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New MATH for Cancer
New MATH for Cancer
Mon, 2013-05-20
A new method of measuring the variety of genetic mutations found in cells within a tumor appears to predict treatment outcomes of patients with the most common type of head and neck cancer. In the May 20 issue of the journal Cancer, HMS investigators at Massachusetts General Hospital and Massachusetts Eye and Ear described how their way of measuring tumor heterogeneity was a better predictor of survival than are most traditional risk factors in a small group of patients with squamous cell carcinoma of the head and neck.
"Our findings will eventually allow better matching of treatments to individual patients, based on this characteristic of their tumors," said Edmund Mroz, HMS associate professor of physiology in the Department of Otology and Laryngology at Mass General's Center for Cancer Research and lead author of the Cancer paper. "This method of measuring heterogeneity can be applied to most types of cancer, so our work should help researchers determine whether a similar relationship between heterogeneity and outcome occurs in other tumors."
For decades investigators have hypothesized that tumors with a high degree of genetic heterogeneity—the result of different subgroups of cells undergoing different mutations at different DNA sites—would be more difficult to treat because particular subgroups might be more likely to survive a particular drug or radiation or to have spread before diagnosis. While recent studies have identified specific genes and proteins that can confer treatment resistance in tumors, there previously has been no convenient way to measure tumor heterogeneity.
Working in the laboratory of James Rocco, who is the HMS Daniel Miller Associate Professor of Otology and Laryngology at Mass Eye and Ear, Mroz and his colleagues developed their new method by analyzing advanced gene-sequencing data to produce a value reflecting the genetic diversity within a tumor—not only the number of genetic mutations but how broadly particular mutations are shared within different subgroups of tumor cells. They first described this measure, called mutant-allele tumor heterogeneity (MATH), in the March 2013 issue of Oral Oncology. But that paper was able to show only that patients with known factors predicting poor outcomes—including specific mutations in the TP53 gene or a lack of infection with the human papillomavirus (HPV)—were likely to have higher MATH values.
In the current study, the investigators used MATH to analyze genetic data from the tumors of 74 patients with squamous cell head and neck carcinoma for whom they had complete treatment and outcome information. Not only did they find that higher MATH values were strongly associated with shorter overall survival—with each unit of increase reflecting a 5 percent increase in the risk of death—but that relationship was also seen within groups of patients already at risk for poor outcomes. For example, among patients with HPV-negative tumors, those with higher MATH values were less likely to survive than those with lower MATH values. Overall, MATH values were more strongly related to outcomes than were most previously identified risk factors. MATH values also improved outcome predictions based on all other risk factors the researchers examined.
The impact of MATH values on outcome appeared strongest among patients treated with chemotherapy, which may reflect a greater likelihood that highly heterogeneous tumors contain treatment-resistant cells, Mroz said. He also noted that what reduces the chance of survival appears to be the subgroups of cells with different mutations within a tumor, not the process of mutation itself.
"If all the tumor cells have gone through the same series of mutations, a single treatment might still be able to kill all of them," he said. "But if there are subgroups with different sets of mutations, one subgroup might be resistant to one type of treatment, while another subgroup might resist a different therapy."
In addition to combining MATH values with clinical characteristics to better predict a patient's chance of successful treatment, MATH could someday help determine treatment choice—directing the use of more-aggressive therapies against tumors with higher values, while allowing patients with lower values to receive less-intense standard treatment, Mroz noted. While MATH will probably be just as useful at predicting outcomes for other solid tumors, that remains to be shown in future studies, the investigators said.
"Our results have important implications for the future of oncology care," said Rocco, who is director of the Mass Eye and Ear/Mass General Head and Neck Molecular Oncology Research Laboratory and senior author of the Cancer paper. "MATH offers a simple, quantitative way to test hypotheses about intratumor genetic heterogeneity, including the likelihood that targeted therapy will succeed. The results also raise important questions about how genetic heterogeneity develops within a tumor and whether heterogeneity can be exploited therapeutically."
The study was supported by National Institute of Dental and Craniofacial Research grants R01DE022087 and RC2DE020958, National Cancer Institute grant R21CA119591, Cancer Prevention Research Institute of Texas grant RP100233, and the Bacardi MEEI Biobank Fund. Mass General has filed a patent application for the MATH measure.
Mind-body Genomics
Mind-body Genomics
Wed, 2013-05-01
A new study from investigators at the Benson-Henry Institute for Mind/Body Medicine at Massachusetts General Hospital and Beth Israel Deaconess Medical Center finds that eliciting the relaxation response—a physiologic state of deep rest induced by practices such as meditation, yoga, deep breathing and prayer—produces immediate changes in the expression of genes involved in immune function, energy metabolism and insulin secretion.
"Many studies have shown that mind/body interventions like the relaxation response can reduce stress and enhance wellness in healthy individuals and counteract the adverse clinical effects of stress in conditions like hypertension, anxiety, diabetes and aging," said Herbert Benson, HMS professor of medicine at Mass General and co-senior author of the report.
Benson is director emeritus of the Benson-Henry Institute.
"Now for the first time we've identified the key physiological hubs through which these benefits might be induced," he said.
Published in the open-access journal PLOS ONE, the study combined advanced expression profiling and systems biology analysis to both identify genes affected by relaxation response practice and to determine the potential biological relevance of those changes.
"Some of the biological pathways we identify as being regulated by relaxation response practice are already known to play specific roles in stress, inflammation and human disease. For others, the connections are still speculative, but this study is generating new hypotheses for further investigation," said Towia Libermann, HMS associate professor of medicine at Beth Israel Deaconess and co-senior author of the study.
Benson first described the relaxation response—the physiologic opposite of the fight-or-flight response—almost 40 years ago, and his team has pioneered the application of mind/body techniques to a wide range of health problems. Studies in many peer-reviewed journals have documented how the relaxation response both alleviates symptoms of anxiety and many other disorders and also affects factors such as heart rate, blood pressure, oxygen consumption and brain activity.
In 2008, Benson and Libermann led a study finding that long-term practice of the relaxation response changed the expression of genes involved with the body's response to stress. The current study examined changes produced during a single session of relaxation response practice, as well as those taking place over longer periods of time.
The study enrolled a group of 26 healthy adults with no experience in relaxation response practice, who then completed an 8-week relaxation-response training course.
Before they started their training, they went through what was essentially a control group session: Blood samples were taken before and immediately after the participants listened to a 20-minute health education CD and again 15 minutes later. After completing the training course, a similar set of blood tests was taken before and after participants listened to a 20-minute CD used to elicit the relaxation response as part of daily practice.
The sets of blood tests taken before the training program were designated "novice," and those taken after training completion were called "short-term practitioners." For further comparison, a similar set of blood samples was taken from a group of 25 individuals with 4 to 25 years' experience regularly eliciting the relaxation response through many different techniques before and after they listened to the same relaxation response CD.
Blood samples from all participants were analyzed to determine the expression of more than 22,000 genes at the different time points.
The results revealed significant changes in the expression of several important groups of genes between the novice samples and those from both the short- and long-term sets. Even more pronounced changes were shown in the long-term practitioners.
A systems biology analysis of known interactions among the proteins produced by the affected genes revealed that pathways involved with energy metabolism, particularly the function of mitochondria, were upregulated during the relaxation response. Pathways controlled by activation of a protein called NF-κB—known to have a prominent role in inflammation, stress, trauma and cancer—were suppressed after relaxation response elicitation. The expression of genes involved in insulin pathways was also significantly altered.
"The combination of genomics and systems biology in this study provided great insight into the key molecules and physiological gene interaction networks that might be involved in relaying beneficial effects of relaxation response in healthy subjects," said Manoj Bhasin, HMS assistant professor of medicine, co-lead author of the study, and co-director of the Beth Israel Deaconess Genomics, Proteomics, Bioinformatics and Systems Biology Center.
Bhasin noted that these insights should provide a framework for determining, on a genomic basis, whether the relaxation response will help alleviate symptoms of diseases triggered by stress. The work could also lead to developing biomarkers that may suggest how individual patients will respond to interventions.
Benson stressed that the long-term practitioners in this study elicited the relaxation response through many different techniques—various forms of meditation, yoga or prayer—but those differences were not reflected in the gene expression patterns.
"People have been engaging in these practices for thousands of years, and our finding of this unity of function on a basic-science, genomic level gives greater credibility to what some have called 'new age medicine,' " he said.
