tbuckley/cabot-search huggingface dataset:
Attenuation of Oxidative Injury With Targeted Expression of NADPH Oxidase 2 Short Hairpin RNA Prevents Onset and Maintenance of Electrical Remodeling in the Canine Atrium
Authors: Shin Yoo, Anna Pfenniger, Jacob Hoffman, Wenwei Zhang, Jason Ng, Amy Burrell, David A. Johnson, Georg Gussak, Trent Waugh, Suzanne Bull, Brandon Benefield, Bradley P. Knight, Rod Passman, J. Andrew Wasserstrom, Gary L. Aistrup, Rishi Arora
Journal: Circulation (2020)

Atrial fibrillation (AF) is the most common heart rhythm disorder in adults and a major cause of stroke. Unfortunately, current treatments of AF are suboptimal because they are not targeted to the molecular mechanisms underlying AF. Using a highly novel gene therapy approach in a canine, rapid atrial pacing model of AF, we demonstrate that NADPH oxidase 2 (NOX2) generated oxidative injury causes upregulation of a constitutively active form of acetylcholine-dependent K+ current (IKACh), called IKH; this is an important mechanism underlying not only the genesis, but also the perpetuation of electric remodeling in the intact, fibrillating atrium.To understand the mechanism by which oxidative injury promotes the genesis and maintenance of AF, we performed targeted injection of NOX2 short hairpin RNA (followed by electroporation to facilitate gene delivery) in atria of healthy dogs followed by rapid atrial pacing. We used in vivo high-density electric mapping, isolation of atrial myocytes, whole-cell patch clamping, in vitro tachypacing of atrial myocytes, lucigenin chemiluminescence assay, immunoblotting, real-time polymerase chain reaction, immunohistochemistry, and Masson trichrome staining.First, we demonstrate that generation of oxidative injury in atrial myocytes is a frequency-dependent process, with rapid pacing in canine atrial myocytes inducing oxidative injury through the induction of NOX2 and the generation of mitochondrial reactive oxygen species. We show that oxidative injury likely contributes to electric remodeling in AF by upregulating IKACh by a mechanism involving frequency-dependent activation of PKCε (protein kinase C epsilon). The time to onset of nonsustained AF increased by >5-fold in NOX2 short hairpin RNA-treated dogs. Furthermore, animals treated with NOX2 short hairpin RNA did not develop sustained AF for up to 12 weeks. The electrophysiological mechanism underlying AF prevention was prolongation of atrial effective refractory periods, at least in part attributable to the attenuation of IKACh. Attenuated membrane translocation of PKCε appeared to be a likely molecular mechanism underlying this beneficial electrophysiological remodeling.NOX2 oxidative injury (1) underlies the onset, and the maintenance of electric remodeling in AF, as well, and (2) can be successfully prevented with a novel, gene-based approach. Future optimization of this approach may lead to a novel, mechanism-guided therapy for AF.
Use of Biologics to Treat Relapsing and/or Refractory Eosinophilic Granulomatosis With Polyangiitis: Data From a European Collaborative Study
Authors: Alice Canzian, Nils Venhoff, Maria Letizia Urban, Silvia Sartorelli, Anne‐Marie Ruppert, Matthieu Groh, Nicolas Girszyn, Camille Taillé, François Maurier, Vincent Cottin, Claire de Moreuil, Vincent Germain, Maxime Samson, Marie Jachiet, Laure Denis, Virginie Rieu, Perrine Smets, Grégory Pugnet, Alban Deroux, Cécile‐Audrey Durel, Achille Aouba, Pascal Cathébras, Christophe Deligny, Stanislas Faguer, Helder Gil, Bertrand Godeau, François Lifermann, Sophie Phin‐Huynh, Marc Ruivard, Philippe Bonniaud, Xavier Puéchal, Jean‐Emmanuel Kahn, Jens Thiel, Lorenzo Dagna, Loïc Guillevin, Augusto Vaglio, Giacomo Emmi, Benjamin Terrier
Journal: Arthritis & Rheumatology (2020)

