OTUB1/NDUFS2 axis promotes pancreatic tumorigenesis through protecting against mitochondrial cell death.

Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

Terminal deoxynucleotidyl transferase expression in different subtypes of childhood B-cell acute lymphoblastic leukemia.

The lack of expression of terminal deoxynucleotidyl transferase (TdT) is frequently associated with KMT2A-rearranged subtype of pediatric acute lymphoblastic leukemia (ALL). However, this association has not been investigated extensively in the Asian population. A retrospective analysis of TdT expression in pediatric B-cell ALL (B-ALL) was performed in patients treated using the Taiwan Pediatric Oncology Group (TPOG) ALL 2002 and 2013 protocols. Among the 331 patients with B-ALL, 12 patients showed TdT negativity at initial diagnosis. Among these, eight patients showed KMT2A rearrangement (66.7%). Other patients showing negative TdT expression had ETV6::RUNX1, MEF2D-rearranged, and other B-ALL subtypes. However, in the context of KMT2A-rearranged B-ALL (n = 20), only eight patients showed TdT negativity. The 5-year event-free survival and overall survival of patients with and without TdT expression were 83.8% versus 46.8% (P <0.001) and 86.3% versus 55.4% (P = 0.004), respectively. Moreover, several aberrant markers, such as CD2, CD56, CD7, and CD117, were rarely expressed in the B-ALL samples, and if expressed, they were enriched in specific genetic subtypes. The results of this study indicate that immunophenotypic features are correlated with specific genetic subtypes of childhood B-ALL.

Predictive Model of Restart-Up Pressure Drop after Shutdown for Heavy Oil-Water Ring Transportation Pipeline.

Aiming at the problem of restart-up for a heavy oil-water ring transportation pipeline due to instability and damage of the water ring, based on the self-developed design of a small indoor loop simulation experimental device and taking four kinds of ordinary heavy oil in the Lvda oilfield as the research object, the change trend of restart-up pressure drop with time is experimentally studied when the pipeline is restarted-up after shutdown at a constant water flow. On the basis of the regression analysis of the orthogonal restart-up experimental data of four factors (oil holdup, oil viscosity, standstill period, and water cleaning superficial velocity) and mixed levels by the statistical product and service solutions statistical analysis software, a multivariate nonlinear restart-up maximum pressure drop prediction model is established. Through analysis of the characteristics of each stage of the restart-up process, an exponential decay model of restart-up pressure drop with time is created. The research results show that the variations in restart-up pressure drop with time can be divided into two stages: the attenuation stage and the equilibrium stage. The predicted value of restart-up pressure drop with time is in good agreement with the measured one, and the goodness of fit is very close to 1. The maximum restart-up pressure drop rises along with the increase in oil holdup, oil viscosity, standstill period, and water cleaning superficial velocity. The restart-up time prolongs with the increase in oil holdup, oil viscosity, and standstill period but shortens with the increase in water cleaning superficial velocity.

A new illudane sesquiterpene from the edible fungus Pholiota nameko.

Fungi have different genetic expression abilities and biosynthetic pathways under different cultivation conditions, which can produce various secondary metabolites. The "one strain many compounds" strategy is used to activate silent biosynthetic genes of fungi to produce various compounds, which is an effective method. In order to discover various new compounds in the edible fungus Pholiota nameko, a fermentation strategy involving precursor feeding and enzyme inhibitor addition has been employed. A new illudane sesquiterpene (1), along with one known indole diterpenoid alkaloid, cladosporine A (2) were isolated from the extracts of liquid culture of P. nameko. The new compound was identified by combination of 1D and 2D NMR, MS, optical rotation, and ECD calculations. We conducted experiments on the cytotoxicity of all isolated compounds on three cancer cell lines, but we did not observe any significant cytotoxicity (IC50 > 40 µM).

Lenvatinib plus pembrolizumab in the patients with advanced previously treated endometrial cancer: A cost-effectiveness analysis in the United States and in China.

