tbuckley/cabot-search huggingface dataset:
Beta thalassemia major and Noonan syndrome — Two genetic disorders manifest in the blood film
Authors: Bing Tseu, Wenchee Siow, Beena Pushkaran, Beth Cheesebrough, Barbara J. Bain
Journal: American Journal of Hematology (2020)

The patient, now a 7-year-old boy, was born by uncomplicated delivery at term with dysmorphic features: a large forehead, a triangular face and a simian crease. He was subsequently found to have pulmonary stenosis and underwent genetic testing for Noonan syndrome; he was found to be heterozygous for a de novo 182A > G mutation in PTPN11 (amino acid substitution Asp61Gly). His hemoglobin concentration (Hb) was normal at birth but in the first week of life he was noted to have monocytosis with a monocyte count of 3-5 × 109/L. By 3 months of age, he had developed hepatosplenomegaly in association with a leukocytosis (white cell count [WBC] 26 × 109/L) with neutrophilia (12.6 × 109/L) and monocytosis (6.4 × 109/L). In addition, there was a microcytic anemia (Hb 91 g/L and mean cell volume 64.3 fL). There was a family history of β thalassemia major and high performance liquid chromatography showed hemoglobins F and A2 only. Thalassemia major was confirmed by genetic testing. Since diagnosis, the patient has been maintained on regular transfusion. By the age of a year he had developed massive splenomegaly and required splenectomy. The leukocyte abnormalities have persisted throughout but without progression. Currently he has a WBC of 48.8 × 109/L, neutrophils 31.2 × 109/L, monocytes 7.2 × 109/L, eosinophils 1.6 × 109/L, and basophils 0.1 × 109/L. He has post-splenectomy thrombocytosis with a platelet count of 497 × 109/L. His blood film (pretransfusion) shows evidence of β thalassemia major and asplenia with hypochromic microcytes, nucleated red cells (top left), α chain inclusions (top left and top right) and Howell-Jolly bodies (top right). In addition, there is evidence of continuing myeloproliferation with neutrophilia, monocytosis and circulating granulocyte precursors (bottom left and bottom right). Transient abnormal myelopoiesis is well recognized in neonates with Noonan syndrome.1, 2 Resolution usually occurs over months or years2 but sometimes there is an aggressive clinical course or development of juvenile myelomonocytic leukemia (JMML). A neoplastic clone may emerge, for example with acquisition of an NRAS or KRAS mutation or monosomy 7, but this is not necessarily associated with aggressive disease.3 Interestingly, myeloproliferation has been strongly associated with sporadic rather than inherited Noonan syndrome, with the spectrum of mutations differing somewhat between cases of Noonan syndrome with and without myeloproliferation, and also differing from the spectrum seen in de novo JMML.1, 4 Our patient is unusual in that myeloproliferation has persisted so far for 7 years but without disease progression or evolution. The authors declare no potential conflict of interest.
Hematopoetic expression of Chi3l1 (BRP-39) is required for helminth immunity
Authors: Miranda Curtiss, Natalia Ballesteros Benavides, Betty Mousseau, Beatriz Leon-Ruiz, Andre Ballesteros-Tato, Chad Steele, Alison Humbles, Troy Randall, Frances Lund
Journal: Journal of Allergy and Clinical Immunology (2020)
Rare genetic variants in interleukin-37 link this anti-inflammatory cytokine to the pathogenesis and treatment of gout
Authors: Viola Klück, Rosanne C van Deuren, Giulio Cavalli, Amara Shaukat, Peer Arts, Maartje C Cleophas, Tania O Crișan, Anne-Kathrin Tausche, Philip Riches, Nicola Dalbeth, Lisa K Stamp, Jennie Harré Hindmarsh, Tim L Th A Jansen, Matthijs Janssen, Marloes Steehouwer, Stefan Lelieveld, Maartje van de Vorst, Christian Gilissen, Lorenzo Dagna, Frank L Van de Veerdonk, Elan Z Eisenmesser, SooHyun Kim, Tony R Merriman, Alexander Hoischen, Mihai G Netea, Charles A Dinarello, Leo AB Joosten
Journal: Annals of the Rheumatic Diseases (2020)

