tbuckley/cabot-search huggingface dataset:
Abstract 5273: Multi-omics approaches reveal potential role for corticosterone in prostate cancer
Authors: Iqbal Mahmud, Bongyong Lee, Ranjan Perera, Timothy J. Garrett
Journal: Cancer Research (2019)

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer in American men. In 2018, 164,690 new cancer cases and 29,430 cancer deaths are projected to occur in the United States. Currently, there is no efficient diagnostic and safe treatment option for the management of PCa. Using Ultra-High Performance Liquid Chromatography coupled High Resolution Mass Spectrometry (UHPLC-HRMS), we globally profiled more than 1400 metabolites across 79 urine samples related to PCa (19 control, 23 benign prostate hyperplasia (BPH), 11 prostatitis, and 26 PCa samples). Among all, corticosterone was identified as a top differential metabolite. Corticosterone levels were markedly elevated in PCa urine samples and modest but significant elevation of the corticosterone in BPH and prostatitis urine samples compared to controls, with an excellent area under the receiver operating characteristic curve of 0.95, 0.94, and 0.93, respectively. In addition, the expression of corticosterone biosynthetic gene, Steroid 11-beta-hydroxylase (CYP11B1), was elevated in PCa tissues, cell lines, and urine samples, while Corticosteroid 11-beta-dehydrogenase isozyme 2 (HSD11B2), which metabolize corticosterone, were markedly reduced in prostate tumors. With the understanding that androgen signaling is the key factor for prostate cancer, we investigated the role of androgen in regulating CYP11B1 and HSD11B2. We analyzed several androgen treated PCa cell lines derived global gene expression datasets and revealed that treatment with androgen increase in CYP11B1 expression and a concomitant decrease in HSD11B2 expression levels. Interestingly, we uncover that genetic knockdown of Androgen Receptor (AR) diminished CYP11B1 expression and alternatively, increased HSD11B2. Moreover, AR based chromatin occupancy (ChIP-seq) data also suggest direct binding of AR to the promoter of CYP11B1 in multiple PCa cells. The role of corticosterone in PCa is previously unknown. Our multi-omics approaches thus indicate that corticosterone might be potential prognostic marker for PCa. The tumor biology and mechanism through which corticosterone associates with PCa is being investigated in our laboratory. Citation Format: Iqbal Mahmud, Bongyong Lee, Ranjan Perera, Timothy J. Garrett. Multi-omics approaches reveal potential role for corticosterone in prostate cancer [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 5273.
Abstract 15998: Effectiveness and Safety of Apixaban Compared to Other Oral Anticoagulants Among Non-Valvular Atrial Fibrillation Patients With Coronary Artery Disease or Peripheral Arterial Disease: A Propensity Score Matched Analysis of Four Large Databases
Authors: Gregory Y Lip, Allison Keshishian, Xiaoyan Li, Melissa Hamilton, Cristina Masseria, Kiran Gupta, Xuemei Luo, Jack Mardekian, Keith Friend, Anagha Nadkarni, Xianying Pan, Steve Deitelzweig
Journal: Circulation (2017)

Introduction: In the ARISTOTLE trial, apixaban reduced both stroke/systemic embolism (S/SE) and major bleeding (MB) compared to warfarin among non-valvular atrial fibrillation (NVAF) patients, and ...
Serial circulating tumor DNA (ctDNA) monitoring to predict response to treatment in metastatic gastrointestinal cancers
Authors: A. Parikh, K. Kanter, A. Mojtahed, J. Schneider, E. Van Seventer, M. Fish, J. Allen, L. Blaszkowsky, J. Wo, J. Clark, B. Giantonio, L. Goyal, T. Hong, R. Nipp, E. Roeland, C. Weekes, A. Zhu, D. Ryan, I. Fetter, N. Horick, R. Corcoran
Journal: Annals of Oncology (2019)
The dimerization of Δ9-tetrahydrocannabinolic acid A (THCA-A)
Authors: Arben Cuadari, Federica Pollastro, Juan D. Unciti-Broceta, Diego Caprioglio, Alberto Minassi, Annalisa Lopatriello, Eduardo Muñoz, Orazio Taglialatela-Scafati, Giovanni Appendino
Journal: Acta Pharmaceutica Sinica B (2019)

