bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Changes in Moderate to Vigorous Physical Activity in Community-Dwelling Older Men and Women: A 2-Year Prospective Cohort Study in Japan
Authors: Chen Tao , Chen Sanmei , Honda Takanori , Nofuji Yu , Kishimoto Hiro , Narazaki Kenji 
Published: June 2023

Background: To examine longitudinal changes in accelerometer-measured moderate to vigorous physical activity (MVPA) and associated factors of changes in MVPA among community-dwelling older Japanese men and women over 2 years of follow-up. Methods: In total, 601 participants (72.2 [5.4] y, 40.6% men) were included. MVPA was assessed at baseline (2011) and follow-up (2013) using triaxial accelerometers. Sex-stratified multiple linear regression models were used to identify associated factors of changes in MVPA. Results: On average, a significant decrease in MVPA over 2 years was observed only in women (P < .001). Higher baseline MVPA levels and older age were significantly associated with a decrease in MVPA over 2 years in both men and women. Men who were currently drinking (vs no) and had faster maximum gait speed showed statistically significant increases in MVPA. Women who had very poor/poor economic status (vs fair/good) and were socially isolated (vs no) showed statistically significant increases in MVPA over 2 years, while those who had fear of falling (vs no) and poor/fair self-rated health (vs good/very good) showed statistically significant decreases in MVPA over 2 years. Conclusions: Our findings showed different associated factors of changes in MVPA by sex, suggesting the importance of accounting for sex differences in terms of developing specific intervention strategies for promoting MVPA among older men and women.
How regional versus global thresholds for physical activity and grip strength influence physical frailty prevalence and mortality estimates in PURE: a prospective multinational cohort study of community-dwelling adults
Authors: Farooqi Maheen , Papaioannou Alexandra , Bangdiwala Shrikant , Rangarajan Sumathy , Leong Darryl 
Published: June 2023

ObjectivesHandgrip strength and physical activity are commonly used to evaluate physical frailty; however, their distribution varies worldwide. The thresholds that identify frail individuals have been established in high-income countries but not in low-income and middle-income countries. We created two adaptations of physical frailty to study how global versus regional thresholds for handgrip strength and physical activity affect frailty prevalence and its association with mortality in a multinational population.Design, setting and participantsOur sample included 137 499 adults aged 35–70 years (median age: 61 years, 60% women) from Population Urban Rural Epidemiology Studies community-dwelling prospective cohort across 25 countries, covering the following geographical regions: China, South Asia, Southeast Asia, Africa, Russia and Central Asia, North America/Europe, Middle East and South America.Primary and secondary outcome measuresWe measured and compared frailty prevalence and time to all-cause mortality for two adaptations of frailty.ResultsOverall frailty prevalence was 5.6% usingglobal frailtyand 5.8% usingregional frailty. Global frailty prevalence ranged from 2.4% (North America/Europe) to 20.1% (Africa), while regional frailty ranged from 4.1% (Russia/Central Asia) to 8.8% (Middle East). The HRs for all-cause mortality (median follow-up of 9 years) were 2.42 (95% CI: 2.25 to 2.60) and 1.91 (95% CI: 1.77 to 2.06) usingglobal frailtyandregional frailty,respectively, (adjusted for age, sex, education, smoking status, alcohol consumption and morbidity count). Receiver operating characteristic curves for all-cause mortality were generated for both frailty adaptations.Global frailtyyielded an area under the curve of 0.600 (95% CI: 0.594 to 0.606), compared with 0.5933 (95% CI: 0.587 to 5.99) forregional frailty(p=0.0007).ConclusionsGlobal frailtyleads to higher regional variations in estimated frailty prevalence and stronger associations with mortality, as compared with regional frailty. However, both frailty adaptations in isolation are limited in their ability to discriminate between those who will die during 9 years’ follow-up from those who do not.
Involving adolescents in the design, implementation, evaluation and dissemination of health research: an umbrella review protocol
Authors: Warraitch Azza , Bruce Delali , Lee Maria , Curran Paul , Khraisha Qusai , Hadfield Kristin 
Published: June 2023

