TRIP13 Plays an Important Role in the Sensitivity of Leukemia Cell Response to Sulforaphane Therapy.

Sulforaphane is one of the most characterized isothiocyanate compounds in cruciferous vegetables and shows anticancer effects, especially antileukemia properties. However, the molecular mechanism of the growth inhibition effect of sulforaphane in acute myeloid leukemia (AML) has not been fully explored. In the present study, a proteomic analysis was performed on the AML cell line U937 responding to sulforaphane treatment to identify novel and efficient therapeutic targets of sulforaphane on AML cells. Key driver analysis was run on the leukemia network, and TRIP13 was identified as a key regulatory factor in sulforaphane-induced growth inhibition in U937 cells. Pretreatment with DCZ0415, an inhibitor of TRIP13, could significantly attenuate sulforaphane-induced cell apoptosis and cell cycle arrest in vitro through the PI3K/Akt/mTOR signaling pathway. In addition, the inhibitory effect of sulforaphane on the tumor volume could also be obviously attenuated by the pretreatment of DCZ0415 in vivo. These results indicate that TRIP13 plays an important role in the sensitivity of leukemia cell response to sulforaphane treatment, and these findings expand the understanding of the mechanism of the antileukemic effect of sulforaphane and provide a new target for the treatment of AML.

Action and therapeutic targets of myosin light chain kinase, an important cardiovascular signaling mechanism.

The global incidence of cardiac diseases is increasing, imposing a substantial socioeconomic burden on healthcare systems. The pathogenesis of cardiovascular disease is complex and not fully understood, and the physiological function of the heart is inextricably linked to well-regulated cardiac muscle movement. Myosin light chain kinase (MLCK) is essential for myocardial contraction and diastole, cardiac electrophysiological homeostasis, vasoconstriction of vascular nerves and blood pressure regulation. In this sense, MLCK appears to be an attractive therapeutic target for cardiac diseases. MLCK participates in myocardial cell movement and migration through diverse pathways, including regulation of calcium homeostasis, activation of myosin light chain phosphorylation, and stimulation of vascular smooth muscle cell contraction or relaxation. Recently, phosphorylation of myosin light chains has been shown to be closely associated with the activation of myocardial exercise signaling, and MLCK mediates systolic and diastolic functions of the heart through the interaction of myosin thick filaments and actin thin filaments. It works by upholding the integrity of the cytoskeleton, modifying the conformation of the myosin head, and modulating innervation. MLCK governs vasoconstriction and diastolic function and is associated with the activation of adrenergic and sympathetic nervous systems, extracellular transport, endothelial permeability, and the regulation of nitric oxide and angiotensin II. Additionally, MLCK plays a crucial role in the process of cardiac aging. Multiple natural products/phytochemicals and chemical compounds, such as quercetin, cyclosporin, and ML-7 hydrochloride, have been shown to regulate cardiomyocyte MLCK. The MLCK-modifying capacity of these compounds should be considered in designing novel therapeutic agents. This review summarizes the mechanism of action of MLCK in the cardiovascular system and the therapeutic potential of reported chemical compounds in cardiac diseases by modifying MLCK processes.

Inflammatory Bowel Disease and Skin Cancer: A Two-Sample Mendelian Randomization Analysis.

Background: At present, numerous clinical studies suggest a correlation between inflammatory bowel disease (IBD) and skin cancer. However, some articles present differing views that IBD does not increase the risk of skin cancer. The presence of potential reverse causality and residual confounding is inherent in conventional observational studies. Thus, this study used a two-sample Mendelian randomization (MR) study design to estimate the causal effect of IBD on the risk of skin cancer, including cutaneous malignant melanoma (CMM, also named melanoma skin cancer) and nonmelanoma skin cancer (NMSC). Design: In this study, a two-sample MR analysis was used to estimate the causal effect of IBD on skin cancer outcomes. The inverse-variance weighted (IVW) method was used as the main MR analysis, with multiple sensitivity analyses conducted to assess the robustness of findings. Results: In examining the association between IBD and NMSC, all p-values of the IVW methods were found to be <0.05, providing evidence for a causal effect of IBD on an increased risk of NMSC. However, IVW for IBD on CMM yielded p-values >0.05, indicating no causal relationship between IBD and CMM. These findings were consistent across other MR methods, with no evidence of pleiotropy or heterogeneity. Sensitivity analyses confirmed the robustness of our results. Conclusion: Using MR analysis, we found evidence for a causal effect of genetic liability for IBD on an increased risk of NMSC. However, our study did not find sufficient evidence to support a significant impact of IBD on CMM outcomes.

