The impact of PET/CT and brain MRI for metastasis detection among patients with clinical T1-category lung cancer: Findings from a large-scale cohort study.

PURPOSE: [18F]-FDG PET/CT and brain MRI are common approaches to detect metastasis in patients of lung cancer. Current guidelines for the use of PET/CT and MRI in clinical T1-category lung cancer lack risk-based stratification and require optimization. This study stratified patients based on metastatic risk in terms of the lesions' size and morphological characteristics. METHODS: The detection rate of metastasis was measured in different sizes and morphological characteristics (solid and sub-solid) of tumors. To confirm the cut-off value for discriminating metastasis and overall survival (OS) prediction, the receiver operating characteristic (ROC) analysis was performed based on PET/CT metabolic parameters (SUVmax/SUVmean/SULpeak/MTV/TLG), followed by Kaplan-Meier analysis for survival in post-operation patients with and without PET/CT plus MRI. RESULTS: 2,298 patients were included. No metastasis was observed in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm. The cut-off of PET/CT metabolic parameters on discriminating metastasis were 1.09 (SUVmax), 0.26 (SUVmean), 0.31 (SULpeak), 0.55 (MTV), and 0.81 (TLG), respectively. Patients undergoing PET/CT plus MRI exhibited longer OS compared to those who did not receive it in solid nodules ≥ 8.0 mm & sub-solid nodules ≥ 10.0 mm (HR, 0.44; p < 0.001); in solid nodules ≥ 8.0 mm (HR, 0.12; p<0.001) and in sub-solid nodules ≥ 10.0 mm (HR; 0.61; p=0.075), respectively. Compared to patients with metabolic parameters lower than cut-off values, patients with higher metabolic parameters displayed shorter OS: SUVmax (HR, 12.94; p < 0.001), SUVmean (HR, 11.33; p <0.001), SULpeak (HR, 9.65; p < 0.001), MTV (HR, 9.16; p = 0.031), and TLG (HR, 12.06; p < 0.001). CONCLUSION: The necessity of PET/CT and MRI should be cautiously evaluated in patients with solid nodules < 8.0 mm and sub-solid nodules < 10.0 mm, however, these examinations remained essential and beneficial for patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm.

Pristimerin Exerts Pharmacological Effects Through Multiple Signaling Pathways: A Comprehensive Review.

Pristimerin, a natural triterpenoid isolated from the plants of southern snake vine and Maidenwood in the family Weseraceae, is anti-inflammatory, insecticidal, antibacterial, and antiviral substance and has been used for its cardioprotective and antitumor effects and in osteoporosis treatment. These qualities explain Pristimerin's therapeutic effects on different types of tumors and other diseases. More and more studies have shown that pristimerin acts in a wide range of biological activities and has shown great potential in various fields of modern and Chinese medicine. While Pristimerin's wide range of pharmacological effects have been widely studied by others, our comprehensive review suggests that its mechanism of action may be through affecting fundamental cellular events, including blocking the cell cycle, inducing apoptosis and autophagy, and inhibiting cell migration and invasion, or through activating or inhibiting certain key molecules in several cell signaling pathways, including nuclear factor κB (NF-κB), phosphatidylinositol 3-kinase/protein kinase B/mammalian-targeted macromycin (PI3K/Akt/mTOR), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated protein kinase 1/2 (ERK1/2), Jun amino-terminal kinase (JNK1/2/3), reactive oxygen species (ROS), wingless/integrin1 (Wnt)/ß-catenin, and other signaling pathways. This paper reviews the research progress of Pristimerin's pharmacological mechanism of action in recent years to provide a theoretical basis for the molecular targeting therapy and further development and utilization of Pristimerin. It also provides insights into improved treatments and therapies for clinical patients and the need to explore pristimerin as a potential facet of treatment.

Osteoporosis and Primary Biliary Cholangitis: A Trans-ethnic Mendelian Randomization Analysis.