"While this and our previous studies focused on healthy participants, we currently are studying how the genomic changes induced by mind/body interventions affect pathways involved in hypertension, inflammatory bowel disease and irritable bowel syndrome. We have also started a study—a collaborative undertaking between Dana-Farber Cancer Institute, Mass General and Beth Israel Deaconess—in patients with precursor forms of multiple myeloma, a condition known to involve activation of NF-κB pathways," said Libermann, who is the director of the Beth Israel Deaconess Medical Center Genomics, Proteomics, Bioinformatics and Systems Biology Center.
The study was supported by Centers for Disease Control and Prevention grants H75 CCH123424 and R01 DP000339, by National Center for Complementary and Alternative Medicine grant R01 AT006464-01, and by National Center for Research Resources grant M01 RR01032.
Adapted from a joint Mass General and Beth Israel Deaconess news release.
Learning from Lassa Virus
Learning from Lassa Virus
Thu, 2013-03-21
Researchers have known that two seemingly distant human maladies—a devastating set of hereditary disorders called Walker-Warburg syndrome and infection with the virus that causes hemorrhagic Lassa fever—both involve a cellular protein involving sugar.
Now an international team has discovered new genetic mutations that cause the severe brain, muscle and eye defects found in children with Walker-Warburg syndrome but also make cells insensitive to the Lassa virus.
The scientists found all known gene defects and identified new mutations in genes critical for coupling sugar groups to a particular protein receptor for Lassa virus, called glycosylated alpha-dystroglycan.
The team, which includes Sean Whelan, HMS professor of microbiology and immunobiology; Hans van Bokhoven of Radboud University Medical Center; and Thijn Brummelkamp of the Netherlands Cancer Institute, published their findings this week in Science.
Defects in how sugar modifies the dystroglycan complex causes Walker-Warburg syndrome, in which affected children usually die at an early age. The Lassa virus is one of many pathogens that hijacks this protein complex in order to enter cells.
Studying Lassa leads to syndrome clues
Viruses need to get inside host cells to amplify and cause disease. The Lassa virus gains entry by binding to dystroglycan, a protein complex on the outside of the cell. This protein complex is heavily decorated with sugars that anchor the cell to its surroundings.
To generate a detailed map of how Lassa virus enters human cells, as well as to identify genes required for successful infection, the scientists infected a unique human cell line in a lab dish. Because these genes are present only in a single copy, they can be readily inactivated. Until recently this genetic trick was possible only in model organisms, such as yeast and fruit flies.
Using the genetic approach of inactivating host gene function by inserting new genetic material, a technique called insertional mutagenesis, the team found human cells that were resistant to Lassa virus infection.
The scientists were able to do the Lassa work safely by replacing the surface protein on another non-lethal virus with the surface protein of Lassa and then testing the ability of that virus to infect and kill the haploid cell-line in which genes had been inactivated by insertional mutagenesis. Only those cells that lacked the components essential for Lassa virus entry survived the infection, whereas others died.
Walker-Warburg mutations identified
The identity of the genes associated with resistance was revealed by deep genetic sequencing of the surviving cells. Among them were genes that encode the known Lassa virus receptor alpha-dystroglycan as well as machinery required to add sugars to this receptor. Mutations in several of these genes are associated with Walker-Warburg syndrome, but not all of the genes had previously been linked with the syndrome.
Based on these findings, researchers scanned the genome of Walker-Warburg patients for defects in these newly discovered genes. Strikingly, several families affected by hereditary Walker-Warburg syndrome of previously unknown cause carried mutations in these genes.
Lassa virus is endemic in regions of Africa and causes thousands of deaths every year. The researchers said it will be interesting to see if, in communities exposed to Lassa virus, the human genome shows traces of the ongoing struggle in the sections encoding the identified host factors that are involved in building the sugar trees on the dystroglycan protein.
Adapted from a Netherlands Cancer Institute news release.
Mitochondrial Quality Control
Mitochondrial Quality Control
Thu, 2013-03-21
Cell biologists studying Parkinson's disease are training their sights on mitochondria, the energy source of the cell, whose activity in neurons appears to go awry in this devastating neurodegenerative illness. A neuron needs its mitochondria to be healthy and mobile, particularly during their continual cycles of fission and fusion in which damaged bits are removed and healthy mitochondria are renewed.
A particular gene that is mutated in early-onset Parkinson's—a subset of the disease that can strike people in their 30s—has opened a window into a mechanism called mitophagy, an important component in this form of cellular housekeeping. When mitochondria are damaged, they must first be identified and then cleared away so they don't fuse with and poison "good" mitochondria. In mitophagy, an unwanted mitochondrion is engulfed and degraded.
Fundamental biochemical pathway
The gene PARKIN and its regulatory companion PINK1 work together in this process, one that involves multiple proteins on the mitochondrial outer membrane that may ultimately serve as potential targets for treatments in Parkinson's. PARKIN was discovered a dozen years ago, but only within the last couple of years have scientists pinpointed its role in mitochondrial quality control.
Wade Harper, the Bert and Natalie Vallee Professor of Molecular Pathology, together with his collaborator Steven Gygi, HMS professor of cell biology, led an HMS Department of Cell Biology team that has identified a fundamental biochemical pathway in which PARKIN resculpts the mitochondrial proteome—the full complement of mitochondrial proteins produced—to promote mitophagy. Harper and his colleagues published their results in Nature this week and share a web portal with a wealth of information about the proteins in this pathway.
The pathway that eradicates damaged mitochondria begins with a process called ubiquitylation. Ubiquitin is a small protein that modifies other proteins in many aspects of biology, including the response to damage that ultimately ends in ridding the cell of such waste. Understanding the sites of modification in target proteins is a key step in elucidating the role of ubiquitin in specific pathways, but this has been a technically challenging area of research. The Gygi and Harper labs recently developed a mass spectrometry-based proteomic methodology to identify ubiquitylation sites in target proteins, potentially on a global scale, and in the current study extended this to the PARKIN system.
Resculpting the mitochondrial proteome
"Identifying actual sites of ubiquitylation provides us not only a visual way to look at the structure and mechanisms of how the PARKIN system works, but it also gives you the potential in the future to make reagents that will let you look in tissue of the brain, for example, and determine whether the pathway is on or off," said Harper.
In defining the near complete repertoire of PARKIN substrates—which they call the PARKIN-dependent ubiquitylome—the researchers reveal how the structure and function of the mitochondrial proteome is resculpted by PARKIN. Indeed, their work identified hundreds of ubiquitylation sites on dozens of proteins.
While this contribution does not have immediate clinical implications, it does serve as a key steppingstone toward a greater understanding of Parkinson's and perhaps other neurodegenerative diseases involving mitochondrial quality control. This challenging work is necessary before contemplating ways to somehow overcome defects in genes such as PARKIN.
"We want to be able to use the data to understand in more detail how PARKIN is regulated and how it is activated and how it is capable of ubiquitylating a dizzying array of proteins on the mitochondrial surface," Harper said. "In addition, we also want to try to test the hypothesis that ubiquitylation of specific mitochondrial proteins is critical for mitophagy."
Clues to Fetal Alcohol Risk
Clues to Fetal Alcohol Risk
Wed, 2013-02-20
Fetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And fetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes fetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.
Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with fetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.
Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signaling pathway that might determine genetic susceptibility for the development of FASD. The study was published online Feb. 19 in the journal Proceedings of the National Academy of Sciences.
"Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity," said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. "And importantly, identifying those mothers whose fetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy."
The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to fetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbors. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).
Charness and his team went on to develop multiple cell lines from that first culture, and that's where they encountered the riddle: In some of those lines, alcohol disrupted L1's adhesive effect, while in others it did not.
"How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?" asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.
Clearly, something else was affecting the protein's sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. "That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition," Charness said.
In the current study, Charness' team and collaborators at the University of North Carolina School of Medicine in Chapel Hill conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules. They focused on what was happening to the L1 molecule inside a cell that could affect an event outside the cell such as disruption by alcohol.
"We found that phosphorylation events that begin inside the cell can render the external portion of the L1 adhesion molecule more vulnerable to inhibition by alcohol," said Xiaowei Dou, HMS instructor in neurology in the Charness Lab and first author on the new study. "Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal portion of the L1molecule."
Phosphorylation plays a significant role in a wide range of cellular processes. By adding a phosphate group to a protein or other molecule, phosphorylation turns many protein enzymes on and off, and thereby alters their function and activity.
The researchers also found that variations in ERK2 activity correlated with differences in L1 sensitivity to alcohol that they observed across cell lines and among different strains of mice. "Dou showed that he could take these cells that had been insensitive to alcohol for 13-14 years, and make them sensitive by ramping up the activity of this kinase" Charness said.
These variations suggest that genes for ERK2 and the signaling molecules that regulate ERK2 activity might influence genetic susceptibility to FASD. Moreover, their identification of a specific locus that regulates the alcohol sensitivity of L1 might facilitate the rational design of drugs that block alcohol neurotoxicity.
