DDRE-20. HIGH-THROUGHPUT SCREENING OF FDA-APPROVED COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS

BACKGROUND Glioma and glioblastoma comprise 28% of all primary central nervous system tumors and cause the majority of primary brain tumor deaths. Despite substantial research into the molecular pathogenesis and genetic landscape of glioma, no currently approved therapies are curative for any glioma or glioblastoma. Patients with glioblastoma have an average survival time of 12-15 months, while patients with grade III gliomas have an average survival time of 3-5 years, and patients with grade II gliomas have an average survival time of 8-15 years. The lack of a curative treatment for these tumors necessitates additional research into novel therapies. METHODS In this study, we developed a high-throughput drug screen and culture system to identify existing FDA-approved therapies with the potential to inhibit glioma viability. RESULTS In total, we screened 39 tumors: 21 glioblastoma, 10 oligodendroglioma, and 8 astrocytoma. Carfilzomib was the most effective compound across the cohort, decreasing the average tumor viability to 39.0% +/- 16.5%SD. Regardless of tumor grade, MGMT methylation, EGFR amplification, tumor recurrence and etiology, tumor histology, prior treatment, and patient gender, carfilzomib significantly reduced cell viability in every tumor; though was not necessarily the most effective compound in each of these groups. We found HDAC inhibition to be the most effective treatment in grade 1 astrocytomas. However, HDAC inhibition was surpassed by carfilzomib and RNA transcription inhibitors in all higher grades. Interestingly, EGFR inhibition, while significantly effective in 36 tumors, was consistently less effective than carfilzomib across the cohort, though did surpass the effectiveness of HDAC inhibition in grade III gliomas. CONCLUSIONS FDA approved compounds can effectively inhibit glioma tumor viability. Specifically, carfilizomib holds great promise. Further in vivo studies are needed to confirm these findings.

Prion diseases: fatal familial insomnia

Introduction. Fatal familial insomnia (FFI) is one of the transmissible spongiform encephathalopathies characterized by neuronal loss, sleep impairment, subsequent non-specific disturbances of autonomic nervous system (e.g. tachycardia) and endocrine dysfunctions. It is fatal autosomal dominant prion disease, which is extremaly rare- FFI affects only about one person per milion annually. The aim of this study is to review the literature and systematize knowledge about fatal familial insomnia.Brief description of the state of knowledge. The causative agent of this disease is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. Major vulnerable regions in FFI are mediodorsal and anterior ventral nuclei of the thalamus. Average survival time after the onset of symptoms is 18 months. Hence molecular mechanisms involved in pathogenesis are poorly understood, the disease is incureable yet. However, there are a number of therapeutic options currently under investigation, e.g. immunotherapy or doxycycline usage.Conclusions. Subsequent researches are essential to improve understending of fatal familial insomnia. The prime issue is to develop functioning therapeutic or preventive treatment. While some of presented terapeutic approches appers promising, all of them require profoud research.

Risk and Clinical Significance of Idiopathic Preterm Birth in Microvillus Inclusion Disease

Microvillus inclusion disease (MVID) is a rare enteropathy caused by mutations in the MYO5B or STX3 gene. MVID is a disease that is difficult to manage with clinical heterogeneity. Therefore, knowledge about factors influencing MVID morbidity and mortality is urgently needed. Triggered by a recent study that reported a high percentage of preterm births in twelve cases of MVID, we have conducted a comprehensive retrospective study involving 88 cases of MVID with reported gestational ages. We found that moderate to late preterm birth occurred in more than half of all cases, and this was particularly prominent in MYO5B-associated MVID. Preterm birth in MVID counterintuitively correlated with higher birth weight percentiles, and correlated with higher stool outputs and a significantly shorter average survival time. Data from this study thus demonstrate an increased risk of preterm birth in MYO5B-associated MVID, with a clinical impact on morbidity and mortality. Adverse effects associated with preterm birth should be taken into account in the care of children diagnosed with MVID. Documentation of gestational age may contribute to a better prognostic risk assessment in MVID.

Spinal metastasis of bronchopulmonary cancer: Interest of a Spine surgery and prognostic scales value

Backgroundlung cancer is the first mortality cause by cancer around the world. Bones metastasis occurrence is a common eventuality in case of lung cancer (40% at the diagnosis). In order to evaluate the indications and measure the effectiveness of surgery in the management of PBC spinal metastases, we report a series of 52 patients.MethodsDuring 6 years, from January 2009 to December 2014 at the Neurosurgery Unit of Marseille North Hospital (France), we studied retrospectively 52 patients records, who underwent a surgery for spinal metastasis of lung cancer. The study was only about patients which metastases were surgically treated. We used Stata software for the computation, and concerning the linear regression, all values under 0.1 were considered significant.Resultsthe average age was 63.6 years (39–80 years) with a sex ratio of 3. Non-small cell lung cancer was the most common, ie 36 cases (69.2%). Rachialgia associated to vertebral fracture with medullar compression was the most common clinical presentation (31 cases or 59.6%). SINS score (spinal instability neoplastic score) was equal or above 7 in 41 cases (78.9%). The general condition (Karnofski) was medium in 35 cases (67.4%). Survival prediction beyond 12 months was null according to Tokuhashi Index. The surgical indication was essentially palliative. Evolution was characterised by painful symptomatology regression in 44 cases (84.6%), stabilization of initially unstable lesion and motor deficit improvement in 48.3 % of cases. The average survival time following the surgery was 16 months.ConclusionOur results show the interest of surgery for pain relief and spinal stabilization in patient with spinal metastasis of lung cancer, and the relativity of predictive survival score.

