Metformin Increases the Response of Cholangiocarcinoma Cells to Gemcitabine by Suppressing Pyruvate Kinase M2 to Activate Mitochondrial Apoptosis.

BACKGROUND: Cholangiocarcinoma (CCA) is a malignant tumor with a high mortality rate. Resistance to chemotherapy remains a major challenge related to cancer treatment, and increasing the sensitivity of cancer cells to therapeutic drugs is a major focus of cancer treatment. AIMS: We purposed to explore the role of Metformin in CCA involved in chemotherapeutic sensitivity and Pyruvate kinase M2 (PKM2) through regulating mitochondrial apoptosis in the present study. METHODS: CCA cell lines of HCC9810 and RBE were treated with Metformin companied with antagonists or agonists of PKM2, cells sensitivity to Gemcitabine, cell migration and invasion along with apoptosis, which is mediated by JC-1 and LDH were assayed. RESULTS: Our results indicated that Metformin and Gemcitabine exhibit synergistic effect on inhibition of cholangiocarcinoma cell viability, cell migration and invasion as well as promotion apoptosis of cholangiocarcinoma cells. In vivo, Metformin combined with Gemcitabine has cooperation in inhibiting the growth of cholangiocarcinoma cell-derived tumors. Moreover, Metformin and Gemcitabine inhibited expression of PKM2 and PDHB in HCC9810 and RBE. CONCLUSION: Our study suggested that Metformin may increase the response of cholangiocarcinoma cells to Gemcitabine by suppressing PKM2 to activate mitochondrial apoptosis.

A critical appraisal of clinical practice guidelines on surgical treatments for spinal metastasis.

PURPOSE: As an important treatment for spinal metastasis, surgery has strict applicable conditions. Although various organizations have formulated different guidelines on surgical treatment for spinal metastasis (SM), there are certain differences in the content, standardization and quality of the guidelines and it is necessary to make a critical appraisal of them. We aim to systematically review and appraise the current guidelines on surgical treatments of SM and summarize the related recommendations with the quality evaluation of supporting evidence, as to provide a reference for the standardization of surgical treatment plans, and help clinical front-line medical workers can make safe and effective clinical decisions faster. METHODS: We searched Pubmed, Web of Science, and Embase for three major databases and online guideline databases. According to certain inclusion and exclusion criteria, the latest guidelines on the surgical treatment of SM were sorted out. AGREE II was used to evaluated the guideline's quality, and we extracted and compared the recommended treatment content of each guideline with evaluating by the evidence-grading scale. RESULTS: Eight guidelines from 2013 to 2019 were included. Seven guidelines are comprehensive guidelines and one related to the reconstructive surgery of SM. Five guidelines were evaluated as "recommended," and three guidelines were evaluated as "recommended with modifications." Regarding the indications of surgery with SM, four guidelines, seven guidelines, seven guidelines, three guidelines and three guidelines recommended surgical treatment for patients with SM with intractable pain, mechanical instability, metastatic epidural spinal cord compression (MESCC), recurrent spinal metastasis (RSM), and survival predication, respectively. Regarding the surgical strategies, three guidelines recommended minimally invasive therapy but had strict indications. Six guidelines and five guidelines recommend palliative surgery and with receiving radiation therapy, respectively. For the aggressive surgery, only one guideline recommended to apply to patients in good general conditions who has isolated symptomatic SM. Regarding the surgical reconstructions, one guideline didn't recommend iliac bone graft and three guidelines recommended PMMA bone cement. CONCLUSION: Most of the guidelines do not provide clear criteria for surgical application and provide more of a basic framework. The level of evidence for these surgical recommendations ranges from LOE B to D, and almost all guidelines recommend vertebroplasty and kyphoplasty, but for palliative and more aggressive surgery, which recommended to personalize specific surgical strategies with multidisciplinary collaboration.

Efficacy and safety of laminoplasty combined with C3 laminectomy for patients with multilevel degenerative cervical myelopathy: a systematic review and meta-analysis.

