tbuckley/cabot-search huggingface dataset:
Abstract 3120: Tumor-infiltrating lymphocyte profiling in hepatitis B virus pre-S2 mutant-positive hepatocellular carcinoma
Authors: Chiao-Fang Teng, Woei-Cherng Shyu, Long-Bin Jeng
Journal: Cancer Research (2018)

Abstract Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), the leading cause of cancer-related deaths worldwide. Pre-S2 mutant is well demonstrated as a HBV oncoprotein that disturbs multiple cellular signaling pathways, leading to HCC development. HCC patients with pre-S2 mutant are recognized as a high-risk population for postoperative recurrence. Plentiful evidences reveal that tumor infiltrating lymphocytes (TILs) play an essential role in the stepwise progression of HCC development, and are closely associated with clinical outcomes. However, to date, the role of pre-S2 mutant in regulation of TILs distribution in HCC remains totally unknown. In this study, we collected plasma and paraffin-embedded liver samples from HBV-related HCC patients. The plasma samples were used for detection of the pre-S2 mutant with polymerase chain reaction-based method. As a result, the patients were divided into two groups: the pre-S2 mutant-positive and -negative groups. The paraffin-embedded liver samples were used for examination of the distribution of specific population of TILs with fluorescent immunohistochemistry staining. We analyzed 6 cases of HBV-related HCC samples, half of which were detected as pre-S2 mutant-positive. The distribution level of the cytotoxic CD3+CD8+ TILs in HCCs was examined. We found that patients with pre-S2 mutant had a considerably lower density of cytotoxic CD3+CD8+ TILs in HCC tissues than patients without pre-S2 mutant. The mean ± SEM of cytotoxic CD3+CD8+ TILs density was 3.74 ± 0.60 and 6.66 ± 0.66 in patients with and without pre-S2 mutant, respectively (p value=0.031). Our result suggests that pre-S2 mutant may have a role in regulation of TILs distribution in HBV-related HCCs. Systematic evaluation of specific population of TILs may help guide development of novel strategies for prognosis and/or therapies of HCC, especially for the HBV-related pre-S2 mutant-positive high-risk patient population. Citation Format: Chiao-Fang Teng, Woei-Cherng Shyu, Long-Bin Jeng. Tumor-infiltrating lymphocyte profiling in hepatitis B virus pre-S2 mutant-positive hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3120.
Abstract 4146: N6Methyladenosine RNA demethylase ALKBH5 as a novel therapeutic target for osteosarcoma
Authors: Pooja Yadav, Panneerdoss Subbarayalu, Nourhan Abdelfattah, Vijay K. Eedunuri, Yidong Chen, Manjeet K. Rao
Journal: Cancer Research (2018)

Abstract Osteosarcoma (OS) is the most prevalent primary bone malignancy that affects children and young adults. Despite several years of research, survival outcome of OS patients has not improved in last three decades. OS is treated with multi-modal chemotherapy, which is highly toxic and does not work well for metastatic and chemo-resistant tumors. Currently there is no FDA approved drug that can serve as an alternative to chemotherapy, warranting an urgent need to find more efficacious and targeted therapeutics for OS. Here, we report that RNA demethylase AlkB Homolog 5 (ALKBH5) may serve as a novel therapeutic adjuvant for treating OS. N6 Methyladenosine (m6 A) is the most common internal mRNA modification, which is modulated by the multi-component RNA methyltransferase complex, RNA demethylase (ALKBH5) and m6A readers . We show that ALKBH5 is amplified in sarcomas and its expression is highly elevated in osteosarcoma patients. We demonstrate that silencing of ALKBH5 inhibits the OS growth and migration without affecting the viability of normal human fetal osteoblast cells. Our results reveal that ALKBH5 depletion impairs the cell cycle progression and induces apoptosis in OS cells. Interestingly, we demonstrate that reduction in ALKBH5 levels suppresses the DNA damage repair capacity of osteosarcoma cells rendering them sensitive to DNA damaging agent like Doxorubicin. Using DR-GFP reporter-based homologous recombination (HR) assay, we show that ALKBH5 depletion leads to reduced HR-mediated DNA repair capacity of osteosarcoma cells. Supporting this, we observed significantly reduced expression of several genes that are known to play critical roles in cell cycle progression and DNA damage repair. In summary, this study shows that ALKBH5 is a critical regulator of OS growth and chemosensitivity. Approaches aimed at silencing ALKBH5 can be potentially used to inhibit osteosarcoma growth and progression as well as sensitize osteosarcoma cells to DNA damaging agents. Citation Format: Pooja Yadav, Panneerdoss Subbarayalu, Nourhan Abdelfattah, Vijay K. Eedunuri, Yidong Chen, Manjeet K. Rao. N6Methyladenosine RNA demethylase ALKBH5 as a novel therapeutic target for osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4146.
Abstract 1037: Comprehensive molecular profiles of gastric cancer patient derived xenograft (PDX) models and its implication in precision cancer medicine
Authors: Jae Eun Lee, Yoon Young Choi, Ju Yeon Lim, Su-Jin Shin, Gunho Lee, Eun Young Kim, Taeil Son, Hyoung-Il Kim, Woo Jin Hyung, Sung Hoon Noh, Hyunki Kim, Minkyu Jung, Sangwoo Kim, Soonmyung Paik, Jae-Ho Cheong
Journal: Cancer Research (2018)

