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News Article | February 21, 2017
Site: www.eurekalert.org

LOS ANGELES - (Feb. 21, 2017) - A new study suggests testosterone treatments may increase the risk of heart disease in older men. It found a 20% increase in arterial plaque among men aged 65 and older who received testosterone replacement therapy for a year, according to the study published today in the Journal of the American Medical Association (JAMA). The multicenter study followed 138 men enrolled in the Testosterone Trials (TTrials), a National Institutes of Health (NIH) funded clinical research trial to determine if testosterone treatment of men aged 65 and older will help their walking, vitality, sexual function, memory, blood count and cardiovascular risk. The researchers reported that the men who received a placebo had just a 1% rise in plaque volumes, while the men who received the testosterone treatments for a year had a 20% increase in total coronary and noncalcified plaque volumes as measured with coronary computed tomographic arteriography (CCTA). "Heart disease remains the No. 1 cause of death in the U. S., and measuring coronary artery atherosclerosis has become a most effective method for evaluating cardiovascular risk," said Matthew J. Budoff, MD, a cardiologist who is an LA BioMed lead researcher and the primary author of the study. "While physicians are increasingly prescribing testosterone replacement for their older male patients, recent studies had reached conflicting conclusions about the potential cardiovascular risks. This finding of a significant increase in plaque volumes among men undergoing testosterone treatments indicates they may face a potentially increased risk of heart disease. However, longer-term research is needed to determine the actual risk." Dr. Budoff was the principal investigator for the study, and Drs. Ronald Swerdloff and Christina Wang, endocrinologists who are also LA BioMed lead researchers, were also investigators and authors of the study. It is one of four studies published today from the TTrials, a coordinated group of seven trials conducted by a team of researchers from LA BioMed and 12 other medical centers in the U.S., in partnership with the National Institute on Aging. "While our previous research has found some benefits from testosterone treatments, this latest study should provide important guidance for physicians and their patients," said Dr. Budoff. "Men who have underlying coronary artery disease or studies showing elevated arterial plaque levels should discuss carefully with their physicians the benefits and risks of testosterone therapy before initiating it or continuing the therapy." These results indicate the need for a larger and longer trial to determine actual risk of testosterone replacement. The study is one of four studies examining testosterone therapy that were published today in JAMA and JAMA Internal Medicine. In addition to the LA BioMed researchers, the authors of this study are: Susan S. Ellenberg, PhD; Cora E Lewis, MD, MSPH; Emile R Mohler III, MD; Nanette K Wenger, MD, MACC, MACP, FAHA; Shalender Bhasin, MD; Elizabeth Barrett-Connor, MD; Alisa Stephens-Shields, PhD; Jane A Cauley, DrPH; Jill P Crandall, MD; Glenn R Cunningham, MD; Kristine E Ensrud, MD, MPH; Thomas M. Gill, MD; Alvin M Matsumoto, MD; Mark E Molitch, MD; Rine Nakanishi, MD; Negin Nezarat, MD; Suguru Matsumoto, MD; Xiaoling Hou, MS; Shehzad Basaria, MD; Susan J. Diem, MD, MPH; Denise Cifelli, MS, and Peter J. Snyder, MD. Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and therapies for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit http://www.


