tbuckley/cabot-search huggingface dataset:
Engineered Tumor–Immune Microenvironment On A Chip to Study T Cell–Macrophage Interaction in Breast Cancer Progression
Authors: Twinkle Jina Minette Manoharan, Kalpana Ravi, Abhirami P. Suresh, Abhinav P. Acharya, Mehdi Nikkhah
Journal: Advanced Healthcare Materials (2024)

Evolving knowledge about the tumor-immune microenvironment (TIME) is driving innovation in designing novel therapies against hard-to-treat breast cancer. Targeting the immune components of TIME has emerged as a promising approach for cancer therapy. While recent immunotherapies aim at restoring antitumor immunity, counteracting tumor escape remains challenging. Hence there is a pressing need to better understand the complex tumor-immune crosstalk within TIME. Considering this imperative, this study aims at investigating the crosstalk between the two abundant immune cell populations within the breast TIME-macrophages and T cells, in driving tumor progression using an organotypic 3D in vitro tumor-on-a-chip (TOC) model. The TOC features distinct yet interconnected organotypic tumor and stromal entities. This triculture platform mimics the complex TIME, embedding the two immune populations in a suitable 3D matrix. Analysis of invasion, morphometric measurements, and flow cytometry results underscores the substantial contribution of macrophages to tumor progression, while the presence of T cells is associated with a deceleration in the migratory behavior of both cancer cells and macrophages. Furthermore, cytokine analyses reveal significant upregulation of leptin and RANTES (regulated on activation, normal T Cell expressed and secreted) in triculture. Overall, this study highlights the complexity of TIME and the critical role of immune cells in cancer progression.
Author Correction: Mucosal vaccine-induced cross-reactive CD8+ T cells protect against SARS-CoV-2 XBB.1.5 respiratory tract infection
Authors: Baoling Ying, Tamarand L. Darling, Pritesh Desai, Chieh-Yu Liang, Igor P. Dmitriev, Nadia Soudani, Traci Bricker, Elena A. Kashentseva, Houda Harastani, Saravanan Raju, Meizi Liu, Aaron G. Schmidt, David T. Curiel, Adrianus C. M. Boon, Michael S. Diamond
Journal: Nature Immunology (2024)
Accurate and sensitive mutational signature analysis with MuSiCal
Authors: Hu Jin, Doga C. Gulhan, Benedikt Geiger, Daniel Ben-Isvy, David Geng, Viktor Ljungström, Peter J. Park
Journal: Nature Genetics (2024)

Abstract Mutational signature analysis is a recent computational approach for interpreting somatic mutations in the genome. Its application to cancer data has enhanced our understanding of mutational forces driving tumorigenesis and demonstrated its potential to inform prognosis and treatment decisions. However, methodological challenges remain for discovering new signatures and assigning proper weights to existing signatures, thereby hindering broader clinical applications. Here we present Mutational Signature Calculator (MuSiCal), a rigorous analytical framework with algorithms that solve major problems in the standard workflow. Our simulation studies demonstrate that MuSiCal outperforms state-of-the-art algorithms for both signature discovery and assignment. By reanalyzing more than 2,700 cancer genomes, we provide an improved catalog of signatures and their assignments, discover nine indel signatures absent in the current catalog, resolve long-standing issues with the ambiguous ‘flat’ signatures and give insights into signatures with unknown etiologies. We expect MuSiCal and the improved catalog to be a step towards establishing best practices for mutational signature analysis.
Correction:<i>Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis</i>
Journal: Annals of the Rheumatic Diseases (2024)

The Patient and public involvement statement should read: An ongoing longitudinal AS cohort was used for the study with the approval of the UHN research ethics board (REB# 21-5565).All patients and healthy controls (HC) provided written consent to participate.AS patients fulfilled the modified New York AS criteria. 30 31AS patients (n=40) had an average age of 47±10 years, while HC (n=28) had an average age of 37±11 years.Table 1 provides the characteristics of all study participants.Subsets of this cohort were chosen for conducting all experiments detailed in this paper, including the sequencing of miRNAs and the immunophenotyping of exosomes.
Dissecting the sequence and structural determinants guiding m6A deposition and evolution via inter- and intra-species hybrids
Authors: Ran Shachar, David Dierks, Miguel Angel Garcia-Campos, Anna Uzonyi, Ursula Toth, Walter Rossmanith, Schraga Schwartz
Journal: Genome biology (2024)

