Dynamic changes of gut microbiota in mouse models of metabolic dysfunction-associated steatohepatitis and its transition to hepatocellular carcinoma.

Dysbiosis of gut microbiota may account for pathobiology in simple fatty liver (SFL), metabolic dysfunction-associated steatohepatitis (MASH), fibrotic progression, and transformation to MASH-associated hepatocellular carcinoma (MASH-HCC). The aim of the present study is to investigate gut dysbiosis in this progression. Fecal microbial rRNA-16S sequencing, absolute quantification, histopathologic, and biochemical tests were performed in mice fed high fat/calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) or control diet (CD) for 2, 16 weeks, or 14 months. Histopathologic examination verified an early stage of SFL, MASH, fibrotic, or MASH-HCC progression with disturbance of lipid metabolism, liver injury, and impaired gut mucosal barrier as indicated by loss of occludin in ileum mucosa. Gut dysbiosis occurred as early as 2 weeks with reduced α diversity, expansion of Kineothrix, Lactococcus, Akkermansia; and shrinkage in Bifidobacterium, Lactobacillus, etc., at a genus level. Dysbiosis was found as early as MAHS initiation, and was much more profound through the MASH-fibrotic and oncogenic progression. Moreover, the expansion of specific species, such as Lactobacillus johnsonii and Kineothrix alysoides, was confirmed by an optimized method for absolute quantification. Dynamic alterations of gut microbiota were characterized in three stages of early SFL, MASH, and its HCC transformation. The findings suggest that the extent of dysbiosis was accompanied with MASH progression and its transformation to HCC, and the shrinking or emerging of specific microbial species may account at least in part for pathologic, metabolic, and immunologic alterations in fibrogenic progression and malignant transition in the liver.

Comparative effectiveness of immunotherapy and chemotherapy in patients with metastatic colorectal cancer stratified by microsatellite instability status.

BACKGROUND: Immunotherapy have demonstrated promising outcomes in patients with high microsatellite instability (MSI) (MSI-H) metastatic colorectal cancer. However, the comparative effectiveness of Immunotherapy and chemotherapy for patients with low MSI (MSI-L), and microsatellite stable (MSS) metastatic colorectal cancer remains unclear. AIM: To investigate immunotherapy vs chemotherapy for treatment of MSI-L/MSS metastatic colorectal cancer, and to evaluate the success of immunotherapy against chemotherapy in managing MSI-H metastatic colorectal cancer during a follow-up of 50 months. METHODS: We conducted a retrospective cohort study using the National Cancer Database (NCDB) to evaluate the overall survival (OS) of patients with metastatic colorectal cancer treated with immunotherapy or chemotherapy. The study population was stratified by MSI status (MSI-H, MSI-L, and MSS). Multivariable Cox proportional hazard models were used to assess the association between treatment modality and OS, adjusting for potential confounders. RESULTS: A total of 21951 patients with metastatic colorectal cancer were included in the analysis, of which 2358 were MSI-H, and 19593 were MSI-L/MSS. In the MSI-H cohort, immunotherapy treatment (n = 142) was associated with a significantly improved median OS compared to chemotherapy (n = 860). After adjusting for potential confounders, immunotherapy treatment remained significantly associated with better OS in the MSI-H cohort [adjusted hazard ratio (aHR): 0.57, 95% confidence interval (95%CI): 0.43-0.77, P < 0.001]. In the MSS cohort, no significant difference in median OS was observed between immunotherapy treatment and chemotherapy (aHR: 0.94, 95%CI: 0.69-1.29, P = 0.715). CONCLUSION: In this population-based study using the NCDB, immunotherapy treatment was associated with significantly improved OS compared to chemotherapy in patients with MSI-H metastatic colorectal cancer, but not in those with MSI-L/MSS metastatic colorectal cancer. Further studies are warranted to determine the optimal therapeutic approach for patients with MSI-L/MSS metastatic colorectal cancer.

