tbuckley/cabot-search huggingface dataset:
Significant localized reduction in cerebral blood flow (CBF) in regions relevant to cognitive function with enzalutamide (ENZA) compared to darolutamide (DARO) and placebo (PBO) in healthy volunteers.
Authors: Steven Williams, Ndaba Mazibuko, Owen O’Daly, Christian Zurth, Fiona Patrick, Caroline Wooldridge, Kristina Graudenz, Iris Kuss, Patricia Cole
Journal: Journal of Clinical Oncology (2020)

326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant after correction for multiple comparisons. A linear mixed effects model was used for predetermined region of interest (ROI) analysis, with physiological parameters as nuisance regressors. Results: Drug-concentration data confirmed similar unbound exposure during MRI scans and a complete washout between treatments. No unexpected safety concerns were noted in the study. Whole-brain analysis showed a significant localized 5.2% reduction in CBF for ENZA in temporo-occipital cortices but no significant CBF reduction with DARO compared to PBO. A significant 5.9% localized reduction in CBF was measured for ENZA vs DARO. ROI analysis showed a significant reduction in CBF for ENZA vs PBO (p = 0.045) and for ENZA vs DARO (p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. A significant reduction was noted in CBF for ENZA vs PBO in right amygdala (p = 0.047). Conclusions: Compared to PBO and DARO, significant localized reductions in CBF were noted for ENZA. These results may be relevant to cognitive function (executive function, memory, and anxiety) with extended treatment and warrant further investigation. Clinical trial information: NCT03704519.
Calcium Signaling in the Oligodendrocyte Lineage: Regulators and Consequences
Authors: Pablo M. Paez, David A. Lyons
Journal: Annual Review of Neuroscience (2020)

Cells of the oligodendrocyte lineage express a wide range of Ca 2+ channels and receptors that regulate oligodendrocyte progenitor cell (OPC) and oligodendrocyte formation and function. Here we define those key channels and receptors that regulate Ca 2+ signaling and OPC development and myelination. We then discuss how the regulation of intracellular Ca 2+ in turn affects OPC and oligodendrocyte biology in the healthy nervous system and under pathological conditions. Activation of Ca 2+ channels and receptors in OPCs and oligodendrocytes by neurotransmitters converges on regulating intracellular Ca 2+ , making Ca 2+ signaling a central candidate mediator of activity-driven myelination. Indeed, recent evidence indicates that localized changes in Ca 2+ in oligodendrocytes can regulate the formation and remodeling of myelin sheaths and perhaps additional functions of oligodendrocytes and OPCs. Thus, decoding how OPCs and myelinating oligodendrocytes integrate and process Ca 2+ signals will be important to fully understand central nervous system formation, health, and function.
Blockade of IL-4/IL-13 Signaling Reprograms IgE-Mediated Immune Memory Responses and Inhibits Anaphylaxis
Authors: Kelly Bruton, Paul Spill, Shabana Vohra, Saba Manzoorr, Owen Baribeau, Malcolm Davidson, Rodrigo Jiménez-Saiz, Susan Waserman, Slava Epelman, Clinton Robbins, Manel Jordana
Journal: Journal of Allergy and Clinical Immunology (2020)
The efficacy of metastasis-directed radiation therapy (MDRT) for oligometastatic castration-resistant prostate cancer (CRPC).
Authors: Akira Nagahara, Tomohiro Kanaki, Akinaru Yamamoto, Yoshiyuki Yamamoto, Yasutomo Nakai, Masashi Nakayama, Ken-Ichi Kakimoto, Koji Konishi, Teruki Teshima, Kazuo Nishimura
Journal: Journal of Clinical Oncology (2020)

