tbuckley/cabot-search huggingface dataset:
Comparing the Efficacy and Safety of First-Line Treatments for Chronic Lymphocytic Leukemia: A Network Meta-Analysis
Authors: Tingyu Wen, Guangyi Sun, Wenxin Jiang, Kat Steiner, Suzannah Bridge, Peng Liu
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background The chronic lymphocytic leukemia treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemotherapy-free regimens. Frequentist network meta-analysis allows for direct and indirect comparisons between different treatments. Methods Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease, objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities. Results A total of 30 eligible trials involved 12 818 patients, and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax in patients aged older than 65 years or with unmutated IGHV. In younger patients with comorbidities, acalabrutinib-obinutuzumab had superior PFS compared with ibrutinib-obinutuzumab, ibrutinib-venetoclax, and obinutuzumab-venetoclax. For older patients with comorbidities, acalabrutinib and acalabrutinib-obinutuzumab outperformed obinutuzumab-venetoclax without statistically difference between them. Minimal residual disease–guided ibrutinib-venetoclax surpassed obinutuzumab-venetoclax in patients without comorbidities. Ibrutinib-obinutuzumab exhibited extended PFS benefits compared with obinutuzumab-venetoclax in patients with mutated IGHV or with del(17p) and/or TP53 mutations. Ibrutinib-venetoclax and ibrutinib-obinutuzumab had lower neutropenia rates than obinutuzumab-venetoclax. Ibrutinib-venetoclax had fewer infections than acalabrutinib and acalabrutinib-obinutuzumab. Acalabrutinib-obinutuzumab caused less diarrhea than ibrutinib-venetoclax but more headaches than ibrutinib-obinutuzumab and obinutuzumab-venetoclax. Obinutuzumab-venetoclax had lower hypertension rates than ibrutinib-obinutuzumab. Ibrutinib-venetoclax had fewer arthralgia than acalabrutinib-obinutuzumab. For any grade secondary primary neoplasms, ibrutinib-venetoclax and obinutuzumab-venetoclax was less than acalabrutinib-obinutuzumab. Conclusion Tailored chemotherapy-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different adverse events spectra.
Association of fluoroquinolones with the risk of spontaneous pneumothorax: nationwide case–time–control study
Authors: Anne Bénard-Laribière, Elodie Pambrun, Serge Kouzan, Jean-Luc Faillie, Julien Bezin, Antoine Pariente
Journal: Thorax (2024)

Introduction Fluoroquinolones can cause severe collagen-associated adverse effects, potentially impacting the pulmonary connective tissue. We investigated the association between fluoroquinolones and spontaneous pneumothorax. Methods A case–time–control study was performed using the nationwide French reimbursement healthcare system database (SNDS). Cases were adults ≥18 years admitted for spontaneous pneumothorax between 2017 and 2022. For each case, fluoroquinolone use was compared between the risk period immediately preceding the admission date (days −30 to −1), and three earlier reference periods (days −180 to −151, −150 to −121, −120 to −91), adjusting for time-varying confounders. OR estimates were corrected for potential exposure-trend bias using a reference group without the event (matched on age, sex, chronic obstructive pulmonary disease history, calendar time). Amoxicillin use was studied similarly to control for indication bias. Results Of the 246 pneumothorax cases exposed to fluoroquinolones (63.8% men; mean age, 43.0±18.4 years), 63 were exposed in the 30-day risk period preceding pneumothorax and 128 in the reference periods. Of the 3316 amoxicillin cases (72.9% men; mean age, 39.4±17.6 years), 1210 were exposed in the 30-day risk period and 1603 in the reference ones. OR adjusted for exposure-trend and covariates was 1.59 (95% CI 1.14 to 2.22) for fluoroquinolones and 2.25 (2.07 to 2.45) for amoxicillin. Conclusion An increased risk of spontaneous pneumothorax was associated with both fluoroquinolone and amoxicillin use, with an even higher association for amoxicillin. This strongly suggests the role of the underlying infections rather than a causal effect of the individual antibiotics and can be considered reassuring regarding a potential lung connective toxicity of fluoroquinolones.
Quantitative analysis of effectiveness and associated factors of exercise on symptoms in osteoarthritis: a pharmacodynamic model-based meta-analysis
Authors: Shun Han, Ting Li, Ying Cao, Zewei Li, Yiying Mai, Tianxiang Fan, Muhui Zeng, Xin Wen, Weiyu Han, Lijun Lin, Lixin Zhu, Siu Ngor Fu, Kim L Bennell, David J Hunter, Changhai Ding, Lujin Li, Zhaohua Zhu
Journal: British Journal of Sports Medicine (2024)