Sensitivity and stability improvement on slippery surface-aggregated substrate for trace heavy metals detection using NELIBS.

The sensitive and stable detection of trace heavy metals in liquid is crucial given its profound impact on various aspects of human life. Currently, nanoparticle-enhanced laser-induced breakdown spectroscopy (NELIBS) with dried droplet method (DDM) is widely applied for heavy metals detection. Nevertheless, the coffee ring effect (CRE) in DDM affects the stability, accuracy, and sensitivity of NELIBS. Here, we developed a slippery surface-aggregated substrate (SS substrate) to suppress the CRE and enrich analytes, and form a plasmonic platform for NELIBS detection. The SS substrate was prepared by infiltrating perfluorinated lubricant into the pores of PTFE membrane. The droplet, with targeted elements and gold nanoparticles, was dried on the SS substate to form the plasmonic platform for NELIBS analysis. Then, trace heavy metal elements copper (Cu) and manganese (Mn) were analyzed by NELIBS. The results of Cu (RSD = 5.60%, LoD = 3.72 µg/L) and Mn (RSD = 7.42%, LoD = 6.37 µg/L), illustrated the CRE suppression and analytes enrichment by the SS substrate. The results verified the realization of stable, accurate and sensitive NELIBS detection. And the LoDs succeeded to reach the standard limit of China (GB/T 14848-2017). Furthermore, the results for groundwater detection (relative error: 5.92% (Cu) and 4.74% (Mn)), comparing NELIBS and inductively coupled plasma mass spectrometry (ICP-MS), validated the feasibility of the SS substrate in practical applications. In summary, the SS substrate exhibits immense potential for practical application such as water quality detection and supervision.

The arrival time and energy of FRBs traverse the time-energy bivariate space like a Brownian motion.

The origin of fast radio bursts (FRBs), the brightest cosmic explosion in radio bands, remains unknown. We introduce here a novel method for a comprehensive analysis of active FRBs' behaviors in the time-energy domain. Using "Pincus Index" and "Maximum Lyapunov Exponent", we were able to quantify the randomness and chaoticity, respectively, of the bursting events and put FRBs in the context of common transient physical phenomena, such as pulsar, earthquakes, and solar flares. In the bivariate time-energy domain, repeated FRB bursts' behaviors deviate significantly (more random, less chaotic) from pulsars, earthquakes, and solar flares. The waiting times between FRB bursts and the corresponding energy changes exhibit no correlation and remain unpredictable, suggesting that the emission of FRBs does not exhibit the time and energy clustering observed in seismic events. The pronounced stochasticity may arise from a singular source with high entropy or the combination of diverse emission mechanisms/sites. Consequently, our methodology serves as a pragmatic tool for illustrating the congruities and distinctions among diverse physical processes.

Mechanisms by which sheep milk consumption ameliorates insulin resistance in high-fat diet-fed mice.

Sheep milk is rich in fat, protein, vitamins and minerals and is also one of the most important sources of natural bioactives. Several biopeptides in sheep milk have been reported to possess antibacterial, antiviral and anti-inflammatory properties, and they may prevent type 2 diabetes (T2D), disease and cancer. However, the precise mechanism(s) underlying the protective role of sheep milk against T2D development remains unclear. Therefore, in the current study, we investigated the effect of sheep milk on insulin resistance and glucose intolerance in high-fat diet (HFD)-fed mice, by conducting intraperitoneal glucose tolerance tests, metabolic cage studies, genomic sequencing, polymerase chain reaction, and biochemical assays. Hyperinsulinemic-euglycemic clamp-based experiments revealed that mice consuming sheep milk exhibited lower hepatic glucose production than mice in the control group. These findings further elucidate the mechanism by which dietary supplementation with sheep milk alleviates HFD-induced systemic glucose intolerance.

Melatonin antagonizes oxidative stress-induced apoptosis in retinal ganglion cells through activating the thioredoxin-1 pathway.

