tbuckley/cabot-search huggingface dataset:
Abstract 16041: Examining the Nocebo Effect of Statins Using Statin Adverse Events Reported in the FDA Adverse Event Reporting System
Authors: Jungyeon Moon, Robert Cohen Sedgh, Cynthia JACKEVICIUS
Journal: Circulation (2020)

Introduction: Comparison of blinded and nonblinded statin trials have confirmed a nocebo effect, most commonly presenting as subjective muscle and nervous system adverse events (AEs). This study evaluated whether the increase in reported statin AEs over time was associated with the nocebo effect by comparing nocebo-related subjective with objective AEs. Method: A retrospective cohort study was conducted using the FDA Adverse Event Reporting System (FAERS) of statin-associated AEs from 1/2010-12/2019. Statins selected for analysis were atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Subjective AEs included fatigue, subjective muscular, and nervous system AEs. Objective AEs were hepatic and objective muscular AEs. We compared the number of subjective and objective AEs using Mann-Whitney U, and evaluated the association between AEs and gender and country using linear regression. Quantitative detection of signals was estimated using reporting odds ratio (ROR). Institutional Review Board review was exempt since we used de-identified public data. Results: Of 2,994,487 statin AE reports, more subjective than objective AEs were reported per quarter (mean ± SD: 4777 ± 1375.45 vs 999 ± 276.95; p&lt;0.0001). Simvastatin-associated reports showed signals for higher objective muscular AEs relative to all other statins (ROR 1.53, 95% CI: 1.49-1.58). Females reported more subjective AEs than males per quarter (fatigue 86.98, p=0.035; subjective muscular AE 417.95, p&lt;0.0001; nervous system AE 273.60, p&lt;0.0001), but fewer objective muscular AEs (-125.23, p&lt;0.0001). More subjective AEs and fewer objective AEs were reported in the US relative to other countries per quarter (p&lt;0.0001). Conclusion: This study found that significantly more subjective than objective AEs are reported for statins. Subjective statin AEs, potentially related to the nocebo effect are reported more often by females than by males, and in the US than in other countries.
TBIO-19. INTEGRATED GENOMIC, PROTEOMIC AND PHOSPHOPROTEOMIC ANALYSIS OF SEVEN TYPES OF PEDIATRIC BRAIN CANCER
Authors: Francesca Petralia, Nicole Tignor, Dmitri Rykunov, Boris Revas, Shrabanti Chowdhury, Azra Krek, Pichae Raman, Jiayi Ji, Yuankun Zhu, Weiping Ma, Xiaoyu Song, David Fenyo, Steven Gygi, Richard Ivey, Antonio Iavarone, Jeffrey Whiteaker, Antonio Colaprico, Alexey Nesvizhskii, Henry Rodriguez, Amanda Paulovich, Tara Hiltke, Adam Resnick, Pei Wang, Brian Rood
Journal: Neuro-Oncology (2020)

Abstract We performed a comprehensive proteogenomic analysis across seven childhood brain tumors for a deeper understanding of their functional biology. Whole genome sequencing, RNAseq, quantitative proteomic profiling and phosphoproteomics were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Unsupervised clustering analysis based on proteomics data reveals eight clusters with distinct protein profiles and pathway activities. While some clusters coincide with histologic diagnoses, a couple of clusters appear to be a mixture of different diagnoses, including one cluster consisting of “aggressive” tumors characterized by poor survival and high stemness scores. By integrating proteomic data with RNAseq and WGS data, we characterize the impact of mutations (H3K27M, BRAFV600E, BRAF fusion) and CNVs upon the proteome across various diagnoses. Multiomics based kinase-substrate association analysis and co-expression network analysis reveal targetable active kinase networks within these tumors. Proteomic data reveals unique biology associated with H3K27M mutation status in HGG and BRAF aberrations in LGG. Characterization of the tumor microenvironment through deconvolution analyses based on multi-omics data reveals 5 distinct tumor clusters associated with different populations of infiltrating immune cells and the relative activity of the immune system based upon the expression of pro-inflammation or immunosuppressive markers. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology including functional insight that helps drive translational efforts.
DDRE-33. MOLECULAR DIFFERENTIATION OF IMIPRIDONES ONC201 AND ONC206
Authors: Varun Prabhu, Caroline Cuoco, Jinkyu Jung, Sara Morrow, Abed Rahman Kawakibi, Blair Willette, Marilyn Day, Lakshmi Anantharaman, Neil Charter, Joseph Rucker, Benjamin Doranz, Joel Basken, Martin Stogniew, Mark Gilbert, R Free, David Sibley, Joshua Allen
Journal: Neuro-Oncology (2020)