Causal relationship between gut microbiota and gastrointestinal diseases: a mendelian randomization study.

BACKGROUND: Recent research increasingly highlights a strong correlation between gut microbiota and the risk of gastrointestinal diseases. However, whether this relationship is causal or merely coincidental remains uncertain. To address this, a Mendelian randomization (MR) analysis was undertaken to explore the connections between gut microbiota and prevalent gastrointestinal diseases. METHODS: Genome-wide association study (GWAS) summary statistics for gut microbiota, encompassing a diverse range of 211 taxa (131 genera, 35 families, 20 orders, 16 classes, and 9 phyla), were sourced from the comprehensive MiBioGen study. Genetic associations with 22 gastrointestinal diseases were gathered from the UK Biobank, FinnGen study, and various extensive GWAS studies. MR analysis was meticulously conducted to assess the causal relationship between genetically predicted gut microbiota and these gastrointestinal diseases. To validate the reliability of our findings, sensitivity analyses and tests for heterogeneity were systematically performed. RESULTS: The MR analysis yielded significant evidence for 251 causal relationships between genetically predicted gut microbiota and the risk of gastrointestinal diseases. This included 98 associations with upper gastrointestinal diseases, 81 with lower gastrointestinal diseases, 54 with hepatobiliary diseases, and 18 with pancreatic diseases. Notably, these associations were particularly evident in taxa belonging to the genera Ruminococcus and Eubacterium. Further sensitivity analyses reinforced the robustness of these results. CONCLUSIONS: The findings of this study indicate a potential genetic predisposition linking gut microbiota to gastrointestinal diseases. These insights pave the way for designing future clinical trials focusing on microbiome-related interventions, including the use of microbiome-dependent metabolites, to potentially treat or manage gastrointestinal diseases and their associated risk factors.

Preoperative diagnosis of solitary pulmonary nodules with a novel hematological index model based on circulating tumor cells.

Objective: Preoperative noninvasive diagnosis of the benign or malignant solitary pulmonary nodule (SPN) is still important and difficult for clinical decisions and treatment. This study aimed to assist in the preoperative diagnosis of benign or malignant SPN using blood biomarkers. Methods: A total of 286 patients were recruited for this study. The serum FR+CTC, TK1, TP, TPS, ALB, Pre-ALB, ProGRP, CYFRA21-1, NSE, CA50, CA199, and CA242 were detected and analyzed. Results: In the univariate analysis, age, FR+CTC, TK1, CA50, CA19.9, CA242, ProGRP, NSE, CYFRA21-1, and TPS showed the statistical significance of a correlation with malignant SPNs (P <0.05). The highest performing biomarker is FR+CTC (odd ratio [OR], 4.47; 95% CI: 2.57-7.89; P <0.001). The multivariate analysis identified that age (OR, 2.69; 95% CI: 1.34-5.59, P = 0.006), FR+CTC (OR, 6.26; 95% CI: 3.09-13.37, P <0.001), TK1 (OR, 4.82; 95% CI: 2.4-10.27, P <0.001), and NSE (OR, 2.06; 95% CI: 1.07-4.06, P = 0.033) are independent predictors. A prediction model based on age, FR+CTC, TK1, CA50, CA242, ProGRP, NSE, and TPS was developed and presented as a nomogram, with a sensitivity of 71.1% and a specificity of 81.3%, and the AUC was 0.826 (95% CI: 0.768-0.884). Conclusions: The novel prediction model based on FR+CTC showed much stronger performance than any single biomarker, and it can assist in predicting benign or malignant SPNs.

