bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of varied dorsiflexion range of motion on landing biomechanics in chronic ankle instability
Authors: Han Seunguk , Lee Hyunwook , Son S. Jun , Hopkins J. Ty 
Published: February 2023

BackgroundLimited dorsiflexion range of motion (DFROM) is a risk factor for lateral ankle sprain. However, varied DFROM exists within the chronic ankle instability (CAI) population, and how the variability may influence altered movement patterns during landing is unclear.ObjectiveThe purpose of this study was to identify different movement strategies during maximal jump landing/cutting among CAI patients classified by varied DFROM.MethodsOne hundred CAI subjects were classified into 3 subgroups based on their DFROM, measured by the weight‐bearing lunge test: a Hypo‐ (≤40°), Normal‐ (40–50°), and Hyper‐DFROM group (≥50°). Participants completed five trials of maximal jump landing/cutting. Lower extremity joint angles and EMG activation of seven muscles were collected from initial contact to toe‐off. Functional analyses of variance were used to evaluate between‐group differences for these outcome variables.ResultsHypo‐DFROM group (14M, 10F) displayed the reduced ankle dorsiflexion and inversion angles with increased hip flexion angle as a compensatory kinematic chain movement strategy. In addition, motion restrictions of the ankle are associated with altered muscle activation in both distal and proximal muscles during landing/cutting. Normal‐DFROM (25M, 30F) and Hyper‐DFROM (11M, 10F) groups also have different movement strategies including greater inversion angle and less EMG activation, which could contribute to further ankle injuries.ConclusionsOur data suggest that limited DFROM negatively affects the ankle joint during demanding movement within the CAI population. These movement patterns in CAI patients with pathomechanical deficits could contribute to further ankle sprains.
The use of human‐derived feeder layers for the cultivation of transplantable human epidermal cell sheet to repair second degree burn wounds
Authors: Mingqi Zhang , Le Wang , Yuqiang Zheng , Na Li , Wei He , Zhuoshi Wang 
Published: February 2023

AbstractBackground and objectivesHuman epidermal cell sheet (human‐ECS) is a feasible treatment option for wound injury. Traditionally, researchers often use murine 3T3 fibroblast cells as feeder layer to support human epidermal cell sheet grafts, thus increase risk to deliver animal‐borne infection. To overcome the potential risks involved with xenotransplantation, we develop human foreskin fibroblast cell as feeder layer culture system and investigate the effects of human‐ECS on second‐degree burn wound healing in mini‐pig in order to develop more effective and safer therapies to enhance wound healing in human.Materials and methodsHuman epidermal keratinocytes and fibroblasts were isolated from foreskin tissue and were co‐cultured to manufacture human‐ECS. The cell morphology was monitored with phase‐contrast microscopy, the stem cell markers were assessed by flow cytometry, and by colony‐forming efficiency (CFE) assay. The structure of human‐ECS was observed by hematoxylin and eosin staining. Expression of cytokines in human‐ECS was confirmed by enzyme‐linked immunosorbent assay. Second‐degree burn wounds were created on the dorsal of miniature pig to evaluate the effect of oil gauze, oil gauze combined with commercial epidermal growth factor (EGF) cream, and oil gauze combined with human‐ECS. Wound healing rate, histological examination, and Masson staining were measured to observe the wound repair efficacy. Real‐time PCR and Western blot were utilized to detect the expression level of EGF and interleukin 6 (IL‐6).ResultsStratified human‐ECS with 6‐7 layers of epidermal cells was successfully cultivated with human‐derived feeder cells, in which epidermal cell highly expressed CD49f and CFE was 3% ± 0.45%. Application of human‐ECS induced a higher wound healing rate than commerical EGF cream and oil gauze control. The expression of EGF in human‐ECS group was higher than those in the other groups; however, the expression of IL‐6 was significantly decreased at day 14 by human‐ECS treatment group.ConclusionsHuman‐derived feeder cells are suitable for cultivation of human‐ECS, avoiding pathogen transmission. Human‐ECS could enhance second‐degree burn wound healing, and its promoting effect involved secreting a variety of cytokines to regulate tissue reparative process.
Associations of Physical Activity With Breast Cancer Risk: Findings From the UK Biobank Prospective Cohort Study
Authors: Parra-Soto Solange , Tumblety Craig , Araya Carolina , Rezende Leandro F.M. , Ho Frederick K. , Pell Jill P. , Celis-Morales Carlos 
Published: February 2023

