tbuckley/cabot-search huggingface dataset:
Systemic Anticancer Therapy and Overall Survival in Patients With Very Advanced Solid Tumors
Authors: Maureen E. Canavan, Xiaoliang Wang, Mustafa S. Ascha, Rebecca A. Miksad, Timothy N. Showalter, Gregory S. Calip, Cary P. Gross, Kerin B. Adelson
Journal: JAMA Oncology (2024)

Importance Two prominent organizations, the American Society of Clinical Oncology and the National Quality Forum (NQF), have developed a cancer quality metric aimed at reducing systemic anticancer therapy administration at the end of life. This metric, NQF 0210 (patients receiving chemotherapy in the last 14 days of life), has been critiqued for focusing only on care for decedents and not including the broader population of patients who may benefit from treatment. Objective To evaluate whether the overall population of patients with metastatic cancer receiving care at practices with higher rates of oncologic therapy for very advanced disease experience longer survival. Design, Setting, and Participants This nationwide population-based cohort study used Flatiron Health, a deidentified electronic health record database of patients diagnosed with metastatic or advanced disease, to identify adult patients (aged ≥18 years) with 1 of 6 common cancers (breast cancer, colorectal cancer, non–small cell lung cancer [NSCLC], pancreatic cancer, renal cell carcinoma, and urothelial cancer) treated at health care practices from 2015 to 2019. Practices were stratified into quintiles based on retrospectively measured rates of NQF 0210, and overall survival was compared by disease type among all patients treated in each practice quintile from time of metastatic diagnosis using multivariable Cox proportional hazard models with a Bonferroni correction for multiple comparisons. Data were analyzed from July 2021 to July 2023. Exposure Practice-level NQF 0210 quintiles. Main Outcome and Measure Overall survival. Results Of 78 446 patients (mean [SD] age, 67.3 [11.1] years; 52.2% female) across 144 practices, the most common cancer types were NSCLC (34 201 patients [43.6%]) and colorectal cancer (15 804 patients [20.1%]). Practice-level NQF 0210 rates varied from 10.9% (quintile 1) to 32.3% (quintile 5) for NSCLC and 6.8% (quintile 1) to 28.4% (quintile 5) for colorectal cancer. No statistically significant differences in survival were observed between patients treated at the highest and the lowest NQF 0210 quintiles. Compared with patients seen at practices in the lowest NQF 0210 quintiles, the hazard ratio for death among patients seen at the highest quintiles varied from 0.74 (95% CI, 0.55-0.99) for those with renal cell carcinoma to 1.41 (95% CI, 0.98-2.02) for those with urothelial cancer. These differences were not statistically significant after applying the Bonferroni-adjusted critical P = .008. Conclusions and Relevance In this cohort study, patients with metastatic or advanced cancer treated at practices with higher NQF 0210 rates did not have improved survival. Future efforts should focus on helping oncologists identify when additional therapy is futile, developing goals of care communication skills, and aligning payment incentives with improved end-of-life care.
mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models
Authors: Xuesong Wang, Christopher A. Cottrell, Xiaozhen Hu, Rashmi Ray, Maria Bottermann, Paula Maldonado Villavicencio, Yu Yan, Zhenfei Xie, John E. Warner, Jordan Renae Ellis-Pugh, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Sergey Menis, Sebastian Rämisch, Saman Eskandarzadeh, Michael Kubitz, Ryan Tingle, Nicole Phelps, Bettina Groschel, Sunny Himansu, Andrea Carfi, Kathrin H. Kirsch, Stephanie R. Weldon, Usha Nair, William R. Schief, Facundo D. Batista
Journal: Science Immunology (2024)