N6-methyladenosine (m6A) is the most abundant mRNA modification, and controls mRNA stability. m6A distribution varies considerably between and within species. Yet, it is unclear to what extent this variability is driven by changes in genetic sequences ('cis') or cellular environments ('trans') and via which mechanisms.
Mapping AML heterogeneity - multi-cohort transcriptomic analysis identifies novel clusters and divergent ex-vivo drug responses
Authors: Jeppe F. Severens, E. Onur Karakaslar, Bert A. van der Reijden, Elena Sánchez-López, Redmar R. van den Berg, Constantijn J. M. Halkes, Peter van Balen, Hendrik Veelken, Marcel J. T. Reinders, Marieke Griffioen, Erik B. van den Akker
Journal: Leukemia (2024)

Subtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n = 1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA-mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A, NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.
Area-Level Socioeconomic Disadvantage and Health Care Spending
Authors: Anna M. Morenz, Joshua M. Liao, David H. Au, Sophia A. Hayes
Journal: JAMA Network Open (2024)

Importance Publicly available, US Census–based composite measures of socioeconomic disadvantage are increasingly being used in a wide range of clinical outcomes and health services research. Area Deprivation Index (ADI) and Social Vulnerability Index (SVI) are 2 of the most commonly used measures. There is also early interest in incorporating area-level measures to create more equitable alternative payment models. Objective To review the evidence on the association of ADI and SVI with health care spending, including claims-based spending and patient-reported barriers to care due to cost. Evidence Review A systematic search for English-language articles and abstracts was performed in the PubMed, Web of Science, Embase, and Cochrane databases (from inception to March 1, 2023). Peer-reviewed articles and abstracts using a cross-sectional, case-control, or cohort study design and based in the US were identified. Data analysis was performed in March 2023. Findings This review included 24 articles and abstracts that used a cross-sectional, case-control, or cohort study design. In 20 of 24 studies (83%), ADI and SVI were associated with increased health care spending. No association was observed in the 4 remaining studies, mostly with smaller sample sizes from single centers. In adjusted models, the increase in spending associated with higher ADI or SVI residence was $574 to $1811 for index surgical hospitalizations, $3003 to $24 075 for 30- and 90-day episodes of care, and $3519 for total annual spending for Medicare beneficiaries. In the studies that explored mechanisms, postoperative complications, readmission risk, and poor primary care access emerged as health care system–related drivers of increased spending. Conclusions and Relevance The findings of this systematic review suggest that both ADI and SVI can play important roles in efforts to understand drivers of health care spending and in the design of payment and care delivery programs that capture aspects of social risk. At the health care system level, higher health care spending and poor care access associated with ADI or SVI may represent opportunities to codesign interventions with patients from high ADI or SVI areas to improve access to high-value health care and health promotion more broadly.
Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts
Authors: Timothy P. DiPeri, Kurt W. Evans, Bailiang Wang, Ming Zhao, Argun Akcakanat, Maria Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Anil Korkut, Kaushik Varadarajan, Burak Uzunparmak, Ecaterina E. Dumbrava, Shubham Pant, Jaffer A. Ajani, Paula R. Pohlmann, V. Behrana Jensen, Milind Javle, Jordi Rodon, Funda Meric-Bernstam
Journal: Cancer Discovery (2024)

