tbuckley/cabot-search huggingface dataset:
Belinostat resolves skin barrier defects in atopic dermatitis by targeting the dysregulated miR-335:SOX6 axis
Authors: Wen Chiy Liew, Gopinath M. Sundaram, Shan Quah, Guo Guang Lum, Jonathan S.L. Tan, Rajkumar Ramalingam, John E.A. Common, Mark B.Y. Tang, E. Birgitte Lane, Steven Tien Guan Thng, Prabha Sampath
Journal: Journal of Allergy and Clinical Immunology (2020)

Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Skin barrier defects contribute to disease initiation and development; however, underlying mechanisms remain elusive.To understand the underlying cause of barrier defect, we investigated aberrant expression of specific microRNAs (miRNAs) in AD. Delineating the molecular mechanism of dysregulated miRNA network, we focused on identification of specific drugs that can modulate miRNA expression and repair the defective barrier in AD.A screen for differentially expressed miRNAs between healthy skin and AD lesional skin resulted in the identification of miR-335 as the most consistently downregulated miRNA in AD. Using in silico prediction combined with experimental validation, we characterized downstream miR-335 targets and elucidated the molecular pathways by which this microRNA maintains epidermal homeostasis in healthy skin.miR-335 was identified as a potent inducer of keratinocyte differentiation; it exerts this effect by directly repressing SOX6. By recruiting SMARCA complex components, SOX6 suppresses epidermal differentiation and epigenetically silences critical genes involved in keratinocyte differentiation. In AD lesional skin, miR-335 expression is aberrantly lost. SOX6 is abnormally expressed throughout the epidermis, where it impairs skin barrier development. We demonstrate that miR-335 is epigenetically regulated by histone deacetylases; a screen for suitable histone deacetylase inhibitors identified belinostat as a candidate drug that can restore epidermal miR-335 expression and rescue the defective skin barrier in AD.Belinostat is of clinical significance not only as a candidate drug for AD treatment, but also as a potential means of stopping the atopic march and further progression of this systemic allergic disease.
Endogenous Opioids at the Intersection of Opioid Addiction, Pain, and Depression: The Search for a Precision Medicine Approach
Authors: Michael A. Emery, Huda Akil
Journal: Annual Review of Neuroscience (2020)

Opioid addiction and overdose are at record levels in the United States. This is driven, in part, by their widespread prescription for the treatment of pain, which also increased opportunity for diversion by sensation-seeking users. Despite considerable research on the neurobiology of addiction, treatment options for opioid abuse remain limited. Mood disorders, particularly depression, are often comorbid with both pain disorders and opioid abuse. The endogenous opioid system, a complex neuromodulatory system, sits at the neurobiological convergence point of these three comorbid disease states. We review evidence for dysregulation of the endogenous opioid system as a mechanism for the development of opioid addiction and/or mood disorder. Specifically, individual differences in opioid system function may underlie differences in vulnerability to opioid addiction and mood disorders. We also review novel research, which promises to provide more detailed understanding of individual differences in endogenous opioid neurobiology and its contribution to opioid addiction susceptibility.
The role of extracellular vesicles and PD-L1 in glioblastoma-mediated immunosuppressive monocyte induction
Authors: Benjamin T Himes, Timothy E Peterson, Tristan de Mooij, Luz M Cumba Garcia, Mi-Yeon Jung, Sarah Uhm, David Yan, Jasmine Tyson, Helen J Jin-Lee, Daniel Parney, Yasmina Abukhadra, Michael P Gustafson, Allan B Dietz, Aaron J Johnson, Haidong Dong, Rachel L Maus, Svetomir Markovic, Fabrice Lucien, Ian F Parney
Journal: Neuro-Oncology (2020)

