Heart failure patients with clogged arteries have a better chance of surviving 10 years if they get bypass surgery plus medicine rather than just drugs alone, according to an international study. Earlier results from the same research raised questions about the benefits of bypass versus medicine alone, but researchers say the long-term evidence clearly favors the surgery. The lead author of the study, Duke University cardiologist Dr. Eric Velazquez, said the results "are so definitive and so robust" that they would likely to lead to stronger recommendations favoring bypass surgery for these patients. Nearly 6 million Americans and 23 million people worldwide have heart failure, and many of them also have artery disease similar to those studied. In recent years, bypass surgery has increasingly been recommended for such patients, along with medicines to ease heart failure symptoms. Concerns were raised when results after nearly five years of research showed about equal number of deaths in bypass patients and in those who got only medicine, despite fewer heart-related deaths in the bypass group. Those findings were published in 2011. The 10-year results were published online Sunday in the New England Journal of Medicine and presented at an American College of Cardiology meeting in Chicago. The study involved 1,200 heart failure patients in 22 countries, including the United States. Most were men around age 60 when the study began. All were taking heart medicines, and about half were assigned to also get bypass surgery. More than half the patients in each group lived beyond the study's first phase. The 10-year results are a look back at all patients studied. A total of 359 bypass patients died from any cause, or about 59 percent, compared with 398 medicine-only patients who died, or 66 percent. Deaths from heart disease-related causes totaled 247 in the bypass group, or 41 percent, versus 297 medicine-only patients, or 49 percent. A journal editorial published with the study says the latest results "solidly support" strengthening treatment guidelines to say that bypass surgery is "probably beneficial" for these patients. The long-term results "are very encouraging" and confirm what many doctors believed about potential benefits of bypass for these patients, said Dr. Ted Feldman, a cardiologist at NorthShore University HealthSystem in Evanston, Illinois. Feldman was not involved in the study. The National Heart, Lung and Blood Institute paid for the study.
Combining the investigative tools of genetics, transcriptomics, epigenetics and metabolomics, a Duke Medicine research team has identified a new molecular pathway involved in heart attacks and death from heart disease. The researchers, publishing online in the journal PLOS Genetics, found that stress on a component of cells called the endoplasmic reticulum (ER) is associated with risk of future heart events, and it can be detected in bits of molecular detritus circulating in the blood. “ER stress has long been linked to Type 1 diabetes and Parkinson’s disease, among others, but this is the first indication that it is also playing a role in common heart attacks and death from heart disease,” said senior author Svati H. Shah, M.D., associate professor of medicine and faculty at the Molecular Physiology Institute at Duke. “It’s also exciting that we are able to measure this ER stress in a small drop of blood, providing a potential way to intercede and lower the risk of a major cardiovascular event.” Even after mapping the human genome and finding genetic traits associated with cardiovascular disease, the mechanisms underlying the inherited susceptibility to this disease have not been fully understood. Shah said the Duke team’s research approach -- using a variety of analytical methods measuring over a million data points in 3,700 patients -- enabled them to fill in some of the missing steps leading to cardiovascular disease, which is often inherited. “With genetics, everyone is lumped together if they share a trait,” Shah said. “But everyone knows if you have two people with the same trait, but one is overweight, smokes and has a bad lifestyle, that person has a different pathway that led to heart disease than someone who is normal weight, doesn’t smoke, eats right and exercises.” The Duke team focused on the intermediates between the genes and the disease pathway. This involved metabolomics -- an analysis of the metabolites, or trace chemicals, left behind as the byproducts from cellular processes. Among a group of 3,700 patients referred for cardiac catheterization in the CATHGEN study, Shah and colleagues performed a genome-wide analysis of specific metabolite levels that had previously been identified as predictors of cardiovascular disease. In their earlier work, the researchers had flagged these metabolites as markers for cardiovascular disease, but had not known how they were generated or what the underlying biological pathways were. The current study resolved that question, finding that these genes were directly linked to ER stress, which occurs when the endoplasmic reticulum organelle becomes overworked in its job managing excess and damaged cellular proteins. Shah and colleagues then took an epigenetics and transcriptomics approach to determine what the differences were between patients with high or low levels of metabolites. Once again, the ER stress pathway came up as a key component. “Using this multi-platform ‘omics’ approach, we identified these novel genetic variants associated with metabolite levels and with cardiovascular disease itself,” Shah said. “We don’t believe that the metabolites themselves are causing heart attacks -- they might just be byproducts of a dysregulated process that people are genetically susceptible to -- but that’s something we need to study further.” In addition to Shah, study authors include William E. Kraus; Deborah M. Muoio; Robert Stevens; Damian Craig; James R. Bain; Elizabeth Grass; Carol Haynes; Lydia Kwee; Xuejun Qin; Dorothy H. Slentz; Deidre Krupp; Michael Muehlbauer; Elizabeth R. Hauser; Simon G. Gregory; and Christopher B. Newgard. The study received funding from the National Heart, Lung and Blood Institute.
