Liver X receptor agonists exert antitumor effects against hepatocellular carcinoma via inducing REPS2 expression.

Recent studies show that liver X receptor (LXR) agonists exert significant antitumor effects in a variety of tumor cell lines including hepatocellular carcinoma (HCC). But the molecular mechanisms underlying LXR antitumor activity are not fully understood. In this study we investigated the effect of LXR agonist T0901317 (T317) on HCC development and its relationship with RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis. We showed that T317 (0.1-0.5 µM) dose-dependently increased REPS2 expression in normal hepatocytes (BNLCL.2 and LO2) and HCC cells (HepG2 and Huh-7). Using promoter activity assay and chromatin immunoprecipitation (CHIP) assay we demonstrated that T317 enhanced REPS2 expression at the transcriptional level via promoting the binding of LXR protein to the LXR-response element (LXRE) in the REPS2 promoter region. We showed that the inhibitory effect of T317 on the proliferation and migration of HCC cells was closely related to REPS2. Moreover, we revealed that T317 (400 nM) increased expression of REPS2 in HepG2 cells, thus inhibiting epidermal growth factor (EGF)-mediated endocytosis of EGFR as well as the downstream activation of AKT/NF-κB, p38MAPK, and ERK1/2 signaling pathways. Clinical data analysis revealed that REPS2 expression levels were inversely correlated with the development of HCC and reduced REPS2 expression associated with poor prognosis, suggesting that REPS2 might be involved in the development of HCC. In conclusion, this study provides new insights into the potential mechanisms of LXR agonist-inhibited HCC.

Transcription factor 21 accelerates vascular calcification in mice by activating the IL-6/STAT3 signaling pathway and the interplay between VSMCs and ECs.

Vascular calcification is caused by the deposition of calcium salts in the intimal or tunica media layer of the aorta, which increases the risk of cardiovascular events and all-cause mortality. However, the mechanisms underlying vascular calcification are not fully clarified. Recently it has been shown that transcription factor 21 (TCF21) is highly expressed in human and mouse atherosclerotic plaques. In this study we investigated the role of TCF21 in vascular calcification and the underlying mechanisms. In carotid artery atherosclerotic plaques collected from 6 patients, we found that TCF21 expression was upregulated in calcific areas. We further demonstrated TCF21 expression was increased in an in vitro vascular smooth muscle cell (VSMC) osteogenesis model. TCF21 overexpression promoted osteogenic differentiation of VSMC, whereas TCF21 knockdown in VSMC attenuated the calcification. Similar results were observed in ex vivo mouse thoracic aorta rings. Previous reports showed that TCF21 bound to myocardin (MYOCD) to inhibit the transcriptional activity of serum response factor (SRF)-MYOCD complex. We found that SRF overexpression significantly attenuated TCF21-induced VSMC and aortic ring calcification. Overexpression of SRF, but not MYOCD, reversed TCF21-inhibited expression of contractile genes SMA and SM22. More importantly, under high inorganic phosphate (3 mM) condition, SRF overexpression reduced TCF21-induced expression of calcification-related genes (BMP2 and RUNX2) as well as vascular calcification. Moreover, TCF21 overexpression enhanced IL-6 expression and downstream STAT3 activation to facilitate vascular calcification. Both LPS and STAT3 could induce TCF21 expression, suggesting that the inflammation and TCF21 might form a positive feedback loop to amplify the activation of IL-6/STAT3 signaling pathway. On the other hand, TCF21 induced production of inflammatory cytokines IL-1ß and IL-6 in endothelial cells (ECs) to promote VSMC osteogenesis. In EC-specific TCF21 knockout (TCF21ECKO) mice, VD3 and nicotine-induced vascular calcification was significantly reduced. Our results suggest that TCF21 aggravates vascular calcification by activating IL-6/STAT3 signaling and interplay between VSMC and EC, which provides new insights into the pathogenesis of vascular calcification. TCF21 enhances vascular calcification by activating the IL-6-STAT3 signaling pathway. TCF21 inhibition may be a new potential therapeutic strategy for the prevention and treatment of vascular calcification.

Signet-ring cell carcinoma of the duodenal bulb presenting with gastrointestinal hemorrhage: a case report and literature review.

