tbuckley/cabot-search huggingface dataset:
Donation-Attributable Risk—A Call to Action
Authors: Jayme E. Locke
Journal: JAMA Surgery (2024)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Futility of Up-Front Resection for Anatomically Resectable Pancreatic Cancer
Authors: Stefano Crippa, Giuseppe Malleo, Vincenzo Mazzaferro, Serena Langella, Claudio Ricci, Fabio Casciani, Giulio Belfiori, Sara Galati, Vincenzo D’Ambra, Gabriella Lionetto, Alessandro Ferrero, Riccardo Casadei, Giorgio Ercolani, Roberto Salvia, Massimo Falconi, Alessandro Cucchetti
Journal: JAMA Surgery (2024)

There are currently no clinically relevant criteria to predict a futile up-front pancreatectomy in patients with anatomically resectable pancreatic ductal adenocarcinoma.
Falls and patterns of physical activity participation over 18 years in the Australian Longitudinal Study on Women’s Health
Authors: Wing S Kwok, Saman Khalatbari-Soltani, Xenia Dolja-Gore, Julie Byles, Juliana S Oliveira, Marina B Pinheiro, Anne Tiedemann, Catherine Sherrington
Journal: British Journal of Sports Medicine (2024)

Objective To explore the relationship between long-term physical activity (PA) participation and falls. Methods Participants in the Australian Longitudinal Study of Women’s Health born 1946–1951 self-reported amounts of PA every 3 years since 1998 (mean age: 54 years, n=11 796). Latent class analysis described profiles of self-reported PA participation over 18 years. Associations between patterns of PA participation and self-reported falls measured in 2019 were examined using multinomial logistic regression adjusted for directed-acyclic graph-informed potential confounders, with the highly active group as the reference category. Results Women were grouped into five PA participation profiles. Compared with consistently highly active patterns (maintaining ≥300 min/week, 22%), consistently lower levels of PA&lt;100 min/week (18%), consistently some PA&lt;150 min/week (18%) and decreasing PA but maintaining≥150 min/week (n=3540, 30%) had higher odds of non-injurious falls (odds Ratio lower level (OR): 1.59, 95% CI 1.29 to 1.97; OR some PA : 1.27, 95% CI 1.04 to 1.55; OR decreasing activity :1.29, 95% CI 1.02 to 1.63) and injurious falls (OR low level : 1.32, 95% CI 1.06 to 1.64; OR some PA : 1.27, 95% CI 1.04 to 1.54; OR decreasing activity : 1.47, 95% CI 1.18 to 1.83). No association was found between increasing PA (≥150 min/week, 11%) for non-injurious (OR 1.07, 95% CI 0.89 to 1.29) and injurious falls (OR 1.07, 95% CI 0.90 to 1.29). After adjusting for potential confounders, consistently lower levels of PA remained associated with increased non-injurious falls odds (OR 1998 survey : 1.40, 95% CI 1.11 to 1.77; OR 2016 survey : 1.35, 95% CI 1.07 to 1.71). Conclusion The increased odds of falls among women with consistently lower levels of PA over 18 years supports ongoing participation of 150+ min/week of PA.
Adolescent Use, Diversion Sources, and Perceived Procurement Difficulty of Prescription Medications
Authors: Sean Esteban McCabe, Emily Pasman, Tim Wilens, Ty S. Schepis, Vita McCabe, Jason Ford, Phil Veliz
Journal: JAMA (2024)

This study examines trends in medical use, nonmedical use, diversion sources, and perceived procurement difficulty of prescription medications for nonmedical use among US adolescents.
Progression-Free Survival for Liver Transplant vs Alternative Therapy in Unresectable Colorectal Liver Metastasis
Authors: Matthew M. Byrne, Mariana Chávez-Villa, Luis I. Ruffolo, Kerollos Nashat Wanis, Brian Belt, Koji Tomiyama, Roberto Hernandez-Alejandro
Journal: JAMA Surgery (2024)

This cohort study compares survival outcomes between patients with unresectable colorectal liver metastasis who received chemotherapy-based multimodal therapy and patients who underwent liver transplant.
Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling
Authors: Jiying Cheng, Min Li, Edyta Motta, Deivi Barci, Wangyang Song, Ding Zhou, Gen Li, Sihan Zhu, Anru Yang, Brian D. Vaillant, Axel Imhof, Ignasi Forné, Sabine Spiegl-Kreinecker, Nu Zhang, Hiroshi Katayama, Krishna P.L. Bhat, Charlotte Flüh, Roland E. Kälin, Rainer Glass
Journal: Cell Reports Medicine (2024)

