bluuebunny/crossref_metadata_2025_split huggingface dataset:
A mixed method, multiperspective evaluation of a near peer teaching programme
Authors: Lydon Sinéad , O’Connor Paul , Mongan Orla , Gorecka Miroslawa , McVicker Lyle , Stankard Aiden , Byrne Dara 
Published: February 2017

ABSTRACTPurpose of studyPeer teaching (PT) has become increasingly popular. PT may offer benefits for students, tutors and institutions. Although resistance to PT has been identified among faculty, research has typically focused on students’ experiences and perceptions, rather than those of the peer tutors or senior doctors/medical faculty. The current study comprised of a comprehensive, multiperspective evaluation of a near PT programme delivered by interns to final-year medical students in the Republic of Ireland.Study designThis study employed a mixed methods design, using both interviews and questionnaires to assess students’ (n=130), interns’ (n=49) and medical faculty’s or senior doctors’ (n=29) perceptions of the programme.ResultsAll three groups were emphatic about the programme’s benefits, although senior doctors and faculty reported significantly more positive attitudes than the others. Mean ratings of the programme’s value, out of 10, were 8.2 among students, 8.2 among interns and 9.1 among senior doctors and faculty. Challenges identified were largely organisational in nature. Perceived benefits for students included the informality of teaching sessions, increased opportunities in the clinical environment and improvements in exam preparedness. Perceived benefits for the interns included improvements in knowledge and teaching ability and experience as a role model.ConclusionsPT programmes have been posited as an ‘easy fix’ to growing numbers of students. However, it is apparent that PT has substantial value outside of this. Future research that conducts economic evaluations of such programmes and that collects objective data on teaching quality and student learning would be of much interest.
A systems genetics approach identifiesTrp53inp2as a link between cardiomyocyte glucose utilization and hypertrophic response
Authors: Seldin Marcus M. , Kim Eric D. , Romay Milagros C. , Li Shen , Rau Christoph D. , Wang Jessica J. , Krishnan Karthickeyan Chella , Wang Yibin , Deb Arjun , Lusis Aldons J. 
Published: February 2017

Cardiac failure has been widely associated with an increase in glucose utilization. The aim of our study was to identify factors that mechanistically bridge this link between hyperglycemia and heart failure. Here, we screened the Hybrid Mouse Diversity Panel (HMDP) for substrate-specific cardiomyocyte candidates based on heart transcriptional profile and circulating nutrients. Next, we utilized an in vitro model of rat cardiomyocytes to demonstrate that the gene expression changes were in direct response to substrate abundance. After overlaying candidates of interest with a separate HMDP study evaluating isoproterenol-induced heart failure, we chose to focus on the gene Trp53inp2 as a cardiomyocyte glucose utilization-specific factor. Trp53inp2 gene knockdown in rat cardiomyocytes reduced expression and protein abundance of key glycolytic enzymes. This resulted in reduction of both glucose uptake and glycogen content in cardiomyocytes stimulated with isoproterenol. Furthermore, this reduction effectively blunted the capacity of glucose and isoprotereonol to synergistically induce hypertrophic gene expression and cell size expansion. We conclude that Trp53inp2 serves as regulator of cardiomyocyte glycolytic activity and can consequently regulate hypertrophic response in the context of elevated glucose content.NEW & NOTEWORTHY Here, we apply a novel method for screening transcripts based on a substrate-specific expression pattern to identify Trp53inp2 as an induced cardiomyocyte glucose utilization factor. We further show that reducing expression of the gene could effectively blunt hypertrophic response in the context of elevated glucose content.
Cardiovascular consequences of the inspiratory muscle metaboreflex: effects of age and sex
Authors: Smith Joshua R. , Alexander Andrew M. , Hammer Shane M. , Didier Kaylin D. , Kurti Stephanie P. , Broxterman Ryan M. , Barstow Thomas J. , Harms Craig A. 
Published: February 2017