BACKGROUND: Primary duodenal cancer (PDC) is rare, especially signet-ring cell carcinoma (SRCC) of the duodenal bulb, and it is commonly misdiagnosed as an ulceration. Here, we report a rare case of SRCC of the duodenal bulb presenting with gastrointestinal hemorrhage in an 82-year-old man. CASE PRESENTATION: An 82-year-old man was admitted for gastrointestinal hemorrhage. Physical examination revealed upper abdominal tenderness and pale appearance, but was otherwise unrevealing. Laboratory workup was significant for anemia. Imaging showed no abnormalities. Two endoscopic evaluations along with interventional embolization were attempted and, unfortunately, adequate hemostasis was not achieved, resulting in distal subtotal gastrectomy, including the duodenal bulb. SRCC of the duodenal bulb was diagnosed based on pathology after surgery. Post-operatively, the patient experienced persistent gastrointestinal bleeding. Family declined further intervention and the patient eventually died one month post-resection. CONCLUSIONS: SRCC in the duodenal bulb is difficult to diagnose. For those with high-risk factors, endoscopic examination and biopsy are recommended. For patients who can receive radical tumor resection, pancreaticoduodenectomy (PD) is considered a first-line option. Early diagnosis and resection have been shown to improve prognosis.

L-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species.

Tuberculosis caused by Mycobacterium tuberculosis remains a major global health concern; M. tuberculosis drug resistance and persistence further fueled the situation. Nutrient supportive therapy was intensively pursued to complement the conventional treatment, as well as their synergy with current antibiotics. To explore whether L-alanine can synergize with fluoroquinolones against M. tuberculosis, M. smegmatis was used as a surrogate in this study. We found that L-alanine can boost the bactericidal efficacy of fluoroquinolones, increasing the production of intracellular reactive oxygen species. This effect is very significant for persisters. Accelerated tricarboxylic acid cycle and/or nucleotide metabolism were observed after the addition of L-alanine. M. smegmatis MSMEG2660 is a homolog of the alanine dehydrogenase (Rv2780, MSMEG2659) negative regulator Rv2779c and involved in the L-alanine potentiation of fluoroquinolone via funneling more alanine into tricarboxylic acid. Deletion mutant of the MSMEG2660 (∆Ms2660) became more susceptible, and more readily revived from persistence. We firstly found that L-alanine can synergize with fluoroquinolones against Mycobacterium, especially the persisters via promoting metabolism. This will inspire new avenue to eliminate Mycobacterium persisters.

Mycobacterium tuberculosis toxin Rv2872 is an RNase involved in vancomycin stress response and biofilm development.

Bacterial toxin-antitoxin (TA) systems are emerging important regulators of multiple cellular physiological events and candidates for novel antibiotic targets. To explore the role of Mycobacterium tuberculosis function, unknown toxin gene Rv2872 was heterologously expressed in Mycobacterium smegmatis (MS_Rv2872). Upon induction, MS_Rv2872 phenotype differed significantly from the control, such as increased vancomycin resistance, retarded growth, cell wall, and biofilm structure. This phenotype change might result from the RNase activity of Rv2872 as purified Rv2872 toxin protein can cleave the products of several key genes involved in abovementioned phenotypes. In summary, toxin Rv2872 was firstly reported to be a endonuclease involved in antibiotic stress responses, cell wall structure, and biofilm development.

Retention in treated wastewater affects survival and deposition of Staphylococcus aureus and Escherichia coli in sand columns.

The fate and transport of pathogenic bacteria from wastewater treatment facilities in the Earth's subsurface have attracted extensive concern over recent decades, while the impact of treated-wastewater chemistry on bacterial viability and transport behavior remains unclear. The influence of retention time in effluent from a full-scale municipal wastewater treatment plant on the survival and deposition of Staphylococcus aureus and Escherichia coli strains in sand columns was investigated in this paper. In comparison to the bacteria cultivated in nutrient-rich growth media, retention in treated wastewater significantly reduced the viability of all strains. Bacterial surface properties, e.g., zeta potential, hydrophobicity, and surface charges, varied dramatically in treated wastewater, though no universal trend was found for different strains. Retention in treated wastewater effluent resulted in changes in bacterial deposition in sand columns. Longer retention periods in treated wastewater decreased bacterial deposition rates for the strains evaluated and elevated the transport potential in sand columns. We suggest that the wastewater quality should be taken into account in estimating the fate of pathogenic bacteria discharged from wastewater treatment facilities and the risks they pose in the aquatic environment.

A mini case report: Klebsiella pneumoniae-induced metastatic neck abscess following laparoscopic appendectomy.