Abstract ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and agonist of ClpP in oncology. In clinical trials, the small molecule has induced durable tumor regressions and clinical benefit in H3 K27M-mutant glioma patients while being well tolerated. ONC206 is a chemical derivative of ONC201 with nanomolar anti-cancer potency. In this study, we describe receptor pharmacology, gene expression profiling, acquired resistance and biodistribution studies that suggest ONC206 exhibits distinct therapeutic properties relative to ONC201. ONC206 exhibited a nanomolar Ki for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Gene expression profiling revealed ONC206 and ONC201 induce distinct signatures in U87 glioblastoma cells, further supporting distinct functional effects. Similarly, T98G glioblastoma cells with acquired resistance to ONC201 or ONC206 reveal partial cross resistance. Finally, rat biodistribution studies revealed nanomolar CSF concentrations that exceed therapeutic thresholds, unlike ONC201. In summary, ONC206 exhibits increased non-competitive DRD2 antagonism, nanomolar potency, distinct biodistribution, differentiated gene expression and disruption of DRD2 dimers relative to ONC201. Thus, ONC206 may be uniquely poised to address tumors that are not addressed by ONC201 or have developed acquired resistance.
The role of hypoxia‐inducible factor 1 in tumor immune evasion
Authors: Li You, Wenda Wu, Xu Wang, Liurong Fang, Vojtech Adam, Eugenie Nepovimova, Qinghua Wu, Kamil Kuca
Journal: Medicinal Research Reviews (2020)

Abstract Hypoxia‐inducible factor 1 (HIF‐1) plays an indispensable role in the hypoxic tumor microenvironment. Hypoxia and HIF‐1 are involved in multiple aspects of tumor progression, such as metastasis, angiogenesis, and immune evasion. In innate and adaptive immune systems, malignant tumor cells avoid their recognition and destruction by HIF‐1. Tumor immune evasion allows cancer cells to proliferate and metastasize and is associated with immunotherapy failure and chemoresistance. In the hypoxic tumor microenvironment, HIF‐1 signaling suppresses the innate and adaptive immune systems to evade immune attack by inducing the expression of immunosuppressive factors and immune checkpoint molecules, including vascular endothelial growth factor, prostaglandin E 2 , and programmed death‐ligand 1/programmed death‐1. Moreover, HIF‐1 blocks tumor‐associated antigen presentation via major histocompatibility complex class I chain‐related/natural killer group 2, member D signaling. Tumor‐associated autophagy and the release of tumor‐derived exosomes contribute to HIF‐1‐mediated immune evasion. This review focuses on recent findings on the potential mechanism(s) underlying the effect of hypoxia and HIF‐1 signaling on tumor immune evasion in the hypoxic tumor microenvironment. The effects of HIF‐1 on immune checkpoint molecules, immunosuppressive molecules, autophagy, and exosomes have been described. Additionally, the potential role of HIF‐1 in the regulation of tumor‐derived exosomes, as well as the roles of HIF‐1 and exosomes in tumor evasion, are discussed. This study will contribute to our understanding of HIF‐1‐mediated tumor immune evasion, leading to the development of effective HIF‐1‐targeting drugs and immunotherapies.
Abstract P079: Alcohol Consumption and Risk of Diabetes in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Xintong He, Natalie Daya, Casey M. Rebholz, Mariana Lazo, Elizabeth Selvin
Journal: Circulation (2018)

