tbuckley/cabot-search huggingface dataset:
Abstract 795: Isatin analog for the treatment of acute myeloid leukemia
Authors: Krishne Gowda, Charyguly Annageldiyev, Dhimant Desai, Shantu Amin, David Claxton, Arati Sharma
Journal: Cancer Research (2018)

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with therapeutic modalities relying on traditional cytotoxic therapies and hematopoietic stem cell transplantation. Current first-line cytotoxic chemotherapy exhibits limited success, with 50% of younger patients and 80% of older patients succumbing to the disease. There is an urgent unmet need for new therapeutics in acute myeloid leukemia (AML) as standard therapy has not changed in the past three decades and outcome remains poor for most patients. Our group has reported cytotoxic potential of dibromo-derivative of isatin, 5,7-dibromo-N-(p-thiocyanomethylbenzyl)isatin (KS99) against variety of solid tumors and multiple myeloma (MM) cells by inhibiting BTK, AKT and tubulin polymerization. In this study, we examined the ability of KS99, to inhibit the growth of panel of human AML cell lines and primary samples collected from AML patients. After 48h exposure, KS99 inhibited the growth of AML cell lines (IC50, 150-225nM) and primary blast samples (IC50, 600-1300nM) in a dose dependent manner. KS99 treatment also selectively reduced the clonogenicity of human acute myeloid leukemia patient cells compared to the hematopoietic stem cells. We also found that KS99 induced apoptosis by modulating expression of Mcl-1 and Bcl-2. Further studies will aim to determine the mechanism of action of KS99 and as a single agent and in combination with anti-leukemia agents and demonstrate the preclinical efficacy in AML animal models including AML patient derived xenografts. Together, these data demonstrate the therapeutic efficacy of Isatin analog and suggest that KS99 should be further developed as a novel therapeutic agent for AML. Citation Format: Krishne Gowda, Charyguly Annageldiyev, Dhimant Desai, Shantu Amin, David Claxton, Arati Sharma. Isatin analog for the treatment of acute myeloid leukemia [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 795.
Abstract 5336: Methylation patterns in hepatoblastoma: A report from the Children's Oncology Group
Authors: Erin Marcotte, Logan G. Spector, Heather Nelson, Gail Tomlinson, Mark Krailo, Lauren Mills, Jenny Poynter
Journal: Cancer Research (2018)

Abstract Introduction. Hepatoblastoma (HB) accounts for over 80% of all liver cancer diagnosed in children under 15 years of age in the United States. Aberrant DNA methylation has been implicated in the pathogenesis of multiple types of cancer, including HB. Global hypomethylation and DNA methylation in the promoter region of selected tumor suppressor genes, including RASSF1A, p16, SOCS1, CASP8, and MT1G, has been observed in previous studies of HB. Methods. A total of 47 flash-frozen samples of HB tumors were available for analysis. These tumors include 26 tumors from cases enrolled in Children's Oncology Group study AEPI04C1 (the HOPE study) and 21 tumors obtained as part of the Children's Oncology Group P9346 HB biology protocol. The Cooperative Human Tissue Network Pediatric Division (CHTN; Columbus, OH) provided 23 normal liver tissue samples from children ages 0—6 to serve as controls in this analysis. Initial multi-dimensional scaling (MDS) plots showed that 8 samples, 2 control and 6 patients, did not cluster with the other samples of the same group and were considered outliers. These 8 samples were removed from the study leaving a total of 62 samples, 21 control and 41 patients, remaining. Differentially methylated regions (DMR) were identified between control and patient samples using the bumphunter algorithm included in the minfi package. We used Ingenuity Pathway Analysis (IPA) to identify pathways that were enriched in the group of CpG with a change in methylation beta value of ≥39% between patients and controls. Results. We found 4833 DMR, which are associated with 3543 genes, when comparing HB patients and controls. Pathway analysis revealed 76 pathways enriched among the DMR. Conclusions. Identification of methylation patterns may elucidate the developmental stage at which HB arose and the at-risk period when environmental exposures could be most harmful. Further, understanding the relevant genetic pathways could lead to the development of new targets for therapy. Citation Format: Erin Marcotte, Logan G. Spector, Heather Nelson, Gail Tomlinson, Mark Krailo, Lauren Mills, Jenny Poynter. Methylation patterns in hepatoblastoma: A report from the Children's Oncology Group [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 5336.
Abstract 20662: Impact of Routine Handheld Focused Cardiac Ultrasonography on the Diagnosis and Management of Hospitalized Cardiac Patients: The CAPITAL FoCUS Registry
Authors: Benjamin Hibbert, Trevor Simard, F Daniel Ramirez, Pietro Di Santo, Christopher Johnson, Michel Turek, Marino Labinaz, Benjamin Chow, Michel R Le May
Journal: Circulation (2016)