Abstract Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance. Significance: We demonstrate that PDXs can be developed from pretreatment and postprogression biopsies in clinical trials and may represent a powerful preclinical tool. We identified amplification of MET as a potential mechanism of acquired resistance to the HER2 inhibitor zanidatamab and MET inhibitors alone and in combination as a therapeutic strategy. This article is featured in Selected Articles from This Issue, p. 695
Hepatitis A Exposure Response and Outbreak Prevention in a Large Urban Jail — Los Angeles County, California, May–July 2023
Authors: Nazia S. Qureshi, Alma J. Villatoro, Ngoc Dung T. Tran, Sulma J. Herrera, Stephen P. Judge, Ling Fang, Sean O. Henderson, Kristy A. Stanley
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Correctional settings provide a high-risk environment for hepatitis A transmission because of the high proportion of homelessness and injection drug use among persons who are incarcerated.On May 30, 2023, Los Angeles County Department of Public Health informed the Communicable Disease Surveillance and Control (CDSC) unit of the Los Angeles County Jail system that a symptomatic incarcerated person had received a positive test result for acute hepatitis A. Upon learning the next day that the patient was a food handler, CDSC staff members identified 5,830 potential contacts of the index patient, 1,702 of whom had been released from the jail.During June 1-12, a total of 2,766 contacts who did not have a documented history of hepatitis A serology or vaccination that could be confirmed from the electronic health record or state immunization registry were identified.These persons were offered hepatitis A vaccination as postexposure prophylaxis; 1,510 (54.6%) accepted vaccination.Contacts who were food handlers without confirmed evidence of immunity and who declined vaccination were removed from food-handling duties for the duration of their potential incubation period.No additional cases were identified.Identifying contacts promptly and using immunization and serology records to ensure rapid delivery of postexposure prophylactic vaccine can help prevent hepatitis A transmission during exposures among incarcerated populations.
Surveillance for Lyme Disease After Implementation of a Revised Case Definition — United States, 2022
Authors: Kiersten J. Kugeler, Austin Earley, Paul S. Mead, Alison F Hinckley
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Lyme disease, a tickborne zoonosis caused by certain species of Borrelia spirochetes, is the most common vectorborne disease in the United States.Approximately 90% of all cases are reported from 15 high-incidence jurisdictions in the Northeast, mid-Atlantic, and upper-Midwest regions.After the implementation of a revised surveillance case definition in 2022, high-incidence jurisdictions report cases based on laboratory evidence alone, without need for additional clinical information.In 2022, 62,551 Lyme disease cases were reported to CDC, 1.7 times the annual average of 37,118 cases reported during 2017-2019.Annual incidence increased most in older age groups, with incidence among adults aged ≥65 years approximately double that during 2017-2019.The sharp increase in reported Lyme disease cases in 2022 likely reflects changes in surveillance methods rather than change in disease risk.Although these changes improve standardization of surveillance across jurisdictions, they preclude detailed comparison with historical data.
Ann Robinson’s research reviews—15 February 2024
Authors: Ann Robinson
Journal: BMJ (2024)

Resmetirom for non-alcoholic steatohepatitisThe global incidence of non-alcoholic fatty liver disease is estimated to be one in 20.About a fifth of cases will cause liver cell inflammation and damage known as non-alcoholic steatohepatitis (NASH).As NASH progresses to severe fibrosis and on to cirrhosis, the risk of death from liver disease increases.Lifestyle changes help early stage NASH, but there's no approved drug treatment as yet.
Long-Term Health Outcomes of Traumatic Brain Injury in Veterans
Authors: Elie Massaad, Ali Kiapour
Journal: JAMA Network Open (2024)

Ian J. Stewart, MD; Jeffrey T. Howard, PhD; Eduard Poltavskiy, PhD; Michael Dore, MD; Megan E. Amuan, MPH; Krista Ocier, PhD, MPH; Lauren E. Walker, MSSW; Karl C. Alcover, PhD; Mary Jo Pugh, PhD
Depths of Dysfunctional Epithelial and Immune Crosstalk in Cystic Fibrosis Revealed
Authors: Lael M. Yonker, T. Bernard Kinane
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Depths of Dysfunctional Epithelial and Immune Crosstalk in Cystic Fibrosis Revealed." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Routes of Drug Use Among Drug Overdose Deaths — United States, 2020–2022
Authors: Lauren J. Tanz, R. Matt Gladden, Amanda T. Dinwiddie, Kimberly D. Miller, Dita Broz, Eliot Spector, Julie O’Donnell
Journal: MMWR Morbidity and Mortality Weekly Report (2024)

