tbuckley/cabot-search huggingface dataset:
Intratumoral IL12 mRNA Therapy Promotes TH1 Transformation of the Tumor Microenvironment
Authors: Susannah L. Hewitt, Dyane Bailey, John Zielinski, Ameya Apte, Faith Musenge, Russell Karp, Shannon Burke, Fabien Garcon, Ankita Mishra, Sushma Gurumurthy, Amanda Watkins, Kristen Arnold, James Moynihan, Eleanor Clancy-Thompson, Kathy Mulgrew, Grace Adjei, Katharina Deschler, Darren Potz, Gordon Moody, David A. Leinster, Steve Novick, Michal Sulikowski, Chris Bagnall, Philip Martin, Jean-Martin Lapointe, Han Si, Chris Morehouse, Maja Sedic, Robert W. Wilkinson, Ronald Herbst, Joshua P. Frederick, Nadia Luheshi
Journal: Clinical Cancer Research (2020)

While immune checkpoint inhibitors such as anti-PD-L1 are rapidly becoming the standard of care in the treatment of many cancers, only a subset of treated patients have long-term responses. IL12 promotes antitumor immunity in mouse models; however, systemic recombinant IL12 had significant toxicity and limited efficacy in early clinical trials.We therefore designed a novel intratumoral IL12 mRNA therapy to promote local IL12 tumor production while mitigating systemic effects.A single intratumoral dose of mouse (m)IL12 mRNA induced IFNγ and CD8+ T-cell-dependent tumor regression in multiple syngeneic mouse models, and animals with a complete response demonstrated immunity to rechallenge. Antitumor activity of mIL12 mRNA did not require NK and NKT cells. mIL12 mRNA antitumor activity correlated with TH1 tumor microenvironment (TME) transformation. In a PD-L1 blockade monotherapy-resistant model, antitumor immunity induced by mIL12 mRNA was enhanced by anti-PD-L1. mIL12 mRNA also drove regression of uninjected distal lesions, and anti-PD-L1 potentiated this response. Importantly, intratumoral delivery of mRNA encoding membrane-tethered mIL12 also drove rejection of uninjected lesions with very limited circulating IL12p70, supporting the hypothesis that local IL12 could induce a systemic antitumor immune response against distal lesions. Furthermore, in ex vivo patient tumor slice cultures, human IL12 mRNA (MEDI1191) induced dose-dependent IL12 production, downstream IFNγ expression and TH1 gene expression.These data demonstrate the potential for intratumorally delivered IL12 mRNA to promote TH1 TME transformation and robust antitumor immunity.See related commentary by Cirella et al., p. 6080.
Incidence, management and outcome of respiratory syncytial virus infection in adult lung transplant recipients: a 9-year retrospective multicentre study
Authors: Hugo Testaert, Margaux Bouet, Florent Valour, Anne Gigandon, Marie-Edith Lafon, François Philit, Agathe Sénéchal, Jean-Sébastien Casalegno, Elodie Blanchard, Jérôme Le Pavec, Florence Ader
Journal: Clinical Microbiology and Infection (2020)
Management of uncertainty
Authors: Dee Mangin
Journal: BMJ (2006)

This patient had adult onset Still's disease with atypical features.1 For general practitioners the presentation of the disease itself is atypical—uncommon enough not to make it on to the initial list of differential diagnoses. The case highlights broader issues around recognition of patterns of illness and dealing with medically unexplained signs and symptoms.1

