of human breast milk that protects infants from intestinal infection. It is also known that the MFG-E8 gene is expressed in the adult gut, but its role there has not been well understood. In a new study, Xiao-Di Tan and colleagues at the Northwestern University Feinberg School of Medicine, Chicago, have identified a crucial role for MFG-E8 in maintenance and repair of the murine intestinal lining.

In a wound-healing experiment with cultured rat intestinal epithelial cells, treatment with MFG-E8 improved cell migration to the site of injury. Additionally, depletion of this protein in mice resulted in decreased intestinal cell migration and localized injury of the intestinal lining. Finally, in septic mice with widespread infection due to puncture of the large intestine, treatment with MFG-E8 improved intestinal cell migration, whereas depletion of MFG-E8 prolonged healing time. These data led the authors to suggest that MFG-E8 might be useful for the treatment of individuals with bowel injuries.

Title: Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium

Author:

Xiao-Di Tan
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Sensing bacteria in the gut keeps inflammation at bay

New data generated in mice by Andrew Gewirtz and colleagues at Emory University, Atlanta, has provided support for the hypothesis that defects in the innate immune system might underlie some cases of inflammatory bowel disease — a group of disorders characterized by inflammation in the intestine.

In the study, mice lacking a protein known as TLR5 (which senses the bacterial protein flagellin and initiates a proinflammatory response) were found to spontaneously develop inflammation of the colon (colitis), whereas normal mice did not spontaneously develop this disease. Just prior to the onset of spontaneous colitis increased numbers of bacteria were detected in the colon, as were very high levels of proinflammatory mediators. The latter observation was surprising given that TLR5-deficient mice lack an immune sensor of bacterial flagellin. However, consistent with the authors idea that this increased proinflammatory response was induced by other sensors of bacterial products, mice lacking TLR4 and TLR5 did not develop colitis. These data indicate that a deficiency in an immune sensor of bacteria can lead to an increased inflammatory response in the intestine of mice.

Title: Deletion of TLR5 results in spontaneous colitis in mice

Author:
Andrew T. Gewirtz
Emory University, Atlanta, Georgia, USA.

Uncovering the mechanisms underlying lung scarring

Pulmonary fibrosis is an incurable disease where the lung becomes scarred due to pathologic accumulation of fibrous scar tissue. Telomerase is a protein most notable for its connections to aging and cancer, but it has also been shown to have increased activity in mice with lung fibrosis. New evidence provided by Sem Phan and colleagues from the University of Michigan Medical School, Ann Arbor, has identified a role for telomerase in the progression of this disease in mice.

Telomerase activity is dependent on the presence of a related protein named TERT. The authors studied the effect of this enzyme in mice with induced lung injury and subsequent fibrosis. They found that mice with reduced TERT levels also had reduced telomerase activity in the lungs, and less severe lung fibrosis. This effect was reversed if the TERT-deficient mice were transplanted with TERT-sufficient bone marrow cells prior to lung injury. Conversely, when normal mice received bone marrow cells from TERT-deficient donors, subsequent telomerase activity and fibrosis of the lung was reduced. From these results, the authors concluded that bone marrow cells expressing TERT are important in the development of pulmonary fibrosis.

Title: Telomerase activity is required for bleomycin-induced pulmonary fibrosis in mice

Author:
Sem H. Phan
University of Michigan Medical School, Ann Arbor, Michigan, USA.

Breast cancer SK(i)P(s)2 the beat

Increased expression of the gene SKP2 has been detected in nearly 50% of breast cancer cases. New data generated by a team of researchers at the University of Michigan, Ann Arbor, has identified the protein FOXP3 as a suppressor of tumor growth promoted by SKP2, leading the team to suggest that defects in the FOXP3 gene that decrease FOXP3 protein expression might cause SKP2 upregulation and subsequent tumor development.

In the study, mammary tumors from mice expressing decreased amounts of FOXP3 were found to have increased amounts of SKP2. Further, in human breast cancer cell lines overexpression of FOXP3 decreased SKP2 levels, whereas knockdown of FOXP3 expression increased SKP2 levels. Additional analysis indicated that downregulation of SKP2 expression was essential for FOXP3 to inhibit the growth of human breast cancer cell lines lacking expression of HER2, another protein that stimulates tumor development. Together, these data led the authors to conclude that FOXP3 is a suppressor of tumor development induced by SKP2.