PURPOSE: Laminoplasty (LP) combined with C3 laminectomy (LN) can effectively achieve spinal cord decompression while maintaining the integrity of the posterior ligament-muscle complex, thereby minimizing cervical muscle damage. However, its necessity and safety remain controversial. This study aimed to compare the safety and efficacy of LP and LP combined with C3 LN in the treatment of patients with multilevel degenerative cervical spondylotic myelopathy (DCM). METHODS: A systematic review and meta-analysis of the literature was performed. A search of PubMed, Web of Science, Embase, and the Cochrane Library databases was conducted from inception through December 2023 and updated in February 2024. Search terms included laminoplasty, laminectomy, C3 and degenerative cervical spondylosis. The literature search yielded 14 studies that met our inclusion criteria. Outcomes included radiographic results, neck pain, neurologic function, surgical parameters, and postoperative complications. We also assessed methodologic quality, publication bias, and quality of evidence. RESULTS: Fourteen studies were identified, including 590 patients who underwent LP combined with C3 LN (modified group, MG) compared to 669 patients who underwent LP (traditional group, TG). The results of the study indicated a statistically significant improvement in cervical range of motion (WMD = 3.62, 95% CI: 0.39 to 6.85) and cervical sagittal angle (WMD = 2.07, 95% CI: 0.40 to 3.74) in the MG compared to the TG at the last follow-up (very low-level evidence). The TG had a higher number of patients with complications, especially C2-3 bone fusion. There was no significant difference found in improvement of neck pain, JOA, NDI, cSVA, T1 slope at latest follow-up. CONCLUSION: LP combined with C3 LN is an effective and necessary surgical method for multilevel DCM patients to maintain cervical sagittal balance. However, due to the low quality of evidence in existing studies, more and higher quality research on the technology is needed in the future.

miR-194-3p regulates epithelial-mesenchymal transition in embryonic epicardial cells via p120/ß-catenin signaling.

The epicardium is integral to cardiac development and facilitates endogenous heart regeneration and repair. While miR-194-3p is associated with cellular migration and invasion, its impact on epicardial cells remains uncharted. In this work we use gain-of-function and loss-of-function methodologies to investigate the function of miR-194-3p in cardiac development. We culture embryonic epicardial cells in vitro and subject them to transforming growth factor ß (TGF-ß) treatment to induce epithelial-mesenchymal transition (EMT) and monitor miR-194-3p expression. In addition, the effects of miR-194-3p mimics and inhibitors on epicardial cell development and changes in EMT are investigated. To validate the binding targets of miR-194-3p and its ability to recover the target gene-phenotype, we produce a mutant vector p120-catenin-3'UTR-MUT. In epicardial cells, TGF-ß-induced EMT results in a notable overexpression of miR-194-3p. The administration of miR-194-3p mimics promotes EMT, which is correlated with elevated levels of mesenchymal markers. Conversely, miR-194-3p inhibitor attenuates EMT. Further investigations reveal a negative correlation between miR-194-3p and p120-catenin, which influences ß-catenin level in the cell adhesion pathway. The suppression of EMT caused by the miR-194-3p inhibitor is balanced by silencing of p120-catenin. In conclusion, miR-194-3p directly targets p120-catenin and modulates its expression, which in turn alters ß-catenin expression, critically influencing the EMT process in the embryonic epicardial cells via the cell adhesion mechanism.

Fluxonium: An Alternative Qubit Platform for High-Fidelity Operations.

Superconducting qubits provide a promising path toward building large-scale quantum computers. The simple and robust transmon qubit has been the leading platform, achieving multiple milestones. However, fault-tolerant quantum computing calls for qubit operations at error rates significantly lower than those exhibited in the state of the art. Consequently, alternative superconducting qubits with better error protection have attracted increasing interest. Among them, fluxonium is a particularly promising candidate, featuring large anharmonicity and long coherence times. Here, we engineer a fluxonium-based quantum processor that integrates high qubit coherence, fast frequency tunability, and individual-qubit addressability for reset, readout, and gates. With simple and fast gate schemes, we achieve an average single-qubit gate fidelity of 99.97% and a two-qubit gate fidelity of up to 99.72%. This performance is comparable to the highest values reported in the literature of superconducting circuits. Thus our work, within the realm of superconducting qubits, reveals an alternative qubit platform that is competitive with the transmon system.

Charge transport spectra in superconductor-InAs/GaSb-superconductor heterostructures.

Charge transport physics in InAs/GaSb bi-layer systems has recently attracted attention for the experimental search for two-dimensional topological superconducting states in solids. Here we report measurement of charge transport spectra of nano devices consisting of an InAs/GaSb quantum well sandwiched by tantalum superconductors. We explore the current-voltage relation as a function of the charge-carrier density in the quantum well controlled by a gate voltage and an external magnetic field. We observe three types of differential resistance peaks, all of which can be effectively tuned by the external magnetic field, and, however, two of which appear at electric currents independent of the gate voltage, indicating a dominant mechanism from the superconductor and the system geometry. By analyzing the spectroscopic features, we find that the three types of peaks identify Andreev reflections, quasi-particle interference, and superconducting transitions in the device, respectively. Our results provide a basis for further exploration of possible topological superconducting state in the InAs/GaSb system.

