tbuckley/cabot-search huggingface dataset:
Obesity, tidal volume, and pulmonary deposition of fine particulate matter in children with asthma
Authors: Nima Afshar-Mohajer, Tianshi David Wu, Rebecca Shade, Emily Brigham, Han Woo, Megan Wood, Rachelle Koehl, Kirsten Koehler, Jason Kirkness, Nadia N. Hansel, Gurumurthy Ramchandran, Meredith C. McCormack
Journal: European Respiratory Journal (2021)

Background Obese children with asthma are more vulnerable to air pollution, especially fine particulate matter (PM 2.5 ), but reasons are poorly understood. We hypothesised that differences in breathing patterns (tidal volume, respiratory rate and minute ventilation) due to elevated body mass index (BMI) may contribute to this finding. Objective To investigate the association of BMI with breathing patterns and deposition of inhaled PM 2.5 . Methods Baseline data from a prospective study of children with asthma were analysed (n=174). Tidal breathing was measured by a pitot-tube flowmeter, from which tidal volume, respiratory rate and minute ventilation were obtained. The association of BMI z-score with breathing patterns was estimated in a multivariable model adjusted for age, height, race, sex and asthma severity. A particle dosimetry model simulated PM 2.5 lung deposition based on BMI-associated changes in breathing patterns. Results Higher BMI was associated with higher tidal volume (adjusted mean difference (aMD) between obese and normal-range BMI of 25 mL, 95% CI 5–45 mL) and minute ventilation (aMD 453 mL·min −1 , 95% CI 123–784 mL·min −1 ). Higher tidal volumes caused higher fractional deposition of PM 2.5 in the lung, driven by greater alveolar deposition. This translated into obese participants having greater per-breath retention of inhaled PM 2.5 (aMD in alveolar deposition fraction of 3.4%, 95% CI 1.3–5.5%), leading to worse PM 2.5 deposition rates. Conclusions Obese children with asthma breathe at higher tidal volumes that may increase the efficiency of PM 2.5 deposition in the lung. This finding may partially explain why obese children with asthma exhibit greater sensitivity to air pollution.
Indeterminate and oncogenic potential: CHIP vs CHOP mutations in AML with NPM1 alteration
Authors: Luca Vincenzo Cappelli, Manja Meggendorfer, Constance Baer, Niroshan Nadarajah, Stephan Hutter, Sabine Jeromin, Frank Dicker, Wolfgang Kern, Torsten Haferlach, Claudia Haferlach, Alexander Höllein
Journal: Leukemia (2021)

Abstract In AML patients, recurrent mutations were shown to persist in remission, however, only some have a prognostic value and persistent mutations might therefore reflect a re-established premalignant state or truly active disease causing relapse. We aimed to dissect the nature of co-mutations in NPM1 mutated AML where the detection of NPM1 transcripts allows highly specific and sensitive detection of complete molecular remission (CMR). We analysed 150 consecutive patients who achieved CMR following intensive treatment by next generation sequencing on paired samples at diagnosis, CMR and relapse (38/150 patients). Patients with persistence or the acquisition of non-DTA ( DNMT3A , TET2 , ASXL1 ) mutations at CMR (23/150 patients, 15%) have a significantly worse prognosis (EFS HR = 2.7, p = 0.003; OS HR = 3.6, p = 0.012). Based on clonal evolution analysis of diagnostic, CMR and relapse samples, we redefine pre-malignant mutations and include IDH1 , IDH2 and SRSF2 with the DTA genes in this newly defined group. Only the persistence or acquisition of CHOP-like (clonal hematopoiesis of oncogenic potential) mutations was significantly associated with an inferior outcome (EFS HR = 4.5, p = 0.0002; OS HR = 5.5, p = 0.002). Moreover, the detection of CHOP-like mutations at relapse was detrimental (HR = 4.5, p = 0.01). We confirmed these findings in a second independent whole genome sequencing cohort.
Protein Kinase C-Dependent Von Willebrand Factor Secretion Is a Dual-Phased Process That Originates from 2 Distinct Intracellular Compartments
Authors: Laura Knipe, Nicola Hellen, Ianina Conte, Marjon Mourik, Aina Masgrau-Fortuny, Bijal Patel, Sayibrinthan Vickneswaran, Matthew Hannah, Tom Carter, Ruben Bierings
Journal: Blood (2017)
Clonally expanded, GPR15-expressing pathogenic effector T <sub>H</sub> 2 cells are associated with eosinophilic esophagitis
Authors: Duncan M. Morgan, Bert Ruiter, Neal P. Smith, Ang A. Tu, Brinda Monian, Brandon E. Stone, Navneet Virk-Hundal, Qian Yuan, Wayne G. Shreffler, J. Christopher Love
Journal: Science Immunology (2021)