IntroductionA lack of awareness on how to engage adolescents in research has been reported as one of the barriers to meaningful youth involvement in health research. Currently, available guidelines on youth involvement are limited in terms of the scope (e.g., focused on limited health research areas), content (e.g., include broad principles) and context (e.g., most guidelines are from high-income countries) for which the guidelines are applicable. To address this, we will develop a set of comprehensive guidelines based on consolidated evidence on youth involvement in health research. To inform these guidelines, we are first conducting an umbrella review to (1) summarise and synthesise findings from reviews on involving adolescents in health research, (2) consolidate the challenges experienced in youth involvement and the recommendations to mitigate these challenges, (3) identify best practices and (4) identify gaps and methodological weaknesses in the extant literature on involving adolescents in health research.Methods and analysisWe will include review articles exploring adolescents’ involvement in studies aiming to improve their physical or mental health. Databases to be searched include Cochrane Database of Systematic Reviews, Medical Literature Analysis and Retrieval System Online (MEDLINE), Scopus, Embase, PsycINFO, PsycArticles, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Epistemonikos and Health Systems Evidence. A grey literature search will be conducted in Web of Science, ProQuest, Google Scholar and PROSPERO, supplemented by a handsearch of the reference lists of eligible reviews, relevant journals, websites of related organisations and input from experts. Data will be analysed using narrative synthesis.Ethics and disseminationEthical approval is not required as we are not collecting participant data as part of this review. The findings of this umbrella review will be disseminated through peer-reviewed publications, participatory workshops and academic conferences.PROSPERO registration numberCRD42021287467.
School-age outcomes of children after perinatal brain injury: a systematic review and meta-analysis
Authors: Rees Philippa , Callan Caitriona , Chadda Karan , Vaal Meriel , Diviney James , Sabti Shahad , Harnden Fergus , Gardiner Julian , Battersby Cheryl , Gale Chris , Sutcliffe Alastair 
Published: June 2023

BackgroundOver 3000 children suffer a perinatal brain injury in England every year according to national surveillance. The childhood outcomes of infants with perinatal brain injury are however unknown.MethodsA systematic review and meta-analyses were undertaken of studies published between 2000 and September 2021 exploring school-aged neurodevelopmental outcomes of children after perinatal brain injury compared with those without perinatal brain injury. The primary outcome was neurodevelopmental impairment, which included cognitive, motor, speech and language, behavioural, hearing or visual impairment after 5 years of age.ResultsThis review included 42 studies. Preterm infants with intraventricular haemorrhage (IVH) grades 3–4 were found to have a threefold greater risk of moderate-to-severe neurodevelopmental impairment at school age OR 3.69 (95% CI 1.7 to 7.98) compared with preterm infants without IVH. Infants with perinatal stroke had an increased incidence of hemiplegia 61% (95% CI 39.2% to 82.9%) and an increased risk of cognitive impairment (difference in full scale IQ −24.2 (95% CI –30.73 to –17.67) . Perinatal stroke was also associated with poorer academic performance; and lower mean receptive −20.88 (95% CI –36.66 to –5.11) and expressive language scores −20.25 (95% CI –34.36 to –6.13) on the Clinical Evaluation of Language Fundamentals (CELF) assessment. Studies reported an increased risk of persisting neurodevelopmental impairment at school age after neonatal meningitis. Cognitive impairment and special educational needs were highlighted after moderate-to-severe hypoxic-ischaemic encephalopathy. However, there were limited comparative studies providing school-aged outcome data across neurodevelopmental domains and few provided adjusted data. Findings were further limited by the heterogeneity of studies.ConclusionsLongitudinal population studies exploring childhood outcomes after perinatal brain injury are urgently needed to better enable clinicians to prepare affected families, and to facilitate targeted developmental support to help affected children reach their full potential.
Training interventions to reduce the risk of injury to the lower extremity joints during landing movements in adult athletes: a systematic review and meta-analysis
Authors: Bathe Chantal , Fennen Lena , Heering Theresa , Greif Alexander , Dubbeldam Rosemary 
Published: June 2023