General practitioners often see the pattern of symptoms described at presentation: a young person with a febrile illness, myalgia, and sore throat. This pattern would prompt a working diagnosis of infection, most likely viral. What triggered the general practitioner to recognise that this woman's symptoms deviated from the pattern and raised enough concern to prompt hospital referral? The …
Epidemiological and clinical characteristics of SARS-CoV-2 infections at a testing site in Berlin, Germany, March and April 2020—a cross-sectional study
Authors: Friederike Maechler, Maximilian Gertler, Julia Hermes, Welmoed van Loon, Frank Schwab, Brar Piening, Shay Rojansky, Franziska Hommes, Franka Kausch, Andreas K. Lindner, Susen Burock, Heike Rössig, Claudia Hartmann, Valerie Kirchberger, Alexander Thieme, Michael Behnke, Petra Gastmeier, Frank P. Mockenhaupt, Joachim Seybold
Journal: Clinical Microbiology and Infection (2020)
Evidence of Variability Of 2D Strain Measures in Human Subjects Referred for Routine Echocardiographic Examination
Authors: Visali Kodali, Samir K. Saha, Rena S. Toole, Ebere O. Chukwu, Satish C. Govind, Anatoli Kiotsekoglou, Lars-Åke Brodin, Aasha S. Gopal
Journal: Circulation (2010)

Evidence of Variability Of 2D Strain Measures in Human Subjects Referred for Routine Echocardiographic Examination
Myocardial Redox State Predicts Post-Operative Clinical Outcome in Patients Undergoing Elective CABG: The Role of NADPH-Oxidase and Uncoupled Nitric Oxide Synthase
Authors: Charalambos Antoniades, Michael Demosthenous, Dimitris Tousoulis, Marios Margaritis, Alexios Antonopoulos, Constantinos Bakogiannis, Costantinos Triantafillou, Keith M Channon, Barbara Casadei, Christodoulos Stefanadis
Journal: Circulation (2010)
Gadoxetic acid-enhanced MRI of macrotrabecular-massive hepatocellular carcinoma and its prognostic implications
Authors: Hyungjin Rhee, Eun-Suk Cho, Ji Hae Nahm, Mi Jang, Yong Eun Chung, Song-Ee Baek, Sunyoung Lee, Myeong-Jin Kim, Mi-Suk Park, Dai Hoon Han, Jin-Young Choi, Young Nyun Park
Journal: Journal of Hepatology (2020)
Abstract 11131: Structure/Function of the Accessory Pathway in a Heritable Canine Model of Wolff-Parkinson-White-Syndrome
Authors: Vadim V Fedorov, Richard B Schuessler, Mark Levin, Wenwen Li, Deborah L Janks, Jennifer Silva, Thomas Kurian, George Van Hare, Sydney N Moise, Igor R Efimov
Journal: Circulation (2010)

Introduction: WPW syndrome results from ventricular pre-excitation through an accessory pathway (AP) and is treated by ablation. Functional properties of APs have been studied using extracellular e...
Network study of nasal transcriptome profiles reveals master regulator genes of asthma
Authors: Anh N. Do, Yoojin Chun, Galina Grishina, Alexander Grishin, Angela J. Rogers, Benjamin A. Raby, Scott T. Weiss, Alfin Vicencio, Eric E. Schadt, Supinda Bunyavanich
Journal: Journal of Allergy and Clinical Immunology (2020)
Probability of Major Depression Classification Based on the SCID, CIDI, and MINI Diagnostic Interviews: A Synthesis of Three Individual Participant Data Meta-Analyses
Authors: Yin Wu, Brooke Levis, John P.A. Ioannidis, Andrea Benedetti, Brett D. Thombs
Journal: Psychotherapy and Psychosomatics (2020)

