Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia.

BACKGROUND: Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies. METHODS: We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia. Utilizing GTEx V8 eQTL and deCODE Genetics pQTL data, we performed a three-step summary-data-based Mendelian randomization (SMR) and protein-protein interaction analysis. This helped assess causal and comorbid loci for these disorders and determine if identified loci share coincidental variations with psychiatric diseases. Additionally, phenome-wide association studies, drug prediction, and molecular docking validated potential drug targets. RESULTS: We found genetic correlations between anxiety, depression, and schizophrenia, and under a meta-analysis of MR from multiple databases, the causal relationships among these disorders are supported. Based on this, three-step SMR and colocalization analyses identified ITIH3 and CCS as being related to the risk of developing depression, while CTSS and DNPH1 are related to the onset of schizophrenia. BTN3A1, PSMB4, and TIMP4 were identified as comorbidity loci for both disorders. Molecules that could not be determined through colocalization analysis were also presented. Drug prediction and molecular docking showed that some drugs and proteins have good binding affinity and available structural data. CONCLUSIONS: Our study indicates genetic correlations and shared risk loci between anxiety, depression, and schizophrenia. These findings offer insights into the underlying mechanisms of their comorbidities and aid in drug development.

Recurrent neural network-based simultaneous cardiac T1, T2, and T1ρ mapping.

The purpose of the current study was to explore the feasibility of training a deep neural network to accelerate the process of generating T1, T2, and T1ρ maps for a recently proposed free-breathing cardiac multiparametric mapping technique, where a recurrent neural network (RNN) was utilized to exploit the temporal correlation among the multicontrast images. The RNN-based model was developed for rapid and accurate T1, T2, and T1ρ estimation. Bloch simulation was performed to simulate a dataset of more than 10 million signals and time correspondences with different noise levels for network training. The proposed RNN-based method was compared with a dictionary-matching method and a conventional mapping method to evaluate the model's effectiveness in phantom and in vivo studies at 3 T, respectively. In phantom studies, the RNN-based method and the dictionary-matching method achieved similar accuracy and precision in T1, T2, and T1ρ estimations. In in vivo studies, the estimated T1, T2, and T1ρ values obtained by the two methods achieved similar accuracy and precision for 10 healthy volunteers (T1: 1228.70 ± 53.80 vs. 1228.34 ± 52.91 ms, p > 0.1; T2: 40.70 ± 2.89 vs. 41.19 ± 2.91 ms, p > 0.1; T1ρ: 45.09 ± 4.47 vs. 45.23 ± 4.65 ms, p > 0.1). The RNN-based method can generate cardiac multiparameter quantitative maps simultaneously in just 2 s, achieving 60-fold acceleration compared with the dictionary-matching method. The RNN-accelerated method offers an almost instantaneous approach for reconstructing accurate T1, T2, and T1ρ maps, being much more efficient than the dictionary-matching method for the free-breathing multiparametric cardiac mapping technique, which may pave the way for inline mapping in clinical applications.

Tumor-stroma ratio predicts prognosis and PD-L1 expression in hepatocellular carcinoma.

BACKGROUND: With the in-depth research on the tumor microenvironment, the tumor stroma is considered to play a leading role in malignant tumor behavior, and PD-L1 is also related to the tumor stroma. The tumor-stroma ratio (TSR) has been regarded as a novel prognostic factor in many cancers. Our study aims to assess the TSR and PD-L1 clinical value in hepatocellular carcinoma (HCC) patients. METHODS: Ninety-five patients who were diagnosed with HCC were included in our study. TSR was estimated on HCC specimen hematoxylin-eosin staining (HE) sections, and the optimal TSR cut-off value was determined by receiver operating characteristic (ROC) curves. The correlation between the TSR and clinicopathologic features was also calculated. Immunohistochemistry (IHC) staining was also carried out to analyze the PD-L1 expression level in HCCs. RESULTS: The optimal TSR cut-off value was 0.525. The median OS of the stroma-high and stroma-low groups was 27 and 36 months, respectively. The median RFS of the stroma-high and stroma-low groups was 14.5 and 27 months, respectively. In the Cox multivariate analysis, the TSR was an independent prognostic factor for HCC overall survival (OS) and recurrence-free survival (RFS) in patients who underwent liver resection. IHC staining revealed TSR-high HCC samples with high PD-L1-positive cell expression. CONCLUSIONS: Our results suggest that the TSR can predict the prognosis of HCC patients who underwent liver resection. The TSR is related to PD-L1 expression and may be a therapeutic target that can dramatically improve HCC patients' clinical outcomes.