Abstract Background: Recent cancer research is focused on precision medicine with the advent of next generation sequencing (NGS) technology and patient tumor derived model systems. Here, we present molecular characteristics of gastric cancer patient derived xenograft (PDX) models and explore the potential of molecularly defined PDX model based drug development. Materials and Methods: We generated PDX models from patient tumors with advanced gastric cancer. The genomic alterations of tumors were profiled by whole exome sequencing (WES), RNA sequencing (RNAseq), targeted sequencing, in-situ hybridization (ISH) and immunohistochemistry (IHC). Further, we developed overcoming strategy of chemotherapy resistance mechanism by combination of signaling pathway inhibitor and standard chemotherapy regimen in “N-of-1” PDX trial. Results: Thirty-five PDX models were successfully established and categorized into four subgroups of The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications: EBV (2.9%), MSI (20.6%), GS (23.5%) and CIN (52.9%) subtypes by TCGA while MSI type (11.4%), MSS/EMT type (17.1%), MSS/TP53+ (31.4%) and MSS/TP53- type (40.0%) by ACRG. In the protein levels by IHC, there were 21 cases (60.0%) of any RTK proteins overexpression; nine of HER2 (25.7%), 14 of EGFR (40.0%), and 16 of c-MET (45.7%). Five tumors (14.3%) were related to PTEN loss and 22 tumors (62.9%) showed p53 overexpression or null. Targeted sequencing identified that ERBB2 (25.7%), KRAS (11.4%), and CCND1 (11.4%) were found frequently amplified gene while PIK3CA (11.4%) and CTNNB1 (8.6%) were found most mutated genes. N-of-1 PDX trial demonstrated that the response to FOLFOX in PDX tumor was concordant with that of corresponding patient. In FOLFOX resistant tumors, multiple signaling pathways were up-regulated and inhibition of these signaling pathways was regressed tumor growth. Conclusions: The utilization of molecularly catalogued gastric cancer PDX models will guide precision medicine for cancer therapy and be a useful tool for drug development and repurposing. Citation Format: Jae Eun Lee, Yoon Young Choi, Ju Yeon Lim, Su-Jin Shin, Gunho Lee, Eun Young Kim, Taeil Son, Hyoung-Il Kim, Woo Jin Hyung, Sung Hoon Noh, Hyunki Kim, Minkyu Jung, Sangwoo Kim, Soonmyung Paik, Jae-Ho Cheong. Comprehensive molecular profiles of gastric cancer patient derived xenograft (PDX) models and its implication in precision cancer medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1037.
Abstract 1649: Impact of linker and conjugation site on tubulysin M ADC stability and in vivo activity
Authors: Patrick J. Burke, Joseph Z. Hamilton, Thomas A. Pires, Christopher I. Leiske, Julia H. Cochran, Jocelyn R. Setter, Kim K. Emmerton, Andrew B. Waight, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey
Journal: Cancer Research (2018)