Background: History and physical examination remains the basis of initial patient evaluation. Increasingly ultraportable handheld ultrasound units are being utilized to perform focused cardiac ultr...
Abstract 5236: ARV-110: An androgen receptor PROTAC degrader for prostate cancer
Authors: Taavi Neklesa, Lawrence B. Snyder, Ryan R. Willard, Nicholas Vitale, Kanak Raina, Jennifer Pizzano, Deborah Gordon, Mark Bookbinder, Jennifer Macaluso, Hanqing Dong, Zheng Liu, Caterina Ferraro, Gan Wang, Jing Wang, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor
Journal: Cancer Research (2018)

Abstract The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Here we report an orally bioavailable small molecule ARV-110 that leads to ubiquitination and degradation of AR. ARV-110 completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) &amp;lt; 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target genes PSA and FKBP5, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, ARV-110 demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. In summary, we report preclinical data on ARV-110, an orally bioavailable androgen receptor PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer. Citation Format: Taavi Neklesa, Lawrence B. Snyder, Ryan R. Willard, Nicholas Vitale, Kanak Raina, Jennifer Pizzano, Deborah Gordon, Mark Bookbinder, Jennifer Macaluso, Hanqing Dong, Zheng Liu, Caterina Ferraro, Gan Wang, Jing Wang, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. ARV-110: An androgen receptor PROTAC degrader for prostate cancer [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 5236.
Pancreatic Bile Salt-Dependent Lipase Induces Smooth Muscle Cells Proliferation
Authors: NathalieAugé, OuafaRebaï, JosetteLepetit-Thévenin, NadineBruneau, Jean-ClaudeThiers, EricMas, DominiqueLombardo, AnneNegre-Salvayre, AlainVérine
Journal: Circulation (2003)

Background— Because bile salt-dependent lipase (BSDL), an enzyme secreted by the pancreatic acinar cells and associated with LDL in circulating blood, also locates with smooth muscle cells (SMCs) in atherosclerotic lesions, we aimed to investigate its effects on SMCs. Methods and Results— Immunohistochemical experiments allowed us to detect an expression of BSDL in atherosclerotic lesions from hypercholesterolemic monkeys and from human arteries. BSDL was found to be associated with SMCs but not with macrophages. BSDL was significantly mitogenic for cultured SMCs. This effect was inhibited by heparin and anti-BSDL antibodies, whereas heat-denaturated and diisopropylfluorophosphate-treated BSDL were inefficient. The mitogenic effect of BSDL was associated with an activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway, which was inhibited by heparin, and involved several mechanisms, among them diacylglycerol and oleic acid production as well as a rapid basic fib...
Tokyo medical school investigates claims that it rigged exam results to turn women away
Authors: Owen Dyer
Journal: BMJ (2018)

One of Japan’s most prestigious medical schools has been reducing the exam scores of all female applicants since 2011 to turn away more women, multiple Japanese news outlets have said, reporting that the practice could be widespread in Japan.

The proportion of women among new students at Tokyo Medical University, a private medical school, has been falling since 2010, when it reached a record high of 38%. This year only 18% of entrants are women, although women still made up 39% of applicants. Male applicants had three times the success rate of women.

