tbuckley/cabot-search huggingface dataset:
P16.26 Surgical Treatment of Pineal Region Tumors
Authors: A. Smolanka, T. Havryliv
Journal: Neuro-Oncology (2017)

Objective: To analyse short-term results and assess long-term follow-up of patients with pineal region tumors which were operated in Uzhhorod Regional Centre of Neurosurgery and Neurology. Methods: 24 patients with pineal region tumors were operated in Uzhhorod Regional Centre of Neurosurgery and Neurology since 2011. Male to female ratio was 1:1. Mean age of the patients was 25.2 years (10 were of paediatric age). Patients were divided into two groups according to tumor type: low-grade - 12 cases (meningioma - 3, pylocytic astrocytoma - 3, pineocytoma - 2, ependymoma - 1, choroid glioma - 1, papillary tumor - 1, xantogranulema - 1) and high-grade - 12 patients (pineoblastoma - 5, anaplastic astrocytoma - 2, glioblastoma -2, teratoma -1, germinoma - 1, choriocarcinoma - 1). The extent of resection was evaluated on early postoperative MRI. Short-term results were determined based on neurological examination one month after surgery in all patients. Long-term results were assessed based on overall survival in patients with high-grade tumors and Karnofsky Performance Scale (KPS) on last follow-up in patients with low-grade tumors. Mean follow up was 24 months (in low-grade group - 34 months). Results: Gross total resection was achieved in 10 cases (41.7%) and in 6 patients near total resection was performed (25%). 4 patients underwent a subtotal resection of the tumor (16.7%) and in 4 cases only partial resection was done (16.7%). Majority of the patients (83.3%) were neurologically stable or improved compared to preoperative status on day 30 follow-up. 2 patients (8.3%) deteriorated after resection of the tumor. Postoperative mortality was 8.3% (large venous infarction and postoperative meningitis). All patients with high-grade tumors underwent radio- and chemotherapy after surgery according to tumor histology. Mean overall survival in this group of patients was 11.6 months. 7 out of 12 patients (58.3%) with low-grade pineal tumors underwent gross total resection. On last follow-up 10 patients (83.3%) with low-grade tumors were KPS 100 and 2 (16.7%) patients were KPS 70. Conclusions: Resection of pineal region tumors is safe (morbidity/mortality - 16.6%). In patients with high-grade pineal tumors surgical strategy should consist of simple debunking as overall survival is poor (11.6 months). Excellent long-term outcome (KPS 100 in 83.3%) in patients with low-grade tumors was achieved with aggressive surgical strategy (gross total resection in 58.3%).
P01.25 The cut-off value correlated with good favorable prognostic outcome in patients with newly diagnosis of glioma
Authors: V. Villani
Journal: Neuro-Oncology (2017)

Objective: Gliomas are the most common primary tumors of the central nervous system (CNS), but despite advances in therapy these tumour remain associated with poor prognosis. The MGMT gene is epigenetically silenced by promoter hypermethylation in gliomas, and this modification has emerged as a relevant predictor of therapeutic response and of good prognosis. Studies with pyrosequencing (PSQ) showed that this technique has a good prediction of survival in addition to high reproducibility and sensitivity than other techniques. However, cut-off values for the percentage methylation are one of the critical issues to determine methylation status using PSQ analysis. Aim of the study is defining the cut-off value correlated with good favorable prognostic outcome. Methods: We collected a tumour samples of glioma patients who underwent surgery or biopsy and were followed at the Neuro-oncology Unit of National Cancer Institute Regina Elena will be included in this study. We collected demographic, clinical and molecular data, as well as data on response to treatments and outcomes (PFS and OS). For pyrosequencing method, we used the modification reagents of MGMT plus kit (Diatech Pharmocogenetics, Jesi Italy) according to the manufacturer’s protocol. Modified DNA was subjected to PCR amplification with a forward primer and a biotinylated reverse primer using the MGMT PLUS” Kit (Diatech pharmacogenetics) and “Rotor-Gene TM 6000” instrument. We performed pyrosequencing methylation assay to evaluate 10 CpG sites in the following region: chr 10:131,265,507-131,265,556) using sequencing primer of MGMT Kit Diatech Pharmocogenetics, Jesi (Ancona), Italy. The pyrosequencing analysis was performed with PyroMarker CpG software 1.0.11 (Qiagen). The software give a mean methylation value for each 10 CpG sites and the totale mean of all 10 CpG sites. Results: We enrolled 177 patients of glioma analyzed with PSQ for MGMT and IDH1. Of them 102 patients are females and 75 are males. The majority of patients are affected by Glioblastoma. Statistical analysis showed that a percentage of methylation higher than 35% resulted significantly correlated with higher PFS respect to a percentage of methylation lower than 35%. Patient with cut off >35% have a rate of PSF at 1 years of 53% while only 4.2% of patients with cut off <35% are disease progression free at 1 years. Discussion: Our preliminary data showed that patients with a cut-off <35% of methylation had a shorter PFS but not significant difference was observed in terms of overall survival. Other studies are warranted on larger population to validate these data.
Sirtuin 3 acts as a negative regulator of autophagy dictating hepatocyte susceptibility to lipotoxicity
Authors: Songtao Li, Xiaobing Dou, Hua Ning, Qing Song, Wei Wei, Ximei Zhang, Chen Shen, Jiaxin Li, Changhao Sun, Zhenyuan Song
Journal: Hepatology (2017)