Construction of a lncRNA-mediated ceRNA network and a genomic-clinicopathologic nomogram to predict survival for breast cancer patients.

Breast cancer (BC) is the most common cancer among women and a leading cause of cancer-related deaths worldwide. The diagnosis of early patients and the prognosis of advanced patients have not improved over the past several decades. The purpose of the present study was to identify the lncRNA-related genes based on ceRNA network and construct a credible model for prognosis in BC. Based on The Cancer Genome Atlas (TCGA) database, prognosis-related differently expressed genes (DEGs) and a lncRNA-associated ceRNA regulatory network were obtained in BC. The patients were randomly divided into a training group and a testing group. A ceRNA-related prognostic model as well as a nomogram was constructed for further study. A total of 844 DElncRNAs, 206 DEmiRNAs and 3295 DEmRNAs were extracted in BC, and 12 RNAs (HOTAIR, AC055854.1, ST8SIA6-AS1, AC105999.2, hsa-miR-1258, hsa-miR-7705, hsa-miR-3662, hsa-miR-4501, CCNB1, UHRF1, SPC24 and SHCBP1) among them were recognized for the construction of a prognostic risk model. Patients were then assigned to high-risk and low-risk groups according to the risk score. The Kaplan-Meier (K-M) analysis demonstrated that the high-risk group was closely associated with poor prognosis. The predictive nomogram combined with clinical features showed performance in clinical practice. In a nutshell, our ceRNA-related gene model and the nomogram graph are accurate and reliable tools for predicting prognostic outcomes of BC patients, and may make great contributions to modern precise medicine.

A novel ultra-low-volume regimen combining 1 L polyethylene glycol and linaclotide versus 2 L polyethylene glycol for colonoscopy cleansing in low-risk individuals: a randomized controlled trial.

BACKGROUND AND AIMS: The single dose of 2 L polyethylene glycol (PEG) has shown high cleaning efficacy and tolerability in low-risk patients. However, the dosage of this regimen is still challenging for many patients. We investigated the efficacy and tolerability of a novel ultra-low-volume regimen using 1 L PEG and linaclotide (1 L PEG+L) versus a single dose of 2 L PEG in low-risk patients. METHODS: In this prospective, randomized, observer-blinded, multicenter study, low-risk adult patients scheduled for colonoscopy were enrolled and randomized (1:1) to receive the 1 L PEG+L regimen or the 2 L PEG regimen. The primary outcome was the effectiveness of bowel cleansing according to the Boston Bowel Preparation Scale. Secondary outcomes included cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate and adenoma detection rate, tolerability, adverse events, and willingness to repeat bowel preparation. The full analysis set (FAS) and per-protocol set (PPS) were used for statistical analyses. RESULTS: A total of 548 patients comprised the FAS, and 522 patients comprised the PPS. Noninferiority on adequate bowel cleansing of 1 L PEG+L vs 2 L PEG was established both in FAS (90.5% vs 91.6%, P = .644) and PPS (90.3% vs 92.4%, P = .390). There were no significant differences regarding the total score and each segment scores of the Boston Bowel Preparation Scale, cecal intubation rate, cecal insertion time, withdrawal time, polyp detection rate, and adenoma detection rate (all, P > .05). However, patients in the 1 L PEG+L group reported less nausea (7.7% vs 17.1%, P < .01) and vomiting (4.0% vs 10.9%, P < .01) and had a higher willingness to repeat bowel preparation (95.2% vs 82.2%, P < .01). CONCLUSIONS: The regimen of 1 L PEG+L was not inferior to 2 L PEG on colon cleansing, with better tolerability and higher willingness to repeat the bowel preparation in a low-risk population. (Clinical trial registration number: ChiCTR2100053273.).

The relationship between processed meat, red meat, and risk of types of cancer: A Mendelian randomization study.