Jones R.J.,University of Houston |
Gu D.,University of Houston |
Bjorklund C.C.,University of Houston |
Kuiatse I.,University of Houston |
And 5 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013
JNJ-26854165 (serdemetan) has previously been reported to inhibit the function of the E3 ligase human double minute 2, and we initially sought to characterize its activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). Serdemetan induced a dose-dependent inhibition of proliferation in both wildtype (wt) and mutant (mut) p53 cell lines, with IC50 values from 0.25 to 3 mM/l, in association with an S phase cell cycle arrest. Caspase-3 activation was primarily seen in wtp53-bearing cells but also occurred in mutp53-bearing cells, albeit to a lesser extent. 293T cells treated with JNJ-26854165 and serdemetanresistant fibroblasts displayed accumulation of cholesterol within endosomes, a phenotype reminiscent of that seen in the ATPbinding cassette subfamily A member-1 (ABCA1) cholesterol transport disorder, Tangiers disease. MM and MCL cells had decreased cholesterol efflux and electron microscopy demonstrated the accumulation of lipid whorls, confirming the lysosomal storage disease phenotype. JNJ-26854165 induced induction of cholesterol regulatory genes, sterol regulatory element-binding transcription factor-1 and -2, liver X receptors a and b, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ-26854165 induced enhanced ABCA1 turnover despite enhancing transcription. Finally, ABCA1 depletion resulted in enhanced sensitivity to JNJ-26854165. Overall, these findings support the hypothesis that serdemetan functions in part by inhibiting cholesterol transport and that this pathway is a potential new target for the treatment of MCL and MM. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Navarro A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS |
Clot G.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS |
Prieto M.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS |
Royo C.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS |
And 12 more authors.
Clinical Cancer Research | Year: 2013
Purpose: microRNAs (miRNA) are posttranscriptional gene regulators that may be useful as diagnostic and/or prognostic biomarkers. We aim to study the expression profiles of a high number of miRNAs and their relationship with clinicopathologic and biologic relevant features in leukemic mantle cell lymphomas (MCL). Experimental Design: Expression profiling of 664 miRNAs was investigated using a high-throughput quantitative real-time PCR platform in 30 leukemic MCLs. Statistical and bioinformatic analyses were conducted to define miRNAs associated with different clinicopathologic parameters. Gene expression profiling was investigated by microarrays in 16 matching cases to study the potential genes and pathways targeted by selected miRNAs. The prognostic value of miR-34a was investigated in 2 independent series of 29 leukemic and 50 nodal MCLs. Results: Robust consensus clustering defined 2 main MCL subgroups with significant differences in the immunoglobulin (IGHV) mutational status, SOX11 expression, genomic complexity, and nodal clinical presentation. Supervised analyses of IGHV and SOX11 categories identified 17 and 22 miRNAs differentially expressed, respectively. Enriched targets of these miRNAs corresponded to relevant pathways in MCL pathogenesis such as DNA stress response, CD40 signaling, and chromatin modification. In addition, we found 7 miRNAs showing prognostic significance independently of IGHV status and SOX11 expression. Among them, miR-34a was also associated with poor prognosis in 2 independent series of leukemic and nodal MCL, and in cooperation with high expression of the MYC oncogene. Conclusion: We have identified miRNAs and target pathways related to clinical and biologic variants of leukemic MCL, and validated miR-34a as a prognostic marker in MCL. © 2013 American Association for Cancer Research.
