tbuckley/cabot-search huggingface dataset:
MEDU-01. INTERACTION BETWEEN MELK AND EZH2 REGULATES MEDULLOBLASTOMA CANCER STEM-LIKE CELLS PROLIFERATION
Authors: Hailong Liu, Qianwen Sun, Yuduo Guo, Chunyu Gu, Yongmei Song, Chunjiang Yu, Youliang Sun, Yongqiang Liu, Hoyee Chow
Journal: Neuro-Oncology (2017)

BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor in children. Although accumulated research suggests that cancer stem-like cells may play a key role in medulloblastoma tumorigenesis, the molecular mechanisms of proliferation still remain elusive and further investigation can provide a novel application for therapeutic target in MB patients. METHODS: The expression of MELK and EZH2 was detected by tissue microarray analysis with 88 MBs and its association with prognosis was identified. Co-location of MELK and EZH2 in MB CSCs and tissues was studied by using confocal and immunostaining. Immunoblotting analysis following co-immunoprecipitation was performed to check the interaction between MELK and EZH2. Through the loss-of-function study by siRNA, CSCs-drived tumor growth was detected. Then we studied the targeted treatment of MB with MELK and EZH2 inhibitor in vivo to confirm the molecular basis of MELK and EZH2. RESULTS: MELK and EZH2 co-located in the nuclei of MB CSCs and MB with extensive nodularity and large cell/anaplastic differed the staining levels as measured using microarray analysis when compared with the other two subgroups. The proportion of MELK positive staining cells was the potential indicator for the survival. MELK bound and phosphorylated EZH2 and its methylation was induced by EZH2 in MB, which regulated the proliferation of CSCs. MELK and EZH2 depletion by siRNA or treatment of inhibitors attenuated the MB CSCs-derived tumor growth in vivo. CONCLUSION: Interaction between MELK and EZH2 is essential for MB CSCs-drived tumor proliferation, thereby identifying a potential therapeutic strategy for MB patients.
Slower Progress of Aortic Valve Calcification With Vitamin K Supplementation
Authors: Vincent M. Brandenburg, Sebastian Reinartz, Nadine Kaesler, Thilo Krüger, Tim Dirrichs, Rafael Kramann, Frederique Peeters, Jürgen Floege, Andras Keszei, Nikolaus Marx, Leon J. Schurgers, Ralf Koos
Journal: Circulation (2017)
The association between immunoglobulin concentrations and prediabetes prevalence in a large Chinese cohort
Authors: Honglei Wang, Yanqi Song, Shaomei Sun, Li Gao, Li Liu, Ge Meng, Hongmei Wu, Yang Xia, Xue Bao, Yeqing Gu, Hongbin Shi, Qian Su, Liyun Fang, Huijun Yang, Xing Wang, Ming Zhou, Qiyu Jia, Kun Song, Qing Zhang, Kaijun Niu
Journal: Metabolism (2017)
Driving after concussion: is it safe to drive after symptoms resolve?
Authors: Julianne D Schmidt, Hannes Devos, Nicole L Hoffman, Maud Ranchet, Abiodun E Akinwuntan, L Stephen Miller
Journal: British Journal of Sports Medicine (2017)

Objective To compare simulated driving performance between concussed and control participants. Design Cross-sectional. Setting Laboratory. Subjects Fourteen concussed participants and 14 non-concussed age and driving experience matched controls with no neurological disorders, medications causing drowsiness, or heavy drugs/alcohol use (Age: 20.3years, 95%CI:19.9,20.7). Intervention Participants completed a 7.6 minute, 20.5km driving simulation task containing curves, crosswalks, accidents, rural/urban areas, pedestrians, overtaking, and evasion. Concussed participants completed driving simulation within 48 hours of becoming asymptomatic (15.9 days post-concussion, 95%CI: 10.7,21.0) and were deemed clinically recovered by a medical professional using a multifaceted concussion evaluation. Outcome measures We compared total number of accidents, tickets, and lane excursions between groups.We also comparedaverage velocity (km/hr), standard deviation of velocity, lateral lane position (m), and lateral lane position standard deviation throughout simulation subsections. One-way ANOVAs were used (α=0.05). Results Concussed participants committed more frequent lane excursions compared to controls (concussed: 10.9, 95%CI:8.3,13.5; controls: 7.4, 95%CI:6.0,8.8; p=0.02). Concussed participants exhibited greater lateral lane position standard deviation compared to controls during the first (concussed: 1.1m, 95%CI: 0.8,1.5; controls: 0.7m, 95%CI:0.6, 0.9; p=0.02) and final curve (concussed: 1.2m, 95%CI:1.1,1.3; controls: 1.0m, 95%CI:0.9,1.1; p=0.04). Conclusions Despite being considered clinically recovered, concussed participants were less able to centre the vehicle in the lane and entered the shoulder more frequently, especially when navigating curves. A concussion may impair visual, motor, and/or cognitive skills necessary to safely drive. Further research is needed to determine when it is safe to return to driving following concussion. Competing interests None.
Alan Hirsch, MD
Authors: William R. Hiatt
Journal: Circulation Research (2017)

