tbuckley/cabot-search huggingface dataset:
Chasing Sequencing Perfection: Marching Toward Higher Accuracy and Lower Costs
Authors: Hangxing Jia, Shengjun Tan, Yong E Zhang
Journal: Genomics Proteomics & Bioinformatics (2024)

Next-generation sequencing (NGS), represented by Illumina platforms, has been an essential cornerstone of basic and applied research. However, the sequencing error rate of 1 per 1000 bp (10-3) represents a serious hurdle for research areas focusing on rare mutations, such as somatic mosaicism or microbe heterogeneity. By examining the high-fidelity sequencing methods developed in the past decade, we summarized three major factors underlying errors and the corresponding 12 strategies mitigating these errors. We then proposed a novel framework to classify 11 preexisting representative methods according to the corresponding combinatory strategies and identified three trends that emerged during methodological developments. We further extended this analysis to eight long-read sequencing methods, emphasizing error reduction strategies. Finally, we suggest two promising future directions that could achieve comparable or even higher accuracy with lower costs in both NGS and long-read sequencing.
Acute Colonic Diverticulitis
Authors: Sarah A. Gunby, Lisa L. Strate
Journal: Annals of Internal Medicine (2024)

Acute colonic diverticulitis is a gastrointestinal condition that is frequently encountered by primary care and emergency department practitioners, hospitalists, surgeons, and gastroenterologists. Clinical presentation ranges from mild abdominal pain to peritonitis with sepsis. It is often diagnosed on the basis of clinical features alone, but imaging is necessary in more severe presentations to rule out such complications as abscess and perforation. Treatment depends on the severity of the presentation, the presence of complications, and underlying comorbid conditions. Medical and surgical treatment algorithms are evolving. This article provides an evidence-based, clinically relevant overview of the epidemiology, diagnosis, and treatment of acute diverticulitis.
Where Are All the Specialists? Current Challenges of Integrating Specialty Care Into Population-Based Total Cost of Care Payment Models
Authors: Jennifer L. Wiler, Lawrence R. Kosinski, Terry L. Mills, James Walton
Journal: Annals of Internal Medicine (2024)

The Centers for Medicare & Medicaid Services Innovation Center (CMMI) has set the goal for 100% of traditional Medicare beneficiaries to be part of an accountable care relationship by 2030. Lack of meaningful financial incentives, intolerable or unpredictable risk, infrastructure costs, patient engagement, voluntary participation, and operational complexity have been noted by the provider and health care delivery community as barriers to participation or reasons for exiting programs. In addition, most piloted and implemented population-based total cost of care (PB-TCOC) payment models have focused on the role of the primary care physician being the accountability (that is, attributable) leader of a patient's multifaceted care team as well as acting as the mayor of the "medical neighborhood," leaving the role of specialty care physicians undefined. Successful provider specialist integration into PB-TCOC models includes meaningful participation of specialists in achieving whole-person, high-value care where all providers are financially motivated to participate; there is unambiguous prospective attribution and clearly defined accountability for each participating party throughout the care journey or episode; there is a known care attribution transition accountability plan; there is actionable, transparent, and timely data available with appropriate data development and basic analytic costs covered; and there is advanced payment to the accountable person or entity for management of the care episode that is part of a longitudinal care plan. Payment models should be created to address the 7 challenges raised here if specialists are to be incented to join TCOC models that achieve CMMI's goal.
The Impact of Health Care Algorithms on Racial and Ethnic Disparities
Authors: Shazia Mehmood Siddique, Kelley Tipton, Brian Leas, Christopher Jepson, Jaya Aysola, Jordana B. Cohen, Emilia Flores, Michael O. Harhay, Harald Schmidt, Gary E. Weissman, Julie Fricke, Jonathan R. Treadwell, Nikhil K. Mull
Journal: Annals of Internal Medicine (2024)