The allegation was first raised by the Yomiuri Shimbun , the country’s most read newspaper. An unnamed source claimed that the discrimination policy was seen as a “necessary evil.”

“Many female students …
PTH-136 Two years on linaclotide: tolerability and treatment satisfaction in patients with irritable bowel syndrome with constipation with and without diarrhoea
Authors: HA Schneier, SJ Shiff, X Hao, JG Chickering, CB Kurtz, MG Currie, JM Johnston
Journal: Gut (2017)

Introduction  Linaclotide (LIN) has been shown to improve abdominal pain and stool frequency and was well tolerated in Phase 3 clinical trials of patients (pts) with irritable bowel syndrome with constipation (IBS-C). Here we evaluate the most common LIN adverse event (AE), diarrhoea, and assess tolerability and treatment satisfaction (Tx sat) in IBS-C pts who rolled over (RO) from a Phase 3 trial into a long-term study (LTS) of LIN.  Method  Pts meeting modified Rome II IBS-C criteria were randomised to oral 290 µg LIN or placebo daily in a 6 month Phase 3 trial. RO pts completed Phase 3 and entered an open-label 18 month LTS. Tx sat (not at all, a little, moderately, quite, very) and AEs, including any reports of diarrhoea, were recorded at all study visits; AE severity was assessed by the investigator based on pt description. In the LTS, pts could interrupt, reduce (145 µg) or withdraw from dosing due to AEs. Tx sat was assessed in pts with and without diarrhoea.  Results  Of 535 IBS-C RO pts in the LTS, 79% had ≥1 AE; 45 pts (8%) withdrew due to an AE; 24 pts (4.5%) reported ≥1 serious AE (SAE). Diarrhoea, the most common AE (171 pts; 32%; 0.29/pt-year), was mostly mild or moderate in severity and led to withdrawal in 18 pts (3%) [Table 1]. There were no diarrhoea-related SAEs. 131 pts (24%) decreased and/or interrupted their LIN dose due to diarrhoea; the majority of these pts continued in the study (Table 2). Pts averaged at least moderate Tx sat; >70% of pts were moderately to very satisfied with LIN treatment regardless of whether they had diarrhoea (figure 1).  Conclusion  During up to 2 years on LIN, IBS-C pts were moderately to quite satisfied with treatment on average. Diarrhoea AEs were generally mild or moderate in severity and infrequently led to study withdrawal. TX sat was similar in LIN-treated pts who did and did not report diarrhoea. LIN was well tolerated.  Disclosure of Interest  H. Schneier: None Declared, S Shiff Conflict with: Allergan plc, Conflict with: Allergan plc, X Hao Conflict with: Ironwood Pharmaceuticals, J Chickering Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals and Allergan plc, Conflict with: Ironwood Pharmaceuticals, C Kurtz Conflict with: Ironwood Pharmaceuticals, M Currie Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals, J Johnston Conflict with: Ironwood Pharmaceuticals, Conflict with: Ironwood Pharmaceuticals
p38 Mitogen-Activated Protein Kinase Mediates a Negative Inotropic Effect in Cardiac Myocytes
Authors: PuLiao, Shi-QiangWang, SuWang, MingZheng, MeiziZheng, Sheng-JunZhang, HepingCheng, YibinWang, Rui-PingXiao
Journal: Circulation Research (2002)