"The only thing this modification blocked was alcohol's ability to inhibit L1," Charness said. "If you're looking for a drug, ideally you're looking for it to block the effects of the toxin without interfering with the target molecule of the toxin."
The findings will also help guide an international consortium in its search for genes linked to families with fetal alcohol spectrum disorders.
"Prenatal alcohol exposure is the leading preventable cause of birth defects and developmental disorders in the United States," said Kenneth Warren, acting director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA),which supported the study. "These new findings are yet another important contribution from researchers who have been at the forefront of scientific discovery in FASD."
This work was supported by the NIAAA Grant R01-AA12974; NIAAA Grant U24-AA014811, as a component of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD); the Medical Research Service, Department of Veterans Affairs; NIAAA Grant AA017124 (CIFASD); NIAAA Grant AA011605; and NIAAA Grant K99/R00-AA018697.
Why 'Good Hair' Matters
Why 'Good Hair' Matters
Thu, 2013-02-14
The first animal model of recent human evolution reveals that a single mutation produced several traits common in East Asian peoples, from thicker hair to denser sweat glands, an international team of researchers reports.
The team, led by researchers from Harvard Medical School, Harvard University, the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Fudan University and University College London, also modeled the spread of the gene mutation across Asia and North America, concluding that it most likely arose about 30,000 years ago in what is today central China. The findings are reported in the cover story of the Feb. 14 issue of Cell.
"This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans," said Pardis Sabeti, associate professor in the Center for Systems Biology and Department of Organismic and Evolutionary Biology at Harvard University, and one of the paper's senior authors. Sabeti is also a senior associate member at the Broad Institute.
"This paper tells a story about human evolution in three parts," said Cliff Tabin, head of the HMS Department of Genetics and co-senior author. "The mouse model links multiple traits to a single mutation, the related association study finds these traits in humans, and computer models tell us where and when the mutation likely arose and spread."
Previous research in Sabeti's lab had identified the mutation as a strong candidate for positive selection. That is, evidence within the genetic code suggested the mutant gene conferred an evolutionary advantage, though what advantage was unclear.
The mutation was found in a gene for ectodysplasin receptor, or EDAR, part of a signaling pathway known to play a key role in the development of hair, sweat glands and other skin features. While human populations in Africa and Europe had one, ancestral, version of the gene, most East Asians had a derived variant, EDARV370A, which studies had linked to thicker scalp hair and an altered tooth shape in humans.
The ectodysplasin pathway is highly conserved across vertebrates — the same genes do the same thing in humans and mice and zebrafish. For that reason, and because its effects on skin, hair and scales can be observed directly, it is widely studied.
This evolutionary conservation led Yana Kamberov, one of two first authors on the paper, to reason that EDARV370A would exert similar biological effects in an animal model as in humans. The HMS research fellow in genetics developed a mouse model with the exact mutation of EDARV370A — a difference of one DNA letter from the original, or wild-type, population. That mouse manifested thicker hair, more densely branched mammary glands and an increased number of eccrine, or sweat, glands.
"This not only directly pointed us to the subset of organs and tissues that were sensitive to the mutation, but also gave us the key biological evidence that EDARV370A could have been acted on by natural selection," Kamberov said.
The findings prompted the team to look for similar traits in human populations. When co-first author Sijia Wang and the team including collaborators at Fudan examined the fingertips of Chinese volunteers at colleges and farming villages, they found that the sweat glands of Han Chinese, who carry the derived variant of the gene, were packed about 15 percent more densely than those of a control population with the ancestral variant.
At the same time, Wang and the team including collaborators at University College London were working to zero in on when and where the mutation arose. Computer models suggested that the derived variant of the gene emerged in central China between 13,175 and 39,575 years ago, with a median estimate of 30,925 years. Researchers concluded the derived variant is at least 15,000 years old, predating the migration from Asia by Native Americans, who also carry the mutation.
That time span suggests that different traits could have been under selection at different times. The mutation's many effects, known as pleiotropy, only complicate the question. If changes to the sweat glands conferred an advantage in new climates — one of the theories the researchers plan to explore further — changes to hair and to mammary glands could have conferred other advantages at other times.
Not all of these advantages need be direct effects on fitness. "When Pardis started this work, I would not have predicted that a gene that makes good hair would top a list of mutations that confer evolutionary advantage among humans," said Bruce Morgan, HMS associate professor of dermatology at Massachusetts General Hospital and co-senior author on the paper. "However, in this case 'good hair' may have a biological meaning because it is genetically linked to a physiologically adaptive trait like increased sweating capacity. A cultural preference for a physically obvious trait like hair type could have arisen because individuals with it were more successful, and this would help increase selection on the new variant."
"That (pleiotropy) makes it harder for us to make a guess," Wang said. "If there were only one associated trait, we could say with confidence that's where the selective advantage comes from. But with many traits, we don't know which is the target of selection, and which are just hitchhiking." Wang intends to focus on that question in his new role, as a Max Planck independent research group leader in dermatogenomics at Chinese Academy of Sciences – Max Planck Partner Institute for Computational Biology in Shanghai.
By leveraging the power of diverse fields, the team is piecing together the foundation for understanding how selected mutations like EDARV370A have impacted human diversity. But, they say, this is only the beginning.
"These findings point to what mutations, when, where and how," said Daniel Lieberman, a professor of human evolutionary biology at Harvard University and a co-senior author on the study. "We still want to know why."
The research was funded by the Harvard University Science and Engineering Committee Seed Fund for Interdisciplinary Science; NIH grants R37 HD032443 and R37 054364; NIH Innovator Award 1DP2OD006514-01; NIAMS BIRT Award AR055256-04S1; the Packard Foundation; the American School of Prehistoric Research; NSFC 30890034; MOST 2011BAI09B00; MOH 201002007; AXA Research Fund; and a LeCHE Marie Curie FP7framework.
Of Men, Not Mice
Of Men, Not Mice
Mon, 2013-02-11
Existing mouse models do not appear to accurately reproduce the human genomic response to serious traumatic injury, including major burns, according to an article appearing in PNAS Early Edition.
The report from a national consortium investigating the role of inflammation in the body's response to injury finds little correlation between the human response to burns, trauma or a bacterial toxin and that of currently used mouse models for those conditions. The authors noted that their results cannot be applied to the use of mouse models for other research purposes.
"Our findings question the validity of using mouse models to mimic inflammatory conditions in humans," said Shaw Warren, HMS associate professor of pediatrics at Massachusetts General Hospital and a co-lead author of the report.
"An additional finding is that the whole-genome responses to these conditions in humans correlated well with each other, suggesting that treatments developed for an inflammatory disease from one cause might also work for inflammatory diseases with different causes," Warren said.
The study is part of the Inflammation and the Host Response to Injury consortium, established in 2001 to investigate how the human body responds to injury, with particular attention to factors that set off excessive, uncontrolled inflammation.
Based at Mass General, the program includes investigators from 20 academic research centers around the country and is led by Ronald G. Tompkins, HMS Sumner M. Redstone Professor of Surgery and director of the Sumner Redstone Burn Center at Mass General. He is a co-corresponding author of the current report.
In 2011, the group reported finding that serious injuries set off a "genomic storm" in the human body, altering around 80 percent of normal gene expression patterns. The current study drew on information from that study and others conducted by the consortium to compare the human genomic response to inflammatory disease with that of mouse models.
The investigators from Mass General, the Stanford University Genome Technology Center and several other research centers combined data from four of their studies of genomic responses to systemic inflammation: two in burn or trauma patients and volunteers treated with a bacterial toxin that produces brief flu-like symptoms and two studies of the responses in mouse models of the three conditions.
While the responses among human patients were very similar, showing changes in the expression of more than 5,500 genes, there was very little correlation with the expression patterns of corresponding genes in the mouse models. Not only was the human genomic response to inflammatory injury much greater—affecting the expression of more than three times as many genes as in the models—but it also lasted longer, up to six months in humans compared with a few days at most in mice.
To confirm their findings, the investigators analyzed data from an additional 20 studies of acute inflammatory disease—10 in humans and 10 in mice—and found a similar lack of correlation between the response of human patients and the mouse models. In all the human studies, the genomic responses were very similar, despite differences in patient age, gender, type and severity of injury or illness, treatment and outcomes.
"Mice have been used in biomedical research for well over 50 years, in part because of the cost, size, convenience, ease of genetic manipulation and social acceptability. But it is often forgotten that mice appear to be much more resistant to inflammation and infection than humans," said Warren.