News Article | February 21, 2017
Site: www.eurekalert.org

LOS ANGELES -- Research published today found testosterone treatment improved bone density and anemia for men over 65 with low testosterone. But the treatment didn't improve patients' cognitive function, and it increased the amount of plaque buildup in participants' coronary arteries, according to four studies published in the Journal of the American Medical Association (JAMA) and JAMA Internal Medicine. A team of researchers from LA BioMed and 12 other medical centers in the U.S., in partnership with the National Institute on Aging, conducted The Testosterone Trials (TTrials), a coordinated group of seven trials, which studied the effects of testosterone treatment for one year as compared to placebo for men 65 and older with low testosterone. Four of those studies were published today. "While we have long known that testosterone levels decrease as men age, very little was known about the effects of testosterone treatment in older men with low testosterone until last year," said Ronald S. Swerdloff, MD, an LA BioMed researcher and co-author of the four studies. "Our first published research last year found benefits to testosterone treatment, and this latest series of studies finds further benefits in terms of improving bone density and anemia. However, the cardiovascular study showed that the testosterone treatment group had increased plaque buildup in coronary arteries, suggesting a possible risk factor." In the cardiovascular trial, researchers assessed coronary artery plaque buildup by CT angiography. That assessment showed more plaque buildup in men treated with testosterone than in men treated with placebo. Nonetheless, in all 788 men in the TTrials, the number of major adverse cardiovascular events was similar in the men treated with testosterone as in the men treated with placebo. "We want to emphasize that this study was exploratory and emphasizes the need for a large-scale, well-controlled, long-term safety trial to determine if there is an increased risk of heart damage or death," Dr. Swerdloff said. "As with all medications the physician and patient need to balance the benefits and risks of treatment." Dr. Christina Wang, an LA BioMed researcher and co-author of the four studies, noted that the researchers also found that testosterone treatment improved bone density and estimated bone strength, as determined by CT. "After one year of treatment, older men with low testosterone significantly increased bone density and estimated bone strength compared to those on placebo," said Dr. Wang. "A larger and longer trial would be needed to determine if testosterone treatment reduces fracture risk." Testosterone treatment also increased hemoglobin concentrations, corrected the anemia of men who had no other identifiable cause of anemia and corrected the anemia of men who had an identifiable cause, such as iron deficiency. While these conclusions proved testosterone to be beneficial to the participants, testosterone treatment did not improve memory or any other measure of cognitive function. "As a result of these findings, physicians may wish to consider measuring testosterone in men age 65 and older who have unexplained anemia and symptoms suggestive of low testosterone levels," said Dr. Swerdloff. The TTrials are now the largest trials to examine the efficacy of testosterone treatment in men 65 and older whose testosterone levels are low due seemingly to age alone. TTrials researchers screened 51,085 men to find 790 who qualified with a sufficiently low testosterone level and who met other criteria. The men enrolled were randomized into two groups: one to take a daily testosterone gel and the other a daily placebo gel, for one year. Efficacy was then evaluated at months three, six, nine and 12. "Final decisions about testosterone treatment for older men will depend on balancing the results from these seven TTrials with the results from a much larger and longer term trial designed to assess cardiovascular and prostate risk in the future," said principal investigator Peter J. Snyder, MD, University of Pennsylvania Perelman School of Medicine professor of medicine in the Division of Endocrinology, Diabetes and Metabolism. In addition to LA BioMed and University of Pennsylvania, the TTrials were conducted at Albert Einstein College of Medicine, Baylor College of Medicine, Brigham and Women's Hospital, University of Alabama at Birmingham, Northwestern University Feinberg School of Medicine, Puget Sound Health Care System, University of California at San Diego School of Medicine, University of Florida School of Medicine, University of Minnesota School of Medicine, University of Pittsburgh School of Public Health and Yale School of Medicine. The Testosterone Trials were supported by a grant from the National Institute on Aging (NIA), National Institutes of Health (U01 AG030644). The TTrials were also supplemented by funds from the National Heart, Lung and Blood Institute, National Institute of Neurological Diseases and Stroke, and National Institute of Child Health and Human Development. AbbVie (formerly Solvay and Abbott Laboratories) also provided funding, AndroGel, and placebo gel. Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and therapies for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit http://www.


Masouminia M.,University of California at Los Angeles | Samadzadeh S.,LA Biomedical | Mendoza A.S.,University of California at Los Angeles | French B.A.,LA Biomedical | And 2 more authors.
Experimental and Molecular Pathology | Year: 2016

