tbuckley/cabot-search huggingface dataset:
Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set
Authors: E A Klein, D Richards, A Cohn, M Tummala, R Lapham, D Cosgrove, G Chung, J Clement, J Gao, N Hunkapiller, A Jamshidi, K N Kurtzman, M V Seiden, C Swanton, M C Liu
Journal: Annals of Oncology (2021)

A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool.This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured.Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%).In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests.NCT02889978.
The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI): A Three-Factor Comorbidity Model
Authors: Max J. Gordon, Andy Kaempf, Andrea Sitlinger, Geoffrey Shouse, Matthew Mei, Danielle M. Brander, Tareq Salous, Brian T. Hill, Hamood Alqahtani, Michael Choi, Michael C. Churnetski, Jonathon B. Cohen, Deborah M. Stephens, Tanya Siddiqi, Xavier Rivera, Daniel Persky, Paul Wisniewski, Krish Patel, Mazyar Shadman, Byung Park, Alexey V. Danilov
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied. Experimental Design: We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset. Results: The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS: any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets. Conclusions: The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
Associations between physical multimorbidity patterns and common mental health disorders in middle-aged adults: A prospective analysis using data from the UK Biobank
Authors: Amy Ronaldson, Jorge Arias de la Torre, Matthew Prina, David Armstrong, Jayati Das-Munshi, Stephani Hatch, Rob Stewart, Matthew Hotopf, Alexandru Dregan
Journal: The Lancet Regional Health - Europe (2021)

We aimed to identify specific patterns of physical multimorbidity, defined as the presence of two or more physical long-term conditions, and to examine the extent to which these specific patterns could predict future incident and persistent common mental health disorders (CMDs) in middle-aged adults enrolled in the UK Biobank.
Acquired Tertiary MET Resistance (MET D1228N and a Novel LSM8-MET Fusion) to Selpercatinib and Capmatinib in a Patient With KIF5B-RET–positive NSCLC With Secondary MET Amplification as Initial Resistance to Selpercatinib
Authors: Viola W. Zhu, Shannon S. Zhang, Jian Zhang, Jeffrey Swensen, Joanne Xiu, Sai-Hong Ignatius Ou
Journal: Journal of Thoracic Oncology (2021)
Effects of Wearing an N95 Respirator or Cloth Mask Among Adults at Peak Exercise
Authors: Matthew Kampert, Tamanna Singh, Debasis Sahoo, Xiaozhen Han, Erik H. Van Iterson
Journal: JAMA Network Open (2021)

For the majority of apparently healthy adults, mask wearing while at rest or during activities of daily living is recommended to be safe and effective for reducing the risk of person-to-person airborne transmission of SARS-Cov-2.1,2 Original research has yet to find evidence showing an effect of mask wearing on clinical indicators of exercise safety.3 In this study, we tested whether mask wearing during exercise stress testing (EST) to peak exhaustion provokes clinically indicated safety concerns.
Advanced Cardiac Life Support Algorithms—Reply
Authors: Takahiro Tsushima, Toral R. Patel, Jayakumar Sahadevan
Journal: JAMA Internal Medicine (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Potential Cost-Effectiveness of Risk-Based Pancreatic Cancer Screening in Patients With New-Onset Diabetes
Authors: Naomi R.M. Schwartz, Lynn M. Matrisian, Eva E. Shrader, Ziding Feng, Suresh Chari, Joshua A. Roth
Journal: Journal of the National Comprehensive Cancer Network (2021)