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.
Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis
Authors: Junqin Li, Ying Wang, Xuping Niu, Jianxiao Xing, Yu Dou, Yuanjun Yao, Yanyang Liang, Zehong Wang, Qiang Wang, Haiyan Feng, Aihong Peng, Yi Guo, Huifang Liang, Yaxin Guo, Juan Li, Ruixia Hou, Yueai Cheng, Tong Qu, Xinhua Li, Guohua Yin, Kaiming Zhang
Journal: British Journal of Dermatology (2024)

Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases.
Asciminib monotherapy in patients with chronic-phase chronic myeloid leukemia with the T315I mutation after ≥1 prior tyrosine kinase inhibitor: 2-year follow-up results
Authors: Jorge E. Cortes, Koji Sasaki, Dong-Wook Kim, Timothy P. Hughes, Gabriel Etienne, Michael J. Mauro, Andreas Hochhaus, Fabian Lang, Michael C. Heinrich, Massimo Breccia, Michael Deininger, Yeow Tee Goh, Jeroen J.W.M. Janssen, Moshe Talpaz, Valle Gomez Garcia de Soria, Philipp le Coutre, Daniel J. DeAngelo, Andrea Damon, Silvia Cacciatore, Fotis Polydoros, Nithya Agrawal, Delphine Rea
Journal: Leukemia (2024)

Abstract Asciminib targets the BCR::ABL1 myristoyl pocket, maintaining activity against BCR::ABL1 T315I , which is resistant to most approved adenosine triphosphate–competitive tyrosine kinase inhibitors. We report updated phase I results (NCT02081378) assessing safety/tolerability and antileukemic activity of asciminib monotherapy 200 mg twice daily in 48 heavily pretreated patients with T315I-mutated chronic-phase chronic myeloid leukemia (CML-CP; data cutoff: January 6, 2021). With 2 years’ median exposure, 56.3% of patients continued receiving asciminib. Overall, 62.2% of evaluable patients achieved BCR::ABL1 ≤1% on the International Scale (IS); 47.6% and 81.3% of ponatinib-pretreated and -naive patients, respectively, achieved BCR::ABL1 IS ≤1%. Of 45 evaluable patients, 48.9% achieved a major molecular response (MMR, BCR::ABL1 IS ≤0.1%), including 34.6% and 68.4% of ponatinib-pretreated and -naive patients, respectively. MMR was maintained until data cutoff in 19 of 22 patients who achieved it. The most common grade ≥3 adverse events (AEs) included increased lipase level (18.8%) and thrombocytopenia (14.6%). Five (10.4%) patients experienced AEs leading to discontinuation, including 2 who discontinued asciminib and died due to COVID-19; these were the only deaths reported. These results show asciminib’s effectiveness, including in almost 50% of ponatinib pretreated patients, and confirm its risk-benefit profile, supporting its use as a treatment option for T315I-mutated CML-CP.
Fibroblasts with high matrix metalloproteinase 2 expression regulate CD8+ T-cell residency and inflammation via CD100 in psoriasis
Authors: Canbin Dong, Jui-Ming Lin, Xiaonian Lu, Junhao Zhu, Lanmei Lin, Jinhua Xu, Juan Du
Journal: British Journal of Dermatology (2024)

