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Chicago, IL (May 6, 2017) -- Genotyping of patients with advanced cirrhosis from hepatitis C virus could help health-care professionals predict the likelihood of improvement after successful hepatitis C treatment, thus minimizing the need for liver transplants. This study was presented at Digestive Disease Week® (DDW) 2017, the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. "Our findings further the move toward precision medicine, because we can potentially use a person's genetic makeup to identify individuals who can benefit most from hepatitis C treatment, even at a very late stage in the progression of their liver disease," said Winston Dunn, MD, the study's lead author and associate professor at the University of Kansas Medical Center. Most patients with hepatitis C virus (HCV) can be cured by direct-acting antiviral agents, but some of those with the more serious decompensated cirrhosis, or liver damage, fail to improve or experience further deterioration even after treatment. Features of decompensated cirrhosis include confusion, swelling and jaundice. Dr. Dunn and his team focused on the Rs738409 single nucleotide polymorphism (RSP), which is a variation in a single base pair of DNA in the PNPLA3 gene; patients possess one of three genotypes -- CC, CG, or GG. The PNPLA3 gene is the most important genetic risk factor for both alcoholic liver disease and nonalcoholic fatty liver disease. The team followed 32 patients with decompensated cirrhosis at the University of Kansas Medical Center who had initially achieved sustained virologic response (SVR). They had become essentially virus-free, using interferon-free direct-acting antiviral medications, such as sofosbuvir/ledipasvir and sofosbuvir/simeprevir. Twelve to 48 weeks after SVR, researchers tracked changes in two measures that assess the severity of chronic liver disease, the Model for End-Stage Liver Disease (MELD) and the Child-Pugh (CPT) scores. Following the antiviral treatment, researchers found that five of the 16 patients with the CG or GG genotypes experienced worsened MELD or CPT scores. In comparison, only one of the patients with the CC genotype worsened in either CPT or MELD scores. "These findings suggest screening for the Rs738409 CG and GG genotypes in hepatitis C patients with decompensated cirrhosis can help to identify individuals who are less likely to recover after achieving a 'cure' of their hepatitis C," added Dr. Dunn. "Until now, we have not had a method to distinguish between the individuals who would recover given equal severity in baseline disease." As next steps, Dr. Dunn noted that his team will examine the underlying mechanisms that may explain why the presence of these genotypes lead to worsened health outcomes. They'll study how fatty liver and insulin resistance impact clinical recovery after treatment with direct-acting antiviral medications, and if these findings correspond to that of the genetic marker for fatty liver (Rs738409). Financial support for this study was provided by the Frontiers Pilot and Collaborative Studies Funding Program. Dr. Winston Dunn will present data from the study, "Rs738409 SNP of PNPLA3 Gene Predicts Clinical Recovery in Patients with Decompensated Hepatitis C Cirrhosis After Attaining Sustained Virological Response" abstract Sa1535, on Saturday, May 7, at 9:30 a.m. CT, in South Hall of McCormick Place. For more information about featured studies, as well as a schedule of availability for featured researchers, please visit http://www. . Digestive Disease Week® (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy, and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 6-9, 2017, at McCormick Place, Chicago. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology. More information can be found at http://www. .


Li T.,University of Kansas Medical Center | Chiang J.Y.L.,Northeast Ohio Medical University
Pharmacological Reviews | Year: 2014

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Li R.,Stowers Institute for Medical Research | Li R.,University of Kansas Medical Center | Albertini D.F.,University of Kansas Medical Center
Nature Reviews Molecular Cell Biology | Year: 2013

Mammalian oocytes go through a long and complex developmental process while acquiring the competencies that are required for fertilization and embryogenesis. Recent advances in molecular genetics and quantitative live imaging reveal new insights into the molecular basis of the communication between the oocyte and ovarian somatic cells as well as the dynamic cytoskeleton-based events that drive each step along the pathway to maturity. Whereas self-organization of microtubules and motor proteins direct meiotic spindle assembly for achieving genome reduction, actin filaments are instrumental for spindle positioning and the establishment of oocyte polarity needed for extrusion of polar bodies. Meiotic chromatin provides key instructive signals while being 'chauffeured' by both cytoskeletal systems. © 2013 Macmillan Publishers Limited. All rights reserved.


Hidaka B.H.,University of Kansas Medical Center
Journal of Affective Disorders | Year: 2012

There has been much speculation about modern environments causing an epidemic of depression. This review aims to (1) determine whether depression rates have increased and (2) review evidence for possible explanations. While available data indicate rising prevalence and an increased lifetime risk for younger cohorts, strong conclusions cannot be drawn due to conflicting results and methodological flaws. There are numerous potential explanations for changing rates of depression. Cross-cultural studies can be useful for identifying likely culprits. General and specific characteristics of modernization correlate with higher risk. A positive correlation between a country's GDP per capita, as a quantitative measure of modernization, and lifetime risk of a mood disorder trended toward significance (p = 0.06). Mental and physical well-being are intimately related. The growing burden of chronic diseases, which arise from an evolutionary mismatch between past human environments and modern-day living, may be central to rising rates of depression. Declining social capital and greater inequality and loneliness are candidate mediators of a depressiogenic social milieu. Modern populations are increasingly overfed, malnourished, sedentary, sunlight-deficient, sleep-deprived, and socially-isolated. These changes in lifestyle each contribute to poor physical health and affect the incidence and treatment of depression. The review ends with a call for future research and policy interventions to address this public health crisis. © 2012 Elsevier B.V. All rights reserved.