Background: Moderate alcohol consumption has been reported to be associated with lower risk for diabetes with some studies showing a U-shaped association. Whether and how the association might differ by gender or obesity status is controversial. Objective: To evaluate the prospective association between alcohol consumption and the long-term risk of diabetes in the Atherosclerosis Risk in Communities (ARIC) Study. Methods: A prospective analysis of 11,263 ARIC participants without prevalent diabetes (55% women, 81%white, mean age 54 years). Alcohol consumption was assessed at visit 1 (1987-1989). Participants were followed-up for incident diabetes defined by fasting glucose more than 126 mg/dL, non-fasting glucose more than 200 mg/dL, self-reported diagnosis of diabetes or use of diabetic medication. We used Cox models to estimate hazard ratios of diabetes risk by drinking categories in women and men, respectively. Results: During a median follow-up of 21 years, there were 3518 incident diabetes cases. In the fully adjusted model, compared to never drinkers, among women, 7-14 drinks/week was associated with a significantly lower risk of diabetes; whereas among men, 14-21 drinks/week was associated with a significantly lower risk ( Table ). There was a significant interaction between drinking categories and smoking status or between drinking categories and body mass index in women. Among women, a U-shaped association was mainly present among non-smokers, and significant decreasing risk is only found among normal-weight and overweight participants, but not obese participants. Conclusion: Low levels of alcohol intake (1-2 drinks per day for women and 2-3 drinks per day for men) are inversely associated with diabetes risk. The association is modified by smoking and body mass index in women.
Putting the BRK on breast cancer: From molecular target to therapeutics
Authors: Hui Li Ang, Yi Yuan, Xianning Lai, Tuan Zea Tan, Lingzhi Wang, Benjamin BoJun Huang, Vijay Pandey, Ruby Yun-Ju Huang, Peter E. Lobie, Boon Cher Goh, Gautam Sethi, Celestial T. Yap, Ching Wan Chan, Soo Chin Lee, Alan Prem Kumar
Journal: Theranostics (2020)

BReast tumor Kinase (BRK, also known as PTK6) is a non-receptor tyrosine kinase that is highly expressed in breast carcinomas while having low expression in the normal mammary gland, which hints at the oncogenic nature of this kinase in breast cancer.In the past twenty-six years since the discovery of BRK, an increasing number of studies have strived to understand the cellular roles of BRK in breast cancer.Since then, BRK has been found both in vitro and in vivo to activate a multitude of oncoproteins to promote cell proliferation, metastasis, and cancer development.The compelling evidence concerning the oncogenic roles of BRK has also led, since then, to the rapid and exponential development of inhibitors against BRK.This review highlights recent advances in BRK biology in contributing to the "hallmarks of cancer", as well as BRK's therapeutic significance.Importantly, this review consolidates all known inhibitors of BRK activity and highlights the connection between drug action and BRK-mediated effects.Despite the volume of inhibitors designed against BRK, none have progressed into clinical phase.Understanding the successes and challenges of these inhibitor developments are crucial for the future improvements of new inhibitors that can be clinically relevant.
Assessment and management of shoulder dislocation
Authors: Lukas PE Verweij, David N Baden, Julia MJ van der Zande, Michel PJ van den Bekerom
Journal: BMJ (2020)

### What you need to know

Shoulder dislocations are painful and have an impact on activities of daily living and participation in sports. Most shoulder dislocations (>95%) occur in the anterior direction and are usually the result of trauma.123 Optimal management can prevent recurrent dislocations and reduce social costs.456 Patients with first time dislocations often receive insufficient information to make a decision about their management.7 Shared decision making must take into consideration the patient’s preferences for surgery or physical therapy, their expectations, and the likelihood of recurrence.6 In this clinical update we present an initial approach for primary care and emergency healthcare providers to assess and manage patients with a traumatic anterior shoulder dislocation.

More than 70% of shoulder dislocations occur in men.123 In a cohort study of 16 763 patients who experienced a first time anterior dislocation in the UK, peak incidence was in men aged 16-20 (80.5 per 100 000 person years) and in women aged 61-70 (28.6 per 100 000 person years).3 These peak incidences are similar in other Western countries, such as Canada, the US, and Norway.23

In young patients, shoulder dislocations …
Photosensitizer-based multimodal PSMA-targeting ligands for intraoperative detection of prostate cancer
Authors: Yvonne H.W. Derks, Mark Rijpkema, Helene I.V. Amatdjais-Groenen, Annemarie Kip, Gerben M. Franssen, J. P. Michiel Sedelaar, Diederik M. Somford, Michiel Simons, Peter Laverman, Martin Gotthardt, Dennis W. P. M. Löwik, Susanne Lütje, Sandra Heskamp
Journal: Theranostics (2020)