ObjectiveAim of this systematic review was to summarise training interventions designed to reduce biomechanical risk factors associated with increased risk of lower extremity landing injuries and to evaluate their practical implications in amateur sports.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, Scopus and SPORTDiscus.Eligibility criteriaTraining intervention(s) aimed at reducing biomechanical risk factors and/or injury rates included the following: (1) prospective or (non-)randomised controlled study design; (2) risk factors that were measured with valid two-dimensional or three-dimensional motion analysis systems or Landing Error Scoring System during jump landings. In addition, meta-analyses were performed, and the risk of bias was assessed.ResultsThirty-one studies met all inclusion criteria, capturing 11 different training interventions (eg, feedback and plyometrics) and 974 participants. A significantly medium effect of technique training (both instruction and feedback) and dynamic strengthening (ie, plyometrics with/without strengthening) on knee flexion angle (g=0.77; 95% CI 0.33 to 1.21) was shown. Only one-third of the studies had training interventions that required minimal training setup and additional coaching educations.ConclusionThis systematic review highlights that amateur coaches can decrease relevant biomechanical risk factors by means of minimal training setup, for example, instructing to focus on a soft landing, even within only one training session of simple technique training. The meta-analysis emphasises implementing technique training as stand-alone or combined with dynamic strengthening into amateur sport training routine.
Defects in intratumoral arginine metabolism attenuate the replication and therapeutic efficacy of oncolytic myxoma virus
Authors: Dryja Parker , Curtsinger Heather D , Bartee Mee Y , Bartee Eric 
Published: June 2023

BackgroundArginine (Arg) is a semiessential amino acid whose bioavailability is required for the in vitro replication of several oncolytic viruses. In vivo, Arg bioavailability is regulated by a combination of dietary intake, protein catabolism, and limited biosynthesis through portions of the urea cycle. Interestingly, despite the importance of bioavailable Arg to support cellular proliferation, many forms of cancer are functionally auxotrophic for this amino acid due to the epigenetic silencing of argininosuccinate synthetase 1 (ASS1), an enzyme responsible for the conversion of citrulline and aspartate into the Arg precursor argininosuccinate. The impact of this silencing on oncolytic virotherapy (OV), however, has never been examined.MethodsTo address this gap in knowledge, we generated tumor cells lacking ASS1 and examined how loss of this enzyme impacted the in vivo replication and therapeutic efficacy of oncolytic myxoma virus (MYXV). We also generated a series of recombinant MYXV constructs expressing exogenous ASS1 to evaluate the therapeutic benefit of virally reconstituting Arg biosynthesis in ASS1−/−tumors.ResultsOur results show that the in vitro replication of oncolytic MYXV is dependent on the presence of bioavailable Arg. This dependence can be overcome by the addition of the metabolic precursor citrulline, however, this rescue requires expression of ASS1. Because of this, tumors formed from functionally ASS1−/−cells display significantly reduced MYXV replication as well as poorer therapeutic responses. Critically, both defects could be partially rescued by expressing exogenous ASS1 from recombinant oncolytic MYXVs.ConclusionsThese results demonstrate that intratumoral defects to Arg metabolism can serve as a novel barrier to virally induced immunotherapy and that the exogenous expression of ASS1 can improve the efficacy of OV in Arg-auxotrophic tumors.
Robust IL-2-dependent antitumor immunotherapy requires targeting the high-affinity IL-2R on tumor-specific CD8+T cells
Authors: LaPorte Kathryn M , Hernandez Rosmely , Santos Savio Alicia , Malek Thomas R 
Published: June 2023

BackgroundDevelopment of interleukin (IL)-2-dependent antitumor responses focus on targeting the intermediate affinity IL-2R to stimulate memory-phenotypic CD8+T and natural killer (NK) cells while minimizing regulatory T cell (Treg) expansion. However, this approach may not effectively engage tumor-specific T effector cells. Since tumor-antigen specific T cells upregulate the high-affinity IL-2R, we tested an IL-2 biologic, mouse IL-2/CD25, with selectivity toward the high-affinity IL-2R to support antitumor responses to tumors that vary in their immunogenicity.MethodsMice were first implanted with either CT26, MC38, B16.F10, or 4T1 and after a tumor mass developed, they were treated with high-dose (HD) mouse (m)IL-2/CD25 alone or in combination with anti-programmed cell death protein-1 (PD-1) checkpoint blockade. Tumor growth was monitored and in parallel the immune signature in the tumor microenvironment (TME) was determined by a combination of multiparameter flow cytometry, functional assays, and enumeration of tumor-reactive T cells.ResultsWe show that HD mIL-2/CD25, which preferentially stimulates the high-affinity IL-2R, but not IL-2/anti-IL-2 complexes with preferential activity toward the intermediate-affinity IL-2R, supports vigorous antitumor responses to immunogenic tumors as a monotherapy that were enhanced when combined with anti-PD-1. Treatment of CT26-bearing mice with HD mIL-2/CD25 led to a high CD8+:Treg ratio in the TME, increased frequency and function of tumor-specific CD8+T effector cells with a less exhausted phenotype, and antitumor memory responses.ConclusionsTargeting the high-affinity IL-2R on tumor-specific T cells with HD mIL-2/CD25 alone or with PD-1 blockade supports antitumor responses, where the resulting memory response may afford long-term protection against tumor re-emergence.
Abstract A075: Characterizing novel aggressive prostate cancer subtypes associated with loss of chromosomes 8p and 16q
Authors: Yette Gabriel A. , Costello James C. , Cramer Scott D. 
Published: June 2023

