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

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi78
Author(s):  
Tadeusz Wroblewski ◽  
Philip Tatman ◽  
Anthony Fringuello ◽  
Sam Scherer ◽  
William Foreman ◽  
...  
Keyword(s):  
Survival Time ◽  
High Throughput ◽  
Great Promise ◽  
Hdac Inhibition ◽  
Average Survival Time ◽  
Egfr Inhibition ◽  
Average Survival ◽  
Tumor Viability ◽  
Effective Compound ◽  
Grade Iii

Abstract 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.

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

2020 ◽  
Vol 7 (2) ◽  
pp. 107-112
Author(s):  
Marian Manciu ◽  
Sorour Hosseini ◽  
Joscelyne Guzman-Gonzalez
Keyword(s):  
Survival Time ◽  
Maximum Entropy ◽  
Time Difference ◽  
Reliable Estimate ◽  
Average Survival Time ◽  
Sample Number ◽  
Time To Event Data ◽  
Entropy Estimator ◽  
Average Survival ◽  
The Difference

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).

Chick survival in the megapode Alectura lathami (Australian brush-turkey)

2002 ◽  
Vol 29 (5) ◽  
pp. 503 ◽  
Author(s):  
Ann Göth ◽  
Uwe Vogel
Keyword(s):  
Survival Time ◽  
Survival Rates ◽  
Chick Survival ◽  
Average Survival Time ◽  
Kaplan Meier ◽  
Average Survival ◽  
Introduced Predators ◽  
Management Plans ◽  
Alectura Lathami ◽  
Breeding Seasons

Megapode chicks live independently from the time of hatching and are thus ideal subjects for investigations into how the lack of parental care can affect chick survival. Here, we present such results for chicks of the Australian brush-turkey (Alectura lathami), radio-tracked in two smallremnant rainforest patches (Mary Cairncross Rainforest Park and Aplin Forest) from their second day of life. Mortality was 88–100% during the first three weeks after hatching. It did not differ between two breeding seasons at Mary Cairncross Rainforest Park, as evident from comparisons of average survival time (in days) and Kaplan–Meier survival estimates. Survival differed, though, between the two sites in the same breeding season: the average survival time was significantly higher at Aplin Forest (8 days compared with 3�days) and the Kaplan–Meier survival estimates decreased less sharply. Predation by cats and birds of prey exerted the greatest influence on survival, but the proportion of deaths caused by these two predators was approximately the same at both sites. The main factor affecting survival was obviously the availability of thickets, which were more abundant at Aplin Forest. The survival rates of chicks released in thickets was significantly higher than of those released in the rainforest, presumably because they were better protected from predators. For chicks living in thickets the likelihood of being killed was lower than expected, but it was higher for those remaining in rainforest. On the basis of these results, we propose that management plans for endangered megapodes should include the identification and protection of large protective thicket habitats for enhancing overall chick survival, apart from controlling introduced predators such as feral cats.

scholarly journals Significance of serum tumor markers monitoring in carcinomas of unknown primary site

2010 ◽  
Vol 67 (9) ◽  
pp. 723-731 ◽  
Author(s):  
Ivica Pejcic ◽  
Svetislav Vrbic ◽  
Sladjana Filipovic ◽  
Mirjana Scekic ◽  
Ivan Petkovic ◽  
...  
Keyword(s):  
Survival Time ◽  
Tumor Markers ◽  
Primary Site ◽  
Ca 125 ◽  
Unknown Primary ◽  
Unknown Primary Site ◽  
Average Survival Time ◽  
Primary Tumors ◽  
Serum Tumor Markers ◽  
Average Survival

