tbuckley/cabot-search huggingface dataset:
N<sup>6</sup>-methyladenosine as a biological and clinical determinant in colorectal cancer: progression and future direction
Authors: Jinming Li, Lei Liang, Yongzhi Yang, Xinxiang Li, Yanlei Ma
Journal: Theranostics (2021)

Colorectal cancer (CRC) is one of the most prevalent cancers and one of the leading causes of cancer death. Recent studies have provided evidence that N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryote, performs many functions in RNA metabolism including translation, splicing, storage, trafficking and degradation. Aberrant regulation of m6A modification in mRNAs and noncoding RNAs found in CRC tissues is crucial for cancer formation, progression, invasion and metastasis. Further, m6A regulators and m6A-related RNAs may become promising biomarkers, prognosis predictors as well as therapeutic targets. Here, we review the biological and clinical roles of m6A modification in CRC, and discuss the potential of m6A in clinical translation.
At the Water's Edge: Coastal Settlement, Transformative Adaptation, and Well-Being in an Era of Dynamic Climate Risk
Authors: William Solecki, Erin Friedman
Journal: Annual Review of Public Health (2021)

With accelerating climate change, US coastal communities are experiencing increased flood risk intensity, resulting from accelerated sea level rise and stronger storms. These conditions place pressure on municipalities and local residents to consider a range of new disaster risk reduction programs, climate resilience initiatives, and in some cases transformative adaptation strategies (e.g., managed retreat and relocation from highly vulnerable, low-elevation locations). Researchers have increasingly understood that these climate risks and adaptation actions have significant impacts on the quality of life, well-being, and mental health of urban coastal residents. We explore these relationships and define conditions under which adaptation practices will affect communities and residents. Specifically, we assess climate and environmental stressors, community change, and well-being by utilizing the growing climate change literature and the parallel social science literature on risk and hazards, environmental psychology, and urban geography work, heretofore not widely integrated into work on climate adaptation.
Regulation of PD-L1 expression in the tumor microenvironment
Authors: Ming Yi, Mengke Niu, Linping Xu, Suxia Luo, Kongming Wu
Journal: Journal of Hematology & Oncology (2021)

Abstract Programmed death-ligand 1 (PD-L1) on cancer cells engages with programmed cell death-1 (PD-1) on immune cells, contributing to cancer immune escape. For multiple cancer types, the PD-1/PD-L1 axis is the major speed-limiting step of the anti-cancer immune response. In this context, blocking PD-1/PD-L1 could restore T cells from exhausted status and eradicate cancer cells. However, only a subset of PD-L1 positive patients benefits from α-PD-1/PD-L1 therapies. Actually, PD-L1 expression is regulated by various factors, leading to the diverse significances of PD-L1 positivity. Understanding the mechanisms of PD-L1 regulation is helpful to select patients and enhance the treatment effect. In this review, we focused on PD-L1 regulators at the levels of transcription, post-transcription, post-translation. Besides, we discussed the potential applications of these laboratory findings in the clinic.
Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor: Double-Edged Swords**Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Robert F. Wilson, Timothy D. Henry
Journal: Journal of the American College of Cardiology (2005)
Astrocytes and Behavior
Authors: Paulo Kofuji, Alfonso Araque
Journal: Annual Review of Neuroscience (2021)

Animal behavior was classically considered to be determined exclusively by neuronal activity, whereas surrounding glial cells such as astrocytes played only supportive roles. However, astrocytes are as numerous as neurons in the mammalian brain, and current findings indicate a chemically based dialog between astrocytes and neurons. Activation of astrocytes by synaptically released neurotransmitters converges on regulating intracellular Ca2+ in astrocytes, which then can regulate the efficacy of near and distant tripartite synapses at diverse timescales through gliotransmitter release. Here, we discuss recent evidence on how diverse behaviors are impacted by this dialog. These recent findings support a paradigm shift in neuroscience, in which animal behavior does not result exclusively from neuronal activity but from the coordinated activity of both astrocytes and neurons. Decoding how astrocytes and neurons interact with each other in various brain circuits will be fundamental to fully understanding how behaviors originate and become dysregulated in disease.
Taurocholic acid inhibits the response to interferon-α therapy in patients with HBeAg-positive chronic hepatitis B by impairing CD8+ T and NK cell function
Authors: Zhen Xun, Jinpiao Lin, Qingqing Yu, Can Liu, Jinlan Huang, Hongyan Shang, Jianhui Guo, Yuchen Ye, Wennan Wu, Yongbin Zeng, Songhang Wu, Siyi Xu, Tianbin Chen, Jing Chen, Qishui Ou
Journal: Cellular and Molecular Immunology (2021)

Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.
Polymeric delivery systems for nucleic acid therapeutics: Approaching the clinic
Authors: Annette I.S. van den Berg, Chae-Ok Yun, Raymond M. Schiffelers, Wim E. Hennink
Journal: Journal of Controlled Release (2021)

Gene therapy using nucleic acids has many clinical applications for the treatment of diseases with a genetic origin as well as for the development of innovative vaccine formulations. Since nucleic acids in their free form are rapidly degraded by nucleases present in extracellular matrices, have poor pharmacokinetics and hardly pass cellular membranes, carrier systems are required. Suitable carriers that protect the nucleic acid payload against enzymatic attack, prolong circulation time after systemic administration and assist in cellular binding and internalization are needed to develop nucleic acid based drug products. Viral vectors have been investigated and are also clinically used as delivery vehicles. However, some major drawbacks are associated with their use. Therefore there has been substantial attention on the use of non-viral carrier systems based on cationic lipids and polymers. This review focuses on the properties of polymer-based nucleic acid formulations, also referred as polyplexes. Different polymeric systems are summarized, and the cellular barriers polyplexes encounter and ways to tackle these are discussed. Finally attention is given to the clinical status of non-viral nucleic acid formulations.
Artificial Intelligence, Social Media and Depression. A New Concept of Health-Related Digital Autonomy
Authors: Sebastian Laacke, Regina Mueller, Georg Schomerus, Sabine Salloch
Journal: The American Journal of Bioethics (2021)

The development of artificial intelligence (AI) in medicine raises fundamental ethical issues. As one example, AI systems in the field of mental health successfully detect signs of mental disorders, such as depression, by using data from social media. These AI depression detectors (AIDDs) identify users who are at risk of depression prior to any contact with the healthcare system. The article focuses on the ethical implications of AIDDs regarding affected users' health-related autonomy. Firstly, it presents the (ethical) discussion of AI in medicine and, specifically, in mental health. Secondly, two models of AIDDs using social media data and different usage scenarios are introduced. Thirdly, the concept of patient autonomy, according to Beauchamp and Childress, is critically discussed. Since this concept does not encompass the specific challenges linked with the digital context of AIDDs in social media sufficiently, the current analysis suggests, finally, an extended concept of health-related digital autonomy.
Cellular Models and High-Throughput Screening for Genetic Causality of Intellectual Disability
Authors: Christopher W. Fell, Vanja Nagy
Journal: Trends in Molecular Medicine (2021)

Intellectual disabilities (ID) are a type of neurodevelopmental disorder (NDD). They can have a genetic cause, including an emerging class of ID centring around Rho GTPases, such as Ras-related C3 botulinum toxin substrate 1 (RAC1). Guidelines for establishing genetic causality include the use of cellular models, which often have morphological aberrations, a long-standing hallmark of ID. Disease cellular models can facilitate high-throughput screening (HTS) of chemical or genetic perturbations, which can provide translatable biological insight. Here, we discuss a class of IDs centring around RAC1. We review novel and established cellular models of ID, including mouse and human primary cells and reprogrammed or induced neurons. Finally, we review progress and remaining challenges in the adoption of HTS methodologies by the community studying neurological disorders.
Abstract 17136: Phosphodiesterase 5 Inhibitor Therapy Improves Clinical Parameters in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-capillary Pulmonary Hypertension
Authors: Tilmann T Kramer, Kristina Orlova, Felix Gerhardt, Daniel Dumitrescu, Henrik ten-Freyhaus, Stephan Baldus, Stephan Rosenkranz
Journal: Circulation (2017)

Introduction: Heart failure with preserved ejection fraction (HFpEF) is frequently associated with pulmonary hypertension (PH). The current guidelines subclassify postcapillary PH into isolated pos...
Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression
Authors: Marina Natoli, John Gallon, Haonan Lu, Ala Amgheib, David J Pinato, Francesco A Mauri, Teresa Marafioti, Ayse U Akarca, Ines Ullmo, Jacey Ip, Eric O Aboagye, Robert Brown, Anastasios Karadimitris, Sadaf Ghaem-Maghami
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC. Methods ERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (LASSO) logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro , using EOC cell lines and patient-derived tumor cells. Results ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+T cells (r=0.46, p=0.0001). In the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). In vitro , baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells. Conclusions These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence tumor immune infiltration and affect antitumor immunity.
Novel invariant features of Good syndrome
Authors: Carmelo Gurnari, Jibran Durrani, Simona Pagliuca, Ashwin Kishtagari, Hassan Awada, Cassandra M. Kerr, Vera Adema, Sunisa Kongkiatkamon, Alan E. Lichtin, Bhumika J. Patel, Valeria Visconte, Mikkael A. Sekeres, James R. Cook, Jaroslaw P. Maciejewski
Journal: Leukemia (2021)
Breast Tumor Microenvironment in Black Women: A Distinct Signature of CD8+ T-Cell Exhaustion
Authors: Song Yao, Ting-Yuan David Cheng, Ahmed Elkhanany, Li Yan, Angela Omilian, Scott I Abrams, Sharon Evans, Chi-Chen Hong, Qianya Qi, Warren Davis, Song Liu, Elisa V Bandera, Kunle Odunsi, Kazuaki Takabe, Thaer Khoury, Christine B Ambrosone
Journal: JNCI Journal of the National Cancer Institute (2020)

