Histopathological, Serological, and Molecular Confirmation of Indigenous Alveolar Echinococcosis Cases in Mongolia

The combined efficacy of a long-lasting insecticidal net (LLIN) and a carbamate-treated plastic sheeting (CTPS) or indoor residual spraying (IRS) for control of insecticide-resistant mosquitoes was evaluated in experimental huts in Burkina Faso. Anopheles gambiae from the area is resistant to pyrethroids and to a lesser extent, carbamates. Relatively low mortality rates were observed with the LLIN (44%), IRS (42%), and CTPS (52%), whereas both combinations killed significantly more mosquitoes (~70% for LLIN + CTPS and LLIN + IRS). Blood feeding by An. gambiae was uninhibited by IRS and CTPS compared with LLIN (43%), LLIN + CTPS (58%), and LLIN + IRS (56%). No evidence for selection of the kdr and ace-1^R alleles was observed with the combinations, whereas a survival advantage of mosquitoes bearing the ace-1^R mutation was observed with IRS and CTPS. The results suggest that the combination of the two interventions constitutes a potential tool for vector-resistance management.     

Potent antiviral activity of north-methanocarbathymidine against Kaposi's sarcoma-associated herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV) infection is a prerequisite for the development of Kaposi's sarcoma (KS). Blocking lytic KSHV replication may hinder KS tumorigenesis. Here, we report potent in vitro anti-KSHV activity of 2'-exo-methanocarbathymidine [North-methanocarbathymidine (N-MCT)], a thymidine analog with a pseudosugar ring locked in the northern conformation, which has previously been shown to block the replication of herpes simplex virus types 1 and 2. N-MCT inhibited KSHV virion production in lytically induced KSHV-infected BCBL-1 cells with a substantially lower 50% inhibitory concentration (IC50) than those of cidofovir (CDV) and ganciclovir (GCV) (IC50, mean +/- standard deviation: 0.08 +/- 0.03, 0.42 +/- 0.07, and 0.96 +/- 0.49 microM for N-MCT, CDV, and GCV, respectively). The reduction in KSHV virion production was accompanied by a corresponding decrease in KSHV DNA levels in the N-MCT-treated BCBL-1 cells, indicating that the compound blocked lytic KSHV DNA replication. A time- and dose-dependent accumulation of N-MCT-triphosphate (TP) was demonstrated in lytically induced BCBL-1 cells, while uninfected cells showed virtually no accumulation. The levels of N-MCT-TP were significantly decreased in the presence of 5'-ethynylthymidine, a potent inhibitor of herpesvirus thymidine kinase, resulting in the abrogation of anti-KSHV activity of N-MCT. N-MCT-TP more effectively blocked in vitro DNA synthesis by KSHV DNA polymerase with an IC50 of 6.24 +/- 0.08 microM (mean +/- standard deviation) compared to CDV-diphosphate (14.70 +/-2.47 microM) or GCV-TP (24.59 +/- 5.60 microM). Taken together, N-MCT is a highly potent and target-specific anti-KSHV agent which inhibits lytic KSHV DNA synthesis through its triphosphate metabolite produced in KSHV-infected cells expressing a virally encoded thymidine kinase.     

Sustainable funding of health initiatives in Wonju, Republic of Korea via a tobacco consumption tax

Wonju is the first municipality in the Republic of Korea to fund the Healthy City project through municipal revenues from the local tobacco consumption tax. We investigated the process of the local tobacco consumption tax being approved as the main source of financing for the local Healthy City project. We also examined the sustainability and sufficiency of the funding by looking at the pricing policies instituted for cigarettes, smoking prevalence, cigarette consumption and revenues from local tobacco consumption as well as the budgetary allocations among programs in the city. The strong initiative of the mayor of Wonju was one of the factors that enabled the earmarking of the local tobacco consumption tax for the Healthy City Wonju project. He consulted academic counselors and persuaded the municipal government and the City Council to approve the bill. Despite the increasing price of cigarettes in Korea, adequate funding can be sustained to cover the short-term and mid-term programs in Wonju for at least 5 years of the mayor's term, because the smoking rate is persistently high. Analyzing the effects of strong leadership on the part of local authorities and the balance between revenues from the tobacco tax and the prevalence of smoking in the face of anti-smoking policies would be helpful for other countries and communities interested in developing sustainable Healthy Cities projects.     

