PMS2 amplification contributes brain metastasis from lung cancer.

BACKGROUND: Lung adenocarcinoma metastasizing to the brain results in a notable increase in patient mortality. The high incidence and its impact on survival presents a critical unmet need to develop an improved understanding of its mechanisms. METHODS: To identify genes that drive brain metastasis of tumor cells, we collected cerebrospinal fluid samples and paired plasma samples from 114 lung adenocarcinoma patients with brain metastasis and performed 168 panel-targeted gene sequencing. We examined the biological behavior of PMS2 (PMS1 Homolog 2)-amplified lung cancer cell lines through wound healing assays and migration assays. In vivo imaging techniques are used to detect fluorescent signals that colonize the mouse brain. RNA sequencing was used to compare differentially expressed genes between PMS2 amplification and wild-type lung cancer cell lines. RESULTS: We discovered that PMS2 amplification was a plausible candidate driver of brain metastasis. Via in vivo and in vitro assays, we validated that PMS2 amplified PC-9 and LLC lung cancer cells had strong migration and invasion capabilities. The functional pathway of PMS2 amplification of lung cancer cells is mainly enriched in thiamine, butanoate, glutathione metabolism. CONCLUSION: Tumor cells elevated expression of PMS2 possess the capacity to augment the metastatic potential of lung cancer and establish colonies within the brain through metabolism pathways.

Effect of corneal cross-linking on biomechanical changes following transepithelial photorefractive keratectomy and femtosecond laser-assisted LASIK.

Purpose: To evaluate the change in corneal biomechanics in patients with postoperative ectasia risk when combining two common laser vision correction procedures (tPRK and FS-LASIK) with cross-linking (in tPRK Xtra and FS-LASIK Xtra). Methods: The study included 143 eyes of 143 myopic, astigmatic patients that were divided into non-cross-linked refractive surgery groups (non-Xtra groups, tPRK and FS-LASIK) and cross-linked groups (Xtra groups, tPRK Xtra and FS-LASIK Xtra) according to an ectasia risk scoring system. The eyes were subjected to measurements including the stress-strain index (SSI), the stiffness parameter at first applanation (SP-A1), the integrated inverse radius (IIR), the deformation amplitude at apex (DA), and the ratio of deformation amplitude between apex and 2 mm from apex (DARatio2mm). The measurements were taken preoperatively and at 1, 3, and 6 months postoperatively (pos1m, pos3m, and pos6m). Posterior demarcation line depth from the endothelium (PDLD) and from the ablation surface (DLA) were recorded at pos1m. Results: SP-A1 significantly decreased, while IIR, deformation amplitude, and DARatio2mm increased significantly postoperatively in all four groups (p < 0.01)-all denoting stiffness decreases. In the FS-LASIK group, the changes in IIR, DA, and DARatio2mm were 32.7 ± 15.1%, 12.9 ± 7.1%, and 27.2 ± 12.0% respectively, which were significantly higher (p < 0.05) compared to 20.1 ± 12.8%, 6.4 ± 8.2%, and 19.7 ± 10.4% in the FS-LASIK Xtra group. In the tPRK group, the change in IIR was 27.3 ± 15.5%, significantly larger than 16.9 ± 13.4% in the tPRK Xtra group. The changes of SSI were minimal in the tPRK (-1.5 ± 21.7%, p = 1.000), tPRK Xtra (8.4 ± 17.9%, p = 0.053), and FS-LASIK Xtra (5.6 ± 12.7%, p = 0.634) groups, but was significant in the FS-LASIK group (-12.1 ± 7.9%, p < 0.01). After correcting for baseline biomechanical metrics, preoperative bIOP and the change in central corneal thickness (△CCT) from pre to pos6m, the changes in the IIR in both FS-LASIK and tPRK groups, as well as DA, DARatio2mm and SSI in the FS-LASIK group remained statistically greater than their corresponding Xtra groups (all p < 0.05). Most importantly, after correcting for these covariates, the changes in DARatio2mm in the FS-LASIK Xtra became statistically smaller than in the tPRK Xtra (p = 0.017). Conclusion: The statistical analysis results indicate that tPRK Xtra and FS-LASIK Xtra effectively reduced the biomechanical losses caused by refractive surgery (tPRK and FS-LASIK). The decrease in corneal overall stiffness was greater in FS-LASIK than in tPRK, and the biomechanical enhancement of CXL was also higher following LASIK than after tPRK.