Preliminary reports indicate that more than 109,000 drug overdose deaths occurred in the United States in 2022; nearly 70% of these involved synthetic opioids other than methadone, primarily illegally manufactured fentanyl and fentanyl analogs (IMFs).Data from the western United States suggested a transition from injecting heroin to smoking IMFs.CDC analyzed data from the State Unintentional Drug Overdose Reporting System to describe trends in routes of drug use in 27 states and the District of Columbia among overdose deaths that occurred during January 2020-December 2022, overall and by region and drugs detected.From January-June 2020 to July-December 2022, the percentage of overdose deaths with evidence of injection decreased 29.1%, from 22.7% to 16.1%, whereas the percentage with evidence of smoking increased 73.7%, from 13.3% to 23.1%.The number of deaths with evidence of smoking increased 109.1%, from 2,794 to 5,843, and by 2022, smoking was the most commonly documented route of use in overdose deaths.Trends were similar in all U.S. regions.Among deaths with only IMFs detected, the percentage with evidence of injection decreased 41.6%, from 20.9% during January-June 2020 to 12.2% during July-December 2022, whereas the percentage with evidence of smoking increased 78.9%, from 10.9% to 19.5%.Similar trends were observed among deaths with both IMFs and stimulants detected.Strengthening public health and harm reduction services to address overdose risk related to diverse routes of drug use, including smoking and other noninjection routes, might reduce drug overdose deaths.* https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm(Accessed January 11, 2024).to smoking IMFs; however, limited data exist on recent changes in routes of drug use for all drugs, and for IMFs beyond the western United States † (3,4).Routes of drug use have implications for overdose risk, infectious disease transmission, other comorbidities, and harm reduction services (5).
Decentralized Clinical Trials as a New Paradigm of Trial Delivery to Improve Equity of Access
Authors: Craig Underhill, Jessica Freeman, Jacqueline Dixon, Mark Buzza, Donna Long, Kate Burbury, Sabe Sabesan, Jacqueline McBurnie, Anne Woollett
Journal: JAMA Oncology (2024)

The need to maintain clinical trial recruitment during the COVID-19 pandemic has precipitated the rapid uptake of digital health for the conduct of clinical trials. Different terms are used in different jurisdictions and clinical contexts, including digital trials, networked trials, teletrials (TT), and decentralized clinical trials (DCT) with a need to agree to terms.
Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma Clinical Trials: An FDA Educational Symposium
Authors: Jason Fangusaro, Robert A. Avery, Michael J. Fisher, Roger J. Packer, Karin S. Walsh, Antoinette Schouten-van Meeteren, Dominik Karres, Diana Bradford, Vishal Bhatnagar, Harpreet Singh, Paul G. Kluetz, Martha Donoghue, Elizabeth S. Duke
Journal: Clinical Cancer Research (2024)

Abstract In October 2022, the FDA Oncology Center of Excellence hosted an educational symposium entitled, “Considering Functional Outcomes as Efficacy Endpoints in Pediatric Low-Grade Glioma (pLGG) Clinical Trials.” The symposium brought together patient advocates, regulators from the FDA and the European Medicines Agency (EMA), and an international group of academic thought leaders in the field of pediatric neuro-oncology to discuss the potential role of functional outcomes, including visual acuity, motor function, and neurocognitive performance, as endpoints in clinical trials enrolling patients with pLGG. The panel discussed challenges and opportunities regarding the selection, implementation, and evaluation of clinical outcome assessments in these functional domains and outlined key considerations for their inclusion in future clinical trial design and role in new drug development.
Traumatic Brain Injury and Subsequent Risk of Brain Cancer in US Veterans of the Iraq and Afghanistan Wars
Authors: Ian J. Stewart, Jeffrey T. Howard, Eduard Poltavskiy, Michael Dore, Megan E. Amuan, Krista Ocier, Lauren E. Walker, Karl C. Alcover, Mary Jo Pugh
Journal: JAMA Network Open (2024)