"By studying and understanding the mechanisms by which mice differ from humans, we may be able to develop treatments that help make humans more resistant to damaging inflammation. We also hope that our article will start a broader discussion among scientists, research organizations, journals and granting and regulatory agencies as to the value of mouse models in different specific circumstances," Warren said.
The study was supported by Defense Advanced Research Projects Agency grant W9111NF-10-1-0271; National Institute on Disability and Rehabilitation Research grant H133A070026; National Institute of General Medical Sciences grants 5P50GM060338, 5R01GM056687, R24GM102656 and 5U54GM062119; and National Human Genome Research Institute grant P01HG000205.
Sue McGreevey is manager for science & research communications at Mass General Public Affairs.
Adapted from a Mass General news release.
Complex Mysteries
Complex Mysteries
Thu, 2013-01-10
It is difficult to overstate the complexity of autism.
Two children born with identical genetic mutations can have profoundly different outcomes—one with typical neural and social development, the other unable to communicate with the world around him.
One in 88 children in the U.S. has autism, according to the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. Hundreds of different genetic abnormalities may contribute to—or inhibit—autism. Many of the known anomalies cluster around genes that control the development of neurons and synapses, but many others are in regions of the genome that are still poorly understood.
Layered on top of the bewildering genetics, scientists are only beginning to understand how environmental factors may affect this condition. Autism, which is characterized by impaired social communication, fixated interests and repetitive behaviors, may occur alone or as part of other developmental syndromes, such as Fragile X, Rett's, and tuberous sclerosis, conditions that also include intellectual delays, epilepsy and a number of gastrointestinal disorders.
Unraveling all of this is like trying to solve a riddle encrypted in a cipher printed on a jigsaw puzzle—with extra pieces mixed in that don't quite match.
This complexity presents fascinating challenges for researchers, but it also makes diagnosing and treating children with autism vexingly difficult. Even with the latest genetic testing, pediatricians still can't predict whether an at-risk child will develop autism, or how severe symptoms will be. And while some genetic analogs for autism have been reversed in animal models, there is currently no treatment for any of the core symptoms of autism for people with the disorder.
Despite its daunting complexity, however, new technologies and techniques and an emphasis on collaborative research are helping scientists unravel the fundamental biological basis for autism, and providing suggestions for new treatments.
A hub for autism research
In 2006, realizing that the challenges of autism's complexity were too great to solve piecemeal, a group of researchers and patient advocates in Boston banded together to form the Autism Consortium. The Consortium, which brings together researchers from Harvard, Boston University, MIT, Tufts, UMASS Medical School and affiliated hospitals and research institutes, affords a platform for collaboration, enabling diverse groups to share samples of patient and animal data. The organization hosts an annual meeting that highlights biomedical and clinical advances.
"The history of science isn't just a history of great ideas, it's a history of new tools," said Steve Hyman, HMS professor of neurobiology and Harvard professor of stem cell and regenerative biology, at a Consortium meeting at HMS last fall.
"Galileo's novel use of the telescope allowed him to revolutionize our understanding of the workings of the solar system," said Hyman. "Galileo was a really smart guy, but without the tool, no new conception of the universe, no excommunication—none of that stuff."
Those new tools—including genomic resources, engineering tools, cellular models, and organizational models and partnerships to facilitate data sharing and collaboration—are opening windows for understanding the biological bases for autism.
One challenge to understanding the biology of autism is purely physiological: the disorder is hidden in the folds of the brain. Researchers can't biopsy living brain tissue, and the image resolution of many imaging techniques is severely limited. Because autism is a disease of neural systems and circuits and a disorder of human social behavior, studying nerve cells in the lab and animal models provides limited insight.
Nicholas Lange, HMS associate professor of psychiatry at McLean Hospital and Harvard School of Public Health associate professor of biostatistics, has worked on brain imaging techniques that are beginning to shed some light on the physiology of the brains of people with autism. This is another area with a great deal of unmapped territory to explore. In a recent essay in Nature, Lange emphasized that we still need to better understand the great breadth and depth of healthy typical and atypical neurobiology and the diversity of the types of brain features in autism, and that without that foundational biology all attempts at diagnosing autism by brain imaging are futile.
"Brain scans, neuronal subtyping and genetics are the signposts showing us where and how to look, see, ponder, hypothesize and test," Lange said. "We start where we are and delve more deeply into the biological etiology and treatment of autism."
Some members of the Consortium are planning to grow neurons from stem cells as a way of examining how neurons from patients with different genomic profiles develop and operate.
Others are developing new techniques to look at how the neurons perform at the synaptic level, using high-resolution, high-speed imaging to visualize a single pulse of neurotransmitters in order to see what happens each time a neuron fires.
"You need that excruciating, exquisite level of detail so you can watch signals in real time," said Mriganka Sur, director of the Simons Center for the Social Brain at MIT. Researchers will also need to scale these tiny neuronal interactions to see how they interrelate in complex neural networks, he added.
"One of the greatest challenges is determining how these genes map onto the development of the social brain," Sur said.
Synaptic tuning
One reason autism is so complex is that the process of brain development itself is incredibly dynamic, according to Christopher Walsh, chief of the Division of Genetics at Boston Children's Hospital and HMS Bullard Professor of Pediatrics and Neurology.
Walsh began his career as a developmental neurobiologist and focused on genetics as a method of getting to the root of neural development. In 2008, working with samples of consanguineous Middle Eastern families to find recessive genes related to developmental disorders, Walsh identified a handful of new genetic components of autism, including both protein encoding genes and the codons surrounding genes that act as on-off switches for genes.
Michael Greenberg, chair of the neurobiology department at HMS and Nathan Marsh Pusey Professor of Neurobiology, had previously identified those genes as key players in experience-dependent learning.
"When neurons become active, they turn on a lot of genes," Walsh said. When a person is learning a new behavior, repeated experience activates genes that, over time, strengthen some connections in the brain and weaken others. This building and pruning of neural pathways shapes the networks that record and enable learned behaviors.
This kind of learning is essential to developing the complex social behaviors impaired in autism, and it turns out that several of the genomic anomalies associated with autism are related to regulators that signal these synaptic shaping and pruning genes when to turn on and off.
If the genes involved in making proteins to build those connections don't turn on at the right time, or if they shut down too soon, they might not build an important connection; if they stay on too long, connections can be overly strengthened.
"You could think of it as synaptic tuning," Walsh said. "When a synapse fires, it doesn't just fire once, it fires repeatedly at a certain frequency. "Hearing" the right tune is what stimulates the next synapse," he said. "In autism, for certain kinds of complex tasks, like social communication, you might say that you've lost that tuning mechanism."
Walsh said a variety of drugs under development to treat synaptic deficiencies in far-flung disorders from Fragile X to Alzheimer's might prove effective in treating autism.
Gene hunting
A handful of genetic anomalies related to autism have been identified, but some researchers believe that more than 100 genes may contribute to autism, and that those genes are just the beginning of a series of complex biochemical pathways, many of which remain uncharted territory.
Researchers in the Greenberg lab are studying the genetic and molecular machinery that builds brains; that is, the proteins that coax embryonic stem cells into becoming neurons as well as the switches that help promote and prune synapses. When this developmental process goes awry, conditions such as autism can result. For example, Greenberg discovered how the loss of a key enzyme related to the molding of synapses could explain the devastating developmental deficits that occur in Angelman syndrome, which causes a constellation of developmental problems in children, including mental disability and, in some cases, autism.
There are more than 300 genes that trigger these synaptic changes. Many of the genes that Greenberg's molecular and cellular studies have identified as playing important roles in the modification of synaptic connections have been identified as sites for genetic anomalies that may contribute to autism. Researchers probing these links include Walsh and Mark Daly, HMS associate professor of medicine at Massachusetts General Hospital's Center for Human Genetic Research.
"One piece of the puzzle isn't enough to open up the biology and crack something as complex as autism," said Daly, who is also director of computational biology for the Medical and Population Genetics Program of the Broad Institute of Harvard and MIT.
Working with the samples available through the Autism Consortium, Daly's lab has now sequenced the genomes of hundreds of families, identifying several novel genetic contributions to autism.
"By this time next year, we will have several thousand families sequenced. We'll have a much bigger set of those puzzle pieces," Daly said.
Recent technical advances have made gene sequencing much more accessible. A decade ago it took 10 years and cost $1 billion to sequence a human genome. Now it can be done in one week or less for a few thousand dollars. Still, the work of understanding sequenced genomes remains challenging, Daly said.
Differences in the genomes of any two healthy individuals are vast. When researchers sort through all that unique data, in billions of combinations of bases in the genetic code, identifying the differences that are characteristic of autism is no simple task.
