tbuckley/cabot-search huggingface dataset:
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure
Authors: Milton Packer, Stefan D Anker, Javed Butler, Gerasimos Filippatos, Stuart J Pocock, Peter Carson, James Januzzi, Subodh Verma, Hiroyuki Tsutsui, Martina Brueckmann, Waheed Jamal, Karen Kimura, Janet Schnee, Cordula Zeller, Daniel Cotton, Edimar Bocchi, Michael Böhm, Dong-Ju Choi, Vijay Chopra, Eduardo Chuquiure, Nadia Giannetti, Stefan Janssens, Jian Zhang, Jose R Gonzalez Juanatey, Sanjay Kaul, Hans-Peter Brunner-La Rocca, Bela Merkely, Stephen J Nicholls, Sergio Perrone, Ileana Pina, Piotr Ponikowski, Naveed Sattar, Michele Senni, Marie-France Seronde, Jindrich Spinar, Iain Squire, Stefano Taddei, Christoph Wanner, Faiez Zannad
Journal: New England Journal of Medicine (2020)

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.
Abstract B54: Adipogenic chemokines, body mass index, and ovarian cancer survival
Authors: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel
Journal: Clinical Cancer Research (2020)

Abstract Objectives: Obesity affects more than one-third of US adults and promotes the development and progression of many cancers. One mechanism by which obesity may influence ovarian cancer is via adipocyte-tumor cell communication, including the production of chemotactic cytokines, or chemokines, in the tumor microenvironment. Our goal was to measure adipogenic chemokine expression and examine associations with body mass index (BMI) and ovarian cancer survival. Methods: We selected 25 chemokines from laboratory experiments that modeled adipogenesis, of which 22 had expression data available for 302 high-grade serous ovarian cancer cases from The Cancer Genome Atlas (TCGA). We measured mRNA expression using Taqman quantitative real-time polymerase chain reaction (QPCR) in 50 high-grade serous tumor samples and ascertained BMI from electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). We also evaluated peri-diagnosis BMI (± 4 weeks) from EMR for 298 tumor registry-confirmed (165 serous and 133 nonserous) cases. Expression data were log transformed and dichotomized at median values; associations with disease-free survival (DFS) and overall survival (OS) were quantified using proportional hazards regression. Results: In TCGA analyses, two ligands and one receptor had significant associations with better (CCL8 and CXCL13) and worse (CX3CR1) OS, respectively. Higher CXCL13 expression was also associated with better DFS in VUMC tumors, but significance was attenuated after adjustment for clinical covariates. CX3CR1 was not expressed in all tumors but was positively associated with BMI (Pearson’s r=0.69, P=0.019). Finally, among all 298 tumor registry-confirmed VUMC cases, BMI was not associated with OS, although higher BMI was associated with a 4% significantly increased risk of death among 133 nonserous cases. Conclusions: Our findings suggest that obesity impacts chemokine expression in the tumor microenvironment and ovarian cancer survival. Further, differences between serous and nonserous subtypes may influence the relationship between obesity and ovarian cancer prognosis. Citation Format: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel. Adipogenic chemokines, body mass index, and ovarian cancer survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B54.
Scotland to create patient champion role
Authors: Bryan Christie
Journal: BMJ (2020)

A patient safety commissioner is to be appointed in Scotland to champion the views of people who have been harmed by treatments provided by the health service.

It is one of the central recommendations following a review led by life the peer Julia Cumberlege into three treatments—Primodos, sodium valproate, and pelvic mesh—that resulted in birth defects, learning difficulties, and life changing complications for thousands of women.1 Although the review’s recommendations were directed at the healthcare system in England, Scotland has decided to act on creating …
Abstract 1626: A novel mouse model of hepatocellular carcinoma induced by c-myc overexpression
Authors: Jinjin Wang, Dan Feng, Haiyan Zhu, Lei Ci, Zhipeng Wan, Ruilin Sun
Journal: Cancer Research (2020)

