tbuckley/cabot-search huggingface dataset:
LGG-37. ASSESSMENT OF EARLY STAGE AUTOPHAGY INHIBITION IN BRAFV600E BRAIN TUMOR CELL RESPONSE TO CHEMOTHERAPY
Authors: Shadi Zahedi, Brent E Fitzwalter, Daniel L Gustafson, Andrew Morin, Michele Desmarais, Lindsey M Hoffman, Jean M Mulcahy Levy
Journal: Neuro-Oncology (2018)

We have previously shown CNS tumors with the BRAFV600E mutation are autophagy dependent and late stage autophagy inhibition improves responses to targeted BRAF inhibitors (BRAFi) in sensitive and BRAFi resistant cells. Autophagy is a multi-stage process. Progress within the field has led to the development of agents targeting both early (initiation) and late (fusion) stages. Defining the most effective means of autophagy inhibition will be vital to future clinical trials. We evaluated early stage inhibition as a potential therapy for autophagy dependent CNS tumors. BRAFi-sensitive and BRAFi-resistant AM38 and 794 cell lines were evaluated for response to pharmacologic and genetic inhibition of ULK1 and VPS34, two crucial subunits of autophagy initiation complexes, in the presence or absence of a BRAFi, Vemurafenib. Pharmacologic inhibition of these targets reduced cell survival in a dose dependent manner, irrespective of RAFi sensitivity, as monitored by short-term and long-term growth assays. shRNA knockdown of ULK1 or VPS34 confirmed this autophagy specific effect. The combination of early stage inhibition and BRAFi was synergistic and led to higher cell death following treatments. Extent of autophagy inhibition was assessed by western blot and flow cytometry. Cells exhibited reduced autophagic flux upon treatment with pharmacologic and genetic early stage autophagy inhibition confirming the effects are related to autophagy. Inhibition of ULK1 and VPS34 are potentially viable clinical targets in autophagy dependent CNS tumors. Further evaluation is needed to determine if early stage autophagy inhibition is as potent as late stage inhibition to determine the optimal clinical target for patients.
RONC-21. THE RELATIONSHIP BETWEEN VENTRICULAR SIZE AND WHOLE BRAIN IRRADIATION DOSE IN CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
Authors: Stephanie Toll, Marjorie Jones, Emi J Yoshida, Arthur Olch, Girish Dhall, Kenneth Wong
Journal: Neuro-Oncology (2018)

Advanced radiation techniques, such as intensity-modulated-radiation-therapy (IMRT), aim to limit radiation to adjoining tissues by conforming beams to a well-defined volume. In intracranial germinomas, whole-ventricular IMRT decreases the volume of radiation to surrounding parenchyma. This study examined the relationship between ventricular size and radiation dose to surrounding tissue. We retrospectively reviewed age, sex, ventricular and brain size, intended ventricular dose, and volume of brain that received 12 Gy (V12) of patients diagnosed with germ cell tumors at our institution treated with whole-ventricular IMRT over 14 years. Variables were assessed for correlation and statistical significance. Forty-seven patients were analyzed. The median whole-ventricular IMRT dose was 24 Gy with a median boost dose of 30 Gy. The median ventricular size was 234.25 cm3 and median brain volume was 1408 cm3. There was no significant difference between the means of ventricular size of suprasellar compared to pineal tumors (p=0.95). The median V12 of the brain, including the ventricles, was 58.86%. The strongest correlation was between ventricular size and V12, with a r2 of 0.472 (p<0.001). A multiple regression analysis indicated that boost dose and boost planning target volume significantly predicted the V12 (p<0.001). Although whole-ventricular IMRT limited radiation to surrounding tissue in our patient population, on average almost 60% of the brain received at least 12 Gy. This study suggests that there is a positive correlation between ventricular size and the volume of brain parenchyma receiving at least 12 Gy with minor contribution from the boost phase of treatment.
Resurgence risk for measles, mumps and rubella in France in 2018 and 2020
Authors: Guillaume Béraud, Steven Abrams, Philippe Beutels, Benoit Dervaux, Niel Hens
Journal: Eurosurveillance (2018)