Abstract Background Psoriasis is a T cell-mediated chronic inflammatory skin condition characterized by the interaction of T cells with various cell types, forming an inflammatory microenvironment that sustains psoriatic inflammation. Homeostasis of these tissue-resident T cells is supported by fibroblasts, the primary structural cells in the dermis. In psoriasis, there is increased expression of matrix metalloproteinase 2 (MMP2), mediating structural alterations in skin tissues and modulating inflammation. Additionally, the CD100–plexin-B2 (PLXNB2) axis is known to enhance psoriasis inflammation via keratinocytes, and CD103 levels are associated with the severity of psoriasis upon relapse. Objectives To elucidate the role of fibroblasts and the MMP2–CD100 axis in modulating psoriasis inflammation. Methods CD100 expression and function in psoriasis were assessed using immunofluorescence, enzyme-linked immunosorbent assay, single-cell transcriptome sequencing, cellular interaction analyses and quantitative reverse transcriptase polymerase chain reaction. CD8+ T cells from people with psoriasis were isolated using magnetic beads, to investigate the regulatory effect of MMP2 on CD100 expression on their membranes. Single-cell transcriptome sequencing, spatial transcriptome sequencing, mimetic timing analysis, immunofluorescence and flow cytometry were used to determine the origin of MMP2 and its impact on CD103+ CD8+ T cells. The hypotheses were further validated in vivo using MMP2 and CD100 inhibitors. Results Soluble CD100 (sCD100) was significantly upregulated in both psoriatic lesions and peripheral blood, amplifying psoriasis inflammation by promoting the production of inflammatory cytokines by keratinocytes, fibroblasts and endothelial cells via the sCD100–PLXNB2 axis. Fibroblasts that highly expressed MMP2 (MMP2hi) exacerbated psoriasis symptoms by facilitating CD100 shedding from CD8+ T-cell membranes. Additionally, it was shown that fibroblasts enhance the upregulation of the CD8+ T-cell residency factor CD103 in co-cultures with CD8+ T cells. Inhibitors targeting MMP2 and CD100 were effective in reducing inflammation in an imiquimod-induced psoriasis model. Conclusions Our findings underscore the pivotal role of MMP2hi fibroblasts in the amplification and recurrence of inflammatory responses in psoriasis. These fibroblasts augment psoriasis inflammation through the CD100–PLXNB2 axis by facilitating CD100 shedding on CD8+ T-cell membranes and by upregulating CD103, thereby enhancing CD8+ T-cell residency.
Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib
Authors: Jennifer A. Woyach, Daniel Jones, Wojciech Jurczak, Tadeusz Robak, Árpád Illés, Arnon P. Kater, Paolo Ghia, John C. Byrd, John F. Seymour, Susan Long, Nehad Mohamed, Samon Benrashid, Tzung-Huei Lai, Gary De Jesus, Richard Lai, Gerjan de Bruin, Simon Rule, Veerendra Munugalavadla
Journal: Blood (2024)

Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from patients with relapsed/refractory CLL in ELEVATE-RR (NCT02477696; median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up, 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF, 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and 1 ibrutinib-treated patient had emergent TP53/BTK comutations. Emergent PLCG2 mutations occurred in 3 acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.
Metastasis-Free Survival Versus Treatment-Free Survival in Biochemically Recurrent Prostate Cancer: The EMBARK Trial
Authors: David J. Einstein, Meredith M. Regan, Julia S. Stevens, David F. McDermott, Ravi A. Madan
Journal: Journal of Clinical Oncology (2024)

What is most important to patients with BCR prostate cancer? Metastasis-free versus treatment-free survival.
Evolution of the spectrum of drugs associated with acute generalized exanthematous pustulosis over time: A pharmacovigilance study
Authors: Ilaria Matei, Thomas Bettuzzi, Bastien Peiffer, Saskia Ingen-Housz-Oro, Emilie Sbidian, Bénédicte Lebrun-Vignes
Journal: Journal of the American Academy of Dermatology (2024)
miR-99b-5p, miR-380-3p, and miR-485-3p are novel chemosensitizing miRNAs in high-risk neuroblastoma
Authors: Holly Holliday, Jessica Yang, Eoin Dodson, Iva Nikolic, Alvin Kamili, Madeleine Wheatley, Niantao Deng, Sarah Alexandrou, Thomas P. Davis, Maria Kavallaris, C. Elizabeth Caldon, Joshua McCarroll, Katleen De Preter, Pieter Mestdagh, Glenn M. Marshall, Kaylene J. Simpson, Jamie Fletcher, Alexander Swarbrick
Journal: Molecular Therapy (2024)
Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling
Authors: Joseph Adu-Amankwaah, Adebayo Oluwafemi Adekunle, Ziqing Tang, Aisha Bushi, Rubin Tan, Lu Fu, Zheng Gong, Ziyu Ma, Richard Mprah, Marie Louise Ndzie Noah, Prosperl Ivette Wowui, Jeremiah Ong'achwa Machuki, Xiuhua Pan, Tao Li, Hong Sun
Journal: Metabolism (2024)
Controlling the hospital aquatic reservoir of multidrug-resistant organisms: a cross-sectional study followed by a nested randomized trial of sink decontamination
Authors: Gaud Catho, Charlotte Cave, Rebecca Grant, Jennifer Carry, Yves Martin, Gesuele Renzi, Aude Nguyen, Niccolò Buetti, Jacques Schrenzel, Stephan Harbarth
Journal: Clinical Microbiology and Infection (2024)

