tbuckley/cabot-search huggingface dataset:
Passive Prophylactic Administration with a Single Dose of Anti–Fel d 1 Monoclonal Antibodies REGN1908–1909 in Cat Allergen–induced Allergic Rhinitis: A Randomized, Double-Blind, Placebo-controlled Clinical Trial
Authors: Mohamed H. Shamji, Iesha Singh, Janice A. Layhadi, Constance Ito, Angeliki Karamani, Lubna Kouser, Hanisah Sharif, Jiaqian Tang, Sava Handijiev, Rebecca V. Parkin, Stephen R. Durham, Ana Kostic, Jamie M. Orengo, Michelle DeVeaux, Mohamed Kamal, Neil Stahl, George D. Yancopoulos, Claire Q. Wang, Allen R. Radin
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Rationale: Sensitization to Fel d 1 (Felis domesticus allergen 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy, are only moderately effective, and allergen immunotherapy has limited use because of safety concerns. Objectives: To explore the relationship among the pharmacokinetic, clinical, and immunological effects of anti-Fel d 1 monoclonal antibodies (REGN1908-1909) in patients after treatment. Methods: Patients received REGN1908-1909 (n = 36) or a placebo (n = 37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and Days 8, 29, and 85. Cytokine and chemokine concentrations in nasal fluids were measured, and REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. Measurements and Main Results: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen-neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid and was detected in an inhibition assay. Type 2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES [regulated upon activation, normal T-cell expressed and secreted]) in nasal fluid were inhibited in REGN1908-1909-treated patients compared with placebo (P < 0.05 for all); IL-13 and IL-5 concentrations correlated with Total Nasal Symptom Score improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined were more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. Conclusions: A single, passive-dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients and was underscored by suppression of FcεRI-, FcεRII-, and T-helper cell type 2-mediated allergic responses. Clinical trial registered with www.clinicaltrials.gov (NCT02127801).
Urgent lessons from COVID 19: why the world needs a standing, coordinated system and sustainable financing for global research and development
Authors: Nicole Lurie, Gerald T Keusch, Victor J Dzau
Journal: The Lancet (2021)

The research and development (R&D) ecosystem has evolved over the past decade to include pandemic infectious diseases, building on experience from multiple recent outbreaks. Outcomes of this evolution have been particularly evident during the COVID-19 pandemic with accelerated development of vaccines and monoclonal antibodies, as well as novel clinical trial designs. These products were developed, trialled, manufactured, and authorised for use in several countries within a year of the pandemic's onset. Many gaps remain, however, that must be bridged to establish a truly efficient and effective end-to-end R&D preparedness and response ecosystem. Foremost among them is a global financing system. In addition, important changes are required for multiple aspects of enabling sciences and product development. For each of these elements we identify priorities for improved and faster functionality. There will be no better time than now to seriously address these needs, however difficult, as the ravages of COVID-19 continue to accelerate with devastating health, social, and economic consequences for the entire community of nations.
What Is the Acceptable Noninferiority Limit for Nodal Recurrences When Ascertaining Sentinel Lymph Node Biopsy as an Alternative to Neck Dissection for Early Oral and Oropharyngeal Cancers?
Authors: Deep Chakrabarti, Naseem Akhtar, Shiv Rajan, Sumaira Qayoom, Vijay Kumar, Arun Chaturvedi, Mranalini Verma, Rajeev Gupta, Madan Lal Brahma Bhatt, Shirin Parveen
Journal: Journal of Clinical Oncology (2021)
AID overexpression leads to aggressive murine CLL and nonimmunoglobulin mutations that mirror human neoplasms
Authors: Pablo Elías Morande, Xiao-Jie Yan, Julieta Sepulveda, Noé Seija, María Elena Marquez, Natalia Sotelo, Cecilia Abreu, Martina Crispo, Gabriel Fernández-Graña, Natalia Rego, Therence Bois, Stephen P. Methot, Florencia Palacios, Victoria Remedi, Kanti R. Rai, Alejandro Buschiazzo, Javier M. Di Noia, Marcelo A. Navarrete, Nicholas Chiorazzi, Pablo Oppezzo
Journal: Blood (2021)
Abstract 19121: Prediction of Sudden Cardiac Death in Patients with Mild to Moderate Chronic Heart Failure: A Comparative Study of Early Repolarization and Fragmented QRS
Authors: Kentaro Ozu, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takashi Naito, Tadao Fujimoto, Takumi Kondo, Kaoruko Sengoku, Hironori Yamomoto, Tsutomu Kawai, Satoshi Takahashi, Masatake Fukunami
Journal: Circulation (2012)