Objective To describe the efficacy and safety of biologics for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA). Methods A retrospective European collaborative study was conducted in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease. Results Among the 147 patients with EGPA included in the study, 63 received rituximab (RTX), 51 received mepolizumab (MEPO), and 33 received omalizumab (OMA). At the time of inclusion, the median Birmingham Vasculitis Activity Score (BVAS) was 8.5 (interquartile range [IQR] 5–13) in the RTX group, while the median BVAS in the OMA group was 2 (IQR 1–4.5) and the median BVAS in the MEPO group was 2 (IQR 1–5). In patients receiving RTX, the median BVAS declined both at 6 months (median 1, IQR 0–4.5) and at 12 months (median 0, IQR 0–2), and the frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 49%, 24%, 24%, and 3%, respectively. For the treatment of glucocorticoid (GC)–dependent asthma, patients who received MEPO had a much better GC‐sparing effect and overall response than did patients who received OMA. The frequency of remission, partial response, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the OMA group and 78%, 10%, 8%, and 4%, respectively, in the MEPO group. Remission rates at 12 months were 76% and 82% among patients receiving MEPO at a doses of 100 mg and 300 mg, respectively. Conclusion These results suggest that RTX could be effective in treating relapses of EGPA vasculitis. MEPO is highly effective with a good safety profile in patients with GC‐dependent asthma. Our data suggest that 100 mg MEPO monthly could be an acceptable dosage for first‐line therapy in selected instances of EGPA, recognizing, however, that this has not been compared to the validated dosage of 300 mg monthly.
Should You Recommend Direct-to-Consumer Genetic Testing for This Patient?
Authors: Gerald W. Smetana, Jason L. Vassy, Erin Hofstatter, Howard Libman
Journal: Annals of Internal Medicine (2020)

In recent years, the number of patients choosing to have direct-to-consumer (DTC) genetic testing without involving their clinicians has increased substantially. For example, the number of subscribers to a commonly used testing site has grown to more than 10 million. These services have been heavily marketed in the United States and often include information about ancestry; genetic traits; and, increasingly, disease risk. In clinical care, genetic testing by a physician is accompanied by both pre- and posttest counseling by a trained genetic counselor. However, there are not enough genetic counselors to meet the needs of all persons contemplating DTC genetic testing. Formal genetic counseling includes preparation of a family pedigree; a discussion about potential benefits, the possibility that some information might be stressful to receive or difficult to understand, and the potential for disclosure of genetic information; and a detailed informed consent process. Some DTC tests for genetic susceptibilities look for only a few known mutations in a particular gene (such as BRCA1); a negative test result does not exclude the possibility of a clinically important mutation. A positive DTC genetic test result that might change clinical management should be followed by a confirmatory test through a genetics laboratory. Here, 2 expert physicians—a general internist and a medical oncologist with genetics experience—discuss an approach to counseling a patient who is considering DTC testing to learn more about his ancestry and his risk for metabolic syndrome.
Extended Validation of Novel 3D Quantitative Coronary Angiography-Based Software to Calculate vFFR
Authors: Tara Neleman, Kaneshka Masdjedi, Laurens J.C. Van Zandvoort, Mariusz Tomaniak, Jurgen M.R. Ligthart, Karen T. Witberg, Alise A. Vermaire, Eric Boersma, Nicolas M. Van Mieghem, Joost Daemen
Journal: JACC. Cardiovascular imaging (2020)
Perioperative Treatment in Muscle-invasive Bladder Cancer: Analysis of Secondary Endpoints in a Randomized Trial Comparing Gemcitabine and Cisplatin Versus Dose-dense Methotrexate, Vinblastine, Adriamycin, and Cisplatin
Authors: Irbaz Bin Riaz, Syed A. Hussain
Journal: European Urology (2020)
Abstract PO-069: SRMS correlated with immune infiltration and lung cancer: Allusion for COVID-19
Authors: Beesetti Swarna, Yong-Dong Wang, Malia B. Potts
Journal: Clinical Cancer Research (2020)