Abstract The tubulysins are a potent class of microtubule-disrupting agents consisting of natural products and designed analogues that have become a compelling cytotoxic payload for drug-targeting applications. This is due in large part to their high cytotoxic potency on cancer cells, including those that express transporters conferring the multidrug resistance (MDR+) phenotype. All potent tubulysin natural products contain an acetoxy group at the C11-position in the central tubuvaline residue. Deacetylation results in &amp;gt;100-fold loss of cellular and biochemical potency, underscoring the importance of this structural element. Recently, we developed quaternary ammonium linker systems to conjugate tertiary amine-containing payloads, and applied them to the tubulysins. In this work, protease- and β-glucuronidase-cleavable quaternary ammonium linkers of tubulysin M were evaluated as ADC payloads. In vitro, both dipeptide and glucuronide linker systems provided ADCs with comparable biologic properties. However, in vivo, linker chemistry and conjugation site were important parameters impacting acetate group stability. Higher degrees of stability translated to greater activity in xenograft models. ADCs were prepared with both dipeptide and glucuronide linkers as heterogeneous ADCs loaded at an average of 4-drugs/Ab (DAR 4), and as homogeneous ADCs loaded at 2-drugs/Ab (DAR 2) at the engineered S239C sites. Increased in vivo acetate stability was observed for glucuronide-based conjugates relative to the dipeptide analogue. Further stabilization was achieved by conjugating at the S239C sites (DAR 2) relative to native antibody cysteines (DAR 4). Tubulysin M acetate stabilization by both linker and conjugation site selection resulted in increased ADC potency in preclinical models and, combined, serves as an enabling strategy for antibody-mediated tubulysin M drug delivery. Citation Format: Patrick J. Burke, Joseph Z. Hamilton, Thomas A. Pires, Christopher I. Leiske, Julia H. Cochran, Jocelyn R. Setter, Kim K. Emmerton, Andrew B. Waight, Peter D. Senter, Robert P. Lyon, Scott C. Jeffrey. Impact of linker and conjugation site on tubulysin M ADC stability and in vivo activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1649.
Electrophysiological Effects of 4-Hydroxynonenal, an Aldehydic Product of Lipid Peroxidation, on Isolated Rat Ventricular Myocytes
Authors: AruniBhatnagar
Journal: Circulation Research (1995)

Abstract Aldehydic products of lipid peroxidation, such as 4-hydroxynonenal (4-HNE), have been implicated in the etiology of pathological changes under oxidative stress. To identify the mechanism by which 4-HNE alters cellular excitability, its effects on isolated rat ventricular myocytes were studied. Superfusion with 100 to 880 μmol/L 4-HNE led to a time- and concentration-dependent rigor shortening of myocytes. A reduction in [Ca2+]o and inhibition of transsarcolemmal Ca2+ transport by 1 mmol/L La3+ did not affect either the magnitude or the time course of 4-HNE–induced myocyte rigor. Superfusion of myocytes with 400 μmol/L 4-HNE led to an increase in the action potential duration, progressive depolarization of the resting membrane potential, and an increase in the input resistance (Rin) of the myocyte (phase I), followed by a loss of electrical excitability. Continued superfusion with 4-HNE resulted in membrane hyperpolarization and a prominent decrease in the Rin (phase II). The decrease in Rin coinc...
Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese
Authors: JunHata, ToshiharuNinomiya, YoichiroHirakawa, MasaharuNagata, NaokoMukai, SeijiGotoh, MasayoFukuhara, FumieIkeda, KentaroShikata, DaigoYoshida, KojiYonemoto, MasahiroKamouchi, TakanariKitazono, YutakaKiyohara
Journal: Circulation (2013)

Background—Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results—We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s ...
Routine universal screening for Lynch syndrome in colorectal cancer patients in the community setting.
Authors: Jeffrey M. Goldberg, Andrea L. Lewis, Michelle Alabek, Cara Dreher, Sandra Elane Brooks
Journal: Journal of Clinical Oncology (2012)