PURPOSE: To investigate the cost-effectiveness of lenvatinib plus pembrolizumab (LP) compared to chemotherapy as a second-line treatment for advanced endometrial cancer (EC) from the United States and Chinese payers' perspective. METHODS: In this economic evaluation, a partitioned survival model was constructed from the perspective of the United States and Chinese payers. The survival data were derived from the clinical trial (309-KEYNOTE-775), while costs and utility values were sourced from databases and published literature. Total costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) were estimated. The robustness of the model was evaluated through sensitivity analyses, and price adjustment scenario analyses was also performed. RESULTS: Base-case analysis indicated that LP wouldn't be cost-effective in the United States at the WTP threshold of $200 000, with improved effectiveness of 0.75 QALYs and an additional cost of $398596.81 (ICER $531392.20). While LP was cost-effective in China, with improved effectiveness of 0.75 QALYs and an increased overall cost of $62270.44 (ICER $83016.29). Sensitivity analyses revealed that the above results were stable. The scenario analyses results indicated that LP was cost-effective in the United States when the prices of lenvatinib and pembrolizumab were simultaneously reduced by 61.95% ($26.5361/mg for lenvatinib and $19.1532/mg for pembrolizumab). CONCLUSION: LP isn't cost-effective in the patients with advanced previously treated endometrial cancer in the United States, whereas it is cost-effective in China. The evidence-based pricing strategy provided by this study could benefit decision-makers in making optimal decisions and clinicians in general clinical practice. More evidence about budget impact and affordability for patients is needed.

Associations of maternal serum concentration of iron-related indicators with birth outcomes in Chinese: a pilot prospective cohort study.

BACKGROUND: Previous studies of maternal iron and birth outcomes have been limited to single indicators that do not reflect the comprehensive relationship with birth outcomes. We aimed to investigate the relationship between maternal iron metabolism and neonatal anthropometric indicators using comprehensive iron-related indicators. METHODS: A total of 914 Chinese mother-child dyads were enrolled in this prospective study. Subjects' blood samples were collected at ≤ 14 weeks of gestation. Serum concentrations of iron-related indicators were measured by enzyme-linked immunosorbent assay (ELISA). Femur length was measured by B-ultrasound nearest delivery. Neonatal anthropometric indicators were collected from medical records. RESULTS: After adjustment for potential covariates, higher iron (per one standard deviation, SD increase) was detrimentally associated with - 0.22 mm lower femur length, whereas higher transferrin (per one SD increase) was associated with 0.20 mm higher femur length. Compared with normal subjects (10th-90th percentiles), subjects with extremely high (> 90th percentile) iron concentration were detrimentally associated with lower femur length, birth weight, and chest circumference, and a higher risk of low birth weight, LBW (HR: 3.92, 95%CI: 1.28, 12.0). Subjects with high concentration of soluble transferrin receptor, sTFR and transferrin (> 90th percentile) were associated with higher femur length. Subjects with low concentration of iron and ferritin concentrations (< 10th percentile) were associated with a higher risk of LBW (HR: 4.10, 95%CI: 1.17, 14.3) and macrosomia (HR: 2.79, 95%CI: 1.06, 7.35), respectively. CONCLUSIONS: Maternal iron overload in early pregnancy may be detrimentally associated with neonatal anthropometric indicators and adverse birth outcomes.

Ganoderic acids alleviate atherosclerosis by inhibiting macrophage M1 polarization via TLR4/MyD88/NF-κB signaling pathway.

BACKGROUND AND AIMS: Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid infiltration and plaque formation in blood vessel walls. Ganoderic acids (GA), a class of major bioactive compounds isolated from the Chinese traditional medicine Ganoderma lucidum, have multiple pharmacological activities. This study aimed to determine the anti-atherosclerotic effect of GA and reveal the pharmacological mechanism. METHODS: ApoE-/- mice were fed a high-cholesterol diet and treated with GA for 16 weeks to induce AS and identify the effect of GA. Network pharmacological analysis was performed to predict the anti-atherosclerotic mechanisms. An invitro cell model was used to explore the effect of GA on macrophage polarization and the possible mechanism involved in bone marrow dereived macrophages (BMDMs) and RAW264.7 cells stimulated with lipopolysaccharide or oxidized low-density lipoprotein. RESULTS: It was found that GA at 5 and 25 mg/kg/d significantly inhibited the development of AS and increased plaque stability, as evidenced by decreased plaque in the aorta, reduced necrotic core size and increased collagen/lipid ratio in lesions. GA reduced the proportion of M1 macrophages in plaques, but had no effect on M2 macrophages. In vitro experiments showed that GA (1, 5, 25 µg/mL) significantly decreased the proportion of CD86+ macrophages and the mRNA levels of IL-6, IL-1ß, and MCP-1 in macrophages. Experimental results showed that GA inhibited M1 macrophage polarization by regulating TLR4/MyD88/NF-κB signaling pathway. CONCLUSIONS: This study demonstrated that GA play an important role in plaque stability and macrophage polarization. GA exert the anti-atherosclerotic effect partly by regulating TLR4/MyD88/NF-κB signaling pathways to inhibit M1 polarization of macrophages. Our study provides theoretical basis and experimental data for the pharmacological activity and mechanisms of GA against AS.

NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis.

BACKGROUND: NUDT21 (Nudix Hydrolase 21) has been shown to play an essential role in multiple biological processes. Pancreatic adenocarcinoma (PAAD) is one of the most fatal cancers in the world. However, the biological function of NUDT21 in PAAD remains rarely understood. The aim of this research was to identify the prediction value of NUDT21 in diagnosis, prognosis, immune infiltration, and signal pathway in PAAD. METHODS: Combined with the data in online databases, we analyzed the expression, immune infiltration, function enrichment, signal pathway, diagnosis, and prognosis of NUDT21 in PAAD. Then, the biological function of NUDT21 and its interacted protein in PAAD was identified through plasmid transduction system and protein mass spectrometry. Expression of NUDT21 was further verified in clinical specimens by immunofluorescence. RESULTS: We found that NUDT21 was upregulated in PAAD tissues and was significantly associated with the diagnosis and prognosis of pancreatic cancer through bioinformatic data analysis. We also found that overexpression of NUDT21 enhanced PAAD cells proliferation and migration, whereas knockdown NUDT21 restored the effects through in vitro experiment. Moreover, NDUFS2 was recognized as a potential target of NUDT21.We further verified that the expression of NDUFS2 was positively correlated with NUDT21 in PAAD clinical specimens. Mechanically, we found that NUDT21 stabilizes NDUFS2 and activates the PI3K-AKT signaling pathway. CONCLUSION: Our investigation reveals that NUDT21 is a previously unrecognized oncogenic factor in the diagnosis, prognosis, and treatment target of PAAD, and we suggest that NUDT21 might be a novel therapeutic target in PAAD.

Pediatric-inspired regimen for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia: a prospective study from China.

Several international centers have used and reported pediatric-inspired regimens for adolescent and adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL). However, there is a lack of prospective data on the Chinese population. Herein, we performed a prospective study with a pediatric-inspired regimen (IH-2014 regimen) in treating adolescent and adult Ph- ALL patients in our center. From 2014 to 2021, a total of 415 patients aged between 14 and 65 years (median age, 27) were included in this study. After a median follow-up of 40.8 months, the 5-year overall survival, disease-free survival, and event-free survival rates were 53.8%, 51.1% and 45.0%, respectively. The regimen was generally well tolerated and safe, and the overall chemotherapy-related mortality was 3.6%. Age ≥ 40 years and persistent detectable minimal residual disease (MRD) post-induction were independent prognostic factors. Traditional risk factors for adult patients combined with MRD post-induction exhibit predictive significance for survival and relapse, which is helpful in the selection of subsequent treatment. Patients with high risk factors who can achieve deep MRD response after induction do not derive benefit from allogeneic hematopoietic stem cell transplantation.

Dietary consumption trend and its correlation with global cancer burden: A quantitative and comprehensive analysis from 1990 to 2019.