The renewed interest in dimeric salicylates as broad-spectrum anti-inflammatory and anti-diabetic agents provided a rationale to investigate the dimerization of the substituted salicylate Δ9-tetrahydrocannabinolic acid (THCA-A, 3a) as a strategy to solve its instability to decarboxylation and to generate analogues and/or pro-drugs of this native pre-cannabinoid. Activation of the carboxylic group with the DCC-HOBt-DMAP protocol afforded a high yield of the OBt ester 4, that was next converted into the highly crystalline di-depsidic dimer 5 upon treatment with DMAP. The mono-depsidic dimer 6 was also formed when the reaction was carried out with partially decarboxylated THCA-A samples. The structure of the depsidic dimers was established by spectroscopic methods and by aminolysis of 5 into the pre-cannabinoid amide 7. Both dimers showed excellent shelf stability and did not generate significant amounts of Δ9-THC upon heating. However, only the didepsidic dimer 5 activated PPAR-γ, the major target of pre-cannabinoids, but strong binding to serum proteins abolished this activity, also shielding it from the action of esterases.
Abstract 730: Genomic characterization of hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a rare and aggressive kidney cancer
Authors: Pankaj Vats, Yuping Zhang, Sarvana Mohan Dhanashekaran, Narayanan Sathiya Pandi, Xuhong Cao, Fengyun Su, Sudhanshu Shukla, Rui Wang, Marcin Cieslik, Jincheng Pan, Christopher J. Ricketts, Prem Kumar Kumpati, Ajjai Alva, Marston W. Linehan, Rohit Mehra, Arul M. Chinnaiyan
Journal: Cancer Research (2019)

Abstract Background Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a rare autosomal-dominant syndromic disorder associated with germline FH mutations. Affected individuals have a predisposition to cutaneous and uterine leiomyoma’s, and are at increased risk of developing a renal cell carcinoma (HLRCC- associated RCC) with aggressive clinical outcome. However, aside from FH bi-allelic loss, additional genomic features of HLRCC are currently poorly understood. Method Five cases of HLRCC-associated RCC were characterized using integrated next generation sequencing (NGS) technology. This included an index case where multiple tumor sites (kidney, lung, liver, lymph node, skin, and uterine) from a single patient were characterized. For integrative analysis, in-house data were combined with five RCC cases with FH bi-allelic loss from The Cancer Genome Atlas Study. Single cell sequencing was carried out on normal human kidney to study the cell of origin for HLRCC- associated RCC. Results: Integrative NGS profiling and analysis of HLRCC-associated RCC tumors (n=10) revealed several important observations such as 1) a high frequency loss of whole chromosomes, which is reminiscent of tumors arising from the distal nephron, 2) low mutational burden similar to that observed in other kidney tumors and, 3) a HLRCC specific gene expression signature and discovery of a novel therapeutic candidate (HLRCC-TC1). Importantly, among renal tumors, HLRCC-TC1 was specifically expressed in HLRCC and other RCCs with poor clinical outcome. Application of siRNAs and neutralizing antibodies to HLRCC-TC1 reduced cell proliferation of the HLRCC cell line UOK262, but did not for that of control cell lines. Conclusion: The observed FH bi-allelic mutation along with recurrent chromosome-wide losses and integrative analysis with human kidney single cell sequencing data support a distal nephron origin for HLRCC- associated RCC. In addition, our study provides evidence for nominating HLRCC-TC1 as a novel cancer-specific therapeutic target. Further studies are needed to conduct an in-depth characterization of HLRCC-TC1. Citation Format: Pankaj Vats, Yuping Zhang, Sarvana Mohan Dhanashekaran, Narayanan Sathiya Pandi, Xuhong Cao, Fengyun Su, Sudhanshu Shukla, Rui Wang, Marcin Cieslik, Jincheng Pan, Christopher J. Ricketts, Prem Kumar Kumpati, Ajjai Alva, Marston W. Linehan, Rohit Mehra, Arul M. Chinnaiyan. Genomic characterization of hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a rare and aggressive kidney cancer [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 730.
the Safety and Efficacy of Pomalidomide in Combination with Cyclophosphamide and Dexamethasone (PCD) in the Transplant-Ineligible Patients with Relapsed and/or Refractory Multiple Myeloma (MM) Who Had Lenalidomide Plus Dexamethasone (LD) Following Frontline Bortezomib Combined Chemotherapy, Open-Labeled, Multicenter Phase II Study
Authors: Ho Sup Lee, Chang-Ki Min, Kihyun Kim, Seok Jin Kim, Je-Jung Lee, Inho Kim, Jin Seok Kim, Hyeon-Seok Eom, Dok Hyun Yoon, Cheolwon Suh, Ho-Jin Shin, Yeung-Chul Mun, Min Kyoung Kim, Sung-Nam Lim, Chul Won Choi, Hye Jin Kang, Sung-Soo Yoon
Journal: Blood (2017)
Abstract 14856: Availability of Cath Lab Facilities and Contemporary Inter-Hospital Transfer Patterns for the Management of Acute Coronary Syndromes Patients: Findings From the EPICOR Asia Study
Authors: Yong Huo, Stephen Wai-Luen Lee, Jitendra Pal Singh Sawhney, Hyo-Soo Kim, Rungroj Krittayaphong, Vo Thanh Nhan, Angeles Alonso, Nobuya Hayashi, Lin Zhang, Ya Ling Han, Junbo Ge, Tiong Kiam Ong, Chee Tang Chin
Journal: Circulation (2013)

