tbuckley/cabot-search huggingface dataset:
Computed tomography imaging of macrophage phagocytic activity in abdominal aortic aneurysm
Authors: Jakub Toczek, Parnaz Boodagh, Nowshin Sanzida, Mean Ghim, Mani Salarian, Kiran Gona, Gunjan Kukreja, Saranya Rajendran, Linyan Wei, Jinah Han, Jiasheng Zhang, Jae-Joon Jung, Morven Graham, Xinran Liu, Mehran M Sadeghi
Journal: Theranostics (2021)

Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome
A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection
Authors: Hejun Liu, Meng Yuan, Deli Huang, Sandhya Bangaru, Fangzhu Zhao, Chang-Chun D. Lee, Linghang Peng, Shawn Barman, Xueyong Zhu, David Nemazee, Dennis R. Burton, Marit J. van Gils, Rogier W. Sanders, Hans-Christian Kornau, S. Momsen Reincke, Harald Prüss, Jakob Kreye, Nicholas C. Wu, Andrew B. Ward, Ian A. Wilson
Journal: Cell Host & Microbe (2021)
Epilepsy channelopathies go neddy: stabilizing NaV1.1 channels by neddylation
Authors: Stephen C. Cannon
Journal: Journal of Clinical Investigation (2021)

Loss-of-function mutations of SCN1A encoding the pore-forming α subunit of the NaV1.1 neuronal sodium channel cause a severe developmental epileptic encephalopathy, Dravet syndrome (DS). In this issue of the JCI, Chen, Luo, Gao, et al. describe a phenocopy for DS in mice deficient for posttranslational conjugation with neural precursor cell expressed, developmentally downregulated 8 (NEDD8) (neddylation), selectively engineered in inhibitory interneurons. Pursuing the possibility that this phenotype is also caused by loss of NaV1.1, Chen, Luo, Gao, and colleagues show that interneuron excitability and GABA release are impaired, NaV1.1 degradation rate is increased with a commensurate decrease of NaV1.1 protein, and NaV1.1 is a substrate for neddylation. These findings establish neddylation as a mechanism for stabilizing NaV1.1 subunits and suggest another pathomechanism for epileptic sodium channelopathy.
Dimethyl fumarate induces ferroptosis and impairs NF-κB/STAT3 signaling in DLBCL
Authors: Anja Schmitt, Wendan Xu, Philip Bucher, Melanie Grimm, Martina Konantz, Heike Horn, Myroslav Zapukhlyak, Philipp Berning, Marc Brändle, Mohamed-Ali Jarboui, Caroline Schönfeld, Karsten Boldt, Andreas Rosenwald, German Ott, Michael Grau, Pavel Klener, Petra Vockova, Claudia Lengerke, Georg Lenz, Klaus Schulze-Osthoff, Stephan Hailfinger
Journal: Blood (2021)
Molecular Characterization of Biliary Tract Cancer Predicts Chemotherapy and Programmed Death 1/Programmed Death‐Ligand 1 Blockade Responses
Authors: Jihoon G. Yoon, Min Hwan Kim, Mi Jang, Hoguen Kim, Ho Kyoung Hwang, Chang Moo Kang, Woo Jung Lee, Beodeul Kang, Choong‐kun Lee, Min Goo Lee, Hyun Cheol Chung, Hye Jin Choi, Young Nyun Park
Journal: Hepatology (2021)