Three previous individual participant data meta-analyses (IPDMAs) reported that, compared to the Structured Clinical Interview for the DSM (SCID), alternative reference standards, primarily the Composite International Diagnostic Interview (CIDI) and the Mini International Neuropsychiatric Interview (MINI), tended to misclassify major depression status, when controlling for depression symptom severity. However, there was an important lack of precision in the results.To compare the odds of the major depression classification based on the SCID, CIDI, and MINI.We included and standardized data from 3 IPDMA databases. For each IPDMA, separately, we fitted binomial generalized linear mixed models to compare the adjusted odds ratios (aORs) of major depression classification, controlling for symptom severity and characteristics of participants, and the interaction between interview and symptom severity. Next, we synthesized results using a DerSimonian-Laird random-effects meta-analysis.In total, 69,405 participants (7,574 [11%] with major depression) from 212 studies were included. Controlling for symptom severity and participant characteristics, the MINI (74 studies; 25,749 participants) classified major depression more often than the SCID (108 studies; 21,953 participants; aOR 1.46; 95% confidence interval [CI] 1.11-1.92]). Classification odds for the CIDI (30 studies; 21,703 participants) and the SCID did not differ overall (aOR 1.19; 95% CI 0.79-1.75); however, as screening scores increased, the aOR increased less for the CIDI than the SCID (interaction aOR 0.64; 95% CI 0.52-0.80).Compared to the SCID, the MINI classified major depression more often. The odds of the depression classification with the CIDI increased less as symptom levels increased. Interpretation of research that uses diagnostic interviews to classify depression should consider the interview characteristics.
Endoscopic ultrasound (EUS)-guided fine needle biopsy (FNB) formalin fixed paraffin-embedded (FFPE) pancreatic tissue samples are a potential resource for microbiota analysis
Authors: Andrea C Masi, Yaa E A Oppong, Beate Haugk, Christopher A Lamb, Linda Sharp, James M Shaw, Christopher J Stewart, Kofi W Oppong
Journal: Gut (2020)

We read with great interest the study by Gaiser et al 1; their finding of enrichment of oral bacterial taxa, including Fusobacterium nucleatum , in intraductal papillary mucinous neoplasms with high-grade dysplasia adds to the growing literature on the pancreatic microbiome in pancreatic ductal adenocarcinoma (PDAC).2–4 Previous PDAC microbiome studies have an inherent bias as they are restricted to samples from patients undergoing surgical resection. Less than 20% of patients with PDAC undergo surgery and such cases are not representative of the full gamut of the disease. Additionally there is uncertainty regarding the extent of exogenous bacterial DNA contamination of samples used.

Endoscopic ultrasound (EUS) fine needle biopsy (FNB) is often utilised to make a histological diagnosis in patients with suspected PDAC. Novel needles which provide samples better suited to DNA extraction and gene sequencing5 are available. However, the relatively low biomass of the samples and nature of sample collection present challenges with contamination and technical noise. Recently computational approaches have been developed to remove contaminants in such low biomass …
Re: In the name of common sense: EUCAST breakpoints and potential pitfalls. National dissemination of EUCAST guidelines is a shared responsibility
Authors: Gunnar Kahlmeter, Rafael Cantón, Christian G. Giske, John Turnidge, Christian G. Giske, John Turnidge, Rafael Cantón, Gunnar Kahlmeter, Shampa Das, Sören Gatermann, Gerard Lina, Christoffer Lindemann, Alasdair MacGowan, Joseph Meletiadis, Gian-Maria Rossolini, Jorge Sampaio
Journal: Clinical Microbiology and Infection (2020)
Ensuring editorial continuity and quality of science during the COVID-19 storm: the ICM experience
Authors: Thomas Bein, Alessia Vargiolu, Giuseppe Citerio, Samir Jaber, Miet Schetz, Anders Aneman, Yaseen Arabi, Katherine Brown, Alain Combes, Michael Darmon, Audrey Jong, Sharon Einav, Niall Ferguson, Morten Hylander Møller, Ignacio Martin-Loeches, Paul Mayo, Geert Meyfroidt, Garyphallia Poulakou, Otavio Ranzani, Claudio Sandroni, Manu Shankar-Hari
Journal: Intensive Care Medicine (2020)
Erythrophagocytosis by monocytes: An unusual observation in autoimmune hemolytic anemia
Authors: Charlotte Wilding, Daniel Pelling, Kirstin Lund, Barbara J. Bain
Journal: American Journal of Hematology (2020)