Background: There is increasing concern for the potential impact of health care algorithms on racial and ethnic disparities. Purpose: To examine the evidence on how health care algorithms and associated mitigation strategies affect racial and ethnic disparities. Data Sources: Several databases were searched for relevant studies published from 1 January 2011 to 30 September 2023. Study Selection: Using predefined criteria and dual review, studies were screened and selected to determine: 1) the effect of algorithms on racial and ethnic disparities in health and health care outcomes and 2) the effect of strategies or approaches to mitigate racial and ethnic bias in the development, validation, dissemination, and implementation of algorithms. Data Extraction: Outcomes of interest (that is, access to health care, quality of care, and health outcomes) were extracted with risk-of-bias assessment using the ROBINS-I (Risk Of Bias In Non-randomised Studies – of Interventions) tool and adapted CARE-CPM (Critical Appraisal for Racial and Ethnic Equity in Clinical Prediction Models) equity extension. Data Synthesis: Sixty-three studies (51 modeling, 4 retrospective, 2 prospective, 5 prepost studies, and 1 randomized controlled trial) were included. Heterogenous evidence on algorithms was found to: a) reduce disparities (for example, the revised kidney allocation system), b) perpetuate or exacerbate disparities (for example, severity-of-illness scores applied to critical care resource allocation), and/or c) have no statistically significant effect on select outcomes (for example, the HEART Pathway [history, electrocardiogram, age, risk factors, and troponin]). To mitigate disparities, 7 strategies were identified: removing an input variable, replacing a variable, adding race, adding a non–race-based variable, changing the racial and ethnic composition of the population used in model development, creating separate thresholds for subpopulations, and modifying algorithmic analytic techniques. Limitation: Results are mostly based on modeling studies and may be highly context-specific. Conclusion: Algorithms can mitigate, perpetuate, and exacerbate racial and ethnic disparities, regardless of the explicit use of race and ethnicity, but evidence is heterogeneous. Intentionality and implementation of the algorithm can impact the effect on disparities, and there may be tradeoffs in outcomes. Primary Funding Source: Agency for Healthcare Quality and Research.
Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women
Authors: Cynthia A. Thomson, Aaron K. Aragaki, Ross L. Prentice, Marcia L. Stefanick, JoAnn E. Manson, Jean Wactawski-Wende, Nelson B. Watts, Linda Van Horn, James M. Shikany, Thomas E. Rohan, Dorothy S. Lane, Robert A. Wild, Rogelio Robles-Morales, Aladdin H. Shadyab, Nazmus Saquib, Jane Cauley
Journal: Annals of Internal Medicine (2024)

Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited.
Predicting five-year interval second breast cancer risk in women with prior breast cancer
Authors: Rebecca A Hubbard, Yu-Ru Su, Erin J A Bowles, Laura Ichikawa, Karla Kerlikowske, Kathryn P Lowry, Diana L Miglioretti, Anna N A Tosteson, Karen J Wernli, Janie M Lee
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Annual surveillance mammography is recommended for women with a personal history of breast cancer. Risk prediction models that estimate mammography failures such as interval second breast cancers could help to tailor surveillance imaging regimens to women’s individual risk profiles. Methods In a cohort of women with a history of breast cancer receiving surveillance mammography in the Breast Cancer Surveillance Consortium in 1996-2019, we used Least Absolute Shrinkage and Selection Operator (LASSO)-penalized regression to estimate the probability of an interval second cancer (invasive cancer or ductal carcinoma in situ) in the 1 year after a negative surveillance mammogram. Based on predicted risks from this one-year risk model, we generated cumulative risks of an interval second cancer for the five-year period after each mammogram. Model performance was evaluated using cross-validation in the overall cohort and within race and ethnicity strata. Results In 173 290 surveillance mammograms, we observed 496 interval cancers. One-year risk models were well-calibrated (expected/observed ratio = 1.00) with good accuracy (area under the receiver operating characteristic curve = 0.64). Model performance was similar across race and ethnicity groups. The median five-year cumulative risk was 1.20% (interquartile range 0.93%-1.63%). Median five-year risks were highest in women who were under age 40 or pre- or perimenopausal at diagnosis and those with estrogen receptor-negative primary breast cancers. Conclusions Our risk model identified women at high risk of interval second breast cancers who may benefit from additional surveillance imaging modalities. Risk models should be evaluated to determine if risk-guided supplemental surveillance imaging improves early detection and decreases surveillance failures.
Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer
Authors: Axel Rosendahl Huber, Cayetano Pleguezuelos-Manzano, Jens Puschhof, Joske Ubels, Charelle Boot, Aurelia Saftien, Mark Verheul, Laurianne T. Trabut, Niels Groenen, Markus van Roosmalen, Kyanna S. Ouyang, Henry Wood, Phil Quirke, Gerrit Meijer, Edwin Cuppen, Hans Clevers, Ruben van Boxtel
Journal: Cancer Cell (2024)