240 Background: We have utilized imaging study, especially whole body magnetic resonance imaging (WB-MRI), to detect oligometastatic disease of castration resistant prostate cancer (CRPC) and performed metastasis-directed radiation therapy (MDRT) for oligometastatic disease. We review our institutional experience of MDRT for oligometastatic CRPC. Methods: We retrospectively reviewed the database comprising 26 oligometastatic CRPC patients treated by MDRT for oligometastatic disease combined with baseline androgen deprivation therapy at Osaka International Cancer Institute from January 2013 to August 2019 and investigated treatment efficacy of MDRT. Diagnosis of oligometastatic disease was performed by computed tomography, bone scintigraphy and/or WB-MRI. Treatment efficacy was assessed by change of serum prostate specific antigen (PSA) level and progression free survival (PFS). PFS was analyzed by Kaplan-Meier method and comparison was made by log-rank test. Results: The median age at treatment was 75.5 years (range, 62-86). The oligometastatic diseases were bone in 22 patients, lymph node in 2 patients and both in 2 patients. The number of treated lesions were as follows: 1 lesion for 21 patients, 2 lesions for 4 patients and 3 lesions for 1 patient. WB-MRI was performed in 19 patients (73%). Median dose of MDRT was 35Gy (range, 30-60) for bone and 60Gy (range, 50-60) for lymph node. The median PSA prior MDRT was 6.3 ng/ml (range, 0.5-191). Post MDRT PSA reduction was observed in 24 patients (92%) and over 50% PSA reduction was observed in 14 patients (54%). Median PFS was 8.7 month and patients with over 90 days PSA doubling time (PSADT) showed longer PFS (p=0.0074). Conclusions: Our data suggest that MDRT can achieve PSA reduction in most CRPC patients with oligometastasis and PSADT could be a predictor of disease progression after MDRT.
Results of a Randomized Phase IIb Trial of Nelipepimut-S + Trastuzumab versus Trastuzumab to Prevent Recurrences in Patients with High-Risk HER2 Low-Expressing Breast Cancer
Authors: G. Travis Clifton, Diane Hale, Timothy J. Vreeland, Annelies T. Hickerson, Jennifer K. Litton, Gheath Alatrash, Rashmi K. Murthy, Na Qiao, Anne V. Philips, Jason J. Lukas, Jarrod P. Holmes, George E. Peoples, Elizabeth A. Mittendorf
Journal: Clinical Cancer Research (2020)

Preclinical data provide evidence for synergism between HER2-targeted peptide vaccines and trastuzumab. The efficacy of this combination was evaluated in patients with HER2 low-expressing breast cancer in the adjuvant setting.A phase IIb, multicenter, randomized, single-blinded, controlled trial enrolled disease-free patients after standard therapy completion (NCT01570036). Eligible patients were HLA-A2, A3, A24, and/or A26+, and had HER2 IHC 1+/2+, FISH nonamplified breast cancer, that was node positive and/or hormone receptor-negative [triple-negative breast cancer (TNBC)]. Patients received trastuzumab for 1 year and were randomized to placebo (GM-CSF, control) or nelipepimut-S (NPS) with GM-CSF. Primary outcome was 24-month disease-free survival (DFS). Secondary outcomes were 36-month DFS, safety, and immunologic response.Overall, 275 patients were randomized; 136 received NPS with GM-CSF, and 139 received placebo with GM-CSF. There were no clinicopathologic differences between groups. Concurrent trastuzumab and NPS with GM-CSF was safe with no additional overall or cardiac toxicity compared with control. At median follow-up of 25.7 (interquartile range, 18.4-32.7) months, estimated DFS did not significantly differ between NPS and control [HR, 0.62; 95% confidence interval (CI), 0.31-1.25; P = 0.18]. In a planned exploratory analysis of patients with TNBC, DFS was improved for NPS versus control (HR, 0.26; 95% CI, 0.08-0.81, P = 0.01).The combination of NPS with trastuzumab is safe. In HER2 low-expressing breast cancer, no significant difference in DFS was seen in the intention-to-treat analysis; however, significant clinical benefit was seen in patients with TNBC. These findings warrant further investigation in a phase III randomized trial.
PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients
Authors: Julien Pothlichet, Thierry Rose, Florence Bugault, Louise Jeammet, Annalisa Meola, Ahmed Haouz, Frederick Saul, David Geny, José Alcami, Ezequiel Ruiz-Mateos, Luc Teyton, Gérard Lambeau, Jacques Thèze
Journal: Journal of Clinical Investigation (2020)