Purpose: Although physical activity (PA) has been consistently associated with breast cancer, existing evidence is limited to self-reported physical activity, which is prone to dilution bias. Therefore, this aims to examine the associations of device-measured PA domains with breast cancer risk and whether it differs by menopausal status. Methods: Prospective cohort study. Data from 48,286 women from the UK Biobank cohort were analyzed. A wrist triaxial accelerometer was used to collect physical activity data for light, moderate, vigorous, moderate to vigorous, and total PA. Cox proportional models were performed to examine the association between PA domains, menopausal status, and breast cancer risk. Results: Eight hundred thirty-six breast cancer cases were diagnosed during a median of 5.4 years (interquartile range: 4.7–5.9). For total PA, those in the most active quartile had a 26% lower risk of breast cancer (Hazard ratio [HR]: 0.74; 95% confidence interval [CI], 0.61–0.91) compared with those least active. Similar results were observed for light PA (HR: 0.79; 95% CI, 0.64–0.96), and moderate to vigorous PA (HR: 0.78; 95% CI, 0.64–0.96). However, moderate PA (HR: 0.73; 95% CI, 0.44–1.19) and vigorous PA (HR: 0.77; 95% CI, 0.56–1.05) was nonsignificant. No evidence of interaction between PA domains and menopause status was found (P > .10). Conclusion: High levels of PA are associated with a lower risk of breast cancer with similar magnitude of associations observed across different intensity domains.
Single-Cell Discovery and Multiomic Characterization of Therapeutic Targets in Multiple Myeloma
Authors: Yao Lijun , Wang Julia T. , Jayasinghe Reyka G. , O'Neal Julie , Tsai Chia-Feng , Rettig Michael P. , Song Yizhe , Liu Ruiyang , Zhao Yanyan , Ibrahim Omar M. , Fiala Mark A. , Fortier Julie M. , Chen Siqi , Gehrs Leah , Rodrigues Fernanda Martins , Wendl Michael C. , Kohnen Daniel , Shinkle Andrew , Cao Song , Foltz Steven M. , Zhou Daniel Cui , Storrs Erik , Wyczalkowski Matthew A. , Mani Smrithi , Goldsmith Scott R. , Zhu Ying , Hamilton Mark , Liu Tao , Chen Feng , Vij Ravi , Ding Li , DiPersio John F. 
Published: February 2023

AbstractMultiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy.Significance:Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy.
Application of Novel Breast Biospecimen Cell-Type Adjustment Identifies Shared DNA Methylation Alterations in Breast Tissue and Milk with Breast Cancer–Risk Factors
Authors: Muse Meghan E. , Carroll Connolly D. , Salas Lucas A. , Karagas Margaret R. , Christensen Brock C. 
Published: February 2023

AbstractBackground:DNA methylation patterning is cell-type–specific and altered DNA methylation is well established to occur early in breast carcinogenesis, affecting non-cancerous, histopathologically normal breast tissue. Previous work assessing risk factor–associated alterations to DNA methylation in breast tissue has been limited, with even less published research in breast milk, a noninvasively obtained biospecimen containing sloughed mammary epithelial cells that may identify early alterations indicative of cancer risk.Methods:Here, we present a novel library for the estimation of the cellular composition of breast tissue and milk and subsequent assessment of cell-type–independent alterations to DNA methylation associated with established breast cancer–risk factors in solid breast tissue (n = 95) and breast milk (n = 48) samples using genome-scale DNA methylation measures from the Illumina HumanMethylation450 array.Results:We identified 772 hypermethylated CpGs (P &lt; 0.01) associated with age consistent between breast tissue and breast milk samples. Age-associated hypermethylated CpG loci were significantly enriched for CpG island shore regions known to be important for regulating gene expression. Among the overlapping hypermethylated loci mapping to genes, a differentially methylated region was identified in the promoter region of SFRP2, a gene observed to undergo promoter hypermethylation in breast cancer.Conclusions:Our findings suggest the potential to identify epigenetic biomarkers of breast cancer risk in noninvasively obtained, tissue-specific breast milk specimens.Impact:This work demonstrates the potential of using breast milk as a noninvasive biomarker of breast cancer risk, improving our ability to detect early-stage disease and lowering the overall disease burden.
Cell-Free Urine and Plasma DNA Mutational Analysis Predicts Neoadjuvant Chemotherapy Response and Outcome in Patients with Muscle-Invasive Bladder Cancer
Authors: Christensen Emil , Nordentoft Iver , Birkenkamp-Demtröder Karin , Elbæk Sara K. , Lindskrog Sia V. , Taber Ann , Andreasen Tine G. , Strandgaard Trine , Knudsen Michael , Lamy Philippe , Agerbæk Mads , Jensen Jørgen B. , Dyrskjøt Lars 
Published: February 2023