Co-culture of intestinal organoids with a colibactin-producing pks+ E. coli strain (EcC) revealed mutational signatures also found in colorectal cancer (CRC). E. coli Nissle 1917 (EcN) remains a commonly used probiotic, despite harboring the pks operon and inducing double strand DNA breaks. We determine the mutagenicity of EcN and three CRC-derived pks+ E. coli strains with an analytical framework based on sequence characteristic of colibactin-induced mutations. All strains, including EcN, display varying levels of mutagenic activity. Furthermore, a machine learning approach attributing individual mutations to colibactin reveals that patients with colibactin-induced mutations are diagnosed at a younger age and that colibactin can induce a specific APC mutation. These approaches allow the sensitive detection of colibactin-induced mutations in ∼12% of CRC genomes and even in whole exome sequencing data, representing a crucial step toward pinpointing the mutagenic activity of distinct pks+ E. coli strains.
Author Correction: The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial
Authors: Lindsay B. Kilburn, Dong-Anh Khuong-Quang, Jordan R. Hansford, Daniel Landi, Jasper van der Lugt, Sarah E. S. Leary, Pablo Hernáiz Driever, Simon Bailey, Sébastien Perreault, Geoffrey McCowage, Angela J. Waanders, David S. Ziegler, Olaf Witt, Patricia A. Baxter, Hyoung Jin Kang, Timothy E. Hassall, Jung Woo Han, Darren Hargrave, Andrea T. Franson, Michal Yalon Oren, Helen Toledano, Valérie Larouche, Cassie Kline, Mohamed S. Abdelbaki, Nada Jabado, Nicholas G. Gottardo, Nicolas U. Gerber, Nicholas S. Whipple, Devorah Segal, Susan N. Chi, Liat Oren, Enrica E. K. Tan, Sabine Mueller, Izzy Cornelio, Lisa McLeod, Xin Zhao, Ashley Walter, Daniel Da Costa, Peter Manley, Samuel C. Blackman, Roger J. Packer, Karsten Nysom
Journal: Nature Medicine (2024)
Association of Antiarrhythmic Drug Therapy With Syncope and Pacemaker Implantation in Patients With Atrial Fibrillation
Authors: Yun Gi Kim, Hyoung Seok Lee, Hoseob Kim, Mina Kim, Joo Hee Jeong, Yun Young Choi, Jaemin Shim, Jong-Il Choi, Young-Hoon Kim
Journal: Journal of the American College of Cardiology (2024)
Magnetic natural lipid nanoparticles for oral treatment of colorectal cancer through potentiated antitumor immunity and microbiota metabolite regulation
Authors: Baoyi Li, Menghang Zu, Aodi Jiang, Yingui Cao, Jiaxue Wu, Mohammad-Ali Shahbazi, Xiaoxiao Shi, Rui L. Reis, Subhas C. Kundu, Bo Xiao
Journal: Biomaterials (2024)
End-Stage Heart Failure in Cardiac Sarcoidosis
Authors: Diana Velikanova, Pauli Pöyhönen, Jukka Lehtonen, Piia Simonen, Valtteri Uusitalo, Tapani Vihinen, Kari Kaikkonen, Petri Haataja, Tuomas Kerola, Tuomas T. Rissanen, Ville Vepsäläinen, Aleksi Alatalo, Päivi Pietilä-Effati, Markku Kupari
Journal: Circulation (2024)
Abnormal Progenitor Cell Differentiation and Cardiomyocyte Proliferation in Hypoplastic Right Heart Syndrome
Authors: Yang Yu, Cankun Wang, Shiqiao Ye, Zhaohui Xu, Hui Lin, Karen Texter, Vasudha Shukla, Samir Ghadiali, Qin Ma, Vidu Garg, Ming-Tao Zhao
Journal: Circulation (2024)
Kidney Injury After Minimal Radiographic Contrast Administration in Patients With Acute Coronary Syndromes
Authors: Carlo Briguori, Cristina Quintavalle, Enrica Mariano, Alessandro D’Agostino, Mario Scarpelli, Amelia Focaccio, Giuseppe Biondi Zoccai, Salvatore Evola, Giovanni Esposito, Giuseppe Massimo Sangiorgi, Gerolama Condorelli
Journal: Journal of the American College of Cardiology (2024)
Incidence, Predictors, and Impact of Hospital Readmission After Revascularization for Left Main Coronary Disease
Authors: Ioanna Kosmidou, Bahira Shahim, Ovidiu Dressler, Björn Redfors, Marie-Claude Morice, John D. Puskas, David E. Kandzari, Dimitri Karmpaliotis, W. Morris Brown, Nicholas J. Lembo, Adrian P. Banning, Arie Pieter Kappetein, Patrick W. Serruys, Joseph F. Sabik, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2024)
Exploiting the therapeutic implications of KRAS inhibition on tumor immunity
Authors: Miriam Molina-Arcas, Julian Downward
Journal: Cancer Cell (2024)