Abstract Background Immunosuppression in glioblastoma (GBM) is an obstacle to effective immunotherapy. GBM-derived immunosuppressive monocytes are central to this. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule, expressed by GBM cells and GBM extracellular vesicles (EVs). We sought to determine the role of EV-associated PD-L1 in the formation of immunosuppressive monocytes. Methods Monocytes collected from healthy donors were conditioned with GBM-derived EVs to induce the formation of immunosuppressive monocytes, which were quantified via flow cytometry. Donor-matched T cells were subsequently co-cultured with EV-conditioned monocytes in order to assess effects on T-cell proliferation. PD-L1 constitutive overexpression or short hairpin RNA–mediated knockdown was used to determined the role of altered PD-L1 expression. Results GBM EVs interact with both T cells and monocytes but do not directly inhibit T-cell activation. However, GBM EVs induce immunosuppressive monocytes, including myeloid-derived suppressor cells (MDSCs) and nonclassical monocytes (NCMs). MDSCs and NCMs inhibit T-cell proliferation in vitro and are found within GBM in situ. EV PD-L1 expression induces NCMs but not MDSCs, and does not affect EV-conditioned monocytes T-cell inhibition. Conclusion These findings indicate that GBM EV-mediated immunosuppression occurs through induction of immunosuppressive monocytes rather than direct T-cell inhibition and that, while PD-L1 expression is important for the induction of specific immunosuppressive monocyte populations, immunosuppressive signaling mechanisms through EVs are complex and not limited to PD-L1.
Biologics and Bronchial Thermoplasty for severe refractory asthma treatment: from eligibility criteria to real practice
Authors: Francesco Menzella, Carla Galeone, Patrizia Ruggiero, Chiara Catellani, Diego Bagnasco, Chiara Scelfo, Nicola Facciolongo
Journal: Journal of Allergy and Clinical Immunology (2020)
TNF Superfamily Member 14 (TNFSF14/LIGHT) Is Present In Eosinophilic Esophagitis And Promotes A Pro-Inflammatory Phenotype In Esophageal Fibroblasts
Authors: Mario Cabrero Manresa, Austin Chiang, Lucas Dohil, Howard Brickner, Praveen Akuthota, Nathan Lewis, Michael Croft, Seema Aceves
Journal: Journal of Allergy and Clinical Immunology (2020)
2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases
Authors: Lisa R. Sammaritano, Bonnie L. Bermas, Eliza E. Chakravarty, Christina Chambers, Megan E. B. Clowse, Michael D. Lockshin, Wendy Marder, Gordon Guyatt, D. Ware Branch, Jill Buyon, Lisa Christopher‐Stine, Rachelle Crow‐Hercher, John Cush, Maurice Druzin, Arthur Kavanaugh, Carl A. Laskin, Lauren Plante, Jane Salmon, Julia Simard, Emily C. Somers, Virginia Steen, Sara K. Tedeschi, Evelyne Vinet, C. Whitney White, Jinoos Yazdany, Medha Barbhaiya, Brittany Bettendorf, Amanda Eudy, Arundathi Jayatilleke, Amit Aakash Shah, Nancy Sullivan, Laura L. Tarter, Mehret Birru Talabi, Marat Turgunbaev, Amy Turner, Kristen E. D'Anci
Journal: Arthritis & Rheumatology (2020)

Objective To develop an evidence‐based guideline on contraception, assisted reproductive technologies ( ART ), fertility preservation with gonadotoxic therapy, use of menopausal hormone replacement therapy ( HRT ), pregnancy assessment and management, and medication use in patients with rheumatic and musculoskeletal disease ( RMD ). Methods We conducted a systematic review of evidence relating to contraception, ART , fertility preservation, HRT , pregnancy and lactation, and medication use in RMD populations, using Grading of Recommendations Assessment, Development and Evaluation methodology to rate the quality of evidence and a group consensus process to determine final recommendations and grade their strength (conditional or strong). Good practice statements were agreed upon when indirect evidence was sufficiently compelling that a formal vote was unnecessary. Results This American College of Rheumatology guideline provides 12 ungraded good practice statements and 131 graded recommendations for reproductive health care in RMD patients. These recommendations are intended to guide care for all patients with RMD , except where indicated as being specific for patients with systemic lupus erythematosus, those positive for antiphospholipid antibody, and/or those positive for anti‐Ro/ SSA and/or anti‐La/ SSB antibodies. Recommendations and good practice statements support several guiding principles: use of safe and effective contraception to prevent unplanned pregnancy, pre‐pregnancy counseling to encourage conception during periods of disease quiescence and while receiving pregnancy‐compatible medications, and ongoing physician‐patient discussion with obstetrics/gynecology collaboration for all reproductive health issues, given the overall low level of available evidence that relates specifically to RMD . Conclusion This guideline provides evidence‐based recommendations developed and reviewed by panels of experts and RMD patients. Many recommendations are conditional, reflecting a lack of data or low‐level data. We intend that this guideline be used to inform a shared decision‐making process between patients and their physicians on issues related to reproductive health that incorporates patients’ values, preferences, and comorbidities.
Interim estimates of 2019/20 vaccine effectiveness during early-season co-circulation of influenza A and B viruses, Canada, February 2020
Authors: Danuta M Skowronski, Macy Zou, Suzana Sabaiduc, Michelle Murti, Romy Olsha, James A Dickinson, Jonathan B Gubbay, Matthew A Croxen, Hugues Charest, Agatha Jassem, Mel Krajden, Nathalie Bastien, Yan Li, Gaston De Serres
Journal: Eurosurveillance (2020)

