tbuckley/cabot-search huggingface dataset:
Native Aortic Valve Disease Progression and Bioprosthetic Valve Degeneration in Patients With Transcatheter Aortic Valve Implantation
Authors: Jacek Kwiecinski, Evangelos Tzolos, Timothy R.G. Cartlidge, Alexander Fletcher, Mhairi K. Doris, Rong Bing, Jason M. Tarkin, Michael A. Seidman, Gaurav S. Gulsin, Nicholas L. Cruden, Anna K. Barton, Neal G. Uren, Michelle C. Williams, Edwin J.R. van Beek, Jonathon Leipsic, Damini Dey, Raj R. Makkar, Piotr J. Slomka, James H.F. Rudd, David E. Newby, Stephanie L. Sellers, Daniel S. Berman, Marc R. Dweck
Journal: Circulation (2021)

Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR).In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol.In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P<0.001) and SAVR (r=0.7, P<0.001). On multivariable analysis, 18F-NaF uptake was the only predictor of peak velocity progression (P<0.001).In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.
Neutrophil-specific gain-of-function mutations in <i>Nlrp3</i> promote development of cryopyrin-associated periodic syndrome
Authors: Julien Stackowicz, Nicolas Gaudenzio, Nadine Serhan, Eva Conde, Ophélie Godon, Thomas Marichal, Philipp Starkl, Bianca Balbino, Axel Roers, Pierre Bruhns, Friederike Jönsson, Philippe Moguelet, Sophie Georgin-Lavialle, Lori Broderick, Hal M. Hoffman, Stephen J. Galli, Laurent L. Reber
Journal: The Journal of Experimental Medicine (2021)

Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
Anti-latent TGFβ binding protein 4 antibody improves muscle function and reduces muscle fibrosis in muscular dystrophy
Authors: Alexis R. Demonbreun, Katherine S. Fallon, Claire C. Oosterbaan, Lauren A. Vaught, Nina L. Reiser, Elena Bogdanovic, Matthew P. Velez, Isabella M. Salamone, Patrick G.T. Page, Michele Hadhazy, Mattia Quattrocelli, David Y. Barefield, Lauren D. Wood, J. Patrick Gonzalez, Carl Morris, Elizabeth M. McNally
Journal: Science Translational Medicine (2021)

A high-affinity antibody to LTBP4 stabilizes muscle and promotes improved muscle function in mouse models of muscular dystrophy.
Identification of Smyd4 by chromosome rearrangement as a potential tumor suppressor gene involved in breast cancer development
Authors: Liping Hu, Yiwei Zhu, Chao Qi, Yijun Zhu
Journal: Cancer Research (2008)

184  Aberrant gene function and altered patterns of gene expression are key features of cancer. The identification of genes involved in tumorigenesis is pivotal for the development of diagnostic and therapeutic strategies. To identify the potential tumor suppressor genes, we applied the retroviral Loxp-Cre system to a non-tumorigenic mouse mammary epithelial cell line NOG8 to create random chromosome deletion/translocation. The cells were injected into nude mice for tumor formation. By inverse -PCR and sequencing, we identified the disruption of Smyd4 gene in one tumor. Re-expression of Smyd4 resulted in the growth suppression of tumor cells and the inhibition of tumor formation in nude mice. Microarray studies revealed that Pdgfra expression (platelet derived growth factor receptor alpha polypeptide) was increased in cancer cells compared to the non-tumorigenic mammary epithelial cells. Re-expression of smyd4 reduced the expression of Pdgfra in cancer cells. In human cancers, RT-PCR results revealed that Smyd4 expressions were totally silenced in 1 of 10 breast cancers and 2 of 7 colon cancers. Reduced expression of smyd4 was also found in 7 of the 10 breast cancers cells. These results indicate that smyd4 plays a critical role in breast carcinogenesis at least partly through inhibiting the expression of Pdgfra, and could be a novel target for understanding the initiation, progression, as well as improving treatment of breast cancer.
Immune Thrombocytopenia Treatment
Authors: Paula H.B. Bolton-Maggs, James N. George
Journal: New England Journal of Medicine (2021)