Osteoporosis is a major clinical problem in many autoimmune diseases, including primary biliary cholangitis (PBC), the most common autoimmune liver disease. Osteoporosis is a major cause of fracture and related mortality. However, it remains unclear whether PBC confers a causally risk-increasing effect on osteoporosis. Herein, we aimed to investigate the causal relationship between PBC and osteoporosis and whether the relationship is independent of potential confounders. We performed bidirectional Mendelian randomization (MR) analyses to investigate the association between PBC (8021 cases and 16,489 controls) and osteoporosis in Europeans (the UK Biobank and FinnGen Consortium: 12,787 cases and 726,996 controls). The direct effect of PBC on osteoporosis was estimated using multivariable MR analyses. An independent replication was conducted in East Asians (PBC: 2495 cases and 4283 controls; osteoporosis: 9794 cases and 168,932 controls). Trans-ethnic meta-analysis was performed by pooling the MR estimates of Europeans and East Asians. Inverse-variance weighted analyses revealed that genetic liability to PBC was associated with a higher risk of osteoporosis in Europeans (OR, 1.040; 95% CI, 1.016-1.064; P = 0.001). Furthermore, the causal effect of PBC on osteoporosis persisted after adjusting for BMI, calcium, lipidemic traits, and sex hormones. The causal relationship was further validated in the East Asians (OR, 1.059; 95% CI, 1.023-1.096; P = 0.001). Trans-ethnic meta-analysis confirmed that PBC conferred increased risk on osteoporosis (OR, 1.045; 95% CI, 1.025-1.067; P = 8.17 × 10-6). Our data supports a causal effect of PBC on osteoporosis, and the causality is independent of BMI, calcium, triglycerides, and several sex hormones.

Palliation of malignant esophageal stent esophagorespiratory fistula with rigid bronchoscope and Y silicone trachea stent: experience with seven patients.

Background: Malignant esophageal stent esophagorespiratory fistula (ERF) is an abnormal communication between esophagus and airway among advanced tumor patients with indwelling esophageal stent, which is devastating and life-threatening. This study aims to provide a new feasible treatment scheme for malignant esophageal stent ERF and report its potential advantage compared with double stenting, which was recommended by European Society of Gastrointestinal Endoscopy Guideline. Methods: We retrospectively analyzed the medical data of malignant esophageal stent ERF patients between January 2018 to May 2023 at the First Affiliated Hospital of Guangzhou Medical University and divided them into two groups. Group 1 consisted of patients treated with rigid bronchoscopy to remove the esophageal stent and implant Y silicone trachea stent, while group 2 consisted of patients treated with additional airway stenting without removing the esophageal stent. Demographic parameters, disease diagnoses and treatment, radiological findings before and after the intervention, and complications caused by the stents were obtained and analyzed with chi-squared, Mann-Whitney U, independent-samples t-tests, Kaplan-Meier methods, and log-rank test. Results: Ten patients (seven patients in group 1 and three in group 2) were included. No procedure complications occurred in both groups. The mean Karnofsky Performance Score after the procedure significantly improved compared to the pre-procedure (57.14 vs. 77.14, P=0.001) in group 1, while decreased in group 2 (50 vs. 40, P=0.026). The control of pneumonia in group 1 patients is better than that in group 2. There was significant improvement in the degree of dysphagia after the procedure (3.86 vs. 2.43, P=0.002) in group 1, while no improvement was found in group 2 (4.00 vs. 3.33, P=0.423). The mean survival of group 1 was significantly longer group 2 (381.00 vs. 80.33 days, P<0.001, log-rank test). No patient needed stent repositioning due to migration in both groups. Cause of death in the group 1 included disease progression, novel coronavirus pneumonia, massive hemoptysis, and respiratory insufficiency, while group 2 included severe pneumonia and disease progression. No death was directly attributed to the procedure in both groups. Conclusions: Removing the esophageal stent and implanting Y silicone trachea stent through a rigid bronchoscopy is a safe and feasible treatment for malignant esophageal stent ERF. This procedure can effectively seal the fistula, prevent from recurrent aspiration pneumonia, improve the quality of life, and prolong the survival time.

Immunosuppression induces regression of fibrosis in primary biliary cholangitis with moderate-to-severe interface hepatitis.

BACKGROUND: In patients with primary biliary cholangitis (PBC) treated with ursodeoxycholic acid (UDCA), the presence of moderate-to-severe interface hepatitis is associated with a higher risk of liver transplantation and death. This highlights the need for novel treatment approaches. In this study, we aimed to investigate whether combination therapy of UDCA and immunosuppressant (IS) was more effective than UDCA monotherapy. METHODS: We conducted a multicenter study involving PBC patients with moderate-to-severe interface hepatitis who underwent paired liver biopsies. Firstly, we compared the efficacy of the combination therapy with UDCA monotherapy on improving biochemistry, histology, survival rates, and prognosis. Subsequently we investigated the predictors of a beneficial response. RESULTS: This retrospective cohort study with prospectively collected data was conducted in China from January 2009 to April 2023. Of the 198 enrolled patients, 32 underwent UDCA monotherapy, while 166 received combination therapy, consisting of UDCA combined with prednisolone, prednisolone plus mycophenolate mofetil (MMF), or prednisolone plus azathioprine (AZA). The monotherapy group was treated for a median duration of 37.6 months (IQR 27.5-58.1), and the combination therapy group had a median treatment duration of 39.3 months (IQR 34.5-48.8). The combination therapy showed a significantly greater efficacy in reducing fibrosis compared to UDCA monotherapy, with an 8.3-fold increase in the regression rate (from 6.3% to 52.4%, P < 0.001). Other parameters, including biochemistry, survival rates, and prognosis, supported its effectiveness. Baseline IgG >1.3 × ULN and ALP <2.4 × ULN were identified as predictors of regression following the combination therapy. A predictive score named FRS, combining these variables, accurately identified individuals achieving fibrosis regression with a cut-off point of ≥ -0.163. The predictive value was validated internally and externally. CONCLUSION: Combination therapy with IS improves outcomes in PBC patients with moderate-to-severe interface hepatitis compared to UDCA monotherapy. Baseline IgG and ALP are the most significant predictors of fibrosis regression. The new predictive score, FRS, incorporating baseline IgG and ALP, can effectively identify individuals who would benefit from the combination therapy.

