tbuckley/cabot-search huggingface dataset:
Assessment of the Addition of Oxaliplatin to Fluoropyrimidine-Based Adjuvant Chemotherapy in Patients With High-Risk Stage II Colon Cancer: An ACCENT Pooled Analysis
Authors: Benoist Chibaudel, Morteza Raeisi, Romain Cohen, Greg Yothers, Richard M. Goldberg, Jean-Baptiste Bachet, Norman Wolmark, Takayuki Yoshino, Hans-Joachim Schmoll, Rachel Kerr, Sara Lonardi, Thomas J. George, Einat Shacham-Shmueli, Qian Shi, Thierry André, Aimery de Gramont
Journal: Journal of Clinical Oncology (2024)

PURPOSE The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined. PATIENTS AND METHODS One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage. RESULTS In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; P int = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349). CONCLUSION No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.
Risk Stratification in Older Intensively Treated Patients With AML
Authors: Jurjen Versluis, Marlen Metzner, Ariel Wang, Patrycja Gradowska, Abin Thomas, Niels Asger Jakobsen, Alison Kennedy, Rachel Moore, Emma Boertjes, Christian M. Vonk, Francois G. Kavelaars, Melissa Rijken, Amanda Gilkes, Claire Schwab, H. Berna Beverloo, Markus Manz, Otto Visser, Catharina H.M.J. Van Elssen, Okke de Weerdt, Lidwine W. Tick, Bart J. Biemond, Marie-Christiane Vekemans, Sylvie D. Freeman, Christine J. Harrison, Jonathan A. Cook, Mike Dennis, Steven Knapper, Ian Thomas, Charles Craddock, Gert J. Ossenkoppele, Bob Löwenberg, Nigel Russell, Peter J.M. Valk, Paresh Vyas
Journal: Journal of Clinical Oncology (2024)

PURPOSE AML is a genetically heterogeneous disease, particularly in older patients. In patients older than 60 years, survival rates are variable after the most important curative approach, intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT). Thus, there is an urgent need in clinical practice for a prognostic model to identify older patients with AML who benefit from curative treatment. METHODS We studied 1,910 intensively treated patients older than 60 years with AML and high-risk myelodysplastic syndrome (HR-MDS) from two cohorts (NCRI-AML18 and HOVON-SAKK). The median patient age was 67 years. Using a random survival forest, clinical, molecular, and cytogenetic variables were evaluated in an AML development cohort (n = 1,204) for association with overall survival (OS). Relative weights of selected variables determined the prognostic model, which was validated in AML (n = 491) and HR-MDS cohorts (n = 215). RESULTS The complete cohort had a high frequency of poor-risk features, including 2022 European LeukemiaNet adverse-risk (57.3%), mutated TP53 (14.4%), and myelodysplasia-related genetic features (65.1%). Nine variables were used to construct four groups with highly distinct 4-year OS in the (1) AML development, (2) AML validation, and (3) HR-MDS test cohorts ([1] favorable: 54% ± 4%, intermediate: 38% ± 2%, poor: 21% ± 2%, very poor: 4% ± 1%; [2] 54% ± 9%, 43% ± 4%, 27% ± 4%, 4% ± 3%; and [3] 54% ± 10%, 33% ± 6%, 14% ± 5%, 0% ± 3%, respectively). This new AML60+ classification improves current prognostic classifications. Importantly, patients within the AML60+ intermediate- and very poor-risk group significantly benefited from allo-HCT, whereas the poor-risk patients showed an indication, albeit nonsignificant, for improved outcome after allo-HCT. CONCLUSION The new AML60+ classification provides prognostic information for intensively treated patients 60 years and older with AML and HR-MDS and identifies patients who benefit from intensive chemotherapy and allo-HCT.
Opioid Prescriptions for US Patients Undergoing Long-Term Dialysis or with Kidney Transplant from 2011 to 2020
Authors: Paul L. Kimmel, Chyng-Wen Fwu, Thomas D. Nolin, Ivonne H. Schulman, Shannon S. Givens, Kenneth Wilkins, Susan Mendley, Debbie S. Gipson, Raquel C. Greer, Jenna M. Norton, Kevin E. Chan, Paul W. Eggers
Journal: Journal of the American Society of Nephrology (2024)