Title: FOXP3 is a novel transcriptional repressor for the breast cancer oncogene SKP2

Author:
Yang Liu

University of Michigan, Ann Arbor, Michigan, USA.

Pan Zheng

University of Michigan, Ann Arbor, Michigan, USA.

Source: Karen Honey

Journal of Clinical Investigation Continue reading →

Why do some people always look on the bright side of life when others seem to focus on the negatives? According to new research, it could be down to their genes. The findings, published in the Royal Society journal Proceedings of the Royal Society B, help to explain why some people respond better to stress than others and why some are more prone to emotional disorders such as depression.

A team of scientists led by Professor Elaine Fox from the University of Essex decided to tackle the question of why some people have a more positive outlook by taking a closer look at a gene which is already linked to emotional disorders. The serotonin transporter gene is already widely known to impact on brain release of the chemical serotonin which is involved in mood and well-being.

The researchers showed pairs of images to around 100 healthy individuals. Each pair contained a neutral image and either a positive or a negative one. The scientists monitored where the subjects’ attention was drawn to when they were shown the images, as well as doing a DNA test looking specifically at the serotonin transporter gene.

Everybody has one of three combinations of this gene either two short versions (SS), two long versions (LL) or one of each (SL). The results demonstrated that individuals with two long versions were much more attentive to positive material and had an aversion to the negative images. Those in the SL or SS groups were neither drawn to the positive material nor avoided the negative images.

These underlying differences have a large role to play in how people respond to life events, says Fox.”This is a key mechanism underlying resilience to general life stress,” she says, pointing to the fact that the absence of this protection in the SL and SS groups leaves them more susceptible to anxiety and depression.

Previous studies indicated this bias in psychiatric patients but this is the first study to look at healthy members of the population.

The Royal Society Continue reading →

Scientists at the University of California, San Diego School of Medicine, have identified a protein called Sestrin that serves as a natural inhibitor of aging and age-related pathologies in fruit flies. They also showed that Sestrin, whose structure and biochemical function are conserved between flies and humans, is needed for regulation of a signaling pathway that is the central controller of aging and metabolism. The work, led by Michael Karin, PhD, Distinguished Professor of Pharmacology in UCSD’s Laboratory of Gene Regulation and Signal Transduction, is the cover story of the March 5 issue of the journal Science.

Sestrins are highly conserved small proteins that are produced in high amounts when cells experience stress. Sestrin function, however, remained puzzling until the Karin group found that these proteins function as activators of AMP-dependent protein kinase (AMPK), and inhibitors of the Target of Rapamycin (TOR). AMPK and TOR are two protein kinases that serve as key components of a signaling pathway shown to be the central regulator of aging and metabolism in a variety of model organisms, including the worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and mammals.

AMPK is activated in response to caloric restriction, a condition that slows down aging, whereas TOR is activated in response to over-nutrition, a condition that accelerates aging. Activation of AMPK inhibits TOR, and drugs that activate AMPK or inhibit TOR can delay aging in several different model organisms including mammals. But how the body keeps the activity of these two protein kinases in balance to prevent premature aging was unknown. Additionally, the presence of three different genes encoding Sestrins in mammals made it difficult to identify their exact physiological function in live animals.

The new study took advantage of the finding that the fruit fly Drosophila, whose AMPK-TOR signaling pathway functions in the same manner as its mammalian equivalent, contains a single Sestrin gene. Using a variety of genetic techniques, first author Jun Hee Lee inactivated the Sestrin gene of Drosophila and found that although Sestrin-deficient flies do not exhibit any developmental abnormalities, they suffer from under-activation of AMPK and over-activation of TOR – confirming that Sestrin is needed for keeping this pathway in check. Most importantly, the biochemical imbalance incurred by loss of Sestrin expression resulted in several age-related pathologies.

“Strikingly, the pathologies caused by the Sestrin deficiency included accumulation of triglycerides, cardiac arrhythmia and muscle degeneration that occurred in rather young flies,” said Karin. “These pathologies are amazingly similar to the major disorders of overweight, heart failure and muscle loss that accompany aging in humans.”