Abstract Hepatocellular carcinoma is a fatal liver cancer, and there are limited treatment options for this cancer. c-Myc is a key oncogene in liver cancer, but the specific mechanism of carcinogenesis in liver is unknown. Animal models are widely used to explore the molecular pathogenesis of HCC and test new drug candidates. In this poster, we reported a c-Myc conditional over-expression mouse model (LSL-Myc), which inserts the CAG-Loxp-stop-Loxp-c-Myc-polyA expression cassette into the H11 site. The expression of the Myc gene in this mouse model is regulated by Cre recombinase, which is not normally expressed, but only expressed in Cre-expressing tissue cells. LSL-Myc / Alb-cre double-positive mice were produced by crossing LSL-Myc hybrid mice with Alb-cre mice. In this mouse model, c-Myc was specifically expressed in liver cells. LSL-Myc / Alb-cre double-positive mice show a typical HCC phenotype and show accelerated tumor initiation and rapid HCC progression. Mice can detect significant liver tumorigenesis at 2 months of age, and 100% mice can occur hepatocellular carcinoma. The liver cancer tissues from LSL-Myc / Alb-cre double-positive mice can be transplanted to C57BL/6 mice to establish a mouse-derived PDX model. In summary, this model has the advantages of rapid oncogenesis and high incidence of liver cancer. It is an ideal model for studying the mechanism of c-Myc-driven liver cancer and c-Myc targeted therapy. Citation Format: Jinjin Wang, Dan Feng, Haiyan Zhu, Lei Ci, Zhipeng Wan, Ruilin Sun. A novel mouse model of hepatocellular carcinoma induced by c-myc overexpression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1626.
Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer
Authors: Piotr Przanowski, Song Lou, Rachisan Djiake Tihagam, Tanmoy Mondal, Caroline Conlan, Gururaj Shivange, Ilyas Saltani, Chandrajeet Singh, Kun Xing, Benjamin B. Morris, Marty W. Mayo, Luis Teixeira, Jacqueline Lehmann-Che, Jogender Tushir-Singh, Sanchita Bhatnagar
Journal: Cancer Research (2020)

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1-conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention. SIGNIFICANCE: TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.
Abstract 6239: A novel topical delivery system of carvedilol for skin cancer prevention
Authors: Mengbing Chen, Steven Yeung, Md Abdullah Shamim, Kaitlyn Coronel, Ayaz Shahid, Bradley Andresen, Jeffrey Wang, Ying Huang
Journal: Cancer Research (2020)

Abstract Solar ultraviolet (UV) light-induced non-melanoma skin cancer is the most common type of cancer diagnosed in the United States and remains one of the major public health concerns. There is an urgent need to develop effective and safe skin cancer chemopreventive agents. We have previously demonstrated that carvedilol, an FDA approved β-blocker for cardiovascular diseases, could prevent UV-induced skin cancer in vitro and in vivo. However, the β-adrenergic blockade effects of carvedilol might be a barrier for its repurposing as a cancer chemopreventive agent. In this study, we designed a novel topical formulation, namely carvedilol-loaded transfersomes (T-CAR), to maintain cancer preventive properties of carvedilol while avoiding systemic cardiovascular effects. T-CAR formulations were prepared using different phospholipids and surfactants at various ratios by the thin-film hydration method. The formulations were characterized in terms of particle size, zeta potential, and encapsulation efficiency. An optimal formulation was identified that composes carvedilol, soy phosphatidylcholine (SPC), and Tween 80 at a ratio of 1:3:0.5 with the particle size of 95.84 ± 3.8 nm, the zeta potential of +11.34 ± 0.7 mV, and the encapsulation efficiency of 93.7 ± 5.1%. The in vitro drug release and ex vivo skin permeation studies were performed using Pur-A-Lyzer mini dialysis kit and Franz diffusion cells, respectively. The optimal formulation showed a relative slow in vitro release profile and it could permeate through the porcine ear skin to the same degree as free carvedilol dissolved in acetone. 200 uL of 10 uM carvedilol dissolved in acetone, T-CAR containing the same amount of carvedilol as in acetone group, or the plain transfersome were topically applied to SKH-1 hairless mice 30 minutes before and immediately after single-dose UV irradiation. Compared to carvedilol solution, T-CAR demonstrated the same inhibitory effects against UV-induced epidermis thickening but exhibited increased inhibitory effects against UV-induced cyclobutane pyrimidine dimer (CPD) formation and mRNA expression of pro-inflammatory cytokines IL-1β and IL-6. In addition, carvedilol was not detectable by LC-MS in plasma after topical administration. These findings suggest that T-CAR could be a promising topical carvedilol formulation to prevent UV-associated skin cancer, with enhanced photoprotective effects but neglectable systemic cardiovascular effects. Citation Format: Mengbing Chen, Steven Yeung, Md Abdullah Shamim, Kaitlyn Coronel, Ayaz Shahid, Bradley Andresen, Jeffrey Wang, Ying Huang. A novel topical delivery system of carvedilol for skin cancer prevention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6239.
Lycopene antagonizes lead toxicity by reducing mitochondrial oxidative damage and mitochondria‐mediated apoptosis in cultured hippocampal neurons
Authors: Mingyue Qu, Yanli Ni, Baoshi Guo, Xin Feng, Zheng Jiang
Journal: MedComm (2020)

