Citations

Only a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well‐characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P < 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation. (Hepatology Communications 2018;2:29–34)

Abstract Background: Most ovarian cancer (OC) patients present with advanced disease and ultimately develop chemo-resistant relapses. Stroma plays a significant role in OC behavior including invasiveness, fibrosis and chemoresistance. TGF-β is important for crosstalk between stroma and cancer cells, and stromal activation in cancer has similarities to matrix remodeling in fibrosis. We have shown that TGF-β and fibrosis-inhibitors can suppress OC cell proliferation, migration and invasion. Such inhibitors are available for clinical use, and we have begun to test their efficacy in OC in vivo. Methods: Animal experiments were approved by Mayo Clinic IACUC. Intraperitoneal xenograft models were derived from OVCAR8 (5×106) cells (OV8-CDX) or 0.1 gm OC patient tumor tissue (PDX) in NSG mice. OV8-CDX and PDX PH003 (an aggressive, chemoresistant and ascites-prone model) (n=5-10 mice/arm) were treated with 2 agents and compared to untreated controls (C): 1) C vs. the fibrosis inhibitor Pirfenidone (P, 200 mg/kg, BID, provided by Genentech); 2) C vs. TGF-β receptor I inhibitor Galunisertib (G, 75 mg/kg, BID, provided by Eli Lily). Mice were pretreated for 2 days before xenografting and treated for 4 weeks with ultrasound (US) to measure tumor growth. At day (d) 28, we i) collected tumor (OV8-CDX); or ii) observed until progression (PH003, PH053). OV8-CDX tumors were used for target gene analysis. Results: P treatment delayed tumor growth in OV8-CDX relative to control (C): tumors established in 0/5 (P) vs. 1/5 (C), and 1/5 (P) vs. 4/5 (C) of mice at d14 and d28, respectively. The reduced tumor weight (g) at d28 was also confirmed (0.20±0.10 vs. 0.54±0.23, p=0.02). Similarly, P treatment in PH003 inhibited the tumor growth (tumor area (cm2) at d28: 0.74±0.43 vs. 1.04±0.51, p=0.28), ascites development (volume (ml): 1.14±0.54 vs. 3.37±0.62, p=0.05) and prolonged survival time (p=0.04). G treatment was also associated with delayed tumor establishment in OV8-CDX relative to C: tumors presented in 0/5 (G) vs. 1/5 (C), and 1/5 (G) vs. 4/5 (C) of mice at d14 and d28, respectively. Associated d28 tumor weight was significantly reduced (0.20±0.10 vs. 0.54±0.23, p=0.02) as well. For PH003, G treatment was associated with delayed tumor growth (tumor area at d28: 0.57±0.27 vs. 1.04±0.51, p=0.05), a marked reduction in ascites (volume: 1.25±0.56 vs. 3.37±0.62, p=0.05) and a prolonged survival time (p=0.04) We identified down-regulation of TGF-β signaling-related genes (e.g. TGFB1, TGFBR2) and fibrosis-related biomarkers (e.g. FAP, COL11A1) following drug treatment confirming inhibition of relevant pathways. Conclusion: We report that 2 currently available inhibitors targeting either fibrosis or TGF-β appear to have efficacy in vivo and delay tumor growth in OC PDX models. These results suggest promise for a strategy of targeting the stromal component of OC. Citation Format: Qing Zhang, Xiaonan Hou, Bradley J. Evans, John J. Weroha, William A. Cliby. Inhibitors of fibrosis and TGF-beta delay tumor xenograft growth and reduce ascites in ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 961. doi:10.1158/1538-7445.AM2017-961

ABSTRACTBackground and Objectives: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.Methods: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [11C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region.Results: In comparison to the control group, PSP subjects showed specific uptake of [11C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [11C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum.Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha‐synuclein. © 2017 International Parkinson and Movement Disorder Society