There are no established methods for pancreatic cancer (PAC) screening, but the NCI and the Pancreatic Cancer Action Network (PanCAN) are investigating risk-based screening strategies in patients with new-onset diabetes (NOD), a group with elevated PAC risk. Preliminary estimates of the cost-effectiveness of these strategies can provide insights about potential value and inform supplemental data collection. Using data from the Enriching New-Onset Diabetes for Pancreatic Cancer (END-PAC) risk model validation study, we assessed the potential value of CT screening for PAC in those determined to be at elevated risk, as is being done in a planned PanCAN Early Detection Initiative trial.We created an integrated decision tree and Markov state-transition model to assess the cost-effectiveness of PAC screening in patients aged ≥50 years with NOD using CT imaging versus no screening. PAC prevalence, sensitivity, and specificity were derived from the END-PAC validation study. PAC stage distribution in the no-screening strategy and PAC survival were derived from the SEER program. Background mortality for patients with diabetes, screening and cancer care expenditure, and health state utilities were derived from the literature. Life-years (LYs), quality-adjusted LYs (QALYs), and costs were tracked over a lifetime horizon and discounted at 3% per year. Results are presented in 2020 US dollars, and we took a limited US healthcare perspective.In the base case, screening resulted in 0.0055 more LYs, 0.0045 more QALYs, and $293 in additional expenditures for a cost per QALY gained of $65,076. In probabilistic analyses, screening resulted in a cost per QALY gained of <$50,000 and <$100,000 in 34% and 99% of simulations, respectively. In the threshold analysis, >25% of screen-detected PAC cases needed to be resectable for the cost per QALY gained with screening to be <$100,000.We found that risk-based PAC screening in patients with NOD is likely to be cost-effective in the United States if even a modest fraction (>25%) of screen-detected patients with PAC are resectable. Future studies should reassess the value of this intervention once clinical trial data become available.
Prognostic value of Oncogenetic mutations in pediatric T Acute Lymphoblastic Leukemia: a comparison of UKALL2003 and FRALLE2000T protocols
Authors: Mary M. Taj, Anthony V. Moorman, Lina Hamadeh, Arnaud Petit, Vahid Asnafi, Fanny Alby-Laurent, Ajay Vora, Marc R. Mansour, Rosemary Gale, Sylvie Chevret, John Moppett, André Baruchel, Elizabeth Macintyre
Journal: Leukemia (2021)
The Importance of Being Autophagic
Authors: Ian Ganley
Journal: New England Journal of Medicine (2021)

The components of a well-oiled machine must be kept in optimal condition and be removed or replaced when they become worn out or damaged. The same is true for cells of the body, where proteins and organelles are routinely replaced when they become impaired, toxic, or surplus to requirements. The recycling of these components, be they protein complexes or aggregates, faulty mitochondria, or even intracellular pathogens, is thought to occur largely through autophagy. A word derived from the Greek meaning "to eat oneself," autophagy consists of a family of catabolic lysosomal pathways that mediate the transfer of cytosolic components to . . .
Emergence of measles during the COVID-19 pandemic threatens Pakistan’s children and the wider region
Authors: Muhammad Suleman Rana, Muhammad Masroor Alam, Aamer Ikram, Muhammad Salman, Mohammad Osama Mere, Muhammad Usman, Massab Umair, Syed Sohail Zahoor Zaidi, Yasir Arshad
Journal: Nature Medicine (2021)
Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression
Authors: Meijia Qian, Fangjie Yan, Weihua Wang, Jiamin Du, Tao Yuan, Ruilin Wu, Chenxi Zhao, Jiao Wang, Jiabin Lu, Bo Zhang, Nengming Lin, Xin Dong, Xiaoyang Dai, Xiaowu Dong, Bo Yang, Hong Zhu, Qiaojun He
Journal: Acta Pharmaceutica Sinica B (2021)

Cholangiocarcinoma (CCA) has emerged as an intractable cancer with scanty therapeutic regimens. The aberrant activation of Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are reported to be common in CCA patients. However, the underpinning mechanism remains poorly understood. Deubiquitinase (DUB) is regarded as a main orchestrator in maintaining protein homeostasis. Here, we identified Josephin domain-containing protein 2 (JOSD2) as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner. The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo. Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples. Collectively, this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression, which may provide a potential intervention target for YAP/TAZ-related CCA patients.
Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis
Authors: James G. Krueger, Iain B. McInnes, Andrew Blauvelt
Journal: Journal of the American Academy of Dermatology (2021)

Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors.
Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome
Authors: Margot A Cousin, Blake A Creighton, Keith A Breau, Rebecca C Spillmann, Erin Torti, Sruthi Dontu, Swarnendu Tripathi, Deepa Ajit, Reginald J Edwards, Simone Afriyie, Julia C Bay, Kathryn M Harper, Alvaro A Beltran, Lorena J Munoz, Liset Falcon Rodriguez, Michael C Stankewich, Richard E Person, Yue Si, Elizabeth A Normand, Amy Blevins, Alison S May, Louise Bier, Vimla Aggarwal, Grazia M S Mancini, Marjon A van Slegtenhorst, Kirsten Cremer, Jessica Becker, Hartmut Engels, Stefan Aretz, Jennifer J MacKenzie, Eva Brilstra, Koen L I van Gassen, Richard H van Jaarsveld, Renske Oegema, Gretchen M Parsons, Paul Mark, Ingo Helbig, Sarah E McKeown, Robert Stratton, Benjamin Cogne, Bertrand Isidor, Pilar Cacheiro, Damian Smedley, Helen V Firth, Tatjana Bierhals, Katja Kloth, Deike Weiss, Cecilia Fairley, Joseph T Shieh, Amy Kritzer, Parul Jayakar, Evangeline Kurtz-Nelson, Raphael A Bernier, Tianyun Wang, Evan E Eichler, Ingrid M B H van de Laar, Allyn McConkie-Rosell, Marie T McDonald, Jennifer Kemppainen, Brendan C Lanpher, Laura E Schultz-Rogers, Lauren B Gunderson, Pavel N Pichurin, Grace Yoon, Michael Zech, Robert Jech, Juliane Winkelmann, Adriana S Beltran, Michael T Zimmermann, Brenda Temple, Sheryl S Moy, Eric W Klee, Queenie K-G Tan, Damaris N Lorenzo
Journal: Nature Genetics (2021)
Abstract 2869: Is Ankle Brachial Index a Cost-Effective Screening Tool in Asymptomatic Older Adults?
Authors: Ruth E Taylor-Piliae, Joan M Fair, Ann H Varady, Mark A Hlatky, Linda C Norton, Carlos Iribarren, Stephen P Fortmann
Journal: Circulation (2006)

Background: Previous reports indicate that about 5% of adults aged 40 years or older have an ankle brachial index (ABI) <0.90, an indicator of peripheral vascular disease in the lower extremities (...
Abstract 55: The Natural Course of Myocardial Infarction in Large Animal Models; a Systematic Review and Meta-analysis
Authors: Peter-Paul Zwetsloot, Lisanne E Kouwenberg, Emily S Sena, Joep E Eding, Joost P Sluijter, Gerard Pasterkamp, Pieter A Doevendans, Steven A Chamuleau, Geert P van Hout, Sanne J Jansen of Lorkeers
Journal: Circulation Research (2016)

Background: Large animal models of myocardial infarction (MI) are essential for the development of novel therapeutic strategies. However, it is unclear which experimental factors are independent determinants of disease progression outcomes and the fidelity with which these models resemble MI in humans. The aim of this study was to investigate systematically what independently influences the outcome after MI in large animal models and determine which methodological factors influence primary endpoints and disease progression. Methods: We used control animal data from two meta-analyses of large animal models of MI. We performed univariable and multivariable meta-regression to analyze if potential relevant variables were influencing outcomes; infarct size as a ratio of the area at risk (IS/AAR), as a ratio of the left ventricle (IS/LV) and ejection fraction (EF). Pre-defined independent variables were species, sex, weight, ischemia model (open vs closed), occlusion type (temporary vs permanent), occluded vessel, follow-up duration, use of co-medication, use of immunosuppression and study quality. Outcomes and variables were complemented per dataset if needed. Results: Our analyses yielded 246 relevant studies, reporting 1500, 1221 and 775 control animals for IS/AAR, IS/LV and EF respectively. Multivariable meta-regression showed IS/AAR was influenced by species (p&lt;0.001), sex (p=0.03), co-medication (p=0.01), occlusion type (p&lt;0.001), occluded vessel (p=0.002) and follow-up (p=0.001). For IS/LV occlusion type (p=0.03), occluded vessel (p=0.03) and study quality (p=0.03) showed significant effects. EF measurements revealed that species (p=0.04), sex (p=0.04) and occluded vessel (p=0.05) were independent predictors. Using these variables, we can partially predict these outcomes for certain study setups. Conclusion: Many methodological variations exist in the design of large animal MI studies. This should be taken into account when selecting a model to study therapy efficacy. We provide evidence that disease manifestation and progression greatly depend on certain biological characteristics, e.g. location of MI and sex of the patient. It is therefore possible that therapies have a different effect in specific patient populations.
Methotrexate and glucocorticoids, but not anticytokine therapy, impair the immunogenicity of a single dose of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic inflammatory arthritis
Authors: Serena Bugatti, Ludovico De Stefano, Silvia Balduzzi, Maria Immacolata Greco, Terenzj Luvaro, Irene Cassaniti, Laura Bogliolo, Iolanda Mazzucchelli, Bernardo D’Onofrio, Michele di Lernia, Eleonora Mauric, Daniele Lilleri, Fausto Baldanti, Antonio Manzo, Carlomaurizio Montecucco
Journal: Annals of the Rheumatic Diseases (2021)