Background: Identification of patients with chronic heart failure (CHF) at risk for sudden cardiac death (SCD) is an important objective. Early repolarization pattern (ERP) and fragmented QRS (fQRS) on the standard 12-lead ECG have recently been associated with an increased risk of life-threatening ventricular arrhythmias in patients with chronic coronary artery disease. However, there is little information available on the comparison of the prognostic significance for SCD between ERP and fQRS in patients with CHF. Methods: We studied 132 consecutive outpatients (NYHA class: 2.0±0.6), with radionuclide left ventricular ejection fraction less than 40% (30±7%), who were enrolled in our prospective cohort study. All patients underwent the standard 12-lead ECG at enrollment. We assessed the presence of ERP, using the criteria of J-point elevation ≥0.1 mV in at least 2 inferior or lateral leads. fQRS was defined by the presence of &gt;2 notches on the R wave or the S wave and had to be present in &gt;or=2 contiguous inferior (II, III, aVF), lateral (I, aVL, V(6)) or anterior (V(1) to V(5)) leads. The primary endpoint of this study was SCD. Results: At enrollment, 16 and 30 patients had ERP and fQRS, respectively. During the mean follow-up period of 6.7±3.5 yrs, 26 patients had SCD. Kaplan-Meier analysis showed that SCD was observed significantly more frequently in patients with than without ERP (63% vs 14%, p&lt;0.0001), and also in patients with than without fQRS in ≥ 2 territories (anterior and inferior, anterolateral or inferolateral), (45% vs 17%, p=0.044). A multivariate Cox analysis revealed that ERP was significantly and independently associated with SCD (hazard ratio 3.7 (95%CI 1.6-8.6), p=0.002), although fQRS in ≥2 territories showed a significant association with SCD (p=0.034) at univariate analysis . Conclusion: ERP in inferior leads would be more strongly associated with an increased risk of SCD in patients with mild to moderate CHF, in comparison to fragmented QRS.
2passtools: two-pass alignment using machine-learning-filtered splice junctions increases the accuracy of intron detection in long-read RNA sequencing
Authors: Matthew T. Parker, Katarzyna Knop, Geoffrey J. Barton, Gordon G. Simpson
Journal: Genome biology (2021)

Abstract Transcription of eukaryotic genomes involves complex alternative processing of RNAs. Sequencing of full-length RNAs using long reads reveals the true complexity of processing. However, the relatively high error rates of long-read sequencing technologies can reduce the accuracy of intron identification. Here we apply alignment metrics and machine-learning-derived sequence information to filter spurious splice junctions from long-read alignments and use the remaining junctions to guide realignment in a two-pass approach. This method, available in the software package 2passtools ( https://github.com/bartongroup/2passtools ), improves the accuracy of spliced alignment and transcriptome assembly for species both with and without existing high-quality annotations.
Epidemiological dynamics of enterovirus D68 in the United States and implications for acute flaccid myelitis
Authors: Sang Woo Park, Margarita Pons-Salort, Kevin Messacar, Camille Cook, Lindsay Meyers, Jeremy Farrar, Bryan T. Grenfell
Journal: Science Translational Medicine (2021)

Mathematical modeling predicts an enterovirus D68, and therefore acute flaccid myelitis, outbreak in the absence of nonpharmaceutical interventions in 2020.
Trends in knowledge of HIV status and efficiency of HIV testing services in sub-Saharan Africa, 2000–20: a modelling study using survey and HIV testing programme data
Authors: Katia Giguère, Jeffrey W Eaton, Kimberly Marsh, Leigh F Johnson, Cheryl C Johnson, Eboi Ehui, Andreas Jahn, Ian Wanyeki, Francisco Mbofana, Fidèle Bakiono, Mary Mahy, Mathieu Maheu-Giroux
Journal: The Lancet HIV (2021)

