Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics

It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities

AW-NI-5: COST-EFFECTIVENESS OF INTENSIVE VERSUS STANDARD BLOOD-PRESSURE CONTROL AMONG HYPERTENSIVE PATIENTS IN TAIWAN: A SIMULATION MODELLING STUDY

Objective: Based on the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial and A Randomized Trial of Intensive versus Standard Blood-Pressure Control (SPRINT) trial, the 2022 Taiwan hypertension guidelines recommend the definition of hypertension as 130/80mmHg and a universal BP target of \u3c 130/80 mmHg. Based on the guidelines, we aimed to analyze the lifetime cost-effectiveness of intensive versus standard blood-pressure control from the perspective of Taiwan national payer. Design and method: A simulation model was employed to apply the SPRINT treatment effects for hypertensive patients aged 50–54 and 55–64 years and STEP treatment effects for those aged 65–74 and 75+ years. The medical costs and utility were extracted from national sources or published data to a hypothetical cohort of SPRINT-eligible and STEP-eligible patients in Taiwan. Incremental cost-effectiveness ratio (ICER) against the willing-to-pay threshold at the one-time gross domestic product (GDP) per capita was used to evaluate whether intensive versus standard blood-pressure control was cost-effective. Results: Intensive blood-pressure control produced more lifetime medical costs than standard control, i.e., US$39,348–22,978 versus US$20,239–33,414, while intensive treatment also contributed to more quality-adjusted life-year (QALY), i.e., 7.60–16.28 versus 7.37–15.74. ICER values of intensive versus standard treatment were approximate US$10,989 (NT$329,670), US$11,220(NT$336,600), US$11,485(NT$344,550), and US$11,865(NT$355,950) per QALY gained for hypertensive patients aged 50–54, 55–64, 65–74, and 75+ from the perspective of Taiwanese national payer. Simulation results indicated that intensive treatment is very likely to be cost-effective, i.e., all probabilities are greater than 99.8% below the willing-to-pay threshold of US$36,000 (NT$1,080,000). Conclusions: In this simulation study, intensive blood-pressure control in the Taiwanese population produced fewer cardiovascular events and acceptable costs per QALY gained, enormously below the willing-to-pay threshold. The cost-effectiveness of intensive blood-pressure control was consistent across different ages, and the advantage was more predominant in younger hypertensive patients

Rational design of Al2O3/2D perovskite heterostructure dielectric for high performance MoS2 phototransistors.

Two-dimensional (2D) Ruddlesden-Popper perovskites are currently drawing significant attention as highly-stable photoactive materials for optoelectronic applications. However, the insulating nature of organic ammonium layers in 2D perovskites results in poor charge transport and limited performance. Here, we demonstrate that Al2O3/2D perovskite heterostructure can be utilized as photoactive dielectric for high-performance MoS2 phototransistors. The type-II band alignment in 2D perovskites facilitates effective spatial separation of photo-generated carriers, thus achieving ultrahigh photoresponsivity of >108 A/W at 457 nm and >106 A/W at 1064 nm. Meanwhile, the hysteresis loops induced by ionic migration in perovskite and charge trapping in Al2O3 can neutralize with each other, leading to low-voltage phototransistors with negligible hysteresis and improved bias stress stability. More importantly, the recombination of photo-generated carriers in 2D perovskites depends on the external biasing field. With an appropriate gate bias, the devices exhibit wavelength-dependent constant photoresponsivity of 103-108 A/W regardless of incident light intensity

Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor

Backgrounds Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are limited in solid tumors due to the hostile tumor microenvironment (TME). Combination therapy could be a promising approach to overcome this obstacle. Recent studies have shown that sphingosine 1-phosphate receptor (S1PR)3 has tremendous potential in regulating the immune environment. However, the functional significance of S1PR3 in T-cell-based immunotherapies and the molecular mechanisms have not been fully understood.Methods Here, we studied the combination of EpCAM-specific CAR T-cell therapy with pharmacological blockade of S1PR3 against solid tumor. We have applied RNA sequencing, flow cytometry, ELISA, cellular/molecular immunological technology, and mouse models of solid cancers.Results Our study provided evidence that S1PR3 high expression is positively associated with resistance to programmed cell death protein-1 (PD-1)-based immunotherapy and increased T-cell exhaustion. In addition, pharmacological inhibition of S1PR3 improves the efficacy of anti-PD-1 therapy. Next, we explored the possible combination of S1PR3 antagonist with murine EpCAM-targeted CAR-T cells in immunocompetent mouse models of breast cancer and colon cancer. The results indicated that the S1PR3 antagonist could significantly enhance the efficacy of murine EpCAM CAR-T cells in vitro and in vivo. Mechanistically, the S1PR3 antagonist improved CAR-T cell activation, regulated the central memory phenotype, and reduced CAR-T cell exhaustion in vitro. Targeting S1PR3 was shown to remodel the TME through the recruitment of proinflammatory macrophages by promoting macrophage activation and proinflammatory phenotype polarization, resulting in improved CAR-T cell infiltration and amplified recruitment of CD8+T cells.Conclusions This work demonstrated targeting S1PR3 could increase the antitumor activities of CAR-T cell therapy at least partially by inhibiting T-cell exhaustion and remodeling the TME through the recruitment of proinflammatory macrophages. These findings provided additional rationale for combining S1PR3 inhibitor with CAR-T cells for the treatment of solid tumor