Chromosome 12 Open Reading Frame 49 Promotes Tumor Growth and Predicts Poor Prognosis in Colorectal Cancer.

BACKGROUND AND AIMS: Little is known about the role of chromosome 12 open reading frame 49 (C12ORF49)-induced metabolic signal transduction in tumor growth. We investigated the relationship between C12ORF49 expression and prognosis in colorectal cancer (CRC) patients. METHODS: C12ORF49 protein expression was measured in CRC tissues by Western blot and immunohistochemistry staining. Knock out of C12ORF49 in CRC cells was then performed, and the role of C12ORF49 in CRC cell proliferation and growth was examined. The expression of C12ORF49 in CRC was analyzed in Gene Expression Profiling Interactive Analysis (GEPIA) databases. A prognosis model with 11 C12ORF49-associated genes (CAGs) was generated by TCGA databases. RESULTS: C12ORF49 expression was significantly higher in CRC tumor tissue than in non-tumor tissue. Furthermore, in vitro and in vivo loss-of-function experiments, showed that C12ORF49 plays critical roles in promoting tumor cell growth. There was a significant correlation between C12ORF49 protein and the presence of tumor necrosis. C12ORF49 is critical for its interaction with SREBF1, TMEM41A, and S1PR3 in the poor prognosis of CRC. CONCLUSIONS: Our results suggest that C12ORF49 plays a key role in CRC tumor growth.

Autoimmune hemolytic anemia in patients with relapsed Hodgkin's lymphoma after treatment with penpulimab, a monoclonal antibody against programmed death receptor-1.

In August 2021, penpulimab, an anti-programmed cell death 1 (PD-1) monoclonal antibody, was approved in China for the treatment of adult patients with relapsed or refractory classic Hodgkin's lymphoma who completed at least second-line chemotherapy. Penpulimab is currently in clinical trials in China and Australia for the treatment of nasopharyngeal cancer and non-small cell lung cancer. Several clinical studies have shown that penpulimab is safe and effective, and no immune-related adverse events (irAEs) above grade 3 were observed. A 60-year-old woman with relapsed Hodgkin's lymphoma developed nausea and fatigue after receiving penpulimab monotherapy (200 mg every 2 weeks). Ten days after the second injection, the patient's condition worsened, and biochemical test results confirmed autoimmune hemolytic anemia (AIHA), with a hemoglobin level of 70 g/L (normal range, 115-150 g/L), an unconjugated bilirubin level of 19.08 µmol/L (normal range, 0-17 µmol/L), and positive direct antiglobulin test (DAT) results. On the same day, we treated her with prednisone (2 mg/kg), but her hemoglobin level continued to decline to 51 g/L one day after hormone therapy, so she received an intravenous infusion of washed red blood cells and underwent plasmapheresis, which eventually resolved the AIHA. Considering that the hemoglobin level was < 65 g/L and the irAE was grade 4, penpulimab was discontinued, and the symptoms of AIHA disappeared. From this event, we know that severe AIHA can occur after penpulimab use similar to other PD-1 antibodies. In this case, plasmapheresis showed a good therapeutic effect and should be used as a supplementary means when hormonal and immunosuppressive therapies cannot provide rapid symptom relief. In addition, we recommend regular direct antiglobulin testing, as well as haptoglobin, lactate dehydrogenase and other hemolysis-related laboratory tests, in patients prescribed penpulimab and similar drugs for the early diagnosis and treatment of AIHA.

