An integrative pan-cancer analysis of WWC family genes and functional validation in lung cancer.

The WW and C2 domain containing (WWC) protein family functions as scaffolds regulating cell proliferation and organ growth control through the Hippo signaling pathway. However, their pan-cancer dysregulation and mechanistic roles in signaling transduction have remained unclear. We performed integrated pan-cancer analyses of WWC family gene expression using data from The Cancer Genome Atlas (TCGA) across 33 different cancer types. Prognostic relevance was evaluated by survival analyses. WWC genetic alterations, DNA methylation, pathway activities, drug response, and tumor immunology were analyzed using online databases. Furthermore, we examined the functional roles of WWCs in lung cancer cells. We observed aberrant WWC expression in various cancers, which associated with patient prognosis. WWC hypermethylation occurred in many cancers and exhibited negative correlation with expression, alongside mutations linked to poor outcomes. Pathway analysis implicated WWCs as Hippo pathway scaffolds, while drug sensitivity analysis suggested associations with diverse chemotherapies. Additionally, pan-cancer analyses elucidated vital immunomodulatory roles for WWC through heterogeneous correlations with immune cell infiltrates, checkpoint molecules, tumor mutation burden, microsatellite instability, and chemokine pathways across cancers. Experimentally, WWCs suppressed lung cancer cell proliferation, migration, and invasion while enhancing apoptosis and paclitaxel chemosensitivity. Mechanistically, WWCs bound large tumor suppressor 1 and 2 (LATS1/2) kinases to stimulate phosphorylation cascades, thereby inhibiting nuclear translocation of the Yes-associated protein (YAP) oncoprotein. Taken together, our multi-omics characterization provides comprehensive evidence for WWCs as putative tumor suppressors across cancers via Hippo pathway modulation. WWCs may serve as prognostic markers and therapeutic targets in lung cancer.

Femoral nerve block using lower concentration ropivacaine preserves quadriceps strength while providing similar analgesic effects after knee arthroscopy.

PURPOSE: Femoral nerve block (FNB) is widely used in patients undergoing knee arthroscopy. However, the most commonly used concentration of ropivacaine (0.2% or above) may cause an unexpected decrease in the muscle strength of the quadriceps. Therefore, a lower concentration of ropivacaine (0.1%) for FNB was administered to investigate the effect on quadriceps strength and postoperative pain after knee arthroscopy. METHODS: This was a double-blind, randomized, controlled trial (ChiCTR2000041404). A total of 83 patients scheduled for elective knee arthroscopy were randomized to receive 0.1% or 0.2% ropivacaine for FNB under ultrasound guidance. The primary outcomes were quadriceps strength and numerical rating scale (NRS) pain score. Quadriceps strength was measured before surgery and 6 h and 24 h after surgery, while NRS score was recorded before surgery, at the postanaesthesia care unit (PACU), and 6 h and 24 h after surgery. Multiple linear regression tests were used to compare the differences in quadriceps strength and NRS score between the two groups. Two-factor analysis of variance, using the factors group and time of measurement, was used for repeated NRS scores. Secondary outcomes included knee mobility, side effects, patient satisfaction, and length of hospital stay. RESULTS: The mean (SD) quadriceps strength at 6 h after surgery was 7.5 (5.7) kg for the 0.1% ropivacaine group and 3.0 (4.4) kg for the 0.2% ropivacaine group. The mean difference adjusted for baseline characteristics was - 5.2 (95% CI - 7.2 to - 3.1) kg (P < 0.001). There was no significant difference between the two groups in quadriceps strength at 24 h after surgery. The mean differences in the average NRS score and maximum NRS score in the PACU were - 0.6 (P = 0.008) and - 1.0 (P < 0.001), respectively. There was no significant difference in NRS score at 6 h or 24 h after surgery. Two-factor analysis of variance showed no significant difference in the interaction factors of time and group for average NRS score and maximum NRS score. CONCLUSIONS: Compared with 0.2% ropivacaine, 0.1% ropivacaine for FNB preserved quadriceps strength at 6 h after knee arthroscopy while providing similar analgesic effects. LEVEL OF EVIDENCE: I.