tbuckley/cabot-search huggingface dataset:
P01.15 Mitochondrial poisoning as a novel therapy for glioblastoma
Authors: N. Gomez-Roman, K. Stevenson
Journal: Neuro-Oncology (2017)

BACKGROUND: Glioblastoma (GBM) is the most common and lethal adult brain tumour. Increased oxidative phosphorylation is observed in orthotopic GBM mouse models and in human GBM, suggesting that targeting mitochondrial function might be a promising strategy in this disease. The mitochondrial inhibitor ME-344 (MEI-Pharma) has shown activity in pre-clinical in vivo models of ovarian cancer and improved progression-free survival in early phase human clinical studies in small cell lung cancer. The aim of our study was to investigate therapeutic activity and mechanisms of action of ME-344 in preclinical models of GBM. Materials and Methods: Experiments were performed on three GBM cell lines (patient-derived cell lines E2 and G7, and the established cell line U87MGLuc2) grown in stem-cell enriched conditions in conventional two-dimensional (2D) cultures, a clinically relevant 3D in vitro model of GBM and an orthotopic xenograft model (U87MGLuc). Cells and intracranial tumours were treated with ME-344 alone and in combination with radiation (0–6 Gy in vitro, 3x3Gy in vivo). Results: In both cell viability and clonogenic survival assays, ME-344 showed potent cytotoxicity against all GBM cell lines in both 2D and 3D conditions. Dose dependent cytotoxicity was observed with 3D cultures being more resistant than 2D and G7 cells being more resistant than E2 cells (G7 2D EC50=0.028 μg/ml, G7 3D EC50=0.056; E2 2D EC50=0.018 μg/ml, E2 3D EC50=0.032 μg/ml). The U87MGLuc2 cell line exhibited similar sensitivity in 2D and 3D conditions (2D EC50=0.025, 3D EC50=0.022 μg/ml). In vitro, ME-344 triggered profound morphological and cell cycle effects including G2/M arrest, increased mitotic fraction and, in the most sensitive cell lines (U87MGLuc and E2), mitotic catastrophe. These events were preceded by mitochondrial fission and were apoptosis-independent. ME-344 treatment induced senescence in the sensitive cell lines U87MGLuc2 and E2 cell lines whereas in the more resistant G7 cell line an autophagy cell survival program was activated. Accumulation of mitotic cells following ME-344 treatment was recapitulated in orthotopic GBM xenografts in vivo, although very few mitotic catastrophe events were observed 24 hrs after treatment. ME-344 demonstrated therapeutic efficacy as a single agent in U87MGLuc2 orthotopic xenografts by extending mouse survival compared to vehicle (Log Rank Mantel-Cox p=0.043). Results from the combination of ME-344 with ionising radiation in our mouse model are awaited. Conclusions: The mitochondrial inhibitor ME-344 had single agent activity against all GBM cell lines tested in vitro and in an orthotopic GBM mouse model in vivo, suggesting that this treatment has clinical potential. Mitochondrial inhibition induced prolonged mitotic arrest resulting in mitotic catastrophe. We expect these cell cycle effects to radiosensitise cells improving further GBM outcomes.
Early detection of breast cancer using a unique tumor specific antibody.
Authors: Lopamudra Das Roy, Ru Zhou, Laura Jeffords Moore, Lloye M Dillon, Rahul Puri, Kim Lyerly, Jeffrey R Marks, Pinku Mukherjee
Journal: Journal of Clinical Oncology (2015)