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer.

BACKGROUND: Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME. METHODS: We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes. RESULTS: Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0-12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97-18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006). The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib. ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1ß.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy. CONCLUSIONS: In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Multiple evidence reveals two new species and new distributions of Calocybe species (Lyophyllaceae) from northeastern China.

The Calocybe species possess notable economic and medicinal value, demonstrating substantial potential for resource utilization. The taxonomic studies of Calocybe are lacking in quality and depth. Based on the specimens collected from northeast China, this study provides a detailed description of two newly discovered species, namely Calocybebetulicola and Calocybecystidiosa, as well as two commonly found species, Calocybedecolorata and Calocybeionides. Additionally, a previously unrecorded species, C.decolorata, has recently been discovered in Jilin Province, China. The two newly discovered species can be accurately distinguished from other species within the genus Calocybe based on their distinct morphological characteristics. The primary distinguishing features of C.betulicola include its grayish-purple pileus, grayish-brown to dark purple stipe, smaller basidiomata, absence of cellular pileipellis, and its habitat on leaf litter within birch forests. Calocybecystidiosa is distinguished by its growth on the leaf litter of coniferous forests, a flesh-pink pileus, a fibrous stipe with a white tomentose covering at the base, non-cellular pileipellis, larger basidiospores, and the presence of cheilocystidia. The reconstruction of phylogenetic trees using combined ITS, nLSU, and tef1-α sequences, employing maximum likelihood and Bayesian inference analyses, showed that C.betulicola formed a cluster with C.decurrens, while C.cystidiosa clustered with C.vinacea. However, these two clusters formed separate branches themselves, which also supported the results obtained from our morphological studies. A key to the Calocybe species reported from northeast China is provided to facilitate future studies of the genus.

Enzymatic Hydrolysis Optimization of Yak Whey Protein Concentrates and Bioactivity Evaluation of the Ultrafiltered Peptide Fractions.

Yak whey protein concentrates (YWPCs) have good functional properties, but there is still a gap in the study of their peptides. In this study, peptides were obtained by enzymatic hydrolysis, and the bioactivity of each ultrafiltration fraction was evaluated using an optimal process. YWPCs were isolated and purified from yak milk as the raw material. Alkaline protease, trypsin, and papain were used to hydrolyze YWPCs. The protease with the highest degree of hydrolysis (DH) and peptide concentration was selected as the most suitable enzyme. The effects of pH, temperature, time, and the enzyme-to-substrate ratio (E/S) on the DH and peptide concentration were investigated, and response surface methodology was utilized to optimize the hydrolysis process. The hydrolysate was separated using ultrafiltration membranes with molecular weight cut-offs of 10 kDa, 5 kDa, 3 kDa, and 1 kDa. The bioactivity of each ultrafiltration component was analyzed, including the inhibition rates of α-amylase and xanthine oxidase (XOD) activities and the scavenging rates of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) cation radicals. The results indicated that alkaline protease was the best enzyme for hydrolyzing YWPCs. The peptide concentration in the YWPC hydrolysate was the highest (17.21 mg/mL) at a pH of 8 and a concentration of 7500 U/g, after 2.5 h at 62 °C. The enzymatic hydrolysate was ultrafiltered to yield four peptide fractions, of which the <1 kDa peptides exhibited the highest α-amylase inhibitory activity (22.06%), XOD inhibitory activity (17.15%), and ABTS cationic free radical scavenging rate (69.55%). This demonstrates the potential of YWPC hydrolyzed peptides for hypoglycemic, uric acid-lowering, and antioxidant applications, providing a theoretical basis for the high-value utilization of YWPCs.

