Redoxhigh phenotype mediated by KEAP1/STK11/SMARCA4/NRF2 mutations diminishes tissue-resident memory CD8+ T cells and attenuates the efficacy of immunotherapy in lung adenocarcinoma.

Metabolism reprogramming within the tumor microenvironment (TME) can have a profound impact on immune cells. Identifying the association between metabolic phenotypes and immune cells in lung adenocarcinoma (LUAD) may reveal mechanisms of resistance to immune checkpoint inhibitors (ICIs). Metabolic phenotypes were classified by expression of metabolic genes. Somatic mutations and transcriptomic features were compared across the different metabolic phenotypes. The metabolic phenotype of LUAD is predominantly determined by reductase-oxidative activity and is divided into two categories: redoxhigh LUAD and redoxlow LUAD. Genetically, redoxhigh LUAD is mainly driven by mutations in KEAP1, STK11, NRF2, or SMARCA4. These mutations are more prevalent in redoxhigh LUAD (72.5%) compared to redoxlow LUAD (17.4%), whereas EGFR mutations are more common in redoxlow LUAD (19.0% vs. 0.7%). Single-cell RNA profiling of pre-treatment and post-treatment samples from patients receiving neoadjuvant chemoimmunotherapy revealed that tissue-resident memory CD8+ T cells are responders to ICIs. However, these cells are significantly reduced in redoxhigh LUAD. The redoxhigh phenotype is primarily attributed to tumor cells and is positively associated with mTORC1 signaling. LUAD with the redoxhigh phenotype demonstrates a lower response rate (39.1% vs. 70.8%, p = 0.001), shorter progression-free survival (3.3 vs. 14.6 months, p = 0.004), and overall survival (12.1 vs. 31.2 months, p = 0.022) when treated with ICIs. The redoxhigh phenotype in LUAD is predominantly driven by mutations in KEAP1, STK11, NRF2, and SMARCA4. This phenotype diminishes the number of tissue-resident memory CD8+ T cells and attenuates the efficacy of ICIs.

Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Plasma ddPCR for the detection of MET amplification in advanced NSCLC patients: a comparative real-world study.

Background: Mesenchymal-epithelial transition (MET) amplification is a crucial oncogenic driver and a resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) of non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection. However, it is inapplicable when tissue samples are unavailable. Objective: This study assessed the performance of plasma droplet digital polymerase chain reaction (ddPCR) in MET amplification detection in NSCLC patients. Design and methods: A total of 87 NSCLC patients were enrolled, and 94 paired tissue and plasma samples were analyzed for the concordance between FISH and plasma ddPCR/tissue next-generation sequencing (NGS) in detecting MET amplification. In addition, the efficacy of patients with MET amplification using different detection methods who were treated with MET-TKIs was evaluated. Results: Plasma ddPCR showed substantial concordance with FISH (74.1% sensitivity, 92.5% specificity, and 87.2% accuracy with a kappa value of 0.68) and outperformed tissue NGS (kappa value of 0.64) in MET amplification detection. Combined plasma ddPCR and tissue NGS showed substantial concordance with FISH (92.3% sensitivity, 89.2% specificity, and an accuracy of 90.1% with a kappa value of 0.77). The efficacy is comparable in these NSCLC patients with MET amplification detected by FISH and plasma ddPCR who were treated with MET-TKIs. Conclusion: Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection.

m6A-Mediated Upregulation of Imprinted in Prader-Willi Syndrome Induces Aberrant Apical-Basal Polarization and Oxidative Damage in RPE Cells.

Purpose: To reveal the clinical significance, pathological involvement and molecular mechanism of imprinted in Prader-Willi syndrome (IPW) in RPE anomalies that contribute to AMD. Methods: IPW expression under pathological conditions were detected by microarrays and qPCR assays. In vitro cultured fetal RPE cells were used to study the pathogenicity induced by IPW overexpression and to analyze its upstream and downstream regulatory networks. Results: We showed that IPW is upregulated in the macular RPE-choroid tissue of dry AMD patients and in fetal RPE cells under oxidative stress, inflammation and dedifferentiation. IPW overexpression in fetal RPE cells induced aberrant apical-basal polarization as shown by dysregulated polarized markers, disrupted tight and adherens junctions, and inhibited phagocytosis. IPW upregulation was also associated with RPE oxidative damages, as demonstrated by intracellular accumulation of reactive oxygen species, reduced cell proliferation, and accelerated cell apoptosis. Mechanically, N6-methyladenosine level of the IPW transcript regulated its stability with YTHDC1 as the reader. IPW mediated RPE features by suppressing MEG3 expression to sequester its inhibition on the AKT serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway. We also noticed that the mTOR inhibitor rapamycin suppresses the AKT/mTOR pathway to alleviate the IPW-induced RPE anomalies. Conclusions: We revealed that IPW overexpression in RPE induces aberrant apical-basal polarization and oxidative damages, thus contributing to AMD progression. We also annotated the upstream and downstream regulatory networks of IPW in RPE. Our findings shed new light on the molecular mechanisms of RPE dysfunctions, and indicate that IPW blockers may be a promising option to treat RPE abnormalities in AMD.

