tbuckley/cabot-search huggingface dataset:
Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8<sup>+</sup>T cells
Authors: Sandeep Kumar, Sunil Kumar Singh, Navin Viswakarma, Gautam Sondarva, Rakesh Sathish Nair, Periannan Sethupathi, Matthew Dorman, Subhash C Sinha, Kent Hoskins, Gregory Thatcher, Basabi Rana, Ajay Rana
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background The mitogen-activated protein kinases (MAPKs) are important for T cell survival and their effector function. Mixed lineage kinase 3 (MLK3) (MAP3K11) is an upstream regulator of MAP kinases and emerging as a potential candidate for targeted cancer therapy; yet, its role in T cell survival and effector function is not known. Methods T cell phenotypes, apoptosis and intracellular cytokine expressions were analyzed by flow cytometry. The apoptosis-associated gene expressions in CD8 + CD38 + T cells were measured using RT 2 PCR array. In vivo effect of combined blockade of MLK3 and CD70 was analyzed in 4T1 tumor model in immunocompetent mice. The serum level of tumor necrosis factor-α (TNFα) was quantified by enzyme-linked immunosorbent assay. Results We report that genetic loss or pharmacological inhibition of MLK3 induces CD70-TNFα-TNFRSF1a axis-mediated apoptosis in CD8 + T cells. The genetic loss of MLK3 decreases CD8 + T cell population, whereas CD4 + T cells are partially increased under basal condition. Moreover, the loss of MLK3 induces CD70-mediated apoptosis in CD8 + T cells but not in CD4 + T cells. Among the activated CD8 + T cell phenotypes, CD8 + CD38 + T cell population shows more than five fold increase in apoptosis due to loss of MLK3, and the expression of TNFRSF1a is significantly higher in CD8 + CD38 + T cells. In addition, we observed that CD70 is an upstream regulator of TNFα-TNFRSF1a axis and necessary for induction of apoptosis in CD8 + T cells. Importantly, blockade of CD70 attenuates apoptosis and enhances effector function of CD8 + T cells from MLK3 −/− mice. In immune-competent breast cancer mouse model, pharmacological inhibition of MLK3 along with CD70 increased tumor infiltration of cytotoxic CD8 + T cells, leading to reduction in tumor burden largely via mitochondrial apoptosis. Conclusion Together, these results demonstrate that MLK3 plays an important role in CD8 + T cell survival and effector function and MLK3-CD70 axis could serve as a potential target in cancer.
Tapering Antipsychotic Treatment
Authors: Mark Abie Horowitz, Robin M. Murray, David Taylor
Journal: JAMA Psychiatry (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Neural Progenitor Cells Alter Chromatin Organization and Neurotrophin Expression in Response to 3D Matrix Degradability
Authors: Christopher M. Madl, Bauer L. LeSavage, Margarita Khariton, Sarah C. Heilshorn
Journal: Advanced Healthcare Materials (2020)

Abstract Neural progenitor cells (NPCs) are promising therapeutic candidates for nervous system regeneration. Significant efforts focus on developing hydrogel‐based approaches to facilitate the clinical translation of NPCs, from scalable platforms for stem cell production to injectable carriers for cell transplantation. However, fundamental questions surrounding NPC‐hydrogel interactions remain unanswered. While matrix degradability is known to regulate the stemness and differentiation capacity of NPCs, how degradability impacts NPC epigenetic regulation and secretory phenotype remains unknown. To address this question, NPCs encapsulated in recombinant protein hydrogels with tunable degradability are assayed for changes in chromatin organization and neurotrophin expression. In high degradability gels, NPCs maintain expression of stem cell factors, proliferate, and have large nuclei with elevated levels of the stemness‐associated activating histone mark H3K4me3. In contrast, NPCs in low degradability gels exhibit more compact, rounded nuclei with peripherally localized heterochromatin, are non‐proliferative yet non‐senescent, and maintain expression of neurotrophic factors with potential therapeutic relevance. This work suggests that tuning matrix degradability may be useful to direct NPCs toward either a more‐proliferative, stem‐like phenotype for cell replacement therapies, or a more quiescent‐like, pro‐secretory phenotype for soluble factor‐mediated therapies.
Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab
Authors: Scott V. Bratman, S. Y. Cindy Yang, Marco A. J. Iafolla, Zhihui Liu, Aaron R. Hansen, Philippe L. Bedard, Stephanie Lheureux, Anna Spreafico, Albiruni Abdul Razak, Svetlana Shchegrova, Maggie Louie, Paul Billings, Bernhard Zimmermann, Himanshu Sethi, Alexey Aleshin, Dax Torti, Kayla Marsh, Jenna Eagles, Iulia Cirlan, Youstina Hanna, Derek L. Clouthier, Scott C. Lien, Pamela S. Ohashi, Wei Xu, Lillian L. Siu, Trevor J. Pugh
Journal: Nature Cancer (2020)
Application of the Reverse Fragility Index to Statistically Nonsignificant Randomized Clinical Trial Results
Authors: Muhammad Shahzeb Khan, Gregg C. Fonarow, Tim Friede, Noman Lateef, Safi U. Khan, Stefan D. Anker, Frank E. Harrell, Javed Butler
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Interpreting randomized clinical trials (RCTs) and their clinical relevance is challenging when<i>P</i>values are either marginally above or below the<i>P</i> = .05 threshold. <h3>Objective</h3> To use the concept of reverse fragility index (RFI) to provide a measure of confidence in the neutrality of RCT results when assessed from the clinical perspective. <h3>Design, Setting, and Participants</h3> In this cross-sectional study, a MEDLINE search was conducted for RCTs published from January 1, 2013, to December 31, 2018, in<i>JAMA</i>, the<i>New England Journal of Medicine</i>(<i>NEJM</i>), and<i>The Lancet.</i>Eligible studies were phase 3 and 4 trials with 1:1 randomization and statistically nonsignificant binary primary end points. Data analysis was performed from August 1, 2019, to August 31, 2019. <h3>Exposures</h3> Single vs multicenter enrollment, total number of events, private vs government funding, placebo vs active control, and time to event vs frequency data. <h3>Main Outcomes and Measures</h3> The primary outcome was the median RFI with interquartile range (IQR) at the<i>P</i> = .05 threshold. Secondary outcomes were the number of RCTs in which the number of participants lost to follow-up was greater than the RFI; the median RFI with IQR at different<i>P</i>value thresholds; the median reverse fragility quotient with IQR; and the correlation between sample sizes, number of events, and<i>P</i>values of the RCT and RFI. <h3>Results</h3> Of the 167 RCTs included, 76 (46%) were published in the<i>NEJM</i>, 50 (30%) in<i>JAMA,</i>and 41 (24%) in<i>The Lancet.</i>The median (IQR) sample size was 970 (470-3427) participants, and the median (IQR) number of events was 251 (105-570). The median (IQR) RFI at the<i>P</i> = .05 threshold was 8 (5-13). Fifty-seven RCTs (34%) had an RFI of 5 or lower, and in 68 RCTs (41%) the number of participants lost to follow-up was greater than the RFI. Trials with<i>P</i>values ranging from<i>P</i> = .06 to<i>P</i> = .10 had a median (IQR) RFI of 3 (2-4). When compared, median (IQR) RFIs were not statistically significant for single-center vs multicenter enrollment (5 [4-13] vs 8 [5-13];<i>P</i> = .41), private vs government-funded studies (9 [5-13] vs 8 [5-13];<i>P</i> = .34), and time-to-event primary end points vs frequency data (9 [5-14] vs 7 [4-13];<i>P</i> = .43). The median (IQR) RFI at the<i>P</i> = .01 threshold was 12 (7-19) and at the<i>P</i> = .005 threshold was 14 (9-21). <h3>Conclusions and Relevance</h3> This cross-sectional study found that a relatively small number of events (median of 8) had to change to move the primary end point of an RCT from nonsignificant to statistically significant. These findings emphasize the nuance required when interpreting trial results that did not meet prespecified significance thresholds.