Abstract
Roughly 15% of the 268,490 men newly diagnosed with prostate cancer (PCa) will die from the disease. Pinpointing the drivers of aggressive PCa is the first step to improve patient outcomes. Correlative analyses have linked genetic aberrations, including copy number alterations due to loss of large genomic regions, to poor prostate cancer prognosis. Many groups have connected the loss of chromosome 8p and 16q to aggressive PCa, yet the genes on these regions responsible for aggressive phenotypes are unknown. Mining TCGA data, we identified minimum consensus deletions and associated gene expression with disease recurrence to nominate 48 genes on 8p and 58 genes on 16q for further study. We designed a pooled double knockout library to test all pairwise gene combinations of the nominated 8p-16q genes. Gene pairs will be targeted by 16 paired crRNA cassettes consisting of four crRNAs per gene and paired in all combinations. This library will be combined with stably expressing Cas12a prostate epithelial cell lines to screen for gene combinations that drive excessive cell proliferation. This will help pinpoint specific PCa tumor suppressors in combined 8p and 16q loss.
Citation Format: Gabriel A. Yette, James C. Costello, Scott D. Cramer. Characterizing novel aggressive prostate cancer subtypes associated with loss of chromosomes 8p and 16q [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A075.
Abstract A080: Male-biased metabolic and structural muscular changes driven by testosterone flare-like conditions
Authors: Fenimore John M. , Springer Danielle , Edmonston Elijah , Nagashima Kunio , Sowalsky Adam , Young Howard 
Published: June 2023

Abstract
Background: During the first 1 to 3 weeks of LHRH-agonist therapy for recurrent or metastatic prostate cancer, an initial increase in testosterone is associated with a condition known as "flare." Flare often is accompanied by fatigue, increases in immune infiltrate in prostate cancer and cardiovascular distress. Cardiovascular myopathies and fatigue have been associated with chronic inflammatory responses and activated cell-mediated immunity. Methods and Results: Using a model of autoimmune mice with persistent low-level expression of proinflammatory interferon gamma (IFN-g), we found fatigue and aberrant cardiovascular activity in the form of reduced ejection fraction responding to exercise in male but not female mice. This finding suggests that male hormone has a potential role for impacting cardiovascular fatigue with a more activated immune environment. Furthermore, analysis of cardiovascular tissues revealed an increase in factors associated with fatigue, such as lactic acid production and changes in expression of genes associated with an increase in anaerobic respiration and poor mitochondrial performance in cardiac musculature. Conclusion: These results indicate that the chronic expression of IFN-g may be synergetic with androgen to produce a male-biased fatigue and muscle dysfunction. Considering that the most frequent side effects to activated immune therapies to cancer in males undergoing CAR-T therapies are fatigue and cardiomyopathies we believe this insight may be beneficial to patients of other therapies as well. Understanding the biological effects of therapy driven flare may offer opportunities for physiological interventions in patients undergoing persistent or intermittent LHRHa therapy.
Citation Format: John M. Fenimore, Danielle Springer, Elijah Edmonston, Kunio Nagashima, Adam Sowalsky, Howard Young. Male-biased metabolic and structural muscular changes driven by testosterone flare-like conditions [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A080.
Abstract B056: Homoharringtonine, a translational inhibitor, induces dramatic apoptosis in prostate cancer xenografts
Authors: Ohtsu Akira , Arai Seiji , Sawada Tatsuhiro , Kato Mai , Maeno Yuta , Miyazawa Yoshiyuki , Sekine Yoshitaka , Suzuki Kazuhiro 
Published: June 2023