Purpose: Little is known about acute coronary syndromes (ACS) management in relation to inter-hospital transfer and the potential role of on- or off-site cath lab facilities in Asia. This study des...
Abstract 16926: Cardiac Ultrasound Has the Potential to Detect Tension Pneumothorax as a Reversible Cause of Cardiac Arrest - An Experimental Porcine Study
Authors: Philip Caap, Rasmus Aagaard, Erik Sloth, Bo Løfgren, Asger Granfeldt
Journal: Circulation (2015)

Introduction: Survival from cardiac arrest (CA) with a non-shockable rhythm is unlikely unless a reversible cause is identified and treated. Tension pneumothorax (tPTX) is a potentially reversible cause of CA, however the diagnosis can easily be missed. Cardiac ultrasound has the potential to detect reversible causes of CA. tPTX is believed to compress the heart and great vessels, causing the diameter of the right ventricle (RV) to decrease. In ventricular fibrillation and hypoxia induced CA blood accumulates on the right side of the heart causing RV distension, however the cardiac ultrasonographic characteristics of tPTX before and during CA are unknown. Hypotheses: 1) In the period up to CA tPTX will decrease RV diameter compared to hypoxia induced CA. 2) At the onset of CA and start of CPR the RV diameter will increase, abolishing group difference. Methods: Pigs were randomized to CA induced by either unilateral tPTX (n=9) or hypoxia (n=9). tPTX was induced by injecting increments of air into the intrapleural cavity to a total volume of 50 ml/kg (90% of total lung capacity), while hypoxia was induced by gradually reducing the tidal volume over 30 min. tPTX was decompressed after 7 cycles of CPR. Subcostal 5-chamber ultrasound images of the RV were obtained during induction of CA and CPR. The primary endpoints were RV diameter at the onset CA and after 3 cycles of CPR. Results: At baseline the RV diameter was (mean (95%CI)): 24.2 (21.1-27.4) mm in the tPTX group and 24.2 (20.6-27.8) mm in the hypoxia group. Induction of CA, elicited a decrease in RV diameter in the tPTX group to 16.8 (13.0-20.6) mm and an increase in the hypoxia group to 36.2 (32.5-40.0) mm (p-value for comparison to baseline and between groups at CA; p&lt;0.01). After three cycles of CPR RV diameter was significantly smaller in the tPTX group at 11.8 (7.3-16.2) mm when compared to the hypoxia group of 28.2 (24.5-31.9) mm (p&lt;0.01). Immediately after decompression no difference existed between groups: tPTX 28.9 (23.4-34.3) mm vs. hypoxia 29.2 (20.1-38.2) mm (p = 0.94). Conclusion: tPTX causes a significantly smaller diameter of the RV compared to hypoxia prior to CA. This difference persisted during CPR, enabling cardiac ultrasound to detect tPTX as a reversible cause of CA. There was no RV difference after tPTX decompression.
Abstract 11204: Antithrombin Protects against Cardiac Ischemia/Reperfusion Injury via Inhibiting the NF-κβ Signaling Pathway
Authors: Jingying Wang, Xiaoyan Yan, Likui Yang, Alireza R Rezaie, Ji Li
Journal: Circulation (2012)

