bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nivolumab/Relatlimab: A Novel Addition to Immune Checkpoint Inhibitor Therapy in Unresectable or Metastatic Melanoma
Authors: Phillips Allison L. , Reeves David J. 
Published: October 2022

Objective: The aim of this article is to assess available data regarding use of nivolumab/relatlimab for adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma. Data Sources: A search of PubMed conducted from August 2019 to August 2022 with the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in 14 publications. Study Selection and Data Extraction: Relevant clinical trials written in English language were analyzed. Data Synthesis: Nivolumab/relatlimab was approved by the Food and Drug Administration following results of a phase 1/2 trial and phase 2/3 RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression free survival (PFS) of 10.1 months in the first-line setting without new safety signals. The PFS benefits appear greatest in those with programmed cell death-ligand 1 (PD-L1) <1% and lymphocyte activation gene-3 (LAG-3) ≥1%. Adverse effects commonly experienced were immune related in nature and require early identification and prompt management. Grade 3 or 4 adverse effects occurred in 18.9% of patients. Relevance to Patient Care and Clinical Practice: For patients 12 years of age and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers a new first-line treatment option. Evaluation of PD-L1 expression along with concomitant use of medications with potential interactions should be evaluated when deciding if nivolumab/relatlimab is the most appropriate treatment option. Conclusions: Nivolumab/relatlimab adds an additional first-line treatment option demonstrating promising improved PFS for patients with unresectable or metastatic melanoma, particularly those with PD-L1 <1% and/or LAG 3 ≥1%. Additional uses of nivolumab/relatlimab may be on the horizon as further clinical trials are ongoing.
Autoantigen spermatid nuclear transition protein 1 enhances pro-inflammatory cytokine production stimulated by anti-DNA autoantibodies in macrophages
Authors: Uprety Laxmi Prasad , Park Yong Hwan , Jang Young-Ju 
Published: October 2022

Introduction Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), is associated with high fatality rate in patients. The pathogenesis of lupus nephritis is complex and has not been fully elucidated. Kidney inflammation, renal cell damage, and accumulation of immune complexes in the glomerular basement membrane often occur in patients with lupus nephritis. Spermatid nuclear transition protein 1 (TNP1) might be a potentially interesting autoantigen in exploring the pathogenesis and therapy of lupus nephritis. Objective This study aimed to explore the effect of TNP1 and its complexes with anti-double-stranded DNA antibodies on the levels of interleukin-6 (IL-6) and interferon-α (IFN-α) in vitro. Methods We studied the effect of the synthetic peptide of the autoantigen on the pathogenic characteristics of the G2-6 and G5-8 antibodies in mouse macrophages, using enzyme-linked immunosorbent assay, quantitative RT-PCR, western blotting, and flow cytometry. Results The antibodies exhibited cross-reactivity to spermatid TNP1 in direct-binding and competitive enzyme-linked immunosorbent assay. Results of quantitative RT-PCR and western blotting revealed that the antibodies alone enhanced the levels of IL-6 and IFN-α transcripts and proteins, respectively. Flow cytometry revealed that treatment with the autoantigen enhanced the cell-penetrating activities of G2-6 and G5-8 and remarkably increased the cytokine levels. Conclusion TNP1 enhanced the cell-penetrating activities of anti-dsDNA auto-Abs, G2-6 and G5-8, and remarkably increased the levels of IL-6 and IFN-α in macrophages, suggesting that TNP1 and cell-penetrating pathogenic anti-dsDNA auto-Abs is potential targets for future therapeutic approaches to treat LN/SLE.
Prognostic significance of atrial cardiopathy in patients with acute ischemic stroke
Authors: Wu Yueyang , Yang Xiaomeng , Jing Jing , Meng Xia , Li Zixiao , Pan Yuesong , Jiang Yong , Yan Hongyi , Huang Xinying , Liu Liping , Zhao Xingquan , Wang Yilong , Li Hao , Wang Yongjun 
Published: October 2022