1512 Background: Identification of colorectal cancer (CRC) cases that are due to Lynch Syndrome (LS) is important to prevent secondary malignancies or development of additional malignancies among relatives. Utilization of clinical criteria to select CRC patients for laboratory testing fails to identify a significant proportion of patients whose CRC is due to LS. Therefore, universal screening for LS among CRC patients has been advocated by the Evaluation of Genomic Applications in Practice and Prevention Working Group. However, the feasibility of routine universal screening has not been evaluated in a community-based, non-research setting. We implemented a universal screening protocol for LS as part of routine care of CRC at Norton Healthcare, a multi-institutional community-based healthcare organization. Methods: Beginning in October 2009, all resected CRC tumors automatically underwent immunohistochemistry analysis (IHC) for Lynch Syndrome-associated mismatch repair gene (MMR) expression. Selected patients who underexpressed MLH1 also underwent testing for the BRAF V600E mutation. Patients who had a BRAF V600E mutation were considered to have sporadic CRC. All other patients with abnormal IHC were automatically referred for genetic counseling. We retrospectively reviewed the outcomes of genetic counseling in all patients referred through this universal screening protocol. Results: Between October 2009 and December 2011, 388 patients underwent resection of CRC, all of whom had IHC for MMR expression. Seventy patients were identified as having abnormal IHC. Sixty-two had MLH1/PMS2 underexpression, of which 18 underwent BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6 underexpression. Nine patients have been confirmed to have LS, 31 have been found not to have LS, and 19 are in the process of evaluation. Seven patients declined genetic counseling, and 4 died before they could be adequately evaluated. Conclusions: Universal screening for CRC due to LS, using IHC with select BRAF V600E mutation testing and automated referral for genetic counseling, is feasible in the community setting. Funded in part with federal funds: NCI, NIH, Contract No. HHSN261200800001.
Intravenous remifentanil patient-controlled analgesia versus intramuscular pethidine for pain relief in labour (RESPITE): an open-label, multicentre, randomised controlled trial
Authors: Matthew J A Wilson, Christine MacArthur, Catherine A Hewitt, Kelly Handley, Fang Gao, Leanne Beeson, Jane Daniels
Journal: The Lancet (2018)
cGMP-Dependent Protein Kinase Regulation of the L-Type Ca2+ Current in Rat Ventricular Myocytes
Authors: KotaroSumii, NicholasSperelakis
Journal: Circulation Research (1995)

Abstract Regulation of L-type Ca2+ channel current [ICa(L)] by cGMP-dependent protein kinase (PK-G) was investigated in ventricular myocytes from 2- to 21-day-old rats using whole-cell voltage clamp with internal perfusion. ICa(L) was elicited by a depolarizing pulse to +10 mV from a holding potential of −40 mV. Stimulated ICa(L) (by 2 μmol/L isoproterenol) was inhibited to the basal level by internal perfusion with 50 nmol/L PK-G (activated by 8Br-cGMP, 0.1 μmol/L). When ICa(L) was enhanced by Bay K 8644 (1 μmol/L), the enhanced basal ICa(L) was also reduced by PK-G. Basal ICa(L) (nonstimulated through the cAMP/cAMP-dependent protein kinase [PK-A] pathway) was also inhibited to various degrees (large, medium, or small) by internal application of PK-G (25 nmol/L). The average inhibition was 42.1% (n=36), and there were no differences in the inhibition during development. The inhibition by PK-G was blocked by the PK-G substrate peptide (cG-PKI, 300 μmol/L) and by heat inactivation of the PK-G. Relatively s...
Microvascular Outcomes in Patients With Diabetes After Bariatric Surgery Versus Usual Care
Authors: Rebecca O'Brien, Eric Johnson, Sebastien Haneuse, Karen J. Coleman, Patrick J. O'Connor, David P. Fisher, Stephen Sidney, Andy Bogart, Mary Kay Theis, Jane Anau, Emily B. Schroeder, David Arterburn
Journal: Annals of Internal Medicine (2018)

Bariatric surgery improves glycemic control in patients with type 2 diabetes mellitus (T2DM), but less is known about microvascular outcomes.
Global DNA 5‐Hydroxymethylcytosine and 5‐Formylcytosine Contents Are Decreased in the Early Stage of Hepatocellular Carcinoma
Authors: Jiao Liu, Jinhua Jiang, Jiezhen Mo, Dan Liu, Dan Cao, Hailin Wang, Yufei He, Hongyang Wang
Journal: Hepatology (2018)

