tbuckley/cabot-search huggingface dataset:
Spatial transcriptomic analysis reveals local effects of intratumoral fusobacterial infection on DNA damage and immune signaling in rectal cancer
Authors: William P. Duggan, Batuhan Kisakol, Ina Woods, Mohammedreza Azimi, Heiko Dussmann, Joanna Fay, Tony O’Grady, Barry Maguire, Ian S. Reynolds, Manuela Salvucci, Daniel J. Slade, Deborah A. McNamara, John P. Burke, Jochen H.M. Prehn
Journal: Gut Microbes (2024)

Mucinous colorectal cancer (CRC) is a common histological subtype of colorectal adenocarcinoma, associated with a poor response to chemoradiotherapy. The commensal facultative anaerobes fusobacteria, have been associated with poor prognosis specifically in mesenchymal CRC. Interestingly, fusobacterial infection is especially prevalent in mucinous CRC. The objective of this study was therefore to increase our understanding of beneficial and detrimental effects of fusobacterial infection, by contrasting host cell signaling and immune responses in areas of high vs. low infection, using mucinous rectal cancer as a clinically relevant example. We employed spatial transcriptomic profiling of 106 regions of interest from 8 mucinous rectal cancer samples to study gene expression in the epithelial and immune segments across regions of high versus low fusobacterial infection. Fusobacteria high regions were associated with increased oxidative stress, DNA damage, and P53 signaling. Meanwhile regions of low fusobacterial prevalence were characterized by elevated JAK-STAT, Il-17, Il-1, chemokine and TNF signaling. Immune masks within fusobacterial high regions were characterized by elevated proportions of cytotoxic (CD8+) T cells (p = 0.037), natural killer (NK) cells (p < 0.001), B-cells (p < 0.001), and gamma delta T cells (p = 0.003). Meanwhile, fusobacteria low regions were associated with significantly greater M2 macrophage (p < 0.001), fibroblast (p < 0.001), pericyte (p = 0.002), and endothelial (p < 0.001) counts.
Closing the Cervical Cancer Screening Gap—Reaching Sexual and Gender Diverse Populations
Authors: Andrew Fisher, Jessica R. Long, Julie Chor
Journal: JAMA Network Open (2024)

Kelley Baumann, BA; Hannah Matzke, MS, PhD; Caryn E. Peterson, PhD, MS; Stacie Geller, PhD; Rey Flores, MA, BSW; Nikhil G. Prachand, MPH; Hunter K. Holt, MD, MAS
Examining Safer Opioid Supply Policies
Authors: Owen J. Chen, Xi Zhang, Julia X. X. Luo
Journal: JAMA Internal Medicine (2024)

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Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial
Authors: Jordi Rodón, Silvia Damian, Muhammad Furqan, Jesús García-Donas, Hiroo Imai, Antoine Italiano, Iben Spanggaard, Makoto Ueno, Tomoya Yokota, Maria Luisa Veronese, Natalia Oliveira, Xin Li, Aidan Gilmartin, Michael Schaffer, Lipika Goyal
Journal: Nature Medicine (2024)

Abstract Fibroblast growth factor receptor ( FGFR ) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1–FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR- altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1 – FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .
Pro: “Is Spread Through Air Spaces an In Vivo Phenomenon or an Inducible Artifact?”
Authors: Yan Li, Prasad S. Adusumilli, Teh-Ying Chou, Kyuichi Kadota, Mari Mino-Kenudson, Mauro Papotti, Natasha Rekhtman, Yukako Yagi, Yasushi Yatabe, William D. Travis
Journal: Journal of Thoracic Oncology (2024)