Those of us in the vascular medicine community, his family, professional colleagues, friends, and patients are devastated.But the light of Alan Hirsch cannot be quenched, and his light will shine in the darkness of our loss.I have been a close friend and professional colleague of Alan for the past 25 years, primarily regarding his work in vascular medicine but extending to our personal lives as we journeyed through the challenges and joys of life.He loved the wilderness in the Rocky Mountains, Minnesota, and abroad.Adventure travel and his family occupied his time outside his profession
αSGT: A critical determinant of androgen receptor function in prostate cancer
Authors: Grant Buchanan, Carmela Ricciardelli, Jennifer Prescott, Jonathan M. Harris, Zoe C-L Yu, Li Jia, Lisa M. Butler, Howard I. Scher, William Gerald, Gerhard A. Coetzee, Wayne D. Tilley
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5346 

The maturation, activation and function of nuclear receptors depend upon their chaperone mediated folding. Here we report that a novel co-chaperone, small glutamine-rich tetratricopeptide repeat containing protein (αSGT), interacts with the androgen receptor (AR) to control both its subcellular localization and sensitivity of ligand-dependent activation in prostate cancer cells. Overexpression of αSGT sequesters AR in the cytoplasm in the absence of 5α-dihydrotestosterone (DHT), reducing basal cross-talk activation by more than 90%, as well as inhibiting the sensitivity of ligand-dependent nuclear translocation and activation. In contrast knock-down of αSGT increased AR sensitivity to DHT. In clinical prostate cancer samples, quantitative immunohistochemical analysis of AR and αSGT immunoreactivity revealed that a decrease in the ratio of AR:αSGT was associated with an increase in the relative amount of cytoplasmic compared to nuclear AR. Moreover, there was a net increase in the ratio of AR:αSGT in metastatic prostate cancer samples [2.08(+0.36), n=64] compared to primary tumors [0.99(+0.12), n=32; p=0.003], which may in part explain the increase in sensitivity of AR signaling associated with the failure of androgen ablation therapies and the development of a castrate-resistant phenotype. We propose that αSGT is a critical AR co-chaperone regulating androgen signaling, and that perturbation of the AR:αSGT ratio alters the capacity of ligand to activate the AR and stimulate the growth of prostate cancer cells.
Therapy of Advanced Non–Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan
Authors: Rebecca Suk Heist, Michael J. Guarino, Gregory Masters, W. Thomas Purcell, Alexander N. Starodub, Leora Horn, Ronald J. Scheff, Aditya Bardia, Wells A. Messersmith, Jordan Berlin, Allyson J. Ocean, Serengulam V. Govindan, Pius Maliakal, Boyd Mudenda, William A. Wegener, Robert M. Sharkey, David M. Goldenberg, D. Ross Camidge
Journal: Journal of Clinical Oncology (2017)