Background Large measles and mumps outbreaks recently occurred throughout Europe and the United States. Aim : Our aim was to estimate and map the risk of resurgence for measles, mumps and rubella in France. Methods : We used a multi-cohort model combining seroprevalence information, vaccine coverage and social contact data. Results : The overall outbreak risk for France in 2018 was highest for mumps, remained significant for measles despite a recent measles outbreak and was low for rubella. Outbreak risks were heterogeneous between departments, as the effective reproduction numbers for 2018 ranged from 1.08 to 3.66. The seroprevalence, and therefore the risk of measles and rubella infection, differed significantly between males and females. There was a lower seroprevalence, and therefore a higher risk, for males. Infants of less than 1 year would be seriously affected in a future outbreak of measles, mumps or rubella, but the highest overall caseload contribution would come from teenagers and young adults (10–25 years old). Conclusions : The high risk for teenagers and young adults is of concern in view of their vulnerability to more severe measles, mumps and rubella disease and complications.
CRAN-03. PEDIATRIC PROLACTINOMA: INITIAL PRESENTATION, TREATMENT, AND LONG-TERM PROGNOSIS
Authors: Anika Hoffmann, Sarah Adelmann, Alexander Claviez, Hermann L Müller
Journal: Neuro-Oncology (2018)

Prolactinoma is a rare pituitary adenoma secreting prolactin. Studies on diagnostics, treatment and prognosis in pediatric prolactinoma patients are rare. PATIENTS AND We analyzed clinical presentation, response to treatment, and prognosis of 27 paediatric prolactinoma patients (10m/17f) based on patients’ records. Tumors included 6 microadenomas (tumor volume: median 0.2 cm3, range: 0.01–0.4 cm3; serum prolactin at diagnosis: median 101 ng/ml, range: 33–177 ng/ml) 15 macroadenomas (volume: median 3.3 cm3, range: 0.4–25.8 cm3; prolactin: median 890 ng/ml, range: 87–8624), and 3 giant adenomas (volume: median 44.5 cm3, range: 38.6–93.5 cm3; prolactin: median 4720 ng/ml, range: 317–10400); data for 3 patients were not available. Dopamine agonist treatment (n=22) was safe and effective, leading to reductions in tumor size (p<0.01) and prolactin levels (p<0.01). Threat to vision was the indication for decompressing surgery in 3 of 7 operated patients. No patient was irradiated. Long-term functional capacity was not impaired when compared with other sellar masses (n=235). In pediatric prolactinoma, diagnosis is based on hyperprolactinemia and imaging. Dopamine agonist treatment is effective and safe. Overall-survival and functional capacity as a measure of quality of survival were not impaired, indicating an optimistic prognosis. Surgery should be considered only in emergency situations of threatened visual function, not presenting a fast response to dopamine agonist treatment. Severe side effects of medication and lack of efficacy should be considered as contraindications.
Geographic and sociodemographic variation of cardiovascular disease risk in India: A cross-sectional study of 797,540 adults
Authors: Pascal Geldsetzer, Jennifer Manne-Goehler, Michaela Theilmann, Justine I. Davies, Ashish Awasthi, Goodarz Danaei, Thomas A. Gaziano, Sebastian Vollmer, Lindsay M. Jaacks, Till Bärnighausen, Rifat Atun
Journal: PLoS Medicine (2018)