Objective This study aims to evaluate the time point and magnitude of peak effectiveness of exercise and the effects of various exercise modalities for osteoarthritis (OA) symptoms and to identify factors that significantly affect the effectiveness of exercise. Design Pharmacodynamic model-based meta-analysis (MBMA). Data sources Embase, PubMed, Cochrane Library, Web of Science and Scopus were searched for randomised controlled trials (RCTs) examining the effect of exercise for OA from inception to 20 November 2023. Eligibility criteria RCTs of exercise interventions in patients with knee, hip or hand OA, using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales or Visual Analogue Scale (VAS) pain scores as outcome measures, were included. The minimum clinically important difference (MCID) for WOMAC total, pain, stiffness, function and VAS pain was 9.0, 1.6, 0.8, 5.4 and 0.9, respectively. Results A total of 186 studies comprising 12 735 participants with symptomatic or radiographic knee, hip or hand OA were included. The effectiveness of exercise treatments peaked at 1.6–7.2 weeks after initiation of exercise interventions. Exercise was more effective than the control, but the differences in the effects of exercise compared with control on all outcomes were only marginally different with the MCID (7.5, 1.7, 1.0, 5.4 and 1.2 units for WOMAC total, pain, stiffness, function and VAS pain, respectively). During a 12-month treatment period, local exercise (strengthening muscles and improving mobilisations of certain joints) had the best effectiveness (WOMAC pain decreasing by 42.5% at 12 weeks compared with baseline), followed by whole-body plus local exercise. Adding local water-based exercise (eg, muscle strengthening in warm water) to muscle strengthening exercise and flexibility training resulted in 7.9, 0.5, 0.7 and 8.2 greater improvements in the WOMAC total score, pain, stiffness and function, respectively. The MBMA models revealed that treatment responses were better in participants with more severe baseline symptom scores for all scales, younger participants for the WOMAC total and pain scales, and participants with obesity for the WOMAC function. Subgroup analyses revealed participants with certain characteristics, such as female sex, younger age, knee OA or more severe baseline symptoms on the WOMAC pain scale, benefited more from exercise treatment. Conclusion Exercise reaches peak effectiveness within 8 weeks and local exercise has the best effectiveness, especially if local water-based exercise is involved. Patients of female sex, younger age, obesity, knee OA or more severe baseline symptoms appear to benefit more from exercise treatment than their counterparts.
Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres
Authors: Jun Pyo Hong, Ran Joo Choi, Jin-Kyoung Shim, Kibyeong Kim, Ryong Nam Kim, HyeJoung Cho, Seo Jin Kim, Sohyun Kim, Nam Hwa Kim, Hun Ho Park, Ju Hyung Moon, Eui Hyun Kim, Wan-Yee Teo, Seungsoo Chung, Jong Hee Chang, Seok-Gu Kang
Journal: Neuro-Oncology (2024)

Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs).
Quality of Treatment Selection for Medicare Beneficiaries With Cancer
Authors: Aaron P. Mitchell, Sonia Persaud, Akriti Mishra Meza, Hannah E. Fuchs, Prabal De, Sara Tabatabai, Nirjhar Chakraborty, Pranam Dey, Niti U. Trivedi, Sham Mailankody, Victoria Blinder, Angela Green, Andrew S. Epstein, Bobby Daly, Lindsey Roeker, Peter B. Bach, Mithat Gönen
Journal: Journal of Clinical Oncology (2024)