Key Points The rate of prescription of opioid medication decreased between 2011 and 2020 for patients with ESRD. The risk of death for dialysis and kidney transplant patients increased as morphine milligram equivalents in prescriptions increased. Background Pain is important for patients with kidney failure, but opioid medication prescriptions are associated with morbidity and mortality. The Centers for Disease Control and Prevention issued opioid prescription guidelines in 2016 and 2022, associated with dramatically decreased prescription rates in the United States. It is critical to know whether nationwide opioid prescription rates for patients with kidney failure have decreased. Methods We analyzed the United States Renal Data System database from 2011 to 2020 to describe trends in the proportion of patients with ESKD who received one or more, or long-term, opioid prescriptions, examined factors associated with long-term opioid prescriptions, and evaluated associations of all-cause death with short-term or long-term opioid prescriptions. Results From 2011 to 2022, the percentage of patients with kidney failure (dialysis and kidney transplant) who received at least one or more, or who had received long-term, opioid medication prescriptions decreased steadily, from 60% to 42%, and from 23% to 13%, respectively (both P for trend &lt; 0.001). The largest reductions in prescription rates were for hydrocodone and oxycodone. Similar trends existed for dialysis and kidney transplant patients. Women, the poor, and those in rural settings were more likely to receive long-term opioid prescriptions. Prescription rates were highest in White patients and those aged 45–64 years. Short-term and long-term opioid medication prescriptions were associated with higher mortality in both dialysis and kidney transplant patients. Conclusions The opioid prescription rates of patients with ESKD decreased between 2011 and 2020. Higher mortality risk was associated with both short-term and long-term opioid prescriptions. Mortality risk was monotonically associated with morphine milligram equivalents in patients with kidney failure who received long-term opioid prescriptions.
Immunobiology of primary sclerosing cholangitis
Authors: Martin Cornillet, Daniel Geanon, Annika Bergquist, Niklas K. Björkström
Journal: Hepatology (2024)

Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.
Impact of Inpatient Percutaneous Coronary Intervention Volume on 30-Day Readmissions After Acute Myocardial Infarction-Cardiogenic Shock
Authors: Kannu Bansal, Mohak Gupta, Mohil Garg, Neel Patel, Alexander G Truesdell, Mir Babar Basir, Syed Tanveer Rab, Tariq Ahmad, Navin K Kapur, Nihar Desai, Saraschandra Vallabhajosyula
Journal: JACC Heart Failure (2024)
Relationship Between Calcified Plaque Burden, Vascular Inflammation, and Plaque Vulnerability in Patients With Coronary Atherosclerosis
Authors: Daichi Fujimoto, Daisuke Kinoshita, Keishi Suzuki, Takayuki Niida, Haruhito Yuki, Iris McNulty, Hang Lee, Hiromasa Otake, Junya Shite, Maros Ferencik, Damini Dey, Tsunekazu Kakuta, Ik-Kyung Jang
Journal: JACC. Cardiovascular imaging (2024)
Hypofractionated Preoperative Radiation Should Not Yet Be Used as Standard of Care for Extremity and Truncal Soft Tissue Sarcoma
Authors: Elizabeth H. Baldini, B. Ashleigh Guadagnolo, Kilian E. Salerno, Peter Chung, Andrew J. Bishop, Anusha Kalbasi, Aisha Miah, Meena Bedi, Jeremy P. Harris, Ivy Petersen, Charles Gillham, Lisette M. Wiltink, Kaled M. Alektiar, Rick L. Haas, David G. Kirsch
Journal: Journal of Clinical Oncology (2024)

Hypofractionated radiation therapy regimens should not be used as standard of care for localized soft tissue sarcoma
A randomized study of 6 vs 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse.
Authors: J-Y Blay, C Schiffler, O Bouché, M Brahmi, F Duffaud, M Toulmonde, B Landi, W Lahlou, D Pannier, E Bompas, F Bertucci, L Chaigneau, O Collard, M Pracht, C Henon, I Ray-Coquard, K Armoun, S Salas, M Spalato-Ceruso, A Adenis, B Verret, N Penel, C Moreau-Bachelard, A Italiano, A Dufresne, S Metzger, S Chabaud, D Perol, A Le Cesne
Journal: Annals of Oncology (2024)
Adaptive cognitive control circuit changes associated with problem-solving ability and depression symptom outcomes over 24 months
Authors: Xue Zhang, Adam Pines, Patrick Stetz, Andrea N. Goldstein-Piekarski, Lan Xiao, Nan Lv, Leonardo Tozzi, Philip W. Lavori, Mark B. Snowden, Elizabeth M. Venditti, Joshua M. Smyth, Trisha Suppes, Olusola Ajilore, Jun Ma, Leanne M. Williams
Journal: Science Translational Medicine (2024)

Mechanistically targeted behavioral interventions are a much-needed strategy for improving outcomes in depression, especially for vulnerable populations with comorbidities such as obesity. Such interventions may change behavior and outcome by changing underlying neural circuit function. However, it is unknown how these circuit-level modifications unfold over intervention and how individual differences in early circuit-level modifications may explain the heterogeneity of treatment effects. We addressed this need within a clinical trial of problem-solving therapy for participants with depression symptoms and comorbid obesity, focusing on the cognitive control circuit as a putative neural mechanism of action. Functional magnetic resonance imaging was applied to measure the cognitive control circuit activity at five time points over 24 months. Compared with participants who received usual care, those receiving problem-solving therapy showed that attenuations in cognitive control circuit activity were associated with enhanced problem-solving ability, which suggests that this circuit plays a key role in the mechanisms of problem-solving therapy. Attenuations in circuit activity were also associated with improved depression symptoms. Changes in cognitive control circuit activity at 2 months better predicted changes in problem-solving ability and depression symptoms at 6, 12, and 24 months, with predictive improvements ranging from 17.8 to 104.0%, exceeding baseline demographic and symptom characteristics. Our findings suggest that targeting the circuit mechanism of action could enhance the prediction of treatment outcomes, warranting future model refinement and improvement to pave the way for its clinical application.
Inhibition of CCL7 improves endothelial dysfunction and vasculopathy in mouse models of diabetes mellitus
Authors: Ting-Ting Chang, You-Zhen Li, Hsiao-Wei Mo, Ching Chen, Liang-Yu Lin, Chia-Chi Chang, Jaw-Wen Chen
Journal: Science Translational Medicine (2024)

Diabetic vascular disease is a major complication of diabetes mellitus (DM). Chemokine C-C motif ligand 7 (CCL7) attracts macrophages and monocytes, amplifying inflammatory processes in the vasculature. We hypothesized a causal role for CCL7 in diabetic vasculopathy. CCL7 concentrations were higher in the plasma of patients with type 2 DM, as well as in supernatants from their endothelial progenitor cells (EPCs). High-glucose stimulation increased the secretion of CCL7 from human dermal microvascular endothelial cells (HDMECs) through the c-Fos and c-Jun signaling pathways. CCL7 inhibition using knockdown or neutralization antibody treatment reversed the high glucose–induced impaired tube formation and migration abilities of EPCs, human aortic endothelial cells, human coronary artery endothelial cells, and HDMECs. Administration of recombinant human CCL7 protein impaired tube formation and migration abilities by down-regulating the AKT–endothelial nitric oxide synthase and AKT/nuclear factor erythroid 2–related factor 2/heme oxygenase–1/vascular endothelial growth factor/stromal cell–derived factor–1 pathways and by up-regulating ERK/phosphorylated p65/interleukin-1β/interleukin-6/tumor necrosis factor–α pathways through CC chemokine receptor 3 in endothelial cells. Ccl7 knockout in streptozotocin-treated mice showed improved neovasculogenesis in ischemic limbs and accelerated wound repair, with increased circulating EPCs and capillary density. CCL7 antibody treatment in db/db mice and high-fat diet–induced hyperglycemia mice showed improved neovasculogenesis in ischemic limbs and wound areas, accompanied by up-regulation of angiogenic proteins and down-regulation of inflammatory proteins. Endothelial cell–specific Ccl7 -knockout mice showed ameliorated diabetic vasculopathy in streptozotocin-induced DM. This study highlights the potential of CCL7 as a therapeutic target for diabetic vasculopathy.
A skin-interfaced microfluidic platform supports dynamic sweat biochemical analysis during human exercise
Authors: Soongwon Cho, Samy M. Shaban, Ruihao Song, Haohui Zhang, Dasom Yang, Min-Jae Kim, Yirui Xiong, Xiuyuan Li, Kenneth Madsen, Sarena Wapnick, Shifan Zhang, Ziyu Chen, Jiwon Kim, Gianna Guinto, Michelle Li, Minkyu Lee, Ravi F. Nuxoll, Shaghayegh Shajari, Jin Wang, Seongeun Son, Jihoon Shin, Alexander J. Aranyosi, Donald E. Wright, Tae-il Kim, Roozbeh Ghaffari, Yonggang Huang, Dong-Hwan Kim, John A. Rogers
Journal: Science Translational Medicine (2024)