Background and Aims Biliary tract cancer (BTC) exhibits diverse molecular characteristics. However, reliable biomarkers that predict therapeutic responses are yet to be discovered. We aimed to identify the molecular features of treatment responses to chemotherapy and immunotherapy in BTCs. Approach and Results We enrolled 121 advanced BTC patients (68 cholangiocarcinomas [33 intrahepatic, 35 extrahepatic], 41 gallbladder cancers, and 12 Ampulla of Vater cancers) whose specimens were analyzed by clinical sequencing platforms. All patients received first‐line palliative chemotherapy; 48 patients underwent programmed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) blockade therapy after failed chemotherapy. Molecular and histopathological characterization was performed using targeted sequencing and immunohistochemical staining to investigate treatment response‐associated biomarkers. Genomic analysis revealed a broad spectrum of mutational profiles according to anatomical location. Favorable responses to chemotherapy were observed in the small‐duct type compared with the large‐duct type intrahepatic cholangiocarcinoma, with frequent mutations in BRCA1‐associated protein‐1/isocitrate dehydrogenase 1/2 and KRAS proto‐oncogene, GTPase/SMAD family member 4 genes, respectively. The molecular features were further analyzed in BTCs, and transforming growth factor beta and DNA damage response pathway‐altered tumors exhibited poor and favorable chemotherapy responses, respectively. In PD‐1/PD‐L1 blockade‐treated patients, KRAS alteration and chromosomal instability tumors were associated with resistance to immunotherapy. The majority of patients (95.0%) with these resistance factors show no clinical benefit to PD‐1/PD‐L1 blockade and low tumor mutational burdens. Low tumor‐infiltrating lymphocyte (TIL) density in tumors with these resistance factors indicated immune‐suppressive tumor microenvironments, whereas high intratumoral TIL density was associated with a favorable immunotherapy response. Conclusions This study proposes predictive molecular features of chemotherapy and immunotherapy responses in advanced BTCs using clinical sequencing platforms. Our result provides an intuitive framework to guide the treatment of advanced BTCs benefiting from therapeutic agents based on the tumors’ molecular features.
Housing environment and early childhood development in sub-Saharan Africa: A cross-sectional analysis
Authors: Yaqing Gao, Long Zhang, Ashish Kc, Yinping Wang, Siyu Zou, Chunyi Chen, Yue Huang, Xiaoyi Mi, Hong Zhou
Journal: PLoS Medicine (2021)

Background The influence of the safety and security of environments on early childhood development (ECD) has been under-explored. Although housing might be linked to ECD by affecting a child’s health and a parent’s ability to provide adequate care, only a few studies have examined this factor. We hypothesized that housing environment is associated with ECD in sub-Saharan Africa (SSA). Methods and findings From 92,433 children aged 36 to 59 months who participated in Multiple Indicator Cluster Survey (MICS) in 20 SSA countries, 88,271 were tested for cognitive and social–emotional development using the Early Childhood Development Index (ECDI) questionnaire and were thus included in this cross-sectional analysis. Children’s mean age was 47.2 months, and 49.8% were girls. Children were considered developmentally on track in a certain domain if they failed no more than 1 ECDI item in that domain. In each country, we used conditional logistic regression models to estimate the association between improved housing (housing with finished building materials, improved drinking water, improved sanitation facilities, and sufficient living area) and children’s cognitive and social–emotional development, accounting for contextual effects and socioeconomic factors. Estimates from each country were pooled using random-effects meta-analyses. Subgroup analyses were conducted by the child’s gender, maternal education, and household wealth quintiles. On-track cognitive development was associated with improved housing (odds ratio [OR] = 1.15, 95% CI 1.06 to 1.24, p &lt; 0.001), improved drinking water (OR = 1.07, 95% CI 1.00 to 1.14, p = 0.046), improved sanitation facilities (OR = 1.15, 95% CI 1.03 to 1.28, p = 0.014), and sufficient living area (OR = 1.06, 95% CI 1.01 to 1.10, p = 0.018). On-track social–emotional development was associated with improved housing only in girls (OR = 1.14, 95% CI 1.04 to 1.25, p = 0.006). The main limitations of this study included the cross-sectional nature of the datasets and the use of the ECDI, which lacks sensitivity to measure ECD outcomes. Conclusions In this study, we observed that improved housing was associated with on-track cognitive development and with on-track social–emotional development in girls. These findings suggest that housing improvement in SSA may be associated not only with benefits for children’s physical health but also with broader aspects of healthy child development.
Gender differences in the provision of intensive care: a Bayesian approach
Authors: Atanas Todorov, Fabian Kaufmann, Ketina Arslani, Ahmed Haider, Susan Bengs, Georg Goliasch, Núria Zellweger, Janna Tontsch, Raoul Sutter, Bigna Buddeberg, Alexa Hollinger, Elisabeth Zemp, Mark Kaufmann, Martin Siegemund, Cathérine Gebhard, Caroline E. Gebhard
Journal: Intensive Care Medicine (2021)