Lead (Pb) exhibits serious adverse effects on the central nervous system, and the major pathogenic mechanism of Pb toxicity is oxidative stress. As one of the carotenoid family members with potent antioxidant properties, lycopene has shown its protections by inhibiting oxidative stress damage in numerous models of neurotoxicity. The current study was designed to explore the possible protective property in primary cultured rat hippocampal neurons challenged with Pb. We observed that 5 μM lycopene pretreatment for 4 h efficiently ameliorated Pb-caused damage in cell viability, accumulation of reactive oxygen species (ROS), and apoptosis in a dose-dependent manner. Moreover, lycopene (5 μM) attenuated the 50 μM Pb-induced mitochondrial ROS production, improved the activities of mitochondrial respiratory chain enzymes and ATP production, and ameliorated the 50 μM Pb-induced depolarization of mitochondrial membrane potential as well as opening of mitochondrial permeability transition pores. In addition, 5 μM lycopene restored the imbalance of Bax/Bcl-2, inhibited translocation of cytochrome c, and reduced caspase-3 activation. Taken together, these findings indicate that lycopene antagonizes against Pb-induced neurotoxicity and the underlying mechanism probably involves reduction of mitochondrial oxidative damage and mitochondria-mediated apoptosis.
Abstract 5027: The mu-opioid receptor antagonist methylnaltrexone can decrease tumorigenesis in head and neck squamous cell carcinoma
Authors: Aysegul Gorur, Miguel Patino, Ted Shi, Hideaki Takahashi, Jeffrey N. Myers, Juan P. Cata
Journal: Cancer Research (2020)

Abstract Head and neck cancer (HNC) is the sixth leading cause of cancer in the world, and the third most common neoplasia in developing countries [1]. Patients with HNC may suffer significant pain, for which opioids are commonly given. However, recent reports suggest that opioids may promote cancer progression by action on the mu-opioid receptor (MOR) [2, 3]. The goal of this research was to test the hypothesis that the MOR antagonist methylnaltrexone (MTNX) can decrease tumorigenesis in HN squamous cell carcinoma (SCC). First, we confirmed via RNAseq and western blot analyses that FaDu cells (a HNSCC line) express MOR. Then, we performed cyclic adenosine monophosphate (cAMP) activation enzyme-linked immunosorbent assay to evaluate the activity of MOR after activation with [D-Ala2N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), a selective MOR agonist. Short term (1hr) treatment with DAMGO decreased cAMP levels, suggesting full activity of the receptor. We conducted similar cAMP activity assays using MNTX. Our dose-dependent (10nM-1µM) experiments revealed that 1hr exposure of cells to MTNX inhibited cAMP activity, but not after 48 hrs of treatment, consistent with an inverse or partial agonist effect at low doses. To assess the impact of our findings on FaDu cell behaviors, we conducted in vitro proliferation, colony formation, and migration assays. MTNX at different concentrations (0.1nM, 1nM, 10nM, 100nM and 1µM) inhibited FaDu cell proliferative and metastatic cell behaviors (p&amp;lt;0.05). To translate our results to in vivo, we inoculated the tongue of athymic nude mice with FaDu cells (200,000 cells/30 mL). Starting the day of cell inoculation, we randomly treated the animals with MNTX (subcutaneously, 1µg/kg, 10 µg/kg, and 100µg/kg) versus placebo (saline only) for 17 consecutive days. In vivo experiments demonstrated that administration of MTNX at three different concentrations delayed tumor progression and reduced tumor growth and formation compared to placebo (p&amp;lt;0.0001). Overall, our results suggest that MTNX inhibits tumorigenesis of HNSCC, possibly by acting on MOR. 1. Siegel, R.L. et al, Cancer statistics, 2018. CA Cancer J Clin, 2018. 68(1): p. 7-30. 2. Lennon, F.E., et al, The mu-opioid receptor in cancer progression: is there a direct effect? Anesthesiology, 2012. 116(4): p. 940-5. 3. Patino, M.A., et al., The impact of intraoperative opioid use on survival after oral cancer surgery. Oral Oncol, 2017. 74: p. 1-7. Citation Format: Aysegul Gorur, Miguel Patino, Ted Shi, Hideaki Takahashi, Jeffrey N. Myers, Juan P. Cata. The mu-opioid receptor antagonist methylnaltrexone can decrease tumorigenesis in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5027.
Abstract A47: Preclinical efficacy of CPI-1688, a novel EZH2 inhibitor, in epithelial ovarian cancer with alterations in the SWI/SNF chromatin remodeling complex
Authors: Elizabeth Magno, Sergey Karakashev, Jennifer Mertz, Patrick Trojer, Rugang Zhang
Journal: Clinical Cancer Research (2020)