Lipotoxicity induced by saturated fatty acids (SFAs) plays a central role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); however, the exact mechanisms remain to be fully elucidated. Sirtuin 3 (SIRT3) is a nicotinamide adenine dinucleotide–dependent deacetylase located primarily inside mitochondria. In this study, we demonstrated that an SFA‐rich high‐fat diet (HFD) was more detrimental to the liver than an isocaloric unsaturated HFD rich in fatty acids. Unexpectedly, SIRT3 expression and activity were significantly elevated in the livers of mice exposed to the SFA‐rich HFD. Using cultured HepG2 and AML‐12 hepatocytes, we demonstrated that unlike monounsaturated fatty acids, SFAs up‐regulate SIRT3 expression and activity. SIRT3 overexpression renders both the liver and hepatocytes susceptible to palmitate‐induced cell death, which can be alleviated by SIRT3 small interfering RNA (siRNA) transfection. In contrast, SIRT3 suppression protects hepatocytes from palmitate cytotoxicity. Further studies revealed that SIRT3 acts as a negative regulator of autophagy, thereby enhancing the susceptibility of hepatocytes to SFA‐induced cytotoxicity. Mechanistic investigations revealed that SIRT3 overexpression causes manganese superoxide dismutase deacetylation and activation, which depleted intracellular superoxide contents, leading to adenosine monophosphate–activated protein kinase (AMPK) inhibition and mammalian target of rapamycin C1 activation, resulting in autophagy suppression. In contrast, SIRT3 siRNA gene silencing enhanced autophagy flux. A similar result was observed in the liver tissue of SIRT3 knockout mice. Conclusion : Our data indicate that SIRT3 is a negative regulator of autophagy whose activation by SFAs contributes to lipotoxicity in hepatocytes and suggest that restraining SIRT3 overactivation can be a potential therapeutic choice for the treatment of NAFLD as well as other metabolic disorders, with lipotoxicity being the principal pathomechanism. (H epatology 2017;66:936–952).
THE IMPACT OF RUNNING INJURIES IN RELATION TO OTHER REASONS FOR DISCONTINUED RUNNING IN NOVICE RUNNERS
Authors: Michael Lejbach Bertelsen, Sten Rasmussen, Rasmus Østergaard Nielsen
Journal: British Journal of Sports Medicine (2017)

