bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of the Campus Recreation Center in Creating a Community
Authors: Dalgarn Melinda K. 
Published: March 2019

The Student Recreation Center provides a state-of-the-art facility and a comprehensive recreation program for students, faculty, staff, alumni, and spouses. It aids in the education and development of the whole person and serves as a place of employment for students. More than just a place to exercise, the recreation center also serves as a venue for education: users develop positive self-esteem, enhance their social relationships, and improve their interpersonal skills. The recreation center provides a unique site for programs and activities aimed at meeting the needs, interests, and expectations of a diverse community. Opportunities for interaction, collaboration, and unification are essential if campuses are to develop a sense of community. Reports from the Carnegie Foundation for the Advancement of Teaching and the Wingspread Group on Higher Education serve to challenge university administrators in their struggle to create a sense of community. In as much as campus recreation centers have the capacity to engage members of the campus community in exciting, creative, and unique experiences they can provide the means to attract diverse populations. Often open 16–18 hours each day, there is no other single facility on a college campus that can provide as many varied activities with such wide appeal. Conventional programs such as intramurals, sport clubs and aerobics programs serve individuals in a variety of sports and recreational activities from basketball to scuba diving. Wellness programs offer health and educational services and outdoors recreation programs provide opportunities to develop skills for life-long enjoyment. Student recreation centers can serve as sites for day camp programs for children. Community members at large receive passes at nominal fees when student enrollment declines during the summer months. Recreation centers provide opportunities for students to interact with one another, as well as other sectors of the community. Research shows that this aids in both recruitment and retention. University administrators must continue their efforts to foster student learning and personal development. Student recreation centers can contribute significantly to that end by providing the facilities, programs, services and personnel to help meet those challenges.
‘Next Generation Youth Well-being Study:’ understanding the health and social well-being trajectories of Australian Aboriginal adolescents aged 10–24 years: study protocol
Authors: Gubhaju Lina , Banks Emily , Ward James , D’Este Catherine , Ivers Rebecca , Roseby Robert , Azzopardi Peter , Williamson Anna , Chamberlain Catherine , Liu Bette , Hotu Cheri , Boyle Jacqueline , McNamara Bridgette , Eades Sandra J 
Published: March 2019

IntroductionAustralian Aboriginal and/or Torres Strait Islander (hereafter referred to as ‘Aboriginal’) adolescents (10–24 years) experience multiple challenges to their health and well-being. However, limited evidence is available on factors influencing their health trajectories. Given the needs of this group, the young age profile of the Aboriginal population and the long-term implications of issues during adolescence, reliable longitudinal data are needed.Methods and analysisThe ‘Next Generation: Youth Well-being Study’ is a mixed-methods cohort study aiming to recruit 2250 Aboriginal adolescents aged 10–24 years from rural, remote and urban communities in Central Australia, Western Australia and New South Wales. The study assesses overall health and well-being and consists of two phases. During phase 1, we qualitatively explored the meaning of health and well-being for adolescents and accessibility of health services. During phase 2, participants are being recruited into a longitudinal cohort. Recruitment is occurring mainly through community networks and connections. At baseline, participants complete a comprehensive survey and undertake an extensive age relevant clinical assessment. Survey and clinical data will be linked to various databases including those relating to health services; medication; immunisation; hospitalisations and emergency department presentations; death registrations; education; child protection and corrective services. Participants will receive follow-up surveys approximately 2 years after their baseline visit. The ‘Next Generation’ study will fill important evidence gaps by providing longitudinal data on the health and social well-being of Aboriginal adolescents supplemented with narratives from participants to provide context.Ethics and disseminationEthics approvals have been sought and granted. Along with peer-reviewed publications and policy briefs, research findings will be disseminated via reports, booklets and other formats that will be most useful and informative to the participants and community organisations.
The Peripheral Analgesic Effect of Meperidine in Reducing Propofol Injection Pain Is Not Naloxone-Reversible
Authors: Pang Wei-Wu , Mok Martin S. , Huang Shyuan , Chung Yung-Tai , Hwang Min-Ho 
Published: March 2019