BackgroundMonitoring knowledge of HIV status among people living with HIV is essential for an effective national HIV response. This study estimates progress and gaps in reaching the UNAIDS 2020 target of 90% knowledge of status, and the efficiency of HIV testing services in sub-Saharan Africa, where two thirds of all people living with HIV reside.MethodsFor this modelling study, we used data from 183 population-based surveys (including more than 2·7 million participants) and national HIV testing programme reports (315 country-years) from 40 countries in sub-Saharan Africa as inputs into a mathematical model to examine trends in knowledge of status among people living with HIV, median time from HIV infection to diagnosis, HIV testing positivity, and proportion of new diagnoses among all positive tests, adjusting for retesting. We included data from 2000 to 2019, and projected results to 2020.FindingsAcross sub-Saharan Africa, knowledge of status steadily increased from 5·7% (95% credible interval [CrI] 4·6–7·0) in 2000 to 84% (82–86) in 2020. 12 countries and one region, southern Africa, reached the 90% target. In 2020, knowledge of status was lower among men (79%, 95% CrI 76–81) than women (87%, 85–89) across sub-Saharan Africa. People living with HIV aged 15–24 years were the least likely to know their status (65%, 62–69), but the largest gap in terms of absolute numbers was among men aged 35–49 years, with 701 000 (95% CrI 611 000–788 000) remaining undiagnosed. As knowledge of status increased from 2000 to 2020, the median time to diagnosis decreased from 9·6 years (9·1–10) to 2·6 years (1·8–3·5), HIV testing positivity declined from 9·0% (7·7–10) to 2·8% (2·1–3·9), and the proportion of first-time diagnoses among all positive tests dropped from 89% (77–96) to 42% (30–55).InterpretationOn the path towards the next UNAIDS target of 95% diagnostic coverage by 2025, and in a context of declining positivity and yield of first-time diagnoses, disparities in knowledge of status must be addressed. Increasing knowledge of status and treatment coverage among older men could be crucial to reducing HIV incidence among women in sub-Saharan Africa, and by extension, reducing mother-to-child transmission.FundingSteinberg Fund for Interdisciplinary Global Health Research (McGill University); Canadian Institutes of Health Research; Bill & Melinda Gates Foundation; Fonds the recherche du Québec—Santé; UNAIDS; UK Medical Research Council; MRC Centre for Global Infectious Disease Analysis; UK Foreign, Commonwealth & Development Office.
The risk of COVID-19 in patients with bullous pemphigoid and pemphigus: A population-based cohort study
Authors: Khalaf Kridin, Yochai Schonmann, Orly Weinstein, Enno Schmidt, Ralf J. Ludwig, Arnon D. Cohen
Journal: Journal of the American Academy of Dermatology (2021)

The burden of COVID-19 in patients with bullous pemphigoid (BP) and pemphigus is yet to be evaluated.To assess the risks of COVID-19 and COVID-19-associated hospitalization and mortality in patients with BP and pemphigus and to delineate determinants of severe COVID-19 illness among these patients.A population-based cohort study compared COVID-19 and its complications in patients with BP (n = 1845) and pemphigus (n = 1236) with age-, sex-, and ethnicity-matched control subjects.The risks of COVID-19 (hazard rate [HR], 1.12; 95% confidence interval [CI], 0.72-1.73; P = .691) and COVID-19-associated hospitalization (HR, 1.58; 95% CI, 0.84-2.98; P = .160) was comparable between patients with BP and controls. The risk of COVID-19-associated mortality was higher among patients with BP (HR, 2.82; 95% CI, 1.15-6.92; P = .023). The risk of COVID-19 (HR, 0.81; 95% CI, 0.44-1.49; P = .496), COVID-19-associated hospitalization (HR, 1.41; 95% CI, 0.53-3.76; P = .499), and COVID-19-associated mortality (HR, 1.33; 95% CI, 0.15-11.92; P = .789) was similar in patients with pemphigus and their controls. Systemic corticosteroids and immunosuppressants did not predispose COVID-19-positive BP and pemphigus patients to a more severe illness.Retrospective data collection.Patients with BP experience increased COVID-19-associated mortality and should be monitored closely. Maintaining systemic corticosteroids and immunosuppressive adjuvant agents during the pandemic is not associated with worse outcomes.
New Insights into the Molecular Profile of Penile Squamous Cell Carcinoma
Authors: Bradley A. McGregor, Guru P. Sonpavde
Journal: Clinical Cancer Research (2021)