Efficacy of lumbar kinetic chain training for staged rehabilitation after percutaneous endoscopic lumbar discectomy.

BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) is a promising minimally invasive treatment for lumbar disc herniation (LDH). Postoperative rehabilitation can improve patient outcomes. Not only rehabilitation for surgical trauma but also rehabilitation for lumbar spine and lower kinetic chain dysfunction should be performed. The aims of this study were to investigate the efficacy of a lumbar kinetic chain training for staged rehabilitation after PELD for LDH. METHODS: Fifty one LDH patients treated with PELD were studied. After surgery, patients underwent lumbar kinetic chain training for staged rehabilitation( staged group) or regular low back rehabilitation (regular group). The staged rehabilitation programme included three phases from 2 to 6, 7-12, and 13-24 weeks postoperatively, and different physical therapies were performed during these phases. The low back pain visual analogue scale (VAS), JOA score, ODI, SF-36, and cross-sectional area of the lumbar multifidus on MRI were assessed, and gait analysis was performed. RESULTS: Twenty five patients in staged group and twenty six patients in regular group were included. There were no significant differences in age or sex between the two groups at baseline (p > 0.05). The VAS score decreased and the JOA and SF-36 scores increased in both groups from baseline to 6 weeks (P < 0.05). In the staged group, compared with the regular group, the VAS and ODI scores were lower and the JOA and SF-36 scores were higher at 6 weeks (P < 0.05); the VAS and ODI scores were lower and the SF-36 score was higher at 12 weeks (P < 0.05); the SF-36 score was higher at 24 weeks (P < 0.05); the cross-sectional area of the lumbar multifidus showed no differences at 12 weeks (P > 0.05); and the left-right support ratio of gait was higher at 24 weeks (P < 0.05). CONCLUSIONS: The staged rehabilitation programme for LDH after PELD promoted postoperative recovery, and the efficacy of lumbar kinetic chain training was higher than that of regular low back muscle exercise.

Development of a Broad-Specific Competitive ELISA for First-Generation Cephalosporin Antibiotics in Animal-Derived Foods Samples.

The abuse of antibiotics, such as the cephalosporins in livestock and aquaculture productions, usually causes the widespread antibiotic resistance due to their growth-promoting effects. In this study, cephalexin was chosen as the hapten molecule to prepare a broad-spectrum rabbit polyclonal antibody for cephalosporin antibiotics. The obtained antibody exhibited broad cross-reactivity ranging from 0.05% to 100% with 10 cephalosporins. Based on this antibody, we developed a broad-specific indirect competitive ELISA (ic-ELISA) for cefalexin, cefradine, cefadroxil and cefazolin with the half maximal inhibitory concentration (IC50) ranging from 0.72 to 2.99 ng/mL in working buffer. For animal-derived food samples with spiked cephalosporins, the ic-ELISA exhibited an excellent recovery ranging from 72.3% to 95.6%. To verify the accuracy of this proposed ic-ELISA, its detection performance was evaluated utilizing the high-performance liquid chromatography with satisfactory results. This study confirmed that: firstly, the prepared antibody can be used as a class-specific recognition element to develop immunoassays for cephalosporin antibiotics; and secondly, the developed ic-ELISA provided a new tool for broad-spectrum detection of first-generation cephalosporins in animal-derived foods.

Early Versus Delayed Surgical Repair and Referral for Patients With Bile Duct Injury: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of the study was to systematically review and meta-analyze the available evidence regarding the association between timing of repair or referral and clinical outcomes in bile duct injury (BDI). BACKGROUND: Surgical repair is recommended for patients with complex BDI following laparoscopic cholecystectomy. However, consensus on the timing of surgery or referral to a specialist is lacking. METHODS: We searched PubMed, Embase, Cochrane Library, and Scopus for eligible studies. The coprimary outcomes were repair failure in follow-up and postoperative complications. We pooled odds ratios (ORs) using random-effects models. RESULTS: We included 32 studies. The rate of repair failure was significantly higher for early versus delayed repair [OR 1.65, 95% confidence interval (CI) 1.14-2.37, P= 0.007], lower for early versus delayed referral (OR 0.28, 95% CI 0.17-0.45, P < 0.001), but did not differ substantially for on-table versus postcholecystectomy repair (OR 2.06, 95% CI 0.89-4.73, P = 0.09). Regarding postoperative complications, early referral outperformed delayed referral (OR 0.24, 95% CI 0.09-0.68, P= 0.007); however, we found no significant differences between early and delayed repair (OR 1.34, 95% CI 0.96-1.87, P= 0.08), or between on-table and postcholecystectomy repair (OR 1.13, 95% CI 0.42-3.07, P= 0.81). At the cutoff time point of 6 weeks, early repair was associated with increased rates of repair failure (OR 4.03; P < 0.001), postoperative complications (OR 2.18; P < 0.001), and biliary stricture (OR 6.23; P < 0.001). CONCLUSIONS: Among patients with BDI, early referral and delayed repair appear to confer favorable outcomes.