With inspiratory muscle metaboreflex activation, we hypothesized that, compared with their younger counterparts, older men and women would exhibit greater 1) increases in mean arterial pressure (MAP) and limb vascular resistance (LVR) and 2) decreases in limb blood flow (Q̇L) but 3) no sex differences would be present in older adults. Sixteen young adults [8 young men (YM) and 8 young women (YW), 18–24 yr] and 16 older adults [8 older men (OM) and 8 older women (OW), 60–73 yr] performed inspiratory resistive breathing tasks (IRBTs) at 2% and 65% of their maximal inspiratory pressure. During the IRBTs, breathing frequency was 20 breaths/min with a 50% duty cycle. At baseline and during the IRBTs, MAP was measured via automated oscillometry, Q̇Lwas determined via Doppler ultrasound, and LVR was calculated. The 65% IRBT led to significantly greater increases in MAP in OW (15.9 ± 8.1 mmHg) compared with YW (6.9 ± 1.4 mmHg) but not ( P > 0.05) between OM (12.3 ± 5.7 mmHg) and YM (10.8 ± 5.7 mmHg). OW (−20.2 ± 7.2%) had greater ( P < 0.05) decreases in Q̇Lcompared with YW (−9.4 ± 10.2%), but no significant differences were present between OM (−22.8 ± 9.7%) and YM (−22.7 ± 11.3%) during the 65% IRBT. The 65% IRBT led to greater ( P < 0.05) increases in LVR in OW (48.2 ± 25.5%) compared with YW (19.7 ± 15.0%), but no differences ( P > 0.05) existed among OM (54.4 ± 17.8%) and YM (47.1 ± 23.3%). No significant differences were present in MAP, Q̇L, or LVR between OM and OW. These data suggest that OW exhibit a greater inspiratory muscle metaboreflex compared with YW, whereas no differences between OM and YM existed. Finally, sex differences in the inspiratory muscle metaboreflex are not present in older adults.NEW & NOTEWORTHY Premenopausal women exhibit an attenuated inspiratory muscle metaboreflex compared with young men; however, it is unknown whether these sex differences are present in older adults. Older women exhibited a greater inspiratory muscle metaboreflex compared with premenopausal women, whereas no differences were present between older and younger men.
Combined long-term caffeine intake and exercise inhibits the development of diabetic nephropathy in OLETF rats
Authors: Suzuki Masato , Shindo Daisuke , Suzuki Ryuichiro , Shirataki Yoshiaki , Waki Hidefumi 
Published: February 2017

This study was performed to examine the effects of long-term caffeine-intake, with and without exercise, on the progression of diabetic nephropathy (DN) in an obese diabetic rat model. Thirty-two male Otsuka Long-Evans Tokushima fatty (OLETF) rats were assigned to sedentary (OLETF-Sed), exercise (OLETF-Ex), caffeine-intake (OLETF-Caf), and combined (OLETF-Caf + Ex) groups. Caffeine-intake groups were fed rat chow containing caffeine (90.7 ± 4.7 mg/kg/day). The OLETF-Ex and OLETF-Caf + Ex groups were able to run voluntarily at any time using a rotatory wheel. Body weight (BW) and blood pressure (BP) were measured weekly from 24 to 29 wk of age. Pre- and posttreatment serum glucose, insulin, and creatinine concentrations were measured, and a 24 h urine sample was collected for measurement of creatinine clearance (Ccr) and albumin excretion (UEAlb). After treatment, the kidneys were removed for morphological analysis. The OLETF-Caf and OLETF-Caf + Ex groups exhibited no BP increase during the study. Both the caffeine-intake groups exhibited a significant increase in urine volume (UV), electrolyte excretion, and Ccr, and decreased UEAlb, following treatment. Furthermore, no structural damage was observed in the kidneys of rats from either caffeine-intake group, whereas the OLETF-Sed and OLETF-Ex groups exhibited DN progression. This study demonstrates that caffeine-intake alone and/or combined with exercise significantly decreases BW and improves glucose intolerance, without the progression of DN. Further research should be performed to examine whether the quantities of caffeine contained in a normal human daily intake also have a protective effect against kidney damage. NEW & NOTEWORTHY The present study showed that caffeine administration alone and/or combined with exercise results in an improvement of diabetic nephropathy (DN), including an increase in creatinine clearance and urinary Na excretion, a decrease in urinary protein excretion, and in renal morphological findings. To our knowledge, there are no other studies showing that caffeine administration inhibits DN progression.
Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer
Authors: Thomas Jeffrey D. , Longen Charles G. , Oyer Halley M. , Chen Nan , Maher Christina M. , Salvino Joseph M. , Kania Blase , Anderson Kelsey N. , Ostrander William F. , Knudsen Karen E. , Kim Felix J. 
Published: February 2017

Abstract
Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and ARv567es as well as full-length AR. Treatment of mice xenografted with ARV-driven CRPC tumors with a drug-like small-molecule Sigma1 inhibitor significantly inhibited tumor growth associated with elimination of AR and ARV7 in responsive tumors. Together, our data show that Sigma1 modulators can be used to suppress AR/ARV–driven prostate cancer cells via regulation of pharmacologically responsive Sigma1-AR/ARV interactions, both in vitro and in vivo. Cancer Res; 77(9); 2439–52. ©2017 AACR.
Armed Oncolytic Adenovirus–Expressing PD-L1 Mini-Body Enhances Antitumor Effects of Chimeric Antigen Receptor T Cells in Solid Tumors
Authors: Tanoue Kiyonori , Rosewell Shaw Amanda , Watanabe Norihiro , Porter Caroline , Rana Bhakti , Gottschalk Stephen , Brenner Malcolm , Suzuki Masataka 
Published: February 2017