Background The risk of running injuries in novice runners is 17.8 (16.7–19.1) per 1000 h of running (Videbæk 2015). This might lead to the conclusion that running injuries are one of the main reasons for discontinued running. However the impact of running injuries in relation to other reasons for discontinued running remains to be investigated. Objective To investigate the proportion of novice runners that sustained an injury before discontinuing running. Design Observational prospective cohort study with a 1-year follow-up. Setting Novice runners. Participants 930 healthy novice runners, age 18–65, with less than 10 km of total running volume during the past year and no injury in the lower extremities or back 3 months preceding baseline. Interventions The participants were equipped with a GPS watch and running shoes and instructed to upload their running to a web-based diary during the 1-year follow-up. They could keep the shoes and watch if they completed a total of 52 training sessions or more. Main Outcome Measurements Discontinued running dichotomized (i) yes still running (ii) no training uploads for the remainder of the 1 year follow up (defined after data collection began), whereas the latter, was further dichotomized into (i) injured (a priori defined as 1 week time loss definition) (ii) injury free. Results A total of 9% (7%–11%) had discontinued running after 90 days. Of these, 20% (11%–29%) had sustained a running injury. After 180 days the proportion discontinuing rose to 16% (14%–18%). Amongst these 16%, injured accounted for 24% (17%–31%). Finally, after 270 days the proportion who discontinued was 27% (24%–30%), with an injury proportion of 23% (18%–28%). Conclusions Running injuries are common in novice runners who discontinue running. The developments of injury prevention strategies are important if more inactive persons should be successfully included in running.
A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide (EC) followed by docetaxel (D) with or without celecoxib (Cx) or trastuzumab (Tr) according to HER2 status, as primary chemotherapy (PCT) for localized invasive breast cancer (BC) patients (pts): results of the planned interim analysis
Authors: Brigitte Sigal-Zaffrani, Marie-Christine Mathieu, Philippe Bertheau, Jean Marc Guinebretiere, Jean-Yves Pierga, Suzette Delaloge, Marc Espie, Etienne Brain, Patricia De Cremoux, Frederique Spyratos, Michel Marty, Bernard Asselain
Journal: Cancer Research (2007)

3511  Aims: (1) to assess antitumor activity of sequential EC (75/750 mg/m²) q3w x 4 followed by D (100 mg/m²) q3w x 4, with the randomized addition of Cx (Her2-ve pts) or Tr (Her2+ve pts) vs no additional treatment, in terms of externally reviewed pathological complete response (pCR, defined as absence of residual invasive breast carcinoma and of nodal involvement,)on the first 170 pts randomized form may 2004 to april 2006 , and (2) to correlate these responses to Circulating tumour cells (CTC) , gene expression profile (GEP) (RTPCR, DNA array), p53 function (Yeast functional assay),  Results (table 1)  Discussion:  This planned interim ITT analysis (Fleming’s sequential design) confirms that presurgical addition of Tr to D in ECD sequence improves the pCR rate,yet not to the extent reported with a protracted co-administration before surgery (JCO 23:3676). We also observed a lower pCR rate than previously described with similar PCT. CTC lack sensitivity and specificity due to the low number of detected cells (median 1.5/ml).Ongoing analysis of p53 mutations - a major predictor of pCR with anthracycline-based chemotherapy - and of GEP will be reported and should help clarifying these apparent discrepancies.  Supported by PHRC AOM/2002/02117, Pfizer Inc., Roche Pharma, Sanofi-Aventis
P09.51 Simultaneous application of TTFields (Optune®) and radiation in a 60-year old male patient: a case report
Authors: S. Scharl, O. Kölbl
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM) is the most abundant primary brain tumor and among the deadliest cancers. Standard treatment consists of maximal safe surgery, concomitant radio chemotherapy and adjuvant temozolomide treatment. Nonetheless most patients suffer from recurrent disease and short overall survival. Therefore, new efficient treatment options are needed. Optune is a novel treatment modality shown to be superior in a large clinical phase III trial. Clinical implications and preclinical data indicate that early and concomitant application of Optune might improve clinical outcome. Materials and Methods: We present a 60-year old male patient diagnosed with GBM in the left postcentral region. Initial treatment consisted of surgery and postoperative radio-chemotherapy referring to the Stupp-Protocol. Optune treatment was initiated concurrent to adjuvant chemotherapy. Progression occurred after 4 cycles of temozolomide. Treatment with Optune was conducted throughout stereotactic radiotherapy treatment. The treatment plan was carried out according to standard protocol. Radiation was administered in 6 fractions. Cone-Beam-CT was used to verify and correct patient positioning. Optune transducer arrays were only taken off for one fraction during radiation therapy. Results: The combination therapy was feasible and safe. No adverse effects, others than expected could be observed. Besides artefacts in the CT for treatment planning due to the Transducer Arrays, we could proceed with the radiation therapy. Conclusions: Here we report the first case of radiotherapy with concomitant Optune treatment. Radiation with concomitant Optune seems to be feasible and safe. Together with the preclinical findings, our case implicates a new treatment scheme for the treatment of GBM. Clinical trials with larger patient numbers are needed to evaluate safety and efficacy developing the concomitant use of radiation and Optune as new treatment option and potentially improve the outcome of patients with GBM.
P12.25 Venous thromboembolism (VTE) after meningioma resection, a retrospective case series
Authors: I. S. Muskens, D. J. Cote, M. L. D. Broekman, W. B. Gormley, L. S. Aglio, I. F. Dunn, T. R. Smith
Journal: Neuro-Oncology (2017)