Gout is characterised by severe interleukin (IL)-1-mediated joint inflammation induced by monosodium urate crystals. Since IL-37 is a pivotal anti-inflammatory cytokine suppressing the activity of IL-1, we conducted genetic and functional studies aimed at elucidating the role of IL-37 in the pathogenesis and treatment of gout.Variant identification was performed by DNA sequencing of all coding bases of IL37 using molecular inversion probe-based resequencing (discovery cohort: gout n=675, controls n=520) and TaqMan genotyping (validation cohort: gout n=2202, controls n=2295). Predictive modelling of the effects of rare variants on protein structure was followed by in vitro experiments evaluating the impact on protein function. Treatment with recombinant IL-37 was evaluated in vitro and in vivo in a mouse model of gout.We identified four rare variants in IL37 in six of the discovery gout patients; p.(A144P), p.(G174Dfs*16), p.(C181*) and p.(N182S), whereas none emerged in healthy controls (Fisher's exact p-value=0.043). All variants clustered in the functional domain of IL-37 in exon 5 (p-value=5.71×10-5). Predictive modelling and functional studies confirmed loss of anti-inflammatory functions and we substantiated the therapeutic potential of recombinant IL-37 in the treatment of gouty inflammation. Furthermore, the carrier status of p.(N182S)(rs752113534) was associated with increased risk (OR=1.81, p-value=0.031) of developing gout in hyperuricaemic individuals of Polynesian ancestry.Here, we provide genetic as well as mechanistic evidence for the role of IL-37 in the pathogenesis of gout, and highlight the therapeutic potential of recombinant IL-37 for the treatment of gouty arthritis.
Efficacy of Baricitinib in Patients with Atopic Dermatitis and Atopic Comorbidities: Results of Pooled Data from 2 Phase 3 Monotherapy Randomized, Double-Blind, Placebo-Controlled 16-week Trials (BREEZE-AD1 and BREEZE-AD2)
Authors: Andreas Wollenberg, Mark Boguniewicz, Jeffrey Travers, Jacob Thyssen, Orin Goldblum, Susan Ball, Luna Sun, Sherry Chen, Jonathan Silverberg
Journal: Journal of Allergy and Clinical Immunology (2020)
Diet and Food-Purchasing Habits among Black and White Children with Food Allergy
Authors: Amaziah Coleman, Adam Robinson, Iman Abdikarim, Hemant Sharma, Annika Chura, Amal Assa'ad, Aame Andy-Nweye, Susan Fox, Mahboobeh Mahdavinia, Mary Tobin, Jamie Fierstein, Jialing Jiang, Pamela Newmark, Lucy Bilaver, Alexandria Bozen, Olivia Negris, Christopher Warren, Jacqueline Pongracic, Audrey Brewer, Ruchi Gupta
Journal: Journal of Allergy and Clinical Immunology (2020)
Predictive capacity of miRNA-375 in identifying teratoma in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND).
Authors: Alexander P. Kenigsberg, John T. Lafin, Xiaosong Meng, Dreaux Abe, Anna Savalyeva, Nirmish Singla, Solomon L. Woldu, Yair Lotan, Payal Kapur, Vitaly Margulis, James F. Amatruda, Aditya Bagrodia
Journal: Journal of Clinical Oncology (2020)

416 Background: Traditional tumor markers for testicular germ cell tumor (TGCT), lactate dehydrogenase (LDH), beta-human chorionic gonadotropin (hCG), and alpha-fetoprotein (AFP), have limited sensitivity in detecting residual tumor on PC-RPLND. Micro-RNAs (miRNA) have emerged as a promising serum markers to predict residual TGCT on RPLND. Previous reports have suggested high levels of miRNA-375 in teratoma. The purpose of this study was to evaluate serum miRNA-375 as a tumor marker for PC-RPLND teratoma. Methods: We prospectively collected pre-surgical serum samples from consecutive GCT patients undergoing PC-RPLND. Serum miRNA-375-3p and -5p expression was validated and quantified by qPCR. Receiver operating characteristic (ROC) analysis and logistic regression were utilized to evaluate test characteristics and predictors of teratoma. Results: 40 patients underwent PC-RPLND. 18 had benign pathology, 2 viable TGCT, 19 teratoma, and 1 embryonal rhabdomyosarcoma. 3 miRNA specimens were excluded as outliers. miRNA-375-5p was undetectable in all samples examined. ROC analysis of miRNA-375-3p revealed an area under the curve of 0.503. Of 19 patients with teratoma, 16 had elevated miRNA-375-3p (84.2% sensitivity). 6/17 with benign pathology had normal mi-RNA-375-3p (35.3% specificity). 16/27 with positive tests harbored teratoma (59.3% positive predictive value). 6/9 with negative miRNA-375-3p had benign disease (66.7% negative predictive value). Univariate analysis demonstrated that clinical stage, pre-RPLND LDH, AFP, hCG, N/L ratio, and miRNA-375-3p were not significant predictors of teratoma. Conclusions: miRNA-375 does not predict teratoma on PC-RPLND. Tissue expression of miRNA-375 did not translate to serum expression in our study. Reliable predictors of teratoma on PC-RPLND remain elusive.
Five-year results from a phase I/II study of moderately hypofractionated intensity-modulated radiation therapy (IMRT) for localized prostate cancer including simultaneously integrated boost and pelvic lymph node (LN) coverage.
Authors: Anthony Ricco, Nitai Mukhopadhyay, Diane Holdford, Vicki Skinner, Siddharth Saraiya, Drew Moghanaki, Mitchell Steven Anscher, Michael G. Chang, Xiaoyan Deng
Journal: Journal of Clinical Oncology (2020)