This study aimed to explore the role of melatonin in oxidative stress-induced injury on retinal ganglion cells and the underlying mechanisms. The immortalized RGC-5 cells were treated with H2O2 to induce oxidative injury. Cell viability was measured by Cell Counting Kit-8, and apoptosis was determined by flow cytometry and western blot assays. Reactive oxygen species (ROS), lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels were examined to evaluate oxidative stress levels. In addition, Thioredoxin-1 (Trx1) was silenced in RGC-5 cells using small interfering RNA followed by signaling pathway examination to explore the underlying mechanisms of melatonin in alleviating oxidative injury. Melatonin pre-treatment significantly alleviated H2O2-induced apoptosis in RGC-5 cells. Melatonin also markedly reversed the upregulation of cleaved-caspase 3, cleaved-caspase 9, and Bax expression and downregulation of Bcl-2 expression induced by H2O2. Further analyses presented that melatonin significantly attenuated the increase of ROS, LDH, and MDA levels in RGC-5 cells after H2O2 treatment. Melatonin also abolished the downregulated expression of Superoxide dismutase type 1, Trx1, and Thioredoxin reductase 1, and the reduced activity of thioredoxin reductase in RGC-5 cells after H2O2 treatment. Notably, Trx1 knockdown significantly mitigated the protective effect of melatonin in alleviating H2O2-induced apoptosis and oxidative stress, while administration of compound C, a common inhibitor of c-Jun N-terminal kinase (JNK) signaling, partially reversed the effect of Trx1 silencing, thereby ameliorating the apoptosis and oxidative injury induced by H2O2 in RGC-5 cells. Melatonin could significantly alleviate oxidative stress-induced injury of retinal ganglion cells via modulating Trx1-mediated JNK signaling pathway.

Identification of Burkholderia gladioli pv. cocovenenans in Black Fungus and Efficient Recognition of Bongkrekic Acid and Toxoflavin Producing Phenotype by Back Propagation Neural Network.

Burkholderia gladioli pv. cocovenenans is a serious safety issue in black fungus due to the deadly toxin, bongkrekic acid. This has triggered the demand for an efficient toxigenic phenotype recognition method. The objective of this study is to develop an efficient method for the recognition of toxin-producing B. gladioli strains. The potential of multilocus sequence typing and a back propagation neural network for the recognition of toxigenic B. cocovenenans was explored for the first time. The virulent strains were isolated from a black fungus cultivation environment in Qinba Mountain area, Shaanxi, China. A comprehensive evaluation of toxigenic capability of 26 isolates were conducted using Ultra Performance Liquid Chromatography for determination of bongkrekic acid and toxoflavin production in different culturing conditions and foods. The isolates produced bongkrekic acid in the range of 0.05-6.24 mg/L in black fungus and a highly toxin-producing strain generated 201.86 mg/L bongkrekic acid and 45.26 mg/L toxoflavin in co-cultivation with Rhizopus oryzae on PDA medium. Multilocus sequence typing phylogeny (MLST) analysis showed that housekeeping gene sequences have a certain relationship with a strain toxigenic phenotype. We developed a well-trained, back-propagation neutral network for prediction of toxigenic phenotype in B. gladioli based on MLST sequences with an accuracy of 100% in the training set and an accuracy of 86.7% in external test set strains. The BP neutral network offers a highly efficient approach to predict toxigenic phenotype of strains and contributes to hazard detection and safety surveillance.

Triglyceride-glucose index as a valuable predictor for aged 65-years and above in critical delirium patients: evidence from a multi-center study.