Common complications following laparoscopic appendectomy include wound infection, bleeding, intra-abdominal abscess, small bowel obstruction, stump leakage, and stump appendicitis. Here, we presented a case reporting detailing a rare complication following laparoscopic appendectomy: the development of a metastatic neck abscess induced by Klebsiella pneumoniae(K. pneumoniae). A 49-year-old male underwent emergency laparoscopic surgery with prophylactic antibiotic administration for acute appendicitis. Subsequently, he experienced persistent neck pain and fever postoperatively, prompting further investigation. Pus and blood cultures revealed K. pneumoniae, with magnetic resonance imaging confirming the presence of a neck abscess. Antibiotic therapy was adjusted, and surgical drainage of the abscess was performed after multidisciplinary consultation. The patient was discharged without complications. While rare, metastatic abscesses following appendectomy warrant consideration, particularly in K. pneumoniae infections. Comprehensive clinical assessment, imaging, and laboratory evaluation are crucial for timely diagnosis and management of such complications.

The concept, influence, and mechanism of human work interruptions based on the grounded theory.

With the development of mobile communication technology and the transformation of work methods and modes, work interruptions have become ubiquitous challenges for employees in the workplace. Less attention has been paid to work interruptions in China, especially the research on human work interruptions, which is different from virtual work interruptions. The present study carried out an in-depth interview with 29 employees. Based on the grounded theory method, a psychological and behavioral mechanism model of employees facing human work interruptions, namely, the "human work interruptions-cognitive appraisals-affective responses-behavioral changes" model, was constructed. It is found that (1) cognitive appraisals are the causes of different affective responses and behavioral changes of human work interruptions; (2) cognitive appraisals are feedback behaviors that refer to the reappraisals of the effectiveness and appropriateness of individuals' affective responses and behavioral changes; and (3) personal traits and environmental characteristics at work influence the affective responses and behavioral changes of human work interruptions at the individual and organizational level. The model constructed in this study further extends the interruption theory and provides implications on how to process human work interruptions in human resource management practice.

Do human work interruptions bring positive affective responses?-Based on the mediation of coping potential and the moderation of polychronicity.

This research aims to investigate the impact of human work interruptions on positive affective responses and their underlying mechanisms in the Chinese context. In the first stage, this study conducted face-to-face semi-structured interviews with 29 employees representing diverse industries. The grounded theory research method was used to extract the construct of human work interruption, identify its core attributes, and capture the naturally emerging storyline of "human work interruptions - coping potential - polychronicity - positive affective responses". In the second stage, a theoretical model was constructed and validated using 362 questionnaires. The results indicate that in the Chinese context: (1) human work interruptions can trigger positive affective responses; (2) coping potential mediates the relationship between human work interruptions and positive affective responses; (3) when individuals have a higher level of polychronicity, the impact of human work interruptions on positive affective responses via coping potential is enhanced. The findings of this study effectively address the hypothesis of the "positive aspect" of work interruptions proposed by management scholars and contribute to the existing literature on work interruptions and positive affective responses. Moreover, this research provides practical and theoretical implications for managers and employees in managing and coping with human work interruptions.

MiR-195-5p suppresses gastric adenocarcinoma cell progression via targeting OTX1.

Gastric adenocarcinoma (GAC) caused by malignant transformation of gastric adenocytes is a malignancy with high incidence. MiR-195-5p modulates a variety of cancers. One of its target genes, orthodenticle homeobox 1 (OTX1), is believed to be a key modulator of tumor progression. We aim to analyze the mechanism of miR-195-5p and OTX1 in GAC. MiR-195-5p and OTX1 mRNA levels in GAC cells were tested via qRT-PCR. OTX1 protein and EMT-related protein levels were examined through western blot. Several cell functional assays were designed to measure changes in cell malignant behaviors. Dual luciferase assay verified the targeting relation of miR-195-5p and OTX1. These experimental results showed significantly low miR-195-5p expression and significantly high OTX1 expression in GAC cells. Enforced miR-195-5p level repressed cell malignant progression and accelerated cell apoptosis in GAC. Increased OTX1 weakened the above-mentioned effect caused by overexpressing miR-195-5p. Thus, miR-195-5p restrained migration, proliferation, invasion and epithelial-mesenchymal transition process of GAC cells, and promoted cell apoptosis through regulating OTX1. A new insight is provided for searching for biomarkers or therapeutic targets of GAC.

Is Work Time Control Good for Innovation? A Two-Stage Study to Verify the Mediating and Moderating Processes.