Comprehensive analysis of clinicopathological profiles in adenosquamous carcinoma of the lung.

OBJECTIVES: Adenosquamous carcinoma (ASC), an uncommon subtype within non-small cell lung cancer (NSCLC), manifests distinctive traits of aggressiveness, embodying a fusion of both adenocarcinoma (AC) and squamous cell carcinoma (SCC) components. The clinicopathological characteristics of distinct subtypes of ASC remain unclear. METHODS: This retrospective study included 226 patients diagnosed with lung ASC who consecutively underwent surgical resection at Shanghai Pulmonary Hospital, Tongji University, between January 2015 and March 2021. Data regarding the clinical features and pathological features were collected. RESULTS: Out of this study cohort, 125 patients exhibited AC-predominant ASC, while 81 had SCC-predominant ASC. No significant differences were observed between the two subgroups in terms of age, gender, smoking history, primary site, and T, N classification. AC-Predominant ASC displayed a higher susceptibility to genetic alterations compared to SCC-Predominant ASC (P=0.02). Additionally, we showed that irrespective of the predominant pathological subtype in ASC, when lymph node metastasis occurred, the lymph node biopsies were more likely to exhibit AC, and a chi-square test confirmed that the primary predominant pathological subtype was not associated with the lymph node metastasis subtype. CONCLUSIONS: In conclusion, we describe an overview of ASC in the Chinese population, and upon stratifying into predominant pathological subgroups, we observed a higher frequency of driver gene mutations in AC-predominant ASC. We found that the AC component in ASC has a higher propensity for lymph node metastasis. These findings may suggest the predominant role of the AC component within the context of ASC.

Genetic evidence of the causal relationship between chronic liver diseases and musculoskeletal disorders.

BACKGROUND: Chronic liver diseases constitute a major global public health burden, posing a substantial threat to patients' daily lives and even survival due to the potential development of musculoskeletal disorders. Although the relationship between chronic liver diseases and musculoskeletal disorders has received extensive attention, their causal relationship has not been comprehensively and systematically investigated. METHODS: This study aimed to assess the causal relationships between viral hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC), liver cirrhosis, and hepatocellular carcinoma (HCC) with osteoporosis, osteoarthritis, and sarcopenia through bidirectional Mendelian randomization (MR) research. The traits related to osteoporosis and osteoarthritis included both overall and site-specific phenotypes, and the traits linked to sarcopenia involved indicators of muscle mass and function. Random-effect inverse-variance weighted (IVW), weighted median, MR-Egger, and Causal Analysis Using the Summary Effect Estimates were used to evaluate causal effects, with IVW being the main analysis method. To enhance robustness, sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-PRESSO global test, funnel plots, leave-one-out analyses, and latent causal variable model. RESULTS: The forward MR analysis indicated that PSC can reduce forearm bone mineral density (beta = - 0.0454, 95% CI - 0.0798 to - 0.0110; P = 0.0098) and increase the risk of overall osteoarthritis (OR = 1.012, 95% CI 1.002-1.022; P = 0.0247), while HCC can decrease grip strength (beta = - 0.0053, 95% CI - 0.008 to - 0.0025; P = 0.0002). The reverse MR analysis did not find significant causal effects of musculoskeletal disorders on chronic liver diseases. Additionally, no heterogeneity or pleiotropy was detected. CONCLUSIONS: These findings corroborate the causal effects of PSC on osteoporosis and osteoarthritis, as well as the causal impact of HCC on sarcopenia. Thus, the implementation of comprehensive preventive measures is imperative for PSC and HCC patients to mitigate the risk of musculoskeletal disorders, ultimately improving their quality of life.

In-depth proteomic analysis identifies key gene signatures predicting therapeutic efficacy of anti-PD-1/PD-L1 monotherapy in non-small cell lung cancer.