PURPOSE The Medicare part D Low-Income Subsidy (LIS) improves access to oral cancer drugs, but provides no assistance for clinician-administered/part B drugs. This analysis assessed the association between LIS participation and receipt of optimal cancer treatment. METHODS We investigated initial systemic therapy using SEER-Medicare data (2015-2017) and National Comprehensive Cancer Network (NCCN) Evidence Blocks (EB) as the standard for treatment recommendations. We included cancer clinical scenarios wherein (1) ≥one treatment was optimal (higher efficacy and safety scores) versus other treatments; (2) identifiable in SEER-Medicare (eg, not defined by clinical data unavailable in registry data or claims); and (3) both EB and ASCO Value Framework agreed regarding optimal treatment. We fit logistic regression models to assess the association between receipt of systemic therapy ( v no therapy) and patient and provider characteristics. Contingent on receipt of treatment, we modeled the likelihood of receiving a treatment ranked (by EB scores) within the highest or lowest quartile for that cancer type. RESULTS Nine thousand two hundred and ninety patients were included across 11 clinical scenarios. Fifty-seven percent (5,336) of patients received any systemic therapy and 43% (3,954) received no systemic therapy. Compared with non-LIS participants, LIS participants were less likely to receive any systemic therapy versus no systemic therapy (odds ratio, 0.64 [95% CI, 0.57 to 0.72]). Contingent on receiving systemic therapy, LIS participants received treatment ranked within the worst quartile 24.8% of the time, compared with 21.9% of non-LIS patients (adjusted prevalence difference, 4.3% [95% CI, 0.5 to 8.2]). CONCLUSION LIS participants were less likely to receive systemic therapy at all and were more likely to receive treatments that receive low NCCN EB scores.
Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274
Authors: Matthew D. Galsky, Johannes Alfred Witjes, Jürgen E. Gschwend, Matthew I. Milowsky, Michael Schenker, Begoña P. Valderrama, Yoshihiko Tomita, Aristotelis Bamias, Thierry Lebret, Shahrokh F. Shariat, Se Hoon Park, Mads Agerbaek, Gautam Jha, Frank Stenner, Dingwei Ye, Fabio Giudici, Santanu Dutta, Margarita Askelson, Federico Nasroulah, Joshua Zhang, Lynne Brophy, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2024)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported . CheckMate 274 is a phase III, randomized, double-blind trial of adjuvant nivolumab versus placebo for muscle-invasive urothelial carcinoma (MIUC) at high risk of recurrence after radical resection. The primary end points of disease-free survival (DFS) in intent-to-treat (ITT) and tumor PD-L1 expression ≥1% populations were met. We report results at an extended median follow-up of 36.1 months in the ITT population. In addition, we report interim overall survival (OS) data for the first time and an exploratory analysis among patients with bladder primary tumors (muscle-invasive bladder cancer [MIBC]). Consistent DFS benefit with nivolumab versus placebo was observed in both the ITT (hazard ratio [HR], 0.71 [95% CI, 0.58 to 0.86]) and PD-L1 ≥1% (HR, 0.52 [95% CI, 0.37 to 0.72]) patients. The HR for OS with nivolumab versus placebo was 0.76 (95% CI, 0.61 to 0.96) in the ITT population and 0.56 (95% CI, 0.36 to 0.86) in the PD-L1 ≥1 population. Continuous benefit in nonurothelial tract recurrence-free survival and distant metastasis-free survival was also observed in both patient populations. The exploratory analysis of patients with MIBC also showed continued efficacy benefits, irrespective of PD-L1 status. No new safety signals were reported. Overall, these results further support adjuvant nivolumab as a standard of care for high-risk MIUC after radical resection.
Efficacy and Safety of Admilparant, an LPA<sub>1</sub> Antagonist in Pulmonary Fibrosis: A Phase 2 Randomized Clinical Trial
Authors: Tamera J. Corte, Juergen Behr, Vincent Cottin, Marilyn K. Glassberg, Michael Kreuter, Fernando J. Martinez, Takashi Ogura, Takafumi Suda, Marlies Wijsenbeek, Elchonon Berkowitz, Brandon Elpers, Sinae Kim, Hideaki Watanabe, Aryeh Fischer, Toby M. Maher
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) have high morbidity and mortality; thus, novel treatments are needed.
Safety and efficacy of iron supplementation with 3 months of daily ferrous sulphate in children living with HIV and mild-to-moderate anaemia in Uganda: a double-blind, randomised, placebo-controlled trial
Authors: Anne E P Frosch, Victor Musiime, Christopher Staley, Andrea L Conroy, Diana Rutebarika, Gilbert Ategeka, Sarah E Cusick
Journal: The Lancet HIV (2024)
Global radiotherapy demands and corresponding radiotherapy-professional workforce requirements in 2022 and predicted to 2050: a population-based study
Authors: Hongcheng Zhu, Melvin Lee Kiang Chua, Imjai Chitapanarux, Orit Kaidar-Person, Catherine Mwaba, Majed Alghamdi, Andrés Rodríguez Mignola, Natalia Amrogowicz, Gozde Yazici, Zouhour Bourhaleb, Humera Mahmood, Golam Mohiuddin Faruque, Muthukkumaran Thiagarajan, Abdelkader Acharki, Mingwei Ma, Martin Harutyunyan, Hutcha Sriplung, Yuntao Chen, Rolando Camacho, Zhen Zhang, May Abdel-Wahab
Journal: The Lancet Global Health (2024)
Mechanisms and consequences of myeloid adhesome dysfunction in atherogenesis
Authors: Irina Zhevlakova, Huan Liu, Tejasvi Dudiki, Detao Gao, Valentin Yakubenko, Svyatoslav Tkachenko, Olga Cherepanova, Eugene A Podrez, Tatiana V Byzova
Journal: Cardiovascular Research (2024)

