tbuckley/cabot-search huggingface dataset:
Early administration of MPC-n(IVIg) selectively accumulates in ischemic areas to protect inflammation-induced brain damage from ischemic stroke
Authors: Weili Jin, Ye Wu, Ning Chen, Qixue Wang, Yunfei Wang, Yansheng Li, Sidi Li, Xing Han, Eryan Yang, Fei Tong, Jialing Wu, Xubo Yuan, Chunsheng Kang
Journal: Theranostics (2021)

Ischemic stroke is an acute and severe neurological disease, which leads to disability and death.Immunomodulatory therapies exert multiple remarkable protective effects during ischemic stroke.However, patients suffering from ischemic stroke do not benefit from immunomodulatory therapies due to the presence of the blood-brain barrier (BBB) and their off-target effects.Methods: We presented a delivery strategy to optimize immunomodulatory therapies by facilitating BBB penetration and selectively delivering intravenous immunoglobulin (IVIg) to ischemic regions using 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules, MPC-n(IVIg), synthesized using MPC monomers and ethylene glycol dimethyl acrylate (EGDMA) crosslinker via in situ polymerization.In vitro and in vivo experiments verify the effect and safety of MPC-n(IVIg).Results: MPC-n(IVIg) efficiently crosses the BBB and IVIg selectively accumulates in ischemic areas in a high-affinity choline transporter 1 (ChT1)-overexpression dependent manner via endothelial cells in ischemic areas.Moreover, earlier administration of MPC-n(IVIg) more efficiently deliver IVIg to ischemic areas.Furthermore, the early administration of low-dosage MPC-n(IVIg) decreases neurological deficits and mortality by suppressing stroke-induced inflammation in the middle cerebral artery occlusion model. Conclusion:Our findings indicate a promising strategy to efficiently deliver the therapeutics to the ischemic target brain tissue and lower the effective dose of therapeutic drugs for treating ischemic strokes.
Long non-coding RNAs regulated NF-κB signaling in cancer metastasis: Micromanaging by not so small non-coding RNAs
Authors: Shaniya Ahmad, Madiha Abbas, Mohammad Fahad Ullah, Moammir H. Aziz, Ozal Beylerli, Majid Ali Alam, Mansoor Ali Syed, Shahab Uddin, Aamir Ahmad
Journal: Seminars in Cancer Biology (2021)

Cancer metastasis is a major reason for the cancer-associated deaths and a role of long non-coding RNAs (lncRNAs) in cancer metastasis is increasingly being realized. Among the many oncogenic pathways, NF-κB signalling's involvement in cancer metastasis as a key inflammation-regulatory transcription factor has been a subject of interest for long time. Accumulating data from in vitro as well as in vivo studies along with analysis of clinical cancer tissues points to regulation of NF-κB signalling by lncRNAs with implications toward the onset of cancer metastasis. LncRNAs FOXD2-AS1, KRT19P3 and the NF-κB interacting lncRNA (NKILA) associate with lymph node metastasis and poor prognosis of individual cancers. The role of epithelial-mesenchymal transition (EMT) in cancer metastasis is well known. EMT is regulated by NF-κB and regulation of NF-κB/EMT-induced metastasis by lncRNAs remains a hot topic of research with indications for such roles of lncRNAs MALAT1, SNHG15, CRNDE and AC007271.3. Among the many lncRNAs, NKILA stands out as the most investigated lncRNA for its regulation of NF-κB. This tumor suppressive lncRNA has been reported downregulated in clinical samples representing different human cancers. Mechanistically, NKILA has been consistently shown to inhibit NF-κB activation via inhibition of IκBα phosphorylation and the resulting suppression of EMT. NKILA is also a target of natural anticancer compounds. Given the importance of NF-κB as a master regulatory transcription factor, lncRNAs, as the modulators of NF-κB signaling, can provide alternate targets for metastatic cancers with constitutively active NF-κB.
Diagnostic accuracy of rapid antigen tests in asymptomatic and presymptomatic close contacts of individuals with confirmed SARS-CoV-2 infection: cross sectional study
Authors: Ewoud Schuit, Irene K Veldhuijzen, Roderick P Venekamp, Wouter van den Bijllaardt, Suzan D Pas, Esther B Lodder, Richard Molenkamp, Corine H GeurtsvanKessel, Jans Velzing, Robin C Huisman, Lieke Brouwer, Timo L Boelsums, Gregorius J Sips, Kimberly S M Benschop, Lotty Hooft, Janneke H H M van de Wijgert, Susan van den Hof, Karel G M Moons
Journal: BMJ (2021)

