The mitochondria-independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib-mediated mcl-1 downregulation and mitochondrial membrane destabilization

Background: Nelfinavir is an HIV protease inhibitor that has been used for a long period of time to treat HIVinfected individuals. It has recently emerged that nelfinavir could represent a prospective new anti-cancer drug, prompting us to test the effect of nelfinavir on leukemia cells. Methods: By combining in vitro and ex vivo studies, the effect of nelfinavir on leukemia cells and non-malignant, bone marrow-derived tissue cells was analyzed. Results: At a concentration of 9 mu g/ml, nelfinavir induced death of 90% of HL60, IM9, and Jurkat cells. At the same concentration and treatment conditions, less than 10% of aspirated human bone marrow cells showed nelfinavir-induced cell damage. Nelfinavir-induced death of leukemia cells was accompanied by activation of caspases 3, 7, and 8. Despite caspase activation, the upregulation of the anti-apoptotic bcl-2 family member protein mcl-1 that resulted from nelfinavir treatment stabilized the mitochondrial membrane potential, resulting in primarily mitochondria-independent cell death. Pharmacological downregulation of mcl-1 expression by treatment with sorafenib (2 mu g/ml) significantly enhanced nelfinavir-induced apoptosis even at lower nelfinavir concentrations (5 mu g/ml), but did not have additional detrimental effects on non-malignant bone marrow cells. Conclusions: The ability of nelfinavir to induce apoptosis in leukemia cells as a single agent in a mitochondria-independent manner might suggest it could be used as a second or third line of treatment for leukemia patients for whom standard mitochondria-directed treatment strategies have failed. Combination treatment with nelfinavir and sorafenib might further enhance the efficacy of nelfinavir even on chemo-resistant leukemia cells

National Guidelines for the prevention of mother-to-child transmission of HIV across Europe - how do countries differ?

Objectives: The aim was to summarize national prevention of mother-to-child transmission (PMTCT) guidelines across Europe and to identify differences between these. Methods: A survey was conducted using a structured questionnaire sent to experts in 25 European countries from January to March 2012, requesting a copy of the national guidelines. Responses were received from 23 countries. Results: Twenty-two (96%) countries supported a policy to recommend antenatal HIV screening for all pregnant women (15: opt-out strategy; 8: opt-in strategy). For HIV-positive women in whom the only indication for antiretroviral therapy (ART) was PMTCT, the recommended gestational age for commencing ART varied from 12 to 28 weeks: initiation before 19 weeks gestation was recommended in guidelines from nine countries; in France, the UK and the Netherlands, there was a wide range, from 14 to 24 weeks, whereas the Swiss and Ukrainian guidelines recommended starting at 24-28 weeks and the German/Austrian and Lithuanian at 28 weeks. Six national guidelines recommended inclusion of Zidovudine in antenatal ART regimens, and seven (37%) allowed continuation of Efavirenz for women conceiving on this drug. According to nine guidelines, zidovudine should always be used intrapartum. Eighteen national guidelines stated that HIV-positive women on successful ART can have a vaginal delivery. Viral load thresholds for vaginal delivery were <1000 copies/ml in 5 countries, <400 copies/ml in 3 and <50 copies/ml in 11 countries. Conclusion: There are important differences across Europe in national PMTCT guidelines, with most variation seen where the evidence-base remains limited. Such differences should be considered when interpreting research and surveillance finding

German-austrian recommendations for HIV1-therapy in pregnancy and in HIV1-exposed newborn - update 2008

German-Austrian recommendations for HIV1-therapy in pregnancy - Update 2008 Bernd Buchholz (University Medical Centre Mannheim, Pediatric Clinic), Matthias Beichert (Mannheim, Gynecology and Obstetrics Practice), Ulrich Marcus (Robert Koch Institute, Berlin), Thomas Grubert, Andrea Gingelmaier (Gynecology Clinic of the Ludwig Maximilians University of Munich), Dr. med. Annette Haberl (HIV-Department, J. W. Goethe-University Hospital, Frankfurt), Dr. med. Brigitte Schmied (Otto-Wagner Spital, Wien)

Prevalence of human papillomavirus infection of the anal canal in women: A prospective analysis of high-risk populations