Investigation of the underlying genes and mechanism of familial hypercholesterolemia through bioinformatics analysis.

BACKGROUND: Familial hypercholesterolemia (FH) is one of the commonest inherited metabolic disorders. Abnormally high level of low-density lipoprotein cholesterol (LDL-C) in blood leads to premature atherosclerosis onset and a high risk of cardiovascular disease (CVD). However, the specific mechanisms of the progression process are still unclear. Our study aimed to investigate the potential differently expressed genes (DEGs) and mechanism of FH using various bioinformatic tools. METHODS: GSE13985 and GSE6054 were downloaded from the Gene Expression Omnibus (GEO) database for bioinformatic analysis in this study. First, limma package of R was used to identify DEGs between blood samples of patients with FH and those from healthy individuals. Then, the functional annotation of DEGs was carried out by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Ontology (GO) analysis. Based on Search Tool for the Retrieval of Interacting Genes (STRING) tool, we constructed the Protein-Protein Interactions (PPIs) network among DEGs and mined the core genes as well. RESULTS: A total of 102 communal DEGs (49 up-regulated and 53 down-regulated) are identified in FH samples compared with control samples. The functional changes of DEGs are mainly associated with the focal adhere and glucagon signaling pathway. Ten genes (ITGAL, TLN1, POLR2A, CD69, GZMA, VASP, HNRNPUL1, SF1, SRRM2, ITGAV) were identified as core genes. Bioinformatic analysis showed that the core genes are mainly enriched in numerous processes related to cell adhesion, integrin-mediated signaling pathway and cell-matrix adhesion. In the transcription factor (TF) target regulating network, 219 nodes were detected, including 214 DEGs and 5 TFs (SP1, EGR3, CREB, SEF1, HOX13). In conclusion, the DEGs and hub genes identified in this study may help us understand the potential etiology of the occurrence and development of AS. CONCLUSION: Up-regulated ITGAL, TLN1, POLR2A, VASP, HNRNPUL1, SF1, SRRM2, and down-regulated CD69, GZMA and ITGAV performed important promotional effects for the formation of atherosclerotic plaques those suffering from FH. Moreover, SP1, EGR3, CREB, SEF1 and HOX13 were the potential transcription factors for DEGs and could serve as underlying targets for AS rupture prevention. These findings provide a theoretical basis for us to understand the potential etiology of the occurrence and development of AS in FH patients and we may be able to find potential diagnostic and therapeutic targets.

Prognostic value of serum high-density lipoprotein cholesterol in patients with gallbladder cancer.

OBJECTIVES: the aim of this study was to evaluate the prognostic significance of preoperative serum lipid in patients with gallbladder cancer (GBC). METHODS: ninety-nine patients with GBC between October 2009 and December 2013 were reviewed in this retrospective study. Total serum cholesterol (TC), total triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein A (Apo-A), apolipoprotein B (Apo-B) and free fatty acids (FFA) were measured before surgery. The correlation of serum lipid levels with clinical data, including gender, age, tumor size, lymph nodes metastasis, tumor differentiation, distant metastasis and TNM stage were analyzed by univariate and multivariate survival analysis to evaluate independent prognostic factors. RESULTS: compared with the normal HDL-C group (n = 57), the overall survival rate among GBC patients with low HDL-C levels (n = 42) was reduced (p < 0.05). However, there were no significant differences in overall survival for patients with different levels of TC, TG, Apo-A, Apo-B, LDL-C or FFA. The serum level of HDL-C was associated with TNM stage (p < 0.05) and distant metastasis (p < 0.001). The multivariate prognosis analysis showed that HDL-C and lymph nodes metastasis were independent prognostic factors (p < 0.05). A prognostic evaluation model based on HDL-C and lymph nodes metastasis was established. CONCLUSION: preoperative serum HDL-C level was closely associated with distant metastasis of patients with GBC. HDL-C level may be a valuable prognostic factor for GBC patients. The combination of HDLC and lymph nodes metastasis can better predict the prognosis of GBC.