OBJECTIVE: The aim of this study was to estimate the effect of dietary consumption on cancer burden and formulate an effective solution. METHODS: Dietary consumption, number of cancer deaths, disability-adjusted life years, and corresponding age-standardized rates were extracted from the Global Burden of Disease Study 2019. The annual percentage change was used to quantify the temporal trends in cancer burden and dietary consumption. Age, sex, location, and sociodemographic index were stratified to further analyze the discrepancy in cancer burden attributable to dietary intake. RESULTS: Five cancers (breast, colon and rectal, tracheal, bronchus and lung, esophageal, and stomach) were documented to be associated with dietary consumption in the Global Burden of Disease database. The age-standardized death rate and age-standardized disability-adjusted life years rate in 2019 were 7.56 and 1168.77 per 100 000 population, respectively. For most cancers, the age-standardized death rate and age-standardized disability-adjusted life years rate displayed a decreasing tendency, with annual percentage change varying from -3.60 to -0.29 and from -3.64 to -0.03 from 1990 to 2019, respectively. The age-standardized death rate and age-standardized standardized disability-adjusted life years rate were higher in men than in women (9.68 vs 5.79 and 213.16 vs 129.18, respectively). In addition, the diet-related cancer burden in higher sociodemographic index regions exceeded that in lower sociodemographic index regions. CONCLUSION: Dietary consumption has a considerable influence on cancer burden, among which colon and rectal cancer burden account for the largest proportion. Increasing the intake of whole grains, milk, fiber, calcium, vegetables, and fruits and reducing the consumption of processed meat and sodium are instrumental in lowering the disease burden of cancer. The quantitative analysis of dietary consumption would provide a more detailed reference for diet-related decision makers and raise awareness of healthy dietary habits in diet management departments, food production enterprises, and the general public.

Predicting 1-, 3-, 5-, and 8-year all-cause mortality in a community-dwelling older adult cohort: relevance for predictive, preventive, and personalized medicine.

Background: Population aging is a global public health issue involving increased prevalence of age-related diseases, and concomitant burden on medical resources and the economy. Ninety-two diseases have been identified as age-related, accounting for 51.3% of the global adult disease burden. The economic cost per capita for older people over 60 years is 10 times that of the younger population. From the aspects of predictive, preventive, and personalized medicine (PPPM), developing a risk-prediction model can help identify individuals at high risk for all-cause mortality and provide an opportunity for targeted prevention through personalized intervention at an early stage. However, there is still a lack of predictive models to help community-dwelling older adults do well in healthcare. Objectives: This study aims to develop an accurate 1-, 3-, 5-, and 8-year all-cause mortality risk-prediction model by using clinical multidimensional variables, and investigate risk factors for 1-, 3-, 5-, and 8-year all-cause mortality in community-dwelling older adults to guide primary prevention. Methods: This is a two-center cohort study. Inclusion criteria: (1) community-dwelling adult, (2) resided in the districts of Chaonan or Haojiang for more than 6 months in the past 12 months, and (3) completed a health examination. Exclusion criteria: (1) age less than 60 years, (2) more than 30 incomplete variables, (3) no signed informed consent. The primary outcome of the study was all-cause mortality obtained from face-to-face interviews, telephone interviews, and the medical death database from 2012 to 2021. Finally, we enrolled 5085 community-dwelling adults, 60 years and older, who underwent routine health screening in the Chaonan and Haojiang districts, southern China, from 2012 to 2021. Of them, 3091 participants from Chaonan were recruited as the primary training and internal validation study cohort, while 1994 participants from Haojiang were recruited as the external validation cohort. A total of 95 clinical multidimensional variables, including demographics, lifestyle behaviors, symptoms, medical history, family history, physical examination, laboratory tests, and electrocardiogram (ECG) data were collected to identify candidate risk factors and characteristics. Risk factors were identified using least absolute shrinkage and selection operator (LASSO) models and multivariable Cox proportional hazards regression analysis. A nomogram predictive model for 1-, 3-, 5- and 8-year all-cause mortality was constructed. The accuracy and calibration of the nomogram prediction model were assessed using the concordance index (C-index), integrated Brier score (IBS), receiver operating characteristic (ROC), and calibration curves. The clinical validity of the model was assessed using decision curve analysis (DCA). Results: Nine independent risk factors for 1-, 3-, 5-, and 8-year all-cause mortality were identified, including increased age, male, alcohol status, higher daily liquor consumption, history of cancer, elevated fasting glucose, lower hemoglobin, higher heart rate, and the occurrence of heart block. The acquisition of risk factor criteria is low cost, easily obtained, convenient for clinical application, and provides new insights and targets for the development of personalized prevention and interventions for high-risk individuals. The areas under the curve (AUC) of the nomogram model were 0.767, 0.776, and 0.806, and the C-indexes were 0.765, 0.775, and 0.797, in the training, internal validation, and external validation sets, respectively. The IBS was less than 0.25, which indicates good calibration. Calibration and decision curves showed that the predicted probabilities were in good agreement with the actual probabilities and had good clinical predictive value for PPPM. Conclusion: The personalized risk prediction model can identify individuals at high risk of all-cause mortality, help offer primary care to prevent all-cause mortality, and provide personalized medical treatment for these high-risk individuals from the PPPM perspective. Strict control of daily liquor consumption, lowering fasting glucose, raising hemoglobin, controlling heart rate, and treatment of heart block could be beneficial for improving survival in elderly populations. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00342-4.