Background/Aim. Unknown primary tumors represent a heterogeneous group of malignancies that are indicative of ominous prognosis. Cancer of unknown primary site (CUP) is defined as the lack of any detectable primary site after full evaluation, and accounts for approximately 3-5% of all newly diagnosed patients with malignancies. The aim of this report was to present the prognostic and predictive value of 8 serum tumor markers in this group of patients. Methods. The study involved 63 patients. On histological examination, all the patients were presented with metastatic tumors whose primary site (origin) could not be detected with noninvasive diagnostic techniques. Following the routine light microscopy, all histological findings were classified into one of the following three groups: plano-cellular carcinoma - 8 patients; adenocarcinoma - 33 patients; unclassifiable (undifferentiated) carcinoma - 22 patients. In all the cases we evaluated 8 serum tumor markers: alpha-fetoproteins (AFP), chronic gonadotrophin beta submit, human (beta-HCG), neuron specific enolase (NSE), marker of malignant ovarian tumors (CA 125), prostate-specific antigene (PSA), marker of malignant brest tumor (CA 15-3), marker of malignant pancreas tumor and gastrointestinal tumor (Ca 19-9), carcinoembryonic antigen (CEA) at the time of diagnosis. The patients on chemotherapy had the markers determined after the third and sixth chemocycle, i.e. at the time of illness progression observation, if present. The patients responding to chemotherapy with complete response (CR), partial response (PR) or stable disease (SD) had the markers determined after three-month periods until the time of relapse or progression. Chemotherapy was applied in 32 patients (20 females and 12 males), aged 29-70 years, who met the inclusion criteria. The following chemotherapy regimen was used: doxorubicin 50mg/m2 (day 1), cisplatin 60mg/m2 (day 1), and etoposide 120 mg/m2 (days 1-3). The period between two chemotherapy cycles was three weeks, and maximum five weeks in the case of prolonged hematological toxicity. Results. Most commonly elevated were NSE values (82.54%), while AFP values were least commonly elevated (11.11%). Average survival time was 17.89 months (95%CI 12.96; 22.83). The probability of 24 months' survival was 0.228. The group of 32 patients treated with chemotherapy had 12 (37.5%) fatal outcomes in the observed period (72 months). Average survival time was 26.6 months (95% CI 19.5; 33.7). Average tumor marker values before and after the chemotherapy were significantly lower for NSE and CA 125. Survival was significantly better in cases of NSE and CA 125 decrease of more than 20%. Conclusion. Increased values of serum tumor markers are very often in CUP. The tumors show nonspecific overexpression of tumor markers. The NSE and CA 125 levels show good correlation with response to the given chemotherapy. However, a routine evaluation of commonly used serum tumor markers has not been proven of any prognostic and predictive assistance.

THE EFFECT OF CHLORPROMAZINE GIVEN WITH REINFUSION ON THE MORTALITY RATE FROM STANDARDIZED HEMORRHAGIC SHOCK IN THE RAT

1956 ◽  
Vol 34 (2) ◽  
pp. 217-221 ◽  
Author(s):  
G. F. Carruthers ◽  
C. W. Gowdey
Keyword(s):  
Mortality Rate ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Survival Time ◽  
Group Differences ◽  
Control Group ◽  
Control Groups ◽  
Average Survival Time ◽  
Anesthetized Rats ◽  
Average Survival

Anesthetized rats were subjected to a standardized hemorrhagic shock procedure; one group (20 animals) served as controls and another group (eight animals) was injected with chlorpromazine. The treated animals died very quickly: only one survived more than 12 hr. and none 48 hr.; the average survival time of 18 control fatalities was 14.0 hr., and two lived. Of the various cardiovascular and respiratory indices measured, only the post-reinfusion arterial pressure was different in the treated from that in the control group. Differences between the control groups in this and in an earlier series (Downie and Stevenson (1955)) can probably be accounted for by differences in the temperature of the laboratory.