Genomic alterations in penile squamous cell carcinoma (PSCC) appear similar to squamous cell carcinomas of the head and neck and esophagus but not lung, skin, bladder, and cervix. PSCCs display genomic heterogeneity, low mutation burden, and potentially actionable alterations in the Notch, DNA repair, kinase, and cell-cycle pathways.See related article by Chahoud et al., p. 2560.
Abstract 11962: Real World Data of Fatal Events Within One Year After Initiating Adaptive Servo Ventilation Therapy in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Atsushi Umeyama
Journal: Circulation (2019)

Introduction: SERVE-HF trial showed ASV therapy was harmful for patient with heart failure with reduced ejection fraction (HFrEF). However, we have experienced that ASV therapy improved patient’s p...
The EMA covid-19 data leak, and what it tells us about mRNA instability
Authors: Serena Tinari
Journal: BMJ (2021)

Leaked documents show that some early commercial batches of Pfizer-BioNTech's covid-19 vaccine had lower than expected levels of intact mRNA, prompting wider questions about how to assess this novel vaccine platform, writes <b>Serena Tinari</b>
Abstract IA006: Metastasis initiating cells and ecosystems
Authors: Joan Massagué
Journal: Cancer Research (2021)

Abstract Metastasis, the spread of cancer cells from primary tumors to distant organs, in the main cause of cancer death. Metastasis is initiated and sustained by a subset of cancer cells with stem-like and immune evasive properties, called metastasis initiating cells (MICs). We are investigating the mechanisms underlying the emergence and selection of MICs within primary tumors, and their microenvironment interactions during metastasis formation and resistance to therapy. Our recent progress suggests that MICs in carcinomas result from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter a slow-cycling state for dormancy, evade immune surveillance, establish profitable interactions with organ-specific niches, and co-opt systemic factors to establish metastatic growth and recurrence after therapy. Our current work on lung adenocarcinoma and breast cancer MICs is providing insights into the emergence and regenerative phenotype of these cells and their mechanisms of brain colonization and avoidance of immune surveillance. An improved understanding of the molecular detereminant of MIC phenotypes and their host ecosystems could yield therapeutic approaches to improve patient outcomes. Citation Format: Joan Massagué. Metastasis initiating cells and ecosystems [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA006.
Lab under the Skin: Microneedle Based Wearable Devices
Authors: Hazhir Teymourian, Farshad Tehrani, Kuldeep Mahato, Joseph Wang
Journal: Advanced Healthcare Materials (2021)

Abstract While the current smartwatches and cellphones can readily track mobility and vital signs, a new generation of wearable devices is rapidly developing to enable users to monitor their health parameters at the molecular level. Within this emerging class of wearables, microneedle‐based transdermal sensors are in a prime position to play a key role in synergizing the significant advantages of dermal interstitial fluid (ISF) as a rich source of clinical indicators and painless skin pricking to allow the collection of real‐time diagnostic information. While initial efforts of microneedle sensing focused on ISF extraction coupled with either on‐chip analysis or off‐chip instrumentation, the latest trend has been oriented toward assembling electrochemical biosensors on the tip of microneedles to allow direct continuous chemical measurements. In this context, significant advances have recently been made in exploiting microneedle‐based devices for real‐time monitoring of various metabolites, electrolytes, and therapeutics and toward the simultaneous multiplexed detection of key chemical markers; yet, there are several grand challenges that still exist. In this review, we outline current progress, recent trends, and new capabilities of microneedle‐empowered sensors, along with the current unmet challenges and a future roadmap toward transforming the latest innovations in the field to commercial products.
SEMS trial: Result of a prospective, multi-institutional phase II clinical trial of surgery in early metastatic seminoma.
Authors: Siamak Daneshmand, Clint Cary, Timothy A. Masterson, Lawrence Einhorn, Stephen A. Boorjian, Christian K. Kollmannsberger, Anne K. Schuckman, Alan So, Peter C. Black, Aditya Bagrodia, Eila C. Skinner, Mehrdad Alemozaffar, Timothy C. Brand, Scott E. Eggener, Phillip M. Pierorazio, Kelly Lynn Stratton, Lucia Nappi, Craig R. Nichols, Brian Hu
Journal: Journal of Clinical Oncology (2021)