Idiopathic thrombocytopenia (ITP) has a long history. In 1025, Avicenna described in the Canon of Medicine a patient with characteristics of ITP, which became known as "idiopathic thrombocytopenic purpura." Splenectomy was the first effective treatment, beginning in 1916, achieving a complete response without recurrence in most patients.1 Glucocorticoids were introduced as therapy for the disease in 1949, and the term "idiopathic" became obsolete in 1950 when William Harrington, then a hematology fellow at Washington University in St. Louis, transfused blood into himself from a woman with the disease whose platelet count had not increased after splenectomy. Within hours, Harrington's platelet . . .
Macrophage targeted theranostic strategy for accurate detection and rapid stabilization of the inflamed high-risk plaque
Authors: Joon Woo Song, Hyeong Soo Nam, Jae Won Ahn, Hyun-Sang Park, Dong Oh Kang, Hyun Jung Kim, Yeon Hoon Kim, Jeongmoo Han, Jah Yeon Choi, Seung-Yul Lee, Sunwon Kim, Wang-Yuhl Oh, Hongki Yoo, Kyeongsoon Park, Jin Won Kim
Journal: Theranostics (2021)

Inflammation plays a pivotal role in the pathogenesis of the acute coronary syndrome. Detecting plaques with high inflammatory activity and specifically treating those lesions can be crucial to prevent life-threatening cardiovascular events.
Probiotics for periodontal health—Current molecular findings
Authors: Trang Nguyen, Hanna Brody, Alan Radaic, Yvonne Kapila
Journal: Periodontology 2000 (2021)

Abstract Dysbiosis of the oral microbiome is associated with a variety of oral and systemic diseases, including periodontal disease. Oral dysbiosis in periodontal disease leads to an exacerbated host immune response that induces progressive periodontal tissue destruction and ultimately tooth loss. To counter the disease‐associated dysbiosis of the oral cavity, strategies have been proposed to reestablish a “healthy” microbiome via the use of probiotics. This study reviews the literature on the use of probiotics for modifying the oral microbial composition toward a beneficial state that might alleviate disease progression. Four in vitro and 10 preclinical studies were included in the analysis, and these studies explored the effects of probiotics on cultured biofilm growth and bacterial gene expressions, as well as modulation of the host response to inflammation. The current molecular findings on probiotics provide fundamental evidence for further clinical research for the use of probiotics in periodontal therapy. They also point out an important caveat: Changing the biofilm composition might alter the normal oral flora that is beneficial and/or critical for oral health.
Major adverse cardiovascular events in survivors of immune‐mediated thrombotic thrombocytopenic purpura
Authors: Max A. Brodsky, Senthil Sukumar, Sruthi Selvakumar, Lisa Yanek, Sarah Hussain, Marshall A. Mazepa, Evan M. Braunstein, Alison R. Moliterno, Thomas S. Kickler, Robert A. Brodsky, Spero R. Cataland, Shruti Chaturvedi
Journal: American Journal of Hematology (2021)

Cardiovascular disease is a leading cause of death in survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP), but the epidemiology of major adverse cardiovascular events (MACE) in iTTP survivors is unknown. We evaluated the prevalence and risk factors for MACE, defined as the composite of non-fatal or fatal myocardial infarction (MI), stroke, and cardiac revascularization, during clinical remission in two large iTTP cohorts (Johns Hopkins University and Ohio State University). Of 181 patients followed for ≥ 3 months after recovery from acute iTTP, 28.6% had a MACE event over a median follow up of 7.6 years. Stroke was the most common type of MACE (18.2%), followed by non-fatal MI (6.6%), cardiac revascularization (4.9%) and fatal MI (0.6%). Compared to the general United States population, iTTP survivors were younger at first stroke in remission (males [56.5 years vs. 68.6 years, p = 0.031], females [49.7 years vs. 72.9 years, p < 0.001]) or MI in remission (males [56.5 years vs. 65.6 years, p < 0.001] and females [53.1 years vs. 72.0 years, p < 0.001]). Age (HR 1.03 [95% CI 1.002-1.054]), race (Black/Other vs. White) (HR 2.32 [95% CI 1.12-4.82]), and diabetes mellitus (HR 2.37 [95% CI 1.09-0.03]) were associated with MACE in a Cox regression model also adjusted for sex, hypertension, obesity, hyperlipidemia, chronic kidney disease, atrial fibrillation, autoimmune disease, and relapsing iTTP. Remission ADAMTS13 activity was not significantly associated with MACE. In conclusion, iTTP survivors experience high rates of MACE and may benefit from aggressively screening for and managing cardiovascular risk factors.
Polymorphic tandem repeats in the thymidylate synthase gene correlate with thymidylate synthase activity in normal tissues but not in malignant tissues of colorectal cancer patients
Authors: Robert Mauritz, Ines J. Beumer, Cees J. Van Groeningen, Herbert M. Pinedo, Godefridus J. Peters
Journal: Cancer Research (2004)