In the context of atherosclerosis, macrophages exposed to oxidized low-density lipoprotein (oxLDL) exhibit cellular abnormalities, specifically in adhesome functions, yet the mechanisms and implications of these adhesive dysfunctions remain largely unexplored.
Optimized lipid nanoparticles enable effective CRISPR/Cas9-mediated gene editing in dendritic cells for enhanced immunotherapy
Authors: Kuirong Mao, Huizhu Tan, Xiuxiu Cong, Ji Liu, Yanbao Xin, Jialiang Wang, Meng Guan, Jiaxuan Li, Ge Zhu, Xiandi Meng, Guojiao Lin, Haorui Wang, Jing Han, Ming Wang, Yong-Guang Yang, Tianmeng Sun
Journal: Acta Pharmaceutica Sinica B (2024)

Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLANmCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.
When I use a word . . . Academic skepticism
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

Of five types of skepticism, dogmatic skepticism, nihilistic skepticism, Voltairian skepticism, philosophical skepticism, and scientific skepticism, the first two are irrelevant to academic skepticism and may even be inimical to it. The other three all contribute to academic skepticism, and the most important of the three is scientific skepticism, in which curiosity leads to ideas, which result in hypotheses, which are then tested, repeatedly if necessary, until a body of facts emerges. Such facts can then be subjected to the formulation of theories that explain how and why the facts came to be. Skepticism is an integral part of this process, although it should not be overdone.
In situ phosphorus-modified Mg2Ge/Zn-Cu composite with improved mechanical, degradation, biotribological properties, and in vitro and in vivo osteogenesis and osteointegration performance for biodegradable bone-implant applications
Authors: Xian Tong, Xinkun Shen, Zhiqiang Lin, Runqi Zhou, Yue Han, Li Zhu, Shengbin Huang, Jianfeng Ma, Yuncang Li, Cuie Wen, Jixing Lin
Journal: Bioactive Materials (2024)
Comprehensive mutational profiling identifies new driver events in cutaneous leiomyosarcoma
Authors: Louise van der Weyden, Martin Del Castillo Velasco-Herrera, Saamin Cheema, Kim Wong, Jacqueline M Boccacino, Victoria Offord, Alastair Droop, David R A Jones, Ian Vermes, Elizabeth Anderson, Claire Hardy, Nicolas de Saint Aubain, Peter M Ferguson, Emily L Clarke, William Merchant, Carolin Mogler, Derek Frew, Paul W Harms, Carlos Monteagudo, Steven D Billings, Mark J Arends, Ingrid Ferreira, Thomas Brenn, David J Adams
Journal: British Journal of Dermatology (2024)