A new catalog of human genes reveals that people have many different ways to build proteins. This listing of options can help doctors sort through mutations to learn which ones cause genetic diseases — and which ones don’t. An international group of researchers banded together to compile the catalog, an inventory of the exome — the small portion of the human genome that produces proteins — of 60,706 adults from different populations around the world. Researchers in the Exome Aggregation Consortium, known as ExAC, report the findings online October 30 at bioRxiv.org. “This is one of the most useful resources ever created for medical testing for genetic disorders,” says Heidi Rehm, a clinical lab director at Harvard Medical School who is not a member of the consortium. A journal reviewing the work for publication prohibits the ExAC researchers from speaking with journalists about the manuscript posted on bioRxiv.org, one researcher involved in the project told Science News. The work has yet to be peer-reviewed and researchers are not allowed to “publicize” their findings before they have been vetted by their peers. Other researchers have already viewed the manuscript on bioRxiv.org and pointed out a few minor flaws, including broken links and formatting errors. No one has yet criticized the data or analysis. “This work is both technically very impressive … and will be a fantastic mine of information to explore over the next years, and also hugely useful in clinical genetics settings,” says Gilean McVean, a statistical geneticist at the University of Oxford. Looking at just the protein-coding parts of the genome is a good start, he adds, “but we will need the full spectrum of the whole genome to ultimately make sense of what causes disease.” Among the people who donated DNA to the project, the ExAC researchers found more than 7.4 million genetic variants, letters in the DNA instructions for building proteins that differ from one person to another. On average, people had one genetic variant for every eight base pairs, the information-carrying chemicals that make up DNA. Those variants aren’t spread evenly among genes, though. The researchers found that 3,230 genes are almost devoid of any harmful variants. That finding provides “an exquisitely detailed view into what genetic perturbations are ‘biologically permissible,’” McVean says. Genes that don’t have mutations are likely to be ones important for human development and survival, says Rehm. Such genes, when mutated, may cause severe genetic disease or stop an embryo from developing so no living person would carry mutations in those genes. For other genes, “lightning does strike several times in the same spot,” says Tuuli Lappalainen, a geneticist at the New York Genome Center and Columbia University. About 43 percent of new mutations in a child that are not also present in the parents turned out to be copycats of variants carried by other people in the ExAC database. That means that doctors who just look for new mutations to explain a child’s genetic disease could mistake these types of mutations for disease-causing ones even though they are harmless. The Exome Aggregation Consortium (ExAC) has compiled genetic information from 60,706 individuals, nearly 10 times as many people and from more diverse backgrounds than previous efforts. The Exome Sequencing Project (ESP) of the National Heart, Lung and Blood Institute contains data on the protein-producing parts of the genome of 6,503 people. The 1000 Genomes project cataloged the entire genomes of 2,504 people. The exome project may help medical geneticists avoid making similar mistakes due to not knowing how rare variants are. The data have revealed that some variants are not as uncommon as researchers previously believed. For instance, some variants rarely show up in some populations, but are relatively common in people from another part of the world. Finns are a good example: Finland had a small founding population so some mutations are found in Finns more frequently than in other Europeans. In addition, an average participant in the exome project harbors about 53 variants that have previously been classified as disease-causing. But, on average, 41 of those mutations are found relatively frequently in at least one population, where they do not cause disease, the data show. The ExAC team discovered an example of such false accusation when it investigated 192 variants that had previously been implicated in disease. These variants were rarely found in people in the limited datasets researchers could access before. But the ExAC data show that many of those variants are found in more than 1 percent of healthy South Asian or Latino people, indicating that they are probably not the culprits. The misleading mutations include a variant thought to cause a liver disease known as North American Indian Childhood Cirrhosis when children inherit two copies of the variant. That variant was found in 226 Latin Americans, including four people who had two copies of the gene but didn’t have the liver disease. That result suggests that the variant isn’t the source of the liver disease. Researchers outside the ExAC team have had access to the data for more than a year, but those scientists have agreed not to publish large-scale findings until after the ExAC team reports their methods and analysis in a scientific journal. Lappalainen says she expects ExAC’s official debut to be accompanied by multiple companion papers, followed by researchers using the data in other types of studies. Those studies may guide doctors toward better diagnosis of genetic diseases and suggest treatments. Already, thousands of patients may need to have their cases reevaluated in light of the new data, Rehm says. Editor's Note: This story was updated November 20, 2015, to correct the description of participants in the study. People with diseases were included, so not all were healthy.