BACKGROUND: The triglyceride-glucose index (TyG), an established indicator of insulin resistance, is closely correlated with the prognosis of several metabolic disorders. This study aims to investigate the association between the TyG index and the incidence of critical delirium in patients aged 65 years and older. METHODS: We focused on evaluating patients aged 65 years and older diagnosed with critical delirium. Data were obtained from the Medical Information Database for Intensive Care (MIMIC-IV) and the eICU Collaborative Research Database (eICU-CRD). Multivariate logistic regression and restricted cubic spline (RCS) regression were used to determine the relationship between the TyG index and the risk of delirium. RESULTS: Participants aged 65 years and older were identified from the MIMIC-IV (n = 4,649) and eICU-CRD (n = 1,844) databases. Based on optimal thresholds derived from RCS regression, participants were divided into two cohorts: Q1 (< 8.912), Q2 (≥ 8.912). The logistic regression analysis showed a direct correlation between the TyG index and an increased risk of critical delirium among ICU patients aged 65 and older. These findings were validated in the eICU-CRD dataset, and sensitivity analysis further strengthened our conclusions. In addition, the subgroup analysis revealed certain differences. CONCLUSION: This study highlights a clear, independent relationship between the TyG index and the risk of critical delirium in individuals aged 65 years and older, suggesting the importance of the TyG index as a reliable cardio-cerebrovascular metabolic marker for risk assessment and intervention.

Adipose­derived stem cell­mediated alphastatin targeting delivery system inhibits angiogenesis and tumor growth in glioma.

Malignant glioma is a highly vascularized tumor. Therefore, inhibition of angiogenesis is an effective treatment strategy for it. Alphastatin is a 24­amino acid peptide that has been demonstrated to inhibit glioma angiogenesis and tumor growth. Adipose­derived stem cells (ADSCs) are considered an ideal targeted drug delivery system for glioma therapy due to their targeted tropism for cancer and the intrinsic attribute of autologous transplantation. The aim of the present study was to construct an ADSC­mediated alphastatin targeted delivery system and investigate its effects on angiogenesis in glioma. The sequence encoding the human neurotrophin­4 signal peptide and alphastatin fusion gene fragment was transferred into ADSCs using a lentiviral vector to construct the ADSC­mediated alphastatin targeted delivery system (Al­ADSCs). Flow cytometry was used to detect the stem cell surface markers of Al­ADSCs. Western blot analysis and ELISA were used to detect the expression and secretion of alphastatin peptide in Al­ADSCs. Cell migration assay was used to detect the tendency of Al­ADSCs to target CD133+ glioma stem cells (GSCs). The effects of Al­ADSCs on angiogenesis in vitro were detected by tube formation assay. A Cell Counting Kit­8 assay was used to detect the effects of Al­ADSCs on endothelial cell (EC) proliferation. Wound healing assay was used to examine the effects of Al­ADSCs on EC migration. Intracranial xenograft models were constructed and in vivo fluorescence imaging was used to examine the effects of Al­ADSCs on glioma growth. Fluorescence microscopy was used to detect the distribution of Al­ADSCs in glioma tissue and CD133 immunofluorescence staining was used to detect the effects of Al­ADSCs on GSCs in glioma tissue. The results revealed that ADSCs exhibited more marked tropism to GSCs than to other types of cells (P<0.01). Al­ADSCs maintained the surface markers of ADSCs and there was no significant difference between the ADSCs and Al­ADSCs regarding tropism to GSCs (P=0.639 for GSCs­SHG44 cells; and P=0.386 for GSCs­U87 cells). Al­ADSCs were able to successfully secrete and express alphastatin peptide and inhibited EC­mediated angiogenesis (P<0.01) and EC migration (P<0.01) and proliferation (P<0.01) in vitro. In vivo, Al­ADSCs were detected in glioma tissue and were able to inhibit tumor growth. In addition, the Al­ADSCs reduced the number of GSCs and microvascular density (P<0.01) in the tumors. Overall, the results of the present study indicated that the Al­ADSCs were able to target glioma tissue and inhibit glioma angiogenesis and tumor growth. This anti­angiogenic targeted therapy system may provide a new strategy for the treatment of glioma.

Coffee-Associated Endophytes: Plant Growth Promotion and Crop Protection.