The DNA damage response (DDR) and the blood-tumor barrier (BTB) restrict chemotherapeutic success for primary brain tumors like glioblastomas (GBMs). Coherently, GBMs almost invariably relapse with fatal outcomes. Here, we show that the interaction of GBM and myeloid cells simultaneously induces chemoresistance on the genetic and vascular levels by activating GP130 receptor signaling, which can be addressed therapeutically. We provide data from transcriptomic and immunohistochemical screens with human brain material and pharmacological experiments with a humanized organotypic GBM model, proteomics, transcriptomics, and cell-based assays and report that nanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation. GBM mouse models recapitulating intratumoral humanin release show accelerated BTB formation. GP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy. Altogether, we describe an overarching mechanism for TMZ resistance and outline a translatable strategy with predictive markers to improve chemotherapy for GBMs.
Darzi 2.0: A full diagnostic assessment of the NHS may require uncomfortable investigations
Authors: Becks Fisher
Journal: BMJ (2024)

A full diagnostic assessment of the NHS may require uncomfortable investigations While a focus on funding and workforce is inevitable, Ara Darzi and his team must not overlook dysfunction in central structures in their review of NHS performance, says Becks Fisher Becks Fisher GP and director of research and policy 1The phrase "Darzi review" has a familiar ring to it.Sixteen years on from High Quality Care for All-Ara Darzi's landmark 2008 review of "quality" in the English NHS-another Labour government has commissioned Darzi to conduct an independent investigation of NHS performance. 1 2 This won't be a repeat of the previous review.Details on process for the current review are scant, but with reporting expected this September, the two month window is far shorter than the year spent on Darzi's 2008 work. 3And unlike that review, which produced wide ranging and detailed recommendations, Wes Streeting, the secretary of state for health and social care, has been clear that he views this as a "warts and all" diagnostic assessment.
Strategic targeting of Cas9 nickase induces large segmental duplications
Authors: Yuki Sugiyama, Satoshi Okada, Yasukazu Daigaku, Emiko Kusumoto, Takashi Ito
Journal: Cell Genomics (2024)

Gene/segmental duplications play crucial roles in genome evolution and variation. Here, we introduce paired nicking-induced amplification (PNAmp) for their experimental induction. PNAmp strategically places two Cas9 nickases upstream and downstream of a replication origin on opposite strands. This configuration directs the sister replication forks initiated from the origin to break at the nicks, generating a pair of one-ended double-strand breaks. If homologous sequences flank the two break sites, then end resection converts them to single-stranded DNAs that readily anneal to drive duplication of the region bounded by the homologous sequences. PNAmp induces duplication of segments as large as ∼1 Mb with efficiencies exceeding 10% in the budding yeast Saccharomyces cerevisiae. Furthermore, appropriate splint DNAs allow PNAmp to duplicate/multiplicate even segments not bounded by homologous sequences. We also provide evidence for PNAmp in mammalian cells. Therefore, PNAmp provides a prototype method to induce structural variations by manipulating replication fork progression.
A phase 2, multicenter study of TILs treatment in advanced tumors with alterations in the SWI/SNF complex: The TILTS study.
Authors: Juan Martin-Liberal, Elena Garralda, Jesus Garcia Donas, Juan Jose Soto, Carles Codony, Silvia Martín-Lluesma, Susana Muñoz, Vladimir Galvao, M. Julia Lostes-Bardaji, Marta Rotxés, Sergio Querol, Luciano Rodriguez, Ainhoa Muñoz, Rafael Moreno, Xavier Garcia del Muro, Ramón Alemany, Alena Gros, Josep M. Piulats
Journal: Journal of Clinical Oncology (2024)

