tbuckley/cabot-search huggingface dataset:
Anti–SARS-CoV-2 and Autoantibody Profiles in the Cerebrospinal Fluid of 3 Teenaged Patients With COVID-19 and Subacute Neuropsychiatric Symptoms
Authors: Christopher M. Bartley, Claire Johns, Thomas T. Ngo, Ravi Dandekar, Rita L. Loudermilk, Bonny D. Alvarenga, Isobel A. Hawes, Colin R. Zamecnik, Kelsey C. Zorn, Jessa R. Alexander, Anne E. Wapniarski, Joseph L. DeRisi, Carla Francisco, Kendall B. Nash, Sharon O. Wietstock, Samuel J. Pleasure, Michael R. Wilson
Journal: JAMA Neurology (2021)

Neuropsychiatric manifestations of COVID-19 have been reported in the pediatric population.To determine whether anti-SARS-CoV-2 and autoreactive antibodies are present in the cerebrospinal fluid (CSF) of pediatric patients with COVID-19 and subacute neuropsychiatric dysfunction.This case series includes 3 patients with recent SARS-CoV-2 infection as confirmed by reverse transcriptase-polymerase chain reaction or IgG serology with recent exposure history who were hospitalized at the University of California, San Francisco Benioff Children's Hospital and for whom a neurology consultation was requested over a 5-month period in 2020. During this period, 18 total children were hospitalized and tested positive for acute SARS-CoV-2 infection by reverse transcriptase-polymerase chain reaction or rapid antigen test.Detection and characterization of CSF anti-SARS-CoV-2 IgG and antineural antibodies.Of 3 included teenaged patients, 2 patients had intrathecal anti-SARS-CoV-2 antibodies. CSF IgG from these 2 patients also indicated antineural autoantibodies on anatomic immunostaining. Autoantibodies targeting transcription factor 4 (TCF4) in 1 patient who appeared to have a robust response to immunotherapy were also validated.Pediatric patients with COVID-19 and prominent subacute neuropsychiatric symptoms, ranging from severe anxiety to delusional psychosis, may have anti-SARS-CoV-2 and antineural antibodies in their CSF and may respond to immunotherapy.
Lipidomic landscape in cancer: Actionable insights for membrane‐based therapy and diagnoses
Authors: Prema K. Agarwala, Ritu Aneja, Shobhna Kapoor
Journal: Medicinal Research Reviews (2021)

Abstract Cancer cells display altered cellular lipid metabolism, including disruption in endogenous lipid synthesis, storage, and exogenous uptake for membrane biogenesis and functions. Altered lipid metabolism and, consequently, lipid composition impacts cellular function by affecting membrane structure and properties, such as fluidity, rigidity, membrane dynamics, and lateral organization. Herein, we provide an overview of lipid membranes and how their properties affect cellular functions. We also detail how the rewiring of lipid metabolism impacts the lipidomic landscape of cancer cell membranes and influences the characteristics of cancer cells. Furthermore, we discuss how the altered cancer lipidome provides cues for developing lipid‐inspired innovative therapeutic and diagnostic strategies while improving our limited understanding of the role of lipids in cancer initiation and progression. We also present the arcade of membrane characterization techniques to cement their relevance in cancer diagnosis and monitoring of treatment response.
Under pressure: when does the NHS reach “breaking point”?
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Health leaders and patient facing staff have warned that the NHS is at “breaking point” as it confronts covid-19, winter pressures, and the backlog from the pandemic. In response, the government has said the health service is facing “sustainable pressure.” So, who is right? And what do these terms mean?

The short answer is that these terms have no set definition when it comes to the NHS, and that can lead to a contradictory narrative.