Long-term trend of future Cancer onset: A model-based prediction of Cancer incidence and onset age by region and gender.

OBJECTIVES: This study provided estimates of cancer incidence rate and onset age by Socio-demographic Index (SDI) regions and gender from 2020 to 2040, aiming to clarify the long-term patterns of future cancer onset. METHOD: Based on the incidence data from the Global Burden of Diseases (GBD) 2019 study, we constructed the Bayesian age-period-cohort model to calculate the age-standardized incidence rates (ASIR) of cancers from 2020 to 2040. Using the average annual percentage change (AAPC) to quantify the trends of ASIR and the onset age. In addition, the incidences in 2019 were fixed to distinguish the age onset changes caused by demographic and incidence from 2020 to 2040. RESULTS: Globally, two-thirds of cancers have escalating trends of incidence rate, and the proportion of cancer weighted average onset age above 60 years old will grow from 62% to 76% between 2020 and 2040. In five SDI regions, the proportion of weighted average onset age above 60 years old will rise above 10% in the next 20 years and increase sequentially with the rise of the SDI level. Preclude sex-specific cancers, the onset age is younger in men than in women in 2040. Rule out the influence of changing demographics, half of cancer's morbidity has a youth-oriented tendency globally, which is concentrated in hormone-related and digestive tract cancer. CONCLUSION: From 2020 to 2040, the incidence and onset age changes demonstrate marked geographic and gender variations in the cancer spectrum. Cancer incidence and onset age are predicted to continuously increase worldwide in the future.

[Effect of Sunitinib on Pyroptosis of Drug-Resistant Leukemia K562/ADR Cells and Its Pathway].

OBJECTIVE: To investigate the inducing effect of sunitinib on the death of drug-resistant leukemia K562/ADR cells and the related signaling pathway. METHODS: K562/ADR cells were treated with different concentrations of sunitinib, and the cells were collected at 24, 48, 72, and 96 hours, respectively. MTS assay was used to detect the effect of sunitinib on the proliferation of K562/ADR cells, and the appropriate sunitinib intervention time and concentration were determined. QPCR and Western blot were used to detect the mRNA and protein expression levels of apoptosis-related genes in K562/ADR cells treated with sunitinib. Four different cell death inhibitors Nec-1, VX-765, CQ and Fer-1 were used to detect the death mode of K562/ADR cells treated with sunitinib. QPCR and Western blot were used to detect the mRNA and protein expression levels of pyroptosis-related genes in K562/ADR cells treated with sunitinib. RESULTS: Sunitinib significantly inhibited the proliferation of K562/ADR cells in a time - and concentration-dependent manner(R48 H=0.9579, r4 µg/ml=0.9740). The IC50 of sunitinib was (3.96±0.14) µg/ml at 48 hours. The mRNA and protein expression levels of apoptosis-related genes Bax, BCL-2 , Caspase-3 and Caspase-9 in K562/ADR cells treated with sunitinib did not change significantly. After treatment with four different cell death inhibitors, only the pyroptosis inhibitor VX-765 could significantly reverse the inhibitory effect of sunitinib on the proliferation of K562/ADR cells (P<0.01). The mRNA and protein expression levels of pyroptosis-related genes Caspase-1, Caspase-4, Caspase-5, NLRP3, GSDMD and IL-1ß in K562/ADR cells treated with sunitinib were significantly increased (P<0.01). CONCLUSION: Sunitinib can induce pyroptosis in drug-resistant leukemia K562/ADR cells. Further study of the signaling pathways related to pyroptosis may provide experimental basis for the treatment of drug-resistant leukemia.