It is currently unclear whether management and outcomes of critically ill patients differ between men and women. We sought to assess the influence of age, sex and diagnoses on the probability of intensive care provision in critically ill cardio- and neurovascular patients in a large nationwide cohort in Switzerland. Retrospective analysis of 450,948 adult patients with neuro- and cardiovascular disease admitted to all hospitals in Switzerland between 01/2012 and 12/2016 using Bayesian modeling. For all diagnoses and populations, median ages at admission were consistently higher for women than for men [75 (64;82) years in women vs. 68 (58;77) years in men, p < 0.001]. Overall, women had a lower likelihood to be admitted to an intensive care unit (ICU) than men, despite being more severely ill [odds ratio (OR) 0.78 (0.76–0.79)]. ICU admission probability was lowest in women aged > 65 years (OR women:men 0.94 (0.89–0.99), p < 0.001). Women < 45 years had a similar ICU admission probability as men in the same age category [OR women:men 1.03 (0.94–1.13)], in spite of more severe illness. The odds to die were significantly higher in women than in men per unit increase in Simplified Acute Physiology Score (SAPS) II (OR 1.008 [1.004–1.012]). In the care of the critically ill, our study suggests that women are less likely to receive ICU treatment regardless of disease severity. Underuse of ICU care was most prominent in younger women < 45 years. Although our study has several limitations that are imposed by the limited data available from the registries, our findings suggest that current ICU triage algorithms could benefit from careful reassessment. Further, and ideally prospective, studies are needed to confirm our findings.
Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition
Authors: Shuaizhang Li, Jinghua Zhao, Ruili Huang, Jameson Travers, Carleen Klumpp-Thomas, Wenbo Yu, Alexander D. MacKerell, Srilatha Sakamuru, Masato Ooka, Fengtian Xue, Nisha S. Sipes, Jui-Hua Hsieh, Kristen Ryan, Anton Simeonov, Michael F. Santillo, Menghang Xia
Journal: Environmental Health Perspectives (2021)

Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models.To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993.
Abstract PO-039: Radiation therapy enhances anti-tumor activity of a MET CAR T-based immunotherapy approach for glioblastoma multiforme
Authors: Lusine Hovhannisyan, Daniel M. Aebersold, John Maher, Adrian F. Ochsenbein, Carsten Riether, Michaela Medova, Yitzhak Zimmer
Journal: Clinical Cancer Research (2021)

Abstract Glioblastoma multiforme (GBM) is the most prevalent primary malignant brain tumor, which has an aggressive phenotype and mostly fatal recurrence after standard therapy. MET, the hepatocyte growth factor (HGF) receptor is a relevant target for GBM treatment as it is expressed in up to 50% of cases and its expression, which may be induced by radiation therapy (RT), can potentially contribute to RT-resistance of GBM stem cells, and tumor recurrence. MET-based chimeric antigen (CAR) T cell therapy is currently being evaluated in several solid tumor working settings. A combination of T cell-based therapies with RT may improve the efficacy of the CAR T cell therapy through by the RT-induced immune activation via release of cytokines and induction of antigen expression, similarly as has been observed when combining RT with immune checkpoint inhibitors. Here we investigated the combination of MET-targeting CAR T cells with RT for GBM treatment, hypothesizing enhanced anti-tumor effects. The current study used a panel of MET-proficient and MET-deficient human GBM and GBM stem-like cell lines. Cells have been irradiated with a single dose of 0, 2, 5, or 10 Gy and RT impact on MET expression has been assessed at various time points after RT administration. Results show MET increase after RT in some cell lines. To test MET-targeting CAR T effect on the GBM cell lines, CAR constructs that are based on HGF-MET binding elements have been introduced into virus-producing cells and used for human T cells transduction to generate MET-targeting CAR T cells. CAR T cells co-cultured with GBM cell lines in vitro have specifically and significantly decreased viability of MET-positive cancer cells. Data resulting from combination of RT and CAR T cells treatment suggest that radiation exhibits an enhancement of CAR T cells anti-tumor killing activity, indicating a synergism between the two modalities. In conclusion, our data are the first to indicate the efficacy of a MET-based CAR T immunotherapy approach in GBM cell lines. The results also demonstrate a basis for the combination of a MET CAR T modality together with RT. The mechanisms for understanding the interaction between RT and the MET CAR T cells are under investigation. Citation Format: Lusine Hovhannisyan, Daniel M. Aebersold, John Maher, Adrian F. Ochsenbein, Carsten Riether, Michaela Medova, Yitzhak Zimmer. Radiation therapy enhances anti-tumor activity of a MET CAR T-based immunotherapy approach for glioblastoma multiforme [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-039.
Identification of Dukes C colorectal cancer patients with poor prognosis following surgery utilizing oligonucleotide microarray analysis
Authors: Diego Arango, Pia Alhopuro, Heli Sammalkorpi, Antti Kokko, Sampsa Hautaniemi, Harri Lähdesmäki, Mogens Kruhøffer, Torben Ørntoft, Lauri Aaltonen
Journal: Cancer Research (2004)

