Designed Extension of Survival Studies: Application to Clinical Trials with Unrecognized Heterogeneity

It is well known that unrecognized heterogeneity among patients, such as is conferred by genetic subtype, can undermine the power of randomized trial, designed under the assumption of homogeneity, to detect a truly beneficial treatment. We consider the conditional power approach to allow for recovery of power under unexplained heterogeneity. While Proschan and Hunsberger (1995) confined the application of conditional power design to normally distributed observations, we consider more general and difficult settings in which the data are in the framework of continuous time and are subject to censoring. In particular, we derive a procedure appropriate for the analysis of the weighted log rank test under the assumption of a proportional hazards frailty model. The proposed method is illustrated through application to a brain tumor trial

The Influence of Information Security Stress on Security Policy Compliance: A Protection Motivation Theory Perspective

The occurrence of security incidents will not only cause substantial loss to the enterprise but also serious damage to goodwill. An enterprise has to formulate and implement effective security policies to reduce the occurrence of security incidents. However, the process of promoting the security policy will put stress on employees. The focus of this paper is whether these pressures will affect staff\u27s compliance with the security policies based on the protection motivation theory. This study uses a survey method and 324 responses are collected. The results show that security task stress and security job stress have a significant impact on the formation of security role stress. Security role stress impacts threat and coping appraisals leading to security compliance

DESIGNED EXTENSION OF SURVIVAL STUDIES: APPLICATION TO CLINICAL TRIALS WITH UNRECOGNIZED HETEROGENEITY

Abstract: It is well known that unrecognized heterogeneity among patients, such as is conferred by genetic subtype, can undermine the power of a randomized trial, designed under the assumption of homogeneity, to detect a truly beneficial treatment. We consider the conditional power approach to allow for recovery of power under unexplained heterogeneity. While Proschan and Hunsberger (1995) confined the application of conditional power design to normally distributed observations, we consider more general and difficult settings in which the data are in the framework of continuous time and are subject to censoring. In particular, we derive a procedure appropriate for the analysis of the weighted log rank test under the assumption of a proportional hazards frailty model. The proposed method is illustrated through application to a brain tumor trial

Template-free synthesis of hierarchical hollow V2O5 microspheres with highly stable lithium storage capacity

Hollow V2O5 microspheres were successfully synthesized by a solvothermal method and subsequent calcination. The rigid hollow V2O5 cathode prepared in isopropanol solvent exhibited excellent cycling performance and rate capability. Within a voltage window of 2.5 to 4 V, a maximum specific discharge capacity of 128 mA h g−1 was delivered at 1 A g−1. Even after 500 cycles, the capacity retention was 92.2%.published_or_final_versio

Unusual case of spontaneous uterine rupture in a single gestational primipara

AbstractSpontaneous rupture of the primiparous uterus is a rare but catastrophic obstetrical emergency. It is usually associated with prior uterine surgery, trauma, or placental abnormality. To remind physicians to include this condition in their differential diagnosis of acute abdominal pain in pregnant patients, we describe an interesting case of spontaneous uterine rupture that clinically mimicked bowel perforation. A 27-year-old single primiparous pregnant woman presented with sudden onset of severe abdominal pain and peritoneal signs, with absence of vaginal bleeding at 26 weeks’ gestation. The usual risk factors for uterine rupture, such as advanced maternal age, scarred uterus due to mode of previous delivery, or unusual pregnancy, were not present in our patient. Based on clinical examination, abdominal sonography and magnetic resonance imaging, uterine rupture was suspected and eventually confirmed at exploratory laparotomy. No uterine pathological abnormality was noted on the microscopic examination The preterm newborn expired after surgery. Since surgical intervention is the only definitive treatment, emergency physicians should be aware of this rare complication. Emergency physicians should be aware of spontaneous uterine rupture in pregnant patients, even in the absence of risk factors

Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci

<p>Abstract</p> <p>Background</p> <p>Spinocerebellar ataxia type 8 (SCA8) involves the expression of an expanded CTG/CAG combined repeats (CR) from opposite strands producing CUG expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and a polyglutamine expansion protein (ataxin 8, ATXN8). The pathogenesis of SCA8 is complex and the spectrum of clinical presentations is broad.</p> <p>Results</p> <p>Using stably induced cell models expressing 0, 23, 88 and 157 CR, we study the role of ATXN8OS transcripts in SCA8 pathogenesis. In the absence of doxycycline, the stable ATXN8OS CR cell lines exhibit low levels of ATXN8OS expression and a repeat length-related increase in staurosporine sensitivity and in the number of annexin positive cells. A repeat length-dependent repression of ATXN8OS expression was also notable. Addition of doxycycline leads to 25~50 times more ATXN8OS RNA expression with a repeat length-dependent increase in fold of ATXN8OS RNA induction. ChIP-PCR assay using anti-dimethyl-histone H3-K9 and anti-acetyl-histone H3-K14 antibodies revealed increased H3-K9 dimethylation and reduced H3-K14 acetylation around the ATXN8OS cDNA gene in 157 CR line. The repeat length-dependent increase in induction fold is probably due to the increased RNA stability as demonstrated by monitoring ATXN8OS RNA decay in cells treated with the transcriptional inhibitor, actinomycin D. In cells stably expressing ATXN8OS, RNA FISH experiments further revealed ribonuclear foci formation in cells carrying expanded 88 and 157 CR.</p> <p>Conclusion</p> <p>The present study demonstrates that the expanded CUG-repeat tracts are toxic to human cells and may affect ATXN8OS RNA expression and stability through epigenetic and post-transcriptional mechanisms.</p

Toll-like receptor 9 agonist enhances anti-tumor immunity and inhibits tumor-associated immunosuppressive cells numbers in a mouse cervical cancer model following recombinant lipoprotein therapy

BACKGROUND: Although cytotoxic T lymphocytes (CTLs) play a major role in eradicating cancer cells during immunotherapy, the cancer-associated immunosuppressive microenvironment often limits the success of such therapies. Therefore, the simultaneous induction of cancer-specific CTLs and reversal of the immunosuppressive tumor microenvironment may be more effectively achieved through a single therapeutic vaccine. A recombinant lipoprotein with intrinsic Toll-like receptor 2 (TLR2) agonist activity containing a mutant form of E7 (E7m) and a bacterial lipid moiety (rlipo-E7m) has been demonstrated to induce robust CTL responses against small tumors. This treatment in combination with other TLR agonists is able to eliminate large tumors. METHODS: Mouse bone marrow-derived dendritic cells (DCs) were employed to determine the synergistic production of pro-inflammatory cytokines upon combination of rlipo-E7m and other TLR agonists. Antigen-specific CTL responses were investigated using immunospots or in vivo cytolytic assays after immunization in mice. Mice bearing various tumor sizes were used to evaluate the anti-tumor effects of the formulation. Specific subpopulations of immunosuppressive cells in the tumor infiltrate were quantitatively determined by flow cytometry. RESULTS: We demonstrate that a TLR9 agonist (unmethylated CpG oligodeoxynucleotide, CpG ODN) enhances CTL responses and eradicates large tumors when combined with rlipo-E7m. Moreover, combined treatment with rlipo-E7m and CpG ODN effectively increases tumor infiltration by CTLs and reduces the numbers of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) in the tumor microenvironment. CONCLUSION: These findings suggest that the dramatic anti-tumor effects of the recombinant lipoprotein together with CpG ODN may reflect the amplification of CTL responses and the repression of the immunosuppressive environment. This promising approach could be applied for the development of additional therapeutic cancer vaccines

Production of Active Nonglycosylated Recombinant B-Chain of Type-2 Ribosome-Inactivating Protein from Viscum articulatum and Its Biological Effects on Peripheral Blood Mononuclear Cells

Type-2 ribosome-inactivating proteins, composed of a toxic A-chain and lectin-like B-chain, display various biological functions, including cytotoxicity and immunomodulation. We here cloned the lectin-like B-chain encoding fragment of a newly identified type-2 RIP gene, articulatin gene, from Viscum articulatum, into a bacterial expression vector to obtain nonglycosylated recombinant protein expressed in inclusion bodies. After purification and protein refolding, soluble refolded recombinant articulatin B-chain (rATB) showed lectin activity specific toward galactoside moiety and was stably maintained while stored in low ionic strength solution. Despite lacking glycosylation, rATB actively bound leukocytes with preferential binding to monocytes and in vitro stimulated PBMCs to release cytokines without obvious cytotoxicity. These results implicated such a B-chain fragment as a potential immunomodulator