An 8-year-old Lebanese boy presented with symptomatic anemia with a short history of abdominal pain, vomiting, and passing dark urine. He was pale, jaundiced and hypotensive with tachycardia. He had attended the Accident and Emergency department 48 hours earlier with loss of appetite, vomiting, and lethargy. At that time hemoglobin concentration (Hb) had been 116 g/L and urine dipstick had shown a trace of blood. On re-presentation his blood count showed an Hb of 53 g/L and a reticulocyte count of 16% (255 × 109/L). A blood film was leucoerythroblastic and showed spherocytosis, small red cell agglutinates, and polychromatic macrocytes (Images). There were infrequent examples of erythrophagocytosis by monocytes, but not by neutrophils (Images). The impression of rapid onset, severe autoimmune hemolytic anemia was confirmed by further investigations: bilirubin 96 μmol/L, conjugated bilirubin 12 μmol/L, lactate dehydrogenase 1300 U/L and haptoglobin undetectable. Serology showed a positive direct antiglobulin test: immunoglobulin (Ig) G 4+, IgA 3+, IgM 1+ and C3d−. A pan-reactive autoantibody was detected. A Donath–Landsteiner test was negative. Extensive virological studies were negative and no antinuclear activity or other autoantibody was detected. The final diagnosis was mixed warm and cold autoimmune hemolytic anemia without any underlying autoimmune disease. In view of the history, this may have been triggered by an unidentified infection. The child responded well to emergency transfusion, corticosteroids, and intravenous immunoglobulin with resolution of the hemolysis and disappearance of the erythrophagocytosis. Erythrophagocytosis by neutrophils is a characteristic feature of paroxysmal cold hemoglobinuria. Otherwise the observation of erythrophagocytosis, by monocytes or neutrophils, in immune hemolytic anemia is quite uncommon. It is likely that in this patient it reflected the severity of the rapid onset hemolytic process. The authors declare no conflict of interest with the content of this paper. Data sharing is not applicable to this article as no new data were created or analyzed in this study.
Development of New Tuberculosis Drugs: Translation to Regimen Composition for Drug-Sensitive and Multidrug-Resistant Tuberculosis
Authors: Jacqueline P. Ernest, Natasha Strydom, Qianwen Wang, Nan Zhang, Eric Nuermberger, Véronique Dartois, Rada M. Savic
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Tuberculosis (TB) kills more people than any other infectious disease. Challenges for developing better treatments include the complex pathology due to within-host immune dynamics, interpatient variability in disease severity and drug pharmacokinetics-pharmacodynamics (PK-PD), and the growing emergence of resistance. Model-informed drug development using quantitative and translational pharmacology has become increasingly recognized as a method capable of drug prioritization and regimen optimization to efficiently progress compounds through TB drug development phases. In this review, we examine translational models and tools, including plasma PK scaling, site-of-disease lesion PK, host-immune and bacteria interplay, combination PK-PD models of multidrug regimens, resistance formation, and integration of data across nonclinical and clinical phases.We propose a workflow that integrates these tools with computational platforms to identify drug combinations that have the potential to accelerate sterilization, reduce relapse rates, and limit the emergence of resistance.
Affinity maturation is required for pathogenic monovalent IgG4 autoantibody development in myasthenia gravis
Authors: Miriam L. Fichtner, Casey Vieni, Rachel L. Redler, Ljuvica Kolich, Ruoyi Jiang, Kazushiro Takata, Panos Stathopoulos, Pablo A. Suarez, Richard J. Nowak, Steven J. Burden, Damian C. Ekiert, Kevin C. O’Connor
Journal: The Journal of Experimental Medicine (2020)

