tbuckley/cabot-search huggingface dataset:
Abstract 3595: DSP-0692, a selective SCD inhibitor, enhances the anti-tumor activity of anti-PD1 antibody
Authors: Eiji Sugaru, Yudai Furuta, Yoshikazu Nagagaki, Satoshi Ikeda, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Shingo Tojo, Miki Hashizume, Yasushi Matsuki, Hitoshi Ban
Journal: Cancer Research (2019)

Abstract SCD (Stearoyl-CoA Desaturase), a key enzyme for lipid metabolism, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. We have previously shown that the identification and the functional characterization of DSP-0692, a novel and selective SCD inhibitor. SCD expression was induced in tumor cells cultured in sphere conditions, which were resistant to conventional agents within therapeutic concentration. DSP-0692 showed strong growth inhibition when tumor cells were cultured in sphere conditions, but had little impact on cells cultured under adherent conditions. In addition, DSP-0692 decreased the expression of stemness-related genes in tumor cells as well as in tumor tissues. Treatment with DSP-0692 suppressed tumor growth in multiple models both in single agent or in combination with conventional chemotherapies. DSP-0692 also inhibited WNT/beta-catenin signaling pathway through two different mechanisms (inhibition of Wnt3A secretion and nuclear translocation of beta-catenin). DSP-0692 exhibited lower IC50 value to sphere cells carrying mutations related to WNT/beta-catenin signaling pathway than those without these mutations. Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers. However, despite successes in the clinical setting, only a limited subpopulation respond to PD-1 blockade. We hypothesized that the deregulated lipid metabolism of tumor cells and microenvironment function as a barrier to antitumor immunity, and therefore that normalization of lipid metabolism with DSP-0692 might restore response to immunotherapy. Combination of DSP-0692 with anti-PD-1 antibody in the syngeneic CT-26 colon model, a resistant model to anti-PD-1 antibody, augmented tumor regressions relative to each single agent alone. DSP-0692 induced PD-L1 and PD-L2 expression in CT-26 cells, indicating that it is one of a mechanism of restoration of the effect of anti-PD-1 antibody. Our data suggest that remodeling the lipogenic tumor microenvironment has potential to convert patients resistant to immunotherapy into those who may receive clinical benefit of immunotherapy. Citation Format: Eiji Sugaru, Yudai Furuta, Yoshikazu Nagagaki, Satoshi Ikeda, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Shingo Tojo, Miki Hashizume, Yasushi Matsuki, Hitoshi Ban. DSP-0692, a selective SCD inhibitor, enhances the anti-tumor activity of anti-PD1 antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3595.
Cognitive Effects of MDMA in Laboratory Animals: A Systematic Review Focusing on Dose
Authors: Madeline M. Pantoni, Stephan G. Anagnostaras
Journal: Pharmacological Reviews (2019)

±3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic, psychoactive drug that is primarily used recreationally but also may have some therapeutic value. At low doses, MDMA produces feelings of relaxation, empathy, emotional closeness, and euphoria. Higher doses can produce unpleasant psychostimulant- and hallucinogen-like adverse effects and therefore are usually not taken intentionally. There is considerable evidence that MDMA produces neurotoxicity and cognitive deficits at high doses; however, these findings may not generalize to typical recreational or therapeutic use of low-dose MDMA. Here, we systematically review 25 years of research on the cognitive effects of MDMA in animals, with a critical focus on dose. We found no evidence that doses of less than 3 mg/kg MDMA—the dose range that users typically take—produce cognitive deficits in animals. Doses of 3 mg/kg or greater, which were administered most often and frequently ranged from 5 to 20 times greater than an average dose, also did not produce cognitive deficits in a slight majority of experiments. Overall, the preclinical evidence of MDMA-induced cognitive deficits is weak and, if anything, may be the result of unrealistically high dosing. While factors associated with recreational use such as polydrug use, adulterants, hyperthermia, and hyponatremia can increase the potential for neurotoxicity, the short-term, infrequent, therapeutic use of ultra low-dose MDMA is unlikely to pose significant cognitive risks. Future studies must examine any adverse cognitive effects of MDMA using clinically relevant doses to reliably assess its potential as a psychotherapeutic.
The combined treatment of 150 kHz Tumor Treating Fields (TTFields) and sorafenib shows In vitro and in vivo efficacy in hepatocellular carcinoma
Authors: S. Davidi, K. Gotlib, E. Zeevi, R. Shnaiderman, T. Voloshin, M. Giladi, A. Kinzel, U. Weinberg, E. Kirson, Y. Palti
Journal: Annals of Oncology (2019)
Invasive strep A outbreak in Essex leaves 12 people dead
Authors: Elisabeth Mahase
Journal: BMJ (2019)

