Goodman (Japan)

Mitochondrial homeostasis is maintained through complex regulatory mechanisms, including the balance of mitochondrial dynamics involving fusion and fission processes. A central player in this regulation is the ubiquitin-proteasome system (UPS), which controls the degradation of pivotal mitochondrial proteins. In this study, we identified cullin-RING E3 ligase 2 (CRL2) and its substrate receptor, FEM1B, as critical regulators of mitochondrial dynamics. Through proteomic analysis, we demonstrate here that FEM1B controls the turnover of PLD6, a key regulator of mitochondrial dynamics. Using structural and biochemical approaches, we show that FEM1B physically interacts with PLD6 and that this interaction is facilitated by the direct association of FEM1B with the mitochondrial import receptor TOM20. Ablation of FEM1B or disruption of the FEM1B-TOM20 interaction impairs PLD6 degradation and induces mitochondrial defects, phenocopying PLD6 overexpression. These findings underscore the importance of FEM1B in maintaining mitochondrial morphology and provide further mechanistic insights into how the UPS regulates mitochondrial homeostasis.

Abstract Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). Although essential in muscle, we identified ETF dehydrogenase (ETFDH) as one of the most dispensable metabolic genes in neoplasia, and its expression is reduced across human cancers. ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilization but paradoxically increases cancer cell bioenergetics and accelerates neoplastic growth by retrograde activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerate neoplastic growth.

The brown alga Padina (Dictyotales, Ochrophyta) is found worldwide, predominantly in tropical to subtropical waters. Due to their similar appearances, distinguishing between different Padina species is challenging. Historically, morphological characte

Abstract Genomic germline and somatic variations may impact drug binding and even lead to resistance. However, designing a different drug for each mutant may not be feasible. In this study, we identified the most common cancer somatic mutations from the Catalogue of Somatic Mutations in Cancer (COSMIC) that occur in structurally characterized binding sites of approved therapeutic antibodies. We found two HER2 mutations, S310Y and S310F, that substantially compromise binding of Pertuzumab, a widely used therapeutics, and lead to drug resistance. To address these mutations, we designed a multi-specific version of Pertuzumab, that retains original function while also bindings these HER2 variants. This new antibody is stable and inhibits HER3 phosphorylation in a cell-based assay for all three variants, suggesting it can inhibit HER2-HER3 dimerization in patients with any of the variants. This study demonstrates how a small number of carefully selected mutations can add new specificities to an existing antibody without compromising its original function, creating a single therapeutic antibody that targets multiple common variants, making a drug that is not personalized yet its activity may be.

Access to care varies between countries. It is theorized that income-based disparities in access may be reduced in countries with universal health insurance relative to the United States, but data are currently limited. We hypothesized that income-based differences in total hip arthroplasty (THA) utilization and outcomes would be larger in the United States than in Canada. We retrospectively compared all patients undergoing THA from 2012 to 2018 in Pennsylvania, the United States, and Ontario, Canada. We compared age-standardized and sex-standardized per-capita THA utilization in the United States and Canada overall and across different income strata, where income strata were defined by neighborhood income quintile. We also examined income-based differences in rates of 1-year revision, 90-day mortality, and 90-day readmission. Overall THA utilization per 10,000 people per year was higher across all income groups in Pennsylvania compared with Ontario (15.1 versus 8.8, P < 0.001 in lowest-income quintile; 21.4 versus 12.6, P < 0.001 in highest-income quintile). Income-based differences in utilization in the highest-income vs lowest-income quintile groups were greater in Ontario (43.2%) than Pennsylvania (41.7%). The adjusted odds for the lowest-income group compared with the highest-income group of 1-year revision were greater in Ontario compared with Pennsylvania ( P = 0.03), and risk of 90-day mortality and 90-day readmission was similar between the regions. Income-based differences in THA utilization were more notable in Ontario than in Pennsylvania. In addition, patients in low-income communities in Ontario were at equal or greater risk relative to high-income community patients for adverse outcomes compared with patients in Pennsylvania. Income-based disparities in THA utilization and outcomes were smaller in the United States than in Canada, in contrast to what might be expected. III.

Abstract Genomic germline and somatic variations may impact drug binding and even lead to resistance. However, designing a different drug for each mutant may not be feasible. In this study, we identified the most common cancer somatic mutations from the Catalogue of Somatic Mutations in Cancer (COSMIC) that occur in structurally characterized binding sites of approved therapeutic antibodies. We found two HER2 mutations, S310Y and S310F, that substantially compromise binding of Pertuzumab, a widely used therapeutics, and lead to drug resistance. To address these mutations, we designed a multi-specific version of Pertuzumab, that retains original function while also bindings these HER2 variants. This new antibody is stable and inhibits HER3 phosphorylation in a cell-based assay for all three variants, suggesting it can inhibit HER2-HER3 dimerization in patients with any of the variants. This study demonstrates how a small number of carefully selected mutations can add new specificities to an existing antibody without compromising its original function, creating a single drug that targets multiple common variants, making a drug that is not personalized yet its activity may be.

Copy number gains in genes coding for Rho activating exchange factors as well as losses affecting genes coding for RhoGAP proteins are common in breast cancer (BC), suggesting that elevated Rho signaling may play an important role. Extra copies and overexpression of RHOC also occur, although a role for RhoC overexpression in driving tumor formation has not been assessed in vivo. To this end, we report on the development of a Rosa26 (R26)-targeted Cre-conditional RhoC overexpression mouse (R26RhoC). This mouse was crossed to two models for ERBB2/NEU+ breast cancer: one based on expression of an oncogenic ErbB2/Neu cDNA downstream of the endogenous ErbB2 promoter (FloxNeoNeuNT), the other, a metastatic model that is based on high-level expression from MMTV regulatory elements (NIC). RhoC overexpression dramatically enhanced mammary tumor formation in FloxNeoNeuNT mice but showed a more subtle effect in the NIC line, which forms multiple mammary tumors after a very short latency. RhoC overexpression also enhanced mammary tumor formation in an activated Pik3ca model for breast cancer (Pik3caH1047R). The transforming effect of RhoC was associated with epithelial/mesenchymal transition (EMT) in ErbB2/NeuNT and Pik3caH1047R systems. Thus, our study reveals the importance of elevated wildtype Rho protein expression as a driver of breast tumor formation and highlights the significance of Copy Number Abberations that affect Rho signalling.