Pathogenic muscle-specific tyrosine kinase (MuSK)-specific IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The development of these unique autoantibodies is not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCAs), and monovalent antigen-binding fragments (Fabs) to investigate how affinity maturation contributes to binding and immunopathology. Mature mAbs, UCA mAbs, and mature monovalent Fabs bound to MuSK and demonstrated pathogenic capacity. However, monovalent UCA Fabs bound to MuSK but did not have measurable pathogenic capacity. Affinity of the UCA Fabs for MuSK was 100-fold lower than the subnanomolar affinity of the mature Fabs. Crystal structures of two Fabs revealed how mutations acquired during affinity maturation may contribute to increased MuSK-binding affinity. These findings indicate that the autoantigen drives autoimmunity in MuSK MG through the accumulation of somatic mutations such that monovalent IgG4 Fab-arm-exchanged autoantibodies reach a high-affinity threshold required for pathogenic capacity.
Abstract 17776: Protection From Obesity and Systemic Insulin Resistance by Hepatocyte Growth Factor in Mice
Authors: Masaaki Iwabayashi, Yoshiaki Taniyama, Junya Azuma, Kazuma Iekushi, Fumihiro Sanada, Amarnath Chatterjee, Hiromi Rakugi, Ryuichi Mirishita
Journal: Circulation (2012)

Background: Obesity and related disorders constitute the greatest threat to global human health. Circulating hepatocyte growth factor (HGF) level is known to increase in a diverse variety of inflam...
Splanchnic Vein Thrombosis in Overt Myeloproliferative Neoplasms: The Mayo Clinic Experience with 107 Unselected Consecutive Cases
Authors: Sravanthi Lavu, Naseema Gangat, Animesh Pardanani, Curtis A. Hanson, Rhett P. Ketterling, Aneel A. Ashrani, Patrick S Kamath, Ayalew Tefferi
Journal: Blood (2017)
Chromosome 8 Abnormalities (8p Losses and 8q Gains) in Patients with Chronic Lymphocytic Leukemia (CLL) and Del(17p)
Authors: Gonzalo Blanco, Anna Puiggros, María Rodríguez-Rivera, Carme Melero, María Dolores García-Malo, Rosa Collado, Margarita Ortega, María José Calasanz, Elisa Luño, María Teresa Vargas, Javier Grau, Carolina Martínez-Laperche, Alberto Valiente, José Cervera, Ángeles Piñán, Jose María Hernández-Rivas, Ana Batlle, Marta Salido, Francisco Ortuño, MªTeresa Ardanaz, Ana Ferrer, David Ivars, Alicia Rodriguez, Pau Abrisqueta, Blanca Espinet
Journal: Blood (2014)
Gene Expression of the Erythroid Regulator Erythroferrone (ERFE) is Highly Deregulated in CD71+ Erythroprogenitor Cells of Patients with Myelodysplastic Syndromes and Demonstrates Prognostic Relevance
Authors: Maximilian Mossner, Alexandra Stöhr, Florian Nolte, Johann-Christoph Jann, Stephanie Fey, Verena Nowak, Julia Obländer, Jovita Pressler, Claudia D Baldus, Torsten J Schulze, Martin Neumann, Wolf-Karsten Hofmann, Daniel Nowak
Journal: Blood (2014)
Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome
Authors: Mikko Myllymäki, Robert Redd, Christopher R. Reilly, Wael Saber, Stephen R. Spellman, Christopher J. Gibson, Zhen-Huan Hu, Tao Wang, Esther H. Orr, Jaclyn G. Grenier, Maxine M. Chen, David P. Steensma, Corey Cutler, Immaculata De Vivo, Joseph H. Antin, Donna Neuberg, Suneet Agarwal, R. Coleman Lindsley
Journal: Blood (2020)
One-by-One Comparison of Lymph Nodes Between 18F-FDG Uptake and Pathological Diagnosis in Esophageal Cancer
Authors: Shuntaro Yoshimura, Miwako Takahashi, Susumu Aikou, Yasuhiro Okumura, Keiichi Jinbo, Haruna Onoyama, Masayuki Urabe, Koichiro Kawasaki, Koichi Yagi, Masato Nishida, Kazuhiko Mori, Hiroharu Yamashita, Sachiyo Nomura, Keitaro Koyama, Toshimitsu Momose, Hiroyuki Abe, Tetsuo Ushiku, Masashi Fukayama, Yasuyuki Seto
Journal: Clinical Nuclear Medicine (2020)