As a part of job resources, work time control is essential for innovation. We examine how work time control impacts knowledge employees' innovation in the workplace. A two-stage study was conducted to verify the mediating and moderating processes. In Study 1, adopting the job demands-resources model as a theoretical framework, we conducted a laboratory test to find the relation between work time control, job engagement, job burnout, and innovation, and verified the path between work time control and innovation. In Study 2, drawing on the job demands-resources model verified by Study 1 and self-regulation theory, it is proposed that during the psychological process in the workplace, job engagement plays a mediating role, and the vocational delay of gratification plays a moderating role between work time control and innovation. A total of 254 knowledge employees from diverse organizations participated in the survey study. After taking demographic variables, job demands, and neuroticism as control variables, the results showed that job engagement would mediate the relationship between work time control and innovation. A higher level of delay of gratification buffered the effect of a higher level of work time control on innovation. All these findings verified and expanded knowledge on work time control and innovation literature, showing that work time control is important for innovation. Based on Chinese cultural background, managers should offer employees the opportunity to conduct self-control training and encourage them with great freedom to foster employee innovation.

Case report: A rare occurrence of triple malignancy of the stomach, rectum and liver in a single patient.

Malignant tumors of the digestive system are common worldwide; however, it is extremely rare for more than two malignancies to occur simultaneously. Here, we report a case with a triple malignancy of the digestive system, including gastric, rectal, and hepatic tumors. The patient underwent surgical resection of three tumors followed by chemotherapy. Negative image-based screenings and the absence of serum tumor biomarkers elevation were found at 2.5 years after the surgery, indicating the absence of recurrence and metastasis of cancers.

Correlation between LRP1B Mutations and Tumor Mutation Burden in Gastric Cancer.

BACKGROUND: It has been shown that low-density lipoprotein receptor-related protein 1B (LRP1B) mutations correlate with tumor mutation burden (TMB) and prognosis in patients with melanoma and non-small-cell lung cancer, while the relationship between LRP1B mutations and TMB in gastric cancer needs further study. This study is aimed at exploring the relationship between LRP1B mutations and TMB in gastric cancer. METHODS: Mutation frequency profiles of the genes in patients with gastric cancer in TCGA-STAD dataset were analyzed by bioinformatics analysis. The relationship among LRP1B mutations, TMB, and patient clinical features in gastric cancer was investigated by the chi-square test. The TMB prediction capacity based on LRP1B mutation status was evaluated by ROC curves. RESULTS: LRP1B is one of the top 10 genes with high gene mutation frequency in gastric cancer. The mutation status of LRP1B in gastric cancer patients was significantly correlated with age and TP53 and MUC16 mutation status. The result of ROC curve analysis revealed that the mutation status of LRP1B could be considered as an indicator of the degree of TMB in patients with gastric cancer. CONCLUSION: This study presented the relationship between TMB and LRP1B mutations in gastric cancer, providing a novel perspective for gastric cancer prognosis and therapy.

Peroxisome Proliferator-Activated Receptor-Gamma Reduces ER Stress and Inflammation via Targeting NGBR Expression.

Increased Nogo-B receptor (NGBR) expression in the liver improves insulin sensitivity by reducing endoplasmic reticulum stress (ER stress) and activating the AMPK pathway, although it remains elusive the mechanisms by which NGBR is induced. In this study, we found that PPARγ ligands (rosiglitazone or pioglitazone) increased NGBR expression in hepatic cells and HUVECs. Furthermore, promoter analysis defined two PPREs (PPARγ-responsive elements) in the promoter region of NGBR, which was further confirmed by the ChIP assay. In vivo, using liver-specific PPARγ deficient (PPARγLKO) mice, we identified the key role of PPARγ expression in pioglitazone-induced NGBR expression. Meanwhile, the basal level of ER stress and inflammation was slightly increased by NGBR knockdown. However, the inhibitory effect of rosiglitazone on inflammation was abolished while rosiglitazone-inhibited ER stress was weakened by NGBR knockdown. Taken together, these findings show that NGBR is a previously unrecognized target of PPARγ activation and plays an essential role in PPARγ-reduced ER stress and inflammation.

Facile Fabrication of Highly Perforated Hollow Metallic Cylinder with Changeable Micro-Orifices by Electroforming-Extrusion Molding Hybrid Process.