Blacks tend to have a stronger inflammatory immune response than Whites. We hypothesized that racial differences in host immunity also manifest in the tumor microenvironment, constituting part of a distinct aggressive tumor biology underlying higher mortality in Black women.Pathological and gene expression profiling approaches were used for characterizing infiltrating immune cells in breast tumor microenvironment from 1315 patients from the Women's Circle of Health Study. Racial differences in tumor immune phenotypes were compared, with results validated in a publicly accessible dataset. Prognostic associations of immune phenotypes were assessed in 3 independent cohorts.We found marked and consistent differences in tumor immune responses between Black and White patients. Not only did tumors from Blacks display a stronger overall immune presence but also the composition and quality of immune infiltrates differed, regardless of tumor subtypes. Black patients had a stronger CD4+ and B-cell response, and further, a more exhausted CD8+ T-cell profile. A signature indicating a higher ratio of exhausted CD8+ T cells to total CD8+ T cells (ExCD8-r) was consistently associated with poorer survival, particularly among hormone receptor-positive patients. Among hormone receptor-negative patients, combinations of the absolute fraction of CD8+ T cells and ExCD8-r signature identified the CD8lowExCD8-rhigh subgroup, the most prevalent among Blacks, with the worst survival.Our findings of a distinct exhausted CD8+ T-cell signature in Black breast cancer patients indicate an immunobiological basis for their more aggressive disease and a rationale for the use of immune checkpoint inhibitors targeting the exhaustion phenotype.
Di-methylation of CD147-K234 Promotes the Progression of NSCLC by Enhancing Lactate Export
Authors: Ke Wang, Wan Huang, Ruo Chen, Peng Lin, Tao Zhang, Yun-Feng Ni, Hao Li, Jiao Wu, Xiu-Xuan Sun, Jie-Jie Geng, Yu-Meng Zhu, Gang Nan, Wei Zhang, Xi Chen, Ping Zhu, Huijie Bian, Zhi-Nan Chen
Journal: Cell Metabolism (2021)
Randomized Phase II Study of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Mucosal Melanoma
Authors: Xieqiao Yan, Xinan Sheng, Zhihong Chi, Lu Si, Chuanliang Cui, Yan Kong, Bixia Tang, Lili Mao, Xuan Wang, Bin Lian, Siming Li, Xue Bai, Li Zhou, Jie Dai, Hong Yao, Jun Guo
Journal: Journal of Clinical Oncology (2021)

Mucosal melanoma (MM) is a highly vascularized tumor with an extremely poor prognosis. In this randomized, open-label, phase II study, we characterized the efficacy and safety of bevacizumab in combination with carboplatin plus paclitaxel (CPB) in patients with previously untreated advanced MM.Patients were randomly assigned in a 2:1 ratio to receive carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2) once every 4 weeks in combination with (CPB arm, 5 mg/kg) or without (CP arm) bevacizumab once every 2 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS), objective response rate, and adverse events.We recruited 114 patients to our study. The median PFS was significantly longer in the CPB arm (4.8 months; 95% CI, 3.6 to 6.0 months) than in the CP arm (3.0 months; 95% CI, 1.7 to 4.3 months) (hazard ratio, 0.461; 95% CI, 0.306 to 0.695; P < .001). Objective response rates were 19.7% and 13.2%, respectively (P = .384). The median OS was also significantly longer in the CPB arm than in the CP arm (13.6 v 9.0 months; hazard ratio, 0.611; 95% CI, 0.407 to 0.917; P = .017). No new safety signals were observed.PFS and OS were significantly better in patients with metastatic MM who received bevacizumab in addition to CPB than in those who received CPB alone. A phase III study should be performed to confirm these benefits (ClinicalTrials.gov identifier: NCT02023710).
Investigation of a monoclonal antibody against enterotoxigenic <i>Escherichia coli</i>, expressed as secretory IgA1 and IgA2 in plants
Authors: Audrey Y-H Teh, Lisa Cavacini, Yue Hu, Ozan S. Kumru, Jian Xiong, David T. Bolick, Sangeeta B. Joshi, Clemens Grünwald-Gruber, Friedrich Altmann, Mark Klempner, Richard L. Guerrant, David B. Volkin, Yang Wang, Julian K-C. Ma
Journal: Gut Microbes (2021)