e22153 Background: Breast cancer (BC) remains the second leading cause of cancer-related deaths for women in the US. Mammography has improved early detection, but can miss up to 25 percent of BC since mammogram sensitivity is less than 50% in women with dense breast tissue. BC is often detected in these women when a lump is discovered and the cancer is late stage. There is a critical need for an accurate diagnostic for these women. The tumor form of MUC1 (designated TMUC1),a transmembrane glycoprotein, is aberrantly glycosylated and overexpressed in ~95% of BC. We have developed an antibody (TAB004), which specifically recognizes TMUC1. Methods: 1) Using TAB004, a GMP-grade ELISA kit was used to test circulating levels of TMUC1 in sera of patients. We have tested ~250 patient sera (includes normal, benign, and malignant) collected from Duke University Cancer Center, National Cancer Institute (NCI), Early detection research network (EDRN) reference set, and Fox Chase Biorepositories. The samples represented the major BC subtypes (Luminal A, Luminal B, Triple Negative, and HER2 type). 2) Expression of bound TMUC1 on BC tissue was determined with Immunohistochemistry (IHC) using TAB004. 3) We quantified surface expression of TMUC1 using Cy5-conjugated TAB004 and flow cytometry on a panel of over 30 human BC cell lines that represented the major subtypes. 4) Finally, TAB004 conjugated to a fluorophore was used to image human BC tumors in vivo in mice. Results: 1) TMUC1 ELISA results show statistically significant differentiation between normal/benign and malignant sera distributions (p = .000 to .056 from the various institutions). 2) IHC results show strong TMUC1 expression in malignant tissue sparing normal tissue. 3) Flow cytometry data shows that all BC subtypes expressed TMUC1. 4) In vivo imaging shows localization of TAB004-fluorophore to the tumor. Conclusions: A unique tumor specific antibody based serum ELISA can be used for the early detection of breast cancer in women with dense breast tissue. Clinical adoption of the TAB004 based serum ELISA in conjunction with mammography will lead to early detection of BC in these women.
Effect of molecular genotyping to predict outcomes in patients with metastatic pancreatic cancer.
Authors: Jason Edward Faris, Darrell R. Borger, Carlos Fernandez-del Castillo, Jeffrey W. Clark, Lawrence Scott Blaszkowsky, Andrew X. Zhu, Jill N. Allen, Janet E. Murphy, Cristina Ferrone, Lipika Goyal, Nabeel Bardeesy, Gabriel Dan Duda, Hui Zheng, David Tsai Ting, Eunice Lee Kwak, Keith D Lillemoe, Jennifer Yon-Li Wo, A. John Iafrate, David P. Ryan, Theodore S. Hong
Journal: Journal of Clinical Oncology (2014)

4128 Background: The majority (85-90%) of patients (pts) with MPC have mutations in KRAS. Pts with wild type (WT) KRAS, as well as pts with codon-specific KRAS mutations (KRASm) may be associated with distinct presentations and survival. We utilized a molecular genotyping test, SNaPshot, to detect tumor-specific mutations. Methods: The molecular genotypes of 150 pts with MPC that received treatment at the MGH Cancer Center were analyzed. The SNaPshot assay utilizes DNA extracted from formalin-fixed paraffin-embedded tissue and detects sequence variants in a panel of 14 cancer genes. Demographic and clinical characteristics were tabulated, and statistical analysis performed to evaluate correlations between genotype, demographics, clinical characteristics, and outcomes. Overall survival (OS) since diagnosis and OS since metastatic disease were analyzed using Kaplan Meier method and compared using log-rank test. Categorical variables were compared using chi-square test or Fisher's exact test. Continuous variables were compared using ANOVA or nonparametric test. Results: Median age was 63. There were 92 males and 58 females. 98 pts presented with tumors of the head/uncinate and 52 of the body/tail. 71 patients underwent Whipple surgery prior to development of MPC. There were 49 pts with G12D, 38 with G12V, 22 with G12R, and 13 with other KRASm. 28 pts were KRAS WT, including 24 pts without detectable mutations in any gene assayed. Median OS since metastatic disease for the entire cohort was 10 mo (CI: 8.6-12.2). Patients with KRAS G12R had superior OS since metastatic disease (15.6 months, CI 9.4-47.6 mo) relative to patients with G12D mutations (6.1 mo, CI 4.5-12.2 mo) and to patients with KRAS non-G12R mutations (8.9mo, CI 6.0-11.3mo) (p=0.02 for each comparison). 25 pts presented with lung-only metastatic disease at diagnosis, with median OS of 22.4 mo (CI, 10-47.5 mo); 10/25 (40%) were KRAS WT or KRAS 12R. Conclusions: Molecular genotyping of pancreatic cancer identified subgroups of patients with distinct clinical presentation and survival. KRAS mutation n OS since metastatic disease (mo) G12R 22 15.6 (9.4-47.6) WT 28 12.1 (9.5-17.1) Non-G12R 100 8.9 (6.0-11.3) G12V 38 8.2 (5.2-14.5) G12D 49 6.1 (4.5-12.2)
P09.55 Opening the ventricle during surgery is associated with survival among patients with newly diagnosed glioblastoma treated with carmustine wafers: a multi-center retrospective study
Authors: Y. Sonoda, T. Kumabe, T. Tominaga, H. Kinouchi, H. Shimizu, K. Ogasawara, M. Suzuki
Journal: Neuro-Oncology (2017)