The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.
Effect of concurrent proton pump inhibitors (PPI) use in patients (pts) treated with immune checkpoint inhibitors (ICI) for metastatic urothelial carcinoma (mUC).
Authors: Rafael Morales-Barrera, Natalia Vidal Casinello, Teresa Bonfill, Montserrat Domenech, Cristina Suarez Rodriguez, Javier Puente, Julia Giner Joaquin, Mariona Figols, Isabel Galante, Albert Carrion, Hector Lopez, Macarena Gonzalez, Sarai Roche, Joaquin Mateo, Enrique Gallardo Diaz, Carlos Fernández Sáez, Claudia Maria Valverde Morales, Ines de Torres, Juan Morote, Joan Carles
Journal: Journal of Clinical Oncology (2020)

500 Background: PPI are widely used in pts with cancer. PPI are associated with anti-inflammatory properties and direct effects on neutrophils and monocytes that might prevent inflammation. We investigate the role of PPI on outcomes of pt receiving ICI in mUC. Methods: Medical records from pts with mUC treated with ICI from May 2013 to May 2019 using a multi-institutional database was evaluated. Use of PPI was defined: 30 days prior, during the treatment and 30 days after the last dose of ICI. ORR were assessed according to RECIST v1.1. The X 2 test was used to determine differences in rates. PFS and OS were estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: Overall, 115 pts received therapy with ICI. Of these pts, 20 were not included due to the absence of information about PPI. Thus, 95 pts were included for the analysis. 50 (52.6%) pts received PPI. Median age was 68 years, 79 pts (83.2%) were male, 78 pts (82.1%) had ECOG PS 0-1, 20 pts (21.1%) had liver metastasis and 36 pts (37.9%) received ICI treatment as frontline therapy. ICI prescribed were atezolizumab (58.9%), pembrolizumab (17.9%), durvalumab (12.6%), nivolumab (6.3%) and durvalumab/tremelimumab (4.2%). Pts with no PPIs use had higher ORR (CR [8.9%] +PR [14.4%]) compared to those pt who use PPIs (CR [4.4%] + PR [8.9%]) (P=0.197). Median PFS was 10.05 mo (95% CI: 3.86-16.27) for non PPI users and 3.87 mo (95% CI:1.84-5.91) for PPI users (P=0.04). Median OS was 19.71 mo (95% IC:8.93-30.49) for non PPI users and 7.9 mo (4.4-11.45) for PPI users (P=0.072). Conclusions: We have observed shorter PFS and trend toward lower OS and ORR for PPI users. The real impact of PPI should be confirmed in prospective studies.
Rapidly Evolving Necrotic Plaques and Nodules in a Middle-aged Woman
Authors: Laurel L. Wessman, Kevin J. Gaddis, David R. Pearson
Journal: JAMA Dermatology (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 Dermatology 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 Dermatology journal
Long noncoding RNA <i>SNHG12</i> integrates a DNA-PK–mediated DNA damage response and vascular senescence
Authors: Stefan Haemmig, Dafeng Yang, Xinghui Sun, Debapria Das, Siavash Ghaffari, Roberto Molinaro, Lei Chen, Yihuan Deng, Dan Freeman, Norman Moullan, Yevgenia Tesmenitsky, A.K.M. Khyrul Wara, Viorel Simion, Eugenia Shvartz, James F. Lee, Tianlun Yang, Galina Sukova, Jarrod A. Marto, Peter H. Stone, Warren L. Lee, Johan Auwerx, Peter Libby, Mark W. Feinberg
Journal: Science Translational Medicine (2020)