Abstract
Introduction: We have previously shown that prostate cancer is primed to undergo apoptosis with BH3 mimetics targeting anti-apoptotic proteins, including BCL2, BCLXL, and MCL1 (Arai S, Balk SP et al. Clin Cancer Res 2018). We have also revealed that receptor tyrosine kinase inhibitors induced MCL1 degradation through integrated stress response and mitochondrial E3 ubiquitin ligase MARCH5 (Arai S, Balk SP et al. eLife 2020). Thus, we hypothesized that drugs targeting mitochondria might decrease MCL1 and induce apoptosis in prostate cancer. Methods: In this study, we have conducted a small-scale screening of a commercially available drug library (84 compounds) that is supposed to target mitochondria in prostate cancer cells. We have selected the top 5 drugs that could decrease prostate cancer cell growth at 1 μM levels. Results: Homoharringtonine, an FDA-approved translational inhibitor for chronic myelogenous leukemia, decreased cell growth within nM levels in multiple prostate cancer cell lines in vitro. Mechanistically, homoharringtonine rapidly reduced several proteins (MCL1, AR, AR-V7, and c-MYC) through translational inhibition and significantly induced apoptosis in prostate cancer cells in vitro. Importantly, homoharringtonine dose-dependently led to the regression of prostate cancer xenografts in vivo. Conclusions: Homoharringtonine might be a good candidate drug to treat prostate cancer.
Citation Format: Akira Ohtsu, Seiji Arai, Tatsuhiro Sawada, Mai Kato, Yuta Maeno, Yoshiyuki Miyazawa, Yoshitaka Sekine, Kazuhiro Suzuki. Homoharringtonine, a translational inhibitor, induces dramatic apoptosis in prostate cancer xenografts [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B056.
Abstract B068: Treatment combinations targeting MCL-1 and BCL-xL exert synergistic anti-tumor effects in AR-V7 expressing CRPC cell lines
Authors: Napoli Giulia C. , Leon Andres F. , Beatson Erica L. , Schmidt Keith T. , Risdon Emily N. , Chau Cindy H. , Price Douglas K. , Figg William D. 
Published: June 2023

Abstract
Therapeutic agents that overcome acquired resistance to current androgen receptor (AR) pathway targeted therapies in patients with castration-resistant prostate cancer (CRPC) remain an unmet clinical need. A multitude of pathways are implicated in acquired treatment resistance, including the PI3K/mTOR/AKT, WNT/β-catenin, and DNA damage repair pathways. Notably, the androgen receptor splice variant 7 (AR-V7) activates the AR pathway in the absence of androgens, playing a crucial role in CRPC progression. An unbiased high throughput drug screen evaluating an array of inhibitors targeting diverse signaling pathways revealed highly synergistic activity of BH3 mimetics in AR-V7 expressing CRPC cell lines (e.g. LNCaP95, 22Rv1, VCaP-CR). Combinations targeting MCL-1 and BCL-xL (S63845 with A-1331852 or Navitoclax) displayed increased antitumor activity compared to those targeting MCL-1 and BCL-2 (S63845 with Venetoclax). Synergy among BCL-xL and MCL-1 targeted combinations was demonstrated using 2D and 3D CellTiter-Glo viability assays. Combination treatments in 3D spheroid cultures of 22RV1 and LNCaP95 cells confirmed the synergy observed in 2D assays. Furthermore, combined BCL-xL and MCL-1 inhibition altered AR-V7 expression and activated c-PARP cleavage. Drug combinations synergistically targeting BCL-xL and MCL-1 should be further explored for the treatment of therapy-resistant CRPC.
Citation Format: Giulia C. Napoli, Andres F. Leon, Erica L. Beatson, Keith T. Schmidt, Emily N. Risdon, Cindy H. Chau, Douglas K. Price, William D. Figg. Treatment combinations targeting MCL-1 and BCL-xL exert synergistic anti-tumor effects in AR-V7 expressing CRPC cell lines [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B068.