In this PRO-CON debate, you will read very different perspectives about a simple question regarding an observation under the microscope: What is the significance of tumor cells in the air spaces of the lung parenchyma beyond the tumor edge of a resected lung cancer? An important underlying question is whether this entire PRO-CON debate is a mere academic exercise or whether spread through air spaces (STAS), as currently defined, describes a clinically useful phenomenon. The journey of STAS began with a complete paradigm shift to reverse the thinking that all air space tumor cells beyond the edge of lung cancers are an artifact. This led to a new concept where STAS could be separated from artifacts with a definition that has proven to be clinically useful. As with any major change in thinking, it is understandable that there would be some disagreement with this paradigm shift. Nevertheless, after a decade since it was described, many pathologists and clinicians around the world have found STAS to provide important information about the behavior of lung cancer. Numerous PRO-STAS articles supporting the usefulness of STAS have been published with clinical data on many thousands of patients from numerous institutions all over the world. In contrast, for the CON-STAS articles, widespread international representation and data are limited. It is now difficult to ignore the numerous reports and is reasonable to consider how to use the presence of STAS in clinical decisions. Hopefully, this PRO-CON debate will further stimulate clinical and scientific investigations aimed at a better understanding of STAS.
Associations Between a Primary Care-Delivered Alcohol-Related Brief Intervention and Subsequent Opioid-Related Outcomes
Authors: Dan V. Blalock, Sophia A. Berlin, Theodore Berkowitz, Valerie A. Smith, Charles Wright, Rachel L. Bachrach, Janet M. Grubber
Journal: American Journal of Psychiatry (2024)

Objective: The co-occurrence of unhealthy alcohol use and opioid misuse is high and associated with increased rates of overdose, emergency health care utilization, and death. The current study examined whether receipt of an alcohol-related brief intervention is associated with reduced risk of negative downstream opioid-related outcomes. Methods: This retrospective cohort study included all VISN-6 Veterans Affairs (VA) patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening results (N=492,748) from 2014 to 2019. Logistic regression was used to examine the association between documentation of an alcohol-related brief intervention and probability of a new 1) opioid prescription, 2) opioid use disorder (OUD) diagnosis, or 3) opioid-related hospitalization in the following year, controlling for demographic and clinical covariates. Results: Of the veterans, 13% (N=63,804) had "positive" AUDIT-C screen results. Of those, 72% (N=46,216) had a documented alcohol-related brief intervention. Within 1 year, 8.5% (N=5,430) had a new opioid prescription, 1.1% (N=698) had a new OUD diagnosis, and 0.8% (N=499) had a new opioid-related hospitalization. In adjusted models, veterans with positive AUDIT-C screen results who did not receive an alcohol-related brief intervention had higher odds of new opioid prescriptions (adjusted odds ratio [OR]=1.10, 95% CI=1.03-1.17) and new OUD diagnoses (adjusted OR=1.19, 95% CI=1.02-1.40), while new opioid-related hospitalizations (adjusted OR=1.19, 95% CI=0.99-1.44) were higher although not statistically significant. Removal of medications for OUD (MOUD) did not impact associations. All outcomes were significantly associated with an alcohol-related brief intervention in unadjusted models. Conclusions: The VA's standard alcohol-related brief intervention is associated with subsequent lower odds of a new opioid prescription or a new OUD diagnosis. Results suggest a reduction in a cascade of new opioid-related outcomes from prescriptions through hospitalizations.
Correspondence to “The effectiveness of pollen allergen immunotherapy on allergic rhinitis over 18 years: A national cohort study in Denmark”
Authors: Celeste Porsbjerg, Benedikt Fritzsching, Nick Freemantle, Marco Contoli, Andreas Kallsoy Slættanes, Christian Woehlk
Journal: Allergy (2024)

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Targeting pathological cells with senolytic drugs reduces seizures in neurodevelopmental mTOR-related epilepsy
Authors: Théo Ribierre, Alexandre Bacq, Florian Donneger, Marion Doladilhe, Marina Maletic, Delphine Roussel, Isabelle Le Roux, Francine Chassoux, Bertrand Devaux, Homa Adle-Biassette, Sarah Ferrand-Sorbets, Georg Dorfmüller, Mathilde Chipaux, Sara Baldassari, Jean-Christophe Poncer, Stéphanie Baulac
Journal: Nature Neuroscience (2024)