Endophytic microbes are a ubiquitous group of plant-associated communities that colonize the intercellular or intracellular host tissues while providing numerous beneficial effects to the plants. All the plant species are thought to be associated with endophytes, majorly constituted with bacteria and fungi. During the last two decades, there has been a considerable movement toward the study of endophytes associated with coffee plants. In this review, the main consideration is given to address the coffee-associated endophytic bacteria and fungi, particularly their action on plant growth promotion and the biocontrol of pests. In addition, we sought to identify and analyze the gaps in the available research. Additionally, the potential of endophytes to improve the quality of coffee seeds is briefly discussed. Even though there are limited studies on the subject, the potentiality of coffee endophytes in plant growth promotion through enhancing nitrogen fixation, availability of minerals, nutrient absorption, secretion of phytohormones, and other bioactive metabolites has been well recognized. Further, the antagonistic effect against various coffee pathogenic bacteria, fungi, nematodes, and also insect pests leads to the protection of the crop. Furthermore, it is recognized that endophytes enhance the sensory characteristics of coffee as a new field of study.

Comparison of early and late intervention for necrotizing pancreatitis: A systematic review and meta-analysis.

OBJECTIVES: Postponed open necrosectomy or minimally invasive intervention has become the treatment option for necrotizing pancreatitis. Nevertheless, several studies point to the safety and efficacy of early intervention for necrotizing pancreatitis. Therefore, we conducted a systematic review and meta-analysis to compare clinical outcomes of acute necrotizing pancreatitis between early and late intervention. METHODS: Literature search was performed in multiple databases for articles that compared the safety and clinical outcomes of early (<4 weeks from the onset of pancreatitis) versus late intervention (≥4 weeks from the onset of pancreatitis) for necrotizing pancreatitis published up to August 31, 2022. The meta-analysis was performed to determine pooled odds ratio (OR) of mortality rate and procedure-related complications. RESULTS: Fourteen studies were included in the final analysis. For open necrosectomy intervention, the overall pooled OR of mortality rate with the late intervention compared with early intervention was 7.09 (95% confidence interval [CI] 2.33-21.60; I2 = 54%; P = 0.0006). For minimally invasive intervention, the overall pooled OR of mortality rate with the late intervention compared with early intervention was 1.56 (95% CI 1.11-2.20; I2 = 0%; P = 0.01). The overall pooled OR of pancreatic fistula with the late minimally invasive intervention compared with early intervention was 2.49 (95% CI 1.75-3.52; I2 = 0%; P < 0.00001). CONCLUSION: These results showed the benefit of late interventions in patients with necrotizing pancreatitis in both minimally invasive procedures and open necrosectomy. Late intervention is preferred in the management of necrotizing pancreatitis.

Metabolome Sequencing Reveals that Protein Arginine-N-Methyltransferase 1 Promotes the Progression of Invasive Micropapillary Carcinoma of the Breast and Predicts a Poor Prognosis.

Invasive micropapillary carcinoma (IMPC) of the breast is a special histopathologic type of cancer with a high recurrence rate and the biological features of invasion and metastasis. Previous spatial transcriptome studies indicated extensive metabolic reprogramming in IMPC, which contributes to tumor cell heterogeneity. However, the impact of metabolome alterations on IMPC biological behavior is unclear. Herein, endogenous metabolite-targeted metabolomic analysis was done on frozen tumor tissue samples from 25 patients with breast IMPC and 34 patients with invasive ductal carcinoma not otherwise specified (IDC-NOS) by liquid chromatography-mass spectrometry. An IMPC-like state, which is an intermediate transitional morphologic phenotype between IMPC and IDC-NOS, was observed. The metabolic type of IMPC and IDC-NOS was related to breast cancer molecular type. Arginine methylation modification and 4-hydroxy-phenylpyruvate metabolic changes play a major role in the metabolic reprogramming of IMPC. High protein arginine-N-methyltransferase (PRMT) 1 expression was an independent factor related to the poor prognosis of patients with IMPC in terms of disease-free survival. PRMT1 promoted H4R3me2a, which induced tumor cell proliferation via cell cycle regulation and facilitated tumor cell metastasis via the tumor necrosis factor signaling pathway. This study identified the metabolic type-related features and intermediate transition morphology of IMPC. The identification of potential targets of PRMT1 has the potential to provide a basis for the precise diagnosis and treatment of breast IMPC.