Background: Immunotherapy has opened up a new era of individualized treatment for non-small cell lung cancer (NSCLC) with negative driver gene mutations. Anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibodies have been the main options for immunotherapy over the past decade. Screening for predictive markers of anti-PD-1/PD-L1-responsive patients remains a focus in the field of immunotherapy, especially on the protein level in which relevant proteomic biomarkers are still lacking. Methods: We collected samples from 23 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy and were followed up for three years. The proteomic profile of the tumor was obtained by mass spectrometry (MS). Meanwhile, we combined the RNA sequencing (RNA-seq) data of 27 patients treated with anti-PD-1/PD-L1 therapy in a previous study to establish an integrated gene network. Weighted correlation network analysis (WGCNA) and elastic network were implemented to screen the top gene modules for predicting treatment-responsive patients. Gene expression related mutational patterns were also retrieved for validation in the Memorial Sloan-Kettering Cancer Center (MSKCC) cohort. Results: Our results showed the gene expression profile of MOXD1, PHAF1, KRT7, ANKRD30A, TMEM184A, KIR3DL1, and KCNK4 could better predict the durable response to anti-PD-1/PD-L1 therapy, with the specificity and sensitivity of 0.76 and 0.6, respectively. Besides, the mutational gene profile associated with these genes also suggested an association with favorable response in the MSKCC cohort. Patient-specific protein-protein interaction (PPI) network also indicated strong correlation among KRT7, TMEM184A and ANKRD30A. Conclusions: Our study indicated that key gene signatures identified by machine learning model could be utilized for clinical screening of patients who might benefit from anti-PD-1 therapy. Further mechanistic investigations around these genes are warranted.

Converting formaldehyde in methanol with MoO2 under irradiation: A pollution-free strategy for cleaning air.

Direct photocatalytic reduction of toxic formaldehyde (HCHO) in value-added chemicals and fuels is promising because that not only abates the environmental pollution, but also solves the energy shortage. Herein, self-supported MoO2 and MoO3 nanoparticles growing on Mo meshes were comparatively applied to the photocatalytic conversion of HCHO. Under UV-visble lights, MoO2 reduces HCHO in methanol (CH3OH) while MoO3 oxidizes HCHO in carbon oxide and water. Their contrary photocatalytic capacities were revealed. Compared with MoO3, the lower work function of MoO2 enables an electron-rich interface, realizing a complete reduction of 30 ppm HCHO to CH3OH in 30 min. Theoretical calculations clarify that a large number of delocalized electrons on MoO2 attracts HCHO molecule and activates its CO bond, facilitating subsequent hydrogenation and reduction of HCHO to CH3OH. As for MoO3, the wider bandgap and higher potential of valence band govern the photocatalytic oxidation of HCHO.

Effect of Volatile Anesthesia Versus Intravenous Anesthesia on Postoperative Pulmonary Complications in Patients Undergoing Minimally Invasive Esophagectomy: A Randomized Clinical Trial.

BACKGROUND: The effect of intraoperative anesthetic regimen on pulmonary outcome after minimally invasive esophagectomy for esophageal cancer is yet undetermined. The aim of this study was to determine the effect of volatile anesthesia (sevoflurane or desflurane) compared with propofol-based intravenous anesthesia on pulmonary complications after minimally invasive esophagectomy. METHODS: Patients scheduled for minimally invasive esophagectomy were randomly assigned to 1 of 3 general anesthetic regimens (sevoflurane, desflurane, or propofol). The primary outcome was the incidence of pulmonary complications within the 7 days postoperatively, which was a collapsed composite end point, including respiratory infection, pleural effusion, pneumothorax, atelectasis, respiratory failure, bronchospasm, pulmonary embolism, and aspiration pneumonitis. The severity of pulmonary complications, surgery-related complications, and other secondary outcomes were also assessed. RESULTS: Of 647 patients assessed for eligibility, 558 were randomized, and 553 were analyzed. A total of 185 patients were assigned to the sevoflurane group, 185 in the desflurane, and 183 in the propofol group. Patients receiving a volatile anesthetic (sevoflurane or desflurane) had a significantly lower incidence (36.5% vs 47.5%; odds ratio, 0.63; 95% confidence interval, 0.44-0.91; P = .013) and lower severity grade of pulmonary complications (P = .035) compared to the patients receiving propofol. There were no statistically significant differences in other secondary outcomes between the 2 groups. CONCLUSIONS: In patients undergoing minimally invasive esophagectomy, the use of volatile anesthesia (sevoflurane or desflurane) resulted in the reduced risk and severity of pulmonary complications within the first 7 postoperative days as compared to propofol-based intravenous anesthesia.