ADAM-17 is a poor prognostic indicator for patients with hilar cholangiocarcinoma and is regulated by FoxM1.

BACKGROUND: A-disintegrin and metalloproteinases (ADAMs) are members of a family of multidomain transmembrane and secreted proteins. Specific ADAMs are upregulated in human cancers and correlated with tumor progression and poor outcome, but rarely studied in human hilar cholangiocarcinoma (HC). This study aimed to explore the expression profiles of ADAMs and their potential underlying mechanisms promoting cancer progression. METHODS: mRNA expression of ADAM-9, - 10, - 11, - 12, - 15, - 17, - 28, and - 33 was analyzed in human hilar cholangiocarcinoma (HC) samples. Immunohistochemical (IHC) analysis was used to detect the expression of ADAM-10, - 17, - 28, and FoxM1 in HC. The regulation of ADAM-17 by FoxM1 and their functional study was investigated in vivo and in vitro. RESULTS: ADAM-10, - 17, and - 28 were upregulated in tumors compared with matched non-cancerous tissues. IHC analysis revealed increased expression of ADAM-10, - 17, and - 28 in HC cells, and ADAM17 seems to be an independent prognostic factor. ADAM-17 is regulated by FoxM1. A decrease in the expression of ADAM-17 by silencing FoxM1 led to an inhibition of cell proliferation, tumor growth, and the production of tumor necrosis factor α. IHC analysis showed co-expression of FoxM1 and ADAM-17 in HC specimens. CONCLUSIONS: The findings of the present study show an important role of the cross-talk among FoxM1, ADAM-17, and TNFa in HC development and progression.

Egr2 enhances insulin resistance via JAK2/STAT3/SOCS-1 pathway in HepG2 cells treated with palmitate.

Insulin resistance is generally responsible for the pathogenesis of type 2 diabetes mellitus (T2DM). Early growth response proteins-2 (Egr2) has been reported to be able to increase the expression of the suppressors of cytokine signaling-1 (SOCS-1), and impair insulin signaling pathway through suppression of insulin receptor substrates (IRS), including IRS-1 and IRS-2. However, whether Egr2 is directly involved in the development of insulin resistance, and how its potential contributions to insulin resistance still remain unknown. Here, our present investigation found that the expression levels of Egr2 were up-regulated when insulin resistance occurs, and knockdown of Egr2 abolished the effect of insulin resistance in HepG2 cells induced with palmitate (PA). Importantly, inhibition of Egr2 decreased the expression of SOCS-1 as well as reduced phosphorylation of JAK2 and STAT3. And, our data indicated that silencing of Egr2 accelerated hepatic glucose uptake and reversed the impaired lipid metabolism upon insulin resistance. In summary, the present study confirms that Egr2 could deteriorate insulin resistance via the pathway of JAK2/STAT3/SOCS-1 and may shed light on resolving insulin resistance and further the pathogenesis of T2DM.

Post-operative delayed elevation of ALT correlates with early death in patients with HBV-related hepatocellular carcinoma and Post-hepatectomy Liver Failure.

BACKGROUND: Post-hepatectomy Liver Failure (PHLF) remains the primary cause of perioperative death. The kinetics of transaminase levels are usually measured as markers of hepatocellular injury following partial hepatectomy, but their correlation with PHLF and post-operative mortality is unclear. The aim of study was to compare the post-operative transaminase kinetics with short term survival in those patients that developed PHLF. METHODS: A retrospective review of patients with HBV-related HCC and who developed PHLF was performed. Logistic regression analysis was conducted to analyze risk factors for postoperative delayed elevation of ALT (PDE-ALT) PHLF and lethal PHLF. RESULT: Of the 69 patients who developed PHLF 36 (52%) died. In those patients who died the mean ± SD ALT and AST rose from day (POD) 1-3 and continued to fluctuate with highly abnormal levels beyond day 3 with a mean ± SD peak ALT level beyond POD 3 of 1851 ± 1644 U/L (p < 0.001). CONCLUSIONS: The kinetics of the post-operative transaminases were significantly correlated with perioperative mortality in those patients who developed PHLF. PDE-ALT indicates an increased risk of death in HBV-related HCC patients with PHLF.

Individualized nomogram improves diagnostic accuracy of stage I-II gallbladder cancer in chronic cholecystitis patients with gallbladder wall thickening.