AbstractPurpose:To investigate the use of plasma and urine DNA mutation analysis for predicting neoadjuvant chemotherapy (NAC) response and oncological outcome in patients with muscle-invasive bladder cancer.Experimental Design:Whole-exome sequencing of tumor and germline DNA was performed for 92 patients treated with NAC followed by radical cystectomy (RC). A custom NGS-panel capturing approximately 50 mutations per patient was designed and used to track mutated tumor DNA in plasma and urine. A total of 447 plasma samples, 281 urine supernatants, and 123 urine pellets collected before, during, and after treatment were analyzed. Patients were enrolled from 2013 to 2019, with a median follow-up time of 41.3 months after RC.Results:We identified tumor DNA before NAC in 89% of urine supernatants, 85% of urine pellets, and 43% of plasma samples. Tumor DNA levels were higher in urine supernatants and urine pellets compared with plasma samples (P &lt; 0.001). In plasma, detection of circulating tumor DNA (ctDNA) before NAC was associated with a lower NAC response rate (P &lt; 0.001). Detection of tumor DNA after NAC was associated with lower response rates in plasma, urine supernatant, and urine pellet (P &lt; 0.001, P = 0.03, P = 0.002). Tumor DNA dynamics during NAC was predictive of NAC response and outcome in urine supernatant and plasma (P = 0.006 and P = 0.002). A combined measure from plasma and urine supernatant tumor DNA dynamics stratified patients by outcome (P = 0.003).Conclusions:Analysis of tumor DNA in plasma and urine samples both separately and combined has a potential to predict treatment response and outcome.
Identification ofIGF2as Genomic Driver and Actionable Therapeutic Target in Hepatoblastoma
Authors: Abril-Fornaguera Jordi , Torrens Laura , Andreu-Oller Carmen , Carrillo-Reixach Juan , Rialdi Alex , Balaseviciute Ugne , Pinyol Roser , Montironi Carla , Haber Philipp K. , Del Río-Álvarez Álvaro , Domingo-Sàbat Montserrat , Royo Laura , Akers Nicholas K. , Willoughby Catherine E. , Peix Judit , Torres-Martin Miguel , Puigvehi Marc , Cairo Stefano , Childs Margaret , Maibach Rudolf , Alaggio Rita , Czauderna Piotr , Morland Bruce , Losic Bojan , Mazzaferro Vincenzo , Guccione Ernesto , Sia Daniela , Armengol Carolina , Llovet Josep M. 
Published: February 2023

AbstractManagement of hepatoblastoma (HB), the most frequent pediatric liver cancer, is based on surgical resection and perioperative chemotherapy regimens. In this study, we aimed to identify actionable targets in HB and assess the efficacy of molecular therapies in preclinical models of HB. Paired tumor and adjacent tissues from 31 HBs and a validation set of 50 HBs were analyzed using RNA-seq, SNP, and methylation arrays. IGF2 overexpression was identified as the top targetable HB driver, present in 71% of HBs (22/31). IGF2high tumors displayed progenitor cell features and shorter recurrence-free survival. IGF2 overexpression was associated in 91% of cases with fetal promoter hypomethylation, ICR1 deregulation, 11p15.5 loss of heterozygosity or miR483-5p overexpression. The antitumor effect of xentuzumab (a monoclonal antibody targeting IGF1/2) alone or in combination with the conventional therapeutic agent cisplatin was assessed in HB cell lines, in PDX-derived HB organoids and in a xenograft HB murine model. The combination of xentuzumab with cisplatin showed strong synergistic antitumor effects in organoids and in IGF2high cell lines. In mice (n = 55), the combination induced a significant decrease in tumor volume and improved survival compared with cisplatin alone. These results suggest that IGF2 is an HB actionable driver and that, in preclinical models of HB, the combination of IGF1/2 inhibition with cisplatin induces superior antitumor effects than cisplatin monotherapy. Overall, our study provides a rationale for testing IGF2 inhibitors in combination with cisplatin in HB patients with IGF2 overexpression.
Inhibition of LILRB2 by a Novel Blocking Antibody Designed to Reprogram Immunosuppressive Macrophages to Drive T-Cell Activation in Tumors
Authors: Umiker Ben , Hashambhoy-Ramsay Yasmin , Smith Jeff , Rahman Tanzila , Mueller Amy , Davidson Rachel , Meyer Christina , Patankar Gayatri , Alam Mohammad Murshid , Jaffe Sarah , Krukenberg Kristin , Goodman Allison , Spaulding Vikki , Priess Michelle , Dhaneshwar Abha , Wong Masie , Diiorio Alexa , O'Malley Kristin , McGrath Lara , Willer Margaret , Pepper Lauren , Gostissa Monica , Kis-Toth Katalin , Wiederschain Dmitri , Cohen Heather , Shaffer Donald R. 
Published: February 2023