Background Cardiovascular disease (CVD) is the leading cause of mortality in India. Yet, evidence on the CVD risk of India's population is limited. To inform health system planning and effective targeting of interventions, this study aimed to determine how CVD risk—and the factors that determine risk—varies among states in India, by rural–urban location, and by individual-level sociodemographic characteristics. Methods and findings We used 2 large household surveys carried out between 2012 and 2014, which included a sample of 797,540 adults aged 30 to 74 years across India. The main outcome variable was the predicted 10-year risk of a CVD event as calculated with the Framingham risk score. The Harvard–NHANES, Globorisk, and WHO–ISH scores were used in secondary analyses. CVD risk and the prevalence of CVD risk factors were examined by state, rural–urban residence, age, sex, household wealth, and education. Mean CVD risk varied from 13.2% (95% CI: 12.7%–13.6%) in Jharkhand to 19.5% (95% CI: 19.1%–19.9%) in Kerala. CVD risk tended to be highest in North, Northeast, and South India. District-level wealth quintile (based on median household wealth in a district) and urbanization were both positively associated with CVD risk. Similarly, household wealth quintile and living in an urban area were positively associated with CVD risk among both sexes, but the associations were stronger among women than men. Smoking was more prevalent in poorer household wealth quintiles and in rural areas, whereas body mass index, high blood glucose, and systolic blood pressure were positively associated with household wealth and urban location. Men had a substantially higher (age-standardized) smoking prevalence (26.2% [95% CI: 25.7%–26.7%] versus 1.8% [95% CI: 1.7%–1.9%]) and mean systolic blood pressure (126.9 mm Hg [95% CI: 126.7–127.1] versus 124.3 mm Hg [95% CI: 124.1–124.5]) than women. Important limitations of this analysis are the high proportion of missing values (27.1%) in the main outcome variable, assessment of diabetes through a 1-time capillary blood glucose measurement, and the inability to exclude participants with a current or previous CVD event. Conclusions This study identified substantial variation in CVD risk among states and sociodemographic groups in India—findings that can facilitate effective targeting of CVD programs to those most at risk and most in need. While the CVD risk scores used have not been validated in South Asian populations, the patterns of variation in CVD risk among the Indian population were similar across all 4 risk scoring systems.
Partial Tmem106b reduction does not correct abnormalities due to progranulin haploinsufficiency
Authors: Andrew E. Arrant, Alexandra M. Nicholson, Xiaolai Zhou, Rosa Rademakers, Erik D. Roberson
Journal: Molecular Neurodegeneration (2018)

Loss of function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD). Progranulin is a secreted glycoprotein that localizes to lysosomes and is critical for proper lysosomal function. Heterozygous GRN mutation carriers develop FTD with TDP-43 pathology and exhibit signs of lysosomal dysfunction in the brain, with increased levels of lysosomal proteins and lipofuscin accumulation. Homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis (NCL), an earlier-onset lysosomal storage disorder caused by severe lysosomal dysfunction. Multiple genome-wide association studies have shown that risk of FTD in GRN mutation carriers is modified by polymorphisms in TMEM106B, which encodes a lysosomal membrane protein. Risk alleles of TMEM106B may increase TMEM106B levels through a variety of mechanisms. Brains from FTD patients with GRN mutations exhibit increased TMEM106B expression, and protective TMEM106B polymorphisms are associated with decreased TMEM106B expression. Together, these data raise the possibility that reduction of TMEM106B levels may protect against the pathogenic effects of progranulin haploinsufficiency. We crossed Tmem106b +/− mice with Grn +/− mice, which model the progranulin haploinsufficiency of GRN mutation carriers and develop age-dependent social deficits and lysosomal abnormalities in the brain. We tested whether partial Tmem106b reduction could normalize the social deficits and lysosomal abnormalities of Grn +/− mice. Partial reduction of Tmem106b levels did not correct the social deficits of Grn +/− mice. Tmem106b reduction also failed to normalize most lysosomal abnormalities of Grn +/− mice, except for β-glucuronidase activity, which was suppressed by Tmem106b reduction and increased by progranulin insufficiency. These data do not support the hypothesis that Tmem106b reduction protects against the pathogenic effects of progranulin haploinsufficiency, but do show that Tmem106b reduction normalizes some lysosomal phenotypes in Grn +/− mice.
Population Genomics Provide Insights into the Evolution and Adaptation of the Eastern Honey Bee (Apis cerana)
Authors: Chao Chen, Huihua Wang, Zhiguang Liu, Xiao Chen, Jiao Tang, Fanming Meng, Wei Shi
Journal: Molecular Biology and Evolution (2018)