A dozen people have died in Essex after an outbreak of invasive group A streptococcal (iGAS) disease.1

NHS Mid Essex Clinical Commissioning Group (CCG) has reported 32 cases of iGAS to date in the area, mostly among elderly people who had treatment for wounds in care homes and their own homes. The CCG said that 12 people have died as a result of the infection.

Public Health England (PHE) has said it is an “evolving …
Abstract 599: Smoking-associated <i>AHRR</i> demethylation in cord blood DNA: Impact of CD235a+ nucleated red blood cells
Authors: Matthew A. Bergens, Gary S. Pittman, Isabel J. Thompson, Michelle R. Campbell, Xuting Wang, Ma Wan, Cathrine Hoyo, Douglas A. Bell
Journal: Cancer Research (2019)

Abstract Prenatal tobacco smoke exposure is associated with numerous adverse health outcomes at birth and in later life. Numerous studies have demonstrated that Aryl Hydrocarbon Receptor Repressor gene (AHRR) hypomethylation in umbilical cord blood is significantly associated with prenatal tobacco smoke exposure and is suitable as a fetal exposure biomarker. The mechanism driving this demethylation and whether all cord blood cell types are impacted is unclear. Nucleated red blood cells (nucleated CD235a+ cells, nRBCs) are developmentally immature RBCs that display genome-wide demethylation and are observed at increased frequency in the cord blood of smoking mothers. We assessed if nRBC counts or methylation level affected smoking-associated DNA methylation in the AHRR gene as measured in whole cord blood. We analyzed methylation in DNA from whole cord blood, CD14+ monocytes, and nRBCs across four AHRR CpGs using pyrosequencing and also with Illumina 850K arrays (cg05575921) from smoking (n=34) and nonsmoking (n=19) mothers. nRBCs present in cord blood were determined by conventional CBCs and also estimated with a Houseman deconvolution model. AHRR methylation levels were significantly lower in nRBCs relative to whole blood and CD14+ monocytes. Methylation values at each AHRR CpG averaged 14.6% lower in nRBCs (range 0.4% to 24%, p=3.9E-13) relative to CD14+ monocytes with nonsmokers displaying significantly greater hypomethylation in nRBCs than smokers. Methylation levels at each CpG across the AHRR DMR were strongly associated with either self-reported smoking or cord blood cotinine levels in both CD14+ monocytes (r2=0.45, p=4.6E-08) and nRBCs (r2=0.26, p=1.2E-04). The most significant prenatal smoking effect on methylation occurred in CD14+ monocytes at the CpG located at chr5:373490 (-16.7%, p=6.7E-09), 112nt downstream of cg05575921. For subjects with 850K data, adjusting a regression analysis model with estimated cell-type composition, including nRBC counts or estimates, marginally increased the magnitude and significance of the prenatal smoke exposure effect on AHRR cg05575921 methylation. Prenatal tobacco smoke exposure strongly affects DNA methylation in the AHRR gene and this prenatal smoke exposure biomarker is largely unaffected by cord blood cell type composition. Citation Format: Matthew A. Bergens, Gary S. Pittman, Isabel J. Thompson, Michelle R. Campbell, Xuting Wang, Ma Wan, Cathrine Hoyo, Douglas A. Bell. Smoking-associated AHRR demethylation in cord blood DNA: Impact of CD235a+ nucleated red blood cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 599.
Association Between Androgen Deprivation Therapy Use and Diagnosis of Dementia in Men With Prostate Cancer
Authors: Ravishankar Jayadevappa, Sumedha Chhatre, S. Bruce Malkowicz, Ravi B. Parikh, Thomas Guzzo, Alan J. Wein
Journal: JAMA Network Open (2019)