Targeting focal adhesion kinase boosts immune response in KRAS/LKB1 co-mutated lung adenocarcinoma via remodeling the tumor microenvironment.

BACKGROUND: KRAS mutation is one of the most common oncogenic drivers in NSCLC, however, the response to immunotherapy is heterogeneous owing to the distinct co-occurring genomic alterations. KRAS/LKB1 co-mutated lung adenocarcinoma displays poor response to PD-1 blockade whereas the mechanism remains undetermined. METHODS: We explored the specific characteristics of tumor microenvironment (TME) in KL tumors using syngeneic KRASG12DLKB1-/- (KL) and KRASG12DTP53-/- (KP) lung cancer mouse models. The impact of focal adhesion kinase (FAK) inhibitor on KL lung tumors was investigated in vitro and in vivo through evaluation of both KL cell lines and KL lung cancer mouse models. RESULTS: We identified KL tumors as "immune-cold" tumors with excessive extracellular matrix (ECM) collagen deposition that formed a physical barrier to block the infiltration of CD8+T cells. Mechanistically, abundant activated cancer-associated fibroblasts (CAFs) resulted from FAK activation contributed to the formation of the unique TME of KL tumors. FAK inhibition with a small molecular inhibitor could remodel the TME by inhibiting CAFs activation, decreasing collagen deposition and further facilitating the infiltration of anti-tumor immune cells, including CD8+ T cells, DC cells and M1-like macrophages into tumors, hence, converting "immune-cold" KL tumors into "immune-hot" tumors. The combined FAK inhibitor and PD-1 blockade therapy synergistically retarded primary and metastatic tumor growth of KL tumors. CONCLUSIONS: Our study identified FAK as a promising intervention target for KL tumors and provided basis for the combination of FAK inhibitor with PD-1 blockade in the management of KL lung cancers.

Effect of Mechanical Ventilation Mode Type on Postoperative Pulmonary Complications After Cardiac Surgery: A Randomized Controlled Trial.

OBJECTIVES: It is unknown whether there is a difference in pulmonary outcome in different intraoperative ventilation modes for cardiac surgery with cardiopulmonary bypass (CPB). The aim of this trial was to determine whether patients undergoing cardiac surgery with CPB could benefit from intraoperative optimal ventilation mode. DESIGN: This was a single-center, prospective, randomized controlled trial. SETTING: The study was conducted at a single-center tertiary-care hospital. PARTICIPANTS: A total of 1,364 adults undergoing cardiac surgery with CPB participated in this trial. INTERVENTIONS: Patients were assigned randomly (1:1:1) to receive 1 of 3 ventilation modes: volume-controlled ventilation (VCV), pressure-controlled ventilation (PCV), and pressure-controlled ventilation-volume guaranteed (PCV-VG). All arms of the study received the lung-protective ventilation strategy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of postoperative pulmonary complications (PPCs) within the first 7 postoperative days. Pulmonary complications occurred in 168 of 455 patients (36.9%) in the PCV-VG group, 171 (37.6%) in the PCV group, and 182 (40.1%) in the VCV group, respectively. There was no statistical difference in the risk of overall pulmonary complications among groups (p = 0.585). There were no significant differences in the severity grade of PPCs within 7 days, postoperative ventilation duration, intensive care unit stay, postoperative hospital stay, or 30-day postoperative mortality. CONCLUSIONS: Among patients scheduled for cardiac surgery with CPB, intraoperative ventilation mode type did not affect the risk of postoperative pulmonary complications.