The role of lung macrophages in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is an acute and diffuse inflammatory lung injury in a short time, one of the common severe manifestations of the respiratory system that endangers human life and health. As an innate immune cell, macrophages play a key role in the inflammatory response. For a long time, the role of pulmonary macrophages in ARDS has tended to revolve around the polarization of M1/M2. However, with the development of single-cell RNA sequencing, fate mapping, metabolomics, and other new technologies, a deeper understanding of the development process, classification, and function of macrophages in the lung are acquired. Here, we discuss the function of pulmonary macrophages in ARDS from the two dimensions of anatomical location and cell origin and describe the effects of cell metabolism and intercellular interaction on the function of macrophages. Besides, we explore the treatments for targeting macrophages, such as enhancing macrophage phagocytosis, regulating macrophage recruitment, and macrophage death. Considering the differences in responsiveness of different research groups to these treatments and the tremendous dynamic changes in the gene expression of monocyte/macrophage, we discussed the possibility of characterizing the gene expression of monocyte/macrophage as the biomarkers. We hope that this review will provide new insight into pulmonary macrophage function and therapeutic targets of ARDS.

Roxadustat Improves Erythropoietin Antibody-Mediated Pure Red Cell Aplasia in a Patient with Hemodialysis.

Anemia is a common complication of chronic kidney disease (CKD). Recombinant human erythropoietin (rHu-EPO) is used extensively in patients with CKD. However, anti-erythropoietin (anti-EPO) antibody has been reported during rHu-EPO treatment, which causes pure red cell aplasia (PRCA). We presented a case of 75-year-old man, who underwent hemodialysis for 2 years. He developed PRCA during rHu-EPO treatment. The rHu-EPO was immediately discontinued, and the patient was given roxadustat treatment. After 6 months of roxadustat treatment, the anti-EPO antibody was disappeared, and hemoglobin recovered normal range. The results suggest that roxadustat can be used to treat patients with anti-EPO antibody-mediated PRCA without immunosuppressive therapy.

Pharmacokinetics and Pharmacodynamics of Sacubitril/Valsartan in Maintenance Hemodialysis Patients with Heart Failure.

BACKGROUND: Heart failure (HF) is one of the main comorbidities in patients receiving maintenance hemodialysis (HD). Sacubitril/valsartan (SAC/VAL) is widely used in HF patients with reduced ejection fraction (HFrEF) or HF mid-range ejection fraction (HFmrEF). However, the pharmacokinetic (PK) and pharmacodynamic properties of SAC/VAL in HD patients with HF remain uncertain. OBJECTIVES: This study aimed to analyze the efficacy and PK properties of SAC/VAL in HD patients with HFrEF or HFmrEF. METHODS: HD patients with HFrEF or HFmrEF were treated with SAC/VAL 50 or 100 mg twice a day (BID) and the concentrations of valsartan and LBQ657 (active metabolite of SAC) were determined by high-performance liquid chromatography-tandem mass spectrometry during HD and on the days between HD sessions (interval days). N-terminal-pro B-type natriuretic peptide and high-sensitivity troponin T were measured, and left ventricular ejection fraction (LVEF) was evaluated by echocardiography. RESULTS: The mean maximum plasma concentrations (Cmax) of LBQ657 and VAL on the interval days were 15.46 ± 6.01 and 2.57 ± 1.23 mg/L, respectively. Compared with previous values in patients with severe renal impairment and healthy volunteers, these levels both remained within the safe concentration ranges during treatment with SAC/VAL 100 mg BID. Moreover, SAC/VAL significantly improved LVEF in HD patients with HFrEF or HFmrEF (p < 0.05). CONCLUSIONS: HD did not remove the SAC metabolite LBQ657 or VAL in patients with HF. However, SAC/VAL 100 mg BID was safe and effective in patients undergoing HD.

