bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of Game Design, Physical Demands, and Skill Involvement on the Subjective Task Load Associated With Various Small-Sided Games Among Elite Junior Rugby League Players
Authors: Dobbin Nick , Atherton Anthony , Hill Colin 
Published: February 2021

Purpose: To determine if small-sided games (SSGs) could be designed to target specific task loads using the National Aeronautics and Space Administration task load index as well as reporting the influence of the physical and technical demands. Methods: Using a within-session, repeated-measures design, 26 junior rugby league players completed 5 SSGs focused on physical, technical, temporal, cognitive, and frustration task loads. National Aeronautics and Space Administration task load index responses were evaluated after each game; the physical demands were recorded using microtechnology; and skill involvement recorded using video analysis. Results: In each SSG, the task load emphasized (eg, physical load/physical game) emerged with a higher score than the other loads and SSGs. The physical demands were lowest during the physical game (effect size = −3.11 to 3.50) and elicited greater defensive involvements (effect size = 0.12 to 3.19). The highest physical demands and attacking involvements were observed during the temporal game. Lower intensity activities were generally negatively associated with physical, performance, temporal, and total load (η2 = −.07 to −.43) but positively associated with technical, effort, cognitive, and frustration (η2 = .01 to .33). Distance covered in total and at higher speeds was positively associated with physical, effort, performance, total load (η2 = .18 to .65), and negatively associated with technical, frustration, and cognitive load (η2 = −.10 to −.36). Attacking and defensive involvements generally increased the respective task loads (η2 = .03 to .41). Conclusion: Coaches and sport scientists can design SSGs specifically targeted at subjective task loads in a sport-specific manner and through manipulation of the physical and technical demands.
Using web-based technology to improve depression screening in primary care settings
Authors: Jeffrey Jessica , Do Minh-Chau T , Hajal Nastassia , Lin Yu-Hsiang , Linonis Rachel , Grossman Mark S , Lester Patricia E 
Published: February 2021

BackgroundGiven the high rates at which patients present with behavioural health (BH) concerns in primary care (PC), this setting has become the de facto mental health system. As a result, screening for depression and other BH conditions in PC has become a critical target for improving patient outcomes. However, integration of screening into busy PC workflows can be challenging due to barriers such as limited time and resources.MethodologyA digital, cloud-based BH assessment tool, which included electronic health record enhancements, was developed and implemented in two urban PC practices as a prelude to a planned larger-scale implementation. The implementation strategies included a reorganisation of workflows within the PC setting, comprehensive training for staff and PC physicians, and institution of an incentive programme for PC clinic managers. To examine whether the introduction of the cloud-based BH assessment tool and associated implementation strategies was associated with increased screening rates, we compared rates of screening from January through June 2017 to rates of screening from January through June 2018 (subsequent to implementation). We also examined BH symptomatology reported by patients in PC.ResultsFollowing the implementation process, rate of BH screening with Patient Health Questionnaire-2 (PHQ-2) increased from 50.5% to 57% (p<0.00000000000000022) and rates of subsequent screening with PHQ-9, for those scoring at risk, defined as a score of ≥1, on PHQ-2, increased from 34.5% to 91.4% (p<0.00000000000000022). Additionally, high rates of ‘moderate’ and ‘severe’ symptoms of depression (40.3%), anxiety (42.6%) and substance use (26.7% alcohol; 31.2% other substance use) were observed among PC patients.ConclusionsResults suggest that a comprehensive implementation plan, including digitisation of BH assessment, reduced the burden of systematic screening. High rates of BH symptomatology underscore the need for comprehensive BH assessment and systems planning to address the high need for BH services among PC patients.
Prognostic significance of BMI after PCI treatment in ST-elevation myocardial infarction: a cohort study from the Swedish Coronary Angiography and Angioplasty Registry
Authors: Jamaly Shabbar , Redfors Bjorn , Omerovic Elmir , Carlsson Lena , Karason Kristjan 
Published: February 2021