Itaconate inhibits CD103 + T RM cells and alleviates hepatobiliary injury in mouse models of primary sclerosing cholangitis.

BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease characterized by the infiltration of intrahepatic tissue-resident memory CD8 + T cells (T RM ). Itaconate has demonstrated therapeutic potential in modulating inflammation. An unmet need for PSC is the reduction of biliary inflammation, and we hypothesized that itaconate may directly modulate pathogenic T RM . APPROACH AND RESULTS: The numbers of intrahepatic CD103 + T RM were evaluated by immunofluorescence in PSC (n = 32), and the serum levels of itaconate in PSC (n = 64), primary biliary cholangitis (PBC) (n = 60), autoimmune hepatitis (AIH) (n = 49), and healthy controls (n = 109) were determined by LC-MS/MS. In addition, the frequencies and immunophenotypes of intrahepatic T RM using explants from PSC (n = 5) and healthy donors (n = 6) were quantitated by flow cytometry. The immunomodulatory properties of 4-octyl itaconate (4-OI, a cell-permeable itaconate derivative) on CD103 + T RM were studied in vitro. Finally, the therapeutic potential of itaconate was studied by the administration of 4-OI and deficiency of immune-responsive gene 1 (encodes the aconitate decarboxylase producing itaconate) in murine models of PSC. Intrahepatic CD103 + T RM was significantly expanded in PSC and was positively correlated with disease severity. Serum itaconate levels decreased in PSC. Importantly, 4-OI inhibited the induction and effector functions of CD103 + T RM in vitro. Mechanistically, 4-OI blocked DNA demethylation of RUNX3 in CD8 + T cells. Moreover, 4-OI reduced intrahepatic CD103 + T RM and ameliorated liver injury in murine models of PSC. CONCLUSIONS: Itaconate exerted immunomodulatory activity on CD103 + T RM in both in vitro and murine PSC models. Our study suggests that targeting pathogenic CD103 + T RM with itaconate has therapeutic potential in PSC.

A surgical Decision-making scoring model for spontaneous ventilation- and mechanical ventilation-video-assisted thoracoscopic surgery in non-small-cell lung cancer patients.

BACKGROUNDS: Spontaneous ventilation-video-assisted thoracoscopic surgery (SV-VATS) has been applied to non-small cell lung cancer (NSCLC) patients in many centers. Since it remains a new and challenging surgical technique, only selected patients can be performed SV-VATS. We aim to conduct a retrospective single-center study to develop a clinical decision-making model to make surgery decision between SV-VATS and MV (mechanical ventilation) -VATS in NSCLC patients more objectively and individually. METHODS: Four thousand three hundred sixty-eight NSCLC patients undergoing SV-VATS or MV-VATS in the department of thoracic surgery between 2011 and 2018 were included. Univariate and multivariate regression analysis were used to identify potential factors influencing the surgical decisions. Factors with statistical significance were selected for constructing the Surgical Decision-making Scoring (SDS) model. The performance of the model was validated by area under the receiver operating characteristic curve (AUC), calibration curves and decision curve analysis (DCA). RESULTS: The Surgical Decision-making Scoring (SDS) model was built guided by the clinical judgment and statistically significant results of univariate and multivariate regression analyses of potential predictors, including smoking status (p = 0.03), BMI (p < 0.001), ACCI (p = 0.04), T stage (p < 0.001), N stage (p < 0.001), ASA grade (p < 0.001) and surgical technique (p < 0.001). The AUC of the training group and the testing group were 0.72 and 0.70, respectively. The calibration curves and the DCA curve revealed that the SDS model has a desired performance in predicting the surgical decision. CONCLUSIONS: This SDS model is the first clinical decision-making model developed for an individual NSCLC patient to make decision between SV-VATS and MV-VATS.

A+T rich interaction domain protein 3a (Arid3a) impairs Mertk-mediated efferocytosis in cholestasis.

BACKGROUND & AIMS: Macrophages are key elements in the pathogenesis of cholestatic liver diseases. Arid3a plays a prominent role in the biologic properties of hematopoietic stem cells, B lymphocytes and tumor cells, but its ability to modulate macrophage function during cholestasis remains unknown. METHODS: Gene and protein expression and cellular localization were assessed by q-PCR, immunohistochemistry, immunofluorescence staining and flow cytometry. We generated myeloid-specific Arid3a knockout mice and established three cholestatic murine models. The transcriptome was analyzed by RNA-seq. A specific inhibitor of the Mertk receptor was used in vitro and in vivo. Promoter activity was determined by chromatin immunoprecipitation-seq against Arid3a and a luciferase reporter assay. RESULTS: In cholestatic murine models, myeloid-specific deletion of Arid3a alleviated cholestatic liver injury (accompanied by decreased accumulation of macrophages). Arid3a-deficient macrophages manifested a more reparative phenotype, which was eliminated by in vitro treatment with UNC2025, a specific inhibitor of the efferocytosis receptor Mertk. Efferocytosis of apoptotic cholangiocytes was enhanced in Arid3a-deficient macrophages via upregulation of Mertk. Arid3a negatively regulated Mertk transcription by directly binding to its promoter. Targeting Mertk in vivo effectively reversed the protective phenotype of Arid3a deficiency in macrophages. Arid3a was upregulated in hepatic macrophages and circulating monocytes in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Mertk was correspondingly upregulated and negatively correlated with Arid3a expression in PBC and PSC. Mertk+ cells were located in close proximity to cholangiocytes, while Arid3a+ cells were scattered among immune cells with greater spatial distances to hyperplastic cholangiocytes in PBC and PSC. CONCLUSIONS: Arid3a promotes cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes by macrophages during cholestasis. The Arid3a-Mertk axis is a promising novel therapeutic target for cholestatic liver diseases. IMPACT AND IMPLICATIONS: Macrophages play an important role in the pathogenesis of cholestatic liver diseases. This study reveals that macrophages with Arid3a upregulation manifest a pro-inflammatory phenotype and promote cholestatic liver injury by impairing Mertk-mediated efferocytosis of apoptotic cholangiocytes during cholestasis. Although we now offer a new paradigm to explain how efferocytosis is regulated in a myeloid cell autonomous manner, the regulatory effects of Arid3a on chronic liver diseases remain to be further elucidated.

A regulatory variant at 19p13.3 is associated with primary biliary cholangitis risk and ARID3A expression.

Genome-wide association studies have identified 19p13.3 locus associated with primary biliary cholangitis (PBC). Here we aim to identify causative variant(s) and initiate efforts to define the mechanism by which the 19p13.3 locus variant(s) contributes to the pathogenesis of PBC. A genome-wide meta-analysis of 1931 PBC subjects and 7852 controls in two Han Chinese cohorts confirms the strong association between 19p13.3 locus and PBC. By integrating functional annotations, luciferase reporter assay and allele-specific chromatin immunoprecipitation, we prioritize rs2238574, an AT-Rich Interaction Domain 3A (ARID3A) intronic variant, as a potential causal variant at 19p13.3 locus. The risk allele of rs2238574 shows higher binding affinity of transcription factors, leading to an increased enhancer activity in myeloid cells. Genome-editing demonstrates the regulatory effect of rs2238574 on ARID3A expression through allele-specific enhancer activity. Furthermore, knock-down of ARID3A inhibits myeloid differentiation and activation pathway, and overexpression of the gene has the opposite effect. Finally, we find ARID3A expression and rs2238574 genotypes linked to disease severity in PBC. Our work provides several lines of evidence that a non-coding variant regulates ARID3A expression, presenting a mechanistic basis for association of 19p13.3 locus with the susceptibility to PBC.

P4HA2 induces hepatic ductular reaction and biliary fibrosis in chronic cholestatic liver diseases.

BACKGROUNDS: Prolyl-4-hydroxylases (P4Hs) are key enzymes in collagen synthesis. The P4HA subunit (P4HA1, P4HA2, and P4HA3) contains a substrate binding and catalyzation domain. We postulated that P4HA2 would play a key role in the cholangiocyte pathology of cholestatic liver diseases. METHODS: We studied humans with primary biliary cholangitis (PBC) and Primary sclerosing cholangitis (PSC), P4HA2 -/- mice injured by DDC, and P4HA2 -/- /MDR2 -/- double knockout mice. A parallel study was performed in patients with PBC, PSC, and controls using immunohistochemistry and immunofluorescence. In the murine model, the level of ductular reaction and biliary fibrosis were monitored by histology, qPCR, immunohistochemistry, and Western blotting. Expression of Yes1 Associated Transcriptional Regulator (YAP) phosphorylation was measured in isolated mouse cholangiocytes. The mechanism of P4HA2 was explored in RBE and 293T cell lines by using qPCR, Western blot, immunofluorescence, and co-immunoprecipitation. RESULTS: The hepatic expression level of P4HA2 was highly elevated in patients with PBC or PSC. Ductular reactive cholangiocytes predominantly expressed P4HA2. Cholestatic patients with more severe liver injury correlated with levels of P4HA2 in the liver. In P4HA2 -/- mice, there was a significantly reduced level of ductular reaction and fibrosis compared with controls in the DDC-induced chronic cholestasis. Decreased liver fibrosis and ductular reaction were observed in P4HA2 -/- /MDR2 -/- mice compared with MDR2 -/- mice. Cholangiocytes isolated from P4HA2 -/- /MDR2 -/- mice displayed a higher level of YAP phosphorylation, resulting in cholangiocytes proliferation inhibition. In vitro studies showed that P4HA2 promotes RBE cell proliferation by inducing SAV1 degradation, eventually resulting in the activation of YAP. CONCLUSIONS: P4HA2 promotes hepatic ductular reaction and biliary fibrosis by regulating the SAV1-mediated Hippo signaling pathway. P4HA2 is a potential therapeutic target for PBC and PSC.

Educational attainment and endometrial cancer: A Mendelian randomization study.

Background: Low educational attainment has been reported as a risk factor for many diseases. However, conclusion on the association between educational attainment and endometrial cancer (EC) are inconsistent in previous observational studies. This study aims to explore the potential causal association between educational attainment and EC. Methods: A Mendelian Randomization analysis was performed using publicly summary-level data sets of genome-wide association studies (GWAS). A total of 306 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of educational attainment from the Social Science Genetic Association Consortium GWAS summary data of 1,131,881 participants of European ancestry. SNPs of EC were obtained from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium and the UK Biobank involving 121,885 people. We conducted inverse variance weighted (IVW) to estimate the causal effect as our primary outcome. And we perform several sensitivity analyses, including MR-Egger regression, weighted median method, MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier) global test, and leave-one-out sensitivity analysis, to evaluate the effect of pleiotropism on the causal estimates. Results: Genetic predisposition towards 4.2 years of additional educational attainment was associated with 38% lower risk of EC. (odds ratio 0.72, 95% confidence interval 0.62 to 0.83; p = 1.65*10-5). The consistent results of sensitivity analyses indicated our causal estimates were reliable. Genetic predisposition towards longer educational attainment was associated with lower risk of obesity, high waist-to-hip ratio (WHR), and diabetes. Conclusion: This study indicated that low educational attainment was a causal risk factor for EC, especially for EC with endometrioid histology. Low educational attainment might lead to EC through the mediator of obesity, high WHR, and diabetes.

Role of mitophagy in the neurodegenerative diseases and its pharmacological advances: A review.

Neurodegenerative diseases are a class of incurable and debilitating diseases characterized by progressive degeneration and death of cells in the central nervous system. They have multiple underlying mechanisms; however, they all share common degenerative features, such as mitochondrial dysfunction. According to recent studies, neurodegenerative diseases are associated with the accumulation of dysfunctional mitochondria. Selective autophagy of mitochondria, called mitophagy, can specifically degrade excess or dysfunctional mitochondria within cells. In this review, we highlight recent findings on the role of mitophagy in neurodegenerative disorders. Multiple studies were collected, including those related to the importance of mitochondria, the mechanism of mitophagy in protecting mitochondrial health, and canonical and non-canonical pathways in mitophagy. This review elucidated the important function of mitophagy in neurodegenerative diseases, discussed the research progress of mitophagy in neurodegenerative diseases, and summarized the role of mitophagy-related proteins in neurological diseases. In addition, we also highlight pharmacological advances in neurodegeneration.

Intrahepatic activated leukocyte cell adhesion molecule induces CD6highCD4+ T cell infiltration in autoimmune hepatitis.

Background and objectives: Autoimmune hepatitis (AIH) is characterized by the expansion and accumulation of pathogenic T cells in liver. Although CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are involved in the evolution of multiple inflammatory diseases, their roles in the pathogenesis of AIH remain unknown. Herein, we aimed to investigate ALCAM-CD6 axis in AIH development. Methods: Immunohistochemistry was performed to examine hepatic expression of CD6 and ALCAM. The concentration of serum ALCAM was evaluated by ELISA. The phenotypes of liver infiltrating T cells were determined by flow cytometry. Primary human CD4+ T cells were used for functional studies. Results: Our data showed that patients with AIH exhibited significantly higher expression of CD6 in the liver as compared to primary biliary cholangitis (PBC), chronic hepatitis B (CHB), non-alcoholic liver disease (NAFLD), and healthy controls (HC). In addition, hepatic CD6 expression was strongly correlated with disease severity of AIH. CD6 was mainly expressed on CD4+ T cells in the liver and intrahepatic CD6highCD4+ T cells demonstrated stronger proinflammatory response and proliferation features than CD6low counterparts in both AIH and HC. ALCAM, the ligand of CD6, was highly expressed in the hepatocytes of AIH and serum ALCAM was strongly associated with clinical indices of AIH. Interestingly, close spatial location between CD6+CD4+ T cells and ALCAM+ hepatocytes was observed. Finally, we found that CD6highCD4+ T cells showed enhanced capacity of trans-endothelial migration in vitro, which could be promoted by recombinant ALCAM. Conclusions: Our study found that ALCAM-CD6 axis was upregulated in the AIH liver, suggesting a potential target for alleviating AIH.

Family Socioeconomic Position and Lung Cancer Risk: A Meta-Analysis and a Mendelian Randomization Study.

Background: Family socioeconomic position (SEP) in childhood is an important factor to predict some chronic diseases. However, the association between family SEP in childhood and the risk of lung cancer is not clear. Methods: A systematic search was performed to explore their relationship. We selected education level, socioeconomic positions of parents and childhood housing conditions to represent an individual family SEP. Hazard ratios (HRs) of lung cancer specific-mortality were synthesized using a random effects model. Two-sample Mendelian randomization (MR) was carried out with summary data from published genome-wide association studies of SEP to assess the possible causal relationship of SEP and risk of lung cancer. Results: Through meta-analysis of 13 studies, we observed that to compared with the better SEP, the poorer SEP in the childhood was associated with the increased lung cancer risk in the adulthood (HR: 1.25, 95% CI: 1.10 to 1.43). In addition, the dose-response analysis revealed a positive correlation between the poorer SEP and increased lung cancer risk. Same conclusion was reached in MR [(education level) OR 0.50, 95% CI: 0.39 to 0.63; P < 0.001]. Conclusion: This study indicates that poor family socioeconomic position in childhood is causally correlated with lung cancer risk in adulthood. Systematic Review Registration: identifier: 159082.

Serum Biomarkers for Autoimmune Hepatitis Type 1: the Case for CD48 and a Review of the Literature.

In autoimmune hepatitis (AIH), the persisting inflammation contributes to fibrosis progression, for which conventional biochemical markers manifest relatively unsatisfactory prediction. Herein, we assessed the value of serum CD48 (sCD48) as an indicator for inflammation and fibrosis in AIH type 1. The levels of sCD48 were detected first in an exploratory cohort using ELISA. In this cohort, compared with healthy controls (4.90 ng/mL, P < 0.0001), primary biliary cholangitis (7.32 ng/mL, P < 0.0001), and non-alcoholic fatty liver disease (7.76 ng/mL, P < 0.0001), sCD48 levels were elevated in AIH (12.81 ng/mL) and correlated with histological inflammation and fibrosis. Further using multivariate logistic regression analysis, sCD48 was identified as an independent predictor for both significant inflammation (G3-4) and advanced fibrosis (S3-4). Two predictive scores, based on sCD48, were constructed for diagnosing significant inflammation and advanced fibrosis (sCD48-AIH-SI and sCD48-AIH-AF, respectively). Using these data as a premise, predictive abilities were subsequently evaluated and verified in a validation cohort. In the exploratory cohort, the area under the receiver operating characteristic curve of sCD48 and sCD48-AIH-SI, for significant inflammation, were 0.748 and 0.813, respectively. Besides, during treatment follow-up, sCD48 levels gradually decreased from immunosuppression initiation to re-evaluation biopsy, in parallel with aspartate transaminase, total sera IgG, and fibrosis-4 score. For AIH patients in a re-evaluation biopsy cohort, sCD48 could predict significant fibrosis (S2-4). Further using immunohistochemistry, hepatic CD48 expression was elevated in AIH patients and decreased after treatment. In conclusion, sCD48 and sCD48-based predictive scores predict histological inflammation and fibrosis in AIH-1. Detecting sCD48 might help in the clinical management of AIH.