There are many homeostatic mechanisms for coping with stress conditions in cells, including autophagy. In many studies autophagy, as an intracellular pathway which degrades misfolded and damaged protein, and Mallory-Denk Body (MDB) formation have been shown to be protective mechanisms against stress such as alcoholic hepatitis. Alcohol has a significant role in alteration of lipid homeostasis, sterol regulatory element-binding proteins (SREBPs) and peroxidase proliferator-activated receptors through AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK is one of the kinases that regulate autophagy through the dephosphorylation of ATG1. Activation of ATG1 (ULK kinases family) activates ATG6. These two activated proteins relocate to the site of initial autophagosome and activate the other downstream components of autophagocytosis. Many other proteins regulate autophagocytosis at the gene level. CHOP (C/EBP homologous protein) is one of the most important parts of stress-inducible transcription that encodes a ubiquitous transcription factor. In this report we measure the upregulation of the gene that are involved in autophagocytosis in liver biopsies of alcoholic hepatitis and NASH. Electron microscopy was used to document the presence of autophagosomes in the liver cells. Expression of AMPK1, ATG1, ATG6 and CHOP in ASH were significantly (p value < 0.05) upregulated in comparison to control. Electron microscopy findings of ASH confirmed the presence of autophagosomes, one of which contained a MDB, heretofore undescribed. Significant upregulations of AMPK-1, ATG-1, ATG-6, and CHOP, and uptrending of ATG-4, ATG-5, ATG-9, ATR, and ATM in ASH compared to normal control livers indicate active autophagocytosis in alcoholic hepatitis. © 2016


French S.W.,University of California at Los Angeles | Bardag-Gorce F.,LA Biomedical | French B.A.,University of California at Los Angeles | Li J.,University of California at Los Angeles | Oliva J.,LA Biomedical
Experimental and Molecular Pathology | Year: 2011

Innate immunity factors such as conversion of the 26S proteasome to form the immunoproteasome and the Toll-like receptor signaling pathways are activated in chronic hepatitis induced by the carcinogenic drug DDC. Over time, preneoplastic hepatocyte phenotypes appear in the liver parenchyma. These changed hepatocytes expand in number because they have a growth advantage over normal hepatocytes when responding to chronic liver injury. The changed hepatocytes can be identified using immunofluorescent antibodies to preneoplastic cells e.g. FAT10/UbD, A2 macroglobulin, glutathione transpeptidase, alpha fetoprotein, glycipan 3, FAS, and gamma glutamyl transpeptidase. The formation of the preneoplastic cells occurs concomitant with activation of the Toll-like receptor signaling pathways and the transformation of the 26S proteasome to form the immunoproteasome. This transformation is in response to interferon stimulating response element on the promoter of the FAT10/UbD gene. NFκB, Erk, p38 and Jnk are also up regulated. Specific inhibitors block these responses in vitro in a mouse tumor cell line exposed to interferon gamma. Mallory-Denk bodies form in these preneoplastic cells, because of the depletion of the 26S proteasome due to formation of the immunoproteasome. Thus, MDB forming cells are also markers of the preneoplastic hepatocytes. The UbD positive preneoplastic cells regress when the liver injury induced chronic hepatitis subsides. When the drug DDC is refed to mice and chronic hepatitis is activated, the preneoplastic cell population expands and Mallory-Denk bodies rapidly reform. This response is remembered by the preneoplastic cells for at least four months indicating that an epigenetic cellular memory has formed in the preneoplastic cells. This proliferative response is prevented by feeding methyl donors such as S-adenosylmethionine or betaine. Drug feeding reduces the methylation of H 3 K4, 9, and 27 and this response is prevented by feeding the methyl donors. After 8 to 15months of drug withdrawal in mice the preneoplastic liver cells persist as single or small clusters of cells in the liver lobules. Multiple liver tumors form, some of which are hepatocellular carcinomas. The tumors immunostain positively for the same preneoplastic markers as the preneoplastic cells. Similar cells are identified in human cirrhosis and hepatocellular carcinoma indicating the relevance of the drug model described here to the preneoplastic changes associated with human chronic hepatitis and hepatocellular carcinoma. © 2011 Elsevier Inc.