Abstract Objective To assess the diagnostic test accuracy of two rapid antigen tests in asymptomatic and presymptomatic close contacts of people with SARS-CoV-2 infection on day 5 after exposure. Design Prospective cross sectional study. Setting Four public health service covid-19 test sites in the Netherlands. Participants 4274 consecutively included close contacts (identified through test-and-trace programme or contact tracing app) aged 16 years or older and asymptomatic for covid-19 when requesting a test. Main outcome measures Sensitivity, specificity, and positive and negative predictive values of Veritor System (Beckton Dickinson) and Biosensor (Roche Diagnostics) rapid antigen tests, with reverse-transcriptase polymerase chain reaction (RT-PCR) testing as reference standard. The viral load cut-off above which 95% of people with a positive RT-PCR test result were virus culture positive was used as a proxy of infectiousness. Results Of 2678 participants tested with Veritor, 233 (8.7%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 149 were also detected by the rapid antigen test (sensitivity 63.9%, 95% confidence interval 57.4% to 70.1%). Of 1596 participants tested with Biosensor, 132 (8.3%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 83 were detected by the rapid antigen test (sensitivity 62.9%, 54.0% to 71.1%). In those who were still asymptomatic at the time of sampling, sensitivity was 58.7% (51.1% to 66.0%) for Veritor (n=2317) and 59.4% (49.2% to 69.1%) for Biosensor (n=1414), and in those who developed symptoms were 84.2% (68.7% to 94.0%; n=219) for Veritor and 73.3% (54.1% to 87.7%; n=158) for Biosensor. When a viral load cut-off was applied for infectiouness (≥5.2 log10 SARS-CoV-2 E gene copies/mL), the overall sensitivity was 90.1% (84.2% to 94.4%) for Veritor and 86.8% (78.1% to 93.0%) for Biosensor, and 88.1% (80.5% to 93.5%) for Veritor and 85.1% (74.3% to 92.6%) for Biosensor, among those who remained asymptomatic throughout. Specificities were &gt;99%, and positive and negative predictive values were &gt;90% and &gt;95%, for both rapid antigen tests in all analyses. Conclusions The sensitivities of both rapid antigen tests in asymptomatic and presymptomatic close contacts tested on day 5 onwards after close contact with an index case were more than 60%, increasing to more than 85% after a viral load cut-off was applied as a proxy for infectiousness.
Reporting of Death in US Food and Drug Administration Medical Device Adverse Event Reports in Categories Other Than Death
Authors: Christina Lalani, Elysha M. Kunwar, Madris Kinard, Sanket S. Dhruva, Rita F. Redberg
Journal: JAMA Internal Medicine (2021)

In the US, most postmarket medical device safety data are obtained through adverse event reports that are submitted to the US Food and Drug Administration (FDA)'s Manufacturer and User Facility Device Experience (MAUDE) database. Adverse event reports are classified by the reporter as injury, malfunction, death, or other. If the device may have caused or contributed to a death, or if the cause of death is unknown, the FDA requires that the adverse event be reported as a death.To determine the percentage of medical device adverse event reports submitted to the MAUDE database that were not classified as death even though the patient died.In this study, a natural language processing algorithm was applied to the MAUDE database, followed by manual text review, to identify reports in the injury, malfunction, other or missing categories that included at least 1 term that suggested a patient death, such as patient died or patient expired, from December 31, 1991, to April 30, 2020, for any medical device.Manual review of a random sample of 1000 adverse event reports not classified as death and of selected reports for 62 terms that are associated with deaths but were not classified as death.Percentage of adverse event reports in which the patient was said to have died in the narrative section of the report but the reporter classified the report in a category other than death.The terms in the natural language processing algorithm identified 290 141 reports in which a serious injury or death was reported. Of these, 151 145 (52.1%) were classified by the reporter as death and 47.9% were classified as malfunction, injury, other, or missing. For the overall sample, the percentage of reports with deaths that were not classified as deaths was 23% (95% CI, 20%-25%), suggesting that approximately 31 552 reports in our sample had deaths that were classified in other categories. The overall percentage of missed deaths, defined as the percentage of deaths that were classified in other categories, was 17% (95% CI, 16%-19%).Many of the findings of this study suggest that many medical device adverse event reports in the FDA's MAUDE database that involved a patient death are classified in categories other than death. As the FDA only routinely reviews all adverse events that are reported as patient deaths, improving the accuracy of adverse event reporting may enhance patient safety.
Protecting third parties: a decade after Tarasoff
Authors: M. J. Mills, G. Sullivan, Spencer Eth
Journal: American Journal of Psychiatry (1987)

The authors discuss current public policy concerning the treatment of potentially violent psychiatric patients and outline some legal and ethical precedents of the current policy. Therapeutic interventions before and after the Tarasoff decision are compared. The authors make specific recommendations for clinicians, who they believe tend to interpret laws too restrictively. They suggest that courts need to rethink current liability standards so that legal decisions can be more clinically informed. Finally, they believe that legislative interventions which specify that warning the potential victim and notifying the police absolve psychotherapists from liability may lead to reflexive rather than reflective management of violent patients.
Abstract 9878: Pioglitazone Ameliorates Atherosclerotic Lesions with the Modification of the Balance of Effector and Regulatory T Cells in Apolipoprotein E Deficient Mice
Authors: Chiharu Kishimoto, Zuyi Yuan
Journal: Circulation (2011)

BACKGROUND: Pioglitazone (PIO) affects T cell-mediated immunity through actions of peroxisome proliferator activated receptor γ. Effector and regulatory T cells control the development of atherosclerosis, a chronic inflammatory disease affecting the arterial blood vessels. PURPOSE: The aim of this study was to examine whether PIO ameliorates atherosclerosis by altering the balance of effector and regulatory T cells. METHODS AND RESULTS: To explore the effect of PIO on early and advanced atherosclerosis, apolipoprotein E deficient (ApoE-/-)mice were fed western diet and received PIO (20mg/kg/day) by gastric gavage at 6 or 14 weeks of age, respectively for 8 weeks (each n=12). Data showed that PIO markedly inhibited early fatty streak formation. Although the advanced fibrofatty plaque sizes were not significantly reduced, the numbers of smooth muscle cells within lesions were increased and higher collagen concentrations were produced by PIO. In general, macrophage expression in lesions was decreased by PIO. Additionally, the expression of Foxp3+ cells (regulatory T) was increased in lesions and spleens in mice at all PIO treatment stages, whereas the CD4+interferon-γ+/CD4+interleukin-4+cell ratios were reduced. CONCLUSION: PIO inhibited early atherosclerotic lesion formation and increased the stability of advanced atherosclerotic plaques in ApoE-/- mice, which was associated with altering the balance of effector and regulatory T cells.
Ablation of lncRNA <i>Miat</i> attenuates pathological hypertrophy and heart failure
Authors: Liu Yang, Jianxin Deng, Wenxia Ma, Aijun Qiao, Shiyue Xu, Yang Yu, Chan Boriboun, Xiang Kang, Dunzheng Han, Patrick Ernst, Lufang Zhou, Jiawei Shi, Eric Zhang, Tao-Sheng Li, Hongyu Qiu, Shinichi Nakagawa, Seth Blackshaw, Jianyi Zhang, Gangjian Qin
Journal: Theranostics (2021)

Rationale:The conserved long non-coding RNA (lncRNA) myocardial infarction associate transcript (Miat) was identified for its multiple single-nucleotide polymorphisms that are strongly associated with susceptibility to MI, but its role in cardiovascular biology remains elusive.Here we investigated whether Miat regulates cardiac response to pathological hypertrophic stimuli.Methods: Both an angiotensin II (Ang II) infusion model and a transverse aortic constriction (TAC) model were used in adult WT and Miat-null knockout (Miat-KO) mice to induce pathological cardiac hypertrophy.Heart structure and function were evaluated by echocardiography and histological assessments.Gene expression in the heart was evaluated by RNA sequencing (RNA-seq), quantitative real-time RT-PCR (qRT-PCR), and Western blotting.Primary WT and Miat-KO mouse cardiomyocytes were isolated and used in Ca 2+ transient and contractility measurements.Results: Continuous Ang II infusion for 4 weeks induced concentric hypertrophy in WT mice, but to a lesser extent in Miat-KO mice.Surgical TAC for 6 weeks resulted in decreased systolic function and heart failure in WT mice but not in Miat-KO mice.In both models, Miat-KO mice displayed reduced heart-weight to tibia-length ratio, cardiomyocyte cross-sectional area, cardiomyocyte apoptosis, and cardiac interstitial fibrosis and a better-preserved capillary density, as compared to WT mice.In addition, Ang II treatment led to significantly reduced mRNA and protein expression of the Ca 2+ cycling genes Sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) and ryanodine receptor 2 (RyR2) and a dramatic increase in global RNA splicing events in the left ventricle (LV) of WT mice, and these changes were largely blunted in Miat-KO mice.Consistently, cardiomyocytes isolated from Miat-KO mice demonstrated more efficient Ca 2+ cycling and greater contractility.Conclusions: Ablation of Miat attenuates pathological hypertrophy and heart failure, in part, by enhancing cardiomyocyte contractility.
P-183 Laparoscopic colorectal resection for elderly patients aged 80 years or older: A propensity score analysis
Authors: R. Inada, T. Toshima, E. Kuroda, J. Kimura, K. Kumon, N. Takata, Y. Katsura, T. Sato, K. Sui, K. Oishi, T. Murokawa, T. Okabayashi, K. Ozaki, Y. Shibuya
Journal: Annals of Oncology (2021)
Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial
Authors: John C. Byrd, Peter Hillmen, Paolo Ghia, Arnon P. Kater, Asher Chanan-Khan, Richard R. Furman, Susan O'Brien, Mustafa Nuri Yenerel, Arpad Illés, Neil Kay, Jose A. Garcia-Marco, Anthony Mato, Javier Pinilla-Ibarz, John F. Seymour, Stephane Lepretre, Stephan Stilgenbauer, Tadeusz Robak, Wayne Rothbaum, Raquel Izumi, Ahmed Hamdy, Priti Patel, Kara Higgins, Sophia Sohoni, Wojciech Jurczak
Journal: Journal of Clinical Oncology (2021)

Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL).
First-in-human DR5 PET reveals insufficient DR5 expression in patients with gastrointestinal cancer
Authors: Shujing Wang, Hua Zhu, Yingjie Li, Jin Ding, Feng Wang, Lixin Ding, Xinyu Wang, Jun Zhao, Yan Zhang, Yunfeng Yao, Tong Zhou, Nan Li, Aiwen Wu, Zhi Yang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Death receptor 5 (DR5) is a promising therapeutic target for cancer therapy. However, many clinical trials of DR5 agonists failed to show significant therapeutic efficacy in patients with cancer. The study aimed to investigate the feasibility of using 89 Zr-CTB006 positron emission tomography (PET) for noninvasive imaging of DR5 expression in preclinical models and patients with gastrointestinal (GI) cancers. Methods Balb/c, Sp2/0 xenograft and patient-derived tumor xenograft were employed for micro-PET/CT imaging in vivo. In the clinical study, patients with GI cancers planning to undergo surgical operation were enrolled and underwent 18 F-FDG and 89 Zr-CTB006 PET/CT. The tumor tissues were obtained through surgical operation and DR5 expression levels were confirmed by RNAscope. Results Preclinical studies showed that 89 Zr-CTB006 PET could specifically detect DR5 expression levels in vivo. Twenty-one patients, including nine gastric cancers and 12 colorectal cancers, were enrolled. The biodistribution showed high uptake in the liver and spleen and low uptake in the brain, lung and muscle with an acceptable whole-body dosimetry of 0.349 mSv/MBq. Strikingly, the adrenal glands maintained stable high uptake over the entire examination in all patients. The tumor lesions showed different levels of uptake of 89 Zr-CTB006 with a mean maximum standardized uptake value (SUV max ) of 6.63±3.29 (range 1.8–13.8). Tumor tissue was obtained from 18 patients, and 89 Zr-CTB006 uptake in patients with RNAscope scores of 3–4 was significantly higher than that in patients with scores of 0–2. An SUV max of 9.3 at 48 hours and 6.3 at 72 hours could be used to discriminate the DR5 expression status of tumors both with a sensitivity and specificity of 100% and 92.9%, respectively. Conclusions 89 Zr-CTB006 PET/CT is capable of detecting DR5 expression in cancer patients and is a promising approach to screen patients with DR5 overexpression.
Vaccine breakthrough infection and onward transmission of SARS-CoV-2 Beta (B.1.351) variant, Bavaria, Germany, February to March 2021
Authors: Inge Kroidl, Ingo Mecklenburg, Peter Schneiderat, Katharina Müller, Philipp Girl, Roman Wölfel, Andreas Sing, Alexandra Dangel, Andreas Wieser, Michael Hoelscher
Journal: Eurosurveillance (2021)

A breakthrough infection occurred in a fully Comirnaty (BNT162b2) vaccinated healthcare worker with high levels of neutralising antibodies with the SARS-CoV-2 B.1.351 (Beta) variant in February 2021. The infection was subsequently transmitted to their unvaccinated spouse. Sequencing revealed an identical virus in both spouses, with a match of all nine single nucleotide polymorphisms typical for B.1.351. To the best of our knowledge, no transmission of any variant of SARS-CoV-2 from a fully vaccinated person has been described before.
Structural insights into the distinctive RNA recognition and therapeutic potentials of RIG‐I‐like receptors
Authors: Maria Batool, Moon Suk Kim, Sangdun Choi
Journal: Medicinal Research Reviews (2021)