Background: Observational studies have suggested processed and red meat may increase the risk of cancer. However, the causal effects and direction between them were still unclear. We conducted two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of processed meat and red meat on the risk of nine common types of cancer, namely, lung, ovarian, endometrial, breast, kidney, gastric, prostate, skin, and oropharyngeal cancer. Methods: Genome-wide association studies (GWAS) for processed meat and red meat (pork, beef, and mutton) were obtained from the UK Biobank. GWAS of types of cancer in this study were extracted from the genetic consortia and the FinnGen consortium. The inverse variance weighted (IVW) was carried out as the main method for two-sample MR analysis. Sensitivity analyses were used to assess the robustness of the results. Results: Genetically predicted processed meat intake was causally associated with increased risk of lung cancer (OR [odds ratio] = 1.923, 95% CI = 1.084-3.409, P = 0.025). There is no convincing evidence for the associations between genetically determined processed meat, red meat, and the risk of other cancers we studied. Conclusion: Our results suggested that intake of processed meat may increase the risk of lung cancer. These findings provided no evidence to support that consumption of processed and red meat has a large effect on the risk of other cancers we studied. Further research is needed to clarify the results.

Inflammatory bowel disease and cardiovascular disease: A two-sample Mendelian randomization analysis.

Background: Although epidemiological studies have shown a positive relationship between inflammatory bowel disease (IBD) and risk of cardiovascular disease (CVD) outcomes, a solid causal relationship has not been established. Thus, a two-sample Mendelian randomization (MR) study was conducted to explore the potential causal effect between IBD and CVD outcomes. Methods: We performed a two-sample MR analysis to analyze the causal effect of the IBD on CVD outcome by using summary-level genome-wide association studies of European descent. The inverse-variance weighted (IVW) method was used as the main MR analysis, with complementary analyses of MR Egger, maximum likelihood, weighted median, penalized weighted media, simple mode, weighted mode, and MR-PRESSO methods. Multiple sensitivity analyses were used to evaluate the robustness of our results. Results: All P-values were greater than 0.05 in the IVW method, showing no evidence of a causal association between circulating IBD and CVD. Similar results were observed by using other MR methods. No evidence of heterogeneity, pleiotropy, or outlier single-nucleotide polymorphisms was detected. Sensitivity analyses demonstrated the robustness of the results. Conclusion: The findings of this study provided no evidence to support that IBD has a large effect on risk of CVD outcomes, which is in contrast to many previous observational reports. Further studies are needed to determine the potential mechanism of association identified in observational studies.

Three-dimensional BiVO4-based semiconductor photocathode for high efficiency photo-assisted Zn-iodine redox flow batteries.

Aqueous Zn-iodine redox flow batteries have aroused great interest for the features of high capacity, excellent stability, low cost, and high safety, yet the dissatisfying energy efficiency still limits their future advancement. In this work, three-dimensional semiconductor BiVO4nanoparticles decorated hierarchical TiO2/SnO2arrays (BiVO4@TiO2/SnO2) were applied as photocathode in Zn-iodine redox flow batteries (ZIRFBs) for the realization of efficient photo-assisted charge/discharge process. The photogenerated carriers at the solid/liquid interfaces boosted the oxidation process of I-, and thus contributed to a significant elevation in energy efficiency of 14.9% (@0.5 mA cm-2). A volumetric discharge capacity was extended by 79.6% under light illumination, owing to a reduced polarization. The photocathode also exhibited an excellent durability, leading to a stable operation for over 80 h with a maintained high energy efficiency of ∼90% @0.2 mA cm-2. The research offers a feasible approach for the realization of high-energy-efficiency aqueous Zn-iodine batteries towards high-efficiency energy conversion and utilization.

ALD oxygen vacancy-rich amorphous Ga2O3 on three-dimensional urchin-like ZnO arrays for high-performance self-powered solar-blind photodetectors.