299 Background: This study reports the 5 year toxicity and efficacy data of a phase I/II trial of moderately hypofractionated intensity modulated radiation therapy (IMRT) for localized prostate cancer utilizing a simultaneous integrated boost and pelvic lymph node (LN) coverage. Methods: Men with localized prostate cancer were prospectively enrolled and received IMRT to the prostate +/- seminal vesicles (SVs) +/- LNs based on National Comprehensive Cancer Network (NCCN) guidelines. Low-risk (LR) patients received 69.6 Gy in 29 fractions to the prostate alone; intermediate-risk (IR) and high-risk (HR) patients received 72Gy to the prostate, 54Gy to the SVs, and 50.4Gy to LNs (if risk of LN involvement &gt; 15% by the Roach formula) all in 30 fractions. IR and HR patients received androgen deprivation therapy. Results: Fifty-five patients were enrolled and 49 patients evaluable with a median follow up of 60 months. There were 11 (20%) LR, 23 (41.8%) IR, and 21 (38.2%) HR patients. Twenty-five patients (51%) received prostate and LN treatment. At 5 years, the cumulative incidence of late grade 2+ gastrointestinal (GI) and genitourinary (GU) toxicity was 22.6% and 38.2% respectively. Prevalence rates of late grade 2 GI toxicity at 1, 3, and 5 years was 5.8%, 3.9%, and 5.8% respectively. Late grade 2+ GI toxicities that did not resolve by 60 months included 3 out of 52 patients (5.8%). Prevalence rates of late grade 2 GU toxicity at 1, 3, and 5 years rates were 15.4%, 7.7%, and 13.5% respectively. There were 3 patients (5.8%) who experienced grade 3 GU toxicity and no grade 3 GI toxicities. The biochemical relapse free survival at 5 years for the cohort was 88.3%. There were no local, regional, or distant failures, with all patients still alive at last follow up. Conclusions: Moderate hypofractionation of localized prostate cancer utilizing a simultaneous integrated boost and LN coverage produces excellent biochemical control and acceptable acute/late toxicity. This phase I/II trial adds to maturing data with 5 year outcomes which justify its use for cost and patient convenience factors. Clinical trial information: NCT01117935.
Aptamer-guided extracellular vesicle theranostics in oncology
Authors: Phuong H-L Tran, Dongxi Xiang, Tuong N-G Nguyen, Thao T-D Tran, Qian Chen, Wang Yin, Yumei Zhang, Lingxue Kong, Andrew Duan, Kuisheng Chen, Miomio Sun, Yong Li, Yingchun Hou, Yimin Zhu, Yongchao Ma, Guoqin Jiang, Wei Duan
Journal: Theranostics (2020)

In the past decade, the study of exosomes, nanosized vesicles (50-150 nm) released into the extracellular space via the fusion of multivesicular bodies with the plasma membrane, has burgeoned with impressive achievements in theranostics applications. These nanosized vesicles have emerged as key players in homeostasis and in the pathogenesis of diseases owing to the variety of the cargos they can carry, the nature of the molecules packaged inside the vesicles, and the robust interactions between exosomes and target cells or tissues. Accordingly, the development of exosome-based liquid biopsy techniques for early disease detection and for monitoring disease progression marks a new era of precision medicine in the 21st century. Moreover, exosomes possess intrinsic properties - a nanosized structure and unique "homing effects" - that make them outstanding drug delivery vehicles. In addition, targeted exosome-based drug delivery systems can be further optimized using active targeting ligands such as nucleic acid aptamers. Indeed, the aptamers themselves can function as therapeutic and/or diagnostic tools based on their attributes of unique target-binding and non-immunogenicity. This review aims to provide readers with a current picture of the research on exosomes and aptamers and their applications in cancer theranostics, highlighting recent advances in their transition from the bench to the clinic.
Translating Across Circuits and Genetics Toward Progress in Fear- and Anxiety-Related Disorders
Authors: Kerry J. Ressler
Journal: American Journal of Psychiatry (2020)