The hospital water environment is an important reservoir of multidrug-resistant organisms (MDROs) and presents a risk for patient safety. We assessed the effectiveness of thermal and chemical interventions on sinks contaminated with MDRO in the hospital setting.
SIRT5 exacerbates eosinophilic chronic rhinosinusitis by promoting polarization of M2 macrophage
Authors: Xu-Dong Cha, Qing-Yun Zou, Feng-Zhen Li, Tian-Yu Wang, Sheng-Lei Wang, Bo-Yu Cai, Zhi-Wen Cao, Zhen-Hua Ji, Hai-Bin Liu, Wen-Wen Wang, Teng-Fei Li, Cai-Quan Liang, Wen-Wen Ren, Huan-Hai Liu
Journal: Journal of Allergy and Clinical Immunology (2024)
A novel syndrome of silent rhinovirus-associated bronchoalveolitis in children with recurrent wheeze
Authors: W. Gerald Teague, Cameron D. Griffiths, Kelly Boyd, Stella C. Kellams, Monica Lawrence, Thomas L. Offerle, Peter Heymann, William Brand, Ariana Greenwell, Jeremy Middleton, Kristin Wavell, Jacqueline Payne, Marthajoy Spano, Elaine Etter, Brittany Wall, Larry Borish
Journal: Journal of Allergy and Clinical Immunology (2024)
Increases and decreases in liver stiffness measurement are independently associated with the risk of liver-related events in NAFLD
Authors: Samer Gawrieh, Eduardo Vilar-Gomez, Laura A. Wilson, Francis Pike, David E. Kleiner, Brent A. Neuschwander-Tetri, Anna Mae Diehl, Srinivasan Dasarathy, Kris V. Kowdley, Bilal Hameed, James Tonascia, Rohit Loomba, Arun J. Sanyal, Naga Chalasani
Journal: Journal of Hepatology (2024)
A Real-World Assessment of Stage I Lung Cancer Through Electronic Nose Technology
Authors: Gaetano Rocco, Giorgio Pennazza, Kay See Tan, Stijn Vanstraelen, Marco Santonico, Robert J Corba, Bernard J Park, Smita Sihag, Matthew J Bott, Pierfilippo Crucitti, James M Isbell, Michelle S Ginsberg, Hallie Weiss, Raffaele Antonelli Incalzi, Panaiotis Finamore, Filippo Longo, Alessandro Zompanti, Simone Grasso, Stephen B Solomon, Alain Vincent, Alexa McKnight, Michael Cirelli, Carmela Voli, Susan Kelly, Mario Merone, Daniela Molena, Katherine Gray, James Huang, Valerie W Rusch, Manjit S Bains, Robert J Downey, Prasad S Adusumilli, David R Jones
Journal: Journal of Thoracic Oncology (2024)
Abstract P252: Baseline Cognitive and Physical Function and Subsequent Occupational Status in Chinese Adults
Authors: Annie Green Howard, Ellie Balakrishnan, Hsiao Tien, Shufa Du, Bing Zhang, Huijun Wang, John A Batsis, Hillary Spangler, Linda Adair, Penny Gordon-Larsen
Journal: Circulation (2024)