News Article | November 14, 2016
Site: www.eurekalert.org

LOS ANGELES - Bacterial keratitis, an infection of the cornea often caused by contact lenses, malnutrition, or an injury, can lead to corneal scarring, one of the leading causes of blindness around the globe, according to the World Health Organization. It has blinded more than 400,000 children worldwide. Antibiotic drops can save a patient's eyesight by effectively treating these infections before the cornea is scarred. But the antibiotic drops are expensive and often unavailable in third-world countries. Dr. Sherwin Isenberg, MD, an LA BioMed researcher, said the lack of access to effective treatments is one of the reasons for higher rates of blindness in the developing world. Dr. Isenberg has spent nearly three decades studying the use of a low-cost, easily accessible eye drop for preventing and treating eye disease and recently published a new study in the American Journal of Ophthalmology (online edition initially) that reports that these drops are just as effective as antibiotics in treating bacterial keratitis. The researchers found the low-cost eye drops, povidone-iodine 1.25% ophthalmic solution, were as effective for the treatment of bacterial keratitis as two antibiotics, neomycin-polymyxin B-gramicidin and ciprofloxacin 0.3%, in areas of the world where the use of effective topical antibiotics may not be an option. "In many developing nations, these antibiotics are often used for the successful treatment of bacterial keratitis but they're often too expensive for those patients," said Dr. Isenberg. "Povidone-iodine solutions are available worldwide and can be prepared locally from stock solutions or powders, so these eye drops cost just pennies per treatment." Dr. Isenberg, Dr. Gary Holland, the late Dr. Leonard Apt, Madeline Del Signore, R.N. and researchers in India and the Philippines randomized 172 patients who had bacterial keratitis infections and treated half with antibiotics and the other half with the povidone-iodine solution.The researchers found the povidone-iodine solution was as successful in curing the infection as were the two antibiotics. Dr. Isenberg had previously studied the use of povidone-iodine to prevent eye disease in newborns, and found that it was either more effective or as effective as the more expensive treatments. Other studies found the low-cost eye drops were as effective or more effective than antibiotics in treating bacterial and chlamydial conjunctivitis. The World Health Organization estimates that 285 million people worldwide are blind or visually impaired, and 90% of them live in "low-income settlings. It also estimates that 80% of all visual impairment can be prevented or cured. "The use of these low-cost eye drops has already saved the sight of thousands of infants by preventing eye infections that could have caused them to go blind," said Dr. Isenberg. "Now we are finding that we can use these same drops to treat infections that can cause blindness. By proving the effectiveness of these treatments, we hope to prevent blindness in millions of children and adults who suffer from eye infections." Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and therapies for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit http://www.


Oliva J.,LA Biomedical | Zhong J.,LA Biomedical | Buslon V.S.,LA Biomedical | French S.W.,LA Biomedical
Experimental and Molecular Pathology | Year: 2012

In recent years, methyl one-carbon metabolism has received a great deal of attention because the disruption of methyl balance in a variety of genetically modified mice is associated with the development of various forms of liver injury, namely fatty liver disease and hepatocellular carcinoma (HCC). In addition, patients with liver disease often have an abnormal expression of key genes involved in methionine metabolism as well as elevated serum levels of methionine and homocysteine (Hcy). S-adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte proliferation, necrosis and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of numerous forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and HCC. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also showed that it is effective in the treatment of patients with cholestatic liver diseases. We studied the survival of liver cells treated with SAMe and betaine using Hepa 1-6 and E47/C34 cell lines. We showed that exogenous SAMe decreased the number of Hepa 1-6 and E47/C34 cells, and increased the number of dead cells in vitro. Betaine had no significant effect on the number of surviving cells and the number of dead cells. The combination of both methyl donors significantly increased the survival of liver cells and reduced necrosis, compared to SAMe alone. This study showed the inhibition of the proliferation and increased necrosis in response to SAMe on liver cancer cell lines Hepa 1-6 and C34. © 2011 Elsevier Inc.