The mechanisms by which organisms adapt to variable environments are a fundamental question in evolutionary biology and are important to protect important species in response to a changing climate. An interesting candidate to study this question is the honey bee Apis cerana, a keystone pollinator with a wide distribution throughout a large variety of climates, that exhibits rapid dispersal. Here, we resequenced the genome of 180 A. cerana individuals from 18 populations throughout China. Using a population genomics approach, we observed considerable genetic variation in A. cerana. Patterns of genetic differentiation indicate high divergence at the subspecies level, and physical barriers rather than distance are the driving force for population divergence. Estimations of divergence time suggested that the main branches diverged between 300 and 500 Ka. Analyses of the population history revealed a substantial influence of the Earth's climate on the effective population size of A. cerana, as increased population sizes were observed during warmer periods. Further analyses identified candidate genes under natural selection that are potentially related to honey bee cognition, temperature adaptation, and olfactory. Based on our results, A. cerana may have great potential in response to climate change. Our study provides fundamental knowledge of the evolution and adaptation of A. cerana.
LGG-04. UNIFORM VOLUMETRIC MEASURES OF CROSS-PLATFORM MRI ACQUISITIONS IN NF1 OPTIC PATHWAY GLIOMAS: APPLICATION OF DEEP LEARNING TECHNIQUES TO MULTI-CENTER CLINICAL TRIALS
Authors: Awais Mansoor, Robert Avery, Nicholas Stence, Michael Fisher, Emily McCourt, Roger Packer, Nicholas Foreman, Marius Linguraru
Journal: Neuro-Oncology (2018)

To develop a fully automated segmentation application that provides comprehensive volumetric measures of optic pathway gliomas secondary to neurofibromatosis type 1 (NF1-OPG) and can accommodate diverse MRI acquisition protocols and platforms from multi-center clinical trials. High-resolution volumetric T1-weighted brain MRI sequences, acquired as part of routine clinical care in children with NF1-OPG, were gathered from three institutions, each using a different MRI acquisition manufacturer’s platform: Children’s National Health System (CNHS; General Electric), Children Hospital of Philadelphia (CHOP; Siemens), and Children’s Hospital Colorado (CHC; Philips). Volumetric measures of anterior visual pathway (AVP; optic nerves, chiasm, and tracts) were calculated using our novel fully automated segmentation and analysis method. This method utilizes a deep learning convolutional neural network architecture that captures image context and localizes the AVP in MRI of the brain. Once trained, the automated pipeline takes less than 10 seconds for the complete quantification of AVP on a GPU-enabled computer. The average overlap between manual and automated segmentation (DICE score) as well as the volume error was calculated using eight-fold validation criteria across MRI platforms. Thirty-two datasets met the inclusion criteria (CNHS=13, CHOP=13, CHC=6). The average voxel size differed across sites: CNHS (0.47 × 0.47 × 0.5 mm), CHOP (0.82 × 0.82 × 0.9 mm), and CHC (0.34 × 0.34 × 0.5 mm). The preliminary DICE score was 0.658 ± 0.052 with a volume error of 0.864 ± 0.476 ml (9.44 ± 8.19%). Using deep learning technology, our fully automated segmentation application has potential to provide volumetric measures of NF1-OPGs that can accommodate cross-platform MRI acquisition protocols used in clinical trials.
What is the best measure for rewarding quality of care: Defect-free vs. composite scoring? An analysis from the American Heart Association's Get With the Guidelines-Coronary Artery Disease (GWTG-CAD) Program
Authors: A Hernandez, G Fonarow, D Dai, S O'Brien, Kenneth LaBresh, L Schwamm, C Cannon
Journal: Journal of the American College of Cardiology (2007)
Strategies to Prevent Obesity-Related Cancer—Reply
Authors: Greta M. Massetti, William H. Dietz, Lisa C. Richardson
Journal: JAMA (2018)

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Cost of illness for colorectal cancer at low middle income countries Egypt case
Authors: A. Abotaleb
Journal: Annals of Oncology (2018)