Prospective model for predicting renal recovery in cardiac surgery patients with acute kidney injury requiring renal replacement therapy.

AIM: To develop a model for predicting renal recovery in cardiac surgery patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT). METHODS: Data from a prospective randomized controlled trial, conducted in a tertiary hospital to compare the survival effect of two dosages of hemofiltration for continuous RRT in cardiac surgery patients between 20 March 2012 and 9 August 2015, were used to develop the model. The outcome was renal recovery defined as alive and dialysis-free 90 days after RRT initiation. Multivariate logistic regression with a stepwise backward selection of variables based on Akaike Information Criterion was applied to develop the model, which was internally validated using bootstrapping. Model discrimination, calibration and clinical value were assessed using the concordance index (C-Index), calibration plots and decision curve analysis, respectively. RESULTS: Totally, 211 patients with AKI requiring RRT (66.8% male) with median age of 57 years were included. The incidence of renal recovery was 33.2% (n = 70). The model included six variables: body mass index stratification, baseline estimated glomerular filtration rate, hypertension, sepsis, mean arterial pressure and mechanical ventilation. The C-Index for this model was 0.807 (95% CI, 0.744-0.870). After correction by the bootstrap, the C-Index was 0.780 (95% CI, 0.720-0.845). The calibration plots indicated good consistency between actual observations and model prediction of renal recovery. Decision curve analysis demonstrated the model was clinical usefulness. CONCLUSION: We developed and validated a model to predict the chance of renal recovery in cardiac surgery patients with AKI requiring RRT.

Derivation and validation of a model to predict acute kidney injury following cardiac surgery in patients with normal renal function.

BACKGROUND: The study aimed to construct a clinical model based on preoperative data for predicting acute kidney injury (AKI) following cardiac surgery in patients with normal renal function. METHODS: A total of 22,348 consecutive patients with normal renal function undergoing cardiac surgery were enrolled. Among them, 15,701 were randomly selected for the training group and the remaining for the validation group. To develop a model visualized as a nomogram for predicting AKI, logistic regression was performed with variables selected using least absolute shrinkage and selection operator regression. The discrimination, calibration, and clinical value of the model were evaluated. RESULTS: The incidence of AKI was 25.2% in the training group. The new model consisted of nine preoperative variables, including age, male gender, left ventricular ejection fraction, hypertension, hemoglobin, uric acid, hypomagnesemia, and oral renin-angiotensin system inhibitor and non-steroidal anti-inflammatory drug within 1 week before surgery. The model had a good performance in the validation group. The discrimination was good with an area under the receiver operating characteristic curve of 0.740 (95% confidence interval, 0.726-0.753). The calibration plot indicated excellent agreement between the model prediction and actual observations. Decision curve analysis also showed that the model was clinically useful. CONCLUSIONS: The new model was constructed based on nine easily available preoperative clinical data characteristics for predicting AKI following cardiac surgery in patients with normal kidney function, which may help treatment decision-making, and rational utilization of medical resources.

Clinical value of renal phospholipase A2 receptor deposit in the prognosis evaluation and treatment options of idiopathic membranous nephropathy: A retrospective cohort study.