Single-Cell Profiling of Tumor-Associated Neutrophils in Advanced Non-Small Cell Lung Cancer.

Purpose: Neutrophils act as a non-negligible regulator in the initiation and progression of malignancies, playing bifacial roles in the process. Thus, to understand the heterogeneity of tumor-associated neutrophils (TANs) comprehensively in advanced non-small cell lung cancer (NSCLC) at single-cell resolution is necessary and urgent. Materials and Methods: We applied single-cell RNA-sequencing (scRNA-seq) to portray the subtype-specific transcriptome landscape of TANs in advanced NSCLC using nine freshly obtained specimens. The scRNA-seq data were further processed for pseudo-time analysis to depict the developmental trajectory of TANs. Meanwhile, the interplay between TANs and other cell types within tumor microenvironment (TME) was revealed by intercellular interaction analysis. Results: Seven distinct TAN subtypes were defined, of which, the N3 cluster was considered inflammatory phenotype expressing genes encoding multiple chemotactic cytokines, and correlated with inferior overall survival, indicating that N3 might be a pro-tumorigenic TAN subtype. N1 and N5 clusters were considered to be well differentiated and mature neutrophils based on CXCR2 expression and pseudo-time patterns, and both accounted for relatively high proportions in lung adenocarcinoma. In addition, genes related to neutrophil differentiation were discovered. We also found that TAN subtypes interacted most closely with macrophages through chemokine signaling pathways within TME. Conclusion: Our study refined TAN subtypes and mapped the transcriptome landscape of TANs at single-cell resolution in advanced NSCLC, collectively indicating the heterogeneity of TANs in NSCLC. Neutrophil differentiation- and maturation-related genes were also discovered, which shed light on different functions of TAN subclones in tumor immune escape, and may further provide novel targets for immunotherapy.

Evaluating distinct KRAS subtypes as potential biomarkers for immune checkpoint inhibitor efficacy in lung adenocarcinoma.

Background: Despite the acknowledged predictive value of KRAS in immune checkpoint inhibitor (ICI) responses, the heterogeneous behavior of its mutations in this sphere remains largely unexplored. As of now, no studies have definitively categorized KRAS subtype variations as independent prognostic indicators for ICI responses in lung cancer patients. Methods: We analyzed a cohort of 103 patients, all harboring different KRAS mutation subtypes, and complemented this data with information from TCGA and GEO databases. Our research focused on delineating the relationships between KRAS mutation subtypes and factors like immunotherapy markers and immune cell composition, in addition to examining survival rates, drug sensitivity, and PD-L1 responses corresponding to distinct KRAS subtypes. Results: We found that the G12V and G12D subtypes demonstrated elevated expressions of immunotherapy markers, implying a potentially enhanced benefit from immunotherapy. Significant variations were identified in the distribution of naive B cells, activated CD4+ memory T cells, and regulatory T cells (Tregs) across different KRAS mutant subtypes. A notable difference was observed in the Tumor Mutation Burden (TMB) levels across the four KRAS subtypes, with the G12D subtype displaying the lowest TMB level. Furthermore, G12C subtype showcased the worst prognosis in terms of progression-free intervals (PFI), in stark contrast to the more favorable outcomes associated with the G12A subtype. Conclusion: Our study reveals that KRAS mutations exhibit considerable variability in predicting outcomes for LUAD patients undergoing ICI treatment. Thus, the evaluation of KRAS as a biomarker for ICIs necessitates recognizing the potential diversity inherent in KRAS mutations.

Hepatorenal pathologies in TNF-transgenic mouse model of rheumatoid arthritis are alleviated by anti-TNF treatment.