Deficiency of lncRNA SNHG12 impairs DNA damage repair in the vessel wall and predisposes to vascular senescence and atherosclerosis.
Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations
Authors: Zsofia Sztupinszki, Miklos Diossy, Marcin Krzystanek, Judit Borcsok, Mark M. Pomerantz, Viktoria Tisza, Sandor Spisak, Orsolya Rusz, István Csabai, Matthew L. Freedman, Zoltan Szallasi
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. Experimental Design: Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. Results: Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. Conclusions: These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).
Epidemiology of Asthma in Adults of a community hospital. A cross-section study
Authors: Claudio Parisi, Carolina Antonietti, Maria Laura Orazi, Lucrecia Bustamante, Carla Ritchie, Marcos Las Heras, Estefania Juszkiewicz Franze, None graciela svetliza, Sergio Zunino
Journal: Journal of Allergy and Clinical Immunology (2020)
Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.
Authors: Karl Zhou, Phoebe Zhang, Youzhi Tong, Liandong Ma
Journal: Journal of Clinical Oncology (2020)

186 Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]
Development and Validation of a Prognostic Model for Patients with Advanced Lung Cancer Treated with the Immune Checkpoint Inhibitor Atezolizumab
Authors: Ashley M. Hopkins, Ganessan Kichenadasse, Elizabeth Garrett-Mayer, Christos S. Karapetis, Andrew Rowland, Michael J. Sorich
Journal: Clinical Cancer Research (2020)

Immune checkpoint inhibitors (ICI) are a significant advance to the treatment of advanced non-small cell lung cancer (NSCLC); however, their initiation is associated with heterogeneity in outcomes. This study aimed to develop and validate a prognostic tool of survival in patients with advanced NSCLC treated with ICIs.A pretreatment prognostic model was developed and validated using clinicopathologic data. Development data consisted of patients with advanced NSCLC treated with atezolizumab from the randomised trials OAK and POPLAR (n = 751). Data from the single-arm atezolizumab trials BIRCH and FIR (n = 797) were used for external validation. Prognostic scores were categorized into low, intermediate-low, intermediate, intermediate-high, and high-risk prognostic groups. The primary outcome was overall survival (OS), with progression-free survival (PFS) secondary.Pretreatment C-reactive protein (CRP) was the most predictive variable for OS. The prognostic tool was optimally defined by CRP, lactate dehydrogenase, derived neutrophil-to-lymphocyte ratio, albumin, PD-L1 expression, performance status, time since metastatic diagnosis, and metastatic site count. Prognostic groups had significantly different OS (c-statistic = 0.72), with median OS ranging from >24 to 3 months for the low- to high-risk groups. Performance was maintained on validation (c = 0.76). These findings were similar for PFS, with median PFS ranging from 5 months to 1 month for the low- to high-risk groups. Benefit of atezolizumab (vs. docetaxel) was greatest in the low-risk group (>3 months median OS improvement), with little benefit apparent for the highest risk group.A prognostic tool was developed and validated to identify patient groups with distinctly different survival following atezolizumab initiation for advanced NSCLC.
The Glial Perspective on Sleep and Circadian Rhythms
Authors: Gregory Artiushin, Amita Sehgal
Journal: Annual Review of Neuroscience (2020)

While neurons and circuits are almost unequivocally considered to be the computational units and actuators of behavior, a complete understanding of the nervous system must incorporate glial cells. Far beyond a copious but passive substrate, glial influence is inextricable from neuronal physiology, whether during developmental guidance and synaptic shaping or through the trophic support, neurotransmitter and ion homeostasis, cytokine signaling and immune function, and debris engulfment contributions that this class provides throughout an organism's life. With such essential functions, among a growing literature of nuanced roles, it follows that glia are consequential to behavior in adult animals, with novel genetic tools allowing for the investigation of these phenomena in living organisms. We discuss here the relevance of glia for maintaining circadian rhythms and also for serving functions of sleep.
A rational approach to e-cigarettes: challenging ERS policy on tobacco harm reduction
Authors: Charlotta Pisinger, Jørgen Vestbo
Journal: European Respiratory Journal (2020)

<b>Regarding the use of alternative nicotine delivery systems, ERS argues that including e-cigarettes in a harm reduction strategy is not evidence-based and may result in harm. Instead, we should support access to evidence-based smoking cessation methods.</b>http://bit.ly/2TpUCYG