The exploration of efficient self-powered solar-blind photodetectors is essential for applications in future sustainable optoelectronic systems. Herein, we demonstrate a photoelectrochemical (PEC)-type heterojunction-driven solar-blind detector constructed by atomic layer deposition (ALD) of oxygen vacancy-rich amorphous Ga2O3 on three-dimensional urchin-like ZnO nanorod arrays (3D VO-Ga2O3/ZnO). The as-fabricated device achieves excellent solar-blind photodetection performance in terms of a high photoresponsivity of 7.97 mA W-1 at 0 V bias, an ultrahigh light to dark ratio of 6.93 × 104 under 266 nm light illumination as well as fast response and recovery times. The excellent performance originates from abundant oxygen vacancies in a-Ga2O3 as donors, high specific surface area and good interface contact enabled by the 3D ordered nanostructure, and high carrier separation rates benefited from the Ga2O3/ZnO heterojunction. Our research offers a feasible and cost-effective approach towards the realization of a high-performance self-powered photodetection system for various applications.

Ultrathin Co(OH)2 Nanosheets@Nitrogen-Doped Carbon Nanoflake Arrays as Efficient Air Cathodes for Rechargeable Zn-Air Batteries.

Developing highly active, cost-effective, and durable bifunctional oxygen electrocatalysts is an important step for the advancement of rechargeable Zn-air batteries (ZABs). Herein, an efficient bifunctional oxygen electrocatalyst of ultrathin Co(OH)2 nanosheets supported on nitrogen-doped carbon nanoflake arrays (named as Co(OH)2 @NC), is reported, which yields excellent bifunctional activity, i.e., a low overpotential of 285 mV to reach 10 mA cm-2 for oxygen evolution reaction (OER), a high half-wave potential (0.83 V) for oxygen reduction reaction (ORR), and a low potential gap (ΔE) of 0.69 V. The excellent bifunctional catalytic performance can be ascribed to the concerted efforts of cobalt hydroxide toward OER and nitrogen-doped carbon for ORR. The Co(OH)2 @NC nanoflake arrays is further used as binder-free air cathodes for rechargeable Zn-air batteries, exhibiting a high specific capacity of 798.3 mAh gZn -1 , improved stability (a working life of >70 h at 5 mA cm-2 ), as well as a reduced long-term charging voltage, which outperforms the counterparts of NC nanoflake arrays and Pt/C-based air cathodes. One step further, the Co(OH)2 @NC nanoflake arrays on carbon cloth are directly used as binder-free air cathodes for flexible, solid-state ZABs, showing excellent performance under deformation as well.

CircWAC induces chemotherapeutic resistance in triple-negative breast cancer by targeting miR-142, upregulating WWP1 and activating the PI3K/AKT pathway.

BACKGROUND: Chemotherapeutic resistance is the main cause of clinical treatment failure and poor prognosis in triple-negative breast cancer (TNBC). There is no research on chemotherapeutic resistance in TNBC from the perspective of circular RNAs (circRNAs). METHODS: TNBC-related circRNAs were identified based on the GSE101124 dataset. Quantitative reverse transcription PCR was used to detect the expression level of circWAC in TNBC cells and tissues. Then, in vitro and in vivo functional experiments were performed to evaluate the effects of circWAC in TNBC. RESULTS: CircWAC was highly expressed in TNBC and was associated with worse TNBC patient prognosis. Subsequently, it was verified that downregulation of circWAC can increase the sensitivity of TNBC cells to paclitaxel (PTX) in vitro and in vivo. The expression of miR-142 was negatively correlated with circWAC in TNBC. The interaction between circWAC and miR-142 in TNBC cells was confirmed by RNA immunoprecipitation assays, luciferase reporter assays, pulldown assays, and fluorescence in situ hybridization. Mechanistically, circWAC acted as a miR-142 sponge to relieve the repressive effect of miR-142 on its target WWP1. In addition, the overall survival of TNBC patients with high expression of miR-142 was significantly better than that of patients with low expression of miR-142, and these results were verified in public databases. MiR-142 regulated the expression of WWP1 and the activity of the PI3K/AKT pathway. It was confirmed that WWP1 is highly expressed in TNBC and that the prognosis of patients with high WWP1 expression is poor. CONCLUSIONS: CircWAC/miR-142/WWP1 form a competing endogenous RNA (ceRNA) network to regulate PI3K/AKT signaling activity in TNBC cells and affect the chemosensitivity of cells.

Prognostic value of the systemic inflammation response index (SIRI) before and after surgery in operable breast cancer patients.