A spokesperson for the Department of Health and Social Care told The BMJ that there are “various factors,” including bed occupancy …
Post-translational modification of β-catenin by O-glycosylation regulates its nuclear localization and transcriptional activity
Authors: Paul A. Northcott, David W. Andrews, Brian Leber, Ria Sayat, Weija Zhu, Sujata Persad
Journal: Cancer Research (2005)

4515  β-catenin is a multifunctional protein that serves a structural role at cell-cell adherens junctions and a regulatory function as a transcriptional activator mediating Wnt signal transduction. The proliferative effects of Wnt signaling are achieved by stabilization of cytosolic β-catenin, permitting accumulation of the protein and its subsequent translocation to the nucleus where it forms complexes with members of the TCF/LEF family of transcription factors to activate gene transcription. Cytosolic levels of β-catenin are tightly regulated by phosporylation; however, the mechanism(s) responsible for β-catenin nuclear entry is not well understood. Recently, β-catenin was reported to be modified post-translationally by O-glycosylation in breast cancer cells exposed to the intracellular calcium pump inhibitor, thapsigargin (TG). This type of modification involves attachment of β-N-acetylglucosamine (GlcNAc) to serine/threonine residues via an O-glycosidic linkage. In the present study, we demonstrate that β-catenin is modified by at least two distinct patterns of O-glycosylation: one that is recognized by the lectin, wheat germ agglutinin (WGA; w-O-GlcNAc), and another that is detected by a monoclonal antibody specific for O-GlcNAc modification (α-RL-2; r-O-GlcNAc). To evaluate whether O-glycosylation of β-catenin influences its signaling properties, we investigated β-catenin O-GlcNAc status in several cell lines, including the normal breast cell line, MCF-10A, and the breast tumor lines, MCF-7 and MDA-MB-231. These studies revealed that a significant amount of β-catenin in MCF-10A cells is glycosylated in a w-O-GlcNAc manner, while the cancer cells possessed negligible quantities of the w-O-GlcNAc-modified protein. In contrast, r-O-GlcNAc-modified β-catenin was detected at comparable levels in the three cell lines examined. Assessment of β-catenin status in nuclear extracts revealed the protein to be more abundant in the nucleus of the MCF-7 and MDA-MB-231 tumor cells than in normal MCF-10A cells, while w-O-GlcNAc-modified β-catenin was not observed in nuclear fractions prepared from any of the tested cell lines. Treatment of MCF-7 cells with TG induced a time-dependent increase in the abundance of w-O-GlcNAc-modified β-catenin. This increase in the w-O-GlcNAc-modified form of the protein was accompanied by a progressive decrease in its nuclear localization. TG treatment also resulted in an apparent suppression of β-catenin transcriptional activity, as evidenced by the dramatic reduction in the expression of cyclin D1, a major target of β-catenin transcriptional regulation. Collectively, our results suggest that w-O-glycosylation of β-catenin may represent a novel mechanism important in regulation of β-catenin nuclear localization and transcriptional activity.
TCT-170 Angiography- Versus FFR-Based Deferral of Revascularization in Patients With Reduced Ejection Fraction: 10-Year Follow-Up Study
Authors: Emanuele Gallinoro, Pasquale Paolisso, Giuseppe di Gioia, Konstantinos Bermpeis, Alessandro Candreva, Giuseppe Esposito, Davide Fabbricatore, Jozef Bartunek, Marc Vanderheyden, Jeroen Sonck, Carlos Collet, Bernard de Bruyne, Emanuele Barbato
Journal: Journal of the American College of Cardiology (2021)
Rituximab versus cyclophosphamide for remission induction in active, severe antineutrophil cytoplasmic antibody–associated vasculitis: comment on the article by Chung et al
Authors: Siddharth Jain, G. S. R. S. N. K. Naidu, Aman Sharma
Journal: Arthritis & Rheumatology (2021)

Disclosureform Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
CDKL5 deficiency disorder: a pathophysiology of neural maintenance
Authors: Peter C. Kind, Adrian Bird
Journal: Journal of Clinical Investigation (2021)