Shared Makeup Cosmetics as a Route of Demodex folliculorum Infections

Purpose The aim of the study was to examine Demodex survival in makeup cosmetics, i.e., powder cream, mascara, and lipstick, and to determine whether cosmetics shared with others can be a source of D. folliculorum infection. Methods Live D. folliculorum adults were placed in cosmetic samples and their motility was observed under a microscope. The mites were fully or partially immersed in the powder cream and lipstick, and only partially immersed in the mascara. Partial immersion means that only the opisthosoma was covered by the cosmetic, whereas the gnathosoma and podosoma had no contact with the cosmetic. Cessation of motility was regarded as a sign of death. Results In the control (mites placed on a microscope slide with no cosmetics), the survival time was 41.2 h. D. folliculorum that were immersed fully or partially in the lipstick substrate were viable for 38.5 h and 148 h, respectively. The survival time of the mites at full and partial immersion in the powder cream was 0.78 h and 2.16 h, respectively. The average survival time in the mascara was 21 h. Conclusions Makeup cosmetics used by different individuals at short intervals (from several hours to several days) can be a source of transmission of Demodex sp. mites.

A Maximum Entropy Estimator for the Average Survival Time Differences between Two Groups

Background: Statistical methods commonly used in survival analysis typically provide the probability that the difference between groups is due to chance, but do not offer a reliable estimate of the average survival time difference between groups (the difference between median survival time is usually reported). Objective: We suggest a Maximum-Entropy estimator for the average Survival Time Difference (MESTD) between groups. Methods: The estimator is based on the extra survival time, which should be added to each member of the group, to produce the maximum entropy of the result (resulting in the groups becoming most similar). The estimator is calculated only from time to event data, does not necessarily assume hazard proportionality and provides the magnitude of the clinical differences between the groups. Results: Monte Carlo simulations show that, even at low sample numbers (much lower than the ones needed to prove that the two groups are statistically different), the MESTD estimator is a reliable predictor of the clinical differences between the groups, and therefore can be used to estimate from (low sample numbers) preliminary data whether or not the large sample number experiment is worth pursuing. Conclusion: By providing a reasonable estimate for the efficacy of a treatment (e.g., for cancer) even for low sample data, it might provide useful insight in testing new methods for treatment (for example, for quick testing of multiple combinations of cancer drugs).

Developing the novel bioinformatics algorithms to systematically investigate the connections among survival time, key genes and proteins for Glioblastoma multiforme

Background Glioblastoma multiforme (GBM) is one of the most common malignant brain tumors and its average survival time is less than 1 year after diagnosis. Results Firstly, this study aims to develop the novel survival analysis algorithms to explore the key genes and proteins related to GBM. Then, we explore the significant correlation between AEBP1 upregulation and increased EGFR expression in primary glioma, and employ a glioma cell line LN229 to identify relevant proteins and molecular pathways through protein network analysis. Finally, we identify that AEBP1 exerts its tumor-promoting effects by mainly activating mTOR pathway in Glioma. Conclusions We summarize the whole process of the experiment and discuss how to expand our experiment in the future.

Expression of FAP-1 Correlates with Glioblastoma Proliferation, Migration and Treatment Resistance

Background: Glioblastoma (GBM) is the most severe type of brain cancer, with an extremely high mortality rate and the average survival time less than 15 months. Almost in all GBM cases, the residual tumor cells continue to divide uncontrollably, leading to tumor re-establishment, i.e., tumor recurrence, and ultimately death. Therefore, there is an urgent need to identify critical mediators of GBM progression and resistance to therapy. Fas-associated Phosphatase-1 (FAP-1, also known as PTPN13 or PTPL1) is a member of a large protein tyrosine phosphatase family. It has been shown that FAP-1 expression is downregulated in many types of cancers, which leads to unabated signaling and tumor progression and metastasis. The aim of this study is to evaluate the role of FAP-1 in GBM progression and resistance to therapy.Methods: Cell viability assays, radiotherapy and temozolomide response assays, and Western blot were used to analysis of FAP-1 in GBM based on Oncomine.Results: Our results showed that knockdown of FAP-1 enhanced viability and migration of GBM cell lines, and importantly, increased GBM cell resistance to radiotherapy and temozolomide. Conclusions: FAP-1 is important for GBM cells, and may account for GBM resistance to therapy.

Virulence of Metarhizium brunneum (Ascomycota: Hypocreales) Strains Against Stinkbugs Euschistus heros and Dichelops furcatus (Hemiptera: Pentatomidae)

Three strains of fungi belonging to the genus Metarhizium Sorokīn (ARSEF 4556, ARSEF 3297, native strain) were assayed against adults and nymphs of the Neotropical brown stinkbug Euschistus heros (F.) and the green-belly stinkbug Dichelops furcatus (F.). The most virulent strain, ARSEF 4556, caused over 90% mortality. The average survival time of the second and fifth instar nymphs and adults following immersion in 1 × 108 conidia ml−1 was 4.8, 5.7, and 5.2 d, respectively. The second instar nymphs were more susceptible than the adults. The LC50 values and median survival times for second instar and adult E. heros were 1.6 × 107 and 3.1 × 107 conidia ml−1 and 6 and 8 d, respectively. Eggs of E. heros and the closely related stinkbug, D. furcatus, were highly susceptible to ARSEF 4556 with the mean mortality of eggs immersed in 1 × 108 conidia ml−1 being 77.4% and 89.7%, respectively. The strain 3297 showed also good aptitudes for stinkbugs control with mortalities higher than 80% against nymphs and adults and eggs mortalities of 75.5% for E. heros and 79.6% for D. furcatus. This study has shown that it is possible to have a two-pronged control strategy, targeting adults and to reduce oviposition and targeting egg clusters to prevent emergence and dispersal of nymphs. Besides early instars of nymphs have been shown to be more susceptible to the fungal strains than late instars and adults.