4742  Thymidylate synthase (TS) is the target enzyme of 5-fluorouracil (5-FU). High expression of TS has been related to a poor response of colorectal cancer patients to treatment with 5-FU. The enhancer region of the TS gene (TSER) contains a tandem repeat polymorphism that is thought to influence TS expression and might thereby predict response to 5-FU-based treatment: the triple repeat (TSER 3/3) genotype might be associated with higher TS levels and worse survival than the double repeat (TSER 2/2) or heterozygous (TSER 2/3) genotype. Most studies thus far focused on the relation between TS genotype and survival of patients treated with 5-FUbased chemotherapy. Only few studies explored the relation between TS genotype and in vivo TS expression. These previous studies were limited to tumors. This study comprises a retrospective analysis of the TSER polymorphism in normal (liver, mucosa) and malignant (primary tumor and liver metastasis) tissues of 83 patients with advanced colorectal cancer, to explore the relationship between TSER genotype and TS enzyme level (FdUMP-binding, catalytic activity) and mRNA expression. We found 38 patients with the 2R/3R genotype, 23 with the 2R/2R and 22 with the 3R/3R variant. Confirming previous studies we found a high level of homology (97%) between the TS polymorphic status of normal and malignant tissues from the same patients. In malignant tissues no correlation between TSER genotype and TS protein and mRNA levels was observed. In contrast, in normal tissues we found significantly higher TS protein levels (2.4-fold; p = 0.008) and catalytic activity (2.7-fold; p
Genomic basis underlying the metabolome-mediated drought adaptation of maize
Authors: Fei Zhang, Jinfeng Wu, Nir Sade, Si Wu, Aiman Egbaria, Alisdair R. Fernie, Jianbing Yan, Feng Qin, Wei Chen, Yariv Brotman, Mingqiu Dai
Journal: Genome biology (2021)

Abstract Background Drought is a major environmental disaster that causes crop yield loss worldwide. Metabolites are involved in various environmental stress responses of plants. However, the genetic control of metabolomes underlying crop environmental stress adaptation remains elusive. Results Here, we perform non-targeted metabolic profiling of leaves for 385 maize natural inbred lines grown under well-watered as well as drought-stressed conditions. A total of 3890 metabolites are identified and 1035 of these are differentially produced between well-watered and drought-stressed conditions, representing effective indicators of maize drought response and tolerance. Genetic dissections reveal the associations between these metabolites and thousands of single-nucleotide polymorphisms (SNPs), which represented 3415 metabolite quantitative trait loci (mQTLs) and 2589 candidate genes. 78.6% of mQTLs (2684/3415) are novel drought-responsive QTLs. The regulatory variants that control the expression of the candidate genes are revealed by expression QTL (eQTL) analysis of the transcriptomes of leaves from 197 maize natural inbred lines. Integrated metabolic and transcriptomic assays identify dozens of environment-specific hub genes and their gene-metabolite regulatory networks. Comprehensive genetic and molecular studies reveal the roles and mechanisms of two hub genes, Bx12 and ZmGLK44 , in regulating maize metabolite biosynthesis and drought tolerance. Conclusion Our studies reveal the first population-level metabolomes in crop drought response and uncover the natural variations and genetic control of these metabolomes underlying crop drought adaptation, demonstrating that multi-omics is a powerful strategy to dissect the genetic mechanisms of crop complex traits.
68Ga-Exendin-4 PET/CT Differentiates Insulinoma From Accessory Spleen in a Patient Presenting Indeterminate MRI and 68Ga-DOTATATE PET/CT Findings
Authors: Yizhen Pang, Tinghua Meng, Qihang Shang, Zheng Chen, Haojun Chen
Journal: Clinical Nuclear Medicine (2021)