Infection with certain types of human papillomavirus (HPV) has been associated with the development of cervical and anal cancer. Worldwide, the incidence of anal cancer has increased markedly. The present study aimed to evaluate the prevalence of HPV infection of the uterine cervix and anal canal in human immunodeficiency virus (HIV)- and non-HIV-infected risk populations. Cervical and anal HPV swabs and cytology samples were collected from 287 patients at the University Hospital of Munich, Germany between 2011 and 2013. Patients were divided into HIV-negative controls (G1) and two risk groups, including HIV-negative patients with cytological abnormalities of the cervix (G2) and HIV-infected patients (G3). Data, including clinical parameters, were analysed. The risk groups had significantly more positive results for HPV in the anus (71.03 and 83.15% for G2 and G3, respectively), as compared with G1. The predominant HPV genotypes found in the anus were high-risk HPV genotypes, which were significantly correlated with concomittant cervical HPV findings. In the risk groups, a significant association between the cytological findings and HPV detection in the cervix was found, while the results of the anus revealed no significance. The results of the present study suggested that the prevalence of HPV infection in the anal canal of risk populations is high. Furthermore, patients with abnormal cervical cytology results and HIV-infected women, irrespective of their individual cervical findings, may have a risk of concomittant anal high-risk HPV infection. Based on the predominant HPV genotypes found in the study, HPV vaccination could reduce the incidence of anal cancer. Nevertheless, high-risk patients should be intensively screened for anal squamous intraepithelial abnormalities to avoid invasive cancer stages

Etravirine pharmacokinetics in HIV-infected pregnant women

__Background__ The study goal was to describe etravirine pharmacokinetics during pregnancy and postpartum in HIV-infected women. __Methods__ IMPAACT P1026s and PANNA are on-going, non-randomized, open-label, parallel-group, multi-center phase-IV prospective studies in HIV-infected pregnant women. Intensive steady-state 12-h pharmacokinetic profiles were performed from 2nd trimester through postpartum. Etravirine was measured at two labs using validated ultra performance liquid chromatography (detection limits: 0.020 and 0.026 mcg/mL). __Results__ Fifteen women took etravirine 200 mg twice-daily. Etravirine AUC0-12 was higher in the 3rd trimester compared to paired postpartum data by 34% (median 8.3 vs. 5.3 mcg*h/mL, p = 0.068). Etravirine apparent oral clearance was significantly lower in the 3rd trimester of pregnancy compared to paired postpartum data by 52% (median 24 vs. 38 L/h, p = 0.025). The median ratio of cord blood to maternal plasma concentration at delivery was 0.52 (range: 0.19-4.25) and no perinatal transmission occurred. __Conclusion__ Etravirine apparent oral clearance is reduced and exposure increased during the third trimester of pregnancy. Based on prior dose-ranging and safety data, no dose adjustment is necessary for maternal health but the effects of etravirine in utero are unknown. Maternal health and infant outcomes should be closely monitored until further infant safety data are available. __Clinical Trial registration:__ The IMPAACT protocol P1026s and PANNA study are registered at ClinicalTrials.gov under NCT00042289 and NCT00825929

The mitochondria-independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib-mediated mcl-1 downregulation and mitochondrial membrane destabilization

Abstract Background Nelfinavir is an HIV protease inhibitor that has been used for a long period of time to treat HIV-infected individuals. It has recently emerged that nelfinavir could represent a prospective new anti-cancer drug, prompting us to test the effect of nelfinavir on leukemia cells. Methods By combining in vitro and ex vivo studies, the effect of nelfinavir on leukemia cells and non-malignant, bone marrow-derived tissue cells was analyzed. Results At a concentration of 9 μg/ml, nelfinavir induced death of 90% of HL60, IM9, and Jurkat cells. At the same concentration and treatment conditions, less than 10% of aspirated human bone marrow cells showed nelfinavir-induced cell damage. Nelfinavir-induced death of leukemia cells was accompanied by activation of caspases 3, 7, and 8. Despite caspase activation, the upregulation of the anti-apoptotic bcl-2 family member protein mcl-1 that resulted from nelfinavir treatment stabilized the mitochondrial membrane potential, resulting in primarily mitochondria-independent cell death. Pharmacological downregulation of mcl-1 expression by treatment with sorafenib (2 μg/ml) significantly enhanced nelfinavir-induced apoptosis even at lower nelfinavir concentrations (5 μg/ml), but did not have additional detrimental effects on non-malignant bone marrow cells. Conclusions The ability of nelfinavir to induce apoptosis in leukemia cells as a single agent in a mitochondria-independent manner might suggest it could be used as a second or third line of treatment for leukemia patients for whom standard mitochondria-directed treatment strategies have failed. Combination treatment with nelfinavir and sorafenib might further enhance the efficacy of nelfinavir even on chemo-resistant leukemia cells.</p

HIV-Therapie in der Schwangerschaft: Optimierung der Transmissionsverhinderung bei Minimierung unerwünschter Arzneimittelwirkungen