Lee and colleagues at UC San Diego and the Sanford-Burnham Institute in La Jolla, California, went on to demonstrate that feeding flies with drugs that either activate AMPK or inhibit TOR conferred protection against most of these early aging, degenerative symptoms. The researchers also found that over-activation of TOR is likely to accelerate aging of heart and skeletal muscles by disrupting an important “quality control” process called autophagy. Autophagy allows cells to rid themselves of and replace damaged mitochondria, the little power plants that provide all cells, especially muscles, with energy. However, when mitochondria get old, they produce high concentrations of reactive oxygen species (ROS), or free radicals, that can lead to tissue damage.

Karin explained that the process of autophagy – which counteracts aging – allows the replacement of “old” and defective mitochondria with “brand new” mitochondria. Sestrin-deficient flies, however, were found to exhibit accumulation of damaged mitochondria and ROS several days prior to the detection of muscle degeneration. Feeding these flies vitamin E, an antioxidant which neutralizes free radicals, prevented premature muscle degeneration and heart failure.

In future work, the Karin group plans to examine whether the mammalian Sestrins also control aging and metabolism, and whether defects in proper Sestrin expression will provide the explanation to some of the currently unexplainable degenerative diseases associated with old age.

“Maybe one day we will be able to use Sestrin analogs to prevent much of the tissue failure associated with aging, as well as treat a number of degenerative diseases, whose incidence goes up with old age, including sarcopenia and Alzheimer’s disease,” said Karin.

Additional contributors to the study – a collaboration between three laboratories at UC San Diego School of Medicine, UCSD Division of Biology and the Sanford-Burnham Institute – are Andrei V. Budanov, Eek Joong Park, Ryan Birse, Teddy E. Kim, Guy A. Perkins, Karen Ocorr, Mark H. Ellisman, Rolf Bodmer and Ethan Bier.

The research was funded by the National Institutes of Health, the Superfund Basic Research Program and American Cancer Society.

Source:
Debra Kain
University of California – San Diego Continue reading →

Most of our cells possess an internal clock, a group of genes displaying a cyclic expression pattern that reaches a peak once a day. A large number of circadian genes are expressed by organs such as the liver, whose activity needs to be precisely regulated over the course of the day. A team of researchers of the National Centre of Competence in Research Frontiers in Genetics, based at the University of Geneva, Switzerland, reveals that an important regulator of this molecular oscillator is a specific microRNA. The latter belongs to a class of small RNA molecules that regulate the production of proteins in our cells. Thus far, little was known about their function within the circadian clockwork. The study by Ueli Schibler’s team, published in the 1st June edition of Genes & Development, fills in this important gap.

Living beings have adapted to the alternation between night and day by developing an internal clock, located in the brain. It allows synchronising gene expression and physiological functions with geophysical time. In addition, most of our body’s cells possess their own subsidiary oscillators, a group of genes displaying a cyclic expression pattern that reaches a peak every twenty-four hours.

More than 350 genes involved in metabolism, including that of cholesterol and lipids, are expressed in liver cells in a cyclic fashion. Many of them are also influenced by rhythmic food intake. Their activity must therefore be fine-tuned and synchronised with precision to ensure cohesion between diverse metabolic processes.

MicroRNAs induce gene silencing

Ueli Schibler, from the Molecular Biology Department of the University of Geneva, focuses on the mechanisms controlling the tiny oscillators in liver cells. MicroRNAs were among the potential factors likely to be involved in clock gene regulation. The common property of these small molecules lies in their ability to inhibit the synthesis of specific proteins, thus allowing cells to reduce the activity of certain genes at a given time.

“We have studied the role of a microRNA called miR-122, which is highly abundant in liver. It has caught considerable attention for its role in regulating cholesterol and lipid metabolism and in aiding the replication of hepatitis C virus” explains David Gatfield, one of Professor Schibler’s collaborators.

Performance of the molecular oscillator??¦

The researchers’ team has discovered that miR-122 is tightly embedded in the output system of the circadian clock in hepatocytes. This microRNA regulates numerous circadian genes, impinging on the amplitude and duration of their expression. Conversely, the synthesis of miR-122 involves a transcription factor that is otherwise known for its function in the circadian clock.

??¦and viral replication

“It will be exciting to investigate whether the connection between circadian rhythms and miR-122 also extends to this microRNA’s role in hepatitis C virus replication”, points out David Gatfield. Knowing whether viral multiplication is gated to specific times of the day would contribute significantly to our understanding of the life cycle of this formidable pathogen.