Interim results from Canada's Sentinel Practitioner Surveillance Network show that during a season characterised by early co-circulation of influenza A and B viruses, the 2019/20 influenza vaccine has provided substantial protection against medically-attended influenza illness. Adjusted VE overall was 58% (95% confidence interval (CI): 47 to 66): 44% (95% CI: 26 to 58) for A(H1N1)pdm09, 62% (95% CI: 37 to 77) for A(H3N2) and 69% (95% CI: 57 to 77) for influenza B viruses, predominantly B/Victoria lineage.
Epidemiological and biological evidence for protective effect of ginkgo biloba on ovarian cancer
Authors: Bin Ye, Dale Edwards, Ross S. Berkowitz, Samuel C. Mok, Daniel W. Cramer
Journal: Cancer Research (2005)

3484  Anti-oxidants appear to exert apoptotic effects on a number of cancer cell lines and several categories of anti-oxidants have shown to be inversely correlated with cancer risk in epidemiological studies. In the most recent phase of our population-based study of ovarian cancer involving eastern Massachusetts and New Hampshire, we asked about the use of several herbal anti-oxidants including the potent flavonoid anti-oxidant, Ginkgo Biloba. Out of 668 cases with ovarian cancer, 11 (1.6%) said they had regularly used ginkgo at least weekly for a period of 6 months or longer, compared to 30 (4.2%) of controls who said they had used gingko regularly. This translated into a protective effect on ovarian cancer associated with the use of gingko, relative risk (rr) and (95% confidence limits) of RR=0.41 (0.20-0.84). This risk was adjusted for site of study, age, oral contraceptive use, parity and Jewish ethnic background. To explore the biologic rational for this association, we next exposed two ovarian cancer cell lines OVCA433 and OVCA429 representing serous types of cancer to various gingko components. Purified Quecenti, kaempferol, and standardized Ginkgo biloba extract powder were used to treat ovarian cancer cells. After treatment cells for 48 hours with either 100 μM quercetin or kaempferol, we found that OVA433 cell growth was inhibited to levels representing about 70% of that observed in the controls. Treatment with 10, 50, and 100 μM of Ginkgo biloba extract strongly inhibited cell growth in a dose-dependent fashion to 57%, 37% and 23% of that observed in controls. Conversely, treatment of OVCA429 ovarian cancer cells with quercetin and kaempferol at 50 and 100 μM appeared to increase cell growth with both doses to 180% of that observed in control cells. Gingko biloba extracts at 10, 50, 100 μM had no growth or inhibitory effect on OVCa429. Western blot revealed that expression levels of P27 protein in OVCA433 cells were decreased by Ginkgo and quercetin treatment at concentration dependent manner. Our preliminary epidemiolgic data suggest that use of herbal forms of Gingko biloba may be inversely and significantly associated with ovarian cancer risk, while the cell line data is less clear. Gingko biloba in its extracted form, rather that in the form of its key components, quercetin or kaempferol, appears to decrease cell growth in one ovarian cancer cell lines but not another. In the former cell line, the effect may be mediated through inhibition of a key cell cycle pathway of p27.
Safety of BXCL701, a small molecule inhibitor of dipeptidyl peptidases (DPP), with pembrolizumab, (pembro, anti-PD-1) monoclonal antibody, in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rahul Raj Aggarwal, Dan Costin, Vincent J. O'Neill, Cedric R Burg, Diane I. Healey, Johann S. De Bono, Jingsong Zhang, Eric Jay Small
Journal: Journal of Clinical Oncology (2020)