Critical periods are developmental time windows in which functional properties of the brain are particularly susceptible to the organism's experience. It was thought that therapeutic strategies for neurodevelopmental disorders (NDDs) required early life intervention for successful treatment, but previous studies in a mouse model of Rett syndrome indicated that this may not be the case, as some genetic disorders result from disruptions of neuromaintenance. In this issue of the JCI, Terzic et al. provide evidence that defective neuromaintenance also underlies CDKL5 deficiency disorder (CDD). The authors used genetic mouse models to examine the role of CDKL5 protein. Notably, when CDKL5 protein was restored in late adolescent Cdkl5-deficient animals, CDD behavioral defects were reversed. These results suggest that genetically or pharmacologically restoring CDKL5 may treat CDD after symptom onset.
Inpatients at Risk of Contact Vaccinia From Immunized Health Care Workers
Authors: Perry F. Smith, Hwa-Gan Chang, Kent A. Sepkowitz
Journal: JAMA (2003)

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Construction of functional biliary epithelial branched networks with predefined geometry using digital light stereolithography
Authors: Elsa Mazari-Arrighi, Dmitry Ayollo, Wissam Farhat, Auriane Marret, Emilie Gontran, Pascale Dupuis-Williams, Jerome Larghero, Francois Chatelain, Alexandra Fuchs
Journal: Biomaterials (2021)

Cholangiocytes, biliary epithelial cells, are known to spontaneously self-organize into spherical cysts with a central lumen. In this work, we explore a promising biocompatible stereolithographic approach to encapsulate cholangiocytes into geometrically controlled 3D hydrogel structures to guide them towards the formation of branched tubular networks. We demonstrate that within the appropriate mix of hydrogels, normal rat cholangiocytes can proliferate, migrate, and organize into branched tubular structures with walls consisting of a cell monolayer, transport fluorescent dyes into the luminal space, and show markers of epithelial maturation such as primary cilia and continuous tight junctions. The resulting structures have dimensions typically found in the intralobular and intrahepatic biliary tree and are stable for weeks, without any requirement of bulk supporting material, thereby offering total access to the external side of these biliary epithelial constructs.
Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial
Authors: Huabin Hu, Liang Kang, Jianwei Zhang, Zehua Wu, Hui Wang, Meijin Huang, Ping Lan, Xiaojian Wu, Chao Wang, Wuteng Cao, Jiancong Hu, Yan Huang, Liang Huang, Huaiming Wang, Lishuo Shi, Yue Cai, Cailu Shen, Jiayu Ling, Xiaoyu Xie, Yonghua Cai, Xiaowen He, Ruoxu Dou, Jiaming Zhou, Tenghui Ma, Xingwei Zhang, Shuangling Luo, Weihao Deng, Li Ling, Hao Liu, Yanhong Deng
Journal: The Lancet. Gastroenterology & hepatology (2021)
Toll-like receptors and toll-like receptor-targeted immunotherapy against glioma
Authors: Yang Xun, Hua Yang, Bozena Kaminska, Hua You
Journal: Journal of Hematology & Oncology (2021)

Abstract Glioma represents a fast proliferating and highly invasive brain tumor which is resistant to current therapies and invariably recurs. Despite some advancements in anti-glioma therapies, patients’ prognosis remains poor. Toll-like receptors (TLRs) act as the first line of defense in the immune system being the detectors of those associated with bacteria, viruses, and danger signals. In the glioma microenvironment, TLRs are expressed on both immune and tumor cells, playing dual roles eliciting antitumoral (innate and adaptive immunity) and protumoral (cell proliferation, migration, invasion, and glioma stem cell maintenance) responses. Up to date, several TLR-targeting therapies have been developed aiming at glioma bulk and stem cells, infiltrating immune cells, the immune checkpoint axis, among others. While some TLR agonists exhibited survival benefit in clinical trials, it attracts more attention when they are involved in combinatorial treatment with radiation, chemotherapy, immune vaccination, and immune checkpoint inhibition in glioma treatment. TLR agonists can be used as immune modulators to enhance the efficacy of other treatment, to avoid dose accumulation, and what brings more interests is that they can potentiate immune checkpoint delayed resistance to PD-1/PD-L1 blockade by upregulating PD-1/PD-L1 overexpression, thus unleash powerful antitumor responses when combined with immune checkpoint inhibitors. Herein, we focus on recent developments and clinical trials exploring TLR-based treatment to provide a picture of the relationship between TLR and glioma and their implications for immunotherapy.
How the COVID-19 pandemic affects transgender health care - A cross-sectional online survey in 63 upper-middle-income and high-income countries
Authors: Andreas Koehler, Joz Motmans, Leo Mulió Alvarez, David Azul, Karen Badalyan, Koray Basar, Cecilia Dhejne, Dragana Duišin, Bartosz Grabski, Aurore Dufrasne, Natasa Jokic-Begic, Antonio Prunas, Christina Richards, Kirill Sabir, Jaimie Veale, Timo Ole Nieder
Journal: International Journal of Transgender Health (2021)

Due to the COVID-19 pandemic, access to medical care is restricted for nearly all non-acute conditions. Due to their status as a vulnerable social group and the inherent need for transition-related treatments, transgender people are assumed to be affected particularly severely by the restrictions caused by the COVID-19 pandemic.As an ad hoc collaboration between researchers, clinicians and 23 community organizations, we developed a web-based survey in German that was translated into 26 languages. Participants were recruited via community sources, social media channels, and snowball sampling since May 2020. The present sample is based on the data collected until August 9, 2020. We assessed demographical data, health problems, risk factors, COVID-19 data (e.g., contact history), and the influence of the COVID-19 pandemic on access to transgender health care services. To identify factors associated with the experience of restrictions, we conducted multiple logistic regression analysis.5267 transgender people from 63 upper-middle-income and high-income countries participated in the study. Over 50% of the participants had risk factors for a severe course of a COVID-19 infection and were at a high risk of avoiding COVID-19 treatment due to the fear of mistreatment or discrimination. Access to transgender health care services was restricted for 50% of the participants. Male sex assigned at birth and a lower monthly income were significant predictors for the experience of restrictions to health care. 35.0% reported at least one mental health condition and 3.2% have attempted suicide since the beginning of the COVID-19 pandemic.Transgender people suffer under the severity of the pandemic due to the intersections between their status as a vulnerable social group, their high number of medical risk factors, and their need for ongoing medical treatment. The COVID-19 pandemic can potentiate these vulnerabilities, add new challenges for transgender people, and, therefore, can lead to devastating consequences, like severe physical or mental health issues, self-harming behavior, and suicidality.
TCT-109 Ten-Year All-Cause Death After Percutaneous or Surgical Revascularization in Diabetic Patients With Complex Coronary Artery Disease
Authors: Rutao Wang, Chao Gao, Hironori Hara, Kuniaki Takahashi, Masafumi Ono, Hideyuki Kawashima, Neil O'Leary, David Holmes, Robert-Jan Van Geuns, Arie Kappetein, Marie-Angele Morel, Daniel Thuijs, Piroze Davierwala, Timothy O'Brien, Valentin Fuster, Scot Garg, Yoshinobu Onuma, Patrick Serruys
Journal: Journal of the American College of Cardiology (2021)
WHO International Standard for evaluation of the antibody response to COVID-19 vaccines: call for urgent action by the scientific community
Authors: Ivana Knezevic, Giada Mattiuzzo, Mark Page, Philip Minor, Elwyn Griffiths, Micha Nuebling, Vasee Moorthy
Journal: The Lancet Microbe (2021)

The first WHO International Standard and International Reference Panel for anti-SARS-CoV-2 immunoglobulin were established by the WHO Expert Committee on Biological Standardization in December, 2020. The WHO International Antibody Standards are intended to serve as global reference reagents, against which national reference preparations or secondary standards can be calibrated. Calibration will facilitate comparison of results of assays (eg, of the neutralising antibody response to candidate COVID-19 vaccines) conducted in different countries. Use of these standards is expected to contribute to better understanding of the immune response, and particularly of the correlates of protection. This Personal View provides some technical details of the WHO Antibody Standards for SARS-CoV-2, focusing specifically on the use of these standards for the evaluation of the immune response to COVID-19 vaccines, rather than other applications (eg, diagnostic or therapeutic). The explanation with regard to why rapid adoption of the standards is crucial is also included, as well as how funders, journals, regulators, and ethics committees could drive adoption in the interest of public health.
Prediction of early (4‐week) mortality in acute myeloid leukemia with intensive chemotherapy
Authors: Koji Sasaki, Tapan Kadia, Kebede Begna, Courtney D. DiNardo, Gautam Borthakur, Nicholas J. Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia‐Manero, Guillermo Montalban Bravo, Lucia Masarova, Sherry Pierce, Marina Konopleva, Farhad Ravandi, Ayalew Tefferi, Hagop Kantarjian
Journal: American Journal of Hematology (2021)