Scientists have uncovered over the past years the role of microRNAs in crucial physiological functions such as growth and programmed cell death, as well as carcinogenesis. Ueli Schibler’s team adds a stone to this edifice by placing miR-122 within the clock gene machinery.

Source:
Heather Cosel-Pieper

Cold Spring Harbor Laboratory Continue reading →

A lung cancer treatment that inhibits nicotine receptors was shown to double survival time in mice, according to Italian researchers.

The results of the early phase animal model study were reported in the June 15 issue of the American Journal of Respiratory and Critical Care Medicine.

Changes in genes encoding nicotine receptors are strongly associated not only with the tendency to smoke, but with susceptibility to lung cancer. Nicotine exposure also heightens the expression of the nicotine receptors, which leads to increased cell proliferation and inhibition of apoptosis, further setting the stage for cancer.

Patrizia Russo, Ph.D. and Laura Paleari, Ph.D. of the Lung Cancer Unit of the National Cancer Research Institute in Genoa, Italy and colleagues from San Raffaele Pisana Scientific Institute for Research, Hospitalization and Health Care (IRCCS), Catholic University, Campus Biomedico University in Rome, Mario Negri Institute in Milan and CEA Gyf sur Yvette in France showed in past research that an antagonist of nicotine acetylcholine receptors (nAChRs), may serve as an anticancer agent. The antagonist, called d-tubocurarine/?±-Cobratoxin (?±-CbT), specifically targeted the ?±7 subunit of nAChRs, the area primarily associated with increased cell proliferation.

In this study, the authors took the research a step further and showed that ?±-CbT could inhibit non-small cell lung carcinoma (NSCLC) growth and prolong life in non-obese/severe combined immunodeficient (NOD/SCID) mice that had human NSCLC grafted to their lungs. This study attempted to mimic human cancer conditions more closely by delaying treatment until the tumors were well-established. In addition to control mice that were untreated, the researchers randomized one third of the mice to receive standard chemotherapy.

They found that NOD/SCID mice treated with the standard chemotherapy agent, cisplatin, had a 16 percent longer median survival time than untreated mice (p= 0.05). Mice treated with ?±-CbT, however, had an increased median survival time of 1.7-fold over the cisplatin-treated mice and 2.1-fold over the no-treatment controls (p=0.0005).

“The results of this study show that ?±-CbT, a powerful, high-affinity ?±-7-nAChR inhibitor, induces antitumor activity against NSCLC by triggering apoptosis,” wrote Dr. Russo. “The prolonged survival of ?±-CbT-treated animals in our mouse model of NSCLC is most likely the result of several mechanisms, including various antiproliferative and antiangiogenic effects.”

The research also found that unaffected (i.e., noncancerous) cells showed no inhibition of proliferation when treated with ?±-CbT, suggesting that the treatment would have limited if any toxic effects. Dr. Russo and colleagues postulated that this finding may be due to the reduced number of receptor binding sites on normal cells as opposed to cancerous cells. Conversely, they reported that cancer cells with the greatest number of receptor binding sites seemed to respond with the greatest sensitivity to the treatment.

“The goal of this research line is to explore the widest range of possibilities of intervention on the??  ?±7-nAChRs. We hope to move further on towards the clinical setting experimentation phase for the assessment of potentially new treatment strategies for NSCLC,” said Dr. Russo.

An editorial in the same issue of the journal asked if nicotine may be to lung cancer what estrogen is to breast cancer. Eliot R. Spindel, M.D., Ph.D., of Oregon Health & Science University, stated that estrogen can stimulate the development of breast cancer and estrogen-receptor antagonists, such as tamoxifen, provide therapeutic benefit. In support of a carcinogenic role for estrogen, the incidence of breast cancer appears to be decreasing as estrogen hormone replacement therapy is being used less often. Likewise, nicotine may promote lung cancer yet nicotine receptor antagonists may offer treatment options for patients with lung cancer.

John Heffner, M.D., past president of the ATS stated that “this research clearly has profound clinical implications regarding the role of nicotine in stimulating lung cancer and nicotine receptor antagonists in treating the disease. The highly addictive nature of nicotine, however, complicates patients’ ability to quit smoking and avoid ongoing nicotine exposure.”

“This [addictive nature of nicotine] underscores the importance of potential FDA regulation of nicotine in tobacco products to limit exposure to this drug that promotes tumor growth,” wrote Dr. Spindel.