Abstract Background Cutaneous leiomyosarcoma (cLMS) is a rare soft tissue neoplasm, showing smooth muscle differentiation, that arises from the mesenchymal cells of the dermis. To-date, genetic investigation of these tumours has involved studies with small sample sizes and limited analyses that identified recurrent somatic mutations in RB1 and TP53, copy number gain of MYCOD and IGF1R, and copy number loss of PTEN. Objectives To better understand the molecular pathogenesis of cLMS, we comprehensively explored the mutational landscape of these rare tumours to identify candidate driver events. Methods In this retrospective, multi-institutional study, we performed whole-exome sequencing and RNA sequencing on 38 cases of cLMS. Results TP53 and RB1 were identified as significantly mutated, thus, represent validated driver genes of cLMS. COSMIC mutational signatures SBS7a/b and DBS1 were recurrent, thus, ultraviolet light exposure may be an aetiological factor driving cLMS. Analysis of significantly recurrent somatic copy number alterations, which represent candidate driver events, found focal (&amp;lt;10Mb) deletions encompassing TP53 and KDM6B, and amplifications encompassing ZMYM2, MYOCD, MAP2K4 and NCOR1. A larger (24 Mb) recurrent deletion encompassing CYLD was also identified as significant. Significantly recurrent broad copy number alterations, involving at least half of a chromosome arm, included deletions of 6p/q, 10p/q, 11q, 12q, 13q and 16p/q, and amplification of 15q. Notably PTEN is located on 10q, RB1 on 13q and IGFR1 on 15q. Fusion gene analysis identified recurrent CRTC1/3::MAML2 fusions, as well as many novel fusions in individual samples. Conclusions Our analysis of the largest number of cLMS cases to-date highlights the importance of large cohort sizes and the exploration beyond small targeted gene panels when performing molecular analyses, as it allowed a comprehensive exploration of the mutational landscape of these tumours and identification of novel candidate driver events. It also uniquely afforded the opportunity to compare the molecular phenotype of cLMS with LMS of other tissue types, such as uterine and soft tissue LMS. Given that molecular profiling has resulted in the development of novel targeted treatment approaches for uterine and soft tissue LMS, our study now allows the same opportunities to become available for patients with cLMS.
Novel therapeutic strategy for intractable keloids: Suppression of intracellular mechanotransduction and actin polymerisation via Rho-kinase pathway inhibition
Authors: Sally Min, Ki-Myo Kim, Jun Ho Park, Mihyun Lee, Joseph Hwang, Ji-Ung Park
Journal: British Journal of Dermatology (2024)

Abstract Background Keloid is a dermal fibrotic disorder characterised by excessive extracellular matrix production by fibroblasts. Despite the significance of mechanostimulation in fibrotic diseases, its association with keloid pathophysiology or treatment remains unexplored. Objective We investigated the role of mechanical force in keloid formation and elucidated the significance of Rho-associated coiled-coil-containing kinase 1 (ROCK1) as a mechanoresponsive target for keloid treatment. Methods Patient-derived keloid fibroblasts (KFs) were subjected to cyclic stretching ranging from 0 to 20% elongation using a cell-stretching system. We observed the inhibitory effects of the ROCK1 inhibitor Y27632 on KFs and keloid formation. Validation was performed using keloid xenograft severe combined immune-deficient (SCID) mouse model. Results ROCK1 was overexpressed in KFs isolated from patients. Cyclic stretching induced fibroblast proliferation and actin polymerisation by activating Rho/ROCK1 signalling. Treatment with Y27632 downregulated fibrotic markers, reduced the migration capacity of KFs, and induced extensive actin cytoskeleton remodelling. In keloid xenograft SCID mouse model, Y27632 effectively suppressed keloid formation, mitigating inflammation and fibrosis. Conclusions The ROCK1 inhibitor Y27632 is a promising molecule for keloid treatment, exerting its effects through actin cytoskeleton remodelling and nuclear inhibition of fibrotic markers in keloid pathogenesis.