Abstract Cortical malformations such as focal cortical dysplasia type II (FCDII) are associated with pediatric drug-resistant epilepsy that necessitates neurosurgery. FCDII results from somatic mosaicism due to post-zygotic mutations in genes of the PI3K-AKT-mTOR pathway, which produce a subset of dysmorphic cells clustered within healthy brain tissue. Here we show a correlation between epileptiform activity in acute cortical slices obtained from human surgical FCDII brain tissues and the density of dysmorphic neurons. We uncovered multiple signatures of cellular senescence in these pathological cells, including p53/p16 expression, SASP expression and senescence-associated β-galactosidase activity. We also show that administration of senolytic drugs (dasatinib/quercetin) decreases the load of senescent cells and reduces seizure frequency in an Mtor S2215F FCDII preclinical mouse model, providing proof of concept that senotherapy may be a useful approach to control seizures. These findings pave the way for therapeutic strategies selectively targeting mutated senescent cells in FCDII brain tissue.
The evolving pattern of the monoclonal protein improves the IMWG 2/20/20 classification for patients with smoldering multiple myeloma
Authors: Anna de Daniel, Luis Gerardo Rodríguez‐Lobato, Natalia Tovar, M. Teresa Cibeira, David F. Moreno, Aina Oliver‐Caldés, Ignacio Isola, Ester Lozano, Joan Bladé, Laura Rosiñol, Carlos Fernández de Larrea
Journal: HemaSphere (2024)

Abstract The 2/20/20 International Myeloma Working Group (IMWG) score is the most employed risk score in clinical practice to evaluate the risk of progression from smoldering multiple myeloma (SMM) to symptomatic multiple myeloma. However, it faces a serious limitation: The risk score is applied at diagnosis and cannot be reapplied. Since a dynamic accurate patient risk assessment for progression is necessary, we aimed to investigate whether the detection of an evolving pattern in serum M‐protein (SMP) improves the identification of high‐risk patients. Eighty‐three patients diagnosed with SMM between 2011 and 2020 were included. Patients were initially classified applying the 2/20/20 IMWG score at baseline and later reclassified depending on the presence of an SMP evolving pattern into six groups. We regrouped the patients into three final risk groups: low‐risk, intermediate‐risk, and high‐risk. The risk of progression at two years for the high‐risk group was 88% and all patients had progressed at 4 years. The performance measurements were superior for the new 2/20/20‐Evolving score independently for the detection of high‐risk patients. We show that the sequential measurement of the SMP is a noninvasive and widely available test that improves the 2/20/20 IMWG risk score.
Bioethicists Today: Results of the Views in Bioethics Survey
Authors: Leah Pierson, Sophie Gibert, Leila Orszag, Haley K. Sullivan, Rachel Yuexin Fei, Govind Persad, Emily A. Largent
Journal: The American Journal of Bioethics (2024)

Bioethicists influence practices and policies in medicine, science, and public health. However, little is known about bioethicists' views. We recently surveyed 824 U.S. bioethicists on a wide range of ethical issues, including topics related to abortion, medical aid in dying, and resource allocation, among others. We also asked bioethicists about their demographic, religious, academic, and professional backgrounds. We find that bioethicists' normative commitments predict their views on bioethical issues. We also find that, in important ways, bioethicists' views do not align with those of the U.S. public: for instance, bioethicists are more likely than members of the public to think abortion is ethically permissible but are less likely to believe compensating organ donors is. Our demographic results indicate the field of bioethics is far less diverse than the U.S. population—less diverse even than other academic disciplines—suggesting far more work needs to be done to build an inclusive field.
APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease
Authors: Juan Fortea, Jordi Pegueroles, Daniel Alcolea, Olivia Belbin, Oriol Dols-Icardo, Lídia Vaqué-Alcázar, Laura Videla, Juan Domingo Gispert, Marc Suárez-Calvet, Sterling C. Johnson, Reisa Sperling, Alexandre Bejanin, Alberto Lleó, Víctor Montal
Journal: Nature Medicine (2024)
Unpredictability of the Fitness Effects of Antimicrobial Resistance Mutations Across Environments in <i>Escherichia coli</i>
Authors: Aaron Hinz, André Amado, Rees Kassen, Claudia Bank, Alex Wong
Journal: Molecular Biology and Evolution (2024)