Background and ObjectivesMeperidine is frequently used in general anesthesia and perioperative analgesia. In addition to its opioid action, meperidine possesses some local anesthetic properties. A preliminary study using the tourniquet venous retention technique found meperidine to be more effective in reducing propofol injection pain than fentanyl or morphine, both of which were slightly better than placebo. This study was undertaken to evaluate whether this peripheral analgesic effect of meperidine is affected by naloxone.MethodsIn a randomized, double-blind manner, after venous occlusion with a tourniquet, meperidine 40 mg was given intravenously to patients in group A (n = 31), meperidine 40 mg followed by naloxone 0.04 mg to group B (n = 32), meperidine 40 mg followed by naloxone 0.2 mg to group C (n = 30), and normal saline placebo to group D (n = 30). The venous retention of drug(s) was maintained for 1 minute, followed by tourniquet release and intravenous administration of propofol 100 mg. Pain assessment was made immediately after the propofol injection.ResultsAll three groups given meperidine had significantly less propofol injection pain (P < .01) than the group given saline placebo, and there was no difference among groups A, B, and C.ConclusionThe peripheral analgesic effect of meperidine in reducing propofol injection pain is not mediated by its opioid activity.
Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia
Authors: Diaz-Flores Ernesto , Comeaux Evan Q. , Kim Kailyn L. , Melnik Ella , Beckman Kyle , Davis Kara L. , Wu Kevin , Akutagawa Jon , Bridges Olga , Marino Roberta , Wohlfeil Margo , Braun Benjamin S. , Mullighan Charles G. , Loh Mignon L. 
Published: March 2019

Abstract

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199–induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL.

Significance:
These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.
MYC Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells
Authors: Tao Ran , Murad Najiba , Xu Zhenhua , Zhang Peng , Okonechnikov Konstantin , Kool Marcel , Rivero-Hinojosa Samuel , Lazarski Christopher , Zheng Pan , Liu Yang , Eberhart Charles G. , Rood Brian R. , Packer Roger , Pei Yanxin 
Published: March 2019

Abstract

A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease.

Significance:
Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish
Authors: Henderson Fiona , Johnston Hannah R. , Badrock Andrew P. , Jones Emrys A. , Forster Duncan , Nagaraju Raghavendar T. , Evangelou Christos , Kamarashev Jivko , Green Michael , Fairclough Michael , Ramirez Irene Barinaga-Rementeria , He Shuning , Snaar-Jagalska B. Ewa , Hollywood Katherine , Dunn Warwick B. , Spaink Herman P. , Smith Michael P. , Lorigan Paul , Claude Emmanuelle , Williams Kaye J. , McMahon Adam W. , Hurlstone Adam 
Published: March 2019

Abstract

Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumor nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS, which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacologic response.

Significance:
These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.
Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy
Authors: Liu Changlong , Banister Carolyn E. , Buckhaults Phillip J. 
Published: March 2019

Abstract

TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA-approved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53-mutant cancers.

Significance:
These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.
EBF1-Mediated Upregulation of Ribosome Assembly Factor PNO1 Contributes to Cancer Progression by Negatively Regulating the p53 Signaling Pathway
Authors: Shen Aling , Chen Youqin , Liu Liya , Huang Yue , Chen Hongwei , Qi Fei , Lin Jiumao , Shen Zhiqing , Wu Xiangyan , Wu Meizhu , Li Qiongyu , Qiu Liman , Yu Na , Sferra Thomas J. , Peng Jun 
Published: March 2019

Abstract

The RNA-binding protein PNO1 is critical for ribosome biogenesis, but its potential role in cancer remains unknown. In this study, online data mining, cDNA, and tissue microarrays indicated that PNO1 expression was higher in colorectal cancer tissue than in noncancerous tissue, and its overexpression was associated with worse patient survival. Gain-of-function and loss-of-function studies demonstrated that PNO1 knockdown suppressed growth of colorectal cancer cells in vitro and in vivo, while PNO1 overexpression promoted colorectal cancer cell proliferation in vitro. In colorectal cancer cells expressing wild-type p53, PNO1 knockdown enhanced expression of p53 and its downstream gene p21, and reduced cell viability; these effects were prevented by p53 knockout and attenuated by the p53 inhibitor PFT-α. Moreover, PNO1 knockdown in HCT116 cells decreased levels of 18S rRNA, of 40S and 60S ribosomal subunits, and of the 80S ribosome. It also reduced global protein synthesis, increasing nuclear stress and inhibiting MDM2-mediated ubiquitination and p53 degradation. Overexpressing EBF1 suppressed PNO1 promoter activity and decreased PNO1 mRNA and protein, inhibiting cell proliferation and inducing cell apoptosis through the p53/p21 pathway. In colorectal cancer tissues, the expression of EBF1 correlated inversely with PNO1. Data mining of online breast and lung cancer databases showed increased PNO1 expression and association with poor patient survival; PNO1 knockdown reduced cell viability of cultured breast and lung cancer cells. Taken together, these findings indicate that PNO1 is overexpressed in colorectal cancer and correlates with poor patient survival, and that PNO1 exerts oncogenic effects, at least, in part, by altering ribosome biogenesis.