Research progress on PRMTs involved in epigenetic modification and tumour signalling pathway regulation (Review).

Posttranslational modification (PTM) of proteins is essential for increasing protein diversity and maintaining cellular homeostasis, but uncontrolled modification may lead to tumorigenesis. Arginine methylation is a tumorigenesis­related PTM that affects protein function through protein­protein and protein­nucleic acid interactions. Protein arginine methyltransferases (PRMTs) have vital roles in signalling pathways of tumour­intrinsic and tumour­extrinsic microenvironments. The present review summarizes the modifications and functions of PRMTs in histone methylation and nonhistone methylation, their roles in RNA splicing and DNA damage repair and the currently known functions in tumour metabolism and immunotherapy. In conclusion, this article reviews the latest research progress on the role of PRMTs in tumour signal transduction, providing a theoretical basis for clinical diagnosis and treatment. Targeting PRMTs is expected to provide new directions for tumour therapy.

Ecological shifts of salivary microbiota associated with metabolic-associated fatty liver disease.

Introduction: Metabolic-associated fatty liver disease (MAFLD) is the most common chronic liver disease related to metabolic syndrome. However, ecological shifts in the saliva microbiome in patients with MAFLD remain unknown. This study aimed to investigate the changes to the salivary microbial community in patients with MAFLD and explore the potential function of microbiota. Methods: Salivary microbiomes from ten MAFLD patients and ten healthy participants were analyzed by 16S rRNA amplicon sequencing and bioinformatics analysis. Body composition, plasma enzymes, hormones, and blood lipid profiles were assessed with physical examinations and laboratory tests. Results: The salivary microbiome of MAFLD patients was characterized by increased α-diversity and distinct ß-diversity clustering compared with control subjects. Linear discriminant analysis effect size analysis showed a total of 44 taxa significantly differed between the two groups. Genera Neisseria, Filifactor, and Capnocytophaga were identified as differentially enriched genera for comparison of the two groups. Co-occurrence networks suggested that the salivary microbiota from MAFLD patients exhibited more intricate and robust interrelationships. The diagnostic model based on the salivary microbiome achieved a good diagnostic power with an area under the curve of 0.82(95% CI: 0.61-1). Redundancy analysis and spearman correlation analysis revealed that clinical variables related to insulin resistance and obesity were strongly associated with the microbial community. Metagenomic predictions based on Phylogenetic Investigation of Communities by Reconstruction of Unobserved States revealed that pathways related to metabolism were more prevalent in the two groups. Conclusions: Patients with MAFLD manifested ecological shifts in the salivary microbiome, and the saliva microbiome-based diagnostic model provides a promising approach for auxiliary MAFLD diagnosis.

Individual Micron-Sized Aerosol Qualitative Analysis-Combined Raman Spectroscopy and Laser-Induced Breakdown Spectroscopy by Optical Trapping in Air.

