Bcl-2 Antagonist Obatoclax Reactivates Latent HIV-1 via the NF-κB Pathway and Induces Latent Reservoir Cell Apoptosis in Latently Infected Cells.

The implementation of combined antiretroviral therapy (cART) has rendered HIV-1 infection clinically manageable and efficiently improves the quality of life for patients with AIDS. However, the persistence of a latent HIV-1 reservoir is a major obstacle to achieving a cure for AIDS. A "shock and kill" strategy aims to reactivate latent HIV and then kill it by the immune system or cART drugs. To date, none of the LRA candidates has yet demonstrated effectiveness in achieving a promising functional cure. Interestingly, the phosphorylation and activation of antiapoptotic Bcl-2 protein induce resistance to apoptosis during HIV-1 infection and the reactivation of HIV-1 latency in central memory CD4+ T cells from HIV-1-positive patients. Therefore, a Bcl-2 antagonist might be an effective LRA candidate for HIV-1 cure. In this study, we reported that a pan-Bcl-2 antagonist obatoclax induces HIV-1 reactivation in latently infected cell lines in vitro and in PBMCs/CD4+ T cells of HIV-infected individuals ex vivo. Obatoclax promotes HIV-1 transcriptional initiation and elongation by regulating the NF-κB pathway. Obatoclax activates caspase 8 and does not induce the phosphorylation of the antiapoptotic protein Bcl-2 in latent HIV-1 infected cell lines. More importantly, it preferentially induces apoptosis in latently infected cells. In addition, obatoclax exhibited potent anti-HIV-1 activity on target cells. The abilities to reactivate latent HIV-1 reservoirs, inhibit HIV-1 infection, and induce HIV-1 latent cell apoptosis make obatoclax worth investigating for development as an ideal LRA for use in the "shock and kill" approach.

Transurethral Enucleation of Bladder Leiomyoma: A Series of Six Cases and Review of the Literature.

OBJECTIVES: To investigate the feasibility and initial surgical outcomes of transurethral enucleation for 6 patients with bladder leiomyoma. MATERIALS: Six patients (mean age 50.2, range [34-67]) with bladder leiomyoma underwent transurethral enucleation. In each case, the resectoscope was inserted into the bladder. A resecting loop was used to incise the urothelium along the surgical margin of the bladder tumor, and a push was given through the resecting loop to further separate the tumor until it was shelled off the bladder wall. The intact mass was then cut into pieces and flushed out. After the operation, irrigation therapy was given. RESULTS: Surgery was performed successfully in all 6 patients. The mean size of the tumor was 3.9 cm (1.8-6.7 cm). The mean operation time was 60 min (30-100 min). The mean follow-up period was 14.8 months (2-30 months), and no evidence of recurrence was found in all cases. CONCLUSION: Transurethral enucleation is a safe, reliable, and effective surgical technique for selected patients with well-encapsulated tumors and is well suited for further pathological diagnosis and radical treatment.

Novel Application of Cell Penetrating R11 Peptide for Diagnosis of Bladder Cancer.

OBJECTIVE: As a novel cell-permeable peptide, polyarginine (R11) showed great potential as contrast agent to target bladder cancer (BCa) for therapeutic applications. However, its diagnostic ability and uptake efficiency between BCa and normal bladder tissues is unknown. In this study, we investigated the feasibility of R11 conjugated with fluorescein isothiocyanate (FITC-R11) for detecting BCa in clinical practice. METHOD: FITC-R11 was synthesized and incubated with BCa cell lines (T24, 5637, RT4), normal immortalized human bladder epithelial cell line (SVHUC) and clinical specimens from BCa and benign prostate hyperplasia patients. The uptake efficiency was determined by the mean values of relative FITC intensity. Furthermore, FITC-R11 was intravesically injected into the athymic nude mice bearing orthotopic T24-t tumors and pulmonary metastasis of bladder tumor mice models, the fluorescence intensity of bladder tumors and normal bladder tissues was examined, as well as lung tissues. RESULT: After incubation with FITC-R11, the fluorescence intensity of T24, 5637, RT4 and SVHUC cell line was 64678.56 ± 9699.27, 46456.22 ± 2588.06, 33802.02 ± 429.72 and 17785.01 ± 1704.36, respectively (P < 0.05). In the athymic nude mice bearing orthotopic T24-t tumors, FITC-R11 showed elevated accumulation in the bladder tumors compared with normal bladder tissues, FITC-R11 was also accumulated in the lung of pulmonary metastasis mice. Moreover, the uptake efficiency of FITC-R11 in patients' BCa tissues was much higher than in normal bladder tissues (6441.95 vs. 1196.92, P < 0.05), as well as the urine samples of BCa patients and benign prostate hyperplasia patients (30250.37 vs. 4948.42, P < 0.05). CONCLUSION: As compared with normal bladder tissue, FITC-R11 is a more specific molecular probe for BCa, and has the potential application in clinical practice.