"It's a huge computational challenge," Daly said. "We can't yet answer basic questions for families about the potential severity of their children's illnesses, let alone offer any treatment."
Finding—and learning from—biomarkers
One way to solve the autism puzzle is to identify the genes that are implicated in the disorder and then study the pathways and processes that those genes regulate.
Another way is to identify measurable biological features characteristic of autism, and to compare those with the same features in the biology of typical development. If genetics are the pieces of the jigsaw puzzle, biomarkers are part of the picture on the box that shows you what the pieces will look like when they're put together.
HMS researchers at Boston Children's Hospital, for example, have developed a blood test for autism spectrum disorders that outperforms existing genetic tests. It also presents evidence that abnormal immunologic activity affecting brain development may help explain some of autism's origins.
The same is true for many other projects that autism researchers are undertaking to define how the disorder manifests itself physiologically; for example, measuring electrical activity in the brain, monitoring stress levels and predicting the onset of seizures by measuring skin conductivity.
The research not only leads to more objective diagnostic tools, it can also provide crucial insight into the basic biology of the brain, which remains one of the great black boxes of biomedical science.
As complex as the challenges are, researchers say that great progress is being made in sorting out the roles of genes and gene regulators, of toxins and the immune system, of synaptic pruning and stress. Researchers are also building a basic understanding of the function of the social brain from the molecular to the macro level, and beginning to see how the pieces fit together.
"All of these things are in sight now," said Gerald Fischbach, director of the Simons Foundation Autism Research Initiative. "We have the tools to do this."
A Sharper Tool for Genome Engineering
A Sharper Tool for Genome Engineering
Fri, 2013-01-11
A new method for more easily and precisely engineering the human genome may help scientists pin subtle changes in DNA to disease, moving the needle from correlation to causality and potentially improving gene therapy techniques.
Two groups recently reported in Science their success using a tool borrowed from a bacterial immune system called Cas, short for CRISPR-associated systems, which in turn stands for Clustered Regularly Interspaced Short Palindromic Repeats. In bacteria the Cas9 enzyme system uses short stretches of RNA to target and then cut invading viral DNA. Scientists have customized this system to work in human cells, creating an RNA-guided editing tool that allows them to integrate DNA changes into the genomes of living cells, a process called genome engineering.
One of the teams, led by George Church, HMS Robert Winthrop Professor of Genetics, also tested the method in induced pluripotent stem cells (iPSCs), an important milestone on the path to human genome engineering. These cells, taken from a child or adult, have been modified to mimic embryonic cells, which means they can develop into any adult cell type. In experiments, iPSCs offer greater clarity than traditional cell lines as researchers explore gene function in different cell types.
The other team, led by Feng Zhang of the Broad Institute of Harvard and MIT, independently showed the effectiveness of Cas9.
While the Cas9 method is still a long way from the clinic, Church is hopeful.
"We need a lot more experience and optimization, but it looks very promising," he said. "This is much easier than any previous human genome engineering method, and it is relevant to testing the flow of ideas from GWAS [genome-wide association studies] and the Personal Genome Project."
The Cas9 approach, first developed by Harvard University graduate Jennifer Doudna of the University of California, Berkeley, could end up supplanting a technique that Science just last month named one of the top 10 scientific breakthroughs of 2012. For this technique, a class of proteins called TALENs (Transcription Activator-Like Effector Nucleases) zero in on a particular region of the genome, where they can precisely cut DNA and insert or delete a gene. TALENs followed a method from the 1990s that used enzymes called zinc finger nucleases to target specific parts of genomes.
TALENs were easier to design, but, like zinc fingers, they require about 2,000 bases of messenger RNA to encode an enzyme that would cleave DNA at a specific site in a genome. Cas9 needs 1/100 as much RNA; as few as 20 variable bases, embedded in short constant guide RNAs, are sufficient for precise targeting, the scientists showed in human cell lines.
According to Church, also testing Cas9 in iPSCs is particularly noteworthy.
"We need to have human stem cells in culture so we can manipulate the genome and see how the cells differentiate, or fit into tissues," he said. "To change from correlation and speculation to causality, you introduce single changes, one by one, into a test genome and ask which of those or how many of those do you need in order to see the trait. That turns correlation into causation and moves it closer to the gold standard."
The more compact Cas9 system opens the door to engineering multiple changes in different genes and then testing them simultaneously to see what role they play in complex diseases. Large genome-sequencing studies can find a variety of genes active in people with a particular disease, but it takes the kind of multiplex testing Cas9 allows to establish which ones actually matter, Church said.
A decade ago early attempts at gene therapy failed because delivery of a new, corrected gene could inadvertently promote cancer or provoke a harmful immune system response. Newer methods, in addition to having more precise delivery, are also designed to have lower toxicity and generate only a tolerable immune response in the case of a rare off-target event. These newer approaches also make it possible to target an old gene with new information, either knocking it out or changing it precisely.
Cas9 has the potential to accelerate these improvements in gene therapy, but much more testing is necessary to see if it will continue to display the greater efficiency and very low toxicity shown in these early experiments. "But it looks like a very promising starting point," Church said.
This work was supported by NIH grant P50 HG005550. Church and the Science paper's first author, research fellow Prashant Mali, have applied for a patent based on the findings of this study.
Breakthrough Prize for Ruvkun
Breakthrough Prize for Ruvkun
Mon, 2014-11-17
Gary Ruvkun, Harvard Medical School professor of genetics at Massachusetts General Hospital, was named one of six winners of the 2015 Breakthrough Prizes in Life Sciences. Each winner, along with winners in Physics and Mathematics, will receive a $3 million prize.
Ruvkun and Victor Ambros, University of Massachusetts Medical School, were each recognized for the discovery of a new world of genetic regulation by microRNAs, a class of tiny RNA molecules that inhibit translation or destabilize complementary mRNA targets. The other winners in the life sciences include C. David Allis, Alim Louis Benabid, Jennifer A. Doudna and Emmanuelle Charpentier.
The Breakthrough Prizes aim to celebrate scientists and generate excitement about the pursuit of science as a career. Breakthrough Prizes are funded by a grant from Sergey Brin and Anne Wojcicki's foundation, The Brin Wojcicki Foundation; a grant from Mark Zuckerberg's fund at the Silicon Valley Community Foundation; a grant from Jack Ma Foundation; and a grant from Milner Foundation.
The awards were presented at an exclusive Gala co-hosted by founders Sergey Brin and Anne Wojcicki, Jack Ma and Cathy Zhang, Yuri and Julia Milner, Mark Zuckerberg and Priscilla Chan and Vanity Fair editor Graydon Carter at NASA's Ames Research Center. Seth MacFarlane hosted The 2nd Annual Breakthrough Prize Ceremony which also featured Kate Beckinsale, Benedict Cumberbatch, Cameron Diaz, Jon Hamm and Eddie Redmayne as presenters.
"This year's life sciences laureates have made some spectacular discoveries, from a new kind of gene to a Parkinson's treatment that has improved the lives of many," Wojcicki said. "It's energizing to be in the company of such brilliant and fertile minds."
"The world faces many fundamental challenges today, and there are many amazing scientists, researchers and engineers helping us solve them," Zuckerberg said. "This year's Breakthrough Prize winners have made discoveries that will help cure disease and move the world forward. They deserve to be recognized as heroes."


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I've seen guns just not like Wolf.
I've got a 9mm pistol that SHOOTS Wolf just fine, but God-forbid you have to clear a round from the chamber...invariably it'll get hung up on the extractor and become a real pain in the...well anyways with brass it shoots, handles and clears just fine. Other guns, including pistols and rifles of mine, eat the Wolf just fine.
Some guns and some mags just don't like the steel. If yours is one of those, I'd say your experience is a much easier way of showing you to stick to the brass than your steel-ammo-loaded-pistol going "click" in the middle of the night as you stare down an angry home-invader intent on your tv, XBox and possibly yo ass.
Just sayin'

subset: commoncrawl


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Daniel Sherrill - Rackspace Community Affairs Specialist
in Electronics
As we continue on with this robotics season the next person on the list of must-have interviews is Daniel Sherrill who is the Community Affairs Specialist at Rackspace. I like to think of Daniel as the tip of the spear when it comes to Rackspace's community outreach.
Daniel shares the vision Rackspace has through their community involvement with Alamo FIRST and other community projects. He also discusses the value in being an active part of FIRST Robotics.
The Alamo First Show is made possible through the continued support of our Title Sponsor, Rackspace who are the #1 managed cloud company and they are famous for providing their customers fanatical support. We thank you, Rackspace for continuing to provide us with fanatical support.