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the recruitment of eosinophils to the esophagus, resulting in chronic inflammation. We sought to understand the cellular populations present in tissue biopsies of patients with EoE and to determine how these populations are altered between active disease and remission. To this end, we analyzed cells obtained from esophageal biopsies, duodenal biopsies, and peripheral blood of patients with EoE diagnosed with active disease or remission with single-cell RNA and T cell receptor (TCR) sequencing. Pathogenic effector TH2 (peTH2) cells present in the esophageal biopsies of patients with active disease expressed distinct gene signatures associated with the synthesis of eicosanoids. The esophageal tissue-resident peTH2 population also exhibited clonal expansion, suggesting antigen-specific activation. Peripheral CRTH2+CD161- and CRTH2+CD161+ memory CD4+ T cells were enriched for either a conventional TH2 phenotype or a peTH2 phenotype, respectively. These cells also exhibited substantial clonal expansion and convergence of TCR sequences, suggesting that they are expanded in response to a defined set of antigens. The esophagus-homing receptor GPR15 was up-regulated by peripheral peTH2 clonotypes that were also detected in the esophagus. Finally, GPR15+ peTH2 cells were enriched among milk-reactive CD4+ T cells in patients with milk-triggered disease, suggesting that these cells are an expanded, food antigen-specific population with enhanced esophagus homing potential.
Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study
Authors: Milind Javle, Sameek Roychowdhury, Robin Kate Kelley, Saeed Sadeghi, Teresa Macarulla, Karl Heinz Weiss, Dirk-Thomas Waldschmidt, Lipika Goyal, Ivan Borbath, Anthony El-Khoueiry, Mitesh J Borad, Wei Peng Yong, Philip A Philip, Michael Bitzer, Surbpong Tanasanvimon, Ai Li, Amit Pande, Harris S Soifer, Stacie Peacock Shepherd, Susan Moran, Andrew X Zhu, Tanios S Bekaii-Saab, Ghassan K Abou-Alfa
Journal: The Lancet. Gastroenterology & hepatology (2021)
Development and validation of a patient-reported outcome in systemic sclerosis: the Hand scleroDerma lived Experience (HAnDE) scale
Authors: J. Sibeoni, B. Dunogué, A. Dupont, D. Haiddar, N. Benmostefa, B. Falissard, L. Mouthon, A. Révah-Levy, L. Verneuil
Journal: British Journal of Dermatology (2021)

Hand involvement in systemic sclerosis (SSc) is at the core of the disease, with a substantial impact on both functional aspects and quality of life. There is no patient-reported outcome (PRO) scale globally assessing hand involvement in SSc. To develop and validate a PRO scale, the Hand scleroDerma lived Experience (HAnDE) scale, to assess the lived experience of hand involvement in patients with SSc. This was an exploratory sequential mixed-methods study with two phases: (i) PRO development through an inductive process to analyse the structure of lived experience, involving 21 patients with SSc; and (ii) PRO validation by assessing the psychometric properties of the scale among 105 patients with SSc. Phase 1 enabled us to generate the 18-item provisional scale. From Phase 2, the mean (SD) total score of the scale was 29·16 (16·15). The item reduction process retained 16 items with five levels of answers (range 0-64). Internal consistency of the 16-item version was excellent (Cronbach's alpha = 0·946). Construct validity was very good, principal component analysis pointing towards a unidimensional instrument, with one factor explaining 56% of the variance, and concurrent validity being confirmed: Cochin Hand Function Scale r = 0·66; Health Assessment Questionnaire - Disability index r = 0·58; Hospital Anxiety and Depression Scale, anxiety r = 0·51, depression r = 0·4; Mouth Handicap in Systemic Sclerosis scale r = 0·61; 36-Item Short Form Health Survey, physical component r = -0·48, mental component r = -0·46; and Kapandji score r = -0·46. The correlations were statistically significant (P < 0·05). We propose, for future trials and clinical practice in SSc, a new PRO, the HAnDE scale, that assesses all the dimensions - functional, aesthetic, relational, existential and emotional - of the lived experience of hand involvement in SSc.
Glucocorticoids promote CCL20 expression in keratinocytes
Authors: L. Wang, M. Yang, X. Wang, B. Cheng, Q. Ju, D.Z. Eichenfield, B.K. Sun
Journal: British Journal of Dermatology (2021)

