The chaperone heat shock protein 90 (HSP90) crucially supports the maturation, folding, and stability of a variety of client proteins which are of pivotal importance for the survival and ...proliferation of cancer cells. Consequently, targeting of HSP90 has emerged as an attractive strategy of anti-cancer therapy, and it appears to be particularly effective in the context of molecular sensitization towards radiotherapy as has been proven in preclinical models of different cancer entities. However, so far the clinical translation has largely been hampered by suboptimal pharmacological properties and serious hepatotoxicity of first- and second-generation HSP90 inhibitors. Here, we report on NW457, a novel radicicol-derived member of the pochoxime family with reduced hepatotoxicity, how it inhibits the DNA damage response and how it synergizes with ionizing irradiation to induce apoptosis, abrogate clonogenic survival, and improve tumor control in models of colorectal cancer in vitro and in vivo.
To investigate human papillomavirus (HPV) genotypes, HPV DNA load, and behavioral and sociodemographic factors in a series of human immunodeficiency virus (HIV)-seropositive women, and to correlate ...HPV infection with cervical disease according to immune status.
Three hundred seven HIV-seropositive women were tested for the presence of HPV DNA by polymerase chain reaction (PCR) and Southern blot hybridization. Cervical disease was assessed using Papanicolaou smears, colposcopy, and biopsies when necessary. Various risk factors for cervical intraepithelial neoplasia (CIN) were tested using multiple logistic regression analysis.
Cervical disease was diagnosed in 83 (27.0%) of 307 women and HPV infection in 162 (52.8%). High HPV load (as detectable by Southern blot hybridization) was found in 90 (55.6%) of the 162 infected women. Potentially oncogenic or related genotypes were detected in 74 (82.2%) of these 90 cases. High-load HPV infection was twice as frequent in severely immunosuppressed women (CD4 cell count less than 200/microL) as in women with higher CD4 cell counts (P =.002). High-load HPV infection was associated with a high risk of cervical disease (adjusted odds ratio OR 16.8; 95% confidence interval CI 7.0, 40.3). The risk among severely immunosuppressed women was ten times greater than that among women with CD4 cell counts of at least 200/microL. Low-load HPV infection (detected by PCR only) was a risk factor for CIN in severely immunosuppressed women only (adjusted OR 7.4; 95% CI 1.3, 43.0).
Immunosuppression favors cervical high-load HPV infection with oncogenic genotypes and its clinical expression in HIV-seropositive women.
Advanced HIV disease is associated with a high prevalence of cervical squamous intra-epithelial lesions (SIL) and of infection with oncogenic human papillomavirus (HPV) genotypes. Triple-combination ...antiretroviral therapy results in decreased plasma HIV viral load, increased CD4 cell counts and partial restoration of immune functions in patients with severe HIV disease. This study investigated the outcome of SIL in HIV-seropositive women undergoing triple combination antiretroviral treatment.
Forty-nine women who started triple-combination antiretroviral therapy, including a protease inhibitor, were examined prior to and after a median 5-month treatment. We collected cytological, colposcopic and histologic data and assessed the presence of HPV DNA in cervical smears by PCR and Southern blot hybridization (SBH).
The prevalence of SIL decreased from 69 to 53% during follow-up (P < 0.0001). Among 13 women who initially presented with high-grade SIL, conversion to lower grade was observed in two women and a full regression to normality was observed in one. Cytology also returned to normality in nine out of 21 women who initially presented with low-grade SIL. The high prevalence of HPV infection as detected by SBH and PCR was similar at the first and second examinations and the same high-risk viral genotypes were identified at both examinations in all infected patients but one. There was a higher increase in absolute CD4 cells in the subgroup of patients whose lesions regressed (99 versus 50 x 10(6)/l, P=0.03).
Our observations demonstrate that active antiretroviral therapy may result in a reduced prevalence of cervical squamous intra-epithelial lesions despite the absence of clearance of HPV infection.
This paper provides an overview of how to evaluate different blended finance instruments and mechanisms, including equity instruments, debt instruments, first loss capital, guarantees and insurance, ...development impact bonds, performance-based grants, structured funds and syndicated loans. It is structured along the most important and common questions evaluators seek to answer, including how to measure the mobilisation of additional financial resources, and assessing results. It provides a description of the most appropriate methods and tools for answering these questions, highlighting their advantages and disadvantages, and discusses their application.
This paper provides an overview of how to evaluate different blended finance instruments and mechanisms, including equity instruments, debt instruments, first loss capital, guarantees and insurance, ...development impact bonds, performance-based grants, structured funds and syndicated loans. It is structured along the most important and common questions evaluators seek to answer, including how to measure the mobilisation of additional financial resources, and assessing results. It provides a description of the most appropriate methods and tools for answering these questions, highlighting their advantages and disadvantages, and discusses their application.
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