Modulation of photonic skyrmions in a thin metal film structure.

Photonic skyrmions have been a hot topic in recent years. However, modulating the spin distributions of the skyrmions is still a challenging topic. In this paper, we investigate the detailed spin distributions of photonic skyrmions in thin metal film sandwiched by different dielectrics. We find that the ratios of different spin components can be adjusted by the thickness of the metal film, while the absolute value of total spin can be controlled by the frequency of the light source. Therefore, by choosing proper metal thickness in the preparation process and certain beam frequency in actual experiment, we can get the exact type of spin distribution we prefer. In addition, when the dielectric layers are arranged asymmetrically, the spin distributions can also be modulated significantly by adjustig the ratio of the dielectric constants of the upper and lower dielectric layers. Our results provide a new pathway for the modulation of photonic skyrmions.

Lactylation-driven FTO targets CDK2 to aggravate microvascular anomalies in diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of irreversible vision loss in working-age populations. Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase that demethylates RNAs involved in energy homeostasis, though its influence on DR is not well studied. Herein, we detected elevated FTO expression in vitreous fibrovascular membranes of patients with proliferative DR. FTO promoted cell cycle progression and tip cell formation of endothelial cells (ECs) to facilitate angiogenesis in vitro, in mice, and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetic microvascular leakage, and mediated EC-microglia interactions to induce retinal inflammation and neurodegeneration in vivo and in vitro. Mechanistically, FTO affected EC features via modulating CDK2 mRNA stability in an m6A-YTHDF2-dependent manner. FTO up-regulation under diabetic conditions was driven by lactate-mediated histone lactylation. FB23-2, an inhibitor to FTO's m6A demethylase activity, suppressed angiogenic phenotypes in vitro. To allow for systemic administration, we developed a nanoplatform encapsulating FB23-2 and confirmed its targeting and therapeutic efficiency in mice. Collectively, our study demonstrates that FTO is important for EC function and retinal homeostasis in DR, and warrants further investigation as a therapeutic target for DR patients.

Allelic Context of EGFR C797X-Mutant Lung Cancer Defines Four Subtypes With Heterogeneous Genomic Landscape and Distinct Clinical Outcomes.

INTRODUCTION: EGFR C797X (C797S or C797G) mutation is the most frequent on-target mechanism of resistance to osimertinib. The hypothesis that the allelic context of C797X/T790M has implications for treatment is on the basis of sporadic reports and needs validation with larger cohorts. METHODS: We identified patients with EGFR C797X-mutant NSCLC from nine centers who progressed on osimertinib, all analyzed in a single laboratory through next-generation sequencing. We analyzed genomic profiles and assessed associations between clinical outcomes and C797X status. RESULTS: A total of 365 EGFR C797X-mutant cases were categorized into four subtypes on the basis of allelic context: in cis (75.3%), in trans (6.4%), cis&trans (10.4%), and C797X-only (7.9%). Genomically, the cis&trans subtype displayed the highest frequency of concurrent alterations at osimertinib resistance sites (21.1%), while the in cis subtype had the lowest (8.4%). Clinically, cis&trans patients exhibited the worst progression-free survival (PFS) on both previous (median 7.7 mo) and subsequent treatment (median 1.0 mo) and overall survival (median 3.9 mo). In subsequent treatments, in cis patients exhibited superior PFS with combined brigatinib and cetuximab (median 11.0 mo) compared with other regimens (p = 0.005), while in trans patients exhibited variable outcomes with combined first or second- and third-generation EGFR inhibitor (PFS range: 0.7-8.1 mo, median 2.6 mo). Notably, subtype switching was observed after subsequent treatments, predominantly toward the in cis subtype. CONCLUSIONS: Allelic context could define four EGFR C797X-mutant NSCLC subtypes with heterogeneous genetic landscapes and distinct clinical outcomes. Subsequent treatments further complicate the scenario through subtype switching.