Background- Antithrombin (AT) is a plasma serine protease inhibitor (serpin) which regulates proteolytic activity of coagulation proteases of both intrinsic and extrinsic coagulation pathways. In a...
Abstract 4762: Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer cells
Authors: Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hiroki Sato, Takahiro Yoshioka, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka
Journal: Cancer Research (2019)

Abstract Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients. However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistance cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multi-gene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. Citation Format: Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hiroki Sato, Takahiro Yoshioka, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka. Activation of AXL as a preclinical acquired resistance mechanism against osimertinib treatment in EGFR-mutant non-small cell lung cancer 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 4762.
Competing at the top level with Crohn’s disease
Authors: Alyx Treasure
Journal: British Journal of Sports Medicine (2019)

By the time I was 17, I had already spent 2 years going in/out of hospital. Having been told at the age of 9 that I would make the Olympics, I was very focused on my sporting goals. I had no prior family history of Crohn’s. It took 2 years for me to get a diagnosis and this severely affected my athletic development by preventing me from training/competing. I lost my opportunity to go to college in the USA, which had been a long-term ambition, and it would have been easy to give up on the sport.

Fortunately, I didn’t give up. I achieved my ultimate goal to qualify for the Canadian Olympic team in the high jump. I jumped 1.94 metres in the qualifying round, which put me in the Olympic final and helped me to realise my lifelong dream aged 24 years.

When you’re told at 9 years old that you will make the Olympics you become driven, I would remove anything in my path to achieve my target. I was told several times that I had to quit athletics due to my condition, and one doctor advised me to ‘pick health or sport’. I didn’t do well with being told what I could or could not do, and over the years, I have argued with my medical team. However, I needed to be challenged and it is great when you can have open and honest discussions with clinicians. I have valued …
Abstract 228: KSPi-ADCs: ADCs with novel kinesin spindle protein inhibitor payloads and a tailor-made linker chemistry
Authors: Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Anette Sommer, Sandra Berndt, Anne-Sophie Rebstock, Sarah Johannes, Leo Marx, Christoph Mahlert, Simone Greven, Lisa Dietz, Hannah Joerissen, Hilmar Weinmann
Journal: Cancer Research (2019)

