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A subset of antiretroviral therapy-treated persons with human immunodeficiency virus (HIV), referred to as immunological nonresponders (INRs), fails to normalize CD4+ T-cell numbers. In a case-control study involving 26 INRs (CD4 < 250 cells/µL) and 25 immunological responders (IRs; CD4 ≥ 250 cells/µL), we evaluated the potential contribution of transcriptionally competent defective HIV-1 proviruses to poor CD4+ T-cell recovery. Compared to the responders, the INRs had higher levels of cell-associated HIV RNA (P =.034) and higher percentages of HLA-DR+ CD4+ T cells (P <.001). While not encoding replication-competent viruses, the RNA transcripts frequently encoded HIV-1 Gag-p17 and Nef proteins. These transcripts and/or resulting proteins may activate pathway(s) leading to the immunological nonresponse phenotype. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer (1). Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keapl (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be protumorigenic (6). Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. [K-Ras.sup.G12D], [B-Raf.sup.V619E] and [Myc.sup.ERT2] each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing [K-Ras.sup.G12D] and [B-Raf.sup.V619E], and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs [K-Ras.sup.G12D]-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis., To examine the role of ROS in cellular transformation and tumorigenesis, we used an endogenous and conditional oncogenic LSL-[K-Ras.sup.G12D] allele (7). [K-Ras.sup.G12D/+] and [K-Ras.sup.LSL/+] mouse embryonic fibroblasts (MEFs) were compared [...]

HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as "defective" by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant "graveyard" of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cell-cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication. [ABSTRACT FROM AUTHOR]

Purpose: To compare the outcomes of Ex-PRESS device implantation versus trabeculectomy in patients with ocular hypertension after pars plana vitrectomy and silicone oil injection (SOI). Materials and Methods: Twenty-six consecutive eyes with ocular hypertension after pars plana vitrectomy and SOI were included in this study and randomized to one of two groups: A group treated with Ex-PRESS (model P50) placed under a scleral flap (Ex-PRESS group), and a group treated with trabeculectomy (trabeculectomy group). Complete success (intraocular pressure [IOP] <21 mmHg without medication) and qualified success rates (IOP <21 mmHg with one or two glaucoma medications) at 2 years postoperatively were analyzed. Between-groups comparison was performed with the Mann-Whitney U-test for continuous variables, and Fischer exact test for categorical data. Success rates between groups were compared using Kaplan-Meier life analysis and the log-rank test. P < 0.05 was considered statistically significant. Results: In the Ex-PRESS group, complete success was achieved in 73% eyes and qualified success in 81.8% of eyes. In the trabeculectomy group, complete success was achieved in 40% and qualified success was achieved in 60% of eyes. The difference in mean IOP between groups was statistically significant from the 3rd postoperative month onward (P = 0.007 at 3 months, P = 0.003 at 6 months, and P = 0.03 at 24 months). Conclusion: Ex-PRESS implantation was more effective than trabeculectomy in controlling IOP in ocular hypertensives after pars plana vitrectomy and SOI, but the surgical technique may require improvement. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy and the safety of a surgical technique in which classic trabeculectomy ab externo is performed with a double application of low-dose mitomycin C (MMC) in uncontrolled open-angle glaucoma (OAG) patients., Method: A consecutive series of 43 white patients (43 eyes) with uncontrolled primary OAG underwent trabeculectomy surgery. A double application of MMC (0.1%) was performed: the first under the Tenon's capsule for 3 minutes, and the second below the scleral flap for 1 or 2 minutes, according to the risk factors. Complete success was defined as intraocular pressure (IOP) <14 mmHg without any additional glaucoma surgery or medication. Qualified success was defined as IOP <14 mmHg with additional needling revision., Results: Mean preoperative IOP was 29.9 mmHg (SD 3.8) for all eyes evaluated. At 1 day postoperative, mean IOP was 6.7 mmHg (SD 1.26). At the end of the first 2 weeks postoperative, mean IOP was 8.6 mmHg (SD 1.7), at 12 months mean IOP was 11.3 mmHg (SD 1.4; P < 0.0001) and at 24 months mean IOP was 11.4 mmHg (SD 1.5; P < 0.0001). At 3 months, two eyes (5.4%) underwent needling of the bleb for cystic blebs formation., Conclusion: In this study we presented the results after 2 years of follow-up of OAG undergoing trabeculectomy with dual administration of MMC (0.1 mg/mL). After 24 months, complete success was achieved in 93% of patients and a qualified success in 100% of patients.