A seamless thin-walled hollow metallic cylinder with array of micro-perforations is one of the key components for some products. Normally, these micro-perforations are formed by removing material from the given metallic hollow cylinder (pipe or tube) one by one or row by row. To efficiently and flexibly manufacture such a highly perforated hollow cylinder, this paper proposed a hybrid technique combining extrusion moulding process and electroforming process. In the hybrid technique, the extrusion moulding process was used to create polymer extrusion patterns on the outside surface of the given stainless steel (SS) pipe, and then the electroforming process was carried out using the SS pipe as the mandrel. The formation of the polymer extrusion patterns was simulated and extruding molding experiments were carried out to examine the feasibility of the various mandrels. Electroforming experiments were implemented to verify the achievement of the seamless perforated thin-walled hollow cylinder. It was found that five different types of polymer extrusion pattern were able to be obtained on the same extruding pipe just by adjusting some extruding conditions and parameters, and correspondingly four types of perforated hollow cylinder with different tapered orifices are produced after the electroforming process. The obtainable perforations are: perforation with double conic-orifices, perforation with hemispheric orifice and conic orifice, unidirectionally tapered perforation, and straight-walled perforation. The geometric profile of the extrusion patterns is highly dependent on the processing conditions and parameters. The proposed hybrid process represents a promising alternative process to fabricate seamless thin-walled perforated hollow metallic cylinder efficiently, flexibly, and with low cost.

Microstructure and Fracture Behavior of Special Multilayered Steel.

In this research, multilayered steel (MLS), which is composed of middle-carbon martensite steel, high-carbon martensite steel, and a pure Ni thin layer was obtained by the accumulative roll-bonding method. The microstructure and mechanical properties of the MLS were investigated by scanning electron microscopy (SEM), Vickers microhardness, tensile, and bending tests. In-situ SEM tensile tests were used to observe the crack initiation and propagation processes during the tensile loading. The results show that the ultimate tensile strength and bending strength of the MLS can reach 946 MPa and 3153 MPa, and the maximum elongation can reach 18%, which is related to the better combined quality of the interface. The middle and larger martensite layer (ML) becomes the weakest link of tensile fracture and interfacial delamination of the MLS during the tensile processes, because there are lots of large hard blocks Cr23C6 phases distributed in the middle thicker ML layer. Besides, the MLS can withstand larger bending deformation. When the MLS was bent to 180 degrees, neither macro-cracks in the outer side of the bending parts nor interfacial delamination can be found.

Mycobacterium Von Willebrand factor protein MSMEG_3641 is involved in biofilm formation and intracellular survival.

Aim:Mycobacterium tuberculosis in vitro biofilm is associated with the virulence and persistence capability. Our aim is to delineate factors involved in biofilms development. Materials & methods: We performed transposon mutants screen and found that mutation of MSMEG_3641, a homolog of M. tuberculosis Rv1836c, can change M. smegmatis colony morphology and biofilm. Results: MSMEG_3641 contains a vWA domain that is highly conserved among Mycobacteria. The phenotypes of MSMEG_3641 mutants include disrupted biofilm, weakened migration ability and changed colony morphology. All phenotypes might be contributed to the enhanced cell wall permeability and declined cell aggregation ability. Conclusion: To our knowledge, this is the first report concerning the mycobacteria Von Willebrand factor domain function, especially in colony morphology and biofilm development.

miR-125b regulates the drug-resistance of breast cancer cells to doxorubicin by targeting HAX-1.

MircroRNAs (miRNAs) are considered as essential regulators in the tumorigenesis and chemoresistance of multiple cancer types. In the present study, it was demonstrated that the expression levels of miR-125b were significantly downregulated in the tissues of patients with breast cancer (BC), as well as the BC cell lines in vitro. To study the association between chemoresistance and miR-125b in BC, doxorubicin (DOX)-resistant MCF-7 (MCF-7/R) cells were established, and gain- and loss-of-function experiments were performed. It was demonstrated that the overexpression of miR-125b increased the sensitivity of MCF-7/R cells to DOX. Furthermore, it was revealed that the sensitization of miR-125b mimics to DOX-induced cell death was regulated by the hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) vector and HAX-1 small interfering RNA. These results emphasized the notable function of miR-125b and its target of HAX-1 in regulating DOX-resistance. In addition, it was demonstrated that the miR-125b mimics promoted the loss of the mitochondrial membrane potential and the generation of reactive oxygen species induced by DOX treatment in MCF-7/R cells. These data suggest that the miR-125b-HAX-1-mitochondria pathway has a notable function in the treatment of DOX-resistant BC cells, which may provide a novel target for the chemotherapy of BC.