Karen Pittman is an accomplished American actress and singer, born in Mississippi and raised in Nashville, Tennessee. She received her Bachelor of Science in Voice and Opera at Northwestern University and received her Masters of Fine Arts from NYU's Graduate Acting Program. Karen is starring in the Pulitzer Prize winning Broadway play "Disgraced," written by Ayad Akhtar as well as co-starring in the third season of FX's "The Americans." "The Americans" which premiered on January 28, 2015.
Anna and the Angels with guest Karen Anderson
in Spirituality
This week I welcome back dear Karen Anderson to the show to talk about the Angels and how they can help us through our life lessons and challenges!
Spiritual Intuitive Karen Anderson is an internationally known Intuitive, Healer, Teacher, Medium and Radio Host, whose channeled Angelic messages have assisted many around the world. Karen is a third generation intuitive, who as a small child could easily hear the divine guidance of God and the Angels, but did not let this guidance fully encompass her life until the fall of 1997 when a life altering encounter with Heavenly Angels reopened her gift of clairaudience (clear hearing). Today, Karen works very closely with the Angelic Kingdom bringing channeled messages to many. Karen assists attendees in her workshops through insightful direction on how to develop one's own heart-to-heart connection with their Guardian Angel and Spiritual Guides.
You can contact Karen at www.askkarenanderson.com
Truth Front to Back Ep 1 With Desiree Deluca & Karen Fisher
Welcome to the Grand Opening of our new crazy infested show Truth Front & Back Your host for the next steamy 60 minutes are Desiree Deluca & Karen Fisher All listeners call in 646-595-4038 Special Guest for the evening is DR Kelsey Obession The adult star with a PHD
You do not want to miss these 2 hot women giving you the Truth about the industry and adult films raw,bold and graphic
Informative sexy women what else could you ask for?
11:30pm Intro song Star Nels Van Go
11:35 Meet the host and what Truth Front to back is all about
1140 Announcements and First music break Heroine Twerking Like Miley Cyrus
11:45 News The nasty in the world of adult entertainment any comments about anything in the adult world
11:55 2nd music Break Perfect by Alana Evans
12am Guest interview Dr Kelsey Obsession
12:15 3rd music Break star dancing by night core
12:17 phone calls
12 28 outtro say goodnyes and thanks to dollhouse radio
follow Desiree Deluca @boobzillaxxx
follow Karen Fisher @sexykarenfisher
follow Dollhouse Radio @dollhouse_radio
Out of the Fog: Love Expanding Love with Paul Luftenegger
in Spirituality
Paul Luftenegger knows deeply that the power of loving, conscious music transcends and shifts our paradigms from within; ascending more towards love. The lightbody and heart are the center of our soul as we bring forth the light of love from within. He joins Karen to share his belief that we are all creators or our Universe and a part of Omnipresent Love. Paul's new album is "Love Expanding Love." This interview originally aired on Empower Radio.
Bert Martinez joined by Dr. Bertice Berry, David Shenk, Sean Hyman, Karen Davis
in Business
Dr. Bertice Berry best-selling author and award winning lecturer has been named Comedian of The Year, Lecturer of the Year and Entertainer of the Year. She has published 11 best-selling books in both fiction and non-fiction and has won numerous awards and accolades for both her writing and presentations. Berry has had her own nationally syndicated television show and has hosted, interviewed and made numerous television, documentary and radio appearances on a variety of diverse venues including The Tonight Show, Oprah Winfrey
David Shenk award-winning and national-bestselling author of six books, including The Forgetting, Data Smog and The Immortal Game. He is a popular lecturer, a short-film director/producer, and a contributor to National Geographic, Slate, The New York Times, The Wall Street Journal, Gourmet, Harper's, Spy, The New Yorker, The Atlantic, and NPR. His most recent book, The Genius in All of Us: New Insights Into Genetics, Talent, and IQ was welcomed as "a deeply interesting and important book" by the New York Times
Sean Hyman has an extensive background in the financial markets, having spent more than 20 years in the investing trenches. Over that time, he's been a stockbroker at Charles Schwab, a trading course instructor for foreign exchange market maker Forex Capital Markets, a financial writer for numerous outlets, and a key speaker at conferences both nationally and internationally
Karen Davis psychotherapist specializing in individual, couples and family therapy and maintains a private practice in Bloomfield Hills, Michigan. With almost 20 years experience as a psychotherapist, she is currently serving as private practitioner working with a broad spectrum of clients. Among her areas of expertise are anxiety, depression, weight loss, self-esteem and addiction
in Christianity
A messed up life and totally wore out by satan describes where Apostle Karen Dunham had come from. The Lord saved her and her son Blake from the clutches of the mafia 11 years ago, and she has followed Jesus Christ without looking back. From the deepest pit to a position in God is how she describes where the Lord has placed her today.
Karen Dunham first visited Israel around 10 years ago with Swansea Bible College on a governmental invitation. She was introduced to the city of Jericho (an off limits city for tourist) in 2002 on tour, then returned in 2003. She was told by a Jerusalem priest, "if you will feed these people [meaning the Palestinian refugees], 'You will win the city for the Lord." This was the sword of the Lord she ran with.
today she is a Apostle/Director at Living Bread International Church Jerusalem
Past: Living Bread International Church and I Work for the Lord, Atlanta, Ga.
Jamiel Shaw II 17 Executed by an illegal #12-2015: H.R. 1041; Karen Bass NoShow;
In 2008, Jamiel Shaw the 2nd (17 yrs. young), was assassinated three doors from his home; by an illegal alien gangbanger from Mexico. The killer was negligently released from jail (prior gun charges), on March 1, 2008 and assassinated Jamiel the very next day on March 2, 2008. Jamiel's Mother was serving in Iraq at the time. She's still Serving in the Army. The illegal alien killer was sentenced to death row in November, 2012.
On Tonight's broadcast, Jamiel Shaw Sr., will talk about the Execution of his Son & the Deportation of illegal alien gangs http://www.isupportjamielslaw.com/ - tinyurl.com/ld4f26f; H.R. 1041- The Jamiel Shaw, II Memorial Act of 2015 - 2016 http://fb.me/77u1PrZem; Rep. Karen Bass No-Show at her own illegal immigration Townhall; Robin Hvidston https://wethepeoplerising.wordpress.com/, attended Karen Bass & Luis Gutierrez' illegal immigration townhall https://youtu.be/gGpVnzOAq9w; LAPD; The Bad & The Ugly Side of Illegal immigration http://tinyurl.com/okdkgch; Plus Much More! If you can, tune in.
Colour U Cosmetics CEO Karen Stallings, Karrueche Tran, Raven Symone vs. The Bey
Tune in the to the "Ice Cream Convos Morning Show" as we welcome Colour U Cosmetics CEO Karen Stallings to talk about her upcoming event in Atlanta.
We'll also give you the scoop on Karrueche Tran's sit down with Iyanla Vanzant and Raven Symone claps back at the Beyhive!
ABOUT ONENESS with Karen Neumann and guest Fernando Vossa
in Spirituality
ABOUT ONENESS RADIO with guest: Fernando Vossa
Sunday 22 February, 2pm est, 11am pst, 7pm gmt
Fernando Vossa one of the Voices of the Breakthrough Energy Movement
Specialist in Energy Research, Healing Technology and Cosmic Awareness.
learn more: youtube.com/vossamedia - facebook.com/fernando.vossa
The Global Breakthrough Energy Movement (GlobalBEM) is a non-profit volunteer-powered organization dedicated to educating & activating the public about breakthrough energy technologies which are clean, sustainable and world changing.
ABOUT ONENESS, hosted by Karen Neumann is a weekly radio program focused on celebrating the ongoing conscious awakening of our planet and our realization of Oneness.
Call in to speak with Fernando (347) 308-8788. Call in early the lines are sure to fill up. Once the show begins you can call in by pushing the Skype button on the Blog Talk Radio show page. You can also live tweet me (via twitter) during the show with questions and comments @karenneumann
Karen Kimsey House: 2012 Interview on the Voice of Leadership
in Culture
Replaying a timeless interview with one of the earliest recognized luminaries in the coaching profession. Kimsey-House founded CTI in 1992 with Laura Whitworth and Henry Kimsey-House.
Together, they created the Co-Active philosophy of relationship that informs CTI's world-renowned coaching and leadership programs.
Committed to pioneering Co-Activity in challenged environments and troubled populations, Kimsey-House continues to lead CTI workshops and is a dynamic keynote speaker around the world.
Karen is an honored guest speaking about coaching, leadership and her a mission of global, transformative change.