BACKGROUND: Carmustine wafers (CW) were approved in Japan for newly diagnosed and recurrent malignant gliomas during 2013. The ventricle is often opened during surgery to achieve maximum resection. While not generally recommended in such situations, CW implantation might be safely achieved by occluding an opened ventricle using gelform or collagen sheets. However, whether CW implantation actually confers a survival benefit for patients who undergo surgery with an open ventricle to treat glioblastoma remains unclear. METHODS: Clinical, imaging, and survival data were collected in this multicenter retrospective study of 122 consecutive patients with newly diagnosed glioblastoma to determine adverse events and efﬁcacy. RESULTS: Overall, 54 adverse events of all grades developed in 35 (28.6%) patients, with the most common being new seizures (16%). Adverse events did not significantly differ between patients with opened and closed ventricles during surgery. The 10- and 21.7-month, median, progression-free (PFS) and overall survival (OS), respectively did not signiﬁcantly differ according to resection rates. However, median PFS and OS were significantly longer among patients with closed, than open ventricles (12.8 vs. 7.4 months; p = 0.0039 and 26.9 vs. 18.6 months; p = 0.011, respectively). CONCLUSIONS: Implanting CW into the resection cavity during concomitant radiochemotherapy with temozolomide seems to yield better survival rates without increased adverse events. Occlusion of the ventricular opening during surgery might be safe for CW implantation, but less so for treating patients with newly diagnosed glioblastoma.
UNDERSTANDING ATHLETES' USE OF EXERCISE AND NON-EXERCISE BASED INJURY PREVENTION STRATEGIES
Authors: Thomas Love, Camilla Knight, Black Katherine
Journal: British Journal of Sports Medicine (2017)

Background The success of exercise-based injury prevention strategies is limited by poor compliance and adherence. However an understanding of the use and barriers to nutrition and psychological injury prevention strategies is not currently known. This information may prove useful in the multidisciplinary environment of elite sport. Objective The objective of this study was to understand the use of exercise, nutrition and psychology injury prevention strategies, identify barriers/facilitators to implementation and preferred methods of knowledge dissemination to athletes. Design An online survey was developed based upon theories of behaviour change and injury surveillance in multi-sport event guidelines. Setting Elite (International/National standard) athletes from a variety of sports. Participants Athletes were randomly recruited from (n=50). Assessment of Risk Factors Athletes completed a questionnaire assessing risk perceptions, prevention beliefs, injury prevention strategy use, injury location/type target, outcome expectancies, barriers/facilitators to injury strategy use and current/preferred channels of information dissemination. Main Outcome Measurements Exercise, nutrition and psychology injury prevention strategy use and barriers/facilitators to strategy use. Results Preliminary findings indicate athletes did not engage with any evidence-based multi-component injury prevention programmes but the majority of athletes reported using at least one exercise-based strategy (97% of athletes) and nutrition-based strategy (97%), but fewer athletes used at least one psychology-based strategy (75%). The most common barriers reported by athletes were a lack of relative advantage for exercise-based strategies and poor how-to-knowledge, principles-knowledge and trialability particularly for nutrition and psychology-based strategies. The most common facilitators were similar across all three injury prevention strategies. These were a performance benefit, injury prevention benefit, relevance, awareness-knowledge, and usefulness. Conclusions No athletes engaged with an evidence-based injury prevention program but many used at least one exercise, nutrition or psychology injury prevention strategy. Athletes reported experiencing few barriers to exercise-based strategies but poor how-to-knowledge, principles knowledge and trialability for non-exercise based strategies.
P18.09 The patients’ perspective on recurrent therapy in high-grade gliomas: Results of a prospective multicenter study on health-related quality of life.
Authors: M. Renovanz, L. Stöckelmaier, J. König, A. Hickmann, M. Nadji-Ohl, O. Ganslandt, L. Bullinger, C. Wirtz, J. Coburger
Journal: Neuro-Oncology (2017)

