Clinical and multiple gene expression variables in survival analysis of breast cancer: Analysis with the hypertabastic survival model

BACKGROUND: We explore the benefits of applying a new proportional hazard model to analyze survival of breast cancer patients. As a parametric model, the hypertabastic survival model offers a closer fit to experimental data than Cox regression, and furthermore provides explicit survival and hazard functions which can be used as additional tools in the survival analysis. In addition, one of our main concerns is utilization of multiple gene expression variables. Our analysis treats the important issue of interaction of different gene signatures in the survival analysis. METHODS: The hypertabastic proportional hazards model was applied in survival analysis of breast cancer patients. This model was compared, using statistical measures of goodness of fit, with models based on the semi-parametric Cox proportional hazards model and the parametric log-logistic and Weibull models. The explicit functions for hazard and survival were then used to analyze the dynamic behavior of hazard and survival functions. RESULTS: The hypertabastic model provided the best fit among all the models considered. Use of multiple gene expression variables also provided a considerable improvement in the goodness of fit of the model, as compared to use of only one. By utilizing the explicit survival and hazard functions provided by the model, we were able to determine the magnitude of the maximum rate of increase in hazard, and the maximum rate of decrease in survival, as well as the times when these occurred. We explore the influence of each gene expression variable on these extrema. Furthermore, in the cases of continuous gene expression variables, represented by a measure of correlation, we were able to investigate the dynamics with respect to changes in gene expression. CONCLUSIONS: We observed that use of three different gene signatures in the model provided a greater combined effect and allowed us to assess the relative importance of each in determination of outcome in this data set. These results point to the potential to combine gene signatures to a greater effect in cases where each gene signature represents some distinct aspect of the cancer biology. Furthermore we conclude that the hypertabastic survival models can be an effective survival analysis tool for breast cancer patients

Elevated Tumor Lactate and Efflux in High-grade Prostate Cancer demonstrated by Hyperpolarized 13C Magnetic Resonance Spectroscopy of Prostate Tissue Slice Cultures.

Non-invasive assessment of the biological aggressiveness of prostate cancer (PCa) is needed for men with localized disease. Hyperpolarized (HP) 13C magnetic resonance (MR) spectroscopy is a powerful approach to image metabolism, specifically the conversion of HP [1-13C]pyruvate to [1-13C]lactate, catalyzed by lactate dehydrogenase (LDH). Significant increase in tumor lactate was measured in high-grade PCa relative to benign and low-grade cancer, suggesting that HP 13C MR could distinguish low-risk (Gleason score ≤3 + 4) from high-risk (Gleason score ≥4 + 3) PCa. To test this and the ability of HP 13C MR to detect these metabolic changes, we cultured prostate tissues in an MR-compatible bioreactor under continuous perfusion. 31P spectra demonstrated good viability and dynamic HP 13C-pyruvate MR demonstrated that high-grade PCa had significantly increased lactate efflux compared to low-grade PCa and benign prostate tissue. These metabolic differences are attributed to significantly increased LDHA expression and LDH activity, as well as significantly increased monocarboxylate transporter 4 (MCT4) expression in high- versus low- grade PCa. Moreover, lactate efflux, LDH activity, and MCT4 expression were not different between low-grade PCa and benign prostate tissues, indicating that these metabolic alterations are specific for high-grade disease. These distinctive metabolic alterations can be used to differentiate high-grade PCa from low-grade PCa and benign prostate tissues using clinically translatable HP [1-13C]pyruvate MR

Dynamics & Predictions in the Co-Event Interpretation

Sorkin has introduced a new, observer independent, interpretation of quantum mechanics that can give a successful realist account of the 'quantum microworld' as well as explaining how classicality emerges at the level of observable events for a range of systems including single time 'Copenhagen measurements'. This 'co-event interpretation' presents us with a new ontology, in which a single 'co-event' is real. A new ontology necessitates a review of the dynamical & predictive mechanism of a theory, and in this paper we begin the process by exploring means of expressing the dynamical and predictive content of histories theories in terms of co-events.Comment: 35 pages. Revised after refereein

Oncogenic microRNA-4534 regulates PTEN pathway in prostate cancer.

Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Statistical analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy

Pessimistic Software Lock-Elision

Read-write locks are one of the most prevalent lock forms in concurrent applications because they allow read accesses to locked code to proceed in parallel. However, they do not offer any parallelism between reads and writes. This paper introduces pessimistic lock-elision (PLE), a new approach for non-speculatively replacing read-write locks with pessimistic (i.e. non-aborting) software transactional code that allows read-write concurrency even for contended code and even if the code includes system calls. On systems with hardware transactional support, PLE will allow failed transactions, or ones that contain system calls, to preserve read-write concurrency. Our PLE algorithm is based on a novel encounter-order design of a fully pessimistic STM system that in a variety of benchmarks spanning from counters to trees, even when up to 40% of calls are mutating the locked structure, provides up to 5 times the performance of a state-of-the-art read-write lock.National Science Foundation (U.S.) (Grant 1217921

Survival Analysis of Bridge Superstructures in Wisconsin

Although survival analyses have long been used in biomedical research, their application to engineering in general, and bridge engineering in particular, is a more recent phenomenon. In this research, survival (reliability) of bridge superstructures in Wisconsin was investigated using the Hypertabastic accelerated failure time model. The 2012 National Bridge Inventory (NBI) data for the State ofWisconsin were used for the analyses. A recorded NBI superstructure condition rating of 5 was chosen as the end of service life. The type of bridge superstructure, bridge age, maximum span length (MSL) and average daily traffic (ADT) were considered as possible risk factors in the survival of bridge superstructures. Results show that ADT and MSL can substantially affect the survival of bridge superstructures at various ages. The reliability of Wisconsin superstructures at the ages of 50 and 75 years is on the order of 63% and 18%, respectively, when the ADT and MSL values are at Wisconsin’s mean values

Conditional survival analysis for concrete bridge decks

Bridge decks are a significant factor in the deterioration of bridges, and substantially affect long-term bridge maintenance decisions. In this study, conditional survival (reliability) analysis techniques are applied to bridge decks to evaluate the age at the end of service life using the National Bridge Inventory records. As bridge decks age, the probability of survival and the expected service life would change. The additional knowledge gained from the fact that a bridge deck has already survived a specific number of years alters (increases) the original probability of survival at subsequent years based on the conditional probability theory. The conditional expected service life of a bridge deck can be estimated using the original and conditional survival functions. The effects of average daily traffic and deck surface area are considered in the survival calculations. Using Wisconsin data, relationships are provided to calculate the probability of survival of bridge decks as well as expected service life at various ages. The concept of survival dividend is presented and the age when rapid deterioration begins is defined

Разработка и применение современных лабораторных методов в эпидемиологическом мониторинге, диагностики и лечении энтеровирусных инфекций

У роботі проведена порівняльна оцінка специфічності й чутливості тест-системи ПЛР, зі специфічним праймером до ДНК 207 п.н. 5'-нетрансльованої області генома энтеровируса для всіх типів ентеровірусів (крім вірусу поліомієліту) у порівнянні із класичним культуральним методом. А також методологічний підхід спільного використання вищеописаної реакції ПЦР із визначенням антитіл класу Іg до вірусів Коксаки й ЕСНО у системі ІФА діагностики, розробленої авторами, і спектр застосування розробленого комплекс.In work the estimation of specificity and sensitivity of test system PTSR, with specific primers to DNA 207 n.n is spent comparative. 5 '-not broadcast areas генома an enterovirus for all types of enteroviruses (except a poliomyelitis virus) in comparison with classical the virology a method. And also the methodological approach of sharing of above described reaction PCR with definition of antibodies of a class ІgG to viruses Cocsaki and ЕСНО in system IFA of diagnostics developed by authors, and a spectrum of application of the developed complex