In Deutschland werden jährlich 150 bis 200 Kinder von HIV-1-positiven Schwangeren entbunden. Seit 1995/96 beträgt in Deutschland die Rate der vertikalen HIV-1-Transmission nur noch ein bis zwei Prozent. Diese niedrige Transmissionsrate wurde durch antiretrovirale Therapie der HIV-1-positiven Schwangeren, eine primäre Sectio am wehenlosen Uterus sowie eine antiretrovirale Prophylaxe und einen Stillverzicht bei den Neugeborenen erreicht. Mitte 1998 wurde dieses Vorgehen im Rahmen einer interdisziplinären Konsensuskonferenz an neueste Erkenntnisse adaptiert. Aufgrund neuer Forschungsergebnisse, der Neuzulassung von antiretroviralen Substanzen und einer Änderung der Therapierichtlinien bei Erwachsenen wurden bis Mai 2001 diese Empfehlungen erneut interdisziplinär aktualisiert. Die aktuellen Leitlinien enthalten neue Empfehlungen zu Therapieindikation, Beginn, Art und Nebenwirkungen der antiretroviralen Therapie bei der HIV-positiven Schwangeren. Das Vorgehen bei „normaler“ Schwangerschaft, aber auch bei Schwangerschaftsrisiken/-komplikationen wird genau spezifiziert. Erstmalig wurden Empfehlungen zur Schwangerschaftsvorsorge HIV-positiver Frauen und zur Kreißsaalversorgung der HIV-exponierten Neugeborenen aufgenommen.Antiretroviral Therapy During Pregnancy – The German/Austrian Recommendations for Prevention of Perinatal Transmission of HIV and Reduction of Unwanted Drug Effects Since 1995 the rate of vertical HIV-transmission in mothers with known HIV infection has been reduced to 1 to 2 per cent in Germany. This low transmission rate has been achieved by a combination of antiretroviral therapy in pregnant woman, cesarean section before labor, antiretroviral prophylaxis in the newborn and refraining from breast-feeding. After a first update of this combined strategy in 1998 a second update by an interdisciplinary consensus conference became necessary because of new results in research, approval of new antiretroviral drugs and changes in general treatment recommendations for HIV infected adults. The updated guidelines, finalised in May 2001, provide new recommendations on the indications and the starting point for therapy in pregnancy, drugs to be used preferably and updated information on adverse effects of antiretroviral drugs. The procedures for different risk constellations in pregnancy have been specified. Recommendations for monitoring of HIV infected pregnant women in prenatal care and for preventive procedures for the newborn in the delivery room have been included

Information theoretic analysis of hybrid-ARQ protocols in coherent free-space optical systems

Due to copyright restrictions, the access to the full text of this article is only available via subscription.Automatic retransmission request (ARQ) is a feedback-based data link layer technique which enhances the reliability of communication in fading channels. In this paper, we investigate the performance of hybrid-ARQ (H-ARQ) techniques in coherent free-space optical (FSO) communication systems over atmospheric turbulence-induced fading channels. Under the assumption of a Gamma-Gamma statistical fading channel model, we derive outage probability and throughput expressions for three H-ARQ protocols. We further characterize the outage performance at high values of signal-to-noise-ratio (SNR) through diversity and coding gains. Our results provide insight into the performance mechanisms of different H-ARQ protocols in coherent FSO systems and demonstrate that significant performance gains can be achieved through the deployment of H-ARQ particularly in the strong turbulence regime.European Commission ; TUB

Immunohistochemical Labeling of the Inhibin/Activin βC Subunit in Normal Human Placental Tissue and Chorionic Carcinoma Cell Lines

Inhibins and activins are important regulators of the female reproductive system. A novel inhibin subunit, named βC, has been identified and demonstrated to be expressed in several human tissues. We demonstrate here that inhibin βC is expressed in human placenta. Expression of the inhibin βC subunit was demonstrated at the protein level by means of immunohistochemical evaluation and at the transcriptional level by an inhibin βC-specific RT-PCR analysis. Expression of inhibin βC was detected in the human chorionic carcinoma cell lines JEG and BeWo. Although the precise role of this novel inhibin subunit in human placenta development and homeostasis is unclear, analogies with other inhibin subunits and the strong expression of βC in normal human trophoblast cells and chorionic carcinoma cells suggest that βC may be involved in autocrine/paracrine signaling pathways, angiogenesis, decidualization, and tissue remodeling under normal and malignant conditions. Additionally, JEG and BeWo express βC and, therefore, can be used as a cell culture model for further functional analysis of this subunit in the human placenta. (J Histochem Cytochem 58:751–757, 2010