DDRE-10. SCREENING OF EPIGENETIC COMPOUNDS IN GLIOMA AND GLIOBLASTOMA IDENTIFIES NOVEL THERAPEUTICS FOR THEIR POTENTIAL TREATMENT

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi76-vi76
Author(s):  
Philip Tatman ◽  
Tadeusz Wroblewski ◽  
Anthony Fringuello ◽  
Sam Scherer ◽  
William Foreman ◽  
...  
Keyword(s):  
De Novo ◽  
Hdac Inhibitors ◽  
Tumor Grade ◽  
Hdac Inhibition ◽  
Patient Gender ◽  
Average Survival ◽  
Tumor Viability ◽  
Hc Toxin ◽  
Inhibitor Compounds

Abstract BACKGROUND 28% of primary central nervous system tumors are glioma and glioblastoma. These tumors are responsible for 80% of malignant brain neoplasms and most brain tumor related deaths. Despite modern therapies, patients with grade II gliomas have an average survival of 8-15 years, while patients with grade III tumors have an average survival of 3-5 years, and patients with glioblastoma have an average survival of 12-15 months. The lack of a curative treatment for this group of tumors supports additional research and novel approaches to identify more effective therapies. METHODS In this study, we developed a high-throughput drug screen and culture system to identify epigenetic inhibitor compounds with the potential to reduce glioma and glioblastoma viability. RESULTS We screened 33 tumors: 18 glioblastoma, 8 oligodendroglioma, and 7 astrocytoma. The top three most effective compounds across the full glioma cohort were all HDAC inhibitors; in order from most effective: panobinostat (average tumor viability = 52.5% +/-14.1SD; p=2.16x10-61), LAQ824 (average tumor viability = 58.1% +/-18SD; p=1.48x10-45), and HC Toxin (average tumor viability = 64% +/-21.1SD; p= 1.16x10-33). Additionally, HDAC inhibition was also the most effective across each histopathological glioma type: astrocytoma, oligodendroglioma, and glioblastoma. UNC0631(G9a inhibitor) and JIB-04(KDM inhibitor) were the most effective compounds in the six recurrent tumors, though HDAC inhibition was still significantly effective in this group. We also evaluated drug sensitivity with respect to tumor grade, prior treatment, de novo vs progressive etiology, EGFR amplification, IDH mutation, MGMT methylation, and patient gender. CONCLUSIONS After screening a large glioma cohort against a panel of epigenetic inhibitors, we found HDAC inhibition most effectively reduced tumor viability across all histopathological types and grades. These findings require further in vivo validation.

scholarly journals THE ACCUMULATION OF IRON IN TUBERCULOUS AREAS

1932 ◽  
Vol 55 (1) ◽  
pp. 101-108 ◽  
Author(s):  
Valy Menkin
Keyword(s):  
Survival Time ◽  
Ferric Chloride ◽  
Time Of Death ◽  
Average Survival Time ◽  
Experimental Animals ◽  
Intravenous Injections ◽  
Average Survival ◽  
Series Of Experiments

Repeated intravenous injections of ferric chloride are followed by an increase in the survival time of tuberculous rabbits. In the particular series of experiments reported this increase amounts to about 78 per cent over the average survival time of control rabbits. Tuberculous animals repeatedly injected with ferric chloride increase in weight during part of the period of these injections. The level reached in the series studied markedly exceeds that attained by control rabbits. Both control and experimental animals die of generalized tuberculosis. There is no indication at the time of death of any differences in the degree of pathological involvement between the two groups of animals.

Viability of adrenocortical tissue transplanted after freezing and thawing

1955 ◽  
Vol 144 (916) ◽  
pp. 314-328 ◽  
Keyword(s):  
Survival Time ◽  
Low Temperatures ◽  
Endocrine Cells ◽  
Ovarian Tissue ◽  
Cortical Tissue ◽  
Freezing And Thawing ◽  
Average Survival Time ◽  
Salt Diet ◽  
Average Survival ◽  
Low Salt

