Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.

The transcription factor hypoxia-inducible factor-1␣ (HIF-1␣) plays pivotal roles in physiology and pathophysiology. Constitutive or hypoxia-induced HIF-1␣ overexpression is observed in many types of cancers including prostate adenocarcinoma, in which it is associated with resistance to apoptosis and therapeutic agents. BCL-xL, a hypoxia-responsive, anti-apoptotic protein of the Bcl-2 family, is also overexpressed in prostate carcinoma and many other cancers. Despite this connection, whether BCL-xL expression is directly regulated by HIF-1␣ is not known. We used prostate cancer PC-3 cell with constitutive high HIF-1␣ level as a model to address this important question. We first generated prostate cancer PC-3 cells in which HIF-1␣ was stably knocked-down (HIF-KD) by using small interference RNA. BCL-xL was dramatically decreased in HIF-KD PC-3 cells, in parallel with sensitization to apoptosis with caspase-3 activation as well as decreased cell proliferation. We then demonstrated that HIF-1␣ directly regulated BCL-xL transcription by binding to a hypoxia-responsive element in the BCL-xL promoter (؊865 to ؊847) by reporter gene assay, chromatin immunoprecipitation, and electrophoretic mobility shift and supershift assays. HIF-1␣-dependent BCL-xL overexpression may be an important mechanism by which HIF-1␣ protects prostate cancer cells from apoptosis and leads to treatment resistance.

The putative tumor suppressor miR145 is transcriptionally regulated by TP53 and is downregulated in many tumors; however, its role in prostate cancer is unknown. On the other hand, BCL2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) is overexpressed in various tumors, including prostate cancer, and may transcriptionally repress the apoptosis-inducing factor (AIF) gene. Although BNIP3 transcription is controlled by hypoxia-inducible factor 1α (also elevated in prostate cancer), we postulated the posttranscriptional regulation of BNIP3 by miR145 through bioinformatics analysis, and herein we experimentally showed that miR145 negatively regulated BNIP3 by targeting its 3′-untranslated region. Artificial overexpression of miR145 by using adenoviral vectors in prostate cancer PC-3 and DU145 cells significantly downregulated BNIP3, together with the upregulation of AIF, reduced cell growth, and increased cell death. Artificial overexpression of wild-type TP53 in PC-3 cells (which lack TP53 protein) and DU145 cells (in which mutated nonfunctioning TP53 is expressed) significantly upregulated miR145 expression with consequent effects on BNIP3 and cell behavior as with miR145 overexpression. Analysis of prostate cancer (n = 134) and benign prostate (n = 83) tissue sample showed significantly decreased miR145 and increased BNIP3 expression in prostate cancer (P < 0.001), particularly in those with tumor progression, and both molecular changes were associated with unfavorable outcome. Abnormalities of the miR145-BNIP3 pair as part of TP53-miR145-BNIP3-AIF network may play a major role in prostate cancer pathogenesis and progression. Cancer Res; 70(7); 2728-38. ©2010 AACR.

Background: Only clinically validated HPV assays can be accepted in cervical cancer screening. Objectives: To update the list of high-risk HPV assays that fulfil the 2009 international validation criteria (Meijer-2009). Data Sources: PubMed/Medline, Embase, Scopus, references from selected studies; published in January 2014 to August 2020. Study eligibility criteria: HPV test validation studies and primary screening studies, involving testing with an index HPV test and a comparator HPV test with reporting of disease outcome (occurrence of histologically confirmed cervical precancer; CIN2þ). Participants: Women participating in cervical cancer screening. Interventions: Testing with an index and a comparator HPV test of clinician-collected cervical specimens and assessment of disease outcome (

CD2-associated protein (CD2AP) is an adapter protein associating with several membrane proteins, including nephrin, mutated in congenital nephrotic syndrome of the Finnish type, and polycystin-2, mutated in type 2 autosomal dominant polycystic kidney disease. Both proteins have critical roles in the maintenance of the integrity of the nephrons. Previous studies have suggested a role for CD2AP in the regulation of the organization of the actin cytoskeleton, but it has not been known whether the postulated association between CD2AP and actin is direct or mediated by other proteins. In this study, we address this question by using various cellular and biochemical approaches. We show that CD2AP and F-actin partially colocalize in cultured cells and that disruption of the actin cytoskeleton results in disorganization of endogenous CD2AP. Using cytoskeletal fractionation by differential centrifugation, we demonstrate that a proportion of CD2AP associates with the actin cytoskeleton. Furthermore, using pure actin and purified CD2AP fusion proteins in an F-actin coprecipitation assay, we show that CD2AP directly associates with filamentous actin and that this interaction is mediated by means of the COOH terminus of CD2AP. The present results suggest that CD2AP is involved in the regulation of the actin cytoskeleton and indicate that CD2AP may act as a direct adapter between the actin cytoskeleton and cell membrane proteins, such as nephrin and polycystin-2. Alterations in these interactions could explain some of the pathophysiological changes in congenital nephrotic syndrome and polycystic kidney disease.

Figure 1 (facing page). Schematic Representation of the Review and Evaluation Process of the IARC Handbooks for Secondary Prevention of Cervical Cancer.WHO denotes World Health Organization.

Background The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. Methods A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18–45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission. Results In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. Conclusions The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18–associated high-grade genital lesions and persistent infection in women.

Objective To quantify the influence of increasing use of health-care services on rising rates of caesarean section in China. Methods We used data from a population-based survey conducted by the United Nations Population Fund during September 2003 in 30 selected counties in three regions of China. The study sample (derived from birth history schedule) consisted of 3803 births to mothers aged less than 40 years between 1993 and 2002. Multiple logistic regression models were used to estimate the effect of health-care factors on the odds of a caesarean section, controlling for time and selected variables. Findings Institutional births increased from 53.5% in 1993-1994 to 82.2% in 2001-2002, while the corresponding increase in births by caesarean section was from 8.9% to 24.8%, respectively. Decomposition analysis showed that 69% of the increase in rates of caesarean section was driven by the increase in births within institutions. The adjusted odds of a caesarean section were 4.6 times (95% confidence interval, CI: 3.4-11.8) higher for recent births. The adjusted odds were also significantly higher for mothers who had at least one antenatal ultrasound test. Rates of caesarean section in secondary-level facilities markedly increased over the last decade to the same levels as in major hospitals (P < 0.001). Conclusion The upsurge in rates of births by caesarean section in this population cannot be fully explained by increases in institutional births alone, but is likely to be driven by medical practice within secondary-level hospitals and women's demand for the procedure. Une traduction en français de ce résumé figure à la fin de l´article. Al final del artículo se facilita una traducción al español.