5587  Background: Surgical removal of the primary tumor is part of the standard treatment for patients with Dukes C colorectal cancer. However, despite aggressive surgery, approximately 50% of these patients will have disease recurrence and die before 5 years from initial diagnosis. Large multi-institutional clinical trials have demonstrated that 5-fluorouracil (5FU) based adjuvant chemotherapeutic treatment can improve long term survival by 15-20%. Therefore, currently Dukes C patients routinely receive 5FU-based adjuvant therapy in an attempt to reduce their recurrence rate. However, approximately 50% of these patients are surgically cured and undergo chemotherapeutic treatment without benefit, highlighting the need for reliable means of predicting long-term survival of these patients. In this study we utilized oligonucleotide microarray analysis of the level of expression of 18.400 sequences in surgically resected tumors, to identify a subset of patients with poor prognosis after surgery. Materials and Methods: In these experiments, we used a unique set of fresh-frozen Dukes C colorectal tumor samples from patients that underwent surgery as the only form of treatment. These samples were collected before adjuvant chemotherapy was part of the standard treatment for these patients and complete follow-up information is available for at least 5 years. Total RNA was extracted from fresh frozen, microdissected samples of 30 colorectal tumors and 19 normal mucosa samples, biotin-labeled and hybridized to Affymetrix HG-U133A oligonucleotide microarrays. Results: Unsupervised hierarchical clustering accurately separated tumor samples from normal colorectal mucosa samples, demonstrating profound differences in the expression profile of malignant tumor cells. The overall 5-year survival rate of all patients in this study was approximately 50%. However, unsupervised hierarchical clustering identified two groups of patients with very different 5-year survival rate: 22 vs. 72% (p=0.02; Logrank test). Genes showing significant expression differences in tumors from patients with good (over 5-year survival) and bad (under 5 year survival) prognosis could be classified in diverse functional categories, including extracellular matrix remodeling, angiogenesis and immune response. The levels of expression assessed by microarray analysis were confirmed by quantitative Real-Time RT-PCR analysis for some of these genes. Conclusion: Gene expression profiling by microarray analysis could be useful in assessing relative risk of disease recurrence and guiding rationale decisions concerning adjuvant chemotherapy for Dukes C colorectal patients.
The Pandemic Stay-at-Home Order and Opioid-Involved Overdose Fatalities
Authors: Maryann Mason, Ponni Arukumar, Joe Feinglass
Journal: JAMA (2021)

This JAMA Insights describes trends in opioid-involved deaths in Cook County, Illinois (including Chicago), over a 3-year period, with a focus on changes before, during, and after the statewide 11-week COVID-19 stay-at-home order, March-June 2020.
重症下肢虚血,冠動脈疾患,および高血圧は末梢動脈疾患において腎動脈狭窄症のリスク因子である
Authors: Kumakura Hisao, Kanai Hiroyoshi, Endoh Michiko, Araki Yoshihiro, Kasama Shu, Itoh Toshio, Iwasaki Toshiya, Takayama Yoshiaki, Ichikawa Shuichi, Minami Kazutomo, Kurabayashi Masahiko
Journal: Circulation (2013)
Analysis of Brugada syndrome loci reveals that fine-mapping clustered GWAS hits enhances the annotation of disease-relevant variants
Authors: Mel·lina Pinsach-Abuin, Bernat del Olmo, Adrian Pérez-Agustin, Jesus Mates, Catarina Allegue, Anna Iglesias, Qi Ma, Daria Merkurjev, Sergiy Konovalov, Jing Zhang, Farah Sheikh, Amalio Telenti, Josep Brugada, Ramon Brugada, Melissa Gymrek, Julia di Iulio, Ivan Garcia-Bassets, Sara Pagans
Journal: Cell Reports Medicine (2021)