BackgroundObesity along with clustering of cardiovascular risk factors is a promoter for coronary artery disease. On the other hand, a high body mass index (BMI) appears to exert a protective effect with respect to outcomes after a coronary artery event, termed the obesity paradox.MethodsThe Swedish Coronary Angiography and Angioplasty Registry collects information on all patients who undergo percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) in Sweden along with demographic and procedure-related data. We studied the predictability of four categories of BMI for 1-year all-cause mortality in people with STEMI undergoing PCI.ResultsAmong 25 384 patients, mean (SD) age 67.7 (12.1) years and 70.2% male, who underwent PCI for STEMI, a total of 5529 (21.8%) died within 1 year. Using normal weight (BMI 18.5–24.9 kg/m2) as a reference, subjects with obesity (BMI ≥30 kg/m2) had a low 1-year all-cause mortality risk in unadjusted analysis, HR 0.59 (95% CI 0.53 to 0.67). However, after adjustment for age, sex and other covariates, the difference became non-significant, HR 0.88 (95% CI 0.75 to 1.02). Patients with overweight (BMI 25.0–29.9 kg/m2) had the lowest 1-year mortality risk in analysis adjusted for age, sex and other covariates, HR 0.87 (95% CI 0.79 to 0.97), whereas those with underweight (BMI <18.5 kg/m2) had the highest mortality in both unadjusted HR 2.22 (95% CI 1.69 to 2.92) and adjusted analysis, HR 1.62 (95% CI 1.18 to 2.23).ConclusionThe protective effect of obesity with respect to 1-year mortality after coronary intervention became non-significant after adjusting for age, sex and relevant covariates. Instead, overweight people displayed the lowest risk and underweight individuals the highest risk for adjusted all-cause mortality.Trial registration numberNCT02311231.
Adaptive Therapy and the Cost of Drug-Resistant Mutants
Authors: Wodarz Dominik 
Published: February 2021

Abstract
The concept of adaptive cancer therapy proposes that the use of drugs at less than maximum tolerated dose can provide clinical benefits by allowing persisting drug-sensitive cells to competitively suppress drug-resistant cells; this can delay the outgrowth of these cell clones. The adaptive therapy concept has been developed with mathematical models and has subsequently been explored in clinical trials with promising results. In studies performed so far, a fitness cost of drug-resistant cells has been invoked for this treatment approach to be beneficial. In new work, it is shown that a clinical benefit can be achieved even in the absence of a fitness cost for resistant cells, which broadens the applicability of adaptive therapy.
See related article by Strobl et al., p. 1135
Abstract OT-28-06: A phase 1, first in human study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor in subjects with HER2 overexpressing solid tumors
Authors: Grover Natalie , Barton Debora , Ronczka Amy , Bauml Joshua 
Published: February 2021

Abstract
Adoptive T cell therapies have led to remarkable advances among patients with hematologic malignancies, but not in those with solid tumors. Macrophages are actively recruited into and more abundantly present in the tumor microenvironment (TME) as compared to T cells. Tumor- associated macrophages (TAMs), typically evince immunosuppressive behavior, but when engineered to be proinflammatory, may be an ideal vector to administer adoptive cellular therapy in solid tumors. Furthermore, insertion of a CAR confers on the macrophages the ability to selectively recognize and phagocytose antigen overexpressing cancer cells. CAR macrophages can also potentially interact with, stimulate, and present neoantigens to T cells. Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in many cancers, including but not limited to breast and gastroesophageal cancers (Table 1). CT-0508 is a cell product comprised of autologous monocyte-derived pro-inflammatory macrophages expressing an anti-HER2 CAR. In vitro and in vivo studies have shown that CT-0508 leads to cancer cell phagocytosis sparing normal cells, decreased tumor burden and prolonged survival. CT-0508 cells were safe in a semi-immunocompetent mouse model of human HER2 overexpressing ovarian cancer. This is a FIH Phase 1 study to evaluate safety, tolerability, cell manufacturing feasibility, trafficking, and preliminary evidence of efficacy of investigational product CT-0508 on approximately 18 subjects with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 who have failed available therapies including anti-HER2 therapies when indicated.Filgrastim, will be used to mobilize autologous hematopoietic progenitor cells for monocyte collection by apheresis. CT-0508 cell product will be manufactured, prepared and cryopreserved. Group 1 will receive CT-0508 infusion split over D1, 3 and 5. Subjects will be continually assessed for acute and cumulative toxicity. Dose limiting toxicities will be observed and addressed by a Safety Review Committee. Group 2 will receive the full CT-0508 infusion on D1. Pre and post treatment biopsies and blood samples will be collected to investigate correlates of trafficking, persistence, TME modulation, immune response and safety.
Citation Format: Natalie Grover, Debora Barton, Amy Ronczka, Joshua Bauml. A phase 1, first in human study of adenovirally transduced autologous macrophages engineered to contain an anti-HER2 chimeric antigen receptor in subjects with HER2 overexpressing solid tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-06.
Abstract PD10-04: Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens
Authors: Viansone Alessandro , Omarini Claudia , Boggiani Daniela , Sikokis Angelica , Uliana Vera , Pellegrino Benedetta , Piacentini Federico , Michiara Maria , Musolino Antonino 
Published: February 2021