Abstract Background: The non-receptor tyrosine kinase, SRMS (Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites) is a member of the BRK family kinases (BFKs) that represents an evolutionarily conserved relative of the Src family kinases (SFKs) and is shown to restrain autophagy in mammalian cells. Gene enrichment analyses using the Ingenuity Pathway analyses (IPA) of SRMS interacting partners predicted viral infection as a significantly increased cellular processes. However, the correlation between SRMS and prognosis in LUAD (lung adenocarcinoma) and LUSC (lung squamous cell carcinoma) or its impact on COVID-19 is understudied. Methods: We analyzed the expression levels of SRMS, and the correlation between SRMS and immune infiltration level in LUAD and LUSC was investigated using TIMER database. Open Target platform was used to analyze the association of SRMS with disease. In addition, we used GSE30589 databases to elucidate the changes of SRMS expression in vitro after SARS-CoV infection in Vero E6 and MA-104 cells. Results: SRMS was elevated in LUAD and LUSC compared to normal tissues. The expression of SRMS was negatively correlated with the level of immune infiltration of CD8+T cells in LUAD and LUSC. We found that the expression of SRMS increased in vitro after SARS-CoV infection in Vero E6 and MA-104 cells. Conclusion: SRMS expression increased significantly in LUAD and LUSC, and this elevated SRMS was negatively correlated with immune infiltration at tumors. SARS-CoV infection increased the SRMS expression. This suggests that patients with LUAD and LUSC may be more susceptible to SARS-CoV-2 due to increased SRMS levels that inhibit autophagy and alter tumor microenvironment correlated with reduced immune infiltration, which in turn may worsen the prognoses of LUAD and LUSC patients after SARS-CoV-2 infection. Citation Format: Beesetti Swarna, Yong-Dong Wang, Malia B. Potts. SRMS correlated with immune infiltration and lung cancer: Allusion for COVID-19 [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-069.
How Successful Are Medical Thoracoscopists At Predicting Malignancy
Authors: R J Hallifax, J P Corcoran, I Psallidas, N M Rahman
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Introduction  Use of medical thoracoscopy by physicians to diagnose malignant pleural disease is increasing. Thoracoscopy is also used therapeutically to pleurodese (talc poudrage), at the time of biopsy, to minimise pleural effusion recurrence. However, this relies on the physician being confident of their diagnosis macroscopically.  A survey was conducted of regular thoracoscopists to establish the current practise related to medical thoracoscopy and a video of previous thoracoscopies (with known histology) was used to assess the accuracy of macroscopic evaluation of pleural disease.  Methods  20 video clips recorded during thoracoscopy in Oxford were combined into a short video (30 s per clip): including a selection of cases with malignant (13) and benign disease (7), intentionally including some cases which were deemed unclear. A survey of thoracoscopists was conducted via email. Respondents were asked to state whether each clip showed malignant or benign disease, scoring their confidence in their diagnosis (out of 10), whether they predict trapped lung and if they would perform pleurodesis. Gold standard of diagnosis was the histology result.  Results  Procedural survey: 16 physicians responded from 12 tertiary referral centres: 13 consultants and 3 specialist registrars. 15 (94%) had performed >30 thoracoscopies each. Four institutions (25%) perform between >10 thoracoscopies per month; 12 (75%) between 1–10 per month. Only 6 (38%) perform thoracoscopies as day cases. All perform rigid rather than flexible thoracoscopies.  Video survey: Of the 20 video clips, the mean number of correct answers was 12.4 (62%). Respondents were more confident of their answers (out of 10) when correct (7.1/10) than incorrect (6.1/10). In cases deemed malignant, 69% would have performed talc pleurodesis; however, 17% would have pleurodesed patients who had benign disease (See Table). Respondents only correctly predicted trapped lung in 2.6/20 cases (13%).  Conclusion  Despite being experienced thoracoscopists, only 62% correctly diagnosed malignant or benign on video clips. The majority would appropriately perform pleurodesis, but 17% may have inappropriately pleurodesed benign disease. There are limitations to this small survey using short thoracoscopy clips, but this data suggests caution is required when considering making diagnosis on macroscopic appearance and deciding whether the lung is trapped.
Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
Authors: Paul D. Robbins, Diana Jurk, Sundeep Khosla, James L. Kirkland, Nathan K. LeBrasseur, Jordan D. Miller, João F. Passos, Robert J. Pignolo, Tamar Tchkonia, Laura J. Niedernhofer
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.
Sociocultural reflections on face coverings must not ignore the negative consequences
Authors: Esmée S Hanna, Robert Dingwall, Margaret McCartney, Robert West, Ellen Townsend, Jackie Cassell, Graham Martin
Journal: BMJ (2020)