Introduction: All patients undergoing craniotomies have a considerable risk of developing Venous Thromboembolisms (VTE), deep venous thrombosis (DVT) and pulmonary embolism (PE), postoperatively. The incidence of VTE post meningioma resection reportedly ranges from 2.5% to 8.2%. The aim of this study is to evaluate the incidence and associated factors of VTE in meningioma patients at a single institution between 2005-2016. METHODS: After IRB approval, 1211 consecutive meningioma resections in 1105 patients between January 2005 and August 2016 were retrospectively reviewed. From the hospital’s Research Patient Data Registry, age, ethnicity, gender, tumor location and WHO grade were extracted for all patients with a pathologically proven meningioma. Furthermore, International Code of Disease (ICD) codes for VTE, PE, intracranial hemorrhage, coagulation disease, history of VTE and Vena Cava Filter placement were also extracted and used for statistical analysis. All ICD recorded complications were double checked in the patient records. Results: Of the 1211 procedures, 48 (4.0%) were complicated by VTE, 13 (1.1%) by PE and 9 (0.9%) by an intracranial hemorrhage that required a craniotomy. In a multivariate logistic regression model including increased age (65 years or older), history of VTE and gender, only older age (OR: 2.096, 95%-CI: 1.162-3.780, p=0.014) and history of VTE (OR: 3.597, 95%-CI: 1.303-9.829, p=0.013) were significantly associated with development of VTE. In multivariate logistic regression analysis, a coagulation disorder was associated with higher incidence of PE (OR: 12.375 95%-CI: 1.434-106.794, p=0.022) and intracranial hemorrhage that required re-craniotomy (OR: 15.875, 95%-CI: 1.698-130.283, P=0.19). CONCLUSION: 4% of the patients operated for meningioma presented post-operatively with clinically relevant VTEs. Patients with a history of VTE are at risk for development of VTE after craniotomy. Coagulopathy is a risk factor for post-operative PE and surgical intracranial hematoma.
Novel Evidence That Hematopoietic-Specific PLC-β2 Is Required for Normal Homing and Engraftment of Hematopoietic Stem Cells
Authors: Mateusz Adamiak, Ahmed Abdelbaset Ismail, Ahmed Abdel-Latif, Janina Ratajczak, Magdalena Kucia, Mariusz Z Ratajczak
Journal: Blood (2016)
Urban-Rural Differences in Diabetes in China
Authors: Haoyu Wang, Yaxin Lai
Journal: JAMA (2017)

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Medicare Part D Payments for Topical Steroids
Authors: Hannah Song, Adewole Adamson, Arash Mostaghimi
Journal: JAMA Dermatology (2017)

Rising pharmaceutical costs in the United States are an increasing source of financial burden for payers and patients. Although topical steroids are among the most commonly prescribed medications in dermatology, there are limited data on steroid-related spending and utilization.To characterize Medicare and patient out-of-pocket costs for topical steroids, and to model potential savings that could result from substitution of the cheapest topical steroid from the corresponding potency class.This study was a retrospective cost analysis of the Medicare Part D Prescriber Public Use File, which details annual drug utilization and spending on both generic and branded drugs from 2011 to 2015 by Medicare Part D participants who filled prescriptions for topical steroids.Total and potential Medicare and out-of-pocket patient spending. Costs were adjusted for inflation and reported in 2015 dollars.Medicare Part D expenditures on topical steroids between 2011 and 2015 were $2.3 billion. Patients' out-of-pocket spending for topical steroids over the same period was $333.7 million. The total annual spending increased from $237.6 million to $775.9 million, an increase of 226.5%. Patients' annual out-of-pocket spending increased from $41.4 million to $101.8 million, an increase of 145.9%. The total number of prescriptions were 7.7 million in 2011 and 10.6 million in 2015, an increase of 37.0%. Generic medication costs accounted for 97.8% of the total spending during this time period. The potential health care savings and out-of-pocket patient savings from substitution of the cheapest topical steroid within the corresponding potency class were $944.8 million and $66.6 million, respectively.Most topical steroids prescribed were generic drugs. There has been a sharp increase in Medicare and out-of-pocket spending on topical steroids that is driven by higher costs for generics. Use of clinical decision support tools to enable substitution of the most affordable generic topical steroid from the corresponding potency class may reduce drug expenditures.
Recent Sex Chromosome Divergence despite Ancient Dioecy in the Willow Salix viminalis
Authors: Pascal Pucholt, Alison E. Wright, Lei Liu Conze, Judith E. Mank, Sofia Berlin
Journal: Molecular Biology and Evolution (2017)