AbstractTumor-associated macrophages (TAM) play an important role in maintaining the immunosuppressive state of the tumor microenvironment (TME). High levels of CD163+ TAMs specifically are associated with poor prognosis in many solid tumor types. Targeting TAMs may represent a key approach in development of the next generation of cancer immune therapeutics. Members of the leukocyte immunoglobulin-like receptor B (LILRB) family, including LILRB2 (ILT4), are known to transmit inhibitory signals in macrophages and other myeloid cells. Leveraging bulk and single cell RNA-sequencing datasets, as well as extensive immunophenotyping of human tumors, we found that LILRB2 is highly expressed on CD163+ CD11b+ cells in the TME and that LILRB2 expression correlates with CD163 expression across many tumor types. To target LILRB2, we have developed JTX-8064, a highly potent and selective antagonistic mAb. JTX-8064 blocks LILRB2 binding to its cognate ligands, including classical and nonclassical MHC molecules. In vitro, JTX-8064 drives the polarization of human macrophages and dendritic cells toward an immunostimulatory phenotype. As a result, human macrophages treated with a LILRB2 blocker are reprogrammed to increase the activation of autologous T cells in co-culture systems. Furthermore, JTX-8064 significantly potentiates the activity of anti-PD-1 in allogeneic mixed lymphocyte reaction. In a human tumor explant culture, pharmacodynamic activity of JTX-8064 was observed in monotherapy and in combination with anti-PD-1. Collectively, our work provides strong translational and preclinical rationale to target LILRB2 in cancer.
Homogenization of Observed Surface Wind Speed Based on Geostrophic Wind Theory over China from 1970 to 2017
Authors: Zhang Zhengtai , Wang Kaicun 
Published: February 2023

Abstract
The observed surface wind speed (SWS) over China has declined in the past four decades, and recently, the trend has reversed, which is known as SWS stilling and recovery. The observed SWS is vulnerable to changes in nonclimatic factors, i.e., inhomogeneity. Unfortunately, most of the existing studies on the long-term trend of SWS were based on raw datasets without homogenization. In this study, by means of geostrophic wind speed and penalized maximal t test, we conduct a systematic homogeneity test and exploration of the homogenization impact for SWS at over 2000 stations in China from 1970 to 2017. The results show that the inhomogeneity in the observed SWS over China is detectable at 59% of national weather stations. The breakpoint years are mainly concentrated in the late 1970s, mid-1990s, and early 2000s. Overall, 18% of breakpoints are caused by station relocations, and the remaining breakpoints are likely related to anemometer replacement and measurement environment changes that occurred during the mid-1990s and early 2000s. After homogenization, the decreasing trend in SWS during 1970–2017 decreased from −0.15 to −0.05 m s−1 decade−1. The homogenized SWS recovery period advanced from the early twenty-first century to the early 1990s, which is consistent with the SWS variations, excluding the impact of urbanization around weather stations. The phase change in the Western Hemisphere warm pool (WHWP) might be one of the causes of homogenized SWS recovery.
Destinations and Pathways of the Indonesian Throughflow Water in the Indian Ocean
Authors: Guo Yaru , Li Yuanlong , Wang Fan 
Published: February 2023