Blood lactate concentration is an established circulating biomarker for measuring muscle acidity and can be evaluated for monitoring endurance, training routines, or athletic performance. Sweat is an alternative biofluid that may serve similar purposes and offers the advantage of noninvasive collection and continuous monitoring. The relationship between blood lactate and dynamic sweat biochemistry for wearable engineering applications in physiological fitness remains poorly defined. Here, we developed a microfluidic wearable band with an integrated colorimetric timer and biochemical assays that temporally captures sweat and measures pH and lactate concentration. A colorimetric silver nanoplasmonic assay was used to measure the concentration of lactate, and dye-conjugated SiO 2 nanoparticle–agarose composite materials supported dynamic pH analysis. We evaluated these sweat biomarkers in relation to blood lactate in human participant studies during cycling exercise of varying intensity. Iontophoresis-generated sweat pH from regions of actively working muscles decreased with increasing heart rate during exercise and was negatively correlated with blood lactate concentration. In contrast, sweat pH from nonworking muscles did not correlate with blood lactate concentration. Changes in sweat pH and blood lactate were observed in participants who did not regularly exercise but not in individuals who regularly exercised, suggesting a relationship to physical fitness and supporting further development for noninvasive, biochemical fitness evaluations.
PTPRT loss enhances anti–PD-1 therapy efficacy by regulation of STING pathway in non–small cell lung cancer
Authors: Zhuo Chen, Wenxiang Ji, Wenxin Feng, Jingchuan Cui, Yuchen Wang, Fan Li, Jiachen Chen, Ziheng Guo, Liliang Xia, Xiaokuan Zhu, Xiaomin Niu, Yanshuang Zhang, Ziming Li, Alice S. T. Wong, Shun Lu, Weiliang Xia
Journal: Science Translational Medicine (2024)

With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making.
Precision adjuvants for pediatric vaccines
Authors: Anjali Singh, César Boggiano, Dwight E. Yin, Laura Polakowski, Sai P. Majji, Wolfgang W. Leitner, Ofer Levy, Kristina De Paris
Journal: Science Translational Medicine (2024)

Elucidating optimal vaccine adjuvants for harnessing age-specific immune pathways to enhance magnitude, breadth, and durability of immunogenicity remains a key gap area in pediatric vaccine design. A better understanding of age-specific adjuvants will inform precision discovery and development of safe and effective vaccines for protecting children from preventable infectious diseases.
Results From First-in-Human Phase I Dose-Escalation Study of a Novel Bicycle Toxin Conjugate Targeting EphA2 (BT5528) in Patients With Advanced Solid Tumors
Authors: Babar Bashir, Judy S. Wang, Gerald Falchook, Elisa Fontana, Hendrik-Tobias Arkenau, Louise Carter, Rachel Galot, Bristi Basu, Alastair Greystoke, Vivek Subbiah, Debra L. Richardson, Hanna Orr, Gavin Bennett, Rajiv Sharma, Hongmei Xu, Paola Paganoni, Cong Xu, Carly Campbell, Meredith McKean
Journal: Journal of Clinical Oncology (2024)

PURPOSE BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis. MATERIALS AND METHODS The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE. RESULTS Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m 2 once every week to 10.0 mg/m 2 once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m 2 once every 2 weeks was selected as a RP2D. At 6.5 mg/m 2 once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours). CONCLUSION BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m 2 once every 2 weeks.