Sex chromosomes can evolve when recombination is halted between a pair of chromosomes, and this can lead to degeneration of the sex-limited chromosome. In the early stages of differentiation sex chromosomes are homomorphic, and even though homomorphic sex chromosomes are very common throughout animals and plants, we know little about the evolutionary forces shaping these types of sex chromosomes. We used DNA- and RNA-Seq data from females and males to explore the sex chromosomes in the female heterogametic willow, Salix viminalis, a species with ancient dioecy but with homomorphic sex chromosomes. We detected no major sex differences in read coverage in the sex determination (SD) region, indicating that the W region has not significantly degenerated. However, single nucleotide polymorphism densities in the SD region are higher in females compared with males, indicating very recent recombination suppression, followed by the accumulation of sex-specific single nucleotide polymorphisms. Interestingly, we identified two female-specific scaffolds that likely represent W-chromosome-specific sequence. We show that genes located in the SD region display a mild excess of male-biased expression in sex-specific tissue, and we use allele-specific gene expression analysis to show that this is the result of masculinization of expression on the Z chromosome rather than degeneration of female-expression on the W chromosome. Together, our results demonstrate that insertion of small DNA fragments and accumulation of sex-biased gene expression can occur before the detectable decay of the sex-limited chromosome.
SNS-032 is a potent and selective inhibitor of CDK2, 7 and 9 and induces cell death by inhibiting cell cycle progression and the expression of antiapoptotic proteins
Authors: Samer J. Nuwayhid, Jennifer Hyde, Alexey Aleshin, Duncan H. Walker, Michelle R. Arkin
Journal: Cancer Research (2006)

2079  The cell cycle-regulated CDKs, CDK1, 2, and 4 have been extensively studied as potential therapeutic targets in cancer. Recent research has additionally underscored the potential role of several constitutively active CDKs including CDK7 and 9 as cancer targets. Phosphorylation of the c-terminal domain (CTD) of RNA Polymerase II by CDK7 and 9 are critical steps in transcriptional regulation. Inhibition of these kinases is predicted to have the greatest effect on the expression of proteins with short T \(\frac{1}{2}\)  and short-lived mRNA, including proteins involved in apoptotic regulation. CDK7 also activates cell-cycle CDKs 1, 2, 4 and 6. SNS-032 (formerly BMS-387032) has previously been described as a selective inhibitor of CDK2 with potent antitumor activity in animal models. Here we show that in addition to inhibition of CDK2, SNS-032 also inhibits CDK7/cyclinH and CDK9/cyclinT at low nanomolar concentrations in biochemical assays. The compound is highly selective for CDK inhibition; in a panel of 208 kinases, only four non-CDK proteins were inhibited by >50% at 1 μM SNS-032. The cellular pharmacology of SNS-032 mirrors the biochemical data. Cells treated with SNS-032 show a rapid cell cycle arrest and onset of cell death that corresponds with inhibition of multiple substrates of CDK2, 7, and 9. For instance, inhibition of pRb phosphorylation, accumulation of cyclin E protein, and cell-cycle arrest at G1 and G2 are observed in multiple cell lines in a time- and dose-dependent manner, consistent with inhibition of CDK2 and CAK. Furthermore, SNS-032 inhibits CDK9-mediated phosphorylation of Ser2 in the CTD with an IC50= 20 nM. Corresponding with inhibition of RNA polymerase II, the short half-life, anti-apoptotic protein Mcl-1 is rapidly depleted from cells, coincident with the phosphorylation of p53. Expression of Mcl-1 is a candidate predictor of aggressive disease and resistance to chemotherapy in CLL and is essential for survival of B-cell lymphoma and multiple myelomas, supporting the use of SNS-032 as a treatment for these diseases. SNS-032, a selective inhibitor of multiple CDKs involved in apoptosis and cell cycle regulation, has potential for antitumor activity in both solid and hematological cancers. SNS-032 is currently in phase 1 clinical studies.