<h2>Summary</h2> Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The remaining hits represent SNVs in linkage disequilibrium (LD) and are considered redundant and thus frequently marginally reported or exploited. Here, we interrogate the value of integrating the full set of GWAS hits in a locus repeatedly associated with cardiac conduction traits and arrhythmia, <i>SCN5A</i>-<i>SCN10A</i>. Our analysis reveals 5 common 7-SNV haplotypes (Hap1–5) with 2 combinations associated with life-threatening arrhythmia—Brugada syndrome (the risk Hap<sup>1/1</sup> and protective Hap<sup>2/3</sup> genotypes). Hap1 and Hap2 share 3 SNVs; thus, this analysis suggests that assuming redundancy among clustered GWAS hits can lead to confounding disease-risk associations and supports the need to deconstruct GWAS data in the context of haplotype composition.
Abstract PO-082: Radiation therapy enhances the potential of the oncolytic virus in the treatment of osteosarcoma
Authors: Elora Hossain, Fumihiro Higashino
Journal: Clinical Cancer Research (2021)

Abstract Background: Combination of neoadjuvant chemotherapy and surgery is the standard treatment approach for osteosarcoma. Despite aggressive treatment protocol, ~40% of patients do not respond and relapse, the survival rate is poor for these patients. Conditionally replicative adenovirus (CRAds) destroying cancer cell while sparing normal cells is a new treatment approach for cancers. We developed a new oncolytic adenovirus which grows using mRNA stabilization system found in many cancer cells. Our recent report showed that this virus replicated in cancer cells where AU-rich element (ARE) containing mRNA is stabilized. ARE-mRNA is stabilized in the majority types of cancers mediate by binding with HuR (Human antigen R), which exports target ARE-mRNA to the cytoplasm. Radiotherapy (RT) is not a first-line treatment option for osteosarcoma as osteosarcoma cells are not killed by radiation easily. But in certain conditions radiotherapy can be used where surgical resection is not technically possible without undue morbidity or when surgery is refused. In response to ionizing radiation and UV radiation DNA damage response (DDR) can influence HuR action either by the increasing cytoplasmic HuR abundance or affecting the binding affinity to target ARE-mRNA. The purpose of the present study was to analyze the efficacy of the combination treatment of RT and oncolytic adenovirus for osteosarcoma. Materials and Methods: E4rof6-deleted adenovirus (dl355) and human osteosarcoma cell lines U2OS and Saos2 were used in this study. Cell viability assays were carried out to evaluate the cytotoxicity and synergism of dl355 and RT combination. Chou and Talalay’s median-effect method was used to calculate the combination index. CPE assay was used to assess the cytopathic effect of the combination. Viral replication with or without radiation combination was investigated by hexon staining. Western blot analysis was performed to examine viral protein expression. Results: We found that RT treatment enhanced the cytoplasmic relocalization of HuR; thus irradiation up-regulated the propagations of dl355. Also, radiation-induced upregulation of viral protein expression was observed by western blotting. The RT and dl355 combination treatment increased the cytolysis of U2OS, and Saos2 cells in a synergistic manner compared to RT or virus only. Conclusion: Radiotherapy up-regulated of oncolytic adenovirus, which grows using the ARE-mRNA stabilization system, and this cytolytic effect provides a rationale for this combination. This combination approach has the possibility of a promising strategy for osteosarcoma. Citation Format: Elora Hossain, Fumihiro Higashino. Radiation therapy enhances the potential of the oncolytic virus in the treatment of osteosarcoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-082.