PubMed | LA Biomedical
Type: Journal Article | Journal: Experimental and molecular pathology | Year: 2012

In recent years, methyl one-carbon metabolism has received a great deal of attention because the disruption of methyl balance in a variety of genetically modified mice is associated with the development of various forms of liver injury, namely fatty liver disease and hepatocellular carcinoma (HCC). In addition, patients with liver disease often have an abnormal expression of key genes involved in methionine metabolism as well as elevated serum levels of methionine and homocysteine (Hcy). S-adenosylmethionine (SAMe) has rapidly moved from being a methyl donor to a key metabolite that regulates hepatocyte proliferation, necrosis and differentiation. Biosynthesis of SAMe occurs in all mammalian cells as the first step in methionine catabolism in a reaction catalyzed by methionine adenosyltransferase (MAT). Decreased hepatic SAMe biosynthesis is a consequence of numerous forms of chronic liver injury. In an animal model of chronic liver SAMe deficiency, the liver is predisposed to further injury and develops spontaneous steatohepatitis and HCC. SAMe treatment in experimental animal models of liver injury shows hepatoprotective properties. Meta-analyses also showed that it is effective in the treatment of patients with cholestatic liver diseases. We studied the survival of liver cells treated with SAMe and betaine using Hepa 1-6 and E47/C34 cell lines. We showed that exogenous SAMe decreased the number of Hepa 1-6 and E47/C34 cells, and increased the number of dead cells in vitro. Betaine had no significant effect on the number of surviving cells and the number of dead cells. The combination of both methyl donors significantly increased the survival of liver cells and reduced necrosis, compared to SAMe alone. This study showed the inhibition of the proliferation and increased necrosis in response to SAMe on liver cancer cell lines Hepa 1-6 and C34.


News Article | December 27, 2016
Site: www.eurekalert.org

LOS ANGELES - (Dec. 27, 2016) - Intensive Care Units (ICUs), which provide the most expensive and invasive forms of care in a hospital setting, are being used too often for patients who don't need that level of care, according to a new study by LA BioMed and UCLA researchers published in the Journal of the American Medical Association Internal Medicine today. The researchers studied 808 ICU admissions from July 1, 2015 to June 15, 2016 at Harbor-UCLA Medical Center and found that more than half the patients could have been cared for in less expensive and invasive settings. Of the patients in the study, 23.4% were in need of close monitoring but not ICU-level care. Another 20.9% of the patients were critically ill but unlikely to recover because they had underlying illnesses or severity of acute illness. For another 8%, death was imminent or the same outcomes were expected in non-ICU care. "Our study found over 50% of patients admitted to the ICU were categorized into groups suggesting that they were potentially either too well or too sick to benefit from ICU care or could have received equivalent care in non-ICU settings," said Dong W. Chang, MD, an LA BioMed researcher and the corresponding author for the study. "This research indicates that ICU care is inefficient because it is devoting substantial resources to patients who are less likely to benefit from this level of care. These findings are a concern for patients, providers and the health care system because ICU care is frequently invasive and comes at a substantial cost." The researchers added up the number of days each of the patients in the study spent in ICU and found nearly 65% of the total number of days those patients spent in ICU were allocated to care that was considered discretionary monitoring, had a low likelihood of benefit despite critical illness or would have been manageable in non-ICU settings. "While this is a study of just one hospital and results may differ at other medical centers, we suspect that these characteristics of ICU utilization are commonplace and prevalent in many institutions," said Dr. Chang. The researchers also noted that in other hospitals, the ICU may be the most appropriate level of care because the hospitals don't have appropriate levels of care for those patients outside the ICU. "However, there is likely to be a subset of patients in which ICU care leads to unwanted, invasive care without significant clinical benefit," said Dr. Chang. "Refining our ability to identify these patients and developing approaches to improve ICU utilization for those patients are important steps to assure the best care for patients and the most efficient use of the healthcare system's limited resources." Other researchers participating in the study were Daniel Dacosta, MD, LA BioMed, and Martin F. Shapiro, MD, PhD, David Geffen School of Medicine at UCLA. Founded in 1952, LA BioMed is one of the country's leading nonprofit independent biomedical research institutes. It has approximately 100 principal researchers conducting studies into improved treatments and therapies for cancer, inherited diseases, infectious diseases, illnesses caused by environmental factors and more. It also educates young scientists and provides community services, including prenatal counseling and childhood nutrition programs. LA BioMed is academically affiliated with the David Geffen School of Medicine at UCLA and located on the campus of Harbor-UCLA Medical Center. For more information, please visit http://www.

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