Abstract Epithelial ovarian cancer is a paradigm for exploring precision medicine in the context of genetic alteration in the SWI/SNF chromatin remodeling complex. For example, the ARID1A subunit of the SWI/SNF complex is mutated in more than 50% of clear cell ovarian carcinomas. In addition, CARM1 is amplified/overexpressed in ~20% of high-grade serous ovarian cancer. CARM1 is an arginine methyltransferase that asymmetrically dimethylates protein substrates on arginine residues. CARM1 regulates the SWI/SNF genome-wide distribution by post-transcriptionally methylating SWI/SNF core subunit BAF155. EZH2 is the catalytic subunit of the polycomb repressive complex that typically suppresses its gene expression through generating lysine 27 trimethylation on histone H3 (H3K27me3). Our previous studies established that inhibition of the methyltransferase activity of EZH2 is synthetically lethal with ARID1A mutation or CARM1 overexpression due to the antagonistic roles played by the SWI/SNF and EZH2/PRC2 complexes. Here we report the preclinical efficacy of CPI-1688, a highly selective second-generation EZH2 methyltransferase inhibitor, in ARID1A mutated clear-cell ovarian cancer cells and CARM1 overexpressed high-grade serous ovarian cancer cells. Notably, the antitumor effects conferred by CPI-1688 correlate with ARID1A mutation or CARM1 expression status. In addition, at the pharmacodynamic levels, the observed efficacy correlates with a reduction in H3K27me3 both in vitro and in vivo. This suggests that the observed antitumor effects are due to on-target inhibition of EZH2 methyltransferase activity. Finally, this observed selectivity correlates with reactivation of EZH2 target tumor suppressor genes. Together, these results indicate that CPI-1688 is a promising new therapeutic for ovarian cancer with ARID1A mutation or CARM1 overexpression. Citation Format: Elizabeth Magno, Sergey Karakashev, Jennifer Mertz, Patrick Trojer, Rugang Zhang. Preclinical efficacy of CPI-1688, a novel EZH2 inhibitor, in epithelial ovarian cancer with alterations in the SWI/SNF chromatin remodeling complex [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A47.
Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis
Authors: Xuezhen Zeng, Jingying Zhou, Zhewen Xiong, Hanyong Sun, Weiqin Yang, Myth T. S. Mok, Jing Wang, Jingqing Li, Man Liu, Wenshu Tang, Yu Feng, Hector Kwong-Sang Wang, Shun-Wa Tsang, King-Lau Chow, Philip Chun Yeung, John Wong, Paul Bo-San Lai, Anthony Wing-Hung Chan, Ka Fai To, Stephen Lam Chan, Qiang Xia, Jing Xue, Xiao Chen, Jun Yu, Sui Peng, Joseph Jao-Yiu Sung, Ming Kuang, Alfred Sze-Lok Cheng
Journal: Cellular and Molecular Immunology (2020)
Abstract 585: Colitis in tumor-bearing mice undergoing checkpoint inhibitor therapy
Authors: Caitlin S. Parello, Benjamin G. Cuiffo, Kasey Reardon, Alexandria Fusco, Brett Van Dam, Gregory D. Lyng, Stephen T. Sonis
Journal: Cancer Research (2020)

Abstract Checkpoint inhibitor (CPI) therapy represents an exciting new treatment option for patients with advanced malignancies. However, several adverse events (AEs) that affect multiple body systems are associated with CPI treatment, including colitis. The mechanisms mediating these AEs remain to be fully elucidated. That mice treated with CPI fail to develop the spectrum of AEs observed in patients hampers the field's ability to develop supportive care treatment options. Here we sought to examine colitis in tumor bearing mice undergoing CPI therapy. Briefly, naïve TH cells and Treg cells were harvested from C57Bl/6 donor mice and were adoptively transferred into RAG2−/- recipients. Animals were inoculated with B16F10 cells into the left flank seven days later. T cell engraftment was assessed after 13 days, and animals were randomized into treatment groups by rate of T cell engraftment; animals were treated Q3D with either vehicle or anti-CTLA4 for an additional four weeks. Animals were monitored for body weight loss and systemic AEs (gastrointestinal, pulmonary, neurological) daily and tumor volume was measured by digital caliper three times per week. Extent of colitis was evaluated by video endoscopy at several timepoints and colitis severity was scored using a 0-4 scale. Animals developed body weight loss approximately two weeks after T cell transfer and CPI treatment increased the severity of body weight loss observed. Colitis was seen by video endoscopy within a similar timeframe. Mean tumor volume was decreased in animals treated with CPI as compared to those treated with vehicle. Diarrhea, pulmonary symptoms, and neurological symptoms were observed in a subset of animals over the study period; anti-CTLA4 treatment increased the overall incidence of pulmonary symptoms. These data demonstrate the utility of this system for assessment of colitis or other AE supportive care treatment options in the context of CPI-treated, tumor-bearing mice. Citation Format: Caitlin S. Parello, Benjamin G. Cuiffo, Kasey Reardon, Alexandria Fusco, Brett Van Dam, Gregory D. Lyng, Stephen T. Sonis. Colitis in tumor-bearing mice undergoing checkpoint inhibitor therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 585.