The attribution of single particle sources of atmospheric aerosols is an essential problem in the study of air pollution. However, it is still difficult to qualitatively analyze the source of a single aerosol particle using noncontact in situ techniques. Hence, we proposed using optical trapping to combine gated Raman spectroscopy with laser-induced breakdown spectroscopy (LIBS) in a single levitated micron aerosol. The findings of the spectroscopic imaging indicated that the particle plasma formed by a single particle ablation with a pulsed laser within 7 ns deviates from the trapped particle location. The LIBS acquisition field of view was expanded using the 19-bundle fiber, which also reduces the fluctuation of a single particle signal. In addition, gated Raman was utilized to suppress the fluorescence and increase the Raman signal-to-noise ratio. Based on this, Raman can measure hard-to-ionize substances with LIBS, such as sulfates. The LIBS radical can overcome the restriction that Raman cannot detect ionic chemicals like fluoride and chloride in halogens. To test the capability of directly identifying distinctive feature compounds utilizing spectra, we detected anions using Raman spectroscopy and cations using LIBS. Four typical mineral aerosols are subjected to precise qualitative evaluations (marble, gypsum, baking soda, and activated carbon adsorbed potassium bicarbonate). To further validate the application potential for substances with indistinctive feature discrimination, we employed machine learning algorithms to conduct a qualitative analysis of the coal aerosol from ten different origin regions. Three data fusion methodologies (early fusion, intermediate fusion, and late fusion) for Raman and LIBS are implemented, respectively. The accuracy of the late fusion model prediction using StackingClassifier is higher than that of the LIBS data (66.7%) and Raman data (86.1%) models, with an average accuracy of 90.6%. This research has the potential to provide online single aerosol analysis as well as technical assistance for aerosol monitoring and early warning.

PRMT3 regulates the progression of invasive micropapillary carcinoma of the breast.

Invasive micropapillary carcinoma (IMPC) is a special histopathological subtype of breast cancer. Clinically, IMPC exhibits a higher incidence of lymphovascular invasion and lymph node metastasis compared with that of invasive ductal carcinoma (IDC), the most common type. However, the metabolic characteristics and related mechanisms underlying malignant IMPC biological behaviors are unknown. We performed large-scale targeted metabolomics analysis on resected tumors obtained from chemotherapy-naïve IMPC (n = 25) and IDC (n = 26) patients to investigate metabolic alterations, and we integrated mass spectrometry analysis, RNA sequencing, and ChIP-sequencing data to elucidate the potential molecular mechanisms. The metabolomics revealed distinct metabolic profiles between IMPC and IDC. For IMPC patients, the metabolomic profile was characterized by significantly high levels of arginine methylation marks, and protein arginine methyltransferase 3 (PRMT3) was identified as a critical regulator that catalyzed the formation of these arginine methylation marks. Notably, overexpression of PRMT3 was an independent risk factor for poor IMPC prognosis. Furthermore, we demonstrated that PRMT3 was a key regulator of breast cancer cell proliferation and metastasis both in vitro and in vivo, and treatment with a preclinical PRMT3 inhibitor decreased the xenograft tumorigenic capacity. Mechanistically, PRMT3 regulated the endoplasmic reticulum (ER) stress signaling pathway by facilitating histone H4 arginine 3 asymmetric dimethylation (H4R3me2a), which may endow breast cancer cells with great proliferative and metastatic capacity. Our findings highlight PRMT3 importance in regulating the malignant biological behavior of IMPC and suggest that small-molecule inhibitors of PRMT3 activity might be promising breast cancer treatments.

Evolution of the strength characteristics of briquette and raw coal containing fluid.

The mechanical properties of coal containing fluid are an important factor affecting the safe mining of soft coal seams. In particular, for class III-V coal, coal and gas outbursts and other dynamic phenomena are prone to occur due to the influences of gas pressure and groundwater, which seriously threaten the safety and lives of field workers. However, briquette samples are usually used in place of raw coal in laboratory tests conducted on class III-V coal samples. Whether the research conclusions for briquette and raw coal are consistent and whether briquette coal can replace raw coal in research on strength characteristics need to be further verified. In this paper, the evolution of the strength characteristics of fluid-bearing briquette coal and raw coal is studied. The strength characteristics, instability failure characteristics, and acoustic emission characteristics of raw coal and briquette coal under uniaxial and triaxial compression are analyzed in detail. In addition, the influence of the water content and pore pressure on the strength characteristics of class III-V raw coal and briquette coal is further studied. The results show that the failure characteristic of raw coal is overall brittle failure, mainly axial splitting failure, whereas that of briquette is overall ductile failure, mainly cone-shaped continuous spalling. The strength parameters of the raw coal and briquette coal improve under confining pressure, but the internal difference in the raw coal is significantly reduced. The cohesion of the raw coal sample initially increases and then decreases with increasing water content, and the internal friction angle increases with increasing water content. In addition, it is verified that the strength, cohesion, elastic modulus, and deformation modulus of the briquette decrease with increasing pore pressure under different pore pressures, but the strength difference of the class III-V coal decreases under increasing pore pressure. Based on the abovementioned results, the strength parameters of a coal body are estimated using the Hoek-Brown (H-B) criterion. Based on a comparison of the strength parameters of the coal sample and coal body, the estimated strength parameters of the coal body are closer to the actual values on site.