Evolutionary overview of sarcopenia - bibliometric study on the Web of science: A review.

Sarcopenia is an age-related degenerative disease associated with adverse outcomes such as falls, functional decline, weakness, and mortality. Exploring the dynamic evolutionary path and patterns of sarcopenia research topics within a temporal framework from the perspective of strategic coordinate maps and data flow can help identify the development rules of sarcopenia themes. After searching, a total of 16,326 articles were obtained. There are few early research topics, but the development maturity of the topics is high; the number of late research topics continues to increase, showing a trend of diversified development. The differentiation and fusion of the theme evolution path are obvious, and the theme inheritance index is high. The development trend of this research field is promising. The mature and stable professional topics such as "RESISTANCE EXERCISE" and "SURVIVAL" that appeared in the late stage belong to the core topics, while newly emerging topics like "FRACTURES" and "PROTEIN" belong to the marginal topics, indicating that the research on muscle and bone metabolism in the field of sarcopenia has yet to be further in-depth, and the "CANCER" topic is a highly promising research topic with strong development potential.

Heterogeneity in the immune microenvironment of bone metastasis in driver-positive non-small cell lung cancer.

Mutations in epidermal growth factor receptor and anaplastic lymphoma kinase are common driver events in non-small cell lung cancer (NSCLC), which are associated with a high frequency of bone metastases (BMs). While the bone marrow represents a specialized immune microenvironment, the immune repertoire of BMs remains unknown. Considering the higher incidence of BMs in driver gene-positive NSCLCs, and the unique biology of the bone, herein, we assessed the infiltrating immune cells and T cell receptor (TCR) profile of BMs in driver-positive NSCLCs. Immune profile of BMs in driver gene-positive NSCLC were assessed in 10 patients, where 6 had driver gene-positive mutation. TCR and bulk RNA sequencing were performed on malignant bone samples. The diversity and clonality of the TCR repertoire were analyzed. The cellular components were inferred from bulk gene expression profiles computationally by CIBERSORT. Although BMs were generally regarded as immune-cold tumors, immune cell composition analyses showed co-existence of cytotoxic and suppressor immune cells in driver-positive BM samples, as compared to primary lung. Analysis of the TCR repertoire indicated a trend of higher diversity and similar clonality in the driver-positive compared with the driver-negative subsets. In addition, we identified two cases that showed the opposite response to immune checkpoint blockade. A comparison of these two patients' BM samples showed more highly amplified clones, fewer M2 macrophages and more activated natural killer cells in the responder. In summary, BMs in NSCLC are heterogeneous in their immune microenvironment, which might be related to differential clinical outcomes to immune checkpoint blockade.

Genomic and immune characteristics of HER2-mutated non-small-cell lung cancer and response to immune checkpoint inhibitor-based therapy.

The efficacy of immunotherapy in advanced HER2-mutated non-small-cell lung cancer (NSCLC) remains incomprehensively studied. A total of 107 NSCLC patients with de novo HER2 mutations were retrospectively studied at Guangdong Lung Cancer Institute [GLCI cohort, exon 20 insertions (ex20ins): 71.0%] to compare clinical/molecular features and immune checkpoint inhibitor (ICI)-based therapy efficacy between patients with ex20ins and non-ex20ins. Two external cohorts (TCGA, n = 21; META-ICI, n = 30) were used for validation. In the GLCI cohort, 68.2% of patients displayed programmed death-ligand 1 (PD-L1) expression < 1%. Compared with ex20ins patients, non-ex20ins patients had more concurrent mutations in the GLCI cohort (P < 0.01) and a higher tumour mutation burden in the TCGA cohort (P = 0.03). Under ICI-based therapy, advanced NSCLC patients with non-ex20ins had potentially superior progression-free survival [median: 13.0 vs. 3.6 months, adjusted hazard ratio (HR): 0.31, 95% confidence interval (CI): 0.11-0.83] and overall survival (median: 27.5 vs. 8.1 months, adjusted HR: 0.39, 95% CI: 0.13-1.18) to ex20ins patients, consistent with findings in the META-ICI cohort. ICI-based therapy may serve as an option for advanced HER2-mutated NSCLC, with potentially better efficacy in non-ex20ins patients. Further investigations are warranted in clinical practice.

Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes.