NUDT1 promotes the accumulation and longevity of CD103+ TRM cells in primary biliary cholangitis.

BACKGROUND & AIMS: Pyruvate dehydrogenase (PDC)-E2 specific CD8+ T cells play a leading role in biliary destruction in PBC. However, there are limited data on the characterization of these autoantigen-specific CD8+ T cells, particularly in the liver. Herein, we aimed to identify pathogenic intrahepatic CD8+ T-cell subpopulations and investigate their immunobiology in PBC. METHODS: Phenotypic and functional analysis of intrahepatic T-cell subsets were performed by flow cytometry. CD103+ TRM cell frequency was evaluated by histological staining. The transcriptome and metabolome were analyzed by RNA-seq and liquid chromatography-mass spectrometry, respectively. Cytotoxicity of TRM cells against cholangiocytes was assayed in a 3D organoid co-culture system. Moreover, the longevity (long-term survival) of TRM cells in vivo was studied by 2-octynoic acid-BSA (2OA-BSA) immunization, Nudt1 conditional knock-out and adoptive co-transfer in a murine model. RESULTS: Intrahepatic CD103+ TRM (CD69+CD103+CD8+) cells were significantly expanded, hyperactivated, and potentially specifically reactive to PDC-E2 in patients with PBC. CD103+ TRM cell frequencies correlated with clinical and histological indices of PBC and predicted poor ursodeoxycholic acid response. NUDT1 blockade suppressed the cytotoxic effector functions of CD103+ TRM cells upon PDC-E2 re-stimulation. NUDT1 overexpression in CD8+ T cells promoted tissue-residence programming in vitro; inhibition or knockdown of NUDT1 had the opposite effect. Pharmacological blockade or genetic deletion of NUDT1 eliminated CD103+ TRM cells and alleviated cholangitis in mice immunized with 2OA-BSA. Significantly, NUDT1-dependent DNA damage resistance potentiates CD8+ T-cell tissue-residency via the PARP1-TGFßR axis in vitro. Consistently, PARP1 inhibition restored NUDT1-deficient CD103+ TRM cell durable survival and TGFß-Smad signaling. CONCLUSIONS: CD103+ TRM cells are the dominant population of PDC-E2-specific CD8+ T lymphocytes in the livers of patients with PBC. The role of NUDT1 in promoting pathogenic CD103+ TRM cell accumulation and longevity represents a novel therapeutic target in PBC. LAY SUMMARY: Primary biliary cholangitis (PBC) is a rare inflammatory condition of the bile ducts. It can be treated with ursodeoxycholic acid, but a large percentage of patients respond poorly to this treatment. Liver-infiltrating memory CD8+ T cells recognizing the PDC-E2 immunodominant epitope are critical in the pathogenesis of PBC. We identifed the key pathogenic CD8+ T cell subset, and worked out the mechanisms of its hyperactivation and longevity, which could be exploited therapeutically.

Brain-derived neurotrophic factor regulates LYN kinase-mediated myosin light chain kinase activation to modulate nonmuscle myosin II activity in hippocampal neurons.

Myosins belong to a large superfamily of actin-dependent molecular motors. Nonmuscle myosin II (NM II) is involved in the morphology and function of neurons, but little is known about how NM II activity is regulated. Brain-derived neurotrophic factor (BDNF) is a prevalent neurotrophic factor in the brain that encourages growth and differentiation of neurons and synapses. In this study, we report that BDNF upregulates the phosphorylation of myosin regulatory light chain (MLC2), to increases the activity of NM II. The role of BDNF on modulating the phosphorylation of MLC2 was validated by using Western blotting in primary cultured hippocampal neurons. This result was confirmed by injecting BDNF into the dorsal hippocampus of mice and detecting the phosphorylation level of MLC2 by Western blotting. We further perform coimmunoprecipitation assay to confirm that this process depends on the activation of the LYN kinase through binding with tyrosine kinase receptor B, the receptor of BDNF, in a kinase activity-dependent manner. LYN kinase subsequently phosphorylates MLCK, further promoting the phosphorylation of MLC2. Taken together, our results suggest a new molecular mechanism by which BDNF regulates MLC2 activity, which provides a new perspective for further understanding the functional regulation of NM II in the nervous system.

Spontaneous Ventilation Video-Assisted Thoracoscopic Surgery for Non-small-cell Lung Cancer Patients With Poor Lung Function: Short- and Long-Term Outcomes.