375 Background: Chemotherapy or radiotherapy are standard treatments for stage II seminoma, though they are associated with significant long-term treatment-related toxicities. Retroperitoneal lymph node dissection (RPLND) is an established treatment for testicular germ cell tumors but little data exists on its efficacy as a front-line treatment in early metastatic (stage II) seminoma. This is a single-arm, multi-institutional (NCT02537548), phase II study of retroperitoneal lymph node dissection (RLND) as first-line treatment for testicular seminoma with isolated retroperitoneal disease. Methods: Twelve sites in the United States and Canada prospectively enrolled patients (16 years of age) with testicular seminoma and isolated retroperitoneal lymphadenopathy between 1-3 cm in size. Patients were excluded if they received prior therapy (except orchiectomy) for testicular cancer. Open, modified-template RPLND was performed by qualified surgeons with a primary endpoint of 2-year recurrence-free survival. Data on complication rates (short and long-term), pathologic up/downstaging, recurrence patterns, adjuvant therapies, and treatment-free survival were assessed. Results: A total of 55 patients were enrolled and underwent RPLND. Fourteen patients had initial stage I disease who developed isolated retroperitoneal relapse while 41 patients had clinical stage IIA-B at presentation. With a median follow-up of 24 months (8-52 months), there were a total of 10 recurrences. The overall recurrence rate was 18% with a median time to recurrence of 8 months. Of the recurrences, 8 underwent chemotherapy (6 BEP X 3, 1 EP X 4, 1 carbo/etoposide) and 2 underwent additional surgery. The two-year recurrence free survival was 87% and the overall survival was 100%. There were 7 (13%) patients who experienced short-term complications within 1 year of RPLND. Of these, 5 (9%) were classified as Clavien Dindo I-II and 2 (3.6%) were classified as Clavien Dindo III. No patients have reported long-term complications. Conclusions: This trial establishes RPLND as a therapeutic option as a first-line treatment in early metastatic seminoma. The surgery offers cancer control rates similar to those seen in non-seminomatous germ cell tumors. Clinical trial information: NCT02537548.
LNDb challenge on automatic lung cancer patient management
Authors: João Pedrosa, Guilherme Aresta, Carlos Ferreira, Gurraj Atwal, Hady Ahmady Phoulady, Xiaoyu Chen, Rongzhen Chen, Jiaoliang Li, Liansheng Wang, Adrian Galdran, Hamid Bouchachia, Krishna Chaitanya Kaluva, Kiran Vaidhya, Abhijith Chunduru, Sambit Tarai, Sai Prasad Pranav Nadimpalli, Suthirth Vaidya, Ildoo Kim, Alexandr Rassadin, Zhenhuan Tian, Zhongwei Sun, Yizhuan Jia, Xuejun Men, Isabel Ramos, António Cunha, Aurélio Campilho
Journal: Medical Image Analysis (2021)
The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity
Authors: Xinfang Huang, Shumeng Hao, Junli Liu, Yuanyuan Huang, Manman Liu, Chunyuan Xiao, Yan Wang, Siyu Pei, Tao Yu, Jing Xu, Haikun Wang, Dongfang Dai, Xiao Su, Yichuan Xiao
Journal: Cellular and Molecular Immunology (2021)

Abstract T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4 + T cells. Mechanistically, increased ICOS expression on Peli1 -KO CD4 + T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1 -KO cells. As a consequence, Peli1 -deficient CD4 + T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.
Rapid clearance of storage-induced microerythrocytes alters transfusion recovery
Authors: Camille Roussel, Alexandre Morel, Michaël Dussiot, Mickaël Marin, Martin Colard, Aurélie Fricot-Monsinjon, Anaïs Martinez, Charlotte Chambrion, Benoît Henry, Madeleine Casimir, Geoffroy Volle, Mallorie Dépond, Safi Dokmak, François Paye, Alain Sauvanet, Caroline Le Van Kim, Yves Colin, Sonia Georgeault, Philippe Roingeard, Steven L. Spitalnik, Papa Alioune Ndour, Olivier Hermine, Eldad A. Hod, Pierre A. Buffet, Pascal Amireault
Journal: Blood (2021)
Population-scale single-cell RNA-seq profiling across dopaminergic neuron differentiation
Authors: Julie Jerber, Daniel D. Seaton, Anna S. E. Cuomo, Natsuhiko Kumasaka, James Haldane, Juliette Steer, Minal Patel, Daniel Pearce, Malin Andersson, Marc Jan Bonder, Ed Mountjoy, Maya Ghoussaini, Madeline A. Lancaster, John C. Marioni, Florian T. Merkle, Daniel J. Gaffney, Oliver Stegle
Journal: Nature Genetics (2021)