Abstract #1227: A phase I, open-label, dose-escalation, multidose study of MDX-1401 (defucosylated human antiCD30 monoclonal antibody) in patients with CD30-positive refractory/relapsed Hodgkin\#8217;s lymphoma
Authors: Raymond Thertulien, Arthur Frankel, Andrew Evens, Jonathan Kaufman, Stephen Horwitz, Albert Assad, Pina Cardarelli, Jason Tian, Zuoshun Zhang, Marion MacDowall
Journal: Cancer Research (2009)

MDX-1401 is a nonfucosylated, fully human anti-CD30 antibody in which the oligosaccharide of the IgG1 lacks fucose. The absence of fucose confers increased antibody affinity for Fc receptor CD16 (Fc\#947;RIIIa) expressed on NK cells and macrophages and is responsible for antibody dependent cellular cytotoxicity (ADCC), a major mechanism of action for therapeutic antibodies. Preclinical evidence has demonstrated that nonfucosylated antibodies that bind to human CD30 exhibit enhanced ADCC of CD30-expressing cells, as compared to the fucose-containing form of the antibody. MDX-1401, which binds with higher affinity to Fc\#947;RIIIa and has improved ADCC activity, is hypothesized to give higher therapeutic responses in subjects with Hodgkin\#8217;s lymphoma (HL) by targeting the CD30 membrane receptor. A multi-center dose-escalating Phase I study is being conducted to determine the safety and tolerability profile of MDX-1401 in subjects with refractory or relapsed HL. To date, MDX-1401 has been administered intravenously (iv) weekly for 4 weeks to 12 subjects - in cohorts of 3 subjects each - at doses of 0.01, 0.1, 0.3 and 1.0 mg/kg. MDX-1401 has been well tolerated and a maximum tolerated dose has not yet been identified. Of the 12 subjects treated, there have been no reported drug-related serious adverse events, infusion reactions or non-hematologic adverse events. There have been 3 hematologic adverse events (two instances of anemia and one hypophosphatemia) deemed possibly related to study drug. Preliminary data indicate an activity signal both clinically and immunologically at these relatively low doses. Of the 8 subjects with stable disease, tumor burden has been reduced by 40% or more in 2 subjects after 2 treatment cycles. Changes in tumor burden may suggest some dose response relationship. Four subjects have discontinued due to disease progression. Additionally, flow cytometry indicates decreased circulating CD30+ cells in 10 of 12 subjects after one 4-week cycle of weekly iv infusions. Additional subjects are being accrued at higher dose cohorts to more accurately characterize the safety and clinical activity.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1227.
Inflammation-induced PINCH expression leads to actin depolymerization and mitochondrial mislocalization in neurons
Authors: Kalimuthusamy Natarajaseenivasan, Santhanam Shanmughapriya, Prema Velusamy, Matthew Sayre, Alvaro Garcia, Nestor Mas Gomez, Dianne Langford
Journal: Translational Neurodegeneration (2020)

Diseases and disorders with a chronic neuroinflammatory component are often linked with changes in brain metabolism. Among neurodegenerative disorders, people living with human immunodeficiency virus (HIV) and Alzheimer's disease (AD) are particularly vulnerable to metabolic disturbances, but the mechanistic connections of inflammation, neurodegeneration and bioenergetic deficits in the central nervous system (CNS) are poorly defined. The particularly interesting new cysteine histidine-rich-protein (PINCH) is nearly undetectable in healthy mature neurons, but is robustly expressed in tauopathy-associated neurodegenerative diseases including HIV infection and AD. Although robust PINCH expression has been reported in neurons in the brains of patients with HIV and AD, the molecular mechanisms and cellular consequences of increased PINCH expression in CNS disease remain largely unknown. We investigated the regulatory mechanisms responsible for PINCH protein-mediated changes in bioenergetics, mitochondrial subcellular localization and bioenergetic deficits in neurons exposed to physiological levels of TNFα or the HIV protein Tat. Changes in the PINCH-ILK-Parvin (PIP) complex association with cofilin and TESK1 were assessed to identify factors responsible for actin depolymerization and mitochondrial mislocalization. Lentiviral and pharmacological inhibition experiments were conducted to confirm PINCH specificity and to reinstate proper protein-protein complex communication. We identified MEF2A as the PINCH transcription factor in neuroinflammation and determined the biological consequences of increased PINCH in neurons. TNFα-mediated activation of MEF2A via increased cellular calcium induced PINCH, leading to disruption of the PIP ternary complex, cofilin activation by TESK1 inactivation, and actin depolymerization. The disruption of actin led to perinuclear mislocalization of mitochondria by destabilizing the kinesin-dependent mitochondrial transport machinery, resulting in impaired neuronal metabolism. Blocking TNFα-induced PINCH expression preserved mitochondrial localization and maintained metabolic functioning. This study reported for the first time the mechanistic and biological consequences of PINCH expression in CNS neurons in diseases with a chronic neuroinflammation component. Our findings point to the maintenance of PINCH at normal physiological levels as a potential new therapeutic target for neurodegenerative diseases with impaired metabolisms.