Objective: The goal of this study was to explore the feasibility and safety of spontaneous ventilation video-assisted thoracoscopic surgery (SV-VATS) for non-small-cell lung cancer (NSCLC) patients with poor lung function. Methods: NSCLC patients with poor lung function who underwent SV-VATS or mechanical ventilation VATS (MV-VATS) from 2011 to 2018 were analyzed. 1:2 Propensity score matching (PSM) was applied, and the short- and long-term outcomes between the SV-VATS group and the MV-VATS group were compared. Results: Anesthesia time (226.18 ± 64.89 min vs. 248.27 ± 76.07 min; P = 0.03), operative time (140.85 ± 76.07 min vs. 163.12 ± 69.37 min; P = 0.01), days of postoperative hospitalization (7.29 ± 3.35 days vs. 8.40 ± 7.89 days; P = 0.04), and days of chest tube use (4.15 ± 2.89 days vs. 5.15 ± 3.54 days; P = 0.01), the number of N1 station lymph node dissection (2.94 ± 3.24 vs. 4.34 ± 4.15; P = 0.005) and systemic immune-inflammation index (3855.43 ± 3618.61 vs. 2908.11 ± 2933.89; P = 0.04) were lower in SV-VATS group. Overall survival and disease-free survival were not significantly different between the two groups (OS: HR 0.66, 95% CI: 0.41-1.07, P = 0.09; DFS: HR 0.78, 95% CI: 0.42-1.45, P = 0.43). Conclusions: Comparable short-term and long-term outcomes indicated that SV-VATS is a feasible and safe method and might be an alternative to MV-VATS when managing NSCLC patients with poor lung function.

Prediction of distant metastasis and survival prediction of gastric cancer patients with metastasis to the liver, lung, bone, and brain: research based on the SEER database.

BACKGROUND: Gastric cancer (GC) is a globally important disease. It is the 5th most common malignancy and the 4th most common cause of death from cancer in the world. Patients with GC are often at an advanced stage when they are first diagnosed, and their overall prognosis is poor due to locally advanced and distant metastasis. This study sought to establish a predictive model of GC distant metastasis and survival that can be used to guide individualized treatment. METHODS: Patients diagnosed with GC from the Surveillance, Epidemiology, and End Results database were enrolled in the study. Univariate and multivariate logistic regression analyses were used to identify risk and prognostic factors for GC patients with distant metastasis. The factors were then used to construct nomograms to predict the probability of distant metastasis and the survival time of GC patients. Receiver operating characteristic (ROC) curve and decision curve analyses were used to verify the prediction ability of the nomograms. RESULTS: We established a comprehensive nomogram to predict the survival time of GC patients and 4 nomograms to predict distant metastasis. Nomograms could help oncologists to formulate treatment strategies and provide hospice care under an overall management model. CONCLUSIONS: Establishing a prediction model for distant metastasis and the survival of GC patients is of great clinical significance. The prediction of distant metastasis could help clinicians to make individualized assessments of patients and formulate individualized examination measures. Survival prediction models could help oncologists to formulate good treatment strategies and provide hospice care.

miR-498 Targets UBE2T to Inhibit the Proliferation of Malignant Melanoma Cells.

Background: Malignant melanoma is a common malignant tumor and one of the tumors with the fastest growing incidence. The effect of microRNAs on the biological processing of malignant melanoma cells also have been reported. This study explores the ability of miR-498 to regulate the progression of malignant melanoma cells. Methods: The expression of miR-498 was detected by RT-qPCR. The proliferation, invasion, and migration of malignant melanoma cells were measured by cell counting kit-8, clone formation, and transwell assays. Flow cytometry assay detected the percentage of apoptotic cells. Western blot was used to detect the expression of markers related to epithelial-mesenchymal transition. The correction of miR-498 and UBE2T was explored by dual-luciferase assay and Western blot. Results: Overexpression of miR-498 inhibited the proliferation, invasion, migration, and induced cell apoptosis of M14 and A375 cells. In addition, the expression of epithelial-mesenchymal transition-related factors was altered by the overexpression of miR-498. miR-498 can directly target UBE2T 3'-UTR and inhibit UBE2T protein expression. The overexpression of UBE2T reversed the inhibitory effects of miR-498 on the progression of malignant melanoma cells. Furthermore, UBE2T mRNA was significantly highly expressed in malignant melanoma tissues. The high expression of UBE2T was associated with the poor overall survival rate of malignant melanoma patients. Conclusions: Altogether, our findings demonstrated that miR-498 significantly inhibited the proliferation, invasion, migration, and induced apoptosis of malignant melanoma cells and confirmed that miR-498 regulated malignant melanoma cell progression by targeting UBE2T.