Purpose Trop-2, expressed in most solid cancers, may be a target for antibody-drug conjugates (ADCs) in non–small-cell lung cancer (NSCLC). We studied sacituzumab govitecan (IMMU-132), a Trop-2 ADC, for the targeting of SN-38. Patients and Methods We evaluated IMMU-132 in a single-arm multicenter trial in patients with pretreated metastatic NSCLC who received either 8 or 10 mg/kg on days 1 and 8 of 21-day cycles. The primary end points were safety and objective response rate (ORR). Progression-free survival and overall survival were secondary end points. Results Fifty-four patients were treated. In the response-assessable study population (n = 47), which had a median of three prior therapies (range, two to seven), the ORR was 19%; median response duration, 6.0 months (95% CI, 4.8 to 8.3 months); and clinical benefit rate (complete response + partial response + stable disease ≥ 4 months), 43%. ORR in the intention-to-treat (ITT) population was 17% (nine of 54). Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy. Median ITT progression-free survival was 5.2 months (95% CI, 3.2 to 7.1 months) and median ITT overall survival, 9.5 months (95% CI, 5.9 to 16.7 months). Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%). One patient developed a transient immune response, despite patients receiving a median of 10 doses. More than 90% of 26 assessable archival tumor specimens were highly positive (2+, 3+) for Trop-2 by immunohistochemistry, which suggests that Trop-2 is not a predictive biomarker for response. Conclusion IMMU-132 was well-tolerated and induced durable responses in heavily pretreated patients with metastatic NSCLC. This ADC should be studied further in this disease and in other patients with Trop-2–expressing tumors.
In vitro and in vivo evaluation of a highly potent albumin-binding prodrug of 2-pyrrolinodoxorubicin
Authors: Claudia Ryppa, Ralph Graeser, Norbert Esser, Christoph Schaechtele, Henrike Unger, Clemens Unger, Felix Kratz
Journal: Cancer Research (2008)

5679  Albumin-binding prodrugs with doxorubicin, camptothecin, platinum(II) complexes and methotrexate have shown superior antitumor efficacy in preclinical tumor models compared to their parent compounds, and an acid-sensitive doxorubicin prodrug, the 6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is in clinical trials. In this work, we selected 2-pyrrolinodoxorubicin, a derivative of doxorubicin that is 500-1000 more cytotoxic than doxorubicin (1), for the development of an acid-sensitive albumin-binding prodrug. 2-pyrrolinodoxorubicin-EMCH was conveniently prepared by reacting 2-pyrrolinodoxorubicin with ϵ-maleimidocaproic acid hydrazide (EMCH) and subsequent crystallization.  The novel acid-sensitive prodrug bound rapidly to the cysteine-34 position of exogenous and endogenous human serum albumin and released 2-pyrrolinodoxorubicin in a pH-dependent manner. In vitro, two pancreatic cancer cell lines, AsPC1 and MIA-PaCa2, were tested for their sensitivity towards classical doxorubicin, its derivative, 2-pyrrolodoxorubicin, and the prodrug. The IC50 value of conventional doxorubicin was 360 nM for AsPC1 and 35 nM for MIA-PaCa2. As expected, 2-pyrrolodoxorubicin was much more potent, with IC50 values of 408 and 204 pM, respectively. As a prodrug, the IC50 values were increased by an order of magnitude, but were still well below the concentrations of conventional doxorubicin, with IC50 values of 10 and 6 nM. Interestingly, the reduced sensitivity of AsPC1 towards doxorubicin seems to be reverted with the novel compound, also in its prodrug formulation. In an orientating toxicity study in nude, the acid-sensitive prodrug of 2-pyrrolinodoxorubicin showed at least a fourfold shift in the maximum tolerated dose compared to the free drug. In vivo experiments in an orthotopic pancreas carcinoma model (AsPC1) with 600 nmol/kg 2-pyrrolinodoxorubicin-EMCH compared to 150 nmol/kg 2-pyrrolinodoxorubicin are ongoing and results will be presented.  1. Nagy, A., Armatis, P., and Schally, A. V. High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin. Proc. Natl. Acad. Sci. U S A, 93: 2464-2469, 1996.
Introducing the AASLD president: Anna S.F. Lok
Authors: Grace L. Su, Robert J. Fontana
Journal: Hepatology (2017)

1Division of Gastroenterology, Michigan MedicineUniversity of MichiganAnn ArborMI *ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:Grace L. Su, M.D.Gastroenterology Section, VA Ann Arbor Healthcare System2215 Fuller RoadAnn Arbor MI, 48105E‐mail: [email protected]Tel: +1‐734‐845‐5865
Case 4-1996
Authors: L.X. Liu, C.C. Compton
Journal: New England Journal of Medicine (1996)

Presentation of CaseA 40-year-old woman was admitted to the hospital because of the recent onset of paraplegia.Two weeks before admission progressive low back pain developed, which soon radiated to the posterior surfaces of both legs and later to the anterior surfaces. During the next several days the patient had difficulty getting out of the bathtub.Eleven days before admission the pain increased, and urinary retention developed. No motor deficit was detected at another hospital, where radiographs of the lumbar spine showed mild dextroscoliosis, and a computed tomographic (CT) scan, without the intravenous injection of contrast material, revealed a . . .
Impact of Initial CSF Findings on Outcome Among Patients With National Cancer Institute Standard- and High-Risk B-Cell Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group
Authors: Naomi Winick, Meenakshi Devidas, Si Chen, Kelly Maloney, Eric Larsen, Leonard Mattano, Michael J. Borowitz, Andrew Carroll, Julie M. Gastier-Foster, Nyla A. Heerema, Cheryl Willman, Brent Wood, Mignon L. Loh, Elizabeth Raetz, Stephen P. Hunger, William L. Carroll
Journal: Journal of Clinical Oncology (2017)