Cost‐effectiveness analysis of cabozantinib as second‐line therapy in advanced hepatocellular carcinoma

BackgroundIn the CELESTIAL trial for patients with advanced hepatocellular carcinoma (HCC), cabozantinib showed improved survival compared with placebo but comes at a price. We aimed to investigate the cost‐effectiveness of cabozantinib for sorafenib‐resistant HCC from the payer’s perspective of the USA, UK and China.MethodsWe developed Markov models to simulate the patients pre‐treated with first‐line sorafenib following the CELESTIAL trial. Quality‐adjusted life‐years (QALYs) and incremental cost‐effectiveness ratio (ICER) were calculated for the treatment with cabozantinib or best supportive care. The list price for drugs was acquired from the Red Book, the British National Formulary, West China hospital and reported literature. Adverse events, utilities weights, and transition likelihood between states were sourced from the published randomized phase III trial. A willing‐to‐pay threshold was set $150 000/QALY in the USA,$70 671/QALY (£50 000/QALY) in the UK and $26 481/QALY (3x GDP per capita) in China. Deterministic and probabilistic sensitivity analyses were developed to test the models’ uncertainty.ResultsIn the base case, treatment with cabozantinib increased effectiveness by 0.13 QALYs, resulting in an ICER vs best supportive care of$833 497/QALY in the USA, $304 177/QALY in the UK and$156 437/QALY in China. The models were most sensitive to assumptions about transitions to progression with both cabozantinib and best supportive care, the utility associated with being progression free. These results were robust across a range of scenarios and sensitivity analyses, including deterministic and probabilistic analyses.ConclusionsCabozantinib at its current cost would not be a cost‐effective treatment option for patients with sorafenib‐resistant HCC from the payer’s perspective in the USA, UK or China. Substantial discounts are necessary to meet conventional cost‐effectiveness thresholds.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152595/1/liv14257_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152595/2/liv14257.pd

Surveillance of Liver Function in Uveitis with or without Chronic HBV Infection

INTRODUCTION: Immunosuppressive therapy for uveitis may cause liver damage. METHODS: To investigate incidence of liver damage during uveitis treatment, we compared serological Hepatitis B core antibody (HBcAb) status with risk of liver dysfunction in all participants (n = 992), in anterior uveitis (AU) (n = 489), and combined of intermediate, posterior, or panuveitis (IPPU) patients (n = 503). The primary endpoint was incidence of elevated serum alanine aminotransferase level above 2-fold upper limits of normal within 6 months. RESULTS: The incidence rate of primary endpoint for HBcAb-negative and HBcAb-positive patients was 65 and 212 per 1,000 person years, respectively. The absolute rate difference was 147 (95% confidence interval [CI], 80-213) per 1,000 person years. HBcAb positivity was associated with a higher risk for primary endpoint in all participants (adjusted hazard ratio [aHR], 3.53; 95% CI, 1.79-6.99; p value = 2.8 × 10-4) and in IPPU (aHR, 3.80; 95% CI, 1.61-9.01; p value = 0.002). No significant association with primary endpoint was observed for HBcAb positivity in AU (aHR, 3.21; 95% CI, 0.94-10.95; p value = 0.063). AU was mainly treated with topical eye drops (74.0%), whereas IPPU cases received systemic therapy including prednisone (94.0%), cyclosporine (80.9%), or other additionally combined immunomodulatory agents (14.9%). CONCLUSION: Noninfectious uveitis cases with HBcAb positivity have an increased risk of liver damage. This association was predominantly driven by IPPU but was not significant in AU, suggesting that the association is mediated by systemic therapy

Surveillance of Liver Function in Uveitis with or without Chronic HBV Infection

INTRODUCTION: Immunosuppressive therapy for uveitis may cause liver damage. METHODS: To investigate incidence of liver damage during uveitis treatment, we compared serological Hepatitis B core antibody (HBcAb) status with risk of liver dysfunction in all participants (n = 992), in anterior uveitis (AU) (n = 489), and combined of intermediate, posterior, or panuveitis (IPPU) patients (n = 503). The primary endpoint was incidence of elevated serum alanine aminotransferase level above 2-fold upper limits of normal within 6 months. RESULTS: The incidence rate of primary endpoint for HBcAb-negative and HBcAb-positive patients was 65 and 212 per 1,000 person years, respectively. The absolute rate difference was 147 (95% confidence interval [CI], 80-213) per 1,000 person years. HBcAb positivity was associated with a higher risk for primary endpoint in all participants (adjusted hazard ratio [aHR], 3.53; 95% CI, 1.79-6.99; p value = 2.8 × 10-4) and in IPPU (aHR, 3.80; 95% CI, 1.61-9.01; p value = 0.002). No significant association with primary endpoint was observed for HBcAb positivity in AU (aHR, 3.21; 95% CI, 0.94-10.95; p value = 0.063). AU was mainly treated with topical eye drops (74.0%), whereas IPPU cases received systemic therapy including prednisone (94.0%), cyclosporine (80.9%), or other additionally combined immunomodulatory agents (14.9%). CONCLUSION: Noninfectious uveitis cases with HBcAb positivity have an increased risk of liver damage. This association was predominantly driven by IPPU but was not significant in AU, suggesting that the association is mediated by systemic therapy