OBJECTIVE: To examine and quantify liver and kidney lesions and their response to anti-tumor necrosis factor (TNF) therapy in a TNF-Tg mouse model of rheumatoid arthritis (RA). METHODS: Female TNF-Tg (Tg3647) mice were used as the animal model for chronic RA. Ultrasound, immunofluorescence, histological staining, serology tests, and real-time RT-PCR were used to examine the pathological changes in the liver and kidney. RESULTS: TNF-Tg mice showed a significant decrease in the body weight and a dramatic increase in the volumes of the gallbladder, knee cavity, and popliteal lymph nodes. The liver and kidneys of TNF-Tg mice showed increased chronic inflammation and accumulation of immune cells and fibrosis, compared to wild-type (WT) mice. Moreover, upregulation of inflammatory factors and impaired normal function were observed in the liver and kidneys of TNF-Tg mice. Inflammatory infiltration and fibrosis of the liver and kidneys of female TNF-Tg mice were improved after anti-TNF treatment, and better treatment effects were achieved at 4.5-month-old mice when they were received 8 weeks of intervention. CONCLUSIONS: We found that TNF drives the development of liver and kidney pathology in female TNF-Tg mice and that there are limitations to the loss of utility of anti-TNF for the prolonged treatment of RA-associated hepatic and renal injury. This study provides a reliable and clinically relevant animal model for further studies exploring the molecular mechanisms and drug discovery for hepatorenal pathologies in RA.

Verteporfin Suppresses YAP-Induced Glycolysis in Breast Cancer Cells.

OBJECTIVE: The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells. METHODS: We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent in situ hybridization (FISH) assays to assess the interaction between YAP mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated in vitro. Finally, the effect of VP on glycolysis was determined by using 18F-FDG uptake, glucose consumption, and lactate production assays. RESULTS: Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUVmax) determined by 18F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells. CONCLUSION: VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.

Backbone N-methylation of peptides: Advances in synthesis and applications in pharmaceutical drug development.

Peptide-based drugs have garnered considerable attention in recent years owing to their increasingly crucial role in the treatment of diverse diseases. However, the limited pharmacokinetic properties of peptides have hindered their full potential. One prominent strategy for enhancing the druggability of peptides is N-methylation, which involves the addition of a methyl group to the nitrogen atom of the peptide backbone. This modification significantly improves the stability, bioavailability, receptor binding affinity and selectivity of peptide drug candidates. In this review, we provide a comprehensive overview of the advancements in synthetic methods for N-methylated peptide synthesis, as well as the associated limitations. Moreover, we explore the versatile effects of N-methylation on various aspects of peptide properties. Furthermore, we emphasize the efforts dedicated to N-methylated peptide pharmaceuticals that have successfully obtained marketing approval.

Identifying a baicalein-related prognostic signature contributes to prognosis prediction and tumor microenvironment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant and lethal human cancers in the world due to its high metastatic potential, and patients with PDAC have a poor prognosis, yet quite little is understood regarding the underlying biological mechanisms of its high metastatic capacity. Baicalein has a dramatic anti-tumor function in the treatment of different types of cancer. However, the therapeutic effects of baicalein on human PDAC and its mechanisms of action have not been extensively understood. In order to explore the biological characteristic, molecular mechanisms, and potential clinical value of baicalein in inhibiting the metastatic capacity of PDAC. We performed several in vitro, in vivo, and in silico studies. We first examined the potential regulation of baicalein in the metastatic capacity of PDAC cells. We showed that baicalein could dramatically suppress liver metastasis of PDAC cells with highly metastatic potential in mice model. The high-throughput sequencing analysis was employed to explore the biological roles of baicalein in PDAC cells. We found that baicalein might be involved in the infiltration of Cancer-Associated Fibroblasts (CAF) in PDAC. Moreover, a baicalein-related risk model and a lncRNA-related model were built by Cox analysis according to the data set of PDAC from TCGA database which suggested a clinical value of baicalein. Finally, we revealed a potential downstream target of baicalein in PDAC, we proposed that baicalein might contribute to the infiltration of CAF via FGFBP1. Thus, we uncovered a novel role for baicalein in regulation of PDAC liver metastasis that may contribute to its anti-cancer effect. We proposed that baicalein might suppress PDAC liver metastasis via regulation of FGFBP1-mediated CAF infiltration. Our results provide a new perspective on clinical utility of baicalein and open new avenues for the inhibition of liver-metastasis of PDAC.