Ma Y.,University of Kansas Medical Center
Science translational medicine | Year: 2014

Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.


Lutkenhaus J.,University of Kansas Medical Center
Trends in Microbiology | Year: 2012

Bacteria must segregate their DNA and position a septum to grow and divide. In many bacteria, MinD is involved in spatial regulation of the cytokinetic Z ring, and ParAs are involved in chromosome and plasmid segregation. The use of the MinD/ParA family to provide positional information for spatial organization continues to expand with the recognition that orphan ParAs are required for segregating cytoplasmic protein clusters and the polar localization of chemotaxis proteins, conjugative transfer machinery, type IV pili, and cellulose synthesis. Also, some bacteria lacking MinD use orphan ParAs to regulate cell division. Positioning of MinD/ParA proteins is either due to self-organization on a surface or reliance on a landmark protein that functions as a molecular beacon. © 2012 Elsevier Ltd.


Yu A.S.L.,University of Kansas Medical Center
Journal of the American Society of Nephrology | Year: 2015

Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK)proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered. Copyright © 2015 by the American Society of Nephrology.


Nudo R.J.,University of Kansas Medical Center
Frontiers in Human Neuroscience | Year: 2013

The past 20 years have represented an important period in the development of principles underlying neuroplasticity, especially as they apply to recovery from neurological injury. It is now generally accepted that acquired brain injuries, such as occur in stroke or trauma, initiate a cascade of regenerative events that last for at least several weeks, if not months. Many investigators have pointed out striking parallels between post-injury plasticity and the molecular and cellular events that take place during normal brain development. As evidence for the principles and mechanisms underlying post-injury neuroplasticity has been gleaned from both animal models and human populations, novel approaches to therapeutic intervention have been proposed. One important theme has persisted as the sophistication of clinicians and scientists in their knowledge of neuroplasticity mechanisms has grown: behavioral experience is the most potent modulator of brain plasticity. While there is substantial evidence for this principle in normal, healthy brains, the injured brain is particularly malleable. Based on the quantity and quality of motor experience, the brain can be reshaped after injury in either adaptive or maladaptive ways. This paper reviews selected studies that have demonstrated the neurophysiological and neuroanatomical changes that are triggered by motor experience, by injury, and the interaction of these processes. In addition, recent studies using new and elegant techniques are providing novel perspectives on the events that take place in the injured brain, providing a real-time window into post-injury plasticity. These new approaches are likely to accelerate the pace of basic research, and provide a wealth of opportunities to translate basic principles into therapeutic methodologies. © 2013 Nudo.


Bellon M.,University of Kansas Medical Center
Blood | Year: 2013

Adult T-cell leukemia/lymphoma (ATL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATL is classified into 4 distinct clinical diseases: acute, lymphoma, chronic, and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4-year survival of < 5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/β-catenin pathway because of its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of β-catenin but displayed high levels of LEF-1/TCF genes along with elevated levels of β-catenin (LEF-1/TCF target genes) responsive genes. By profiling Wnt gene expression, we discovered that ATL patient leukemia cells shifted expression toward the noncanonical Wnt pathway. Interestingly, ATL cells overexpressed the osteolytic-associated genes-Wnt5a, PTHLH, and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome.


Swerdlow R.H.,University of Kansas Medical Center
Antioxidants and Redox Signaling | Year: 2012

Significance: Mitochondria and brain bioenergetics are increasingly thought to play an important role in Alzheimer's disease (AD). Recent Advances: Data that support this view are discussed from the perspective of the amyloid cascade hypothesis, which assumes beta-amyloid perturbs mitochondrial function, and from an opposite perspective that assumes mitochondrial dysfunction promotes brain amyloidosis. A detailed review of cytoplasmic hybrid (cybrid) studies, which argue mitochondrial DNA (mtDNA) contributes to sporadic AD, is provided. Recent AD endophenotype data that further suggest an mtDNA contribution are also summarized. Critical Issues and Future Directions: Biochemical, molecular, cybrid, biomarker, and clinical data pertinent to the mitochondria- bioenergetics-AD nexus are synthesized and the mitochondrial cascade hypothesis, which represents a mitochondria-centric attempt to conceptualize sporadic AD, is discussed. © 2012, Mary Ann Liebert, Inc.

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