Incomplete resection of prostate cancer (PCa) occurs in 15%-50% of PCa patients. Disease recurrence negatively impacts oncological outcome. The use of radio-, fluorescent-, or photosensitizer-labeled ligands to target the prostate-specific membrane antigen (PSMA) has become a well-established method for the detection and treatment of PCa. Methods: Here, we developed and characterized multimodal [111In]In-DOTA(GA)-IRDye700DX-PSMA ligands, varying in their molecular composition, for use in intraoperative radiodetection, fluorescence imaging and targeted photodynamic therapy of PCa lesions. PSMA-specificity of these ligands was determined in xenograft tumor models and on fresh human PCa biopsies. Results: Ligand structure optimization showed that addition of the photosensitizer (IRDye700DX) and additional negative charges significantly increased ligand uptake in PSMA-expressing tumors. Moreover, an ex vivo incubation study on human tumor biopsies confirmed the PSMA-specificity of these ligands on human samples, bridging the gap to the clinical situation. Conclusion: We developed a novel PSMA-targeting ligand, optimized for multimodal image-guided PCa surgery combined with targeted photodynamic therapy.
Reducing PD-L1 expression with a self-assembled nanodrug: an alternative to PD-L1 antibody for enhanced chemo-immunotherapy
Authors: Shuxian Cai, Ziyi Chen, Yingjie Wang, Min Wang, Junye Wu, Yuhong Tong, Lanlan Chen, Chunhua Lu, Huanghao Yang
Journal: Theranostics (2020)

The binding between the immune checkpoints, programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1), compromises T-cell-mediated immune surveillance. Immune checkpoint therapy using immune checkpoint inhibitors (ICIs) to block PD-L1 on cancer cell membrane or PD-1 on activated T cell membrane can restore antitumor function of T cell. However, the intracellular expression of PD-L1 and its active redistribution to cancer cell membrane may impair the therapeutic benefits of ICIs. To address this issue, herein we develop a nanodrug (MS NPs) capable of reducing PD-L1 expression and enhancing antitumor effects.
SWK-12. PEDIATRIC NEURO-ONCOLOGY PARENT PERSPECTIVE ON ASPECTS OF SOCIAL AND EMOTIONAL SUPPORT FOR ONLINE APPLICATION
Authors: Kendra Koch, Tatum Fettig, Meghan Slining
Journal: Neuro-Oncology (2020)

Abstract Addressing family needs for social/emotional support is part of the duty of oncology care teams. This research presents a (2020) scoping review and a (2019) focus group initiated to explore pediatric neuro-oncology parent experience of social/emotional support in conjunction with developing an online peer application to address family needs. Currently, the value of online support is in the forefront of clinical conversation. The focus group queried eight parents whose children were under neuro-oncology treatment in the Northwest USA. Thematic findings include—parents want supportive peers who have (1) a personal and deep understanding of parenting a child with serious illness (they “get it”); (2) particular characteristics and skills that promote and sustain relationships, including—(a) good social skills, (b) ability to engage in “balanced” (cancer/non-cancer) conversations, (c) individual similarities (beliefs, age of children, cancer diagnosis/treatment), (d) logistic commonalities (location, availability), (e) pro-social personal characteristics (i.e. sense of humor, emotional/social flexibility), and an (f) ability to navigate and maintain social/emotional boundaries. Parents also initiated discussion about “the burden of supportive relationships” and supporting families doing “normal” activities without worrying about treatment side effects and contagions. The literature review supports finding (1) above; reveals the paucity of evidence-based supports available to this population; underscores the critical need for practitioners and researchers to develop more evidence-based supports and interventions for families of children experiencing cancer; and supports practitioners’ consistently assessing parent and sibling social and emotional needs and then consistently referring or intervening when needs are identified.
Comparative evaluation of clinical manifestations and risk of death in patients admitted to hospital with covid-19 and seasonal influenza: cohort study
Authors: Yan Xie, Benjamin Bowe, Geetha Maddukuri, Ziyad Al-Aly
Journal: BMJ (2020)