Abstract Background Transfusion-associated circulatory overload remains underappreciated in the perioperative environment. The authors aimed to characterize risk factors for perioperative transfusion-associated circulatory overload and better understand its impact on patient-important outcomes. Methods In this case–control study, 163 adults undergoing noncardiac surgery who developed perioperative transfusion-associated circulatory overload were matched with 726 transfused controls who did not develop respiratory complications. Univariate and multivariable logistic regression analyses were used to evaluate potential risk factors for transfusion-associated circulatory overload. The need for postoperative mechanical ventilation, lengths of intensive care unit and hospital stay, and mortality were compared. Results For this cohort, the mean age was 71 yr and 56% were men. Multivariable analysis revealed the following independent predictors of transfusion-associated circulatory overload: emergency surgery, chronic kidney disease, left ventricular dysfunction, previous β-adrenergic receptor antagonist use, isolated fresh frozen plasma transfusion (vs. isolated erythrocyte transfusion), mixed product transfusion (vs. isolated erythrocyte transfusion), and increasing intraoperative fluid administration. Patients who developed transfusion-associated circulatory overload were more likely to require postoperative mechanical ventilation (73 vs. 33%; P < 0.001) and experienced prolonged intensive care unit (11.1 vs. 6.5 days; P < 0.001) and hospital lengths of stay (19.9 vs. 9.6 days; P < 0.001). Survival was significantly reduced (P < 0.001) in transfusion recipients who developed transfusion-associated circulatory overload (1-yr survival 72 vs. 84%). Conclusions Perioperative transfusion-associated circulatory overload was associated with a protracted hospital course and increased mortality. Efforts to minimize the incidence of transfusion-associated circulatory overload should focus on the judicious use of intraoperative blood transfusions and nonsanguineous fluid therapies, particularly in patients with chronic kidney disease, left ventricular dysfunction, chronic β-blocker therapy, and those requiring emergency surgery.

Background Results of animal studies assessing efficacy of bone marrow stromal cell therapy for ischemic stroke remain inconsistent. Aims The aims are to assess efficacy of bone marrow stromal cell therapy for ischemic stroke in animal studies. Methods Randomized controlled animal trials assessing efficacy of bone marrow stromal cell therapy were eligible. Stroke therapy academic industry round table was used to assess methodologic quality of included studies. Primary outcomes were total infarction volume and modified Neurological Severity Score. Multiple prespecified sensitivity analyses and subgroup analyses were conducted. Random effects models were used for meta-analysis. Results Thirty-three randomized animal trials were included with a total of 796 animals. The median quality score was 6 (interquartile range, 5–7). Bone marrow stromal cell therapy decreased total infarction volume (standardized mean difference, 0.897; 95% confidence interval, 0.553–1.241; P < .001) at follow-up. Overall standardized mean difference between animals treated with bone marrow stromal cell and controls was 2.47 (95% confidence interval, 1.84–3.11; P < .001) for modified Neurological Severity Score; 1.27 (95% confidence interval, 0.72–1.82; P < .001) for adhesive removal test; and 2.13 (95% confidence interval, 0.65–3.61; P < .001) for rotarod test. Significant heterogeneity among studies was observed. Effect of all outcomes stayed significant in various sensitivity analyses and subgroup analyses, except in a few subgroup analyses with small sample size or with short time follow-up. No significant difference between groups was observed except for study location, in which significantly larger estimates were found in Asian countries. On the basis of this meta-analysis, larger sample sizes are warranted for future animal studies. Conclusions Bone marrow stromal cell therapy significantly decreased total infarction volume and increased neural functional recovery in randomized controlled animal models of ischemic stroke.