Glucocorticoids (GCs) are generally envisioned as immunosuppressive, but in conditions such as rosacea and perioral dermatitis they can lead to increased skin inflammation. In lung epithelia, GCs promote expression of the proinflammatory cytokine CCL20, which contributes to steroid-resistant asthma. In the skin, CCL20 stimulates inflammation by recruiting T helper 17 T lymphocytes and dendritic cells, and is elevated in papulopustular rosacea.To understand if, and how, GCs affect CCL20 expression in human keratinocytes. CCL20 expression was assessed by quantitative reverse transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay.Selective inhibition of candidate genes and signalling pathways was performed using RNA interference and chemical inhibitors. The binding of activated GC receptor to genomic DNA was determined by chromatin immunoprecipitation, and enhancer activity of genomic sequences was measured with a reporter assay.We found that GC treatment increased CCL20 expression in human keratinocytes and murine skin, both in the undisturbed state and with tumour necrosis factor-α stimulation. GC repressed proinflammatory signalling pathways, including nuclear factor kappa B and p38/mitogen-activated protein kinase, but these inhibitory effects were opposed by the direct binding of activated GC receptor to the CCL20 enhancer, promoting CCL20 expression.Viewed together, these findings demonstrate a mechanism by which GCs induce expression of CCL20 in keratinocytes, which may contribute to the inflammation seen in steroid-exacerbated skin conditions.
Genetic landscape of melanoma in China reveals enrichment of fusions in driver-negative melanoma.
Authors: Xiaohua Lin, Fan Zhang, Jie Liu, Yanling Niu, Chunyang Wang, Wei Li, Tonghui Ma
Journal: Journal of Clinical Oncology (2021)

e21577 Background: Melanoma in China has unique characteristics, especially compared with those in euramerican white race. In european and american countries, nearly 90% of melanoma patients are cutaneous melanoma; while 60% of melanoma in China are acral melanoma, accompanied with a considerable proportion of mucosal melanoma. Mapping the mutation landscape of melanoma in China can provide an important basis for targeted therapy of melanoma patients. Methods: Tissue samples from 223 patients with melanoma were sequenced using multi-gene NGS panel Onco PanScan to detect somatic mutations in melanoma. Results: As a result, BRAF (24.2%) and NRAS (15.7%) were the top two most mutated driver genes. In BRAF, V600E was the most common mutation, which accounted for 80% of all BRAF mutations. And Q61R/K was the most common mutation in NRAS, which accounted for 68.6% of all NRAS mutations. As to CNVs, the most frequently amplified genes were CCND1 (23, 10.3%), CDK4 (18, 8.1%), MDM2 (17, 7.6%), FGF19 (16, 7.2%), FGF4 (13, 5.8%), FGF3 (12, 5.4%), KIT (12, 5.4%), RICTOR (12, 5.4%). At the same time, a small number of EGFR, HER2, MET, MYC amplifications were detected. Interestingly, a considerable proportion of CNVs were related with hyperprogressive disease, including amplification of MDM2, CCND1, FGF3, FGF4, FGF19. Except for SNVs and CNVs, 16 gene fusions were detected in 13 samples (5.8%), among which the frequency of fusions involving BRAF, ALK, RAF1 was 2.2% (5/223), 1.3% (3/223) and 1% (2/223) respectively. Among these 16 fusions, only 4 fusions (AGAP3-BRAF, GTF2I-BRAF, TPM3-ALK, DCTN1-ALK) were reported previously, leaving the remaining 12 fusions new detected. As was reported, AGAP3-BRAF fusion was the mechanism by which melanoma patients with BRAF V600E mutations developed resistance to vemurafenib; GTF2I-BRAF fusion mediated the activation of MAPK pathway in fibrous astrocytoma. At last, we also compared the frequency of fusion detected in driver-positive and driver-negative melanoma (no somatic mutations detected in BRAF, HRAS, KRAS, NRAS, NF1, KIT, GNAQ, GNA11), and the result showed the frequency of fusion detected in driver-negative melanoma was significantly higher (9/78, 11.5% vs. 4/145, 2.8%). Conclusions: Through DNA-based NGS, the mutation landscape of Chinese melanoma patients was depicted. BRAF was the most frequently mutated driver gene with the main mutation type of V600E (19.7%) which was significantly lower than that of white race in TCGA-SKCM database (44.2%). On the other hand, DNA-based NGS can detect potentially druggable fusions, and compared with driver positive melanoma patients, fusions were enriched in patients with no driver mutations detected. Perhaps for driver negative melanoma patients, RNA-based NGS should be used to detect more potential druggable fusions which would bring clinical benefit.
駆出率低下を伴う心不全に対する医療療法の滴定【JST・京大機械翻訳】
Authors: J Greene Stephen, C Fonarow Gregg, D DeVore Adam, P Sharma Puza, Vaduganathan Muthiah, M Albert Nancy, I Duffy Carol, Hill C. Larry, McCague Kevin, Patterson J. Herbert, A Spertus John, Thomas Laine, B Williams Fredonia, F Hernandez Adrian, Butler Javed
Journal: Journal of the American College of Cardiology (2019)
Quantification of Specific Antibodies Against SARS-CoV-2 in Breast Milk of Lactating Women Vaccinated With an mRNA Vaccine
Authors: Erika Esteve-Palau, Araceli Gonzalez-Cuevas, M. Eugenia Guerrero, Clara Garcia-Terol, M. Carmen Alvarez, David Casadevall, Vicens Diaz-Brito
Journal: JAMA Network Open (2021)