Anxiety and fear-related disorders are common and disabling, and they significantly increase risk for suicide and other causes of morbidity and mortality. However, there is tremendous potential for translational neuroscience to advance our understanding of these disorders, leading to novel and powerful interventions and even to preventing their initial development. This overview examines the general circuits and processes thought to underlie fear and anxiety, along with the promise of translational research. It then examines some of the data-driven "next-generation" approaches that are needed for discovery and understanding but that do not always fit neatly into established models. From one perspective, these disorders offer among the most tractable problems in psychiatry, with a great deal of accumulated understanding, across species, of neurocircuit, behavioral, and, increasingly, genetic mechanisms, of how dysregulation of fear and threat processes contributes to anxiety-related disorders. One example is the progressively sophisticated understanding of how extinction underlies the exposure therapy component of cognitive-behavioral therapy approaches, which are ubiquitously used across anxiety and fear-related disorders. However, it is also critical to examine gaps in our understanding between reasonably well-replicated examples of successful translation, areas of significant deficits in knowledge, and the role of large-scale data-driven approaches in future progress and discovery. Although a tremendous amount of progress is still needed, translational approaches to understanding, treating, and even preventing anxiety and fear-related disorders offer great opportunities for successfully bridging neuroscience discovery to clinical practice.
Toward personalization of asthma treatment according to trigger factors
Authors: Katarzyna Niespodziana, Kristina Borochova, Petra Pazderova, Thomas Schlederer, Natalia Astafyeva, Tatiana Baranovskaya, Mohamed-Ridha Barbouche, Evgeny Beltyukov, Angelika Berger, Elena Borzova, Jean Bousquet, Roxana S. Bumbacea, Snezhana Bychkovskaya, Luis Caraballo, Kian Fan Chung, Adnan Custovic, Guillermo Docena, Thomas Eiwegger, Irina Evsegneeva, Alexander Emelyanov, Peter Errhalt, Rustem Fassakhov, Rezeda Fayzullina, Elena Fedenko, Daria Fomina, Zhongshan Gao, Pedro Giavina-Bianchi, Maia Gotua, Susanne Greber-Platzer, Gunilla Hedlin, Natalia Ilina, Zhanat Ispayeva, Marco Idzko, Sebastian L. Johnston, Ömer Kalayci, Alexander Karaulov, Antonina Karsonova, Musa Khaitov, Elena Kovzel, Marek L. Kowalski, Dmitry Kudlay, Michael Levin, Svetlana Makarova, Paolo Maria Matricardi, Kari C. Nadeau, Leyla Namazova-Baranova, Olga Naumova, Oleksandr Nazarenko, Paul M. O’Byrne, Faith Osier, Alexander N. Pampura, Carmen Panaitescu, Nikolaos G. Papadopoulos, Hae-Sim Park, Ruby Pawankar, Wolfgang Pohl, Harald Renz, Ksenja Riabova, Vanitha Sampath, Bülent E. Sekerel, Elopy Sibanda, Valérie Siroux, Ludmila P. Sizyakina, Jin-Lyu Sun, Zsolt Szepfalusi, Tetiana Umanets, Hugo P.S. Van Bever, Marianne van Hage, Margarita Vasileva, Erika von Mutius, Jiu-Yao Wang, Gary W.K. Wong, Sergii Zaikov, Mihaela Zidarn, Rudolf Valenta
Journal: Journal of Allergy and Clinical Immunology (2020)