Introduction: Whether atrial cardiopathy is associated with stroke prognosis remains unclear. We evaluated the association between atrial cardiopathy markers and outcomes in patients with ischemic stroke using a nationwide prospective registry. Patients and methods: Based on the Third China National Stroke Registry, we evaluated different atrial cardiopathy markers including increased P-wave terminal force in V1 (PTFV1), advanced interatrial block (aIAB), prolonged P-wave duration, prolonged P-wave dispersion, paroxysmal supraventricular tachycardia, premature atrial contractions, prolonged PR interval, and severe left atrial enlargement in ischemic stroke patients. The outcomes were death and ischemic stroke recurrence at 1 year. The association between atrial cardiopathy markers and outcomes was analyzed using Cox regression models. Results: At 1-year follow-up, 486 (3.4%) patients had died and 1317 (9.3%) patients had experienced ischemic stroke recurrence. After adjustment for clinical risk factors including atrial fibrillation, PTFV1 > 5000 μV·ms (adjusted hazard ratio [HR] 1.70, 95% confidence interval [CI]: 1.18–2.45, p = 0.004) and aIAB (adjusted HR 1.47, 95% CI: 1.14–1.91, p = 0.003) were significantly associated with mortality. PTFV1 > 5000 μV·ms was significantly associated with ischemic stroke recurrence (adjusted HR 1.54, 95% CI: 1.22–1.96, p = 0.0004). This association was observed although we excluded patients diagnosed with atrial fibrillation. Discussion and Conclusion: Atrial cardiopathy markers, especially PTFV1 and aIAB, are significantly associated with a higher risk of poor prognosis in patients with ischemic stroke.
The impact of early PEG-asparaginase discontinuation in young adults with ALL: a post hoc analysis of the CALGB 10403 study
Authors: Aldoss Ibrahim , Yin Jun , Wall Anna , Mrózek Krzysztof , Liedtke Michaela , Claxton David F. , Foster Matthew C. , Appelbaum Frederick R. , Erba Harry P. , Litzow Mark R. , Tallman Martin S. , Stone Richard M. , Larson Richard A. , Advani Anjali S. , Stock Wendy , Luger Selina M. 
Published: October 2022

Abstract
Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, a similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup Cancer and Leukemia Group B (CALGB) 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as &lt;4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range, 1-6), with 57 (32%) patients with ED. The ED patients were older (median, 26 vs 23 years; P = .023). Survival was apparently lower for ED patients compared with those receiving ≥4 doses, but this finding was not statistically significant (hazard ratio [HR], 1.82; 95% confidence interval [CI], 0.97-3.43; P = .06), with corresponding 5-year overall survival (OS) rates of 66% and 80%, respectively. In patients with standard-risk ALL, the ED of PEG-asparaginase adversely influenced OS (HR, 2.3; 95% CI, 1.02-5.22; P = .04) with a trend toward inferior event-free survival (EFS) (HR, 1.84; 95% CI, 0.92-3.67; P = .08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P = .64) or EFS (P = .32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high white blood cell count at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.
SpotitPy: a semi-automated tool for object-based co-localization of fluorescent labels in microscopy images
Authors: Akalestou-Clocher Alexia , Kalamara Vivian , Topalis Pantelis , Garinis George A. 
Published: October 2022

Abstract
Background
In fluorescence microscopy, co-localization refers to the spatial overlap between different fluorescent labels in cells. The degree of overlap between two or more channels in a microscope may reveal a physical interaction or topological functional interconnection between molecules. Recent advances in the imaging field require the development of specialized computational analysis software for the unbiased assessment of fluorescently labelled microscopy images.

Results
Here we present SpotitPy, a semi-automated image analysis tool for 2D object-based co-localization. SpotitPy allows the user to select fluorescent labels and perform a semi-automated and robust segmentation of the region of interest in distinct cell types. The workflow integrates advanced pre-processing manipulations for de-noising and in-depth semi-automated quantification of the co-localized fluorescent labels in two different channels. We validated SpotitPy by quantitatively assessing the presence of cytoplasmic ribonucleoprotein granules, e.g. processing (P) bodies, under conditions that challenge mRNA translation, thus highlighting SpotitPy benefits for semi-automatic, accurate analysis of large image datasets in eukaryotic cells. SpotitPy comes in a command line interface or a simple graphical user interphase and can be used as a standalone application.

Conclusions
Overall, we present a novel and user-friendly tool that performs a semi-automated image analysis for 2D object-based co-localization. SpotitPy can provide reproducible and robust quantifications for large datasets within a limited timeframe. The software is open-source and can be found in the GitHub project repository: (https://github.com/alexiaales/SpotitPy).
Effects of computer-aided rowing exercise systems on improving muscle strength and function in older adults with mild knee osteoarthritis: a randomized controlled clinical trial
Authors: Lin Pei-Ling , Yu Lee-Fen , Kuo Shu-Fen , Wang Xin-Miao , Lu Liang-Hsuan , Lin Chueh-Ho 
Published: October 2022

Abstract
Background
Osteoarthritis (OA) is common in aged adults and can result in muscle weakness and function limitations in lower limbs. Knee OA affects the quality of life in the elderly. Technology-supported feedback to achieve lower impact on knee joints and individualized exercise could benefit elderly patients with knee OA. Herein, a computer-aided feedback rowing exercise system is proposed, and its effects on improving muscle strength, health conditions, and knee functions of older adults with mild knee OA were investigated.