Nonpharmacological Interventions for Management of the Pain-Fatigue-Sleep Disturbance Symptom Cluster in Breast Cancer Patients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

Background: The pain-fatigue-sleep disturbance symptom cluster is commonly experienced by breast cancer patients, and a variety of nonpharmacological interventions are used to treat this symptom cluster. Objective: To compare the efficacy of nonpharmacological interventions in improving the symptoms of the pain-fatigue-sleep disturbance symptom cluster in breast cancer patients. Methods: A comprehensive literature search was conducted in the PubMed, EMBASE, Cochrane Library, CINAHL, CNKI, and Wanfang databases to identify randomized controlled studies from database inception to May 2022. Two reviewers independently performed data retrieval and risk of bias assessments. The consistency model was used to conduct network meta-analyses (NMA) based on the frequentist framework to assess the interventions, which were ranked by the surface under the cumulative ranking curve (SUCRA). Finally, the CINeMA application was used to evaluate the results of the NMA and the evidence of quality. The results Twenty-three eligible studies assessing 14 interventions were included. According to SUCRA values, among the management effects of the three symptoms, the effect of progressive muscle relaxation (PMR) ranked first, followed by mindfulness-based stress reduction (MBSR). The overall evidence quality of our study ranges from very low to moderate. Conclusion: PMR and MBSR were effective interventions for the pain-fatigue-sleep disturbance symptom cluster in breast cancer patients. Clinical recommendations prioritize PMR for symptom management, followed by MBSR. However, this should be interpreted cautiously, as the confidence in the evidence was not high.

Cost-effectiveness analysis of an orphan drug tebentafusp in patients with metastatic uveal melanoma and a call for value-based pricing.

The normative regimens recommendations for treating metastatic uveal melanoma (mUM) are absent in the US. Recently, a phase III randomized clinical trial revealed that tebentafusp yielded a conspicuously longer overall survival than the control group. Based on the prominent efficacy, this study aimed to assess whether tebentafusp is cost-effective compared to the control group in patients with untreated mUM. A three-state partitioned survival model was developed to assess the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) from the perspective of US payers. Scenario analyses and sensitivity analyses were conducted to explore the conclusion uncertainty. Compared with control group, tebentafusp therapy yielded an additional 0.47 QALYs (1.19 vs. 0.72 QALYs) and an incremental cost of $444 280 ($633 822 vs. $189 542). The resultant ICER of $953 230/QALY far outweighed the willingness-to-pay threshold of $200 000/QALY. The ICER was always more than $750 000/QALY in all the univariable and probabilistic sensitivity analyses. Scenario analyses indicated that reducing the unit price of tebentafusp to $33.768/µg was associated with a favorable result of tebentafusp being cost-effective. For treatment-naive patients with mUM, the cost of tebentafusp therapy was not worth the improvement in survival benefits at the current price compared to the investigator's choice of therapy. The cost-effectiveness of tebentafusp could be promoted using value-based pricing.

Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial.

Overall survival (OS) benefits of neoadjuvant immunotherapy remain elusive in locally advanced esophageal squamous cell carcinomas (ESCC). Here, we reported the results of a phase 1b trial of neoadjuvant PD-L1 blockade with adebrelimab in resectable ESCC. Patients received two neoadjuvant doses of adebrelimab followed by surgery. The primary endpoints were safety and feasibility; secondary endpoints included pathologic complete response (pCR) and OS. Our data showed the primary endpoints of safety and feasibility had been met. Common treatment-related adverse events were anorexia (32%) and fatigue (16%), without grade 3 or more adverse events. Of the 30 patients enrolled in the trial, 25 underwent successful resection without surgery delay and 24% had major pathologic responses including a pCR rate of 8%. The 2-year OS was 92%. Responsive patients had an immune-enriched tumor microenvironment phenotype, whereas nonresponsive patients had greater infiltration of cancer-associated fibroblasts at baseline. Clonotypic dynamics of pre-existing intratumoral T cells was a hallmark of responsive patients. These findings provide a rational for neoadjuvant anti-PD-L1 monotherapy as a therapeutic strategy for patients with resectable ESCC. ClinicalTrials.gov identifier: NCT04215471 .

Influence of ADT on B7-H3 expression during CRPC progression from hormone-naïve prostate cancer.