140 Background: BXCL701 (talabostat previously PT100) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) specifically DPP4, DPP8 and DPP9, which trigger macrophage cell death via pyroptosis resulting in proinflammatory stimulation of the innate immunity pathway. BXCL701 also inhibits fibroblast activation protein (FAP) releasing the FAP-mediated block of T-cell migration into the tumor. Expression of PD-L1 correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor responses were observed when BXCL701 was used with checkpoint inhibition. Methods: A phase 1b, multicenter study was undertaken. Eligible patients (pts) had progressing mCRPC (PCWG3), at least 1 line of systemic therapy and ≤ 2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anti-cancer therapy, and an ECOG PS of ≤ 2. Pts received fixed dose pembro (200mg IV q21 days) with escalating doses of BXCL701 (0.4mg and 0.6mg PO QD days 1-14 of 21-day cycles) using a 3 X 3 design. The key endpoints were safety and identification of the recommended phase 2 dose (RP2D) for the combination. Composite response (RECIST, PSA, CTC) was also assessed. Results: 3 pts were treated at the initial dose level for at least 4 cycles. All pts remain on treatment. No DLT or SAEs were reported. Grade 3 treatment related adverse events (TRAE) were limited to thrombocytopenia with transfusion in 1 pt. The only TRAE reported in more than one pt was hypocalcemia (2 pts). Safety assessment of BXCL701+pembro is ongoing at the final dose escalation cohort. As DPP9 is amplified in approximately 17% of treatment associated small cell/neuroendocrine prostate cancer (tSCNC) compared to 5% or less in the broader prostate cancer population, the Phase 2 portion of this study will be limited to patients with evidence of t-SCNC or de novo SCNC, an aggressive phenotype with poor outcomes. Conclusions: BXCL701 0.4mg QD on days 1 to 14 of 21-day cycle plus pembrolizumab 200 mg IV on day 1 every 21 days is safe in pts with mCRPC. The final dose escalation supporting RP2D will be presented. Clinical trial information: NCT03910660.
Risk of fall and clinical fracture associated with androgen receptor inhibitors: A systematic review and meta-analysis.
Authors: Zin Myint, Harry D. Momo, Danielle E. Otto, Donglin Yan, Robert S. DiPaola, Peng Wang, Jill Kolesar
Journal: Journal of Clinical Oncology (2020)

71 Background: Patients treated with androgen receptor inhibitors (ARIs) report a higher incidence of falls; although a potential mechanism of action is unknown. This systematic review evaluates the relative risk (RR) of fall and fracture in prostate cancer (PCa) patients that receive ARIs. Methods: We conducted a comprehensive literature search using Cochrane, Scopus and MedlinePlus databases from inception through August 2019, and evaluated all published prospective phase II, III and IV randomized controlled trials that treated PCa patients with ARIs. Reported fall and fractures as adverse events (AEs) were extracted for analysis. Retrospective, phase I, non-randomized phase II, and studies with control arms that used one of the ARIs were excluded. A mixed effects model was used to estimate effects of ARI on the RR, with the included studies treated as random effects and study arms treated as fixed effects in the pooled analysis. Sample size for each study was used to weight the mixed model. Results: Eleven studies met our inclusion criteria. The total population was 11,382; 6536 were in the ARI arm and 4846 in the control (CTL) arm. Study types were: 8 phase III; 2 phase II; 1 phase IV. Subjects in the ARI arm received enzalutamide, apalutamide or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations while in the CTL arm received placebo, bicalutamide or abiraterone. Treatment duration ranged from 5.4 to 20.5 mo for ARI vs. 5.4 to 18.3 mo for CTL. The reported incidence of fall was 481 (7.4%) in ARI and 201 (4.1%) for CTL. The incidence of fracture was 204 (3.1%) in ARI and 93 (1.9%) in control. The use of ARI was associated with an increased risk: all fall grades (RR 1.83; 95% CI 1.56-2.15; p &lt;0.01); high grade fall (RR 1.69; 95% CI 1.09 – 2.62; p=0.019); all grade fracture (RR 1.56; 95% CI 1.23-1.97; p &lt;0.01) and likely high grade fracture (RR 1.62; 95% CI 0.97 – 2.69; p=0.063). Conclusions: The use of ARI significantly increases falls and fractures in PCa patients as assessed by this meta-analysis study. Further studies would be warranted to identify and understand potential mechanisms and develop strategies to decrease falls and fractures associated with ARI use.
Impact of early identification of brain metastases in metastatic renal cell carcinoma (mRCC).
Authors: Ambika Parmar, Sunita Ghosh, Aly-Khan A. Lalani, Aaron Richard Hansen, M. Neil Reaume, Lori Wood, Naveen S. Basappa, Daniel Yick Chin Heng, Jeffrey Graham, Christian K. Kollmannsberger, Denis Soulieres, Rodney H. Breau, Simon Tanguay, Anil Kapoor, Frederic Pouliot, Georg A. Bjarnason
Journal: Journal of Clinical Oncology (2020)