Much comment by advocates and opponents of face coverings has focused on the quality of the evidence base and whether this justifies widespread use.1 Advocacy for face coverings has primarily drawn on research conducted in biomedical settings, and some scholars have explicitly invoked their medical credentials to justify claims to scientific authority.2 Disciplines such as the social sciences and engineering have consequently had limited input into policies on face coverings. Given the challenges that covid-19 has created …
Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy
Authors: Natalia Rodrigues Mantuano, Marina Natoli, Alfred Zippelius, Heinz Läubli
Journal: Journal for ImmunoTherapy of Cancer (2020)

During oncogenesis, tumor cells present specific carbohydrate chains that are new targets for cancer immunotherapy. Whereas these tumor-associated carbohydrates (TACA) can be targeted with antibodies and vaccination approaches, TACA including sialic acid-containing glycans are able to inhibit anticancer immune responses by engagement of immune receptors on leukocytes. A family of immune-modulating receptors are sialic acid-binding Siglec receptors that have been recently described to inhibit antitumor activity mediated by myeloid cells, natural killer cells and T cells. Other TACA-binding receptors including selectins have been linked to cancer progression. Recent studies have shown that glycan-lectin interactions can be targeted to improve cancer immunotherapy. For example, interactions between the immune checkpoint T cell immunoglobulin and mucin-domain containing-3 and the lectin galectin-9 are targeted in clinical trials. In addition, an antibody against the lectin Siglec-15 is being tested in an early clinical trial. In this review, we summarize the previous and current efforts to target TACA and to inhibit inhibitory immune receptors binding to TACA including the Siglec-sialoglycan axis.
Interpreting Biomarker Data After Concussion and Repeated Subconcussive Head Impacts
Authors: James M. Smoliga
Journal: JAMA Neurology (2020)

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Severe SARS-CoV-2 disease in the context of a NF-κB2 loss-of-function pathogenic variant
Authors: Roshini S. Abraham, Joanna M. Marshall, Hye Sun Kuehn, Cesar M. Rueda, Amber Gibbs, Will Guider, Claire Stewart, Sergio D. Rosenzweig, Huanyu Wang, Sophonie Jean, Mark Peeples, Tiffany King, W. Garrett Hunt, Jonathan R. Honegger, Octavio Ramilo, Peter J. Mustillo, Asuncion Mejias, Monica I. Ardura, Masako Shimamura
Journal: Journal of Allergy and Clinical Immunology (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged recently and has created a global pandemic. Symptomatic SARS-CoV-2 infection, termed coronavirus disease 2019 (COVID-19), has been associated with a host of symptoms affecting numerous organ systems, including the lungs, cardiovascular system, kidney, central nervous system, gastrointestinal tract, and skin, among others.
Resolution of Spatial and Temporal Heterogeneity in Bevacizumab-Treated Breast Tumors by Eigenspectra Multispectral Optoacoustic Tomography
Authors: Evangelos Liapis, Uwe Klemm, Angelos Karlas, Josefine Reber, Vasilis Ntziachristos
Journal: Cancer Research (2020)