PURPOSE: Rearranged during transfection (RET) fusions are important genetic drivers in non-small cell lung cancer (NSCLC). Selective RET inhibitors are setting a new paradigm in RET-driven NSCLC. However, the real-world treatment patterns, outcomes and toxicity remain largely unknown. METHODS: Data from RET fusion-positive NSCLC patients treated in our centre were retrospectively analysed. Of them, patients diagnosed before and after August 2018 were included in analysis of treatment patterns; and patients received selective RET inhibitors were eligible for analysis of adverse events (AEs). RESULTS: Patients diagnosed before August 2018 (n = 30) predominantly received chemotherapy and immunotherapy (83%) as initial therapy, while patients diagnosed after August 2018 (n = 39) mainly received selective RET inhibitors (38.5% at first-line; 50.0% at second-line). In the total 69 patients, overall survival (OS) was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients. In the 38 patients received selective RET inhibition, median progression-free survival (PFS) was 11.9 months. AEs ≥ grade 3 occurred in 42.1% patients and were not associated with PFS (p = 0.63) or OS (p = 0.60). Haematological toxicity ≥ grade 3 occurred in 31.6% patients and was the leading cause of drug discontinuation. CONCLUSION: Selective RET inhibitors are increasingly being adopted into clinical practice and are associated with improved OS. However, treatment-related ≥ grade 3 AEs, especially haematologic AEs, occur frequently in real-world setting.

Applications of Circulating Tumor DNA in Immune Checkpoint Inhibition: Emerging Roles and Future Perspectives.

Immune checkpoint inhibitors (ICIs), especially anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies, have made dramatic progress in the treatment of lung cancer, especially for patients with cancers not driven by oncogenes. However, responses are limited to a subset of patients, and which subset of patients will optimally benefit from ICI remains unknown. With the advantage of being minimally invasive and dynamic, noninvasive biomarkers are promising candidates to predict response, monitor resistance, and track the evolution of lung cancer during ICI treatment. In this review, we focus on the application of circulating tumor DNA (ctDNA) in plasma in immunotherapy. We examine the potential of pre- and on-treatment features of ctDNA as biomarkers, and following multiparameter analysis, we determine the potential clinical value of integrating predictive liquid biomarkers of ICIs to optimize patient management. We further discuss the role of ctDNA in monitoring treatment resistance, as well as challenges in clinical translation.

ACE2 pathway regulates thermogenesis and energy metabolism.

Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas1 receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. Ace2 knockout mice (Ace2-/y) and Mas1 knockout mice (Mas1-/-) displayed impaired thermogenesis. Mice transplanted with brown adipose tissue from Mas1-/- display metabolic abnormalities consistent with those seen in the Ace2 and Mas1 knockout mice. In contrast, impaired thermogenesis of Leprdb/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of Ace2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids, and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel potential therapeutic targets for the treatment of metabolic disorders.

[Activation of Permonosulfate by Rhodamine B for BPA Degradation Under Visible Light Irradiation].

Although the activation method of permonosulfate has been gradually developed, its practical application is severely restricted by the high cost and difficult recovery of the catalyst, thereby resulting in secondary pollution. In this study, the application potential of self-decolorization of dyes and degradation of other pollutants through persulfate(PS) activation was examined by building a self-decolorization system. The results showed that the dyes could activate PS under visible light irradiation, which could realize not only the self-decolorization of dyes, but also the degradation of other pollutants. The degradation rates of rhodamine B and bisphenol A could reach 80% and 90%, respectively. This process included both free radical reaction pathways and nonradical reaction pathways. The active oxidants produced in the system included superoxide radicals, sulfate radicals, hydroxyl radicals, and singlet oxygen. The self-decolorization efficiency of dyes was related to the type of dyes, initial concentration of the dyes, dosage of PS, and initial pH of the solution. Meanwhile, the initial concentrations of the dyes and other pollutants had a great influence on the degradation of other pollutants. This study provides a new idea for economic and environmental protection in the PS activation method, and has broad application prospects in the treatment of printing and dyeing wastewater.

Nifuroxazide improves insulin secretion and attenuates high glucose-induced inflammation and apoptosis in INS-1 cells.