SummaryOver the past decade, RAS oncogenic proteins have transitioned from being deemed undruggable to having two clinically approved drugs, with several more in advanced stages of development. Despite the initial benefit of KRAS-G12C inhibitors for patients with tumors harboring this mutation, the rapid emergence of drug resistance underscores the urgent need to synergize these inhibitors with other therapeutic approaches to improve outcomes. RAS mutant tumor cells can create an immunosuppressive tumor microenvironment (TME), suggesting an increased susceptibility to immunotherapies following RAS inhibition. This provides a rationale for combining RAS inhibitory drugs with immune checkpoint blockade (ICB). However, achieving this synergy in the clinical setting has proven challenging. Here, we explore how understanding the impact of RAS mutant tumor cells on the TME can guide innovative approaches to combining RAS inhibition with immunotherapies, review progress in both pre-clinical and clinical stages, and discuss challenges and future directions.
RYR2 Variant and Sudden Death in Patients With Dilated Cardiomyopathy
Authors: Yael Ben-Haim, Martin Bird, David Johnson, Saidi Mohiddin, Liliana Favaloro, Jeppe Dyrberg Andersen, Mary N. Sheppard, Alan Pittman, Marta Futema, Elijah R. Behr
Journal: Journal of the American College of Cardiology (2024)
Optimised prevention of postnatal HIV transmission in Zambia and Burkina Faso (PROMISE-EPI): a phase 3, open-label, randomised controlled trial
Authors: Chipepo Kankasa, Anaïs Mennecier, Beninwendé L D Sakana, Jean-Pierre Molès, Mwiya Mwiya, Catherine Chunda-Liyoka, Morgana D'Ottavi, Souleymane Tassembedo, Maria M Wilfred-Tonga, Paulin Fao, David Rutagwera, Beauty Matoka, Dramane Kania, Ousmane A Taofiki, Thorkild Tylleskär, Philippe Van de Perre, Nicolas Nagot
Journal: The Lancet (2024)
Orthotopic and metastatic tumour models in preclinical cancer research
Authors: Stephen M. Stribbling, Callum Beach, Anderson J. Ryan
Journal: Pharmacology & Therapeutics (2024)