Abstract RNA viruses, including the coronavirus, develop a unique strategy to evade the host immune response by interrupting the normal function of cytosolic retinoic acid‐inducible gene‐I (RIG‐I)‐like receptors (RLRs). RLRs rapidly detect atypical nucleic acids, thereby triggering the antiviral innate immune signaling cascade and subsequently activates the interferons transcription and induction of other proinflammatory cytokines and chemokines. Nonetheless, these receptors are manipulated by viral proteins to subvert the host immune system and sustain the infectivity and replication potential of the virus. RIG‐I senses the single‐stranded, double‐stranded, and short double‐stranded RNAs and recognizes the key signature, a 5′‐triphosphate moiety, at the blunt end of the viral RNA. Meanwhile, the melanoma differentiation‐associated gene 5 (MDA5) is triggered by longer double stranded RNAs, messenger RNAs lacking 2′‐ O ‐methylation in their 5′‐cap, and RNA aggregates. Therefore, structural insights into the nucleic‐acid‐sensing and downstream signaling mechanisms of these receptors hold great promise for developing effective antiviral therapeutic interventions. This review highlights the critical roles played by RLRs in viral infections as well as their ligand recognition mechanisms. In addition, we highlight the crosstalk between the toll‐like receptors and RLRs and provide a comprehensive overview of RLR‐associated diseases as well as the therapeutic potential of RLRs for the development of antiviral‐drugs. Moreover, we believe that these RLR‐based antivirals will serve as a step toward countering the recent coronavirus disease 2019 pandemic.
Latent tuberculosis co-infection is associated with heightened levels of humoral, cytokine and acute phase responses in seropositive SARS-CoV-2 infection
Authors: Anuradha Rajamanickam, Nathella Pavan Kumar, Chandrasekaran Padmapriyadarsini, Arul Nancy, Nandhini Selvaraj, Kushiyasri Karunanithi, Saravanan Munisankar, Shrinivasa BM, Rachel Mariam Renji, T.C. Ambu, Vijayalakshmi Venkataramani, Subash Babu
Journal: Journal of Infection (2021)

Latent Tuberculosis infection (LTBI) is postulated to modulate immune responses and alter disease severity in SARS-CoV-2 co-infection. However, no data exist on the effect of LTBI on the immune responses in SARS-CoV-2 co-infected individuals.
Doctors’ pay: BMA to ask consultants if they would consider industrial action over award
Authors: Abi Rimmer
Journal: BMJ (2021)

Consultants in England will be surveyed on whether they wish to consider any form of action over the award of a 3% pay rise, the BMA has said.

On 21 July the Department of Health and Social Care announced that NHS staff, including consultants, in England will receive a 3% pay rise backdated to April 2021.1 The BMA criticised the “below-inflation” rise, saying that it didn’t go far enough …
Niraparib for Advanced Breast Cancer with Germline <i>BRCA1</i> and <i>BRCA2</i> Mutations: the EORTC 1307-BCG/BIG5–13/TESARO PR-30–50–10-C BRAVO Study
Authors: Nicholas C. Turner, Judith Balmaña, Coralie Poncet, Theodora Goulioti, Konstantinos Tryfonidis, Aafke H. Honkoop, Gabriele Zoppoli, Evangelia Razis, Oskar T. Johannsson, Marco Colleoni, Andrew N. Tutt, William Audeh, Michail Ignatiadis, Audrey Mailliez, Olivier Trédan, Antonino Musolino, Peter Vuylsteke, Maria Jose Juan-Fita, Iain R.J. Macpherson, Bella Kaufman, Luis Manso, Lori J. Goldstein, Susan L. Ellard, István Láng, Kai Yu Jen, Virginie Adam, Saskia Litière, John Erban, David A. Cameron
Journal: Clinical Cancer Research (2021)

Abstract Purpose: To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. Patients and Methods: BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician's choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor–positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results: After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n = 141) versus 3.1 months in the PC arm [n = 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65–1.44; P = 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63–1.42) and 0.65 (95% CI, 0.46–0.93), respectively. ORR was 35% (95% CI, 26–45) with niraparib and 31% (95% CI, 19–46) in the PC arm. Conclusions: Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib's activity in this patient population.