The COVID-19 pandemic has raised questions among individuals who are breastfeeding, both because of the possibility of viral transmission to infants during breastfeeding and, more recently, of the potential risks and benefits of vaccination in this specific population. Previous studies have reported the presence of anti–SARS-CoV-2 antibodies in breast milk of COVID-19–infected lactating women,1 and recently several studies have demonstrated the passage of postvaccine antibodies through breast milk in women vaccinated with novel mRNA-based vaccines.1,2 In the present study, conducted between February and March 2021 at Parc Sanitari Sant Joan de Deu, an urban hospital in Spain, we sought to characterize the levels of specific SARS-CoV-2 antibodies in the breast milk of mRNA-vaccinated women across time, as well as their correlation with serum antibody levels.
Effectiveness of COVID-19 Vaccines in Preventing Hospitalization Among Adults Aged ≥65 Years — COVID-NET, 13 States, February–April 2021
Authors: Heidi L. Moline, Michael Whitaker, Li Deng, Julia C. Rhodes, Jennifer Milucky, Huong Pham, Kadam Patel, Onika Anglin, Arthur Reingold, Shua J. Chai, Nisha B. Alden, Breanna Kawasaki, James Meek, Kimberly Yousey-Hindes, Evan J. Anderson, Monica M. Farley, Patricia A. Ryan, Sue Kim, Val Tellez Nunez, Kathryn Como-Sabetti, Ruth Lynfield, Daniel M. Sosin, Chelsea McMullen, Alison Muse, Grant Barney, Nancy M. Bennett, Sophrena Bushey, Jessica Shiltz, Melissa Sutton, Nasreen Abdullah, H. Keipp Talbot, William Schaffner, Ryan Chatelain, Jake Ortega, Bhavini Patel Murthy, Elizabeth Zell, Stephanie J. Schrag, Christopher Taylor, Nong Shang, Jennifer R. Verani, Fiona P. Havers
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Clinical trials of COVID-19 vaccines currently authorized for emergency use in the United States (Pfizer-BioNTech, Moderna, and Janssen [Johnson & Johnson]) indicate that these vaccines have high efficacy against symptomatic disease, including moderate to severe illness (1-3). In addition to clinical trials, real-world assessments of COVID-19 vaccine effectiveness are critical in guiding vaccine policy and building vaccine confidence, particularly among populations at higher risk for more severe illness from COVID-19, including older adults. To determine the real-world effectiveness of the three currently authorized COVID-19 vaccines among persons aged ≥65 years during February 1-April 30, 2021, data on 7,280 patients from the COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) were analyzed with vaccination coverage data from state immunization information systems (IISs) for the COVID-NET catchment area (approximately 4.8 million persons). Among adults aged 65-74 years, effectiveness of full vaccination in preventing COVID-19-associated hospitalization was 96% (95% confidence interval [CI] = 94%-98%) for Pfizer-BioNTech, 96% (95% CI = 95%-98%) for Moderna, and 84% (95% CI = 64%-93%) for Janssen vaccine products. Effectiveness of full vaccination in preventing COVID-19-associated hospitalization among adults aged ≥75 years was 91% (95% CI = 87%-94%) for Pfizer-BioNTech, 96% (95% CI = 93%-98%) for Moderna, and 85% (95% CI = 72%-92%) for Janssen vaccine products. COVID-19 vaccines currently authorized in the United States are highly effective in preventing COVID-19-associated hospitalizations in older adults. In light of real-world data demonstrating high effectiveness of COVID-19 vaccines among older adults, efforts to increase vaccination coverage in this age group are critical to reducing the risk for COVID-19-related hospitalization.
World Health Organization Cardiovascular Disease Risk Charts: Revised Models to Estimate Risk in 21 Global Regions
Authors: Stephen Kaptoge, Lisa Pennells, Dirk De Bacquer, Marie Therese Cooney, Maryam Kavousi, Gretchen Stevens, Leanne Margaret Riley, Stefan Savin, Taskeen Khan, Servet Altay, Carlos J. Crespo
Journal: The Lancet (2019)
Selective transferrin coating as a facile strategy to fabricate BBB-permeable and targeted vesicles for potent RNAi therapy of brain metastatic breast cancer in vivo
Authors: Yaohua Wei, Yinping Sun, Jingjing Wei, Xinyun Qiu, Fenghua Meng, Gert Storm, Zhiyuan Zhong
Journal: Journal of Controlled Release (2021)
Optimized EBMT Transplant-Specific Risk Score of Patients with Myelodysplastic Syndromes Following Allogeneic Stem Cell Transplantation
Authors: Nico Gagelmann, Matthias Stelljes, Dietrich W Beelen, Dirk-Jan Eikema, Nina Simone Knelange, Ghulam Mufti, Dietger Niederwieser, Henrik Sengeloev, Gerhard Ehninger, Arnon Nagler, Ibrahim Yakoub-Agha, Ellen Meijer, Per Ljungman, Johan Maertens, Lothar Kanz, Lucia Lopez Corral, Arne Brecht, Charles Craddock, Jürgen Finke, Jan J Cornelissen, Paolo Bernasconi, Patrice Chevallier, Jorge Sierra, Marie Robin, Nicolaus Kroeger
Journal: Blood (2017)
Immunogenicity of SARS-CoV-2 Vaccine in Dialysis
Authors: Eduardo Lacson, Christos P. Argyropoulos, Harold J. Manley, Gideon Aweh, Andrew I. Chin, Loay H. Salman, Caroline M. Hsu, Doug S. Johnson, Daniel E. Weiner
Journal: Journal of the American Society of Nephrology (2021)