Source:
Keely Savoie

American Thoracic Society Continue reading →

By using entire islands as experimental laboratories, two Dartmouth biologists have performed one of the largest manipulations of natural selection ever conducted in a wild animal population. Their results, published online on May 9 by the journal Nature, show that competition among lizards is more important than predation by birds and snakes when it comes to survival of the fittest lizard.

“When Tennyson wrote that nature is ‘red in tooth and claw’, I think the image in his head was something like a Discovery Channel version of a lion chasing down a gazelle” said Ryan Calsbeek, an assistant professor of biology at Dartmouth College and a co-author of the study. “While that may often be the case, intense natural selection can also arise through competition. Sometimes, death by competitor can be more important than death by predator”.

To show this effect, the researchers covered multiple small islands in the Bahamas with bird-proof netting to keep predatory birds at bay. Other islands were left open to bird predators, and on still other islands, the researchers added predatory snakes to expose the lizards to both bird and snake predators. Next, they tracked the lizards over the summer to record which lizards lived and which died on the different islands.

“We found repeated evidence that death by predators occurred at random with respect to traits like body size and running ability” said Robert Cox, a post-doctoral researcher at Dartmouth and Calsbeek’s co-author. “But we also found that increasing the density of lizards on an island consistently created strong natural selection favoring larger size and better running ability.”

Calsbeek and Cox explain that in high-density populations, the intensity of competition for food, space, and other resources is likely to increase. In turn, this increased competition favors the biggest, toughest lizards on the island.

“The lizards play for keeps,” said Calsbeek, “and there’s no room for the meek when times get tough”.

Though the researchers note that competition will not always be more important than predation in other species or in different environments, they emphasize that their study has broad social implications because it demonstrates the ability to conduct evolutionary experiments in natural animal populations.

“Many people are skeptical of evolutionary biology because they perceive it as a purely historical science that can’t be tested experimentally. Here, we’re providing a real experimental test of natural selection as it happens in the wild. That’s an exciting way for us to advance the public’s perception of evolution” said Calsbeek.

Source:
Sue Knapp
Dartmouth College Continue reading →

Tiny molecules that help cells regulate which proteins they make might one day help doctors predict which liver-cancer patients are likely to live longer than others, new research suggests.

Researchers compared levels of molecules called microRNA in tumor cells and adjacent nontumor cells from liver-cancer patients, most of whom also had hepatitis and cirrhosis.

The study found that patients with poor disease-free survival had low overall levels of 19 particular microRNAs compared with those showing better survival after 16 years of follow-up.

The work was led by researchers at the Ohio State University Comprehensive Cancer Center in collaboration with investigators at the Mayo Clinic and the University of Oklahoma Health Sciences Center.

The study is published in the journal Clinical Cancer Research.

“The findings must be verified in larger groups of patients, but they suggest that we might improve survival in some liver-cancer cases by adding back those microRNAs as a drug,” says principal investigator Thomas D. Schmittgen, associate professor of pharmacy and a researcher with Ohio State’s Comprehensive Cancer Center.

But that possibility will require years of additional laboratory and preclinical research, Schmittgen says.

Liver cancer, or hepatocellular carcinoma, is the third most common cause of cancer death worldwide, killing some 662,000 people in 2005, according to the World Health Organization. The disease is more common in men and is usually caused by hepatitis infection or cirrhosis of the liver.

For this study, Schmittgen and his collaborators examined specimens from 43 liver tumors, 28 of which were paired with nearby nontumor tissue, and specimens from six normal livers. Two-thirds of the cancerous livers also had hepatitis and cirrhosis.

The researchers examined the levels of 196 different microRNAs in liver-cancer cells vs. nearby noncancer cells, and in liver cells with hepatitis and cirrhosis vs. healthy cells.

Both comparisons showed interesting differences in microRNA levels, but the most important finding came when the researchers looked for a correlation between cancer-cell microRNA levels and disease-free survival times in 25 patients for whom disease-free survival data was available.

The analysis showed that patients with poor survival had generally lower levels of 19 particular microRNAs than did patients with significantly better survival.

“This may also be a good clue as to which microRNAs are most important in liver cancer,” Schmittgen says.

Funding from the National Cancer Institute, the Richard M. Schulze Family Foundation and the Miles and Shirley Fiterman Center for Digestive Diseases at the Mayo Clinic supported this research.

Source: Darrell E. Ward

Ohio State University Medical Center Continue reading →