Abstract
Passage of the Indonesian Throughflow (ITF) water through the Indian Ocean constitutes an essential section of the upper limb of the global ocean conveyor belt. Although existing studies have identified a major exit of the ITF water to the Atlantic Ocean through the Agulhas Current system, our knowledge regarding other possible destinations and primary pathways remains limited. This study applies the Connectivity Modeling System (CMS) particle tracking algorithm to seven model-based ocean current datasets. The results reveal a robust return path of the ITF water to the Pacific Ocean. The partition ratio between the Atlantic and Pacific routes is 1.60 ± 0.54 to 1, with the uncertainty representing interdataset spread. The average transit time across the Indian Ocean is 10–20 years to the Atlantic and 15–30 years to the Pacific. The “transit velocity” is devised to describe the three-dimensional pathways in a quantitative sense. Its distribution demonstrates that the recirculation structures in the southwestern subtropical Indian Ocean favor the exit to the Atlantic, while the Antarctic Circumpolar Current in the Southern Ocean serves as the primary corridor to the Pacific. Our analysis also suggests the vital impact of vertical motions. In idealized tracing experiments inhibiting vertical currents and turbulent mixing, more water tends to linger over the Indian Ocean or return to the Pacific. Turbulence mixing also contributes to vertical motions but only slightly affects the destinations and pathways of ITF water.
Action Video Gaming and Attention in Young Adults: A Systematic Review
Authors: Sampalo Mar , Lázaro Esther , Luna Paula-María 
Published: February 2023

Objective: Existing research in action video games has increased in recent years due to the expansion of their use all over the world. Specifically, there is growing evidence about the positive development of the cognitive functions associated with the use of this kind of video game. Therefore, this work aims to explore the relationship between playing action video games and the development of attention span as well as the impact at the brain level from a functional perspective. Methods: Articles were searched in Scopus, Pubmed, and Web of Science. A total of 196 studies were retrieved, among which 13 studies were systematically reviewed. Results: The review has shown that playing action video games can improve cognitive functions, including attention, with reaction time and processing speed being the aspects that would most benefit from such practice, as well as the development of focused, sustained, and divided attention. Also, there are functional brain changes. Conclusion: It is necessary to deepen the understanding of the association between playing action video games and the development of attention.
Impaired factor V–related anticoagulant mechanisms and deep vein thrombosis associated with A2086D and W1920R mutations
Authors: Shimonishi Naruto , Ogiwara Kenichi , Yoshida Junko , Horie Kyoji , Nakajima Yuto , Furukawa Shoko , Takeyama Masahiro , Nogami Keiji 
Published: February 2023

Abstract
Factor V (FV) plays pivotal roles in both procoagulant and anticoagulant mechanisms. Genetic mutations, FV-W1920R (FVNara) and FV-A2086D (FVBesançon), in the C1 and C2 domains of FV light chain, respectively, seem to be associated with deep vein thrombosis. However, the detailed mechanism(s) through which these mutations are linked to thrombophilia remains to be fully explored. The aim of this study was to clarify thrombotic mechanism(s) in the presence of these FV abnormalities. Full-length wild-type (WT) and mutated FV were prepared using stable, human cell lines (HEK293T) and the piggyBac transposon system. Susceptibility of FVa-A2086D to activated protein C (APC) was reduced, resulting in significant inhibition of APC-catalyzed inactivation with limited cleavage at Arg306 and delayed cleavage at Arg506. Furthermore, APC cofactor activity of FV-A2086D in APC-catalyzed inactivation of FVIIIa through cleavage at Arg336 was impaired. Surface plasmon resonance–based assays demonstrated that FV-A2086D bound to Glu-Gly-Arg-chloromethylketone active site–blocked APC and protein S (P) with similar affinities to that of FV-WT. However, weakened interaction between FVa-A2086D and phospholipid membranes was evident through the prothrombinase assay. Moreover, addition of FVa-A2086D to plasma failed to inhibit tissue factor (TF)-induced thrombin generation and reduce prothrombin times. This inhibitory effect was independent of PC, PS, and antithrombin. The coagulant and anticoagulant characteristics of FV(a)-W1920R were similar to those of FV(a)-A2086D. FV-A2086D presented defects in the APC mechanisms associated with FVa inactivation and FV cofactor activity, similar to FV-W1920R. Moreover, both FV proteins that were mutated in the light chain impaired inhibition of TF-induced coagulation reactions. These defects were consistent with congenital thrombophilia.