Abstract The evolution of antimicrobial resistance (AMR) in bacteria is a major public health concern, and antibiotic restriction is often implemented to reduce the spread of resistance. These measures rely on the existence of deleterious fitness effects (i.e. costs) imposed by AMR mutations during growth in the absence of antibiotics. According to this assumption, resistant strains will be outcompeted by susceptible strains that do not pay the cost during the period of restriction. The fitness effects of AMR mutations are generally studied in laboratory reference strains grown in standard growth environments; however, the genetic and environmental context can influence the magnitude and direction of a mutation's fitness effects. In this study, we measure how three sources of variation impact the fitness effects of Escherichia coli AMR mutations: the type of resistance mutation, the genetic background of the host, and the growth environment. We demonstrate that while AMR mutations are generally costly in antibiotic-free environments, their fitness effects vary widely and depend on complex interactions between the mutation, genetic background, and environment. We test the ability of the Rough Mount Fuji fitness landscape model to reproduce the empirical data in simulation. We identify model parameters that reasonably capture the variation in fitness effects due to genetic variation. However, the model fails to accommodate the observed variation when considering multiple growth environments. Overall, this study reveals a wealth of variation in the fitness effects of resistance mutations owing to genetic background and environmental conditions, which will ultimately impact their persistence in natural populations.
Hybrid Cell Membrane‐Based Nanoplatforms for Enhanced Immunotherapy against Cancer and Infectious Diseases
Authors: Xinran Peng, Li Yang, Peiyan Yuan, Xin Ding
Journal: Advanced Healthcare Materials (2024)

Abstract Immunotherapy based on nanoplatforms is a promising approach to treat cancer and infectious diseases, and it has achieved considerable progress in clinical practices. Cell membrane‐based nanoplatforms endow nanoparticles with versatile characteristics, such as half‐life extension, targeting ability, and immune‐system regulation. However, monotypic cell membrane usually fails to provoke strong immune response for immunotherapy while maintaining good biosafety. The integration of different cell‐membrane types provides a promising approach to construct multifunctional nanoplatforms for improved immunotherapeutic efficacy by enhancing immunogenicity or targeting function, evading immune clearance, or combining with other therapeutic modalities. In this review, the design principles, preparation strategies, and applications of hybrid cell membrane‐based nanoplatforms for cancer and infection immunotherapy are first discussed. Furthermore, the challenges and prospects for the potential clinical translation of hybrid cell membrane‐based nanoplatforms are discussed.
Capecitabine or Capecitabine Plus Oxaliplatin Versus Fluorouracil Plus Cisplatin in Definitive Concurrent Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma (CRTCOESC): A Multicenter, Randomized, Open-Label, Phase 3 Trial
Authors: Ruinuo Jia, Tanyou Shan, Anping Zheng, Yaowen Zhang, Ping Lu, Guifang Zhang, Feng Wang, Zhiqiao Xu, Guobao Zheng, Dongxia Tang, Weiguo Zhang, Wanying Li, Ruonan Li, Yibo Guo, Lina Liu, Xiaoyong Luo, Yingjuan Zheng, Zhiwei Chang, Qiming Wang, Xinshuai Wang, Xiaozhi Yuan, Guoqiang Kong, Shuoguo Li, Ruina Yang, Dan Zhou, Jing Ren, Weijiao Yin, Jingxia Li, Junqian Zhang, Ziqi Wang, Manxi Sheng, Bingyi Xu, Liuyan Li, Xiaoyi Liu, Zhihao Lu, Lixin Wan, Fuyou Zhou, Shegan Gao
Journal: Journal of Clinical Oncology (2024)