The average survival time after bilateral adrenalectomy of rats of the N. I. M. R. hooded strain, maintained on a low salt diet and not having visible accessory tissue, was about 6 days. This survival time was usually too short to permit the establishment of an effective graft, but by feeding NaCl it could be prolonged sufficiently to enable fresh cortical tissue to form grafts which were functional in that the animals survived subsequent transference to low salt diet for 2 weeks. Exposure of the cortical tissue to low temperatures by the methods previously employed for ovarian tissue (Parkes & Smith 1953) greatly decreased the probability that it would form an effective graft, but a number of successful experiments were carried out, especially when a buffered Ringer-Locke medium containing glycerol was substituted for the glycerol-saline previously used. In all, more than a hundred functional grafts were obtained from adreno­cortical tissue which had been exposed to a temperature of — 79°C for up to 24 h. Adrenocortical cells, therefore, like many others, are not necessarily destroyed by ex­posure to low temperatures ( — 79°C), though it seems that optimal conditions are not provided by the technique evolved for gonadal endocrine cells.

scholarly journals Shared Makeup Cosmetics as a Route of Demodex folliculorum Infections

2021 ◽  
Author(s):  
Aleksandra Sędzikowska ◽  
Katarzyna Bartosik ◽  
Renata Przydatek-Tyrajska ◽  
Monika Dybicz
Keyword(s):  
Survival Time ◽  
Microscope Slide ◽  
Average Survival Time ◽  
Partial Immersion ◽  
Short Intervals ◽  
Demodex Folliculorum ◽  
Average Survival

Abstract 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.

scholarly journals Neuroadapted Yellow Fever Virus 17D: Genetic and Biological Characterization of a Highly Mouse-Neurovirulent Virus and Its Infectious Molecular Clone

2001 ◽  
Vol 75 (22) ◽  
pp. 10912-10922 ◽  
Author(s):  
Thomas J. Chambers ◽  
Michael Nickells
Keyword(s):  
Cell Culture ◽  
Survival Time ◽  
Yellow Fever ◽  
Yellow Fever Virus ◽  
Scid Mice ◽  
Fever Virus ◽  
Nucleotide Substitutions ◽  
Average Survival Time ◽  
E Protein ◽  
Average Survival

ABSTRACT A neuroadapted strain of yellow fever virus (YFV) 17D derived from a multiply mouse brain-passaged virus (Porterfield YF17D) was additionally passaged in SCID and normal mice. The virulence properties of this virus (SPYF) could be distinguished from nonneuroadapted virus (YF5.2iv, 17D infectious clone) by decreased average survival time in SCID mice after peripheral inoculation, decreased average survival time in normal adult mice after intracerebral inoculation, and occurrence of neuroinvasiveness in normal mice. SPYF exhibited more efficient growth in peripheral tissues of SCID mice than YF5.2iv, resulting in a more rapid accumulation of virus burden, but with low-titer viremia, at the time of fatal encephalitis. In cell culture, SPYF was less efficient in replication than YF5.2iv in all cell lines tested. The complete nucleotide sequence of SPYF revealed 29 nucleotide substitutions relative to YF5.2iv, and these were distributed throughout the genome. There were a total of 13 predicted amino acid substitutions, some of which correspond to known differences among the Asibi, French viscerotropic virus, French neurotropic vaccine, and YF17D vaccine strains. The envelope (E) protein contained five substitutions, within all three functional domains. Substitutions were also present in regions encoding the NS1, NS2A, NS4A, and NS5 proteins and in the 3′ untranslated region (UTR). Construction of YFV harboring all of the identified coding nucleotide substitutions and those in the 3′ UTR yielded a virus whose cell culture and pathogenic properties, particularly neurovirulence and neuroinvasiveness for SCID mice, generally resembled those of the original SPYF isolate. These findings implicate the E protein and possibly other regions of the genome as virulence determinants during pathogenesis of neuroadapted YF17D virus in mice. The determinants affect replication efficiency in both neural and extraneural tissues of the mouse and confer some limited host-range differences in cultured cells of nonmurine origin.

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