A 55-year-old woman with endogenous hyperinsulinemia hypoglycemia was clinically diagnosed with insulinoma. Contrast-enhanced MRI revealed an inconclusive hypointense lesion in the pancreatic tail, and the enhancement pattern does not support the diagnosis of insulinoma. 68Ga-DOTATATE PET/CT showed intense radioactivity in this nodule, similar to the radioactivity of the adjacent spleen. Therefore, the diagnosis of accessory spleen cannot be excluded. Follow-up with 68Ga-exendin-4 PET/CT also showed intense uptake in this nodule, but no significant uptake in the spleen was observed at this time. Therefore, the insulinoma was unmasked from the spleen, excluding the diagnosis of accessory spleen, and allowing curative surgery.
Analysis of Early Biomarkers Associated With Noise-Induced Hearing Loss Among Shipyard Workers
Authors: Zhuang Jiang, Jiping Wang, Yanmei Feng, Daoyuan Sun, Xunmiao Zhang, Haibo Shi, Jian Wang, Richard Salvi, Hui Wang, Shankai Yin
Journal: JAMA Network Open (2021)

It is important to determine what frequencies and auditory perceptual measures are the most sensitive early indicators of noise-induced hearing impairment.To examine whether hearing loss among shipyard workers increases more rapidly at extended high frequencies than at clinical frequencies and whether subtle auditory processing deficits are present in those with extensive noise exposure but little or no hearing loss.This cross-sectional study collected audiometric data (0.25-16 kHz), survey questionnaires, and noise exposure levels from 7890 shipyard workers in a Shanghai shipyard from 2015 to 2019. Worsening hearing loss was evaluated in the group with hearing loss. Speech processing and temporal processing were evaluated in 610 participants with noise exposure and clinically normal hearing to identify early biomarkers of noise-induced hearing impairment. Data analysis was conducted from November to December 2020.Linear regression was performed to model the increase in hearing loss as function of cumulative noise exposure and compared with a group who were monitored longitudinally for 4 years. Auditory processing tests included speech-in-noise tests, competing sentence tests, dichotic listening tests, and gap detection threshold tests and were compared with a control group without history of noise exposure.Of the 5539 participants (median [interquartile range (IQR)] age, 41.0 [34.0-47.0] years; 3861 [86.6%] men) included in the cross-sectional analysis, 4459 (80.5%) were hearing loss positive and 1080 (19.5%) were hearing loss negative. In younger participants (ie, ≤40 years), the maximum rate of increase in hearing loss was 0.40 (95% CI, 0.39-0.42) dB per A-weighted dB-year (dB/dBA-year) at 12.5 kHz, higher than the growth rates of 0.36 (95% CI, 0.35-0.36) dB/dBA-year at 4 kHz, 0.32 (95% CI, 0.31-0.33) dB/dBA-year at 10 kHz, 0.31 (95% CI, 0.30-0.31) dB/dBA-year at 6 kHz, 0.27 (95% CI, 0.26-0.27) dB/dBA-year at 3 kHz, and 0.27 (95% CI, 0.27-0.28) dB/dBA-year at 8 kHz. In the 4-year longitudinal analysis of hearing loss among 403 participants, the mean (SD) annual deterioration in hearing was 2.70 (2.98) dB/y at 12.5 kHz, almost twice as that observed at lower frequencies (eg, at 3kHz: 1.18 [2.15] dB/y). The auditory processing scores of participants with clinically normal hearing and a history of noise exposure were significantly lower than those of control participants (eg, median [IQR] score on speech-in-noise test, noise-exposed group 1 vs control group: 0.63 [0.55-0.66] vs 0.78 [0.76-0.80]; P < .001).These findings suggest that the increase in hearing loss among shipyard workers was more rapid at 12.5 kHz than at other frequencies; workers with clinically normal hearing but high cumulative noise exposure are likely to exhibit deficits in speech and temporal processing.
Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Disease Flare in Patients With Rheumatoid Arthritis
Authors: Kenneth Frank Baker, Arthur Grant Pratt, John Dudley Isaacs
Journal: JAMA (2021)