<h3>Importance</h3> The association between androgen deprivation therapy (ADT) exposure and dementia is uncertain. <h3>Objective</h3> To analyze the association between ADT exposure and diagnosis of Alzheimer disease or dementia among elderly men with prostate cancer. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results–Medicare linked database. Participants were 154 089 elderly men newly diagnosed with prostate cancer between 1996 and 2003. The analyses were conducted between November 1, 2018, and December 31, 2018. <h3>Exposure</h3> Androgen deprivation therapy. <h3>Main Outcomes and Measures</h3> Patients receiving ADT within 2 years of prostate cancer diagnosis were identified. Survival analysis was used to determine the association between ADT exposure and diagnosis of Alzheimer disease or dementia in the follow-up period. Propensity score and instrumental variable approaches were used to minimize measured and unmeasured selection bias. The association by dose of ADT was also examined. <h3>Results</h3> Of the 295 733 men diagnosed with prostate cancer between 1996 and 2003, 154 089 met the study criteria. Of these, 62 330 (mean [SD] age, 76.0 [6.0] years) received ADT within 2 years of prostate cancer diagnosis, and 91 759 (mean [SD] age, 74.3 [6.0] years) did not receive ADT. Mean (SD) follow-up was 8.3 (4.7) years. Exposure to ADT, compared with no ADT exposure, was associated with a diagnosis of Alzheimer disease (13.1% vs 9.4%; difference, 3.7%; 95% CI, 3.3%-3.9%;<i>P</i> &lt; .001; hazard ratio [HR], 1.14; 95% CI, 1.10-1.18) and dementia (21.6% vs 15.8%; difference, 5.8%; 95% CI, 5.4%-6.2%;<i>P</i> &lt; .001; HR, 1.20; 95% CI, 1.17-1.24). For 1 to 4 doses of ADT, the HR was 1.19 (95% CI, 1.15-1.24) for Alzheimer disease and 1.19 (95% CI, 1.15-1.23) for dementia. For 5 to 8 doses of ADT, the HR was 1.28 (95% CI, 1.22-1.35) for Alzheimer disease and 1.24 (95% CI, 1.19-1.29) for dementia. For more than 8 doses of ADT, the HR was 1.24 (95% CI, 1.16-1.34) for Alzheimer disease and 1.21 (95% CI, 1.15-1.28) for dementia. The number needed to harm was 18 patients (95% CI, 17-19 patients) and 10 patients (95% CI, 9.5-11 patients) for Alzheimer disease and dementia, respectively. <h3>Conclusions and Relevance</h3> Among elderly patients with prostate cancer, ADT exposure was associated with subsequent diagnosis of Alzheimer disease or dementia over a follow-up period of at least 10 years.
Abstract 1655: A structural approach for prioritizing variants in personalized Oncology
Authors: Siao-Han Wong, Brors Benedikt
Journal: Cancer Research (2019)

Abstract In personalized oncology, treatment strategies take individualized genomic aberrations into consideration and relies heavily on how the cancer genomes are interpreted. With immense efforts put into cohort studies, knowledge of pathogenicity at the gene level had been accumulated. On the other hand, the increasing amount of personalized clinical trials and the accompanying need of interpreting pathogenecity at the sub-gene level emphasize the importance of resolving heterogeneous significance within genes. There had been some initiatives where people identified mutation hotspots within genes, looking at either highly recurrent single residues or mutation clusters. The hotspot clusters can be inferred from protein sequences as well as from protein structures, where residues distant in sequence may be brought together through protein folding. Nonetheless, these information are not well utilized in routine clinical settings yet. In this study, we aim to build a consensus list of prevalent mutational events for molecular stratification of patients. This is achieved by collecting sequence and structural mutation hotspots from different algorithms, and further combine structural information to identify their neighboring residues in protein structures. Specifically, around 1400 residue hotspots are collected from CancerHotspots and DominoEffect. An additional of around 250 structural hotspots are identified by three structural algorithms, namely 3DHotSpots, HotMAPS and HotSpot3D. These results are mostly derived from TCGA PanCancer cohorts, with CancerHotspots included more other studies in the analysis. With this consensus information in place, we further set up the mechanism to map from genomic variants to protein sequence and protein structures. This enables us to annotate the variants found in patient genome and see whether they co-localize with hotspot residues, in their structural neighborhood, or in structural informative domains like interaction interfaces. In summary, a higher prevalence of variants might imply higher significance and more well-studied roles than other low prevalent mutant alleles. Transferring this knowledge from the public cohorts helps researchers quickly prioritize variants found in patient genomes. Annotating structural significance of variants further provides us with more confidence in identifying driving events. With these procedures automated, the goal is to help facilitate clinical evaluations to meet the growing number of patients recruited to personalized oncology trials. Citation Format: Siao-Han Wong, Brors Benedikt. A structural approach for prioritizing variants in personalized Oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1655.
Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia
Authors: Zahid Ahmad, Poulabi Banerjee, Sara Hamon, Kuo-Chen Chan, Aurelie Bouzelmat, William J. Sasiela, Robert Pordy, Scott Mellis, Hayes Dansky, Daniel A. Gipe, Richard L. Dunbar
Journal: Circulation (2019)