Abstract
Background: HER2-amplified breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinico-histological characteristics and prognosis of this subgroup of patients. Materials and Methods: Using a retrospective matched cohort design, we collected data from 728 women who were diagnosed with breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinical and histological characteristics of the primary tumor, time to relapse, and survival were analyzed by BRCA and HER2 status. Results: One hundred and twenty HER2-positive, BRCA mutated cases were evaluated with respect to three control groups: HER2-positive, BRCA wild-type (n=136); HER2-negative, BRCA-mutated (n=226); HER2-negative, BRCA wild-type (n=246). Breast cancers with hormone receptor-negative status or high histologic grade (odds ratio=1.7; 95% confidence interval [CI]: 1.0-2.9) were more likely HER2-positive, with no restriction by BRCA mutation status. Disease-free and overall survival for HER2-positive, BRCA mutated cases were lower than those for the other subgroups. An interaction between BRCA mutations and HER2-positive status was found for poorer overall survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Germline BRCA mutations confer worse prognosis in patients with HER2-positive breast cancer. Ongoing trials testing novel therapeutic approaches (e.g. anti-HER2 therapies combined with PARP inhibitors) are warranted.
Citation Format: Alessandro Viansone, Claudia Omarini, Daniela Boggiani, Angelica Sikokis, Vera Uliana, Benedetta Pellegrino, Federico Piacentini, Maria Michiara, Antonino Musolino. Prognostic significance of germline BRCA mutations in patients with HER2-positive breast cancer. Epidemiological analysis in primary BRCA screens [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-04.
Abstract PD15-02: Cx3cl1-cx3cr1 axis in liver metastasis of triple negative breast cancer
Authors: Heo Woohang , Son Hye-Youn , Kim Ju hee , Lee Kyu Jin , Jeon Myeonghee , Li Songbin , Jang Jeehee , Noh Dong-Young , Han Wonsik , Moon Hyeong-Gon 
Published: February 2021

Abstract
Triple negative breast cancer (TNBC) is a breast cancer subtype with increased risk of distant metastasis, especially to visceral organs. However, the detailed molecular mechanism underlying the visceral metastasis of TNBC is unknown. We used three patient-derived xenograft models derived from TNBC tumors with different metastatic capacities. PDX1 and PDX2 model developed distant metastasis in only lung and liver, respectively. In contrast, PDX3 tumor metastasized to both lung and liver. RNA sequencing of the primary tumor and distant metastatic sites of these three PDX models was performed. The gene expression profiles of the primary tumors of the three models showed minimally overlapping genes. However, the microenvironment gene expression profiles, measured by using the sequencing reads aligned to mouse genome, showed distinct difference between the models. Among the differentially expressed genes, we identified Cx3cr1 as a significantly upregulated gene in the liver microenvironment of the PDX models that metastasized to liver. Next, we used 4T1 syngeneic mouse mammary carcinoma model to validate the Cx3cr1 in the mouse liver tissues. Interestingly, the Cx3cr1 up-regulation occurred during the pre-metastatic period, and Cx3cl1, the ligand of the Cx3cr1, was also up-regulated in the liver tissue prior to the development of metastasis suggesting the Cx3cr1 regulates the formation of pre-metastatic niche. Cx3cl1, the ligand of the Cx3cr1, was also up-regulated in the liver tissue prior to the development of metastasis. These data suggest that Cx3cl1 and Cx3cr1-mediated tumor-microenvironment interaction is critical in developing liver metastasis in TNBC. Cx3cl1 increased the invasion and migration of Raw264.7 monocyte/macrophage cells and this effect was abrogated by the Cx3cr1 silencing in Raw264.7 cells or treating Cx3cl1 neutralizing antibody. Pathway analysis of the RNA sequencing data showed that genes involved in extracellular matrix remodeling was significantly dysregulated in the liver tissues including Lysyl Oxidase (Lox). Cx3cl1 treatment in Raw264.7 cells resulted in increased expression of Lox and MMP9 mRNA in three-dimensional culture system. The Raw264.7 cells caused increased invasion of 4T1 cells in vitro. In conclusion, our data suggest that Cx3cl1-Cx3cr1 axis plays critical role during the liver metastasis of TNBC.
Citation Format: Woohang Heo, Hye-Youn Son, Ju hee Kim, Kyu Jin Lee, Myeonghee Jeon, Songbin Li, Jeehee Jang, Dong-Young Noh, Wonsik Han, Hyeong-Gon Moon. Cx3cl1-cx3cr1 axis in liver metastasis of triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-02.
Abstract PD15-05: Sipa1 effects rock pathway in human breast cancer linking to HGF mediated changes in tight junction functions controlling metastasis
Authors: Liu Chang , Ruge Fiona , Ye Lin , Harrison Gregory M. , Jiang Wen G. , Martin Tracey A. 
Published: February 2021