Asthma is a severe and chronic disabling disease affecting more than 300 million people worldwide. Although in the past few drugs for the treatment of asthma were available, new treatment options are currently emerging, which appear to be highly effective in certain subgroups of patients. Accordingly, there is a need for biomarkers that allow selection of patients for refined and personalized treatment strategies. Recently, serological chip tests based on microarrayed allergen molecules and peptides derived from the most common rhinovirus strains have been developed, which may discriminate 2 of the most common forms of asthma, that is, allergen- and virus-triggered asthma. In this perspective, we argue that classification of patients with asthma according to these common trigger factors may open new possibilities for personalized management of asthma.
Characterization of the urinary microbiota in bladder cancer patients.
Authors: Bianca Oresta, Rodolfo Hurle, Massimo Lazzeri, Nicola Frego, Alberto Saita, Cristina Faccani, Vittorio Fasulo, Paolo Casale, Chiara Pozzi, Giorgio Ferruccio Guazzoni, Maria Rescigno
Journal: Journal of Clinical Oncology (2020)

535 Background: Mounting evidence indicates that the microbiota plays an important role in carcinogenesis and response to treatments. The dogma that urine is sterile has been overturned and dysbiosis of the urinary microbiota has been linked to urological disorders. We tested the hypothesis that alteration in urinary microbial community composition may be associated to bladder cancer development and progression. Therefore, we performed a study to characterize the urinary microbiota associated with non-muscle invasive and muscle invasive bladder cancer (NMIBC, MIBC). Methods: Urines were collected with a catheter from BC patients before transurethral resection or cystectomy, and age-matched non-neoplastic subjects. Subjects with prior history of sexually transmitted infection, chronic intestinal inflammation, urinary tract infection and recent usage of antibiotic or immunomodulatory agents were excluded. Bacterial DNA was extracted and amplified for 16S rDNA sequencing. Results: We isolated bacterial DNA from urine samples of 12 non-neoplastic control subjects and 27 BC patients. The most abundant phyla in both groups were Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria, with Bacteroidetes being slightly more abundant in bladder cancer at the expense of Proteobacteria. Interestingly, we found that NMIBC displayed a reduction in the abundance of Sphingobacteriaceae, Bifidobacteriaceae and Enterobacteriaceae. High grade NMIBC and MIBC showed decreased Bifidobacterium and Ruminococcus, which are known to protect from inflammation, and increased Corynebacterium, a potential opportunistic bacteria. No correlation with environmental risk factors (i.e. smoking) was investigated. Conclusions: The urinary microbiota of BC patients displayed a significantly different pattern relative to control group, suggesting that the tumor microenvironment can influence dysbiosis. In particular, we found specific bacteria to associate with aggressive tumors. A better understanding of the urinary microbiota could pave the way for exploring new therapeutic options based on the manipulation of the microbial community. Analysis of additional samples is ongoing.
Abstract 390: Automating a Cardiac Arrest Registry: Challenges and Opportunities
Authors: Ahamed H Idris, Pamela Owens, Samuel McDonald, Raymond Fowler, Heather Herren, Susanne May
Journal: Circulation (2019)

Introduction: A registry for out-of-hospital cardiac arrests facilitates cardiac arrest research, and emergency medical services (EMS) and community health quality improvement programs. Maintaining a cardiac arrest registry is labor intensive and costly, both of which could be reduced through automation. Objective: To determine the feasibility of automating data population of a cardiac arrest registry and to identify the components needed for and barriers to automation. Methods: This is a prospective feasibility study at the Dallas Fort-Worth (DFW) Center for Resuscitation Research. Our cardiac arrest registry was part of the multi-center Resuscitation Outcomes Consortium (ROC) Epistry from 2006 to 2016. Since 2016, we modified and maintained it separately from the ROC and over 20,000 cases have been enrolled. We identified the following critical elements necessary for automated data population of the registry: Create a registry dataset; create Business Associate Agreements with EMS agencies and hospitals; identify EMS and hospital electronic health record programs; develop a search strategy; search for appropriate cases in city servers where EMS patient care reports (PCRs) are stored and download data; move EMS data through our institutional firewall to a secure server; perform the same steps for hospital medical records; match EMS cases with hospital medical records, and automatically populate the registry with EMS and hospital data on a regular basis. Results: At the DFW site, EMS agencies use five different PCR programs and hospitals use two different electronic health record programs. A combination of 13 search terms captured 90% to 100% of appropriate cardiac arrest cases across six EMS agencies. Two different strategies can be used for streaming data across our firewall: A proprietary program entitled “Move-It” or a university generated file transfer protocol. We used a probabilistic logical approach for matching EMS cases with hospital cases. Conclusions: Automating a cardiac arrest registry is feasible. A cardiac arrest registry has many elements that must be considered to accomplish automation. The authors found that the most time consuming element is establishing Business Associate Agreements with all parties that provide data.