PURPOSE This phase 3 trial aimed to compare the efficacy and safety of capecitabine or capecitabine plus oxaliplatin (XELOX) with those of fluorouracil plus cisplatin (PF) in definitive concurrent chemoradiotherapy (DCRT) for inoperable locally advanced esophageal squamous cell carcinoma (ESCC). METHODS Patients were randomly assigned to receive two cycles of capecitabine, XELOX, or PF along with concurrent intensity-modulated radiation therapy. Patients in each arm were again randomly assigned to receive two cycles of consolidation chemotherapy or not. The primary end points were 2-year overall survival (OS) rate and incidence of grade ≥3 adverse events (AEs). RESULTS A total of 246 patients were randomly assigned into the capecitabine (n = 80), XELOX (n = 85), and PF (n = 81) arms. In capecitabine, XELOX, and PF arms, the 2-year OS rate was 75%, 66.7%, and 70.9% (capecitabine v PF: hazard ratio [HR], 0.91 [95% CI, 0.61 to 1.35]; nominal P = .637; XELOX v PF: 0.86 [95% CI, 0.58 to 1.27]; P = .444); the median OS was 40.9 (95% CI, 34.4 to 49.9), 41.9 (95% CI, 28.6 to 52.1), and 35.4 (95% CI, 30.4 to 45.4) months. The incidence of grade ≥3 AEs during the entire treatment was 28.8%, 36.5%, and 45.7%, respectively. Comparing the consolidation chemotherapy with the nonconsolidation chemotherapy groups, the median OS was 41.9 (95% CI, 34.6 to 52.8) versus 36.9 (95% CI, 28.5 to 44) months (HR, 0.71 [95% CI, 0.52 to 0.99]; nominal P = .0403). CONCLUSION Capecitabine or XELOX did not significantly improve the 2-year OS rate over PF in DCRT for inoperable locally advanced ESCC. Capecitabine showed a lower incidence of grade ≥3 AEs than PF did.
Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116)
Authors: Stephen R. Rapp, Emily V. Dressler, W. Mark Brown, James L. Wade, Nguyet Le-Lindqwister, David King, Kendrith M. Rowland, Kathryn E. Weaver, Heidi D. Klepin, Edward G. Shaw, Glenn J. Lesser
Journal: Journal of Clinical Oncology (2024)

To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy.
Diagnostic Strategy Using Color Doppler Ultrasound of Temporal Arteries in Patients With High Clinical Suspicion of Giant Cell Arteritis
Authors: Guillaume Denis, Olivier Espitia, Caroline Allix-Béguec, Céline Dieval, Fanny Lorcerie, Bruno Gombert, Xavier Pouget-Abadie, Claire Toquet, Christian Agard, Alizée Raimbeau, Giovanni Gautier, Jean-Michel Goujon, Géraldine Durand, Cécile Thollot-Karolewicz, Christian Lormeau, Aurélie Grados, Anne Grenot-Mercier, Rony El-Khoury, Agnès Riche, Florence Hospital, Sebastien Visee, Marie-Luce Auriault, Cédric Landron, Mickaël Martin, Christophe Roncato
Journal: Annals of Internal Medicine (2024)

Giant cell arteritis (GCA) is the most prevalent systemic vasculitis in people older than 50 years. Any delay in diagnosis impairs patients' quality of life and can lead to permanent damage, particularly vision loss.
Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians (Version 1, Update Alert)
Authors: Amir Qaseem, Lauri A. Hicks, Itziar Etxeandia-Ikobaltzeta, Tatyana A. Shamliyan, Thomas G. Cooney
Journal: Annals of Internal Medicine (2024)
Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5–17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial
Authors: Michal Juraska, Angela M Early, Li Li, Stephen F Schaffner, Marc Lievens, Akanksha Khorgade, Brian Simpkins, Nima S Hejazi, David Benkeser, Qi Wang, Laina D Mercer, Samuel Adjei, Tsiri Agbenyega, Scott Anderson, Daniel Ansong, Dennis K Bii, Patrick B Y Buabeng, Sean English, Nicholas Fitzgerald, Jonna Grimsby, Simon K Kariuki, Kephas Otieno, François Roman, Aaron M Samuels, Nelli Westercamp, Christian F Ockenhouse, Opokua Ofori-Anyinam, Cynthia K Lee, Bronwyn L MacInnis, Dyann F Wirth, Peter B Gilbert, Daniel E Neafsey
Journal: The Lancet Infectious Diseases (2024)
The Safety of Outpatient Health Care
Authors: David M. Levine, Ania Syrowatka, Hojjat Salmasian, David M. Shahian, Stuart Lipsitz, Jonathan P. Zebrowski, Laura C. Myers, Merranda S. Logan, Christopher G. Roy, Christine Iannaccone, Michelle L. Frits, Lynn A. Volk, Sevan Dulgarian, Mary G. Amato, Heba H. Edrees, Luke Sato, Patricia Folcarelli, Jonathan S. Einbinder, Mark E. Reynolds, Elizabeth Mort, David W. Bates
Journal: Annals of Internal Medicine (2024)

Despite considerable emphasis on delivering safe care, substantial patient harm occurs. Although most care occurs in the outpatient setting, knowledge of outpatient adverse events (AEs) remains limited.