Introduction: According to international statistics colorectal cancer (CRC) is the third most common cancer. Two-thirds of all colorectal cancers occur in the more developed regions of the world. Egypt with the population with 100 million people (CRC) may represent a pressure on health care system and developing some questions need answers like: Are the polices for CRC treatment efficient for the health care system? Does health care system need new treatments? What is the outcome for present treatment polices? The objective of this study is to estimate the total medical cost of illness (CRC) to improve understanding of the economic consequences of different health-care policies from the payer prospective for the last 3 years with analysis of treatments used. Methods: Data from patients aged (18 -60 years) for the last 3 years including direct and indirect health care costs for conventional treatment as it was not including (cost of treatment, complications including, Rehabilitation. Metastatic, outpatients costs). The total (n) of patients enrolled in the national database =20389 weighted average method was used for calculations for cost and consequences. The value of lost productivity using Egyptian estimates for the value of a statistical life year (VSLY). Outcomes was calculated in form of QALY. Several methods were employed to reach an average. Value for a QALY: lost production represented by actual per capita annual proEarnings based on the average national salary and VSLY. Lost production: annual productivity was calculated by dividing the gross domestic product (GDP) by the labour force (ages 20–65). GDP in 2012 came from the World Bank, and the labour force came from CAPMAS. Lost earning: average annual salary was calculated from CAPMAS for the year 2012, and adjusted by the annual salary increase. VSLY: The value of a statistical life (VSL) in Egypt was calculated from the average of the following methods: (a) Examining the ratio between GDP per capita in Egypt to countries with published GDP and VSLductivity of the labour force, lost Uncertainty Analyses: To test the stability of our results to variation in the estimates of the input model parameters, one-dimensional sensitivity analyses were performed. Results: Mean direct cost for CRC is amounted (610) Dollar per patient per year 80% of total expenditures where chemotherapy, surgery represent 4.7% of expenditures and radio therapy represents 1.7%. Costs increase in the metastatic phase than primary phase QALY gained for metastatic patients receiving biological treatment was 1.9 QALY versus .4 QALY with conventional chemotherapy. Conclusion: Reforming treatment polices for CRC in Egypt become a need the new polices should include Early detecting programs reimbursement for of Biological products after establishing treatment guidelines based on multiple criteria including (socioeconomic impact, economic values, efficacy parameters).
MBRS-13. DEVELOPMENT OF NANOPARTICLES WITH ‘IMPROVED DRUG LOADING’ FOR LOCAL DELIVERY TO THE BRAIN IN THE TREATMENT OF MEDULLOBLASTOMA
Authors: Rashidat Animasawun, David Walker, Martin Garnett
Journal: Neuro-Oncology (2018)

Poor CNS penetration by cancer drugs limits their application in sensitive brain tumours such as medulloblastoma. An alternative approach, delivering drugs directly to residual tumour using nanoparticulate delivery systems (NPDS) could reduce some of these problems. The main challenges hindering the clinical translation of the use of NPDS for local delivery of drugs to the residual tumour are inadequate drug loading and erratic release. This study focusses on understanding the conditions required for the development of a NPDS with sufficient drug loading for post-surgical delivery to the residual tumour. This was done by selecting known effective drugs; Etoposide, etoposide phosphate and teniposide and matching them with modified poly (glycerol) adipate based polymers based on the interactions observed between them. Fourier transform infra-red spectroscopy (FTIR), contact angle measurements and drug release experiments have been used to screen the drugs and substituted PGA based polymers. Based on the interactions observed, polymers were matched with the specific drugs. Two types of drug nanoparticles were prepared from these combinations. Drug loaded matrix polymer nanoparticles (NP) were prepared by an interfacial deposition method and a novel process of applying a polymer coating to drug nanoparticles, polymer coated drug nanoparticles (PCDNP) was also developed. The following drug loading results were obtained for etoposide (NP: 5%, PCDNP: 77%) and teniposide (NP: 23%, PCDNP: 32%). This systematic approach to monitor drug and polymer interactions to match polymers to drugs resulted in the formulation of nanoparticles with higher drug loading.