Understanding temporal and spatial hemodynamic heterogeneity as a function of tumor growth or therapy affects the development of novel therapeutic strategies. In this study, we employed eigenspectra multispectral optoacoustic tomography (eMSOT) as a next-generation optoacoustic method to impart high accuracy in resolving tumor hemodynamics during bevacizumab therapy in two types of breast cancer xenografts (KPL-4 and MDA-MB-468). Patterns of tumor total hemoglobin concentration (THb) and oxygen saturation (sO2) were imaged in control and bevacizumab-treated tumors over the course of 58 days (KPL-4) and 16 days (MDA-MB-468), and the evolution of functional vasculature "normalization" was resolved macroscopically. An initial sharp drop in tumor sO2 and THb content shortly after the initiation of bevacizumab treatment was followed by a recovery in oxygenation levels. Rim-core subregion analysis revealed steep spatial oxygenation gradients in growing tumors that were reduced after bevacizumab treatment. Critically, eMSOT imaging findings were validated directly by histopathologic assessment of hypoxia (pimonidazole) and vascularity (CD31). These data demonstrate how eMSOT brings new abilities for accurate observation of entire tumor responses to challenges at spatial and temporal dimensions not available by other techniques today. SIGNIFICANCE: Accurate assessment of hypoxia and vascularization over space and time is critical for understanding tumor development and the role of spatial heterogeneity in tumor aggressiveness, metastasis, and response to treatment.
Epicutaneous immunotherapy protects cashew‐sensitized mice from anaphylaxis
Authors: Benjamin Pelletier, Audrey Perrin, Noémie Assoun, Camille Plaquet, Nathalie Oreal, Laetitia Gaulme, Adeline Bouzereau, Jean‐Louis Labernardière, Mélanie Ligouis, Vincent Dioszeghy, Sophie Wavrin, Katie Matthews, Fabrice Porcheray, Hugh A. Sampson, Pierre‐Louis Hervé
Journal: Allergy (2020)

Abstract Background The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children. Objective We aimed to evaluate the capacity of EPIT to provide protection against cashew‐induced anaphylaxis in a relevant mouse model. Methods The efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew‐sensitized mice. As negative control, sham mice received patches containing excipient. Following treatment, mice were challenged orally to cashew and anaphylactic symptoms, as well as plasmatic levels of mast‐cell proteases (mMCP)‐1/7, were quantified. Results Of 16 weeks of EPIT significantly protects against anaphylaxis by promoting a faster recovery of challenged mice. This protection was characterized by a significant reduction of temperature drop and clinical symptoms, 60 minutes after challenge. This was associated with a decrease in mast‐cell reactivity as attested by the reduction of mMCP‐1/7 in plasma, suggesting that EPIT specifically decrease IgE‐mediated anaphylaxis. Conclusion We demonstrate that EPIT markedly reduced IgE‐mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.
Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium
Authors: Silva Kasela, Victor E. Ortega, Molly Martorella, Suresh Garudadri, Jenna Nguyen, Elizabeth Ampleford, Anu Pasanen, Srilaxmi Nerella, Kristina L. Buschur, Igor Z. Barjaktarevic, R. Graham Barr, Eugene R. Bleecker, Russell P. Bowler, Alejandro P. Comellas, Christopher B. Cooper, David J. Couper, Gerard J. Criner, Jeffrey L. Curtis, MeiLan K. Han, Nadia N. Hansel, Eric A. Hoffman, Robert J. Kaner, Jerry A. Krishnan, Fernando J. Martinez, Merry-Lynn N. McDonald, Deborah A. Meyers, Robert Paine, Stephen P. Peters, Mario Castro, Loren C. Denlinger, Serpil C. Erzurum, John V. Fahy, Elliot Israel, Nizar N. Jarjour, Bruce D. Levy, Xingnan Li, Wendy C. Moore, Sally E. Wenzel, Joe Zein, Charles Langelier, Prescott G. Woodruff, Tuuli Lappalainen, Stephanie A. Christenson
Journal: Genome Medicine (2021)

The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.