Methylation of the fifth position of cytosine (5mC) is an important epigenetic modification of DNA. It has been shown that the oxidized derivatives of 5mC, namely 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxylcytosine (5caC), are in dynamic existence and have distinct regulatory functions. In the current study, we investigated whether there are changes in the contents of all three 5mC‐oxidized derivatives in the hepatocellular carcinoma (HCC) genome and further explored the underlying mechanisms. We showed that both global genomic 5hmC and 5fC contents were decreased significantly in the very early stage (stage 0, Barcelona Clinic Liver Cancer [BCLC] staging) of HCC compared with those of paratumor tissues. Noteworthily, 5fC content continued to decrease in the late stage (BCLC staging from 0 to A) of HCC. The 5caC content in HCC tissues was below the detection threshold. Hepatitis B virus (HBV) infection was associated with 5mC, 5hmC, or 5fC decrease in HCC; and measurements in cell lines integrated with or without HBV DNA showed consistent results. On the other hand, both the expression level of ten‐eleven translocation enzyme 2 (TET2) and α‐ketoglutarate content were decreased significantly in HCC. The significantly positive correlations among the expression levels of DNA methylation–related enzymes in paratumor tissues were generally attenuated or even disappeared in HCC tumor tissues. The decreases of both 5hmC and 5fC contents in genomic DNA were associated with poor prognosis of HCC patients. Conclusion: Global 5hmC and 5fC contents were decreased significantly in the very early stage of HCC; the decrease of 5hmC and 5fC was mainly due to the decrease of 5mC and associated with HBV infection, decreased TET enzyme activity, and uncoordinated expression of DNA methylation–related enzymes.
Abstract 5849: Valproic acid reverses trastuzumab resistance in erbB2-positive breast cancer cells via downregulation of ErbB2/ErbB3 signaling through induction of ErbB family members-targeting miRNAs
Authors: Tingting Lin, Qun Ren, Weimin Zuo, Rong Lin, Hu Zhao, Ping Wang, Jianming Tan, Hui Lyu, Bolin Liu, Shuiliang Wang
Journal: Cancer Research (2018)

Abstract Amplification and/or overexpression of erbB2 occur in approximately 25% of invasive breast cancer and are significantly associated with a worse prognosis for breast cancer patients. Trastuzumab, a humanized monoclonal antibody against erbB2 receptor, has been successfully used in early-stage and metastatic breast cancer therapy of patients with erbB2-overexpressing tumors as monotherapy and in combination with other agents; however, both primary and acquired resistances to trastuzumab are common and currently represent a significant clinical problem. Thus, seeking of novel therapeutic strategies/agents to overcome trastuzumab resistance is vital to improve the survival of breast cancer patients whose tumors overexpress erbB2. In our current study, we explored whether valproic acid (VPA), a clinically used anticonvulsant drug with reported HDACi activity, reverses trastuzumab resistance in erbB2-positive breast cancer cells. We have found that VPA inhibits proliferation of both trastuzumab-sensitive SKBR3 and BT474 cell lines as well as their corresponding trastuzumab-resistant SKBR3-pool2 and BT474-HR20 cell lines in a dose- and time-dependent manner, which is accompanied by significant reduction of cyclin D1 as well as induction of P21. Meanwhile, VPA also induces caspase-dependent apoptosis in all aforementioned four cell lines. More interestingly, VPA not only significantly enhances the anti-proliferative effects of trastuzumab, but also potentiates trastuzumab-induced apoptosis in trastuzumab-sensitive and resistant cells. Our further mechanistic studies revealed that VPA treatment results in significant inactivation of PI3K/Akt signaling via simultaneous down-regulation of ErbB2 and ErbB3 in erbB2-positive breast cancer cancer cells, an effect which could be mainly arrtibuted to induction of ErbB family members-targeting microRNAs including miR-125a, miR-125b and miR-205 by VPA. Taken together, we presented here that VPA reverses trastuzumab resistance in erbB2-positive breast cance cells via downregulation of ErbB2/ErbB3 signaling in a miRNAs-inducing-dependent manner. Our data suggested that further investigation regarding the in vivo therapeutic effect of VAP against trastuzumab-resistant breast cancer should be of especial interest. Citation Format: Tingting Lin, Qun Ren, Weimin Zuo, Rong Lin, Hu Zhao, Ping Wang, Jianming Tan, Hui Lyu, Bolin Liu, Shuiliang Wang. Valproic acid reverses trastuzumab resistance in erbB2-positive breast cancer cells via downregulation of ErbB2/ErbB3 signaling through induction of ErbB family members-targeting miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5849.
Heart failure with preserved ejection fraction in Asia
Authors: Jasper Tromp, Tiew‐Hwa Teng, Wan Ting Tay, Chung Lieh Hung, Calambur Narasimhan, Wataru Shimizu, Sang Weon Park, Houng Bang Liew, Tachapong Ngarmukos, Eugene B. Reyes, Bambang B. Siswanto, Cheuk‐Man Yu, Shu Zhang, Jonathan Yap, Michael MacDonald, Lieng Hsi Ling, Kirsten Leineweber, A. Mark Richards, Michael R. Zile, Inder S. Anand, Carolyn S.P. Lam
Journal: European Journal of Heart Failure (2018)