Patients receiving maintenance dialysis represent a high-risk, immune-compromised population with 15%-25% COVID-19 mortality rate who were unrepresented in clinical trials of mRNA vaccines.
Drugs without benefits? Confronting the challenges of drug-induced interstitial lung disease
Authors: Emma K Denneny, Joanna C Porter
Journal: Thorax (2021)

Drug-induced interstitial lung disease (DILD) with an estimated incidence of approximately 4.1–12.4 cases/million/year is implicated in ~5% of ILD cases.1 Data vary by country, with DILD more commonly diagnosed in Japan, perhaps due to higher reporting.2 The Common Terminology Criteria for Adverse Events (CTCAE) scale3 (table 1) helps quantify severity and treatment includes cessation of the drug and, in more severe cases, corticosteroid use. At least 350 drugs have been implicated in causing lung toxicity, or pneumonitis, across a spectrum from mild radiological infiltrates to life-threatening respiratory failure.4 This heterogeneity of presentation and lack of diagnostic standards, with rechallenge to confirm toxicity rarely justified, makes DILD difficult to identify, even at individual patient level.4 The result is a heavy reliance on databases such as pneumotox5 that collate evidence from the literature, often case reports or small series, but with no large-scale assessment.

View this table:

Table 1 
Common Terminology Criteria for Adverse Events (CTCAE), V.5.0



Jo et al 6 take a different approach using a large, nationally representative dataset of hospitalised patients in Japan to retrospectively identify patients that had developed DILD, severe enough to warrant corticosteroid therapy, after receiving a ‘risk drug’ from one of 42 categories associated with lung toxicity.

We applaud the methodology used in this study which identified 2342 cases of DILD out of ~42 million hospital admissions (0.0056%). For each case the authors selected four controls matched for known DILD risk factors (primary diagnosis, …