BACKGROUND: The new systemic inflammation response index (SIRI) constructed based on neutrophil, monocyte and lymphocyte counts in peripheral blood is considered to be related to the prognosis of a variety of tumours. OBJECTIVE: To evaluate the prognostic value of the SIRI in operable breast cancer patients and establish a nomogram to predict the survival of breast cancer patients. METHODS: A total of 949 patients with operable breast cancer were enrolled in the present study. RESULTS: The overall survival (OS) of breast cancer patients with SIRI ⩽ 0.65 was significantly higher than that of breast cancer patients with SIRI > 0.65 (P< 0.001). A nomogram generated based on SIRI, grade and TNM stage and SIRI predicted the 5- and 10-year survival rates of breast cancer patients more accurately than TNM stage alone. In addition, the change in SIRI relative to baseline at 4 weeks after surgery was closely related to the survival of breast cancer patients. Compared with those with no SIRI changes (absolute value of variation < 25%), breast cancer patients with an increase in SIRI > 75% or 25-75% had worse OS (P< 0.001). CONCLUSIONS: The SIRI before and after surgery is closely related to the prognosis of breast cancer patients.

Rational Design of 3D Hierarchical Ternary SnO2/TiO2/BiVO4 Arrays Photoanode toward Efficient Photoelectrochemical Performance.

BiVO4 as a promising semiconductor absorber is widely investigated as photoanode in photoelectrochemical water splitting. Herein, the rational design of 3D hierarchical ternary SnO2/TiO2/BiVO4 arrays is reported as photoanode for photoelectrochemical application, in which the SnO2 hierarchically hollow microspheres core/nanosheets shell arrays act as conductive skeletons, while the sandwiched TiO2 and surface BiVO4 are working as hole blocking layer and light absorber, respectively. Arising to the hierarchically ordered structure and synergistic effect between each component in the composite, the ternary SnO2/TiO2/BiVO4 photoanode enables high light harvesting efficiency as well as enhanced charge transport and separation efficiency, yielding a maximum photocurrent density of ≈5.03 mA cm-2 for sulfite oxidation and ≈3.1 mA cm-2 for water oxidation, respectively, measured at 1.23 V versus reversible hydrogen electrode under simulated air mass (AM) 1.5 solar light illumination. The results reveal that electrode design and interface engineering play important roles on the overall PEC performance.

[Association of dietary energy intake and energy density with gestational weight gain in Chengdu City].

OBJECTIVE: To determine the association of dietary energy intake and energy density( ED) with gestational weight gain among pregnant women in Chengdu. METHODS: A total of 503 pregnant women who took the prenatal examination in West China Second University Hospital were selected in the prospective study in 2015. ED, computed as the ratio of energy intake( kcal) per weight( g) of foods( kcal/g), was calculated using three methods as follows:( 1) ED1 included foods only, excluding all beverages;( 2) ED2 included foods and milk;( 3) ED3 included foods and beverages. Energy intake were calculated using dietary data respectively collected in the first, second and third trimester of pregnancy by validated 24-hour recalls, in which ED was calculated based on three calculation method. Data on gestational weight gain was calculated by using pre-pregnancy weight and prenatal weight. Excessive gestational weight gain was determined by the 2009 Institute of Medicine( IOM) recommendations for gestational weight gain. Logistic regression analyses were performed to explore the association of energy intake and ED with excessive gestational weight gain. RESULTS: The risk of excessive gestational weight gain was higher among pregnant women whose dietary energy intake during the third trimester of pregnancy was higher( OR = 1. 94, 95% CI 1. 18-3. 23). After adjusting for covariates, ED based on foods and milk during the third trimester of pregnancy was identified as a protect factor of excessive gestational weight gain( OR = 0. 56, 95% CI 0. 34-0. 93). Dietary energy intake and ED in the first and second trimester of pregnancy were not associated with excessive gestational weight gain after adjustment of all covariates. CONCLUSION: Dietary energy intake in the third trimester of pregnancy might be the risk factor of excessive gestational weight gain, while moderate ED may be the protect factor.