Objective: To assess impact of common recurrence therapy in high-grade glioma (HGG) patients on health-related quality of life (HRQoL) in an unselected cohort. Methods: We analyzed the completed European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ-C30 and BN20) of 92 patients within one year after diagnosis of tumor recurrence of a HGG and respective treatment in a prospective cross sectional multicenter study. We evaluated the influence of re-radiation, 2nd and 3rd chemotherapies and number of recurrent surgeries on sum scores for functioning, symptoms and a total score as well as on sub-scores for functioning and neurological symptoms using multivariate mixed models and descriptive statistics. Results: Adjusting for Karnofsky-Performance-Score (KPS) and age, different recurrent therapies did not significantly impact HRQoL. Neither re-radiation nor recurrent surgery significantly influenced HRQoL. Patients receiving second-line chemotherapy showed moderately better physical and role functioning as well as less motor dysfunction than patients receiving third-line chemotherapy. Comparing HRQoL after second-line chemotherapies, patients receiving Temozolomide (TMZ) 7/7 demonstrated a moderately better outcome for cognitive functioning and less communication deficits (p=0.055) than patients treated with Bevacizumab (Bev). Regarding number of recurrent surgeries, we found stable HRQoL scores until 2nd recurrent surgery, whereas after 3rd recurrent surgery HRQoL decreased. Conclusion: Our data show that the currently available treatment options have no negative impact on HRQoL. Thus, treatment decisions can be made individually, without fear of risking HRQoL for better survival. Only, the 3rd recurrent surgery remains a very individual decision even in younger patients with high KPS. However, due to the cross sectional character of the study and the heterogeneity of our patient cohort with recurrent HGGs, further prospective studies are required.
Margaret McCartney: Medical school interview courses are needless and unfair
Authors: Margaret McCartney
Journal: BMJ (2017)

What preparation did you do for your medical school interview? I went to an open evening with a few lectures for prospective students.

We heard how hard it was to get in, how high the attrition rate was. Some people just weren’t cut out for it. I was dimly aware of private schools but hadn’t realised how many there were, how confident their progeny were, or how many badges for prefect, head boy, and sports captain could fit on just one lapel of a blazer.

I wonder how many children born poor decided not to apply, perhaps sensing that this environment wasn’t for them. …
INJURIES IN MEN'S PROFESSIONAL FOOTBALL
Authors: Christian Klein, Hendrik Bloch, Patrick Luig, Thomas Henke, Petra Platen
Journal: British Journal of Sports Medicine (2017)

Background The first step on the way to developing preventive measures is the description of epidemiology within the target group. This is not known for German Men's Professional Football so far. Objective Analysis of injury risk and description of injury patterns. Design Prospective observational cohort study of the season 2014–15. Setting Two highest leagues in German men's football (i.e. Bundesliga, 2. Bundesliga). Patients (or Participants) All first and second division football players who played at least one competitive club match (n=1,358) during the 2014–15 season were included. Interventions (or Assessment of Risk Factors) Analysis of all injuries of the participants that were registered by clubs or physicians with the VBG as part of the occupational accident reporting and that either led to the player's short-term disability (time-loss) or to medical treatment costs (medical-attention). Main Outcome Measurements Prevalence rate and injury incidence, injured body regions, type of injury, medical costs and time loss. Results 1,076 of the 1,358 players (79.2%) were injured. A total of 3,385 injuries were recorded (training: 62.3%, match: 37.3%) which led to a cumulative incidence rate of 2.5 injuries per player and season. Goalkeeper had lower overall risk of injury (2.1 inj./season), but a 3.7 times higher relative risk of concussions than field players. 70.7% of all injuries were lower extremity injuries. Thigh injuries (21.3%) and knee injuries (15.8%) were the most frequent injuries. However, knee injuries caused 37.0% of overall time-loss and 48.4% of overall medical-attention. Conclusions German men's professional football shows a high risk of injury. Injury risk and injury patterns differ by playing position, probably reflecting the specific performance profiles of the respective playing position. Thus prevention needs to be individualised and at least must consider different characteristics of playing positions. For development of expedient preventive measures, injury mechanisms need to be analysed.
Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise
Authors: Paula Mera, Kathrin Laue, Mathieu Ferron, Cyril Confavreux, Jianwen Wei, Marta Galán-Díez, Alain Lacampagne, Sarah J. Mitchell, Julie A. Mattison, Yun Chen, Justine Bacchetta, Pawel Szulc, Richard N. Kitsis, Rafael de Cabo, Richard A. Friedman, Christopher Torsitano, Timothy E. McGraw, Michelle Puchowicz, Irwin Kurland, Gerard Karsenty
Journal: Cell Metabolism (2017)
Abstract 101: MiR-4260 Promotes the Proliferation, Migration, and Tube Formation of Human Umbilical Vein Endothelial Cells
Authors: Qi Sun, Dongcao Lv, Qiulian Zhou, Yihua Bei, Junjie Xiao
Journal: Circulation Research (2015)