Abstract Background: In ovarian cancer (OC), the intraperitoneal fibrosis that accompanies metastasis is a common scenario and associated with significant morbidity and gut dysfunction. Accumulating evidences indicate that Transforming Growth Factor β (TGF-β) signaling pathway plays a key role in cancer associated fibrosis and metastasis. Several TGF-β inhibitors, including Galunisertib (LY2157299) which is a TGF-β receptor I inhibitor, are currently in clinical trials for fibrosis-related diseases and cancer. Our hypothesis is that targeted anti-cancer therapies can block the growth and spread of cancer or specifically address the fibrosis accompanying metastatic peritoneal cancer. In this study, we investigated the efficacy of Galunisertib in inhibiting OC fibrosis and metastasis in vitro. Methods: Five OC cell lines, including SKOV3ip, HeyA8, OVCAR8, OV2008, and PEO4, and one cancer-associated fibroblast (CAF) cell line, TRS3, were tested in this study. We utilized a co-culture system that has successfully been used to study the interactions between cancer cells and local environment, including CAFs. Twenty-three candidate TGF-β signaling- and fibrosis-related genes were selected based on previous studies. RNA and protein from both fibroblast cells and OC cells were collected for RT-qPCR and western blot analysis. MTT assay, Wound healing assay and Matrigel invasion assay were used to study OC cell proliferation, migration and invasion. Chou-Talalay assays were performed to study the interactions between Galunisertib and Carboplatin and Paclitaxel. Results: RT-qPCR results showed that Galunisertib treatment suppresses the expression of both TGF-β receptor I and TGF-β1 which is the most abundant isoform of TGF-β in OC. Western blot results showed that Galunisertib treatment reverses the TGF-β1-induced SMAD2/3 phosphorylation, confirming the efficacy of Galunisertib in TGF-β signaling pathway blockage. Intriguingly, Galunisertib treatment inhibits the expression of candidate fibrosis-related genes, like ACTA2, TIMP3, COL5A1, COL11A1, and VCAN in both OC and CAF cells. Would healing and Transwell invasion assay also demonstrated that Galunisertib treatment effectively reduces both basal and TGF-β1-induced cell migration and invasion (p&lt;0.05). MTT assay showed that Galunisertib is able to inhibit the proliferation of both OC and CAFs cells with IC50 values range from 100-400 μm. Additionally, Galunisertib shows strong synergistic effects with both Carboplatin and Paclitaxel in Chou-Talalay assays. Conclusion: Galunisertib treatment suppresses the expression of TGF-β-dependent fibrosis-related genes from OC cell lines and CAFs. Coincident with this inhibition of fibrosis related genes, galunisrtib reduces cell proliferation, migration, and invasion. These data suggest that targeting the TGF-β pathway is a viable therapeutic approach to reduce both symptoms related to OC-related fibrosis and cancer metastasis in OC. Citation Format: Qing Zhang, William A. Cliby. Galunisertib inhibits ovarian cancer cell fibrosis and metastasis in vitro. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3026.

Abstract Despite the rapid progress in personalized cancer therapy (PCT) for breast cancer, no previous studies have used genomic predictors to choose among multiple chemotherapy regimens. It is unclear that given the current regimens how much PCT can improve the response rate for patients who will receive chemotherapy. In this study, we reanalyzed data from published studies of 1111 breast cancer patients who were treated with neoadjuvant chemotherapies. Those patients were divided into three regimen groups: an anthracycline alone, anthracycline plus paclitaxel, and anthracycline plus docetaxel. We developed a new strategy called PRES (Personalized REgimen Selection) to reassign the optimal regimen to each of the patients. First, a variable selection scheme was developed to identify significant genetic predictors for chemotherapy response. The selected genetic variables were then combined with clinical variables to build random forest models to predict the response of a patient to each regimen using pCR (pathological complete response) as the measure of response. The models were used to assign an optimal regimen to each patient to maximize the chance of pCR. We found that the expected rate of pCR was improved from 21.2% to 39.6% (95% CI: 34.6% - 43.0%). We also found that 31.1% of the patients may have been overtreated and 8.2% patients undertreated. A validation study on 21 cell lines showed that our prediction agrees with their paclitaxel-sensitivity profiles. We performed additional analysis on the Cancer Genome Atlas (TCGA) data and found that 18 of the 19 genes identified are significantly differentially expressed between normal and tumor tissues, and 2 of them, TAF6L and METRN (meteorin), are associated with overall survival. In conclusion, PRES could substantially increase response rates for breast cancer patients who will receive one of the widely-accepted chemotherapy regimens at present. Citation Format: Jinfeng Zhang, Kaixian Yu, Qingxiang Amy Sang, Winston Tan, Mayassa B. Dargham, Jun S. Liu, Ty Lively, Cedric Sheffield. Personalized chemotherapy regimen selection for breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2034.