The effect of driving pressure-guided versus conventional mechanical ventilation strategy on pulmonary complications following on-pump cardiac surgery: A randomized clinical trial.

STUDY OBJECTIVE: Postoperative pulmonary complications occur frequently and are associated with worse postoperative outcomes in cardiac surgical patients. The advantage of driving pressure-guided ventilation strategy in decreasing pulmonary complications remains to be definitively established. We aimed to investigate the effect of intraoperative driving pressure-guided ventilation strategy compared with conventional lung-protective ventilation on pulmonary complications following on-pump cardiac surgery. DESIGN: Prospective, two-arm, randomized controlled trial. SETTING: The West China university hospital in Sichuan, China. PATIENTS: Adult patients who were scheduled for elective on-pump cardiac surgery were enrolled in the study. INTERVENTIONS: Patients undergoing on-pump cardiac surgery were randomized to receive driving pressure-guided ventilation strategy based on positive end-expiratory pressure (PEEP) titration or conventional lung-protective ventilation strategy with fixed 5 cmH2O of PEEP. MEASUREMENTS: The primary outcome of pulmonary complications (including acute respiratory distress syndrome, atelectasis, pneumonia, pleural effusion, and pneumothorax) within the first 7 postoperative days were prospectively identified. Secondary outcomes included pulmonary complication severity, ICU length of stay, and in-hospital and 30-day mortality. MAIN RESULTS: Between August 2020 and July 2021, we enrolled 694 eligible patients who were included in the final analysis. Postoperative pulmonary complications occurred in 140 (40.3%) patients in the driving pressure group and 142 (40.9%) in the conventional group (relative risk, 0.99; 95% confidence interval, 0.82-1.18; P = 0.877). Intention-to-treat analysis showed no significant difference between study groups regarding the incidence of primary outcome. The driving pressure group had less atelectasis than the conventional group (11.5% vs 17.0%; relative risk, 0.68; 95% confidence interval, 0.47-0.98; P = 0.039). Secondary outcomes did not differ between groups. CONCLUSION: Among patients who underwent on-pump cardiac surgery, the use of driving pressure-guided ventilation strategy did not reduce the risk of postoperative pulmonary complications when compared with conventional lung-protective ventilation strategy.

Tumour microenvironment changes after osimertinib treatment resistance in non-small cell lung cancer.

BACKGROUND: Growing evidence suggests that acquired resistance to targeted therapy in non-small cell lung cancer patients is linked to the mutual domestication between the tumour and its surrounding microenvironment. AIM: Our study aims to explore the remodelling of tumour microenvironment after osimertinib treatment resistance. METHODS: We took RNA-seq-based tumour immune infiltration analysis using the TIMER 2.0. We carried out flow cytometry assay and real-time cell analysis to explore the interaction between tumour cells and immune cells. In addition, we analysed exosomes via miRNA-seq and label-free proteomics. RESULTS: Immune infiltration estimation showed a significant decrease in the immune score (P < 0.001), microenvironment score (P < 0.001) and CD8+ T cells (P < 0.05), but an increase in M0 macrophages (P < 0.01) at osimertinib resistance compared to pre-treatment patients. It was demonstrated that exosomes from H1975OR cells could be taken up by macrophages and drove their polarisation towards the M2 phenotype, and the polarised M2 macrophages could reduce the inhibitory effect on tumour cell proliferation. Pre-activated peripheral blood mononuclear cells exhibited a more potent killing effect on H1975OR cells. We also detected a decrease in CD4+HLA-DR- T cells and an increase in CD4+PD1+ T cells after being co-cultured with H1975OR derived exosomes or conditioned medium. Further miRNA-seq and proteomics analysis of exosomes demonstrated that mir-1258-3p and miR-17-5p might participate in this interaction. CONCLUSIONS: An immunosuppressive environment, characterised by decreased T cell infiltration and activation, whereas increased macrophage infiltration and M2 polarisation, was identified at osimertinib resistance. This interaction may be carried out by tumour-derived exosomes.