Purpose Esophagectomy with extended lymph node (LN) dissection is a standard treatment for resectable esophageal cancer to prevent recurrence, but severe, potentially life-threatening postoperative complications are still important issues. Accurate diagnosis of LN metastases would enable the decision to dissect or leave the LNs in regions with high risk of complications. Advancements in intraoperative gamma probe and radioactivity detectors have made intraoperative navigation surgery possible using a radiotracer as a marker. 18 F-FDG is one such candidate markers, and the diagnostic power of FDG through counting the radioactivity close to each LN should be elucidated. Materials and Methods In 20 patients, 1073 LNs including 38 metastatic LNs were prospectively investigated. Preoperative FDG PET was performed on the same day before esophagectomy and visually surveyed in each LN station to identify abnormal uptake. The FDG radioactivity of each individual dissected LN was measured by a well-type counter, and the pathological diagnosis was compared with LN radioactivity on a one-by-one basis and with the preoperative FDG PET findings for each LN station. Results Lymph node station-based analysis showed a sensitivity and specificity of 28.6% and 96.7%, respectively. One-by-one LN-based analysis using a cutoff value obtained from the receiver operating characteristic curve showed a sensitivity and specificity of 94.7% and 78.7%, respectively, demonstrating higher accuracy compared with the use of LN weight or the shortest diameter. Conclusions The FDG uptake by each LN is a potentially useful marker for navigation surgery in esophageal cancer and has higher accuracy than LN weight or diameter.
Inclusion of Older Adults in Randomized Clinical Trials for Systemic Medications for Atopic Dermatitis
Authors: Megan Lam, Jie Wei Zhu, Talha Maqbool, Gaelen Adam, Mina Tadrous, Paula Rochon, Aaron M. Drucker
Journal: JAMA Dermatology (2020)

Despite increasing evidence that atopic dermatitis is common in older adults, it is unclear whether the evidence base for treating atopic dermatitis with systemic therapy is generalizable to that population. Older adults are most at risk for adverse events from medications, given age-related alterations in drug metabolism, increased comorbidity, and polypharmacy. This systematic review examines the representation of older adults in randomized clinical trials (RCTs) of systemic immunomodulatory treatments for atopic dermatitis and whether safety and efficacy data are reported specifically for older individuals. The Cochrane Central Register of Controlled Trials, Embase, MEDLINE databases, and the ClinicalTrials.gov trial register were searched from inception (MEDLINE via Ovid, 1946; Embase via Ovid, 1974) to November 7, 2019. RCTs investigating systemic immunomodulatory treatments for adults with atopic dermatitis were included. Titles, abstracts, and full-text papers were screened, and data were extracted in duplicate. A total of 32 trials with 4547 participants were reviewed. The mean (SD) age of trial participants was 34.4 (5.4) years. The median number of participants per trial was 44 (range, 10-740). Eleven trials (34%) reported explicit upper age limits ranging from 42 to 70 years of age. Most of these trials (n = 9) examined safety and effectiveness of cyclosporine. Twenty-two trials (69%) had other exclusion criteria that might disproportionately exclude older adults. In total, 10 trials (31%) included adults aged 65 years or older. Within 7 trials that reported the proportion of participants aged 65 and older (all evaluating dupilumab), 112 of 2964 participants (4%) were 65 years or older. None of the included trials reported stratified safety or effectiveness data for older adults. Study results suggest that older adults are underrepresented in RCTs of systemic treatment for atopic dermatitis, resulting in a lack of evidence supporting safe clinical use for older adults. Clinicians and patients should be aware of this evidence gap when prescribing systemic therapy for atopic dermatitis. Randomized trials and observational studies that include older patients with atopic dermatitis are needed.