Mouse models of disease play a pivotal role at all stages of cancer drug development. Cell-line derived subcutaneous tumour models are predominant in early drug discovery, but there is growing recognition of the importance of the more complex orthotopic and metastatic tumour models for understanding both target biology in the correct tissue context, and the impact of the tumour microenvironment and the immune system in responses to treatment. The aim of this review is to highlight the value that orthotopic and metastatic models bring to the study of tumour biology and drug development while pointing out those models that are most likely to be encountered in the literature. Important developments in orthotopic models, such as the increasing use of early passage patient material (PDXs, organoids) and humanised mouse models are discussed, as these approaches have the potential to increase the predictive value of preclinical studies, and ultimately improve the success rate of anticancer drugs in clinical trials.
Tumor-Infiltrating Lymphocytes Refine Outcomes in Triple-Negative Breast Cancer Treated with Anthracycline-Free Neoadjuvant Chemotherapy
Authors: Miguel Martín, Rachel Yoder, Roberto Salgado, María del Monte-Millán, Enrique L. Álvarez, Isabel Echavarría, Joshua M. Staley, Anne P. O'Dea, Lauren E. Nye, Shane R. Stecklein, Coralia Bueno, Yolanda Jerez, María Cebollero, Oscar Bueno, José Ángel García Saenz, Fernando Moreno, Uriel Bohn, Henry Gómez, Tatiana Massarrah, Qamar J. Khan, Andrew K. Godwin, Sara López-Tarruella, Priyanka Sharma
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Stromal tumor-infiltrating lymphocytes (sTIL) are associated with pathologic complete response (pCR) and long-term outcomes for triple-negative breast cancer (TNBC) in the setting of anthracycline-based chemotherapy. The impact of sTILs on refining outcomes beyond prognostic information provided by pCR in anthracycline-free neoadjuvant chemotherapy (NAC) is not known. Experimental Design: This is a pooled analysis of two studies where patients with stage I (T&amp;gt;1 cm)–III TNBC received carboplatin (AUC 6) plus docetaxel (75 mg/m2; CbD) NAC. sTILs were evaluated centrally on pre-treatment hematoxylin and eosin slides using standard criteria. Cox regression analysis was used to examine the effect of variables on event-free survival (EFS) and overall survival (OS). Results: Among 474 patients, 44% had node-positive disease. Median sTILs were 5% (range, 1%–95%), and 32% of patients had ≥30% sTILs. pCR rate was 51%. On multivariable analysis, T stage (OR, 2.08; P = 0.007), nodal status (OR, 1.64; P = 0.035), and sTILs (OR, 1.10; P = 0.011) were associated with pCR. On multivariate analysis, nodal status (HR, 0.46; P = 0.008), pCR (HR, 0.20; P &amp;lt; 0.001), and sTILs (HR, 0.95; P = 0.049) were associated with OS. At 30% cut-point, sTILs stratified outcomes in stage III disease, with 5-year OS 86% versus 57% in ≥30% versus &amp;lt;30% sTILs (HR, 0.29; P = 0.014), and numeric trend in stage II, with 5-year OS 93% versus 89% in ≥30% versus &amp;lt;30% sTILs (HR, 0.55; P = 0.179). Among stage II–III patients with pCR, EFS was better in those with ≥30% sTILs (HR, 0.16; P, 0.047). Conclusions: sTILs density was an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated with anthracycline-free CbD chemotherapy. Notably, sTILs density stratified outcomes beyond tumor–node–metastasis (TNM) stage and pathologic response. These findings highlight the role of sTILs in patient selection and stratification for neo/adjuvant escalation and de-escalation strategies.
Biomarkers of Efficacy and Safety of the Academic BCMA-CART ARI0002h for the Treatment of Refractory Multiple Myeloma
Authors: Aina Oliver-Caldes, Marta Español-Rego, Aintzane Zabaleta, Verónica González-Calle, Sergio Navarro-Velázquez, Susana Inogés, Ascensión López-Díaz de Cerio, Valentín Cabañas, Nieves López-Muñoz, Paula Rodríguez-Otero, Juan Luis Reguera, David F. Moreno, Nuria Martínez-Cibrian, Lucía López-Corral, Lorena Pérez-Amill, Beatriz Martin-Antonio, Laura Rosiñol, Joan Cid, Natalia Tovar, Joaquín Sáez-Peñataro, Miriam López-Parra, Eulalia Olesti, Elena Guillén, Sara Varea, Luis Gerardo Rodríguez-Lobato, Anthony M. Battram, Marta Sonia González, Andrés Sánchez-Salinas, Azucena González-Navarro, Valentín Ortiz-Maldonado, Julio Delgado, Felipe Prósper, Manel Juan, Joaquín Martínez-López, José M. Moraleda, Maria Victoria Mateos, Álvaro Urbano-Ispizua, Bruno Paiva, Mariona Pascal, Carlos Fernández de Larrea
Journal: Clinical Cancer Research (2024)

Abstract Purpose: B-cell maturation antigen (BCMA)-chimeric antigen receptor T-cells (CART) improve results obtained with conventional therapy in the treatment of relapsed/refractory multiple myeloma. However, the high demand and expensive costs associated with CART therapy might prove unsustainable for health systems. Academic CARTs could potentially overcome these issues. Moreover, response biomarkers and resistance mechanisms need to be identified and addressed to improve efficacy and patient selection. Here, we present clinical and ancillary results of the 60 patients treated with the academic BCMA-CART, ARI0002h, in the CARTBCMA-HCB-01 trial. Patients and Methods: We collected apheresis, final product, peripheral blood and bone marrow samples before and after infusion. We assessed BCMA, T-cell subsets, CART kinetics and antibodies, B-cell aplasia, cytokines, and measurable residual disease by next-generation flow cytometry, and correlated these to clinical outcomes. Results: At cut-off date March 17, 2023, with a median follow-up of 23.1 months (95% CI, 9.2–37.1), overall response rate in the first 3 months was 95% [95% confidence interval (CI), 89.5–100]; cytokine release syndrome (CRS) was observed in 90% of patients (5% grades ≥3) and grade 1 immune effector cell-associated neurotoxicity syndrome was reported in 2 patients (3%). Median progression-free survival was 15.8 months (95% CI, 11.5–22.4). Surface BCMA was not predictive of response or survival, but soluble BCMA correlated with worse clinical outcomes and CRS severity. Activation marker HLA-DR in the apheresis was associated with longer progression-free survival and increased exhaustion markers correlated with poorer outcomes. ARI0002h kinetics and loss of B-cell aplasia were not predictive of relapse. Conclusions: Despite deep and sustained responses achieved with ARI0002h, we identified several biomarkers that correlate with poor outcomes.