To the Editor We have some questions about the conclusion and implications for clinical practice of the recent study1 examining dose reduction of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with rheumatoid arthritis (RA) in remission.
David Oliver: When organisations’ behaviours betray their value statements
Authors: David Oliver
Journal: BMJ (2021)

Value statements are intended to list the core principles guiding an organisation and its culture, creating a moral compass for it and its employees.1 Health and social care organisations in the UK all have such statements. The NHS constitution sets out values for the entire NHS workforce and range of services.2

I’m not sure, however, that we always live up to those values or even try to. Too often they’re reduced to lip service and generic platitudes that no one could disagree with as principles.3 If researchers reported a thematic analysis or word cloud they’d identify some recurrent themes in the stated values: “person centred,” “patient centred,” “based on individual needs,” “supporting patients and their families,” “respecting choice, dignity, and priorities,” “inclusive,” “coordinated,” …
Deep learning detects acute myeloid leukemia and predicts NPM1 mutation status from bone marrow smears
Authors: Jan-Niklas Eckardt, Jan Moritz Middeke, Sebastian Riechert, Tim Schmittmann, Anas Shekh Sulaiman, Michael Kramer, Katja Sockel, Frank Kroschinsky, Ulrich Schuler, Johannes Schetelig, Christoph Röllig, Christian Thiede, Karsten Wendt, Martin Bornhäuser
Journal: Leukemia (2021)

Abstract The evaluation of bone marrow morphology by experienced hematopathologists is essential in the diagnosis of acute myeloid leukemia (AML); however, it suffers from a lack of standardization and inter-observer variability. Deep learning (DL) can process medical image data and provides data-driven class predictions. Here, we apply a multi-step DL approach to automatically segment cells from bone marrow images, distinguish between AML samples and healthy controls with an area under the receiver operating characteristic (AUROC) of 0.9699, and predict the mutation status of Nucleophosmin 1 ( NPM1 )—one of the most common mutations in AML—with an AUROC of 0.92 using only image data from bone marrow smears. Utilizing occlusion sensitivity maps, we observed so far unreported morphologic cell features such as a pattern of condensed chromatin and perinuclear lightening zones in myeloblasts of NPM1 -mutated AML and prominent nucleoli in wild-type NPM1 AML enabling the DL model to provide accurate class predictions.
COVID-19 and Cancer
Authors: Aakash Desai, Turab J. Mohammed, Narjust Duma, Marina C. Garassino, Lisa K. Hicks, Nicole M. Kuderer, Gary H. Lyman, Sanjay Mishra, David J. Pinato, Brian I. Rini, Solange Peters, Jeremy L. Warner, Jennifer G. Whisenant, William A. Wood, Michael A. Thompson
Journal: JAMA Oncology (2021)

The COVID-19 pandemic has had consequences for patients with cancer worldwide and has been associated with delays in diagnosis, interruption of treatment and follow-up care, and increases in overall infection rates and premature mortality.Despite the challenges experienced during the pandemic, the global oncology community has responded with an unprecedented level of investigation, collaboration, and technological innovation through the rapid development of COVID-19 registries that have allowed an increased understanding of the natural history, risk factors, and outcomes of patients with cancer who are diagnosed with COVID-19. This review describes 14 major registries comprising more than 28 500 patients with cancer and COVID-19; these ongoing registry efforts have provided an improved understanding of the impact and outcomes of COVID-19 among patients with cancer.An initiative is needed to promote active collaboration between different registries to improve the quality and consistency of information. Well-designed prospective and randomized clinical trials are needed to collect high-level evidence to guide long-term epidemiologic, behavioral, and clinical decision-making for this and future pandemics.