p38 Mitogen-activated protein kinase (MAPK) is one of the most ancient signaling molecules and is involved in multiple cellular processes, including cell proliferation, cell growth, and cell death. In the heart, enhanced activation of p38 MAPK is associated with ischemia/reperfusion injury and the onset of heart failure. In the present study, we investigated the function of p38 MAPK in regulating cardiac contractility and its underlying mechanisms. In cultured adult rat cardiomyocytes, activation of p38 MAPK by adenoviral gene transfer of an activated mutant of its upstream kinase, MKK3bE, led to a significant reduction in baseline contractility, compared with uninfected cells or those infected with a control adenoviral vector (Adv-β-galactosidase). The inhibitory effect of MKK3bE on contractility was largely prevented by coexpressing a dominant-negative mutant of p38 MAPK or treating cells with a p38 MAPK inhibitor, SB203580. Conversely, inhibition of endogenous p38 MAPK activity by SB203580 rapidly and ...
Effect of Hydrodynamics-Based Gene Delivery of Plasmid DNA Encoding Interleukin-1 Receptor Antagonist-Ig for Treatment of Rat Autoimmune Myocarditis
Authors: HuiLiu, HaruoHanawa, TsuyoshiYoshida, RaafatElnaggar, ManabuHayashi, RitsuoWatanabe, KenToba, KaoriYoshida, HeChang, YujiOkura, KiminoriKato, MakotoKodama, HirokiMaruyama, JunichiMiyazaki, MikioNakazawa, YoshifusaAizawa
Journal: Circulation (2005)

Background— Interleukin-1 (IL-1) is a powerful and important cytokine in myocarditis. The purpose of this study was to evaluate the effect and possible mechanism of hydrodynamics-based delivery of the IL-1 receptor antagonist (IL-1RA)-immunoglobulin (Ig) gene for treatment of rat experimental autoimmune myocarditis (EAM). Methods and Results— On the day after immunization, rats were transfected with either pCAGGS encoding IL-1RA-Ig or pCAGGS encoding Ig alone. On day 17, IL-1RA-Ig gene therapy was effective in controlling EAM, as monitored by a decreased ratio of heart weight to body weight, reduced myocarditis areas, reduced gene expression of atrial natriuretic peptide in hearts, and improved cardiac function in echocardiographic and hemodynamic parameters. Examination of the expression of IL-1–related genes in purified cells from EAM hearts suggested that ectopic IL-1RA-Ig-acting target cells were αβT cells and noncardiomyocytic noninflammatory cells such as fibroblasts, smooth muscle cells, and endoth...
Abstract 576: A cancer drug atlas enables prediction of parallel drug vulnerabilities
Authors: Ravi Narayan, Piet Molenaar, Jian Teng, Bakhos Tannous, Tom Wurdinger, Jan Koster, Bart Westerman
Journal: Cancer Research (2018)

Abstract Personalized cancer treatments using synergistic combinations of drugs is attractive but proves to be highly challenging. The combinatorial nature of such problems results in an enormous parameter space that cannot be resolved by empirical research, i.e. testing all combinations for all molecularly defined tumors. In addition, effective drug synergy is hard to predict. Here we present an approach to map data of drug-response encyclopedias and represent these as a drug atlas. This atlas consists of a framework of chemotherapeutic responses that represents a drug vulnerability landscape of cancer. Based on data from the literature we found that many synergistic drug combinations show distinct inter therapy responses and drug sensitivities. We confirmed this by performing a drug combination screen against glioblastoma where we used 270 combination experiments. From the identified dual therapies we were able to predict and validate a triple drug synergy which was validated in vivo. This new and generalizable strategy opens the door to unforeseen personalized multidrug combination approaches. Citation Format: Ravi Narayan, Piet Molenaar, Jian Teng, Bakhos Tannous, Tom Wurdinger, Jan Koster, Bart Westerman. A cancer drug atlas enables prediction of parallel drug vulnerabilities [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 576.
Abstract 3894: DPYD-Varifier, a computational model to identify 5-FU toxicity-associated <i>DPYD</i> variants
Authors: Shikshya Shrestha, Cheng Zhang, Calvin R. Jerde, Hu Li, Steven M. Offer, Robert B. Diasio
Journal: Cancer Research (2018)