Background: Hypertriglyceridemia is associated with increased cardiovascular risk and may be caused by impaired lipoprotein clearance. Angiopoietin-like protein 3 (ANGPTL3) inhibits lipoprotein lipase activity, increasing triglycerides and other lipids. Evinacumab, an ANGPTL3 inhibitor, reduced triglycerides in healthy human volunteers and in homozygous familial hypercholesterolemic individuals. Results from 2 Phase 1 studies in hypertriglyceridemic subjects are reported here. Methods: Subjects with triglycerides &gt;150 but ≤450 mg/dL and low-density lipoprotein cholesterol ≥100 mg/dL (n=83 for single ascending dose study [SAD]; n=56 for multiple ascending dose study [MAD]) were randomized 3:1 to evinacumab:placebo. SAD subjects received evinacumab subcutaneously at 75/150/250 mg, or intravenously at 5/10/20 mg/kg, monitored up to day 126. MAD subjects received evinacumab subcutaneously at 150/300/450 mg once weekly, 300/450 mg every 2 weeks, or intravenously at 20 mg/kg once every 4 weeks up to day 56 with 6 months of follow-up. The primary outcomes were incidence and severity of treatment-emergent adverse events. Efficacy analyses included changes in triglycerides and other lipids over time. Results: In the SAD, 32 (51.6%) versus 9 (42.9%) subjects on evinacumab versus placebo reported treatment-emergent adverse events. In the MAD, 21 (67.7%) versus 9 (75.0%) subjects on subcutaneously evinacumab versus placebo and 6 (85.7%) versus 1 (50.0%) on intravenously evinacumab versus placebo reported treatment-emergent adverse events. No serious treatment-emergent adverse events or events leading to death or treatment discontinuation were reported. Elevations in alanine aminotransferase (7 [11.3%] SAD), aspartate aminotransferase (4 [6.5%] SAD), and creatinine phosphokinase (2 [3.2%) SAD, 1 [14.3%] MAD) were observed with evinacumab (none in the placebo groups), which were single elevations and were not dose-related. Dose-dependent reductions in triglycerides were observed in both studies, with maximum reduction of 76.9% at day 3 with 10 mg/kg intravenously ( P &lt;0.0001) in the SAD and of 83.1% at day 2 with 20 mg/kg intravenously once every 4 weeks ( P =0.0003) in the MAD. Significant reductions in other lipids were observed with most evinacumab doses versus placebo. Conclusion: Evinacumab was well-tolerated in 2 Phase 1 studies. Lipid changes in hypertriglyceridemic subjects were similar to those observed with ANGPTL3 loss-of-function mutations. Because the latter is associated with reduced cardiovascular risk, ANGPTL3 inhibition may improve clinical outcomes. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifiers: NCT01749878 and NCT02107872.
Abstract 17739: Modelling Long-QT Syndrome Associated With a Calmodulin Mutation Using Human Induced Pluripotent Stem Cells
Authors: Yuta Yamamoto, Takeru Makiyama, Takeshi Harita, Kenichi Sasaki, Mamoru Hayano, Suguru Nishiuchi, Yimin Wuriyanghai, Hirohiko Kohjitani, Sayako Hirose, Jiarong Chen, Taisuke Ishikawa, Seiko Ohno, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
Journal: Circulation (2015)