Inflammation and oxidative stress are important factors that cause islet ß-cell dysfunction. STAT3 is not only a major factor in cell proliferation and differentiation, but also plays an important role in mediating inflammation. As a potent inhibitor of STAT3, the effect of Nifuroxazide (Nifu) on pancreatic islet cells in a high glucose environment has not been reported. In the present study, we used high concentration glucose-induced INS-1 cells to examine the effects of Nifu on high glucose-induced cell function by glucose-stimulated insulin secretion (GSIS). The effects of Nifu on high glucose-induced oxidative stress were recorded by oxidative factors and antioxidant factors. Simultaneously, the effect of Nifu on the inflammatory response, apoptosis, and STAT3/SOCS3 signal pathway were validated by quantitative real-time PCR (qRT-PCR) and Western blot. Our study indicated that Nifu significantly improved cell vitality and insulin secretion of INS-1 cells induced by high glucose. We found Nifu significantly inhibited pro-oxidative factors (ROS, MDA) and promoted anti-oxidative factors (SOD, GSH-PX, CAT). Meanwhile, qRT-PCR and Western blot results showed that inflammatory and apoptosis factors were remarkably inhibited by Nifu. Further research indicated that Nifu clearly suppressed the activation of the STAT3/SOCS3 signaling pathway. In conclusion, Nifu can significantly improve the insulin secretion function, protect oxidative stress injury, and reduce inflammatory response and apoptosis in high glucose-induced INS-1 cells. Therefore, Nifu has a new positive effect on maintaining the normal function of pancreatic islet cells in a high glucose environment and provides new drug candidates for the treatment and prevention of diabetes.

[Investigation on the Emission Difference of Air Pollutants from Common Residential Coal Stoves and Suggestions for Emission Reduction].

To explore the difference in the emission of air pollutants from coal stoves, five new and common residential coal stoves (square briquette, baffled heat exchange, heating and cooking integrated gasification positive burning, and gasification reverse burning stove) were selected. The emission level of major air pollutants was determined using simulated combustion in the laboratory for quantitatively evaluating the environmental effects of different coal stoves. Moreover, the factors and reasons for the differences were identified, and suggestions for the reduction of emission were proposed. The results showed that: ① the emissions of air pollutants from different coal stoves were significantly different; the heating and cooking integrated stove had the largest emission intensity (2.9 kg ·t-1) of air pollutants (SO2, NOx, and TSP), which was 1.6 times of the average value, and the square briquette stove had the lowest emission level, which was 65% of the average value. ② The emissions of gaseous pollutants from the coal stoves in different combustion stages also showed evident differences. In the high-fire stage, the NOx emission concentration of the square briquette stove was 0.49 mg ·m-3, which was 45%-72% lower than that of the other stoves; the SO2 emission concentration of the gasification reverse burning stove was 1.38 mg ·m-3, which was 28% lower than that of the other stoves. ③ The application technology and combustion type were the main factors affecting the emission levels of the coal stoves. The stove with square briquette technology and gasification reverse burning technology could have great environmental benefit. However, the cost of the two stoves was 20 and 18 thousand yuan, respectively, which was clearly higher than that of the other types of stoves. ④ Considering the difference in the emission of air pollutants from the different stoves, it was suggested to adopt differentiated economic policy and strict emission and product standards, promoting the use of energy-saving and environment-friendly coal stoves to reduce the emission of air pollutants from coal-fired stoves.

Angiotensin-(1-7), the product of ACE2 ameliorates NAFLD by acting through its receptor Mas to regulate hepatic mitochondrial function and glycolipid metabolism.

Nonalcoholic fatty liver disease (NAFLD) is the most general liver disease characterized by a continuum of liver abnormalities ranging from simple fatty liver to advanced stage of nonalcoholic steatohepatitis, cirrhosis, and even hepatocellular carcinoma. The pathological drivers of NAFLD are complex and largely undefined. It is increasingly identified that the imbalance between renin-angiotensin system and ACE2/Ang-(1-7)/Mas axis, as well as mitochondrial dysfunction associated with NAFLD. However, no known empirical research has focused on exploring the effect of the regulation of mitochondrial respiration chain activity by Ang-(1-7)/Mas on the prevention of NAFLD. Here, we evaluated the interaction and relevance of hepatic Ang-(1-7)/Mas-axis challenge with glucolipid metabolism and mitochondrial condition in vivo and in vitro. In this context, we found that Mas deletion in mice contributed to the severe glucose intolerance, insulin resistance, and hepatic steatosis which accompanied by elevated levels of serum/ hepatic alanine aminotransferase, aspartate aminotransferase, and triglycerides, as well as the mitochondrial dysfunction. Whereas forced upregulation of Mas or Ang-(1-7) administration could significantly attenuate these consequences by downregulating the expression of hepatic lipogenic proteins and enzymes for gluconeogenesis. Furthermore, activation of Ang-(1-7)/Mas arm could improve the IRS-1/Akt/AMPK pathway and enhance the mitochondrial energy utilization. Considered together, it is becoming extremely hopeful to provide a new perspective for Ang-(1-7)/Mas axis for the therapeutics of NAFLD.