Computed Tomography Highlights Increased Visceral Adiposity Associated With Critical Illness in COVID-19
Authors: Sofia Battisti, Claudio Pedone, Nicola Napoli, Emanuele Russo, Vanni Agnoletti, Stefano Geniere Nigra, Caterina Dengo, Martina Mughetti, Caterina Conte, Paolo Pozzilli, Emanuela Giampalma, Rocky Strollo
Journal: Diabetes Care (2020)

Obese subjects with coronavirus disease 2019 (COVID-19) are at increased risk of requiring critical care (1), suggesting that excess body fat associates with greater disease severity. BMI does not discriminate between fat and lean body mass and poorly reflects fat distribution. Cardiometabolic diseases and increased systemic inflammation, two conditions associated with visceral adiposity, are also linked to COVID-19 severity and fatality (1,2). The aim of this study was to assess the relationship between abdominal fat distribution and COVID-19 severity. We hypothesized that excess visceral adipose tissue (VAT), as identified by an increased VAT to subcutaneous adipose tissue (SAT) ratio (VAT/SAT), is associated with COVID-19 severity, as defined by intensive care unit (ICU) admission.

This was a single-center cohort study of 441 patients consecutively admitted to the Emergency Department (ED) of the Trauma Center Public Hospital Bufalini, Cesena, Italy, between 26 February and 6 April 2020 for a clinical suspicion of COVID-19. Of these patients, 144 had confirmed COVID-19 based on positive RT-PCR from a nasal and/or throat swab together with high-resolution computed tomography (HR-CT) findings suggestive of COVID-19 pneumonia. Of those, 61 (42%) were admitted to ICU (ICU-COVID-19 group). One-hundred thirty-six patients evaluated in the ED for clinical suspicion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) …
miR-18a Inhibits BMP4 and HIF-1α Normalizing Brain Arteriovenous Malformations
Authors: Nagore I. Marín-Ramos, Thu Zan Thein, Ketan B. Ghaghada, Thomas C. Chen, Steven L. Giannotta, Florence M. Hofman
Journal: Circulation Research (2020)

Brain arteriovenous malformations (AVMs) are abnormal tangles of vessels where arteries and veins directly connect without intervening capillary nets, increasing the risk of intracerebral hemorrhage and stroke. Current treatments are highly invasive and often not feasible. Thus, effective noninvasive treatments are needed. We previously showed that AVM-brain endothelial cells (BECs) secreted higher VEGF (vascular endothelial growth factor) and lower TSP-1 (thrombospondin-1) levels than control BEC; and that microRNA-18a (miR-18a) normalized AVM-BEC function and phenotype, although its mechanism remained unclear.To elucidate the mechanism of action and potential clinical application of miR-18a as an effective noninvasive treatment to selectively restore the phenotype and functionality of AVM vasculature.The molecular pathways affected by miR-18a in patient-derived BECs and AVM-BECs were determined by Western blot, RT-qPCR (quantitative reverse transcription polymerase chain reaction), ELISA, co-IP, immunostaining, knockdown and overexpression studies, flow cytometry, and luciferase reporter assays. miR-18a was shown to increase TSP-1 and decrease VEGF by reducing PAI-1 (plasminogen activator inhibitor-1/SERPINE1) levels. Furthermore, miR-18a decreased the expression of BMP4 (bone morphogenetic protein 4) and HIF-1α (hypoxia-inducible factor 1α), blocking the BMP4/ALK (activin-like kinase) 2/ALK1/ALK5 and Notch signaling pathways. As determined by Boyden chamber assays, miR-18a also reduced the abnormal AVM-BEC invasiveness, which correlated with a decrease in MMP2 (matrix metalloproteinase 2), MMP9, and ADAM10 (ADAM metallopeptidase domain 10) levels. In vivo pharmacokinetic studies showed that miR-18a reaches the brain following intravenous and intranasal administration. Intranasal co-delivery of miR-18a and NEO100, a good manufacturing practices-quality form of perillyl alcohol, improved the pharmacokinetic profile of miR-18a in the brain without affecting its pharmacological properties. Ultra-high-resolution computed tomography angiography and immunostaining studies in an Mgp-/- AVM mouse model showed that miR-18a decreased abnormal cerebral vasculature and restored the functionality of the bone marrow, lungs, spleen, and liver.miR-18a may have significant clinical value in preventing, reducing, and potentially reversing AVM.