The progress with intensive chemotherapy and supportive care measures has improved survival in patients with newly diagnosed acute myeloid leukemia (AML). Given the recent development of effective low intensity therapies, an optimal decision on the therapy intensity may improve survival through the avoidance of early mortality. We reviewed the outcome of 3728 patients with newly diagnosed AML who received intensive chemotherapy between August 1980 and May 2020. Intensive chemotherapy was defined as a cumulative cytarabine dose ≥ 700 mg/m2 during induction therapy. We divided the whole cohort into a training and validation group at a 3:1 ratio. The population was divided into a training (2790 patients) and a validation cohort (938 patients). The median age was 55 years (range, 15-99). Among them, 442 patients (12%) had core-binding factor AML. Binary logistic regression identified older age, worse performance status, hyperbilirubinemia, elevated creatinine, hyperuricemia, cytogenetic abnormalities other than CBF and -Y, and pneumonia as adverse prognostic factors for an early 4-week mortality. This risk classification for early mortality was verified in the validation cohort of patients. In the validation cohort of more recently treated patients from 2000 to 2017, the 4-week mortality rates with intensive chemotherapy were 2%, 14%, and 50% in the low-, high-, and very high-risk group, respectively. The mortality rates with low intensity therapies were 3%, 9%, and 20%, respectively. The risk classification guides treatment intensity by the assessment of age, frailty, organ dysfunction, cytogenetic abnormality, and infection to avoid early mortality.
A pathogen-like antigen-based vaccine confers immune protection against SARS-CoV-2 in non-human primates
Authors: Chang Guo, Yanan Peng, Lin Lin, Xiaoyan Pan, Mengqi Fang, Yun Zhao, Keyan Bao, Runhan Li, Jianbao Han, Jiaorong Chen, Tian-Zhang Song, Xiao-Li Feng, Yahong Zhou, Gan Zhao, Leike Zhang, Yongtang Zheng, Ping Zhu, Haiying Hang, Linqi Zhang, Zhaolin Hua, Hongyu Deng, Baidong Hou
Journal: Cell Reports Medicine (2021)

Activation of nucleic acid sensing Toll-like receptors (TLRs) in B cells is involved in antiviral responses by promoting B cell activation and germinal center responses. In order to take advantage of this natural pathway for vaccine development, synthetic pathogen-like antigens (PLAs) constructed of multivalent antigens with encapsulated TLR ligands can be used to activate B cell antigen receptors and TLRs in a synergistic manner. Here we report a PLA-based coronavirus disease 2019 (COVID-19) vaccine candidate designed by combining a phage-derived virus-like particle carrying bacterial RNA as TLR ligands with the receptor-binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S protein as the target antigen. This PLA-based vaccine candidate induces robust neutralizing antibodies in both mice and non-human primates (NHPs). Using a NHP infection model, we demonstrate that the viral clearance is accelerated in vaccinated animals. In addition, the PLA-based vaccine induces a T helper 1 (Th1)-oriented response and a durable memory, supporting its potential for further clinical development.
Highly flexible and porous silk fibroin microneedle wraps for perivascular drug delivery
Authors: JiYong Lee, Eui Hwa Jang, Jae Ho Kim, SeungHyun Park, Yosup Kang, Sanghyun Park, KangJu Lee, Jung-Hwan Kim, Young-Nam Youn, WonHyoung Ryu
Journal: Journal of Controlled Release (2021)