Passive immunization with antibodies is a promising approach against enterotoxigenic Escherichia coli diarrhea, a prevalent disease in LMICs. The objective of this study was to investigate expression of a monoclonal anti-ETEC CfaE secretory IgA antibody in N. benthamiana plants, with a view to facilitating access to ETEC passive immunotherapy. SIgA1 and SIgA2 forms of mAb 68–81 were produced by co-expressing the light and engineered heavy chains with J chain and secretory component in N. benthamiana. Antibody expression and assembly were compared with CHO-derived antibodies by SDS-PAGE, western blotting, size-exclusion chromatography and LC-MS peptide mapping. N-linked glycosylation was assessed by rapid fluorescence/mass spectrometry and LC-ESI-MS. Susceptibility to gastric digestion was assessed in an in vitro model. Antibody function was compared for antigen binding, a Caco-2 cell-based ETEC adhesion assay, an ETEC hemagglutination inhibition assay and a murine in vivo challenge study. SIgA1 assembly appeared superior to SIgA2 in plants. Both sub-classes exhibited resistance to degradation by simulated gastric fluid, comparable to CHO-produced 68–61 SIgA1. The plant expressed SIgAs had more homogeneous N-glycosylation than CHO-derived SIgAs, but no alteration of in vitro functional activity was observed, including antibodies expressed in a plant line engineered for mammalian-like N glycosylation. The plant-derived SIgA2 mAb demonstrated protection against diarrhea in a murine infection model. Although antibody yield and purification need to be optimized, anti-ETEC SIgA antibodies produced in a low-cost plant platform are functionally equivalent to CHO antibodies, and provide promise for passive immunotherapy in LMICs.
Abstract 14535: Empagliflozin Directly Reverses Markers of Cardiac Remodeling in Human and Murine Failing Cardiomyocytes
Authors: Julian Mustroph, Olivia Wagemann, Maximilian Trum, Simon Lebek, Daniel Tarnowski, Jörg Reinders, Christof Schmid, Simon Schoppka, Michael Hilker, Bernhard Graf, Steffen Pabel, Samuel T Sossalla, Frank Schweda, Lars S Maier, Stefan Wagner
Journal: Circulation (2018)

Background: The EMPA-REG OUTCOME trial showed a reduction in heart failure (HF) hospitalization and mortality in diabetic patients. It is unclear whether diabetes related mechanisms or direct cardi...
Association between prophylactic antibiotic use for transarterial chemoembolization and occurrence of liver abscess: a retrospective cohort study
Authors: Shingo Yoshihara, Hayato Yamana, Manabu Akahane, Miwa Kishimoto, Yuichi Nishioka, Tatsuya Noda, Hiroki Matsui, Kiyohide Fushimi, Hideo Yasunaga, Kei Kasahara, Tomoaki Imamura
Journal: Clinical Microbiology and Infection (2021)

Clinical evidence on prophylactic antibiotics for transarterial chemoembolization (TACE) to prevent liver abscess is limited because liver abscess is a rare event. This study aimed to analyse the association between prophylactic antibiotic use for TACE and the occurrence of liver abscess after TACE.Using the nationwide Diagnosis Procedure Combination database in Japan, we retrospectively identified patients who underwent TACE for hepatic cancer between July 2010 and March 2017. The primary outcome was liver abscess requiring procedural intervention within 30 days of TACE. Secondary outcomes included 30-day in-hospital mortality and length of stay. Propensity score matching was performed to adjust for potential confounding factors and compare outcomes between patients with and without prophylactic antibiotics.Among 167 544 eligible patients, 134 712 received antibiotics and 32 832 did not. In the matched cohort of 29 211 pairs, the proportion of patients with liver abscess requiring procedural intervention was significantly lower in the antibiotics group than in the no-antibiotics group (0.08% vs. 0.22%, p 0.001; relative risk (95% confidence interval), 0.35 (0.22-0.57); absolute risk reduction, 0.0014 (0.0008-0.0021); and number needed to treat, 696 (476-1223)). There was no significant difference in 30-day in-hospital mortality between the groups. The length of stay was longer in the antibiotics group than in the no-antibiotics group (median, 10 vs. 9 days, p < 0.001).Prophylactic antibiotic use in patients undergoing TACE was associated with a reduced occurrence of liver abscess requiring procedural intervention.