Background: Calmodulin ( CALM ) is a ubiquitous Ca2+-sensor molecule, and it modulates various proteins including several ion channels, ryanodine receptor 2, and Ca 2+ /calmodulin-dependent protein kinase. Recently, several studies reported that CALM mutations are associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism remains unknown. Purpose: The present study aims to establish the in-vitro disease model of CALM -related LQTS and elucidate the pathophysiological mechanism using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Methods: The hiPSC clones were generated from a 12-year-old boy with LQTS carrying a missense CALM2 mutation (c.293A&gt;G, p.N98S), and differentiated into cardiomyocytes via embryoid body (EB) formation. The electrophysiological characteristics of CALM2 -N98S hiPSC-CMs, including action potential (AP) and L-type Ca 2+ channel (LTCC) currents, were analyzed by patch-clamp technique, and compared with those of hiPSC-CMs derived from healthy control. Results: The beating rate of CALM2 -N98S EBs was significantly lower than that of control (23.8 ± 1.6 bpm vs 47.3 ± 1.7 bpm, p &lt; 0.01). The corrected AP duration at 90% repolarization (cAPD90) of CALM2 -N98S hiPSC-CMs was significantly prolonged compared to that of control (480.9 ± 59.4 ms vs 201.5 ± 19.5 ms, p &lt; 0.01, Figure). At 1 Hz pacing, CALM2 -N98S hiPSC-CMs exhibited significantly longer APD90 than control (495.5 ± 47.7 ms vs 227.8 ± 21.6 ms, p &lt; 0.01). The time constants of LTCC inactivation tau fast of CALM2 -N98S hiPSC-CMs were significantly larger than those of control at 0, +10, and +20 mV test potentials (Figure). Conclusion: The hiPSC-CMs model of CALM2 -related LQTS successfully recapitulated the disease phenotypes, and elucidated the pathophysiological mechanism: impaired inactivation of LTCC currents. This model might be useful for drug discovery in CALM2 -related LQTS.
Abstract 1327: UM-9107: A selective wild-type and T315I Bcr-Abl inhibitor with in vivo activity against chronic myelogenous leukemia
Authors: Sameer Phadke, Lluis Lopez-Barcons, Taylor K. Johnson, Eric J. Lachacz, Sofia D. Merajver, Matthew B. Soellner
Journal: Cancer Research (2019)

Abstract Purpose: Long-term treatment of chronic myelogenous leukemia (CML) with the Bcr-Abl inhibitor imatinib, is initially successful but gives rise to several drug-resistant mutations. The most prevalent of these is the T315I ‘gatekeeper’ mutation that is sensitive to the second-line therapy, ponatinib. However, ponatinib causes serious vascular adverse events, including fatalities, in over 25% of patients, in part due to its target promiscuity. We have designed a novel Bcr-Abl inhibitor (UM-9107) that shows significant in vitro and in vivo anti-CML activity against wild-type and drug-resistant mutants, including the gatekeeper mutant. Furthermore, UM-9107 has excellent selectivity across the kinome and in vitro surrogate toxicity assessment models demonstrate a low likelihood of vascular adverse events as compared to ponatinib. Experimental Design: We designed a series of compounds to specifically interact with a specific kinked conformation of the phosphate-binding loop of Abl. Since only a small proportion of kinases display this kinked conformation, we hypothesized that our compounds would be selective for Abl. We have analyzed the compound series biochemically and in vitro. The most potent compound, UM-9107, has been comprehensively characterized including: biochemical inhibition, cellular target engagement, kinome-wide profiling, in vitro cell proliferation, pharmacokinetic studies, and in vivo activity in xenograft models of CML. Results: We demonstrate that UM-9107 potently inhibits all clinical mutants of Bcr-Abl, including the T315I gatekeeper mutant. UM-9107 shows robust activity against CML cell lines, comparable to ponatinib, with significantly fewer off-targets, as determined by kinome-wide profiling. Phenotypic profiling of UM-9107 in human primary cells shows low risk of vascular adverse events as indicated by specific biomarker readouts. UM-9107 demonstrates good oral bioavailability and in vivo activity in xenograft models of CML, with low toxicity. Conclusions: The success of imatinib has been revolutionary and has led to an increase in the number of patients on long-term therapy. This inevitably gives rise to drug resistance through point mutations in the Bcr-Abl protein. Our results suggest that UM-9107 is a safe and efficacious preclinical candidate for the treatment of imatinib-resistant CML. Citation Format: Sameer Phadke, Lluis Lopez-Barcons, Taylor K. Johnson, Eric J. Lachacz, Sofia D. Merajver, Matthew B. Soellner. UM-9107: A selective wild-type and T315I Bcr-Abl inhibitor with in vivo activity against chronic myelogenous leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1327.