Synthesis, biological evaluation, and structure-activity relationships of a novel class of apurinic/apyrimidinic endonuclease 1 inhibitors

APE1 is an essential protein that operates in the base excision repair (BER) pathway and is responsible for ≥95% of the total apurinic/apyrimidinic (AP) endonuclease activity in human cells. BER is a major pathway that copes with DNA damage induced by several anticancer agents, including ionizing radiation and temozolomide. Overexpression of APE1 and enhanced AP endonuclease activity have been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy. We report herein the results of a focused medicinal chemistry effort around a novel APE1 inhibitor, N-(3-(benzo[d]thiazol-2-yl)-6-isopropyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl)acetamide (3). Compound 3 and related analogues exhibit single-digit micromolar activity against the purified APE1 enzyme and comparable activity in HeLa whole cell extract assays and potentiate the cytotoxicity of the alkylating agents methylmethane sulfonate and temozolomide. Moreover, this class of compounds possesses a generally favorable in vitro ADME profile, along with good exposure levels in plasma and brain following intraperitoneal dosing (30 mg/kg body weight) in mice.     

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 × 10−57), high mitotic index (p = 5.25 × 10−28), pleomorphism (p = 6.31 × 10−19), ER negative (p = 9.02 × 10−35), PR negative (p = 9.24 × 10−24), triple negative phenotype (p = 6.67 × 10−21), PAM50.Her2 (p = 5.19 × 10−13), PAM50. Basal (p = 2.7 × 10−41), PAM50.LumB (p = 1.56 × 10−26), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10−12), intClust.5 (p = 4.05 × 10−12) and intClust. 10 (p = 7.59 × 10−38) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10−16) and multivariate analysis (p = 9.19 × 10−7). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps < 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps < 0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps < 0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps < 0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer.     

Potential Cellular Signatures of Viral Infections in Human Hematopoietic Cells

Expression profiling of cellular genes was performed using a 10,000 cDNA human gene array in order to identify expression changes following chronic infection of human hematopoietic cells with Kapsosi’s Sarcoma -associated Virus (KSHV) also known as Human Herpesvirus 8 (HHV8) and Human T cell leukemia virus-1 (HTLV-1). We performed cell-free {\it in vitro} infection of primary bone marrow derived CD34+ cells using semi-purified HHV8 and a mature IL-2 dependent T cell line, KIT 225, using highly concentrated viral stocks prepared from an infectious molecular clone of HTLV-1. Thirty days post infection, mRNA was isolated from infected cultures and uninfected controls and submitted for microarray analysis. More than 400 genes were differentially expressed more than two-fold following HHV8 infection of primary bone marrow derived CD34+ cells. Of these 400, interferon regulatory factor 4 (IRF4), cyclin B2, TBP-associated factor, eukaryotic elongation factor and pim 2 were up-regulated more than 3.5 fold. In contrast, less than 100 genes were differentially expressed more than two-fold following chronic infection of a mature T cell line with HTLV-1. Of these, only cdc7 was up-regulated more than 3.5 fold. These data may provide insight into cellular signatures of infection useful for diagnosis of infection as well as potential targets for therapeutic intervention.     

Herbal nutraceutical treatment of chronic prostatitis–chronic pelvic pain syndrome: a literature review

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is the most frequent form of prostatitis, and has a serious impact on patients’ quality of life, and causes severe symptoms. The pain in the pelvic, perineal and penile areas, lower abdominal pain, and pain during urination or ejaculation are the main complaints of CP/CPPS. The underlying complex and unknown pathophysiology of this syndrome have made the management of CP/CPPS and the availability of monotherapy challenging. To identify an effective monotherapy, a plethora of clinical trials failed due to its puzzling etiology. Antibiotics, anti-inflammatory, and a-blockers have been commonly used for the treatment of CP/CPPS, but the desired and complete effects have not been gotten yet. The patients and clinicians are attracted to alternative therapies because of their multi-targeted effects. Attention toward natural compounds effectiveness and safety, supporting the development of a new nutraceutical science. In the alternative remedies for the treatment of prostatic diseases, medicinal herbs, in the form of herb parts or extracts, are getting attention due to their positive effects on prostatic diseases. At present, there is no available detailed literature review about the efficacy of medicinal herbs in the treatment of CP/CPPS. This review aimed to explore the useful medicinal herbs in the treatment of CP/CPPS from different perspectives and their possible mechanism of action in managing CP/CPPS.