AIM: Phospholipase A2 receptor (PLA2R) is a target antigen for idiopathic membranous nephropathy (IMN). However, the association between renal PLA2R antigen and disease prognosis had not been fully investigated. In addition, there was a paucity of studies investigating the difference of therapeutic effects between cyclophosphamide and cyclosporine A in PLA2R-associated IMN. METHODS: This retrospective cohort study recruited 300 eligible patients diagnosed with biopsy-proven IMN between September 2015 and July 2018 in Guangdong Provincial People's Hospital. The remission of proteinuria was compared between PLA2R-associated and non-PLA2R-associated IMN. The difference of therapeutic effects between cyclophosphamide and cyclosporine A were also investigated in PLA2R-associated IMN. RESULTS: The positive rate of renal PLA2R antigen in recruited IMN patients was 82.3%. Non-PLA2R-associated IMN patients had a higher probability to achieve remission than PLA2R-associated IMN patients (Log-rank test, P = .013). Multivariate COX analysis showed that renal PLA2R antigen was an independent risk factor for not achieving remission in IMN patients (Hazard Ratio: 1.619; 95% confidence interval: 1.133 to 2.313; P = .008). In PLA2R-associated IMN, patients receiving cyclophosphamide had a higher probability to achieve remission compared with those receiving cyclosporine A (Log-rank test, P = .018) while there was no difference in renal survival. Multivariate COX regression analysis showed that compared with cyclosporine A, patients receiving cyclophosphamide had a higher probability to achieve remission. CONCLUSION: Phospholipase A2 receptor -associated IMN patients had a lower probability to achieve remission compared with non-PLA2R-associated IMN. Compared with cyclosporine A, cyclophosphamide exerted better therapeutic effects in remission of proteinuria and may be the preferred immunosuppressant for PLA2R-associated IMN. SUMMARY AT A GLANCE This article highlighted the prognostic value of intra-renal phospholipase A2 receptor deposition in idiopathic membranous nephropathy (IMN). Renal phospholipase A2 receptor (PLA2R)-associated IMN patients had a lower probability to achieve remission compared with non-PLA2R-associated IMN.

Canopy Homolog 2 Expression Predicts Poor Prognosis in Hepatocellular Carcinoma with Tumor Hemorrhage.

BACKGROUND/AIMS: Canopy homolog 2 (CNPY2) is a signature gene highly associated with tumor progression, including hepatocellular carcinoma (HCC). The presence of tumor hemorrhage (TH) implies a fast-growing and worse tumor microenvironment. We examined a possible association between CNPY2 levels and TH and evaluated their prognostic values in patients with HCC. METHODS: CNPY2 mRNA and protein levels were respectively determined in two independent cohorts of HCC specimens using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry of tissue microarrays. Kaplan-Meier survival and Cox regression analyses were executed to evaluate the prognosis of HCC. CNPY2 knockout HCC cell lines were established by the CRISPR/Cas9 gene editing system, and the functional role of CNPY2 in HCC cell proliferation and growth was examined in vitro and in vivo. RESULTS: qRT-PCR showed that CNPY2 expression was significantly higher in HCC tumor tissue than in adjacent non-tumor tissue. Immunohistochemistry of HCC tissue microarrays demonstrated that CNPY2 expression was significantly correlated with TH and clinicopathological features indicating worse HCC progression. The prognostic value of CNPY2 expression and TH was validated by Cox proportional hazards analyses. Furthermore, CNPY2 knockout resulted in the significant suppression of MHCC97H cell proliferation, tumor growth, and hemorrhage. Bioinformatics analysis revealed that CNPY2 was closely associated with the expression levels of 6 positive impact genes in HCC, namely, ROMO1, BOLA2, HSF1, ATG4B, ATF4, and DENR, which are implicated in the regulation of the tumor microenvironment. CONCLUSION: CNPY2 is an oncogene that plays a critical role in the progression of HCC with TH. CNPY2 could be exploited as a novel prognostic marker and potential target for therapeutic intervention in HCC.

Red blood cell distribution width as a marker of cerebral infarction in hemodialysis patients.