Abstract
Chimeric antigen receptor–modified T cells (CAR T cells) produce proinflammatory cytokines that increase expression of T-cell checkpoint signals such as PD-L1, which may inhibit their functionality against solid tumors. In this study, we evaluated in human tumor xenograft models the proinflammatory properties of an oncolytic adenovirus (Onc.Ad) with a helper-dependent Ad (HDAd) that expresses a PD-L1 blocking mini-antibody (mini-body; HDPDL1) as a strategy to enhance CAR T-cell killing. Coadministration of these agents (CAd-VECPDL1) exhibited oncolytic effects with production of PD-L1 mini-body locally at the tumor site. On their own, HDPDL1 exhibited no antitumor effect and CAd-VECPDL1 alone reduced tumors only to volumes comparable to Onc.Ad treatment. However, combining CAd-VECPDL1 with HER2.CAR T cells enhanced antitumor activity compared with treatment with either HER2.CAR T cells alone or HER2.CAR T cells plus Onc.Ad. The benefits of locally produced PD-L1 mini-body by CAd-VECPDL1 could not be replicated by infusion of anti-PD-L1 IgG plus HER2.CAR T cells and coadministration of Onc.Ad in an HER2+ prostate cancer xenograft model. Overall, our data document the superiority of local production of PD-L1 mini-body by CAd-VECPDL1 combined with administration of tumor-directed CAR T cells to control the growth of solid tumors. Cancer Res; 77(8); 2040–51. ©2017 AACR.
Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma
Authors: Chen Zhihong , Feng Xi , Herting Cameron J. , Garcia Virginia Alvarez , Nie Kai , Pong Winnie W. , Rasmussen Rikke , Dwivedi Bhakti , Seby Sandra , Wolf Susanne A. , Gutmann David H. , Hambardzumyan Dolores 
Published: February 2017

Abstract
In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1GFP/WT;CCR2RFP/WT double knock-in mice. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the GBM, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2− microglia-like cells. Infiltrating macrophages/monocytes constituted approximately 85% of the total TAM population, with resident microglia accounting for the approximately 15% remaining. Bone marrow–derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via genetic Ccl2 reduction prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm. Cancer Res; 77(9); 2266–78. ©2017 AACR.
Cellular Hierarchy as a Determinant of Tumor Sensitivity to Chemotherapy
Authors: Rodriguez-Brenes Ignacio A. , Kurtova Antonina V. , Lin Christopher , Lee Yu-Cheng , Xiao Jing , Mims Martha , Chan Keith Syson , Wodarz Dominik 
Published: February 2017

Abstract
Chemotherapy has been shown to enrich cancer stem cells in tumors. Recently, we demonstrated that administration of chemotherapy to human bladder cancer xenografts could trigger a wound-healing response that mobilizes quiescent tumor stem cells into active proliferation. This phenomenon leads to a loss of sensitivity to chemotherapy partly due to an increase in the number of tumor stem cells, which typically respond to chemotherapy-induced cell death less than more differentiated cells. Different bladder cancer xenografts, however, demonstrate differential sensitivities to chemotherapy, the basis of which is not understood. Using mathematical models, we show that characteristics of the tumor cell hierarchy can be crucial for determining the sensitivity of tumors to drug therapy, under the assumption that stem cell enrichment is the primary basis for drug resistance. Intriguingly, our model predicts a weaker response to therapy if there is negative feedback from differentiated tumor cells that inhibits the rate of tumor stem cell division. If this negative feedback is less pronounced, the treatment response is predicted to be enhanced. The reason is that negative feedback on the rate of tumor cell division promotes a permanent rise of the tumor stem cell population over time, both in the absence of treatment and even more so during drug therapy. Model application to data from chemotherapy-treated patient-derived xenografts indicates support for model predictions. These findings call for further research into feedback mechanisms that might remain active in cancers and potentially highlight the presence of feedback as an indication to combine chemotherapy with approaches that limit the process of tumor stem cell enrichment. Cancer Res; 77(9); 2231–41. ©2017 AACR.
High-Throughput Genomic Profiling of Adult Solid Tumors Reveals Novel Insights into Cancer Pathogenesis
Authors: Hartmaier Ryan J. , Albacker Lee A. , Chmielecki Juliann , Bailey Mark , He Jie , Goldberg Michael E. , Ramkissoon Shakti , Suh James , Elvin Julia A. , Chiacchia Samuel , Frampton Garrett M. , Ross Jeffrey S. , Miller Vincent , Stephens Philip J. , Lipson Doron 
Published: February 2017