Race Disparities in Proton Radiotherapy Use for Cancer Treatment in Patients Enrolled in Children’s Oncology Group Trials
Authors: Danielle S. Bitterman, Kira Bona, Fran Laurie, Pei-Chi Kao, Stephanie A. Terezakis, Wendy B. London, Daphne A. Haas-Kogan
Journal: JAMA Oncology (2020)

This quality improvement study examines disparities in proton radiotherapy use in patients enrolled in Children’s Oncology Group Trials
Erythematous Nodule With Central Crust on the Nail Fold in an Infant
Authors: Aina Vila-Payeras, Alex Llambrich Mañes, Cristina Nadal Lladó
Journal: JAMA Dermatology (2020)

A girl younger than 2 years presented with a 7-month history of an inflammatory plaque with a central shiny orange crust on her left index finger and no improvement with empiric therapy. What is your diagnosis?
Corrigendum to “Clinical implications of body mass index (BMI) and weight in metastatic breast cancer (BC) patients treated with abemaciclib and endocrine therapy: A pooled individual patient level data analysis of MONARCH 2 and MONARCH 3 trials”
Authors: M.A. Franzoi, L. Ameye, D. Eiger, M. Piccart, M.D.R.A. Brandão, N. Pondé, C. Desmedt, S. Di Cosimo, M. Paesmans, R. Caparica, N. Kotecki, M. Lambertini, C. De Angelis, A.H. Awada, E. de Azambuja
Journal: Annals of Oncology (2020)
Diagnostic value of ultrasound halo count and Halo Score in giant cell arteritis: a retrospective study from routine care
Authors: Juan Molina Collada, Julia Martínez-Barrio, Belén Serrano-Benavente, Isabel Castrejón, Liz Rocío Caballero Motta, Laura Trives Folguera, José María Álvaro-Gracia
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the paper published by van der Geest et al 1 on ‘Novel ultrasonographic Halo Score for giant cell arteritis (GCA): assessment of diagnostic accuracy and association with ocular ischaemia’. The authors aimed to quantify the extent of vascular inflammation by ultrasound (US) in patients with GCA and developed two novel US scoring systems, the halo count and Halo Score, including the assessment of the three temporal artery (TA) segments and axillary arteries. First, we would like to congratulate them for the novelty of their work that opens up new perspectives in the use of US in the assessment of GCA. According to recent EULAR recommendations, US is recommended as the first imaging modality in patients with suspected predominantly cranial GCA.2 The halo sign is the most relevant US finding in GCA and is defined as a homogeneous, hypoechoic wall thickening, well delineated towards the luminal side, visible in two perpendicular planes, most commonly concentric in transverse scan.3 The halo count and Halo Score constitute the first quantitative tools to assess the extent of vascular inflammation by US in GCA.1 According to their findings, a high volume of vascular inflammation on US …
Organ Donation After Euthanasia
Authors: Arthur J. Matas, William D. Payne
Journal: JAMA Surgery (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal