Explore the vast range of titles available.

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In this study, a combination of shRNA‐mediated synthetic lethality screening and transcriptomic analysis revealed the transcription factors YAP/TAZ as key drivers of Sorafenib resistance in hepatocellular carcinoma (HCC) by repressing Sorafenib‐induced ferroptosis. Mechanistically, in a TEAD‐dependent manner, YAP/TAZ induce the expression of SLC7A11, a key transporter maintaining intracellular glutathione homeostasis, thus enabling HCC cells to overcome Sorafenib‐induced ferroptosis. At the same time, YAP/TAZ sustain the protein stability, nuclear localization, and transcriptional activity of ATF4 which in turn cooperates to induce SLC7A11 expression. Our study uncovers a critical role of YAP/TAZ in the repression of ferroptosis and thus in the establishment of Sorafenib resistance in HCC, highlighting YAP/TAZ‐based rewiring strategies as potential approaches to overcome HCC therapy resistance. SYNOPSIS Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib. The transcription factors YAP and TAZ stabilize ATF4 by promoting its nuclear import to cooperatively induce expression of SLC7A11, a cystine importer critical for glutathione synthesis. Glutathione synthesis and homeostasis are required to repress ferroptosis and to maintain Sorafenib resistance in liver cancer cells. Inhibition of Glutathione synthesis re‐sensitizes Sorafenib‐resistant cancer cells to Sorafenib therapy, which then induces ferroptosis and represses tumor growth in murine liver cancer models. Pharmacological repression of the anti‐oxidant pathways regulated by YAP/TAZ and ATF4 could re‐sensitize therapy‐resistant liver cancers to Sorafenib treatment. Graphical Abstract Resistance to therapy occurs in most liver cancer patients treated with Sorafenib, and patients succumb to the disease. A synthetic lethal screen identified a regulatory circuit, which prevents ferroptosis and promotes cancer cell survival, thus promoting resistance to Sorafenib.

Background The relationships between body size changes and the risk of hypertension and metabolic dysfunction-associated steatotic liver disease (MASLD) are still unclear. This study examined the independent and combined influences of child and adult body size on the risk of adulthood hypertension and MASLD. Methods We included 226,420 participants from the UK Biobank who were free of hypertension and liver diseases. Child-to-adult body size categories were identified based on self-reported childhood body size and measured BMI in adulthood. Cox proportional hazard regression models were applied to assess the associations between body size categories and the incidence of hypertension and MASLD. Mediation analyses to address the effect of anthropometric measures and metabolic risk factors were also performed. Results After a median follow-up of approximately 13 years, 28,662 individuals had developed hypertension ( N  = 27,624) and/or MASLD ( N  = 1,692). Low body size in childhood increased the risk of adulthood hypertension and MASLD, regardless of adult body size. Individuals with low child body size and high adult body size exhibited the highest risk for both hypertension (HR 2.01, P  < 0.001) and MASLD (HR 3.28, P  < 0.001). Individuals who had high child body size but average body size in adulthood had risks of the two diseases that were similar to those of persons who had an average body size consistently (all P  > 0.05). Body size changes influenced hypertension through significant natural direct effects and indirect effects via anthropometric and metabolic factors, while their impact on MASLD was primarily mediated by these factors without significant direct effects. Conclusions Childhood leanness exacerbates the risk of hypertension and MASLD in adulthood. Within the follow-up period, normal adult body size would mitigate the detrimental effects of childhood obesity. Thus, attention should be given to reinforcing weight management in children by implementing evidence-based strategies.

Ferroptosis is an emerging form of regulated cell death in an oxidative stress- and iron-dependent manner, primarily induced by the over-production of reactive oxygen species (ROS). Manipulation of ferroptosis has been considered a promising therapeutic approach to inhibit liver tumor growth. Nevertheless, the development of resistance to ferroptosis in liver cancer poses a significant challenge in cancer treatment. Post-translational modifications (PTMs) are crucial enzymatic catalytic reactions that covalently regulate protein conformation, stability and cellular activities. Additionally, PTMs play pivotal roles in various biological processes and divergent programmed cell death, including ferroptosis. Importantly, key PTMs regulators involved in ferroptosis have been identified as potential targets for cancer therapy. PTMs function of two proteins, SLC7A11, GPX4 involved in ferroptosis resistance have been extensively investigated in recent years. This review will summarize the roles of PTMs in ferroptosis-related proteins in hepatocellular carcinoma (HCC) treatment.

States are key actors in global health governance, particularly in the prevention and control of infectious diseases. The emergence and re-emergence of infectious diseases in recent decades pose profound challenges to global health security. As the first coronavirus pandemic, the COVID-19 caused significant damage worldwide, but responses and outcomes varied greatly among states. Using COVID-19 as an example, this study aims to compare the policies and measures implemented by different states during the COVID-19 pandemic and to synthesize experiences to strengthen global health governance for future infectious disease crises. We used Arksey and O'Malley's five-stage scoping review framework and PRISMA methodology was used for literature search and decision on relevant studies. English databases were searched using combinations of keywords and articles examining COVID-19 prevention and control policies in representative countries were included. A comparative analysis across these four states (United States, Sweden, India, and Nigeria) was then conducted to analyse the differences, rationale, and challenges of the approaches taken by these states. A total of 36 studies were included in the analysis. The management of the COVID-19 by states is divided into two main categories: domestic governance and international governance. Domestically, the United States and India have taken more measures, yet notable disparities in infection source control, transmission interruption, vulnerable population protection, collaborative governance, and so on were observed among all four states. Globally, the United States and Sweden were more proactive in international governance, and all four states have variations in their adherence to global regulations, information sharing, resource distribution, and cooperative engagement. Significant disparities occurred during the response to early COVID-19 in four states, which may be due to differences in politics, economy, and culture. To prevent and mitigate the impact of infectious diseases, states should, in future, prioritize solidarity and cooperation, and improve governance domestically and internationally based on national contexts and global health principles.

States are key actors in global health governance, particularly in the prevention and control of infectious diseases. The emergence and re-emergence of infectious diseases in recent decades pose profound challenges to global health security. As the first coronavirus pandemic, the COVID-19 caused significant damage worldwide, but responses and outcomes varied greatly among states. Using COVID-19 as an example, this study aims to compare the policies and measures implemented by different states during the COVID-19 pandemic and to synthesize experiences to strengthen global health governance for future infectious disease crises. We used Arksey and O'Malley's five-stage scoping review framework and PRISMA methodology was used for literature search and decision on relevant studies. English databases were searched using combinations of keywords and articles examining COVID-19 prevention and control policies in representative countries were included. A comparative analysis across these four states (United States, Sweden, India, and Nigeria) was then conducted to analyse the differences, rationale, and challenges of the approaches taken by these states. A total of 36 studies were included in the analysis. The management of the COVID-19 by states is divided into two main categories: domestic governance and international governance. Domestically, the United States and India have taken more measures, yet notable disparities in infection source control, transmission interruption, vulnerable population protection, collaborative governance, and so on were observed among all four states. Globally, the United States and Sweden were more proactive in international governance, and all four states have variations in their adherence to global regulations, information sharing, resource distribution, and cooperative engagement. Significant disparities occurred during the response to early COVID-19 in four states, which may be due to differences in politics, economy, and culture. To prevent and mitigate the impact of infectious diseases, states should, in future, prioritize solidarity and cooperation, and improve governance domestically and internationally based on national contexts and global health principles.

Understanding the mechanisms underlying evasive resistance in cancer is an unmet medical need to improve the efficacy of current therapies. In hepatocellular carcinoma (HCC), aberrant expression of hypoxia-inducible factor 1 α (HIF1α) and increased aerobic glycolysis metabolism are drivers of resistance to therapy with the multi-kinase inhibitor Sorafenib. However, it has remained unknown how HIF1α is activated and how its activity and the subsequent induction of aerobic glycolysis promote Sorafenib resistance in HCC. Here, we report the ubiquitin-specific peptidase USP29 as a new regulator of HIF1α and of aerobic glycolysis during the development of Sorafenib resistance in HCC. In particular, we identified USP29 as a critical deubiquitylase (DUB) of HIF1α, which directly deubiquitylates and stabilizes HIF1α and, thus, promotes its transcriptional activity. Among the transcriptional targets of HIF1α is the gene encoding hexokinase 2 (HK2), a key enzyme of the glycolytic pathway. The absence of USP29, and thus of HIF1α transcriptional activity, reduces the levels of aerobic glycolysis and restores sensitivity to Sorafenib in Sorafenib-resistant HCC cells in vitro and in xenograft transplantation mouse models in vivo. Notably, the absence of USP29 and high HK2 expression levels correlate with the response of HCC patients to Sorafenib therapy. Together, the data demonstrate that, as a DUB of HIF1α, USP29 promotes Sorafenib resistance in HCC cells, in parts by upregulating glycolysis, thereby opening new avenues for therapeutically targeting Sorafenib-resistant HCC in patients.

Background The introduction of novel therapeutic agents has transformed the treatment landscape and significantly improved survival outcomes for patients with multiple myeloma (MM). However, the effects of these advancements on health-related quality of life (HRQoL) and financial toxicity in real-world settings remain insufficiently explored. The aim of this study was to investigate HRQoL and financial toxicity among Chinese patients with MM in the era of novel agents. Methods In this longitudinal, multicentre, real-world study, data from Chinese patients with MM were collected between March 2021 and July 2023. HRQoL was assessed using the EQ-5D-5 L, EQ-VAS and FACT-MM, while financial toxicity was measured using the Comprehensive Score for Financial Toxicity (COST). Patients were evaluated at baseline and at 3-, 6-, 12-, and 24-month follow-up visits. Mixed-effect models were employed to examine the factors associated with HRQoL and financial toxicity over time. Results A total of 441 patients were surveyed at baseline, with 412 (93.5%), 371 (84.1%), 335 (76.0%), and 253 (57.4%) completing the follow-up visits at 3, 6, 12, and 24 months, respectively. At baseline, the mean EQ-5D-5 L, EQ-VAS, FACT-MM, and COST scores were 0.79 (SD = 0.25), 81.96 (SD = 18.73), 117.46 (SD = 21.76), and 21.84 (SD = 5.78), respectively. The EQ-5D-5 L utility values and FACT-MM scores at follow-up visits were significantly higher than those at baseline, whereas the COST scores were significantly lower. Mixed-effect model analyses revealed that higher levels of financial toxicity were significantly associated with lower HRQoL (EQ-5D-5 L: β = 0.006, p  < 0.001; FACT-MM: β = 1.60, p  < 0.001). Moreover, significant interaction effects between socioeconomic status and COST were observed for both the EQ-5D-5 L (β = −0.001, p  < 0.001) and the FACT-MM (β = −0.12, p  < 0.001). Conclusions HRQoL improved moderately over the 24-month follow-up period, whereas financial toxicity progressively worsened. Greater financial toxicity was significantly associated with poorer HRQoL, particularly among patients with lower SES. These findings may inform future health policy development and economic evaluations aimed at improving the quality of care and financial well-being of patients with MM.

Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy. The autophagic and Hippo pathways are both well characterized contributors to cancer. Here, Tang et al show that LATS1, but not LATS2, negatively regulates autophagy by promoting Beclin1 ubiquitination, which restricts lethal autophagy induced by sorafenib treatment in cancer cells.

Background As the number of randomized clinical trials (RCTs) demonstrating the survival benefits of combination therapies in previously treated multiple myeloma (MM) patients increases, it is essential to determine the most cost-effective treatment through robust economic evaluation. This study aims to assess the cost-effectiveness of combination therapies for first/second-relapse MM patients from the perspective of the Chinese healthcare system. Methods A Markov model was developed to evaluate three combination therapy groups based on primary drugs (bortezomib, lenalidomide, and carfilzomib). The economic evaluation was conducted within each group individually, rather than across different groups. Clinical inputs for the model were derived from RCT reports, while healthcare costs were sourced from the Zhejiang Province bidding database and a retrospective analysis. Utility values were obtained through an on-site survey using the Chinese version of the EuroQoL Five-dimensional Five-level Questionnaire. One-way and probabilistic sensitivity analyses were performed to assess the robustness of the base-case results. Results In the bortezomib group, bortezomib-dexamethasone (Vd) yielded 2.42 quality-adjusted life years (QALYs) at a cost of ¥783,775. With a willingness-to-pay (WTP) threshold of three times the 2023 per capita GDP in China (¥258,074), pomalidomide-bortezomib-dexamethasone was the most cost-effective therapy (¥86,129/QALY) in this group. In the lenalidomide group, lenalidomide-dexamethasone (Rd) resulted in 3.06 QALYs at a cost of ¥840,509. Compared to Rd, the incremental cost-effectiveness ratios (ICERs) of elotuzumab-lenalidomide-dexamethasone (¥5,095,300/QALY), ixazomib-lenalidomide-dexamethasone (¥1,605,712/QALY), carfilzomib-lenalidomide-dexamethasone (¥955,255/QALY), and daratumumab-lenalidomide-dexamethasone (¥851,933/QALY) all exceeded the WTP threshold. In the carfilzomib group, carfilzomib-dexamethasone (Kd) resulted in 3.19 QALYs at a cost of ¥1,961,624. Compared to Kd, the ICERs of daratumumab-carfilzomib-dexamethasone (¥2,250,821/QALY) and isatuximab-carfilzomib-dexamethasone (¥4,977,964/QALY) also exceeded the WTP. Sensitivity analyses confirmed the robustness of the base-case results. Conclusions Although this study did not fully account for the heterogeneity of subsequent treatment regimens among first/second-relapse MM patients, it highlights that the substantial financial burden associated with combination therapies involving novel agents poses a significant challenge in justifying their economic value.

Although smart senior care services offer numerous benefits, they have not yet gained widespread acceptance among the general populace, particularly seniors. Numerous related issues have surfaced, with the structural imbalance between supply and demand being most prominent. Currently, there is a lack of research distinguishing between the various categories of demand for smart ageing services and the associated behaviors of older individuals. In this study, we aimed to identify the types of demand and utilization of smart senior care services among Chinese older adults to understand their diverse characteristics and the factors that facilitate certain behaviors. We also analyzed the imbalance between supply and demand for smart senior care services and explored the factors influencing it, thereby providing a reference for optimizing smart senior services. We conducted a cross-sectional study from January to March 2023 and analyzed 1037 valid questionnaires. Three types of smart senior care services were investigated: intelligent information, intelligent consultation, and intelligent monitoring. We identified the demand, utilization, and supply of these services among older individuals. Latent class analysis (LCA) was used to differentiate the heterogeneity of older adults in terms of service demand and utilization. Factors influencing service preferences were analyzed using binary logistic regression based on Andersen's behavioral model. Based on the LCA findings, service demand, and utilization were divided into two categories: positive demand (desire to use the services) or negative demand, and taking action or negative action to use the services. The persons with high demand but low utilization comprised the largest number of older people in this study (69.35%). The results indicated that the number of children (odds ratio (OR) = 1.491), community-provided smart devices (OR = 1.700), number of chronic diseases (OR = 1.218), and self-care capacity (OR = 0.214) are associated with positive demand. Meanwhile, pre-retirement employment, income sources, community device provided, community promotion, region, and self-care ability were significant predictors (p < 0.05) of taking action to use the services. In terms of community supply outcome, income situation had a significant effect on intelligent information services. Income sources were associated with intelligent information and intelligent monitoring services. Pre-retirement employment and housing type variables showed effect on IC services. Community promotion and self-care ability were associated with all three types of service supply (p < 0.05). Older adults expressed a strong demand for smart ageing services; however, difficulties using smart technology remain a serious problem. Further investigation of how family support contributes to the perception and use of care services for older people is needed. Specific policies, such as financial assistance, should be established to support service use. Communities should expand their support and promotion of smart ageing services, focusing on enhancing digital health literacy among seniors to facilitate product utilization. Furthermore, personalized recommendations and applications tailored to the physical conditions of older adults are essential.