Abstract
Genomic profiling is widely predicted to become a standard of care in clinical oncology, but more effective data sharing to accelerate progress in precision medicine will be required. Here, we describe cancer-associated genomic profiles from 18,004 unique adult cancers. The dataset was composed of 162 tumor subtypes including multiple rare and uncommon tumors. Comparison of alteration frequencies to The Cancer Genome Atlas identified some differences and suggested an enrichment of treatment-refractory samples in breast and lung cancer cohorts. To illustrate novelty within the dataset, we surveyed the genomic landscape of rare diseases and identified an increased frequency of NOTCH1 alterations in adenoid cystic carcinomas compared with previous studies. Analysis of tumor suppressor gene patterns revealed disease specificity for certain genes but broad inactivation of others. We identified multiple potentially druggable, novel and known kinase fusions in diseases beyond those in which they are currently recognized. Analysis of variants of unknown significance identified an enrichment of SMAD4 alterations in colon cancer and other rare alterations predicted to have functional impact. Analysis of established, clinically relevant alterations highlighted the spectrum of molecular changes for which testing is currently recommended, as well as opportunities for expansion of indications for use of approved targeted therapies. Overall, this dataset presents a new resource with which to investigate rare alterations and diseases, validate clinical relevance, and identify novel therapeutic targets. Cancer Res; 77(9); 2464–75. ©2017 AACR.
Telomere Length Is Predictive of Breast Cancer Risk inBRCA2Mutation Carriers
Authors: Thorvaldsdottir Birna , Aradottir Margret , Stefansson Olafur A. , Bodvarsdottir Sigridur K. , Eyfjörd Jorunn E. 
Published: February 2017

AbstractBackground: Germline BRCA2 mutations increase risk of breast cancer and other malignancies. BRCA2 has been shown to play a role in telomere protection and maintenance. Telomere length (TL) has been studied as a modifying factor for various diseases, including breast cancer. Previous research on TL in BRCA mutation carriers has produced contradicting results.Methods: We measured blood TL, using a high-throughput monochrome multiplex qPCR method, in a well-defined Icelandic cohort of female BRCA2 mutation carriers (n = 169), sporadic breast cancer patients (n = 561), and healthy controls (n = 537).Results: Breast cancer cases had significantly shorter TL than unaffected women (P &lt; 0.0001), both BRCA2 mutation carriers (P = 0.0097) and noncarriers (P = 0.00006). Using exclusively samples acquired before breast cancer diagnosis, we found that shorter telomeres were significantly associated with increased breast cancer risk in BRCA2 mutation carriers [HR, 3.60; 95% confidence interval (CI), 1.17–11.28; P, 0.025] but not in non-carriers (HR,1.40; 95% CI, 0.89–2.22; P, 0.15). We found no association between TL and breast cancer–specific survival.Conclusions: Blood TL is predictive of breast cancer risk in BRCA2 mutation carriers. Breast cancer cases have significantly shorter TL than unaffected women, regardless of BRCA2 status, indicating that samples taken after breast cancer diagnosis should not be included in evaluations of TL and breast cancer risk.Impact: Our study is built on a well-defined cohort, highly accurate methods, and long follow-up and can therefore help to clarify some previously published, contradictory results. Our findings also suggest that BRCA2 has an important role in telomere maintenance, even in normal blood cells. Cancer Epidemiol Biomarkers Prev; 26(8); 1248–54. ©2017 AACR.
FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma
Authors: Chuk Meredith K. , Chang Jennie T. , Theoret Marc R. , Sampene Emmanuel , He Kun , Weis Shawna L. , Helms Whitney S. , Jin Runyan , Li Hongshan , Yu Jingyu , Zhao Hong , Zhao Liang , Paciga Mark , Schmiel Deborah , Rawat Rashmi , Keegan Patricia , Pazdur Richard 
Published: February 2017

Abstract
On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15–34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666–70. ©2017 AACR.
Abstract P6-12-12: Phase I study of the JAK 1/2 inhibitor ruxolitinib with weekly paclitaxel for the treatment of HER2 negative metastatic breast cancer (MBC)
Authors: Overmoyer B , Regan M , Schlosnagle E , Bunnell C , Freedman R , Tolaney S , Chen W , Mayer E , Partridge A , Silver D , Winer E 
Published: March 2017

Abstract
This abstract was not presented at the symposium.