TPS2674 Background: Tumors associated with SWI/SNF complex (SWI/SNFc) mutations, mainly SMARCA4 and SMARCB1 loss, are a heterogeneous group of malignancies with rhabdoid features that typically affect young patients (pts). These are aggressive malignancies with poor prognosis for which no standard treatment is available. Despite not having a high tumor mutation burden, tumor infiltrating lymphocytes (TILs) are usually present in high numbers. The biologic reasons for this feature are not clearly understood but might be associated to changes in gene expression due to aberrant chromatin remodeling. However, these TILs indicate that tumor antigens are recognized by lymphocytes unveiling a vulnerability that can be exploited by immunotherapy. The objective of the TILTS study is to develop a personalized adoptive cell therapy using TILs in pts affected by these tumors. Methods: Single arm, multi center, phase 2 study of TILs in pts with advanced tumors associated with SWI/SNFc mutations. Pts are treated at 3 centers in Spain: Catalan Institute of Oncology (ICO), Barcelona, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, and Centro Integral Oncológico Clara Campal (HM CIOCC), Madrid. Primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include toxicity evaluation, duration of response (DOR), progression-free survival (PFS) or overall survival (OS). After informed consent is obtained, tumor resection is performed. Total volume of tumor resected should be at least 1.5 cc to assure TIL isolation. Eligible pts enter the treatment phase. TILs are produced under GMP conditions. During the TILs manufacturing process, pts are allowed to receive standard treatment if clinically indicated. Before TIL infusion, pts receive non-myeloablative preconditioning lymphodepletion with daily intravenous (IV) cyclophosphamide (60 mg/kg; IV x2 doses) and daily fludarabine (25 mg/m2; IV x5 doses). Infusion of autologous TILs is given on Day 0 followed by administration of IL-2 at 600,000 international units (IU)/kg every 8-12 hours for a maximum of 6 doses. After 4 weeks, a new tumor biopsy is optional. First image evaluation is performed after 8 weeks from TIL infusion. Pts without progression enter the follow-up phase. An ancillary translational study will explore mechanisms of immunogenicity, antigen recognition, TILs anti-tumor activity, and changes in the stool microbiome and specific TCR population during treatment. Also, tumor immune microenvironment will be analyzed. Clinical trial information: 2023-504632-17-00 . [Table: see text]
Phase 1 study of AM003, a novel individualized immunotherapy, in a basket of advanced solid tumors.
Authors: Irit Carmi Levy, Leanne Amitzi, Erez Lavi, Neta Zilony - Hanin, Zohar Pode, Raanan Berger, Karen Smith
Journal: Journal of Clinical Oncology (2024)

TPS2692 Background: Aummune is developing a unique individualized immunotherapy (‘AM003’), designed to have three activities mediated by three different domains: (1) the ‘Variable Domain, identified de novo for each individual patient, based on its ability to specifically induce cell death on patient’s tumor cells; (2) the ‘General Domain’, designed to engage with immune T cells to cause tumor cell lysis; and (3) a ‘CpG-rich Domain’ that stimulates Antigen Presenting Cells. Aummune’s process begins with sampling the patient’s tumor (via biopsy) and healthy cells (PBMCs). The cancerous cells are grown in a 3D culture and once the cells propagate and reach a critical biomass, they are subjected to Aummune’s proprietary platform for the identification of the Variable Domain. Once a tumoricidal sequence is identified, it is manufactured and the drug product (DP) is assembled at the production facility. Following release, the DP is shipped to the medical site for treatment of the patient. Methods: AM003 is being evaluated as an immune-oncology agent in advanced/metastatic relapsed/refractory solid tumors. A First-In-Human Phase 1, open-label multicenter, dose-escalation study of AM003 is ongoing with the following cohorts: (1) 34mg (2) 68mg and (3) 136 mg of AM003 monotherapy administered intratumorally / local subcutaneously once per week for 4 weeks, followed by 6 doses administered every 2 weeks. Key inclusion criteria include (i) histologically confirmed locally advanced/metastatic solid tumors who received and progressed after, or were intolerant to, at least 1 prior systemic therapy and are not candidates for any therapy known to confer clinical benefit. (ii) lesions that are safely amenable to IT injection. The primary objective is to evaluate the safety and tolerability of AM003. Additional objectives include assessment of preliminary evidence of clinical benefit, pharmacokinetic and pharmacodynamics measurements as well as identification of biomarkers. Endpoints: AEs are assessed according to CTCAE v5, treatment response is determined according to RECIST 1.1 and iRECIST, changes in putative markers are evaluated based on multiple analyses methodologies. 10 patients were included in the dose-escalation part: 1(n=4), 2 (n=3), and 3 (n=3). Cohorts 1, 2 and 3 have been completed without DLTs. The DSMB last reviewed the escalation data in January 2024 and concluded that the trial can continue as planned. Enrollment of 136mg dose expansion is ongoing and completion of the trial will be mid 2024. Clinical trial information: MOH_2022-03-29_010690 .
Novel approach of prophylactic radiation to reduce toxicities comparing 2-step 40 Gy with 56 Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck: A phase III trial (JCOG1912, NEW BRIDGE).
Authors: Tomoya Yokota, Sadamoto Zenda, Takeshi Kodaira, Naomi Kiyota, Yasushi Fujimoto, Koichiro Wasano, Ryo Takahashi, Takashi Mizowaki, Akihiro Homma, Keita Sasaki, Ryunosuke Machida, Yuta Sekino, Haruhiko Fukuda
Journal: Journal of Clinical Oncology (2024)

TPS6121 Background: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. Methods: This study is a multicenter, two-arm, open-label, randomized phase III trial. The main inclusion criteria are as follows: (i) Primary lesions are located in the oropharynx, hypopharynx, or larynx. (ii) Histologically proven SCC on biopsy specimens of the primary lesion. Immunohistochemistry reveals p16 negativity in patients with oropharyngeal cancer. (iii) Clinical stage of III, IVA, or IVB (excluding N3a) based on the 8th UICC-TNM classification. Patients are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m 2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score.Patient accrual was started in May 2021 and the study is now open for accrual. A total of 186 patients have been enrolled as of January 2024. This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100. Clinical trial information: jRCTs031210100 .
Forever Pesticides: A Growing Source of PFAS Contamination in the Environment
Authors: Nathan Donley, Caroline Cox, Kyla Bennett, Alexis M. Temkin, David Q. Andrews, Olga V. Naidenko
Journal: Environmental Health Perspectives (2024)

Environmental contamination by fluorinated chemicals, in particular chemicals from the per- and polyfluoroalkyl substances (PFAS) class, has raised concerns around the globe because of documented adverse impacts on human health, wildlife, and ecosystem quality. Recent studies have indicated that pesticide products may contain a variety of chemicals that meet the PFAS definition, including the active pesticide ingredients themselves. Given that pesticides are some of the most widely distributed pollutants across the world, the legacy impacts of PFAS addition into pesticide products could be widespread and have wide-ranging implications on agriculture and food and water contamination, as well as the presence of PFAS in rural environments.
Discovery of a potent PROTAC degrader for RNA demethylase FTO as antileukemic therapy
Authors: Lu Liu, Yuanlai Qiu, Yuying Suo, Siyao Tong, Yiqing Wang, Xi Zhang, Liang Chen, Yue Huang, Huchen Zhou, Hu Zhou, Ze Dong, Cai-Guang Yang
Journal: Acta Pharmaceutica Sinica B (2024)

The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N 6-methyladenosine (m6A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m6A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m6A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.
Investigation of Peroxisome Proliferator-Activated Receptor Genes as Requirements for Visual Startle Response Hyperactivity in Larval Zebrafish Exposed to Structurally Similar Per- and Polyfluoroalkyl Substances (PFAS)
Authors: Sebastian Gutsfeld, Leah Wehmas, Ifeoluwa Omoyeni, Nicole Schweiger, David Leuthold, Paul Michaelis, Xia Meng Howey, Shaza Gaballah, Nadia Herold, Carolina Vogs, Carmen Wood, Luísa Bertotto, Gi-Mick Wu, Nils Klüver, Wibke Busch, Stefan Scholz, Jana Schor, Tamara Tal
Journal: Environmental Health Perspectives (2024)

Per- and polyfluoroalkyl Substances (PFAS) are synthetic chemicals widely detected in humans and the environment. Exposure to perfluorooctanesulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) was previously shown to cause dark-phase hyperactivity in larval zebrafish.
Pretheranostic agents with extraordinaryNIRF/photoacoustic imaging performanceand photothermal oncotherapy efficacy
Authors: Liu Shi, Zhenzhou Chen, Jiaxin Ou, En Liang, Zhipeng Chen, Qiuyue Fu, Lan Huang, Kui Cheng
Journal: Acta Pharmaceutica Sinica B (2024)

Cervical cancer, the most common gynecological malignancy, significantly and adversely affects women's physical health and well-being. Traditional surgical interventions and chemotherapy, while potentially effective, often entail serious side effects that have led to an urgent need for novel therapeutic methods. Photothermal therapy (PTT) has emerged as a promising approach due to its ability to minimize damage to healthy tissue. Connecting a biothiol detection group to PTT-sensitive molecules can improve tumor targeting and further minimize potential side effects. In this study, we developed a near-infrared fluorescence (NIRF)/photoacoustic (PA) dual-mode probe, S-NBD, which demonstrated robust PTT performance. This innovative probe is capable of activating NIRF/PA signals to enable the detection of biothiols with high emission wavelength (838 nm) and large Stokes shift (178 nm), allowing for in vivo monitoring of cancer cells. Additionally, the probe achieved an outstanding photothermal conversion efficiency of 67.1%. The application of laser irradiation (660 nm, 1.0 W/cm2, 5 min) was able to achieve complete tumor ablation without recurrence. In summary, this seminal study presents a pioneering NIRF/PA dual-mode dicyanoisophorone-based probe for biothiol imaging, incorporating features from PTT for the first time. This pioneering approach achieves the dual objectives of improving tumor diagnosis and treatment.