The ALDH2, IGSF9, and PRDM16 Proteins as Predictive Biomarkers for Prognosis in Breast Cancer.

INTRODUCTION: ALDH2, IGSF9, and PRDM16 play crucial roles in regulating diverse cellular pathophysiologic functions. The current study was to evaluate the effect of the 3 proteins on clinicopathologic features and prognosis of patients with breast cancer. MATERIALS AND METHODS: The formalin-fixed and paraffin-embedded tissue specimens were collected from breast cancer patients by immunohistochemistry (IHC) were analyzed. RESULTS: Of the 216 patients enrolled, ALDH2 high expression was significantly correlated with the age (p = .040), larger tumor size (p = .001), LVI (p < .001), LNM (p < .001), advanced TNM staging (p < .001), PR (p = .027), HER2 status (p = .002), and molecular subtype (p = .003). IGSF9 low expression was significantly correlated with the LV1 (p = .024), LNM (p = .024), advanced TNM staging (p = .001). The low expression of PRDM16 was significantly correlated with age (p = .023), and LNM (p = .014). The A+I-P- expression (13.4%) were markedly correlated with lymphatic vessel invasion (LVI) (p < .001), lymph node metastasis (LNM) (p < .001), advanced TNM staging (p < .001). Furthermore, patients with A+I-P- expression had significantly advanced-stage breast cancer [stage III (72.4%) vs. (23.0%)]. Univariate and multivariate analysis identified variables (ie, larger tumor size, lymph node involvement, and A+I-P- expression) as independent prognostic factors for survival. CONCLUSION: Our results reveal ALDH2 high expression, IGSF9 and PRDM16 low expression, A+I-P- expression was associated with advanced clinicopathological characteristics, and shorter OS and DFS in breast cancer patients. The 3 proteins may be potential prognosis markers and therapeutic targets for breast cancer patients.

Association of Body Mass Index and the Risk of Gastro-Esophageal Cancer: A Mendelian Randomization Study in a Japanese Population.

There are growing concerns that body mass index (BMI) is related to cancer risk at various anatomical sites, including the upper gastrointestinal tract, and the existence of a causal relationship remains unclear. The Mendelian randomization (MR) method uses instrumental genetic variables of risk factors to explore whether a causal relationship exists while preventing confounding. In our study, genome-wide association study (GWAS) data from the BioBank Japan (BBJ) project were used. Genetic variants were chosen as instrumental variables using inverse-variance weighting (IVW), MR-Egger regression and weighted-median methods to estimate the causal relationship between BMI and the risk of gastro-esophageal cancer. We found no evidence to support a causal association between BMI and risk of gastric cancer [odds ratio (OR) =0.99 per standard deviation (SD) increase in BMI; 95% confidence interval (CI): (0.76-1.30); P = 0.96] or esophageal cancer [0.78(0.50-1.22); P = 0.28] using the IVW method. Sensitivity analysis did not reveal any sign of horizontal pleiotropy. Additionally, in the gender-stratified analysis, no causal association was found. Findings from this study do not support a causal effect of BMI on gastro-esophageal cancer risk. However, we cannot rule out a modest or nonlinear effect of BMI.