Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling.

Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.

Manual Acupuncture for Optic Atrophy: A Systematic Review and Meta-Analysis.

Objectives. This systematic review aims to critically evaluate the efficacy of manual acupuncture for optic atrophy. Eight English and Chinese databases, including Cochrane Library, EMbase, PubMed, Chinese National Knowledge Infrastructure (CNKI), Wanfang Database, China Science and Technology Journal Database (VIP), and Chinese Biomedical Literature Database (CBM), as well as ongoing trials registered with the WHO International Clinical Trials Registry Platform, were searched to identify eligible randomized controlled trials (RCTs) studying manual acupuncture for optic atrophy compared to medication alone. The quality of evidence was assessed using Cochrane Collaboration's risk of bias tool. Meta-analysis was performed using Review Manager version 5.3. Nine studies were identified and included for meta-analysis. The meta-analysis showed significant differences in favor of manual acupuncture or manual acupuncture plus medication compared with medication alone in the following outcome measures: visual acuity (MD = 0.18, 95% CI [0.17, 0.20], P < 0.00001), mean sensitivity of visual field (MD = 2.11, 95% CI [1.90, 2.32], P < 0.00001), the latent period of P-VEP100 (MD = -6.80, 95% CI [-8.94, -4.66], P < 0.00001), the total effectiveness (264 eyes) (OR = 3.22, 95% CI [1.88, 5.51], P<0.0001), and the total effectiveness (344 participants) (OR = 4.29, 95% CI [2.56, 7.19], P < 0.00001). Despite statistical advantages of manual acupuncture in the literature, due to serious methodological flaws in study design, it cannot be concluded that manual acupuncture is more effective than medicine alone. It is essential that a properly controlled clinical trial is designed and controls are established to exclude placebo effects.