620 Background: Up to one-third of patients with mRCC can present with asymptomatic brain metastases (BM). Timely identification of BM allows for the delivery of early local interventions, which may lead to improved patient outcomes. To investigate the potential utility of routine intra-cranial imaging, we compared the outcomes of mRCC patients with asymptomatic versus symptomatic BM. Methods: Using the Canadian Kidney Cancer information system (CKCis) database, we identified mRCC patients diagnosed with BM between 2011 and 2018. This cohort was divided into two groups dependent on the presence or absence of neurological symptoms. Baseline patient demographics, clinico-pathological disease characteristics and survival data were extracted. Statistical analysis was through chi-square tests, analysis of variance and Kaplan-Meier method to characterize survival outcomes. Results: 269 mRCC patients with BM were identified with the majority presenting with symptomatic disease (n=163; 61%). No significant differences in clinico-pathological disease characteristics were identified. Median overall survival (OS) from mRCC diagnosis for asymptomatic patients was 33.4 months (interquartile range, IQR 27.8-64.4) versus 34.5 months (20.4-43.4) for symptomatic patients (p=0.35). Median OS from time of BM diagnosis revealed a trend favoring asymptomatic, as compared to symptomatic, patients [24.5 (17.6-24.9) vs. 13.1 months (9.0-20.6), p=0.06]. Factors associated with worse OS from time of BM diagnosis included presentation with symptomatic BM [hazard ratio, HR (95% CI): 1.40 (1.03-1.90), p=0.034] and International Metastatic Renal Cell Carcinoma Consortium Database (IMDC)-characterized intermediate/poor risk disease [HR (95% CI): 1.47 (1.01-2.13), p=0.045]. Conclusions: Routine intra-cranial imaging may lead to earlier identification of BM in mRCC. However, further investigation as to whether this practice improves survival is warranted.
Unilateral Septic Emboli From an Infected Pseudoaneurysm
Authors: Sophia Matos, Morgan Wilson, Rebecca Larson
Journal: JAMA Dermatology (2020)

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Clinical utility of ESGE and ASGE guidelines for prediction of suspected choledocholithiasis in patients undergoing cholecystectomy
Authors: Nitin Jagtap, Yashavanth HS, Manu Tandan, Jahangeer Basha, Radhika Chavan, Zaheer Nabi, Rakesh Kalapala, P. Manohar Reddy, Mohan Ramchandani, Rajesh Gupta, Sundeep Lakhtakia, Santosh Darishetty, G. Venkat Rao, D. Nageshwar Reddy
Journal: Endoscopy (2020)

Abstract Background Recent guidelines from the European Society of Gastrointestinal Endoscopy (ESGE) and American Society for Gastrointestinal Endoscopy (ASGE) recommend risk stratification according to liver function test (LFT) and abdominal ultrasound in patients with suspected choledocholithiasis. We evaluated and validated the clinical utility of these new risk stratification criteria for choledocholithiasis. Methods We retrospectively analyzed prospectively maintained data of patients with suspected choledocholithiasis between January 2016 and December 2018 in patients undergoing cholecystectomy. Patients with common bile duct stricture, cirrhosis, and portal biliopathy were excluded. After LFT and ultrasound, all patients were stratified according to ESGE and ASGE criteria into high, intermediate, and low likelihood of choledocholithiasis. Results 1042 patients were analyzed. Using ESGE guidelines, 213 patients (20.4 %) met high likelihood criteria, 637 (61.1 %) met intermediate, and 192 (18.4 %) met low likelihood criteria. Using ASGE guidelines, 230 (22.1 %), 678 (65.1 %), and 134 (12.9 %) met high, intermediate, and low likelihood criteria, respectively. Specificity and positive predictive value (PPV) of ASGE high likelihood criteria were 96.87 % (95 % confidence interval [CI] 95.37 – 97.98) and 89.57 % (95 %CI 85.20 – 92.75) for choledocholithiasis compared with 98.96 % (95 %CI 97.95 – 99.55) and 96.24 % (95 %CI 92.76 – 98.09), respectively, for ESGE criteria. ASGE classified 17 (7.4 %) additional patients as high likelihood compared with ESGE, only one of whom had choledocholithiasis. ASGE classified 58 (8.6 %) additional patients as intermediate, none of whom had choledocholithiasis. Conclusion This study validates the clinical utility of new ESGE and ASGE criteria for predicting choledocholithiasis. ESGE risk stratification appears more specific than ASGE.