Abstract 5-Fluorouracil (5-FU) is a cornerstone therapy for the treatment of several aggressive tumors. However, nearly 1/3 of patients receiving 5-FU experience severe (grade 3+) adverse 5-FU toxicity. Genetic variations in dihydropyrimidine dehydrogenase (DPD; DPYD gene) are major contributors of 5-FU toxicity. With continued progress in next-generation sequencing technologies, the number of reported genetic variants is substantially increasing; to date, there are more than 450 reported missense variants in the DPYD gene. Only a handful of those variants, including *2A, I560S, D949V, and rs75017182, have been established as predictors of toxicity. Because most of the remaining variants are unstudied, mainly due to their rare occurrence and unequal racial distribution, it is challenging to conduct statistically powered clinical association studies. Therefore, in vitro and computational methods to identify potential toxicity-associated variants have major appeal. The primary goal of the current study was to develop a highly accurate gene-specific in silico classifier to predict deleterious DPYD variants. For this purpose, using a recombinant cellular model, we characterized 69 missense DPYD variants reported in online databases. We then utilized DPD activity data from the 69 variants in combination with data from 87 previously characterized variants (see Offer, SM et al. Cancer Research 2013 &amp; 2014) to develop the DPYD variant classifier model (DPYD-Varifier). DPD protein-specific biochemical and structural features and amino acid conservation scores were integrated into the model's random forest classifier-based algorithm. DPYD-Varifier showed improved accuracy (85% accurate) compared to other in silico tools. Additionally, the model provided mechanistic insights into alterations of DPD function conferred by DPYD variants. In general, deleterious variants were located in closer proximity to important binding/coordinating sites of the DPD protein. Additionally, DPYD-Varifier allowed us to estimate the cumulative allele frequency of all reported deleterious variants in various geographical/racial groups, which can substantially add to our knowledge of DPD deficiency and 5-FU toxicity observed in these populations. In conclusion, the integration of in vitro and accurate computational data from our study permitted classification of relevant DPYD variants, which could be useful to more effectively individualize 5-FU therapy in the future. Citation Format: Shikshya Shrestha, Cheng Zhang, Calvin R. Jerde, Hu Li, Steven M. Offer, Robert B. Diasio. DPYD-Varifier, a computational model to identify 5-FU toxicity-associated DPYD variants [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 3894.
Abstract 12241: Exploring the Interaction Between Nighttime Heart Rate and Heart Rate Variability on Future Cardiovascular Event
Authors: Keita Negishi, Satoshi Hoshide, Tomoyuki Kabutoya, Yukako Ogoyama, Kazuo Eguchi, Kazuomi Kario
Journal: Circulation (2015)

Introduction: High nighttime heart rate or heart rate variability assessed by ambulatory blood pressure monitoring (ABPM) has been reported to be risk for cardiovascular events. However, it is not clear whether these indices provide synergic risk for cardiovascular events. Hypothesis: The aim of this study is to explore the interaction between nighttime heart rate and heart rate variability on future cardiovascular event. Methods: We studied 1418 patients (average age 64.6±11.6 years, male 47.9%) from J-HOP study who were performed ABPM. We divided average nighttime heart rate (NHR) and nighttime heart rate variability (NHRV) defined as standard deviation of nighttime heart rate into decile groups, and defined the top decile group (NHR 70bpm, NHRV 9.7bpm) as abnormal group, respectively. The average follow-up period was 5.0 years and the incidence of cardiovascular event was 56 events. Results: Kaplan-Meier curve showed that the incidence of cardiovascular event with abnormal NHR and NHRV was higher than those without (Figure A and B). When we divided the patients into 4 groups according to those with or without abnormal NHR and with or without abnormal NHRV, the incidence of cardiovascular event for the group with both abnormal NHR and NHRV was the highest among 4 groups (Figure C). After adjustment for age, sex, body mass index, smoking, alcohol, past history of cardiovascular disease, diabetes, dyslipidemia and 24hr systolic blood pressure, abnormal NHR and NHRV, the presence of abnormal HHR and NHRV has a synergic risk for cardiovascular event (Odds ratio, 7.27; 95% confidence interval, 1.53 to 34.60, P&lt;0.013). Conclusions: The presence of nighttime higher heart rate and heart rate variability obtained every 30 minutes by ABPM has a synergic risk for cardiovascular event.