Methods
Thirty-eight older adults with mild knee OA and satisfying the American College of Rheumatology (ACR) clinical criteria participated in this randomized controlled clinical trial. Each subject was randomly assigned to a computer-aided rowing exercise (CRE) group (n = 20) or a control group (CON) (n = 18) that received regular resistance exercise programs two times per week for 12 weeks. Outcome measurements, including the Western Ontario and MacMaster Universities (WOMAC), muscle strength and functional fitness of the lower limbs, were evaluated before and after the intervention.

Results
Participants’ functional fitness in the CRE group exhibited significantly higher adjusted mean post-tests scores, including the WOMAC (p = 0.006), hip abductors strength (kg) (MD = 2.36 [1.28, 3.44], p = 5.67 × 10–5), hip adductors strength (MD = 3.04 [1.38, 4.69], p = 0.001), hip flexors strength (MD = 4.01 [2.24, 5.78], p = 6.46 × 10−5), hip extensors strength (MD = 2.88 [1.64, 4.12], p = 4.43 × 10−5), knee flexors strength (MD = 2.03 [0.66, 3.41], p = 0.005), knee extensors strength (MD = 1.80 [0.65, 2.94], p = 0.003), and functional-reach (cm) (MD = 3.74 [0.68, 6.80], p = 0.018), with large effect sizes (η2 = 0.17–0.42), than those in the CON group after the intervention.

Conclusions
Older adults with knee OA in the CRE group exhibited superior muscle strength, health conditions, and functional fitness improvements after the 12-week computer-aided rowing exercise program than those receiving the conventional exercise approach.

Trial registration
The Institutional Review Board of the Taipei Medical University approved the study protocol (no. N201908020, 27/05/2020) and retrospectively registered at ClinicalTrials.gov (trial registry no. NCT04919486, 09/06/2021).
Evaluation design of the patient-centred pathways of early palliative care, supportive ecosystems and appraisal standard (InAdvance): a randomised controlled trial
Authors: Yang-Huang Junwen , Doñate-Martínez Ascensión , Garcés Jorge , Campos Maria Soledad Gimenez , Romero Raquel Valcarcel , López Maria-Eugenia Gas , Fernandes Adriano , Camacho Mariana , Gama Ana , Reppou Sofia , Bamidis Panagiotis D. , Linklater Gordon , Hines Frances , Eze Jude , Raat Hein ,   on behalf of the InAdvance consortium, Bennett Michael , Dimitrova Vania , Tram Nhu , Luc Marine , Fernández Luis , Salminen Päivi , Blanes Vicent , Valero Zoe , Konstantinidis Evdokimos , Conti Giuseppe 
Published: October 2022

Abstract
Background
Palliative care aims to contribute to pain relief, improvement with regard to symptoms and enhancement of health-related quality of life (HRQoL) of patients with chronic conditions. Most of the palliative care protocols, programmes and units are predominantly focused on patients with cancer and their specific needs. Patients with non-cancer chronic conditions may also have significantly impaired HRQoL and poor survival, but do not yet receive appropriate and holistic care. The traditional focus of palliative care has been at the end-of-life stages instead of the relatively early phases of serious chronic conditions. The ‘Patient-centred pathways of early palliative care, supportive ecosystems and appraisal standard’ (InAdvance) project implements and evaluates early palliative care in the daily clinical routine addressing patients with complex chronic conditions in the evolution towards advanced stages. The objective of the current study is to evaluate the acceptability, feasibility, effectiveness and cost-effectiveness of this novel model of palliative care in the relatively early phases in patients with chronic conditions.

Methods
In this study, a single blind randomised controlled trial design will be employed. A total of 320 participants (80 in each study site and 4 sites in total) will be randomised on a 1:1 basis to the Palliative Care Needs Assessment (PCNA) arm or the Care-as-Usual arm. This study includes a formative evaluation approach as well as a cost-effectiveness analysis with a within-trial horizon. Study outcomes will be assessed at baseline, 6 weeks, 6 months, 12 months and 18 months after the implementation of the interventions. Study outcomes include HRQoL, intensity of symptoms, functional status, emotional distress, caregiving burden, perceived quality of care, adherence to treatment, feasibility, acceptability, and appropriateness of the intervention, intervention costs, other healthcare costs and informal care costs.

Discussion
The InAdvance project will evaluate the effect of the implementation of the PCNA intervention on the target population in terms of effectiveness and cost-effectiveness in four European settings. The evidence of the project will provide step-wise guidance to contribute an increased evidence base for policy recommendations and clinical guidelines, in an effort to augment the supportive ecosystem for palliative care.

Trial registration
ISRCTN, ISRCTN24825698. Registered 17/12/2020.
Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients
Authors: Larach Daniel B. , Lewis Adam , Bastarache Lisa , Pandit Anita , He Jing , Sinha Anik , Douville Nicholas J. , Heung Michael , Mathis Michael R. , Mosley Jonathan D. , Wanderer Jonathan P. , Kheterpal Sachin , Zawistowski Matthew , Brummett Chad M. , Siew Edward D. , Robinson-Cohen Cassianne , Kertai Miklos D. 
Published: October 2022

Abstract
Background
Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery.

