LATS2 condensates organize signalosomes for Hippo pathway signal transduction.

Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.

Cemented versus cementless Oxford unicompartmental knee arthroplasty for the treatment of medial knee osteoarthritis: an updated systematic review and meta-analysis.

OBJECTIVE: This meta-analysis sought to compare the efficacy of cemented versus cementless Oxford unicompartmental knee arthroplasty(UKA) for the treatment of medial knee osteoarthritis. METHODS: A comprehensive search of the following databases was conducted: Pubmed, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Embase, the Web of Science, and MEDLINE. The objective was to identify literature comparing cemented versus cementless Oxford unicompartmental knee arthroplasty for the treatment of medial knee osteoarthritis. Duplicate literature, low-quality literature, literature with incompatible observations, and literature for which the full text was not available were excluded. Two independent researchers employed the Cochrane Risk Assessment Tool and the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the included literature. The data then were extracted and subsequently meta-analyzed using RevMan 5.4. RESULTS: A total of 12 papers were included in the analysis, encompassing a cumulative of 2558 cumulative cases. Of these, 1258 were cemented and 1300 were cementless. A meta-analysis was conducted to compare the outcomes of cemented versus cementless Oxford UKA. The Oxford UKA group exhibited a significantly longer surgery time than the cementless Oxford UKA group [mean difference (MD) = 9.91, 95% confidence interval (CI) (7.64,12.17)]. Additionally, the cemented Oxford UKA group demonstrated a significantly lower knee OKS score compared to the cementless Oxford UKA group. The mean difference (MD) was - 1.58 (95% CI: -2.30, -0.86), indicating a significantly lower score for the cemented Oxford UKA group. Similarly, the mean difference (MD) was - 1.8 for the knee KSS clinical score, indicating a significantly lower score for the cemented Oxford UKA group. The results demonstrated that the knee KSS functional score was significantly lower in the cemented Oxford UKA group than in the cementless Oxford UKA group [MD=-1.72, 95% CI (-3.26, -0.37)]. 95% CI (-3.27,-0.17)], the cemented Oxford UKA group exhibited a significantly higher incidence of radiolucent lines around the prosthesis than the cementless Oxford UKA group [ratio of ratios (OR) = 3.62, 95% CI (1.08,12.13)]. The revision rate was significantly higher in the cemented Oxford UKA group than in the cementless Oxford UKA group [OR = 2.22, 95% CI (1.40,3.53)]. However, no significant difference was observed between the two groups in terms of reoperation rate, five-year prosthesis survival rate, and complication rate. CONCLUSIONS: The findings indicated that, in comparison to cemented Oxford UKA, cementless Oxford UKA resulted in a reduction in surgical time, an improvement in knee OKS score, KSS clinical score, and KSS functional score, and a decrease in the incidence of periprosthetic radiolucent lines and the rate of revisions.

Different modalities of patellar management in primary total knee arthroplasty: a Bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: The primary management modalities for the patella in TKA include patellar resurfacing, patellar non-resurfacing, patellar resurfacing with denervation, and patellar non-resurfacing with denervation. Traditionally, meta-analyses have predominantly focused on examining comparisons between two management modalities. However, this study performed a network meta-analysis to compare all four patellar management interventions to identify the most optimal approach for patellar management in TKA. METHODS: A computer-based search of PubMed, China National Knowledge Infrastructure (CNKI), The Cochrane Library, Web of science, Embase, and MEDLINE databases was performed to identify randomized controlled trials focusing on the four management interventions for the patella in TKA. Comparisons included two-by-two comparisons as well as those involving more than two concurrent comparisons. The search timeframe spanned from inception to June 30, 2023. Two independent authors extracted the data and evaluated the quality of the literature. The Cochrane Collaboration Risk of Bias (ROB) tool was used to evaluate the overall quality of the literature. Subsequently, a network meta-analysis was conducted using the "gemtc" package of the R-4.2.3 software. Outcome measures such as anterior knee pain (AKP), reoperation rate, and patient satisfaction rate were evaluated using odd ratio (OR) and 95% confidence intervals (CI). Additionally, the knee society score (KSS), function score (FS), and range of motion (ROM) were evaluated using mean differences (MD) with associated 95% CI. The different treatment measures were ranked using the surfaces under the cumulative ranking curves (SUCRA). RESULTS: A total of 50 randomized controlled trials involving 9,283 patients were included in the analysis. The findings from this network meta-analysis revealed that patellar resurfacing exhibited significantly lower postoperative reoperation rate (OR 0.44, 95% CI 0.24-0.63) and AKP (OR 0.58, 95% CI 0.32-1) compared to non-resurfacing. Additionally, patellar resurfacing exhibited higher postoperative KSS clinical scores in comparison with non-resurfacing (MD: 1.13, 95% CI 0.18-2.11). However, for postoperative FS, ROM, and patient satisfaction, no significant differences were observed among the four management interventions. CONCLUSION: Patellar resurfacing emerges as the optimal management modality in primary TKA. However, future studies should aim to reduce sources of heterogeneity and minimize the influence of confounding factors on outcomes. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023434418 identifier: CRD42023434418.

SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway.

The activation of YAP/TAZ, a pair of paralogs of transcriptional coactivators, initiates a dysregulated transcription program, which is a key feature of human cancer cells. However, it is not fully understood how YAP/TAZ promote dysregulated transcription for tumor progression. In this study, we employed the BioID method to identify the interactome of YAP/TAZ and discovered that YAP/TAZ interact with multiple components of SRCAP complex, a finding that was further validated through endogenous and exogenous co-immunoprecipitation, as well as immunofluorescence experiments. CUT&Tag analysis revealed that SRCAP complex facilitates the deposition of histone variant H2A.Z at target promoters. The depletion of SRCAP complex resulted in a decrease in H2A.Z occupancy and the oncogenic transcription of YAP/TAZ target genes. Additionally, the blockade of SRCAP complex suppressed YAP-driven tumor growth. In a genetically engineered lung adenocarcinoma mouse model and non-small cell lung cancer patients, SRCAP complex and H2A.Z deposition were found to be upregulated. This upregulation was statistically correlated with YAP expression, pathological stages, and poor survival in lung cancer patients. Together, our study uncovers that SRCAP complex plays a critical role in YAP/TAZ oncogenic transcription by coordinating H2A.Z deposition during cancer progression, providing potential targets for cancer diagnosis and prevention.