Karen Dahlman "Oujia-ologist" Spirits of Ouija" "Four Decades of Communication"
in Spirituality
Karen Dalhman Author and Oujia-ologist
Karen believes that self-empowerment is the key to living a richly rewarding and authentic life. All of her education, life & career experiences and the companies she developed and owned, center around the theme of living a bountiful life through creatively pushing boundaries and expressing inner potentials.
The Spirits of Ouija: Four Decades of Communication,is a "Tell All" book, exploring Karen's personal forty years worth of Spirit Communications via the Ouija Board. She shares the how to's, the don'ts, the warnings and the recommendations so you too can have meaningful and deeply relevant Ouija experiences.
Read about all of the various type of entities with whom Karen has been in contact over the years. Learn how to tap into your Higher Self for divine guidance and learn to listen to this guiding principle that resides within.
Get ready for a phenomenal exploration into consciousness.
You will meet a whole new world awaiting your contact!
From Karen's background and practice as an licensed and board certified art psychotherapist and hypnotherapist, she invites you to tap into and unleash your own unique forms of creativity in one book and in the other book, evolve beyond the stereotypical societal beliefs about what happens when we are dead and learn to communicate with the deceased and discarnate spirits.
She is going to be in our area at an upcoming Convention called "Ouijacon" on April 23rd -25th in Baltimore Maryland.
To learn more or contact Karen please go to her webite below...
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ELIZABETH – School district leaders are encouraging citizens from throughout the community to attend a meeting on the 2010-2011 budget tonight at 7 p.m. at Dwyer Academy, 600 Pearl Street.
Middlesex County to Undertake Massive Road Resurfacing Project
by staff report • • 0 Comments
MIDDLESEX COUNTY – Middlesex County became one of the first counties in the state to put Federal Stimulus Funds to work when the Board of Chosen Freeholders voted to approve a contract to mill and resurface 17 of the busiest county roads.
Perth Amboy & Spotswood Voters To Elect Council Members
by staff report • • 0 Comments
MIDDLSEX COUNTY – Voters in Perth Amboy and Spotswood will choose municipal council members in today's non-partisan election.
School District Leases Former Catholic School Buildings
by staff report • • 0 Comments
ELIZABETH – Early childhood education expands throughout Elizabeth with the use of three former Catholic School buildings acquired through a lease agreement with the Archdiocese of Newark.
Lawmakers Consider Bill To Make More NJ Residents Eligible For COBRA Benefits
by staff report • • 0 Comments
TRENTON – The Senate Commerce Committee unanimously approved legislation sponsored by Senator Joseph Vitale and Senate Majority Leader Barbara Buono, both D-Middlesex, that would offer extended health benefits to residents left jobless as a result of their place of employment closing.
Bill Giving Consumers On-The-Spot Store Rebates Advancing Toward Law
by staff report • • 0 Comments
TRENTON – Legislation to require retailers to charge consumers an advertised after-rebate price – rather than making buyers send in coupons or log on to manufacturer's Web sites to claim their savings – has been released the Assembly Consumer Affairs Committee.
Christie Proposes 2.5 Percent Property Tax Hike Cap
by staff report • • 0 Comments
TRENTON – Governor Chris Christie presented a 33-bill package of reforms aimed at solving New Jersey's property tax crisis. The bill package will put a hard cap on property tax increases and state spending at 2.5 percent, while giving municipalities, school districts, higher education institutions and county governments tools to control their costs and live within the cap.
Task Force Investigating Elizabeth Homicide
by staff report • • 0 Comments
ELIZABETH — Members of the Union County Homicide Task Force are investigating the shooting death of a 43-year-old man who was discovered in Elizabeth early Sunday morning.
Hix Sentenced To 15 Years For Elizabeth Killing
by staff report • • 0 Comments
ELIZABETH — Wayne Bilal Hix, who was convicted for the April 1, 2008 stabbing death of a 51-year-old Elizabeth man, was sentenced to 15 years in prison, Union County Prosecutor Theodore J. Romankow announced today.
Democrats Call For Millionaire's Tax
by staff report • • 0 Comments
TRENTON – Top New Jersey Democrats on Monday unveiled a plan to restore an income tax surcharge on the 16,000 New Jerseyans with taxable incomes of at least $1 million.


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Free Beer & Hot Wings – "Fight Church" Movie Trailer
Check out the trailer for the upcoming movie "Fight Church."
Check out the trailer for the upcoming movie "Fight Church."
We've been closely following the news coming out about 'All Is By My Side,' the upcoming biopic about Jimi Hendrix, from the beginning of its filming to drummer Kenny Aronoff's work on the soundtrack to the lack of support given it by Hendrix's estate.
Will Ferrell takes on 1970s ABA basketball in this week's [Celluloid Hero].
Henry Hill, mobster/FBI informant died today at the age of 69 due to complications from years of smoking. The movie "Goodfellas" was based on the life of Henry Hill (played by actor Ray Liotta)
To read the complete story of Henry Hill, Click here.
Our very own Alice Cooper got caught by Connor, Murphy & Rocco!
We have more passes coming up this week for the "Brew HaHa Craft Beer Festival" at Six Flags Great Adventure on June 30th, 2012 all week long .
So with all this talk of beer, it has me thinking of the classic movie "Strange Brew" with Rick Mo
Celluloid Hero goes foreign and retro this week with "Forbidden Games", a French film from 1952.
Celluloid Hero unleashes the beast within with "We Bought A Zoo", starring Matt Damon and Scarlett Johannson.
This week's Celluloid Hero puts the pedal to the metal with "Drive", starring Ryan Gosling.
Time to play ball in this week's "Celluloid Hero".


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You won't be able to dismiss this by usual means (escape or click button), but you can close it programatically based on user choices or actions.
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Read St. Vincent's Review of Arcade Fire's Reflektor
By Lindsay Zoladz on November 7, 2013 at 11:55 a.m. EST
Photo by Tina Tyrell
Annie Clark (aka St. Vincent) has written a review of Arcade Fire's Reflektor for The Talkhouse, a website that lets musicians write about new albums. (You may remember Lou Reed's rave review of Yeezus, and—shoutout to Hans—Ezra Koenig's hilarious take on Drake's Nothing Was the Same.)
Download David Byrne and St. Vincent's Free Brass Tactics EP
By Jenn Pelly on May 28, 2013 at 10:57 a.m. EDT
Today, David Byrne and St. Vincent are giving away a free companion EP to their collaborative 2012 record, Love This Giant. The Brass Tactics EP collects a previously unreleased Giant bonus track, two remixes, and two live tracks. (The live tracks are versions of St. Vincent's "Marrow" and the Talking Heads' "Road to Nowhere".) Download it for free via the widget below. The pair will tour across North America together again beginning June 12, before heading to Europe in August.
David Byrne and St. Vincent Announce Tour
By Jenn Pelly on February 25, 2013 at 3:20 p.m. EST
Photo by Andreas Laszlo Konrath
In support of last year's collaborative album, Love This Giant, David Byrne and St. Vincent have announced a joint summer tour of North America. They'll play Bonnaroo along the way (and perhaps they'll cover each other's songs again).
Watch an Animated St. Vincent Sing About Being a Bad Girl for Cartoon Sitcom "Bob's Burgers"
By Jenn Pelly on February 12, 2013 at 4:24 p.m. EST
For the uninitiated, "Bob's Burgers" is an animated Fox sitcom that is now in its third season. It's centered on a family, the Belchers, who run a hamburger joint.
Watch David Byrne and St. Vincent on "Letterman"
By Evan Minsker on January 29, 2013 at 5:10 a.m. EST
David Byrne and St. Vincent, fresh off an Australian tour for Love This Giant, made an appearance on the "Late Show with David Letterman" last night. They performed "I Should Watch TV". (In a newsletter, Byrne wrote, "The meaning and significance of doing that song on TV is making my head go funny.")
Watch: St. Vincent and Sleigh Bells' Alexis Krauss Sing "Girls Just Want to Have Fun" With Cyndi Lauper and Rosie O'Donnell
By Evan Minsker on December 9, 2012 at 5:10 p.m. EST
Last year, Cyndi Lauper performed her iconic song "Girls Just Want to Have Fun" with Arcade Fire in New Orleans. And last night, during a benefit concert for her True Colors Fund to help homeless LGBT youth, she performed the song with Sleigh Bells' Alexis Krauss and St. Vincent's Annie Clark. On drums? Rosie O'Donnell. Watch the performance below.
Watch David Byrne and St. Vincent on "Colbert"
By Amy Phillips and Carrie Battan on November 2, 2012 at 7:54 a.m. EDT
David Byrne and St. Vincent, who recently released their joint album Love This Giant, made a an appearance on "The Colbert Report" together last night.