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/μL and blasts with/without ≥ 10 RBCs/μL or ≥ 5 WBCs/μL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/μL plus blasts with/without ≥ 10 RBCs/μL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.
Застосування вітамінів групи В у комплексному лікуванні хворих із захворюваннями органів травлення
Authors: L.M. Shendrik, I.А. Vasilyeva, A.N. Kovalenko, N.V. Chaly
Journal: GASTROENTEROLOGY (2017)

У статті наведені сучасні дані щодо комплекс­ного лікування захворювань органів травлення вітамінами групи В, оскільки вони відіграють велику біологічну роль не тільки як загальнозміцнюючий чинник, що сприяє одужанню, але й як лікувальні засоби, що мають різноманітну фармакодинамічну дію. Вітаміни групи В доцільно включати в комплекс­ну терапію психосоматичних захворювань, особливо таких, як функціональні порушення травної системи, при хронічних ураженнях печінки вірусної і токсичної етіології і захворюваннях кишечника (хронічний коліт, синдром подразненого кишечника). Зроблено висновок про те, що застосування вітамінів групи В лікарями-гастроентерологами здатне істотно підвищити якість фармакотерапії багатьох захворювань органів травлення.
Eliminating HIV-1 Packaging Sequences from Lentiviral Vector Proviruses Enhances Safety and Expedites Gene Transfer for Gene Therapy
Authors: Conrad A. Vink, John R. Counsell, Dany P. Perocheau, Rajvinder Karda, Suzanne M.K. Buckley, Martijn H. Brugman, Melanie Galla, Axel Schambach, Tristan R. McKay, Simon N. Waddington, Steven J. Howe
Journal: Molecular Therapy (2017)
Immunogenicity and safety of the 13-valent Pneumococcal Conjugate vaccine in 23-valent pneumococcal polysaccharide vaccine-naive and pre-immunized patients under treatment with chronic haemodialysis: a longitudinal quasi-experimental phase IV study
Authors: S.J. Vandecasteele, D. De Bacquer, R. Caluwe, S. Ombelet, B. Van Vlem
Journal: Clinical Microbiology and Infection (2017)
Temporal Trends in Adverse Events After Everolimus-Eluting Bioresorbable Vascular Scaffold Versus Everolimus-Eluting Metallic Stent Implantation
Authors: Rocco A. Montone, Giampaolo Niccoli, Federico De Marco, Silvia Minelli, Fabrizio D’Ascenzo, Luca Testa, Francesco Bedogni, Filippo Crea
Journal: Circulation (2017)

Background: Bioresorbable coronary stents have been introduced into clinical practice to improve the outcomes of patients treated with percutaneous coronary intervention. The everolimus-eluting bioresorbable vascular scaffold (BVS) is the most studied of these stent platforms; however, recent trials comparing BVS with everolimus-eluting metallic stents (EES) raised concerns about BVS safety. We aimed to assess the efficacy and safety of BVS versus EES in patients undergoing percutaneous coronary intervention. Methods: We searched Medline, Embase, the Cochrane Central Register of Controlled Trials, scientific sessions abstracts, and relevant Web sites for randomized trials with a follow-up of ≥2 years investigating percutaneous coronary interventions with BVS versus EES. The primary outcomes of our analysis were definite/probable stent thrombosis (ST) and target lesion failure (TLF; device-oriented composite end point of cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization [TLR]). Secondary outcomes were target vessel myocardial infarction, TLR, and cardiac death. We calculated the risk estimates for main outcomes according to a fixed-effect model. Results: We included 7 trials comprising data for 5583 patients randomized to receive either a BVS (n=3261) or an EES (n=2322). Median follow-up was 24 months (range, 24–36 months). Patients treated with BVS had a higher risk of definite/probable ST compared with patients treated with EES (odds ratio, 3.33; 95% confidence interval, 1.97–5.62; P &lt;0.00001). In particular, patients with BVS had a higher risk of subacute, late, and very late ST, whereas the risk of acute ST was similar. Patients treated with BVS compared with EES had a higher risk at 2 years of TLF (odds ratio, 1.47; 95% confidence interval, 1.14–1.90; P =0.003), driven mainly by an increased risk of target vessel myocardial infarction (odds ratio, 1.73; 95% confidence interval, 1.31–2.28; P =0.0001; I 2 =0%) and of TLR (odds ratio, 1.27; 95% confidence interval, 1.00–1.62; P =0.05). Of importance, the risk of TLF and TLR for patients with BVS was higher between 1 and 2 years, whereas there was no difference in the first year. Risk of cardiac death was similar between the 2 groups. Conclusions: Our meta-analysis of randomized trials with a follow-up of ≥2 years demonstrated a higher risk of ST and of TLF in patients treated with BVS compared with EES. Of note, BVS had a higher risk of subacute, late, and very late ST, whereas the risk of TLF and TLR was higher between 1 and 2 years.
Is concussion a risk factor for epilepsy?
Authors: Richard Wennberg, Carmen Hiploylee, Charles H Tator
Journal: British Journal of Sports Medicine (2017)