BACKGROUND: Red blood cell distribution width (RDW) is a cardiovascular biomarker. We evaluated the association between RDW and cerebral stroke risk in hemodialysis patients. METHODS: A cohort of 442 adult patients on hemodialysis was studied. Strokes were defined according to ICD-10 diagnosis codes. Routine complete blood counts, evaluated every 3-6 months, were used for RDW values. RESULTS: Among 442 hemodialysis patients, during the 50-month follow-up, there were 62 cases (14.0%) of cerebral stroke: 41 (9.3%) with cerebral infarction and 21 (4.8%) with cerebral hemorrhage. Compared with nonstroke patients, a significantly higher RDW was measured in patients with cerebral stroke and cerebral infarction. However, no significant difference was seen in RDW between patients with cerebral hemorrhage and nonstroke patients. After adjustment by age, hypertension, albumin, Charlson Comorbidity Score, and C-reactive protein in different multivariable Cox regression models, patients with the highest mean RDW quartile had a 2.55-fold (hazard ratio = 3.55; 95% confidence interval: 1.33-9.51) higher risk of developing cerebral infarction relative to those with the lowest mean RDW quartile. RDW was not an independent risk factor for cerebral hemorrhage. CONCLUSIONS: Increased RDW is an independent risk factor of cerebral infarction in hemodialysis patients.

Hypoxia-induced NIPP1 activation enhances metastatic potential and predicts poor prognosis in hepatocellular carcinoma.

Hypoxia is known to promote hepatocellular carcinoma (HCC) invasion and metastasis and nuclear inhibitor of protein phosphatase 1 (NIPP1) overexpression contributes to the malignant phenotype in HCC. The aim of this study was to investigate the role of NIPP1 in HCC development under hypoxia. We first conducted a study with 106 cases to explore the association of NIPP1 and/or enhancer of zeste homolog 2 (EZH2) expression with poor prognosis in HCC. Then additional 352 independent cases were recruited to validate the results in the first stage. Hypoxia was induced by culturing HCC cells in 1 % O2 or of the treatment with hypoxic agent. The expression levels of NIPP1/EZH2 in both HCC tissues and HCC cell lines were detected by RT-PCR, Western blot, or immunohistochemistry. We also studied the effects of the loss of function of NIPP1 and EZH2 on malignant phenotypes, downstream pathway, and inflammatory factors activities using gene silencing strategy. Overall, we found that NIPP1 and EZH2 were overexpressed in both HCC tissue samples and HCC cell lines. High expression of HIPP1 was associated with poor prognosis and clinicopathological features in patients with advanced HCC. HIPP1 expression positively correlated with the expression of hypoxia marker (carbonic anhydrase IX). Hypoxia induced high expression of NIPP1. NIPP1/EZH2 knockdown in HCC cell lines under hypoxia suppressed the malignant phenotypes, reduced the expression of hypoxia-inducible Factor 1α, downstream molecules of EZH2, and inhibit the activity of inflammatory factors. In conclusion, we found that NIPP1 could be activated by hypoxia and contributed to hypoxia-induced invasive and metastatic potential in HCC.

BTB/POZ domain-containing protein 7: epithelial-mesenchymal transition promoter and prognostic biomarker of hepatocellular carcinoma.

UNLABELLED: Epithelial-mesenchymal transition (EMT) is a critical step in the metastasis of hepatocellular carcinoma (HCC). BTB/POZ domain-containing protein 7 (BTBD7) regulates EMT-associated proteins implicated in HCC progression. However, the role(s) of BTBD7 in HCC have not been identified. Using highly metastatic HCC HCCLM3 cells, immortalized L02 hepatocytes, metastatic HCC animal models, and three independent cohorts of HCC patient specimens, we aimed to determine the involvement of BTBD7 in HCC metastasis. We show that BTBD7 messenger RNA and protein was highly expressed in HCC cells and tumor tissues, with such expression being associated with: enhanced cell motility, venous invasion, and poor prognosis. BTBD7 promoted HCC angiogenesis and metastasis in vitro and in vivo, but did not influence cell proliferation or colony formation. BTBD7 enhancement of HCC invasion and EMT phenotype occurred through activation of a RhoC-Rock2-FAK-signaling pathway, resulting in matrix metalloproteinase-2/9 production and microvessel formation. Applying a predictive risk score model, Cox regression analysis revealed that high BTBD7 expression integrated with high microvessel density was a powerful independent predictive factor of HCC clinical outcome. CONCLUSION: The present study identifies BTBD7 as a novel candidate prognostic factor and a potential therapeutic target of HCC. (HEPATOLOGY 2013; 57:2326-2337).

Urinary messenger RNA of the receptor activator of NF-kappaB could be used to differentiate between minimal change disease and membranous nephropathy.

Podocyte damage and loss together have an important role in the pathogenesis and progression of glomerulonephritis. Glomerulonephritis patients and healthy controls were enrolled in this study. Biochemical, clinical and experimental procedures included measurement of total urinary protein, renal biopsy and gene expression analysis of the receptor activator of NF-kappaB (RANK). The urinary mRNA levels of RANK were significantly higher in the glomerulonephritis group compared to the controls. The urinary RANK level of glomerular subtypes was correlated significantly with proteinuria. The calculated area of RANK mRNA levels under the curve was 0.61 for minimal change disease (MCD), 0.97 for membranous nephropathy (MN), 0.65 for IgA nephropathy (IgAN), 0.70 for lupus nephritis (LN) and 0.70 for focal segmental glomerulosclerosis (FSGS). The urinary mRNA of RANK might be used to differentiate histologic subtypes of glomerulonephritis, particularly between MCD and MN.

[Suppression of hepatocellular carcinoma invasion and metastasis by Rho-kinase inhibitor Fasudil through inhibition of BTBD7-ROCK2 signaling pathway].

OBJECTIVE: To explore the eff ect of Fasudil on the invasion and metastatic abilities of human high metastatic liver cancer cells (HCCLM3) and the underlying mechanisms. METHODS: HCCLM3 cells were incubated with 100 µmol/L Fasudil. Fluorescence staining for F-actin and Transwell assay were performed to observe the invasion ability of HCCLM3 cells. HCCLM3 cells were divided into 3 groups: a negative control group, a Fasudil group and a BTB/ POZ domain containing 7 (BTBD7)-siRNA group. Western blot assay was performed to detect the expression levels of BTBD7, ras homolog family member C (RhoC) and Rho-associated, coiled-coil containing protein kinase 2 (ROCK2), matrix metalloproteinases 2 (MMP2) and MMP9. Zymogram analysis method was performed to detect the expression activities of MMP2 and MMP9. The BTBD7-siRNA group was served as a positive control. RESULTS: In HCCLM3 cells treated with Fasudil, the invasion ability was significant decreased compared with the control group, concomitant with the down-regulated expression levels of BTBD7, RhoC and ROCK2 protein as well as the decreased activities of MMP2 and MMP9. CONCLUSION: Fasudil plays an important role in interfering BTBD7-ROCK2 signaling pathway and suppressing the invasion and metastasis of hepatocellular carcinoma.

The role of platelets in sepsis: A review.

Sepsis, a life-threatening condition characterized by organ dysfunction, results from a complex series of pathophysiological mechanisms including immune dysfunction, an uncontrolled inflammatory response, and coagulation abnormalities. It is a major contributor to global mortality and severe disease development. Platelets, abundant in the circulatory system, are sensitive to changes in the body's internal environment and are among the first cells to respond to dysregulated pro-inflammatory and pro-coagulant reactions at the onset of sepsis. In the initial stages of sepsis, the coagulation cascade, inflammatory response, and endothelial tissue damage perpetually trigger platelet activation. These activated platelets then engage in complex inflammatory and immune reactions, potentially leading to organ dysfunction. Therefore, further research is essential to fully understand the role of platelets in sepsis pathology and to develop effective therapeutic strategies targeting the associated pathogenic pathways. This review delves into the involvement of platelets in sepsis and briefly outlines the clinical applications of associated biomarkers.