Grizzly Bear, St. Vincent, TV on the Radio, Zola Jesus, Matt & Kim Want You to Register to Vote
By Evan Minsker on September 24, 2012 at 1:10 p.m. EDT
Photo of Grizzly Bear by Jaclyn Fidler
Tomorrow, September 25, is National Voter Registration Day. Non-partisan group HeadCount's huge voter registration push involves a social media campaign-- anchored by the hashtag #925NVRD-- in which over 200 musicians, comedians, and celebrities are sharing photographs of themselves holding the organization's "Register to Vote" clipboard. HeadCount is also holding registration events in person in over 30 cities across the country.
Watch: David Byrne and St. Vincent Perform Each Other's Songs
By Evan Minsker on September 16, 2012 at 10:07 p.m. EDT
Last night, David Byrne and St. Vincent kicked off their tour behind Love This Giant. As Consequence of Sound reports, it looks like the tour will feature the duo covering each other's songs, including a few Talking Heads classics. Check out footage below of the duo tackling "Burning Down the House", "Cruel", and "Northern Lights" in Minneapolis.
Watch David Byrne and St. Vincent on "Fallon"
By Evan Minsker on September 11, 2012 at 5:46 a.m. EDTMore
Last night, David Byrne and St. Vincent stopped by "Late Night With Jimmy Fallon" to perform their Love This Giant tracks "Who" and "The Forest Awakes".
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Welcome to the new Home of Savannah Wedding DJRay.net on the web. Professional DJ for weddings, class reunions, announcer, entertainer, Program and Music Director, 30+ years in Savannah, GA. Still having fun hosting pool parties, anniversaries, birthdays, HOA community and business events, 'just for the heck of it to have a party' parties but my forte is WEDDINGS.
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"Hey America, isn't this an old-fashioned shot to the nutsack?" Now titled "Anchorman: The Legend Continues," as promised, a teaser-trailer for the "Anchorman 2" sequel has arrived a few days after the teaser-poster landed (teases!), and after a weekend when it played in front of "The Dictator.". St...Read More »
Ladies and gentlemen, can we please have your attention. We've just been handed an urgent and horrifying news story. We need all of you to stop what you're doing and listen.Read More »
Will Ferrell and Adam McKay have long recognized just how funny Rob Riggle is, casting him in their projects like "The Goods: Live Hard, Sell Hard," "Talladega Nights: The Ballad Of Ricky Bobby," "Step Brothers" and "The Other Guys." Now, they are rallying beh...Read More »
Jay Roach's political comedy "The Campaign" seeks your vote at the box office August 10. With a cast that includes Will Ferrell, Zach Galifianakis and Jason Sudeikis, the trailer should be funnier. So far it looks like the writers rely on familiar star power rather than pushing the envelope.Read More »
It would take a lot more than a Will Ferrell impression to make me want George W. Bush to return for real, but Ferrell's always hilarious fake-Bush was the highlight of last night's SNL. In the cold open, President Obama (Fred Armisen, as usual) entered the bedroom of the Vice Presi...Read More »
Will Ferrell's comedy is both incomparably goofy and totally droll about it, and both sides of his humor kicked in during his guest spot on Late Night with Jimmy Fallon. He was promoting his hosting spot on this week's SNL, but also brought along the trailer for his new political co...Read More »
In some ways, it looks like Will Ferrell and Zach Galifianakis are doing some recycling for "The Campaign." The former has essentially tweaked his George W. Bush while the latter has done the same with his alter ego "brother" Seth and the result is...well, not exactly as hilariou...Read More »
While we'll have to wait until November to see the result of the battle between Mitt Romney and Barack Obama, before then, another gritty campaign will be fought at the multiplex in the "The Campaign."Read More »
Easter is over, spring is here, and in case you haven't noticed, things are going to be getting supersized at the box office over the next the few months. Warner Bros. is getting ready for a busy season and have unveiled a handful of new images from some of their upcoming films.Read More »
While most of the film community's attention is turned towards the recent news that Will Ferrell and Adam McKay are assembling the News Channel 4 team all over again for an "Anchorman" sequel, on a quieter front it comes as no surprise that both have several films in various stages...Read More »


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The TS35 coach is a fully integral mid-sized coach that offers a luxurious and spacious interior for passengers and driver. It is constructed from stainless steel for extra durability and safety and has independent front suspension and automatic transmission, contributing to a smooth, comfortable ride, according to the company.
Temsa TS35 coaches are equipped with a Cummins ISL 345 engine, Allison B500 transmission and three-point seat belts. The Capitol Bus Lines Inc. coach is equipped with REI audio/video, Alcoa rims, driver shades, leatherette seats and a wheelchair lift.
The groups urged planners to add parking near the National Mall for the millions of people who will visit by bus and car over the next several months, kicking off with the National Cherry Blossom Festival.
In their meetings, UMA members shared information about their own businesses and rallied for backing of three critical needs: opposition of FMCSA's proposal to raise the Federal financial responsibility limits, support of Rep. Barletta's proposal to remove CSA scores from public view until the data used to calculate the score can be improved, and support to preserve the current charter service rule.
David Cooper of Pacific Coachways Trailways in Garden Grove, Calif., was presented by Bob Crescenzo, VP, safety & loss control, at Lancer Insurance, the awards event sponsor.
State police said the driver did not speak or understand English and did not know he was supposed to stop in Richmond, Va. The driver was reportedly dragged out of his chair, while the bus was swerving in and out of lanes for a half mile or so.
Suzanne Te Beau Rohde will succeed ABA's sr. VP, Government Affairs and Policy, Clyde Hart, who is retiring after 14 years.
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Watch the official new trailer for Kubrick's masterpiece.
Philosophically ambitious, technically innovative and visually stunning, Stanley Kubrick's sci-fi epic is frequently cited in polls as one of the finest films ever made.
Co-written by the director and novelist Arthur C Clarke, the film charts the progress of 'civilisation' through the influence of mysterious black monoliths on prehistoric apes developing their skills and, later, on astronauts involved in a secret mission to Jupiter. Characteristic of Kubrick's interest in evolution and artificial intelligence (most notably in the astronauts' battle of wits with troublesome computer HAL 9000), the film also displays his desire for technical perfection: Geoffrey Unsworth's camerawork, Douglas Trumbull's pioneering effects and the production design remain enormously impressive to this day. But what's perhaps most striking is the audacity of the measured, largely dialogue-free storytelling, with Kubrick allowing the judiciously chosen music (Ligeti, Khachaturian, the two Strausses) and the crisp, balletic beauty of the images to work their spell. A cinematic milestone, and a huge influence on the development of the sci-fi genre.
Geoff Andrew
"A work of mad, transcendent genius" ★★★★★
Kate Muir, The Times (Classic Film of the Week)
"This chance to see 2001 on the big screen shouldn't be missed" ★★★★★
Peter Bradshaw, The Guardian | Read full review
"Remains as intelligent and provocative as ever" ★★★★★
Joshua Rothkopf, Time Out London | Read full review
"Its imagery, its ambition, and its innovative use of classical music, remain as spellbinding as ever" ★★★★★
Brian Viner, The Daily Mail
"Its illusive majesty continuing to inspire awe… top marks for craftsmanship is an understatement" ★★★★★
David Jenkins, Little White Lies | Read full review
9 March
Taliesin Arts Centre, Swansea
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29 March
Ritz Cinema, Belper
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Cameo Edinburgh
12 April
Arts Cambridge
Neuadd Dwyfor Pwllheli Gwynedd
15 April
The Malthouse Wirksworth Derby
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Liverpool Philharmonic
Sci-Fi: Days of Fear and Wonder
A major celebration of film and TV's original blockbuster genre, from October to December 2014. Together with 02.


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Our plastic utility scoops are available in various sizes and shapes--we even offer a food service shovel. If you need to measure large quantities, a 64 oz. scoop is great. Also, check out our Rubbermaid portioning scoops for a unique style designed to serve multiple purposes. Use them to measure portions with measurement markings on the side or take advantage of the flat edge for easy scooping.
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Capuchino High School Alumni
Pam Herriott
Class of 1965
Denise Davey
Class of 1978
Kimberly Lipke
Class of 1982
Melinda Gibson-Amistoso
Class of 1975
The alumni of CHS in San Bruno, California are encouraged to use this site to relive their time in high school by sharing with former students and teachers of Capuchino High School. You can share memories of those activities that you were involved with at Capuchino HS and you can view other alumni and read what other former students have posted about the time they spent at Capuchino. Capuchino High School alumni can relive their experiences from high school by sharing memories and pictures, reconnecting with those alumni listed, searching for former students and more.