Importance While brain cancer is rare, it has a very poor prognosis and few established risk factors. To date, epidemiologic work examining the potential association of traumatic brain injury (TBI) with the subsequent risk of brain cancer is conflicting. Further data may be useful. Objective To examine whether a history of TBI exposure is associated with the subsequent development of brain cancer. Design, Setting, and Participants A retrospective cohort study was conducted from October 1, 2004, to September 20, 2019, and data analysis was performed between January 1 and June 26, 2023. The median follow-up for the cohort was 7.2 (IQR, 4.1-10.1) years. Veterans Affairs (VA) and Department of Defense (DoD) administrative data on 1 919 740 veterans from the Long-Term Impact of Military-Relevant Brain Injury Consortium–Chronic Effects of Neurotrauma Consortium were included. Exposure The main exposure of interest was TBI severity (categorized as mild, moderate or severe [moderate/severe], and penetrating). Main Outcomes and Measures The outcome of interest was the development of brain cancer based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes in either the DoD/VA medical records or from the National Death Index. Results After 611 107 exclusions (predominately for no encounter during the study period), a cohort including 1 919 740 veterans was included, most of whom were male (80.25%) and non-Hispanic White (63.11%). Median age at index date was 31 (IQR, 25-42) years. The cohort included 449 880 individuals with TBI (mild, 385 848; moderate/severe, 46 859; and penetrating, 17 173). Brain cancer occurred in 318 individuals without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (≤0.06%). After adjustment, moderate/severe TBI (adjusted hazard ratio [AHR], 1.90; 95% CI, 1.16-3.12) and penetrating TBI (AHR, 3.33; 95% CI, 1.71-6.49), but not mild TBI (AHR, 1.14; 95% CI, 0.88-1.47), were associated with the subsequent development of brain cancer. Conclusions and Relevance In this cohort study of veterans of the Iraq and Afghanistan wars, moderate/severe TBI and penetrating TBI, but not mild TBI, were associated with the subsequent development of brain cancer.
Gut enterotype-dependent modulation of gut microbiota and their metabolism in response to xanthohumol supplementation in healthy adults
Authors: Paige E. Jamieson, Eli B. Smart, John A. Bouranis, Jaewoo Choi, Robert E. Danczak, Carmen P. Wong, Ines L. Paraiso, Claudia S. Maier, Emily Ho, Thomas J. Sharpton, Thomas O. Metz, Ryan Bradley, Jan F. Stevens
Journal: Gut Microbes (2024)

Xanthohumol (XN), a polyphenol found in the hop plant (Humulus lupulus), has antioxidant, anti-inflammatory, prebiotic, and anti-hyperlipidemic activity. Preclinical evidence suggests the gut microbiome is essential in mediating these bioactivities; however, relatively little is known about XN's impact on human gut microbiota in vivo. We conducted a randomized, triple-blinded, placebo-controlled clinical trial (ClinicalTrials.gov NCT03735420) to determine safety and tolerability of XN in healthy adults. Thirty healthy participants were randomized to 24 mg/day XN or placebo for 8 weeks. As secondary outcomes, quantification of bacterial metabolites and 16S rRNA gene sequencing were utilized to explore the relationships between XN supplementation, gut microbiota, and biomarkers of gut health. Although XN did not significantly change gut microbiota composition, it did re-shape individual taxa in an enterotype-dependent manner. High levels of inter-individual variation in metabolic profiles and bioavailability of XN metabolites were observed. Moreover, reductions in microbiota-derived bile acid metabolism were observed, which were specific to Prevotella and Ruminococcus enterotypes. These results suggest interactions between XN and gut microbiota in healthy adults are highly inter-individualized and potentially indicate that XN elicits effects on gut health in an enterotype-dependent manner.