To comparatively examine differences in risk of clinical manifestations and death among people admitted to hospital with coronavirus disease 2019 (covid-19) and seasonal influenza.DESIGN Cohort study.SETTING
Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma
Authors: Guangyuan Song, Xingxin Zhu, Zefeng Xuan, Long Zhao, Haijiang Dong, Jian Chen, Zequn Li, Wenfeng Song, Cheng Jin, Mengqiao Zhou, Haiyang Xie, Shusen Zheng, Penghong Song
Journal: Theranostics (2020)

Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide, and its specific mechanism has not been fully elucidated. Inactivation of tumor suppressors may contribute to the occurrence, progression, and recurrence of HCC. DNA methylation is a crucial mechanism involved in regulating the occurrence of HCC. Herein, we aimed to identify the key methylation-related tumor suppressors as well as potential biomarkers and therapeutic targets in HCC. Methods: Combined analysis of TCGA and GEO databases was performed to obtain potential methylation-related tumor suppressors in HCC. Methyl-target sequencing was performed to analyze the methylation level of the GNA14 promoter. The diagnostic value of GNA14 as a predictor of HCC was evaluated in HCC tumor samples and compared with normal tissues. The functional role of GNA14 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro. Subcutaneous tumorigenesis, lung colonization, and orthotopic liver tumor model were performed to analyze the role of GNA14 in vivo.Results: The expression of GNA14 was found to be downregulated in HCC and it was negatively correlated with hepatitis B virus (HBV) infection, vascular invasion, and prognosis of HCC. DNA methylation was demonstrated to be responsible for the altered expression of GNA14 and was regulated by HBV-encoded X protein (HBx). GNA14 regulated the RB pathway by promoting Notch1 cleavage to inhibit tumor proliferation, and might inhibit tumor metastasis by inhibiting the expression of JMJD6. Conclusion: GNA14 could be regulated by HBx by modulating the methylation status of its promoter. We identified GNA14 as a potential biomarker and therapeutic target for HCC.
ETMR-05. SINGLE-CELL RNA-SEQ OF ETMR REVEALS CELL PROGRAMS OF DEVELOPMENTAL HIERARCHY AND CELLULAR DIVERSITY IN THE TUMOR MICROENVIRONMENT
Authors: Flavia W de Faria, Marta Interlandi, Natalia Moreno, Monika Graf, Viktoria Melcher, Thomas K Albert, Kornelius Kerl
Journal: Neuro-Oncology (2020)

Abstract Embryonal tumors with multilayered rosettes (ETMR) are deadly brain malignancies affecting young children. No standard treatment is available and the median survival is less than 12 months. Molecularly, the disease is characterized by the miRNA C19MC cluster amplification, with the expression of multiples miRNAs related to a stem cell program. The discoveries on the purely molecular mechanisms of the disease did not help to create a bridge for new treatment strategies so far and the cellular diversity of ETMR remains poorly understood. In this study, we used single-cell RNA sequencing of murine and human tumors to describe ETMR cellular heterogeneity. Our findings support that intra-tumoral heterogeneity is mainly characterized by 4 cellular programs defining a developmental hierarchy related to different metabolic states: 1) Early quiescent NSC-like cells supported by fatty-acid oxidation 2) Late NSC and NP-like proliferative cells fueled by glycolytic metabolism; 3) Post-mitotic neuroblast-like cells, relying on oxidative-phosphorylation; 4) NSC-like proliferative cells, with metabolic plasticity and capable of performing the three types of metabolism. Tumor-specific ligand-receptor interaction analysis revealed that ETMR exchange with microglia and vascular mural cells (MC) signals related to extracellular matrix (ECM) organization (Cxcl12-CxCr4), stem cell signaling (BMPs-BMP receptors), anti-apoptosis and survival (Ntf3-Ntrk), not seen in the control brain. In addition, the vascular MC showed a cancer-associated fibroblast (CAF) phenotype, with potential prognostic implications, as previously demonstrated for other tumors. This study provides new findings to build up a more robust understanding of ETMR biology and opens space for further studies in the field.