Significance:
This study identifies the ribosome assembly factor PNO1 as a potential oncogene involved in tumor growth and progression of colorectal cancer.
Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial
Authors: Rothé Françoise , Silva Maria Joao , Venet David , Campbell Christine , Bradburry Ian , Rouas Ghizlane , de Azambuja Evandro , Maetens Marion , Fumagalli Debora , Rodrik-Outmezguine Vanessa , Di Cosimo Serena , Rosa Daniela , Chia Stephen , Wardley Andrew , Ueno Takayuki , Janni Wolfgang , Huober Jens , Baselga Jose , Piccart Martine , Loi Sherene , Sotiriou Christos , Dawson Sarah-Jane , Ignatiadis Michail 
Published: March 2019

Abstract

Purpose:
In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with increased pathologic complete response (pCR) rates compared with each therapy alone. Biomarkers allowing to predict treatment response during NAT are needed. We aim to evaluate whether circulating tumor DNA (ctDNA) is associated with response to anti-HER2–targeted therapy.

Experimental Design:
Plasma DNA collected before NAT, at week 2, and before surgery from patients enrolled in the NeoALTTO trial was assessed using digital PCR for PIK3CA and TP53 mutation detection.

Results:
A total of 69 of 455 (15.2%) patients had a PIK3CA and/or TP53 mutation detected in the baseline tumor sample and evaluable ctDNA results from baseline samples. CtDNA was detected in 41%, 20%, and 5% patients before NAT, at week 2, and before surgery, respectively. ctDNA detection before NAT was significantly associated with older age and ER-negative status. ctDNA detection before NAT was associated with decreased odds of achieving pCR (OR = 0.15; 95% CI, 0.034–0.7; P = 0.0089), but not with event-free survival (EFS). Analyses for EFS were underpowered. Interestingly, the patients with HER2-enriched subtype tumors and undetectable ctDNA at baseline had the highest pCR rates. In contrast, patients with persistent ctDNA detection at baseline and week 2 had the lowest rate of pCR.

Conclusions:
ctDNA detection before neoadjuvant anti-HER2 therapies is associated with decreased pCR rates. Interestingly, patients with HER2-enriched tumors and undetectable ctDNA at baseline had the highest pCR rates, therefore appearing as the best candidates for treatment deescalation strategies.
PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma
Authors: Chung Elaine Y. , Mai Yun , Shah Urvi A. , Wei Yongqiang , Ishida Elise , Kataoka Keisuke , Ren Xiaoxin , Pradhan Kith , Bartholdy Boris , Wei Xiaolei , Zou Yiyu , Zhang Jinghang , Ogawa Seishi , Steidl Ulrich , Zang Xingxing , Verma Amit , Janakiram Murali , Ye B. Hilda 
Published: March 2019

AbstractPurpose:To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models.Experimental Design:Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines.Results:PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome.Conclusions:PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.
Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells
Authors: Lee Seung-Cheol , Shestov Alexander A. , Guo Lili , Zhang Qian , Roman Jeffrey C. , Liu Xiaobin , Wang Hong Y. , Pickup Stephen , Nath Kavindra , Lu Pin , Hofbauer Samuel , Mesaros Clementina , Wang Y. Lynn , Nelson David S. , Schuster Stephen J. , Blair Ian A. , Glickson Jerry D. , Wasik Mariusz A. 
Published: March 2019

Abstract

Current methods to evaluate effects of kinase inhibitors in cancer are suboptimal. Analysis of changes in cancer metabolism in response to the inhibitors creates an opportunity for better understanding of the interplay between cell signaling and metabolism and, from the translational perspective, potential early evaluation of response to the inhibitors as well as treatment optimization. We performed genomic, metabolomic, and fluxomic analyses to evaluate the mechanism of action of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (IBR) in mantle cell lymphoma (MCL) cells. Our comprehensive analysis of the data generated by these diverse technologies revealed that IBR profoundly affected key metabolic pathways in IBR-sensitive cells including glycolysis, pentose phosphate pathway, TCA cycle, and glutaminolysis while having much less effects on IBR-poorly responsive cells. Changes in 1H magnetic resonance spectroscopy (MRS)-detectable lactate and alanine concentrations emerged as promising biomarkers of response and resistance to IBR as demonstrated from experiments on various MCL cell lines. The metabolic network analysis on the 13C MRS and 13C LC/MS experimental data provided quantitative estimates of various intracellular fluxes and energy contributions. Glutaminolysis contributed over 50% of mitochondrial ATP production. Administration of the glutaminase inhibitor CB-839 induced growth suppression of the IBR-poorly responsive cells.

Implications:
Our study demonstrates application of the advanced metabolomic/fluxomic techniques for comprehensive, precise, and prompt evaluations of the effects of kinase inhibition in MCL cells and has strong translational implications by potentially permitting early evaluation of cancer patient response versus resistance to kinase inhibitors and on design of novel therapies for overcoming the resistance.