Joint effects of air pollution and genetic susceptibility on incident primary open-angle glaucoma.

BACKGROUND: Air pollutants are important exogenous stimulants to eye diseases, but knowledge of associations between long-term exposure to air pollutants and the risk of primary open-angle glaucoma (POAG) is limited. This study aimed to determine whether long-term exposure to air pollutants, genetic susceptibility, and their joint effects lead to an elevated risk of incident POAG. METHODS: This is a population-based prospective cohort study from UK Biobank participants with complete measures of air pollution exposure and polygenetic risk scores. Cox proportional hazard models were fitted to assess the individual and joint effects of long-term exposure to air pollutants and genetics on the risk of POAG. In addition, the effect modification of genetic susceptibility was examined on an additive or multiplicative scale. RESULTS: Among 434,290 participants with a mean (SD) age of 56.5 (8.1) years, 6651 (1.53 %) were diagnosed with POAG during a median follow-up of 13.7 years. Long-term exposure to air pollutants was associated with an increased risk of POAG. The hazard ratios associated with per interquartile range increase in PM2.5, PM2.5 absorbance, PM10, NO2, and NOX individually ranged from 1.027 (95 % CI: 1.001-1.054) to 1.067 (95 % CI: 1.035-1.099). Compared with individuals residing in low-pollution areas and having low polygenic risk scores, the risk of incident POAG increased by 105.5 % (95 % CI: 78.3 %-136.9 %), 79.7 % (95 % CI: 56.5 %-106.5 %), 103.2 % (95 % CI: 76.9 %-133.4 %), 89.4 % (95 % CI: 63.9 %-118.9 %), and 90.2 % (95 % CI: 64.8 %-119.5 %) among those simultaneously exposed to high air pollutants levels and high genetic risk, respectively. Genetic susceptibility interacted with PM2.5 absorbance and NO2 in an additive manner, while no evidence of multiplicative interaction was found in this study. Stratification analyses revealed stronger effects in Black people and the elderly. CONCLUSION: Long-term air pollutant exposure was associated with an increased risk of POAG incidence, particularly in the population with high genetic predisposition.

Efficacy and dose-response relationships of antidepressants in the acute treatment of major depressive disorders: a systematic review and network meta-analysis.

BACKGROUND: The optimal antidepressant dosages remain controversial. This study aimed to analyze the efficacy of antidepressants and characterize their dose-response relationships in the treatments of major depressive disorders (MDD). METHODS: We searched multiple databases, including the Embase, Cochrane Central Register of Controlled Trials, PubMed, and Web of Science, for the studies that were conducted between January 8, 2016, and April 30, 2023. The studies are double-blinded, randomized controlled trials (RCTs) involving the adults (≥18 years) with MDD. The primary outcomes were efficacy of antidepressant and the dose-response relationships. A frequentist network meta-analysis was conducted, treating participants with various dosages of the same antidepressant as a single therapy. We also implemented the model-based meta-analysis (MBMA) using a Bayesian method to explore the dose-response relationships. RESULTS: The network meta-analysis comprised 135,180 participants from 602 studies. All the antidepressants were more effective than the placebo; toludesvenlafaxine had the highest odds ratio (OR) of 4.52 (95% confidence interval [CI]: 2.65-7.72), and reboxetine had the lowest OR of 1.34 (95%CI: 1.14-1.57). Moreover, amitriptyline, clomipramine, and reboxetine showed a linear increase in effect size from low to high doses. The effect size of toludesvenlafaxine increased significantly up to 80 mg/day and subsequently maintained the maximal dose up to 160 mg/day while the predictive curves of nefazodone were fairly flat in different dosages. CONCLUSIONS: Although most antidepressants were more efficacious than placebo in treating MDD, no consistent dose-response relationship between any antidepressants was observed. For most antidepressants, the maximum efficacy was achieved at lower or middle prescribed doses, rather than at the upper limit.