Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis.

BACKGROUND: The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. METHODS: We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. RESULTS: A total of 33 published studies involving 986 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I2 = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I2 = 83%), 71% (95% CI: 0.63-0.78; I2 = 0), 87% (95% CI: 0.82-0.93; I2 = 45%), and 80% (95% CI: 0.59-1.00; I2 = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. CONCLUSIONS: Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.

Nanoblock-mediated selective oncolytic polypeptide therapy for triple-negative breast cancer.

Rationale: Broad-spectrum oncolytic peptides (Olps) constitute potential therapeutic options for treating heterogeneous triple-negative breast cancer (TNBC); however, their clinical application is limited owing to high toxicity. Methods: A nanoblock-mediated strategy was developed to induce selective anticancer activity of synthetic Olps. A synthetic Olp, C12-PButLG-CA, was conjugated to the hydrophobic or hydrophilic terminal of a poly(ethylene oxide)-b-poly(propylene oxide) nanoparticle or a hydrophilic poly(ethylene oxide) polymer. A nanoblocker, that can significantly reduce the toxicity of Olp, was screened out through hemolytic assay, and then Olps were conjugated to the nanoblock via a tumor acidity-cleavable bond to obtain the selective RNolp ((mPEO-PPO-CDM)2-Olp). The tumor acidity responsive membranolytic activity, in vivo toxicity and anti-tumor efficacy of RNolp were determined. Results: We found that the conjugation of Olps to the hydrophobic core of a nanoparticle but not the hydrophilic terminal or a hydrophilic polymer restricts their motion and drastically reduces their hemolytic activity. We then covalently conjugated Olps to such a nanoblock via a cleavable bond that can be hydrolyzed in the acidic tumor environment, yielding a selective RNolp molecule. At physiological pH (pH 7.4), RNolp remained stable with the Olps shielded by nanoblocks and exhibited low membranolytic activity. At the acidic tumor environment (pH 6.8), Olps could be released from the nanoparticles via the hydrolysis of the tumor acidity-cleavable bonds and exerted membranolytic activity against TNBC cells. RNolp is well tolerated in mice and demonstrated high antitumor efficacy in orthotopic and metastatic mouse models of TNBC. Conclusion: We developed a simple nanoblock-mediated strategy to induce a selective cancer therapy of Olps for TNBC.