Objective It has been stated that concussion is a risk factor for the development of post-traumatic epilepsy, but few data exist to support or refute this statement. We analysed the incidence and prevalence of epilepsy in a large cohort of post-concussion patients. Design Retrospective cohort study. Setting Academic tertiary care centre. Participants 330 consecutive post-concussion patients followed by one concussion specialist (CHT). Exclusion criteria: abnormal brain CT/MRI, GCS ≤ 12 &gt;1 hr post-injury, hospitalisation&gt;48 hrs. Mean number of concussions/patient 3.3 (±2.5), mean age at first clinic visit 28 years (±14.7), mean follow-up after first concussion 7.6 years (±10.8). Assessment of risk factor Independent variable, concussion. Outcome measures Epilepsy incidence (dependent variable); prevalence. Main results Eight patients had medical record documentation of seizures or convulsions or epilepsy. Upon detailed review by an epilepsy specialist (RW) none met criteria for a definite diagnosis of epilepsy: 4 had episodic symptoms incompatible with epileptic seizures (multifocal paraesthesiae, multimodality hallucinations, classic migraine) and normal EEG/MRI investigations; 4 had clear histories of syncopal (n=2) or concussive (n=2) convulsions. Compared to epilepsy prevalence (6.6/1000 individuals) and annual incidence (0.5/1000 individuals) in the general population, there was no difference in this post-concussion cohort (Chi-square=0.218, d.f.1, corr.cont., p=0.64). Conclusions In this large cohort of post-concussion patients we found no evidence of an increased incidence of epilepsy, and the prevalence of epilepsy was lower than in the general population. Concussion is not a significant risk factor for the development of post-traumatic epilepsy, at least in the first decade post-injury. Competing interests None.
IMMU-09. P53 REGULATES IMMUNOGENICITY OF MEDULLOBLASTOMA
Authors: Alexandra Garancher, Robert J. Wechsler-Reya
Journal: Neuro-Oncology (2017)

Immunotherapy has recently emerged as an important strategy for treating cancer, but has not been tested extensively in pediatric brain tumors. To determine whether immunotherapy would be effective in this context, we need robust animal models of brain tumors that have a fully functional immune system. We recently created genetically engineered mouse models of Group 3 (Myc-driven) medulloblastoma, the most aggressive and lethal form of the disease. These models are generated by transducing cerebellar stem cells with viruses encoding Myc and dominant negative p53 (MP model), or Myc and GFI1 (MG model), and transplanting them into the cerebellum of an adult immunodeficient (ID) mouse. To evaluate whether these models can be used to study immunotherapy, we transplanted tumor cells into syngeneic, immunocompetent (IC) hosts. While MP tumors grew robustly in both ID and IC hosts, MG tumors failed to grow when transplanted into IC mice. Depletion of T cells rescued this effect, supporting the notion that MG tumors are being recognized and rejected by the immune system. Notably, knockdown or inactivation of p53 in MG tumors also allowed them to grow in IC hosts, suggesting that p53 mutations may render tumor cells invisible to the immune system. Ongoing studies are focused on understanding the basis of p53-mediated immune regulation, and on developing strategies to overcome it. These studies will provide insight into the interactions between medulloblastoma cells and the immune system, and identify novel approaches to immunotherapy of this tumor. Since p53 is mutated in a large proportion of human cancers, these studies may also have important implications for immunotherapy of other cancers.