Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.

BackgroundProdrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.MethodsHere we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.ResultsIn both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.ConclusionThese results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity

Pregnant women's awareness of sensitivity to cold (hiesho) and body temperature observational study: A comparison of Japanese and Brazilian women

<p>Abstract</p> <p>Background</p> <p>Sensitivity to cold (<it>hiesho</it>) is a serious health problem in Japan, yet it is minimally understood within Western cultures. The purpose of this study was to clarify the divergence between pregnant Japanese woman living in Japan and pregnant Brazilian women living in Brazil in awareness of <it>hiesho </it>and differences between core body and peripheral temperatures.</p> <p>Methods</p> <p>The subjects of this study were 230 pregnant Japanese women living in Japan and 200 pregnant Brazilian women living in Brazil. Data was collected in June/July and November 2005 in Japan and from October 2007 to February 2008 in Brazil. The survey methods consisted of measurement of deep body temperatures and questionnaires.</p> <p>Results</p> <p>67.0% of Japanese women and 57.0% of Brazilian women were aware of <it>hiesho</it>, which showed a significant difference between the Japanese and Brazilian women (p = 0.034). The difference between forehead and sole temperatures was 2.0°C among Japanese and 2.8°C among Brazilians in June-July (p = 0.01). But in November the difference between those temperatures was 5.2°C among Japanese and 2.8°C among Brazilians (p < 0.001).</p> <p>Conclusions</p> <p>There are differences between Japanese and Brazilians both in awareness of <it>hiesho </it>and in body temperatures.</p

Video Capsule Retention in a Zenker Diverticulum

We report the case of a video capsule endoscope lodged within a Zenker diverticulum. The system that was equipped with a real-time viewer showed an unchanging image unlike esophageal or gastric mucosa, suggesting that the capsule was elsewhere. The presence of cervical discomfort suggested video capsule retention in a Zenker diverticulum. The capsule was removed endoscopically and reinserted using a hood-assisted endoscope and the procedure was completed

Practical application of cure mixture model for long-term censored survivor data from a withdrawal clinical trial of patients with major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Survival analysis methods such as the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression (Cox regression) are commonly used to analyze data from randomized withdrawal studies in patients with major depressive disorder. However, unfortunately, such common methods may be inappropriate when a long-term censored relapse-free time appears in data as the methods assume that if complete follow-up were possible for all individuals, each would eventually experience the event of interest.</p> <p>Methods</p> <p>In this paper, to analyse data including such a long-term censored relapse-free time, we discuss a semi-parametric cure regression (Cox cure regression), which combines a logistic formulation for the probability of occurrence of an event with a Cox proportional hazards specification for the time of occurrence of the event. In specifying the treatment's effect on disease-free survival, we consider the fraction of long-term survivors and the risks associated with a relapse of the disease. In addition, we develop a tree-based method for the time to event data to identify groups of patients with differing prognoses (cure survival CART). Although analysis methods typically adapt the log-rank statistic for recursive partitioning procedures, the method applied here used a likelihood ratio (LR) test statistic from a fitting of cure survival regression assuming exponential and Weibull distributions for the latency time of relapse.</p> <p>Results</p> <p>The method is illustrated using data from a sertraline randomized withdrawal study in patients with major depressive disorder.</p> <p>Conclusions</p> <p>We concluded that Cox cure regression reveals facts on who may be cured, and how the treatment and other factors effect on the cured incidence and on the relapse time of uncured patients, and that cure survival CART output provides easily understandable and interpretable information, useful both in identifying groups of patients with differing prognoses and in utilizing Cox cure regression models leading to meaningful interpretations.</p

Applications of Site-Specific Labeling to Study HAMLET, a Tumoricidal Complex of α-Lactalbumin and Oleic Acid

umor cells), and its tumoricidal activity has been well established.-acetylgalactosaminyltransferase II (ppGalNAc-T2) and further conjugated with aminooxy-derivatives of fluoroprobe or biotin molecules.We found that the molten globule form of hLA and αD-hLA proteins, with or without C-terminal extension, and with and without the conjugated fluoroprobe or biotin molecule, readily form a complex with OA and exhibits tumoricidal activity similar to HAMLET made with full-length hLA protein. The confocal microscopy studies with fluoroprobe-labeled samples show that these proteins are internalized into the cells and found even in the nucleus only when they are complexed with OA. The HAMLET conjugated with a single biotin molecule will be a useful tool to identify the cellular components that are involved with it in the tumoricidal activity

Double-blind, comparative study of milnacipran and paroxetine in Japanese patients with major depression [Corrigendum]

Kamijima K, Hashimoto S, Nagayoshi E, Koyama T. Neuropsychiatric Disease and Treatment. 2013;9:555&ndash;565. On page 559, right column, line 10 from the bottom: (0.9 to 1.2) should read (&minus;0.9 to 1.2).Read the original articl