Abstract
Background: SIPA1 (Signal-induced proliferation-associated gene 1) is a mitogen-inducible gene encoding a GTPase-activating protein for Rap1 and Rap2 and has been suggested to be involved in metastatic progression. We have previously shown SIPA1 may regulate barrier function in breast cancer cells as part of hepatocyte growth factor-determined changes and that this may be via a number of regulatory pathways, most likely via the ROCK pathway. Our aim with this current work was to definitively identify which pathway is involved. Methods: After knockdown of SIPA1 in MDA-MB-231 cells, they were treated to a number of inhibitors to proteins involved in pathways involved in TJ barrier function (ROCK, N-WASP, ARPs, WAVEs, MAPK, ERK, PLC-gamma). Following the identification of suitable inhibitor a large scale in vivo study was carried out using a tumour model of SIPA1 knockdown versus WT control was treated with/without inhibitors and immunohistochemistry (IHC) used to assess changes in tumour growth, architecture and protein expression. We also assessed the expression of SIPA-1 in a cohort of human breast cancer tissues using IHC. Results: After knockdown of SIPA1 in MDA-MB-231 cells, we subjected cells to a number of inhibitors to proteins involved in pathways involved barrier function (ROCK, N-WASP, ARPs, WAVEs, MAPK, ERK, PLC-gamma). Analysis of behaviour showed that knockdown cells no longer responded to the ROCK inhibitor (ROCKi Y-27632, p&lt;0.05, n=10). In vivo tumour samples were assessed for expression of ROCKI, expression of phospho-ROCK, and any differences when treated with ROCKi. Control tissues showed good levels of all three proteins (SIPA1, ROCKI and phosphor-ROCK). Knockdown tissues exhibited significantly lower levels of ROCK and phosphor-ROCK (p&lt;0.01, n=12). In control tumours, phosphor-ROCK was increased after treatment with ROCKi; conversely, in SIPA1 knockdown tumours, phosphor-ROCK was decreased after treatment with ROCKi (p&lt;0.05). In SIPA1 knockdown tissues, ROCK and phosphor-ROCK was diffuse in staining pattern when compared to the control where the staining was located at the cell membrane. Conclusion: Our results confirm our hypothesis that SIPA1 is involved in the control of TJ in breast cancer and that this is through the ROCK pathway. Moreover, these results demonstrate that this may be due to the effect that SIPA1 has on cellular ratios of ROCK to phosphor-ROCK in breast cancer.
Citation Format: Chang Liu, Fiona Ruge, Lin Ye, Gregory M. Harrison, Wen G. Jiang, Tracey A. Martin. Sipa1 effects rock pathway in human breast cancer linking to HGF mediated changes in tight junction functions controlling metastasis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-05.
Abstract PD15-10: Identification of BBOX1 as a therapeutic target in triple-negative breast cancer
Authors: Liao Chengheng , Zhang Yang , Fan Cheng , Herring Laura E. , Liu Juan , Locasale Jason W. , Takada Mamoru , Zhou Jin , Zurlo Giada , Hu Lianxin , Simon Jeremy M. , Ptacek Travis S. , Andrianov Victor G. , Loza Einars , Peng Yan , Yang Huanghe , Perou Charles M. , Zhang Qing 
Published: February 2021

Abstract
Triple-negative breast cancer (TNBC), which accounts for 15-20% of breast cancers, causes the highest mortality rate among all breast cancer subtypes. Due to its heterogeneity and lack of estrogen and progesterone receptor or human epidermal growth factor receptor 2 expression, valuable targeted therapy is limited. Therefore, it is critical to identify novel therapeutic targets in TNBC. 2-oxoglutarate (2-OG)-dependent enzymes, including prolyl hydroxylases (EglN1-3), histone demethylases (for example, KDM5A) and DNA hydroxylases (such as TET1-3), are associated with cancer progression. However, the role of these enzymes in TNBC has never been systematically studied. Here, by performing a functional siRNA screening for 2-OG-dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth, while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3 mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1 mediated glycolysis, which leads to apoptosis and impaired cell cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacological inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting previously uncharacterized BBOX1-IP3R3-calcium oncogenic signaling axis in TNBC.
Citation Format: Chengheng Liao, Yang Zhang, Cheng Fan, Laura E. Herring, Juan Liu, Jason W. Locasale, Mamoru Takada, Jin Zhou, Giada Zurlo, Lianxin Hu, Jeremy M. Simon, Travis S. Ptacek, Victor G. Andrianov, Einars Loza, Yan Peng, Huanghe Yang, Charles M. Perou, Qing Zhang. Identification of BBOX1 as a therapeutic target in triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-10.