MicroRNAs (miRNAs, miRs), endogenous small non-coding RNA, have been shown to act as essential regulators in angiogenesis which plays important roles in improving blood flow and cardiac function following myocardial infarction. The current study investigated the potential of miR-4260 in endothelial cell function and angiogenesis using human umbilical vein endothelial cells (HUVEC). Our data demonstrated that overexpression of miR-4260 was associated with increased proliferation and migration of HUVEC using EdU incorporation assay (17.25%±1.31 vs 25.78%±1.24 in nc-mimics vs miR-4260 mimics, respectively) and wound healing assay, respectively. While downregulation of miR-4260 inhibited the proliferation (17.90%±1.37 vs 10.66%±1.41 in nc-inhibitor vs miR-4260 inhibitor, respectively) and migration of HUVEC. Furthermore, we found that miR-4260 mimics increased (129.75±3.68 vs 147±3.13 in nc-mimics vs miR-4260 mimics, respectively), while miR-4260 inhibitor decreased the tube formation of HUVECs in vitro (123.25±2.17 vs 92±4.45 in nc-inhibitor vs miR-4260 inhibitor expression, respectively). Our data indicate that miR-4260 contributes to the proliferation, migration and tube formation of endothelial cells, and might be essential regulators for angiogenesis. Further study is needed to investigate the underlying mechanism that mediates the role of miR-4260 in angiogenesis by identifying its putative downstream target genes.
P08.28 The combination therapy with temozolomide and DWMA-003TS for glioblastoma in vitro and invivo experiments
Authors: C. Kim, K. Hwang
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM) is the most frequent primary malignant brain tumor in adults. Although GBM patients received aggressive treatment, their median survival was less than 14.6 months. It is important to find a new regimen to prolong the survival. The purpose of present study was to investigate the effects of combination therapy with DWMA-003TS and temozolomide by in vitro and in vivo for GBM. Materials and Methods: The antitumor effects of combination therapy on U87MG, U251MG, and LN229 human GBM cell lines were assessed using the cell viability, migration, and invasion assays. Xenograft mouse with U87 cell line divided into three groups, control group which treated with PBS, temozolomide group and combination group treated with temozolomide and DWMA003Ts. We performed the tumor volume measurement and survival analysis with xenograft mouse model. Results: The combination therapy effects on concentration-dependent significantly decreased cell viability in U87MG, U251, and LN229 cell lines. In the cell migration assay, combination therapy was more effective than temozolomide group on the inhibitory effect of the cell migration in three GBM cell lines. Each cell lines abilities to cell invasion were less invasive in the combination group than temozolomide group. In in vivo study, the tumor volume was significantly decreased in the combination group compared with both temozolomide and control groups by using the xenograft model. However, survival analysis data in xenograft mouse model showed no significance between the temozolomide group and combination group. CONCLUSION: We expected that the effects of combination therapy with DWMA-003Ts and temozolomide might attribute to the inhibition of migration and invasion activities. Eventually, this therapy could prolong the survival of glioblastoma patients.
P11.14 Extraventricular neurocytoma with spontaneous turmoral hemorrhage
Authors: E. Seo, N. Yang
Journal: Neuro-Oncology (2017)

Extraventricular neurocytoma is a rare neuroepithelial tumor. Its propensity to occur in cerebral hemisphere is much higher. EVN has a histological resemblance to central neurocytoma. A case of extraventricular neurocytoma with spontaneous tumoral hemorrhage is reported. A 8-year-old male presented with sudden metal deterioration. CT scan revealed huge right parietal subcortical hemorrhage with surrounding low intensity mass and without contact to the ventricular system. After complete microsurgical removal of hemorrhage and mass, the tumor was histologically diagnosed as neurocytoma. Usually, the term “central neurocytoma” is restricted to neurocytic neoplasms arising within the cerebral ventricles. In the majority of the cases, these slow-growing, generally circumscribed lesions become symptomatic by obstructive hydrocephalus. Hemorrhagic onset is sporadically reported in the literature. In contrast to central neurocytomas, neurocytic lesions located within the brain parenchyma, so-called “extraventricular neurocytomas” are very uncommon. In short extraventricular neurocytoma should be considered indifferential diagnosis of complex intracranial masses with bleeding.
P05.07 Extereme neurological variability of chemotherapy induced PRES associated with TMA
Authors: C. Makranz, S. Khutsurauli, Y. Kalish, R. Eliahou, L. Kadouri, M. Gomori, A. Lossos
Journal: Neuro-Oncology (2017)

describes lowering of left Hipp dose while meeting RTOG 0933 criteria for PTV.Patients, who had lower Hipp D100 % in previous clinical trials performed significantly better in certain memory tests.Therefore, decreasing hippocampal dose to as low level as possible is clinically relevant.CON-CLUSION: Unilateral Hipp sparing during WBRT could improve target coverage and/or further decrease dose at spared Hipp.Clinical relevance of suggested planning study remains to be determined. P05.