<h3>Abstract</h3> Histopathological analysis of whole-slide images is the gold standard technique for diagnosis of lung cancer and classifying it into types and subtypes by specialized pathologists. This labor-based approach is time and effort consuming, which led to development of automatic approaches to assist in reducing the time and effort. Deep learning is a supervised classification approach that is well adapted for automatic classification of histopathological images. We aimed to develop a deep learning-based approach for lung adenocarcinoma pattern classification and generalize the proposed approach to the classification of the major non-small cell lung cancer types. Three publicly available datasets were used in this study. A deep learning approach for histopathological image analysis using convolutional neural networks was developed and incorporated into automatic pipelines to accurately classify the predominant patterns on the whole-slide images level and non-small cell lung cancer types on patch-level. The models were evaluated using the confusion matrix to perform an error analysis and the classification report to compute F1-score, recall and precision. As results, the three models have shown an excellent performance with best combination of hyper-parameters for training models. First and second models predicted adenocarcinoma predominant patterns on two different datasets with an accuracy, respectively, of 96.15% and 89.51%. The third model has exceeded an accuracy of 99.72% in classifying major non-small cell lung cancer types. The proposed deep learning-based lung cancer classification approach can be used to assist pathologists in identifying of lung adenocarcinomas patterns.
Free human DNA attenuates the activity of antimicrobial peptides in atopic dermatitis
Authors: Verena Kopfnagel, Sylvia Dreyer, Jana Zeitvogel, Dietmar H. Pieper, Anna Buch, Beate Sodeik, Franziska Rademacher, Jürgen Harder, Thomas Werfel
Journal: Allergy (2021)

Abstract Background The high susceptibility of AD patients to microbial skin infections has been attributed to a deficient antimicrobial peptide (AMP) expression, which is contradicted by a growing amount of recent studies clearly demonstrating that AMP expression is not impaired in lesional skin of AD patients. The reasons for the high susceptibility of AD patients to microbial infections are still unknown. Methods The influence of self‐DNA on the antimicrobial activity of RNase 7, LL‐37, and hBD2 has been investigated using antibacterial and antiviral assays. The amount of self‐DNA on skin has been analyzed by skin rinsings and subsequent quantification using dsDNA assays. DNA source was identified by qPCR. Results Complex formation of the AMPs with self‐DNA significantly impaired their antibacterial activity against Staphylococcus aureus and their antiviral activity against HSV ‐ 1 . The inhibition of the antibacterial activity was dependent on the DNA concentration but not on the length of the DNA molecules. Of note, we detected significant higher amounts of cell‐free self‐DNA in skin rinses taken from lesional AD skin compared to skin rinses from non‐lesional skin and from normal skin of healthy donors. Consequently, rinse solution from AD lesional skin prevented antibacterial activity of LL‐37. Conclusion Our study indicates that extracellular self‐DNA is released in considerable amounts in AD skin lesions and AMP‐self‐DNA‐complex formation leads to a significant loss of antibacterial and antiviral activity in atopic dermatitis. Studies on strategies to reduce the amount of extracellular DNA in AD are needed to identify possible methods relevant in clinical settings.
Blood eosinophil counts in the general population and airways disease: a comprehensive review and meta-analysis
Authors: Victoria S. Benson, Sylvia Hartl, Neil Barnes, Nicholas Galwey, Melissa K. Van Dyke, Namhee Kwon
Journal: European Respiratory Journal (2021)

The clinical context for using blood eosinophil (EOS) counts as treatment-response biomarkers in asthma and COPD requires better understanding of EOS distributions and ranges. We describe EOS distributions and ranges published in asthma, COPD, control (non-asthma/COPD) and general populations.