Androgen deprivation therapy (ADT) is the standard care for advanced prostate cancer (PCa) patients. Unfortunately, although tumors respond well initially, they enter dormancy and eventually progress to fatal/incurable castration-resistant prostate cancer (CRPC). B7-H3 is a promising new target for PCa immunotherapy. CD276 (B7-H3) gene has a presumptive androgen receptor (AR) binding site, suggesting potential AR regulation. However, the relationship between B7-H3 and AR is controversial. Meanwhile, the expression pattern of B7-H3 following ADT and during CRPC progression is largely unknown, but critically important for identifying patients and determining the optimal timing of B7-H3 targeting immunotherapy. In this study, we performed a longitudinal study using our unique PCa patient-derived xenograft (PDX) models and assessed B7-H3 expression during post-ADT disease progression. We further validated our findings at the clinical level in PCa patient samples. We found that B7-H3 expression was negatively regulated by AR during the early phase of ADT treatment, but positively associated with PCa proliferation during the remainder of disease progression. Our findings suggest its use as a biomarker for diagnosis, prognosis, and ADT treatment response, and the potential of combining ADT and B7-H3 targeting immunotherapy for hormone-naïve PCa treatment to prevent fatal CRPC relapse.

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth.

CXCR7 is an atypical chemokine receptor that recruits ß-arrestin (ARRB2) and internalizes into clathrin-coated intracellular vesicles where the complex acts as a scaffold for cytoplasmic kinase assembly and signal transduction. Here, we report that CXCR7 was elevated in the majority of prostate cancer (PCa) cases with neuroendocrine features (NEPC). CXCR7 markedly induced mitotic spindle and cell cycle gene expression. Mechanistically, we identified Aurora Kinase A (AURKA), a key regulator of mitosis, as a novel target that was bound and activated by the CXCR7-ARRB2 complex. CXCR7 interacted with proteins associated with microtubules and golgi, and, as such, the CXCR7-ARRB2-containing vesicles trafficked along the microtubules to the pericentrosomal golgi apparatus, where the complex interacted with AURKA. Accordingly, CXCR7 promoted PCa cell proliferation and tumor growth, which was mitigated by AURKA inhibition. In summary, our study reveals a critical role of CXCR7-ARRB2 in interacting and activating AURKA, which can be targeted by AURKA inhibitors to benefit a subset of patients with NEPC.

Targeting ER stress/PKA/GSK-3ß/ß-catenin pathway as a potential novel strategy for hepatitis C virus-infected patients.

BACKGROUND: Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). The HCC risk, while decreased compared with active HCV infection, persists in HCV-cured patients by direct-acting antiviral agents (DAA). We previously demonstrated that Wnt/ß-catenin signaling remained activated after DAA-mediated HCV eradication. Developing therapeutic strategies to both eradicate HCV and reverse Wnt/ß-catenin signaling is needed. METHODS: Cell-based HCV long term infection was established. Chronically HCV infected cells were treated with DAA, protein kinase A (PKA) inhibitor H89 and endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Western blotting analysis and fluorescence microscopy were performed to determine HCV levels and component levels involved in ER stress/PKA/glycogen synthase kinase-3ß (GSK-3ß)/ß-catenin pathway. Meanwhile, the effects of H89 and TUDCA were determined on HCV infection. RESULTS: Both chronic HCV infection and replicon-induced Wnt/ß-catenin signaling remained activated after HCV and replicon eradication by DAA. HCV infection activated PKA activity and PKA/GSK-3ß-mediated Wnt/ß-catenin signaling. Inhibition of PKA with H89 both repressed HCV and replicon replication and reversed PKA/GSK-3ß-mediated Wnt/ß-catenin signaling in both chronic HCV infection and replicon. Both chronic HCV infection and replicon induced ER stress. Inhibition of ER stress with TUDCA both repressed HCV and replicon replication and reversed ER stress/PKA/GSK-3ß-dependent Wnt/ß-catenin signaling. Inhibition of either PKA or ER stress both inhibited extracellular HCV infection. CONCLUSION: Targeting ER stress/PKA/GSK-3ß-dependent Wnt/ß-catenin signaling with PKA inhibitor could be a novel therapeutic strategy for HCV-infected patients to overcomes the issue of remaining activated Wnt/ß-catenin signaling by DAA treatment. Video Abstract.