Background: Declines in cognitive and physical function in later adulthood can have an impact whether or not individuals remain in the workforce, although the relationship is complex and often bidirectional. Little is also known about how this relationship differs in rural versus urban populations. We capitalized on longitudinal data in an urbanizing population to estimate the differential impact of urbanization level with cognitive and physical function on remaining in the work force. Methods: We used longitudinal data from 5,228 adults in the China Health and Nutrition Survey aged 58+ to assess the association between cognitive and physical function at the 2015 survey with whether older adults remained in the work force, based on self-report of either formal or informal work, in 2018. We defined cognitive function using a global cognitive score based on a subset of the modified Telephone Interview for Cognitive Status (TICS) and physical function using limitations as measured by instrumental activities of daily living (IADLs). Given differences in demographics of working status in urban (urban areas or small towns) versus rural villages, we included an interaction term for cognitive function by urban versus rural village residence. In minimally adjusted models, we controlled for age and gender and in fully adjusted models we additionally adjusted for birth cohort, education, region, marital status, and income. Results: In 2018, 48% of adults lived in rural villages and 41% were currently working. In rural villages, we found individuals with any (versus no) physical limitations in 2015 in were more likely to be working in 2018: Any IADL limitations versus no limitations: (OR=0.47 [95% confidence interval (CI) of 0.34-0.65). However, in urban areas, individuals with any (versus no) physical limitations in 2015 were more likely to be working in 2018: Any IADL limitations versus no limitations: OR=2.44 (1.18,5.03). We found no evidence of differential association between cognitive function and subsequent working status in the total sample or by rural village residence in the minimally or fully adjusted models. Conclusion: Physical (but not cognitive) function at baseline impacts future occupational status differently for those in rural versus urban areas which could reflect differences in the types of work being done as well as differences in the availability of economic resources between rural versus urban areas.
Abstract P246: Geographical Mapping and Cluster Analysis of Ischemic Stroke in Kentucky
Authors: Solina Ngam, Hend Mansoor, Daniel Manion, Jayani Jayawardhana, Chris Delcher
Journal: Circulation (2024)

Background: Stroke death is the third leading cause of death in the United States, the sixth leading cause of death in Kentucky (KY), and ischemic stroke (IS) is the most prevalent type in adults (~85%). Small area estimates of stroke incidence can help identify local interventions to lower the burden of vascular risk factors and risk of recurrent IS in these areas. Therefore, the goals of this study are to calculate small area IS incidence rates, examine clusters, and understand the distribution of IS in KY. Methods: Data was obtained from the Kentucky Hospital Inpatient Discharge and Outpatient Services Databases (HIDOSD) from 2012 to 2021; and the Kentucky Cabinet for Health and Family Services. HIDOSD represents KY emergency department discharges, inpatient data, and ambulatory facility services. We linked 5-digit Zip codes to (n=759) zip code tabulation areas (ZCTA) available from the US Census Bureau. The annualized IS rate per 100,000 was calculated by dividing the mean number of IS hospitalizations from 2012 to 2021 by the ZCTA 2020 population. We categorized IS rates by quartiles and calculated box plots in descriptive analyses. We tested for significant spatial clusters using the Local Moran’s I with Empirical Bayes rate smoothing in GeoDa. Results: From 2012-2021, 90,840 IS hospitalizations were reported in KY. The median IS rate was 226.5 per 100,000. The median rate in the highest quartile was 290.8 (IQR 171.7 - 290.8) vs 171.7 (IQR 171.7 - 290.8) in the lowest quartile. An area of high IS rate clusters (n=20) was identified in southeastern KY with lower clusters dispersed throughout the state. Figure. Conclusions: This 10-year analysis of IS hospitalizations across KY identified areas of potential intervention. Future efforts are needed to identify the social and medical contributors driving burden of IS in these areas and to design interventions targeted to improve health outcomes.