Concomitant genetic alterations having greater impact on the clinical benefit of EGFR-TKIs in EGFR-mutant advanced NSCLC than BIM deletion polymorphism.

BACKGROUND: In previous studies, the predictive role of BIM deletion polymorphism with respect to responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been controversial. The potential reasons for these inconsistent findings were unknown. METHODS: Data from CTONG0901 clinical trial and medical records of Guangdong Lung Cancer Institute (GLCI) were retrospectively pooled. A total of 194 and 141 EGFR-mutant non-small cell lung cancer (NSCLC) patients treated with first- and second-generation EGFR-TKIs were examined in the CTONG0901 and GLCI cohorts, respectively. Sixty-eight patients were treated with third-generation EGFR-TKIs in the GLCI cohort. The BIM gene status was examined by next-generation sequencing. RESULTS: The frequency of BIM deletion polymorphism was 11.3% and 17.0% in CTONG0901 and GLCI cohorts, respectively. For first- and second-generation EGFR-TKIs in CTONG0901 cohort, objective response (ORR) was 54.5% in BIM deletion group versus 56.4% in wild-type BIM group (P = .87); disease control rate (DCR) was 90.9% versus 88.4% (P = 1.00); progression-free survival (PFS) was 10.5 versus 11.2 months (P = .59); and overall survival (OS) was 20.5 versus 20.5 months (P = .73). In GLCI cohort, ORR was 54.2% versus 60.7% (P = .55); DCR was 91.7% versus 96.6% (P = .27); PFS was 10.1 versus 11.6 months (P = .63); and OS was 58.5 versus 45.0 months (P = .93). For third-generation EGFR-TKIs, ORR was 18.2% versus 63.2% (P = .02); DCR was 81.8% versus 96.5%, (P = .12); PFS was 5.8 versus 9.0 months (P = .13); and OS was 30.0 versus 24.8 months (P = .85). Cox regression analysis showed that concomitant genetic alterations could adversely affect the response to EGFR-TKIs, but not BIM deletion. CONCLUSIONS: The presence of BIM deletion showed no relation to an impaired response to first-, second-, and third-generation EGFR-TKIs in NSCLC patients. The factors influencing the response of EGFR-TKIs were concomitant genetic alterations, but not BIM deletion.

Angiotensin-converting enzyme 2 regulates endoplasmic reticulum stress and mitochondrial function to preserve skeletal muscle lipid metabolism.

OBJECTIVE: Endoplasmic reticulum (ER) stress and mitochondrial function affected intramuscular fat accumulation. However, there is no clear evident on the effect of the regulation of ER stress and mitochondrial function by Angiotensin-converting enzyme 2 (ACE2) on the prevention of intramuscular fat metabolism. We investigated the effects of ACE2 on ER stress and mitochondrial function in skeletal muscle lipid metabolism. METHODS: The triglyceride (TG) content in skeletal muscle of ACE2 knockout mice and Ad-ACE2-treated db/db mice were detected by assay kits. Meanwhile, the expression of lipogenic genes (ACCα, SREBP-1c, LXRα, CPT-1α, PGC-1α and PPARα), ER stress and mitochondrial function related genes (GRP78, eIF2α, ATF4, BCL-2, and SDH6) were analyzed by RT-PCR. Lipid metabolism, ER stress and mitochondrial function related genes were analyzed by RT-PCR in ACE2-overexpression C2C12 cell. Moreover, the IKKß/NFκB/IRS-1 pathway was determined using lysate sample from skeletal muscle of ACE2 knockout mice. RESULTS: ACE2 deficiency in vivo is associated with increased lipid accumulation in skeletal muscle. The ACE2 knockout mice displayed an elevated level of ER stress and mitochondrial dysfunctions in skeletal muscle. In contrast, activation of ACE2 can ameliorate ER stress and mitochondrial function, which slightly accompanied by reduced TG content and down-regulated the expression of skeletal muscle lipogenic proteins in the db/db mice. Additionally, ACE2 improved skeletal muscle lipid metabolism and ER stress genes in the C2C12 cells. Mechanistically, endogenous ACE2 improved lipid metabolism through the IKKß/NFκB/IRS-1 pathway in skeletal muscle. CONCLUSIONS: ACE2 was first reported to play a notable role on intramuscular fat regulation by improving endoplasmic reticulum and mitochondrial function. This study may provide a strategy for treating insulin resistance in skeletal muscle.