Abstract Inhibitors of kinesin spindle protein (KSP/Eg5) have raised great interest because of their high antitumor potency which, however, could not be transferred into highly efficient clinical regimens due to dose limiting side effects such as neutropenia. We have developed a new, highly potent pyrrole subclass of KSPis as a novel payload class in ADCs. To increase the therapeutic window, a tailor-made effector chemistry has been designed. The tumor associated protease legumain (LGMN) is utilized for ADC cleavage to provide active metabolites with high and long-lasting exposure in tumors, thus matching the KSPi mode of action. LGMN is a lysosomal asparaginyl endopeptidase overexpressed in solid tumors which is associated with invasion, metastasis and poor survival. In our studies, we show an efficient LGMN mediated linker cleavage and payload release from different ADCs. In addition, the unique LGMN substrate sequence allows for high cleavage specificity and discrimination versus other proteases such as elastase, which has been associated with an undesired extracellular cleavage of e.g. vc-MMAE ADCs resulting in neutropenia. Variations of the linker chemistry were performed to retain high potency of the KSPi-ADCs against tumor cells while decreasing the activation of KSPi-ADCs in cells of healthy organs such as the liver. From this approach, highly potent KSPi-ADCs with improved tumor/organ ratios of active metabolites were obtained. In conclusion, ADC metabolism under legumain control is a versatile strategy to provide KSPi-ADCs with high potency and an improved safety profile. Citation Format: Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Anette Sommer, Sandra Berndt, Anne-Sophie Rebstock, Sarah Johannes, Leo Marx, Christoph Mahlert, Simone Greven, Lisa Dietz, Hannah Joerissen, Hilmar Weinmann. KSPi-ADCs: ADCs with novel kinesin spindle protein inhibitor payloads and a tailor-made linker chemistry [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 228.
Abstract 2623: Modulating native GABAA receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death
Authors: Laura Kallay, Havva Keskin, Alexandra Ross, Manali Rupji, Olivia A. Moody, Xin Wang, Guanguan Li, Taukir Ahmed, Farjana Rashid, Michael Rajesh Stephen, Kirsten A. Cottrill, Austin Nuckois, Maxwell Xu, Deborah E. Martinson, Frank Tranghese, Yanxin Pei, James M. Cook, Jeanne Kowalski, Michael D. Taylor, Andrew Jenkins, Daniel Pomeranz Krummel, Soma Sengupta
Journal: Cancer Research (2019)

Abstract Pediatric brain cancer medulloblastoma standard-of-care results in numerous comorbidities. Medulloblastoma is comprised of four molecular subgroups. Group 3 subgroup patients have the highest relapse rates and 20% survival after standard-of-care. Group 3 tumors have high expression of GABRA5, which codes for the α5 subunit of the γ-aminobutyric acid type A receptor (GABAAR). We are advancing a therapeutic approach for group 3 based on GABAAR modulation using benzodiazepine-derivatives. We performed analysis of GABR and MYC expression in medulloblastoma tumors and used molecular, cell biological, and whole-cell electrophysiology approaches to establish presence of a functional ‘druggable’ GABAAR in group 3 cells. Analysis of expression of 763 medulloblastoma tumors reveals that group 3 tumors share high subgroup-specific and correlative expression of GABR genes, which code for GABAAR subunits α5, β3 and γ2 and 3. There are ~1000 functional α5-GABAARs per group 3 patient-derived cell that mediate a basal chloride-anion efflux of 2x109 ions/sec. Benzodiazepines, designed to prefer α5-GABAAR, impair group 3 cell viability by enhancing chloride-anion efflux with subtle changes in their structure having significant impact on potency. A potent, non-toxic benzodiazepine (‘KRM-II-08’) binds to the α5-GABAAR (0.8 μM EC50) enhancing a chloride-anion efflux that induces mitochondrial membrane depolarization and in response, TP53 upregulation and p53, constitutively phosphorylated at S392, cytoplasmic localization. This correlates with pro-apoptotic Bcl-2-associated death promoter (BAD) protein localization. GABR expression can serve as a diagnostic biomarker for group 3 tumors, while α5-GABAAR is a therapeutic target for benzodiazepine binding, enhancing an ion imbalance that induces apoptosis. Citation Format: Laura Kallay, Havva Keskin, Alexandra Ross, Manali Rupji, Olivia A. Moody, Xin Wang, Guanguan Li, Taukir Ahmed, Farjana Rashid, Michael Rajesh Stephen, Kirsten A. Cottrill, Austin Nuckois, Maxwell Xu, Deborah E. Martinson, Frank Tranghese, Yanxin Pei, James M. Cook, Jeanne Kowalski, Michael D. Taylor, Andrew Jenkins, Daniel Pomeranz Krummel, Soma Sengupta. Modulating native GABAA receptors in medulloblastoma with positive allosteric benzodiazepine-derivatives induces cell death [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 2623.