Methods
We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center (“Vanderbilt” cohort) or Michigan Medicine, the academic medical center of the University of Michigan (“Michigan” cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants.

Results
The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971–1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability.

Conclusion
The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.
Chemotherapy dose per kilogram lean body mass increased dose-limiting toxicity event in male head and neck cancer with taxane and platinum-based induction therapy
Authors: Hung Chuan-Jen , Kang Bor-Hwang , Chang Keng-Ming , Kang Ying-Ying , Yin Chun-Hao , Lee Ching-Chih 
Published: October 2022

Abstract
Background
This study aimed to determine whether drug doses per kilogram of lean body mass (LBM) were associated with dose-limiting toxicity (DLT) events in head and neck cancer (HNC) patients.

Methods
This retrospective cohort study included 179 HNC patients who underwent induction chemotherapy (IC) at a medical center from May 1, 2014, to May 31, 2021. HNC patients’ characteristics, tumor factors, IC regimen and dose, laboratory data, and body composition factors, including lean body mass (LBM) and skeletal muscle index (SMI), derived from CT, MRI, or PET scan images and drug dose per kilogram LBM were recorded. Dose-limiting toxicity (DLT) events were regarded as the primary outcome. Multivariate logistic regression was used to establish a novel risk score for DLT events by the abovementioned variables. The above-mentioned risk score was validated in another cohort.

Results
The overall DLT events during the first cycle of IC for 179 HNC patients was 24%. After stratifying by gender, docetaxel per kilogram LBM > 2.52 mg/kg (adjusted odds ratio [aOR]: 3.18; 95% confidence interval [CI], 1.25–8.09), pre-treatment glutamic pyruvic transaminase (GPT) > 40 U/L (aOR, 2.61; 95% CI, 1.03–6.64), and history of chronic liver diseases (aOR, 3.98; 95% CI, 1.03–15.46) were significant variables in male HNC patients. The DLT events risk was categorized by summation of the above-mentioned risk factors for male HNC patients. Three risk groups were stratified by overall event of 17.6%, 25.8%, and 75%. The above-mentioned risk score had an acceptable discriminatory ability in another validation cohort.

Conclusions
Among male HNC patients treated with IC, docetaxel per kilogram LBM more than 2.52 mg/kg, pre-treatment GPT > 40 U/L, and history of chronic liver disease were significant risk factors for DLT events. Identifying high-risk patients could help physicians prevent severe/fatal complications among HNC patients undergoing IC, especially for the male individuals.
Efficacy and safety of combined targeted therapy and immunotherapy versus targeted monotherapy in unresectable hepatocellular carcinoma: a systematic review and meta-analysis
Authors: Yang Teng-Kai , Yu Ya-Fang , Tsai Chiao-Ling , Li Hsing-Ju , Yang Po-Sheng , Huang Kai-Wen , Cheng Jason Chia-Hsien 
Published: October 2022

Abstract
Background
Cancer therapy has evolved from non-specific cytotoxic agents to a selective, mechanism-based approach that includes targeted agents and immunotherapy. Although the response to targeted therapies for unresectable hepatocellular carcinoma (HCC) is acceptable with the improved survival, the high tumor recurrence rate and drug-related side effects continue to be problematic. Given that immune checkpoint inhibitor alone are not robust enough to improve survival in unresectable HCC, growing evidence supports the combination of targeted therapy and immunotherapy with synergistic effect.

Methods
Online databases including PubMed, EMBASE, Cochrane Library, and Web of Science were searched for the studies that compared targeted monotherapy with the combination therapy of targeted drug and checkpoint inhibitors in unresectable HCC patients. Eligibility criteria were the presence of at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors (version 1.1) for unresectable HCC patients, an Eastern Cooperative Oncology Group performance status of 0–2, and a Child–Pugh score ≤ 7. Outcome measurements include overall survival (OS), progression-free survival (PFS), and treatment-related adverse event (TRAE).

Results
Three phase II/III randomized controlled trials were included in this study. The pooled results showed that combination therapy significantly improved survival than targeted monotherapy, in terms of OS (hazard ratio (HR) = 0.67; 95% confidence interval [CI]: 0.50–0.91) and PFS (HR = 0.58; 95% CI: 0.51–0.67), respectively. In the incidence of grade 3–5 TRAEs, the combination therapy was significantly higher than targeted monotherapy (odds ratio = 1.98; 95% CI: 1.13–3.48).

Conclusion
For unresectable HCC, combined targeted drug and immunotherapy significantly improved survival compared with targeted monotherapy. However, the incidences of AEs of combinational therapy were higher than targeted monotherapy.