BACKGROUND: Early diagnosis of gallbladder cancer (GBC) can remarkably improve the prognosis of patients. This study aimed to develop a nomogram for individualized diagnosis of stage I-II GBC in chronic cholecystitis patients with gallbladder wall thickening. METHODS: The nomogram was developed using logistic regression analyses based on a retrospective cohort consisting of 89 consecutive patients with stage I-II GBC and 1240 patients with gallbladder wall thickening treated at one biliary surgery center in Shanghai between January 2009 and December 2011. The accuracy of the nomogram was validated by discrimination, calibration and a prospective cohort treated at another center between January 2012 and December 2014 (n=928). RESULTS: Factors included in the nomogram were advanced age, hazardous alcohol consumption, long-standing diagnosed gallstones, atrophic gallbladder, gallbladder wall calcification, intraluminal polypoid lesion, higher wall thickness ratio and mucosal line disruption. The nomogram had concordance indices of 0.889 and 0.856 for the two cohorts, respectively. Internal and external calibration curves fitted well. The area under the receiver-operating characteristic curves of the nomogram was higher than that of multidetector row computed tomography in diagnosis of stage I-II GBC (P<0.001). CONCLUSION: The proposed nomogram improves individualized diagnosis of stage I-II GBC in chronic cholecystitis patients with gallbladder wall thickening, especially for those the imaging features alone do not allow to confirm the diagnosis.

PKM2 regulates neural invasion of and predicts poor prognosis for human hilar cholangiocarcinoma.

BACKGROUND: The therapeutic and prognostic value of the glycolytic enzymes hexokinase, phosphofructokinase, and pyruvate kinase (PK) has been implicated in a variety of cancers, while their roles in treatment of and prognosis for hilar cholangiocarcinoma (HC) remain unclear. In this study, we determined the expression of PKM2 in and its impact on biology and clinical outcome of human HC. METHODS: The regulation and function of PKM2 in HC pathogenesis was evaluated using human tissues, molecular and cell biology, and animal models, and its prognostic significance was determined according to its impact on patient survival. RESULTS: We found that expression of hexokinase 1 and the M2 splice isoform of PK (PKM2) was upregulated in HC tissues and that this expression correlated with tumor recurrence and outcome. PKM2 expression was increased in HC cases with chronic cholangitis as demonstrated by isobaric tags for relative and absolute quantification. High PKM2 expression was highly correlated with high syndecan 2 (SDC2) expression and neural invasion. PKM2 downregulation led to a decrease in SDC2 expression. Treatment with metformin markedly suppressed PKM2 and SDC2 expression at both the transcriptional and posttranscriptional levels and inhibited HC cell proliferation and tumor growth. CONCLUSIONS: PKM2 regulates neural invasion of HC cells at least in part via regulation of SDC2. Inhibition of PKM2 and SDC2 expression contributes to the therapeutic effect of metformin on HC. Therefore, PKM2 is an independent prognostic factor and potential therapeutic target for human HC.

Induced and constitutive DNA methylation in a salinity-tolerant wheat introgression line.

Cytosine methylation is a well recognized epigenetic mark. Here, the methylation status of a salinity-tolerant wheat cultivar (cv. SR3, derived from a somatic hybridization event) and its progenitor parent (cv. JN177) was explored both globally and within a set of 24 genes responsive to salinity stress. A further comparison was made between DNA extracted from plants grown under control conditions and when challenged by salinity stress. The SR3 and JN177 genomes differed with respect to their global methylation level, and methylation levels were reduced by exposure to salinity stress. We found the genetic stress- (triggered by a combination of different genomes in somatic hybridization) induced methylation pattern of 13 loci in non-stressed SR3; the same 13 loci were found to undergo methylation in salinity-stressed JN177. For the salinity-responsive genes, SR3 and JN177 also showed different methylation modifications. C methylation polymorphisms induced by salinity stress were present in both the promoter and coding regions of some of the 24 selected genes, but only the former were associated with changes in transcript abundance. The expression of both TaFLS1 (encoding a flavonol synthase) and TaWRSI5 (encoding a Bowman-Birk-type protease inhibitor), which showed both a different expression and a different DNA methylation level between SR3 and JN177, enhanced the salinity tolerance of Arabidopsis thaliana. C methylation changes appear to be a common component of the plant response to stress, and methylation changes triggered by somatic hybridization may contribute to the superior salinity tolerance of SR3.

Effect evaluation of vascular resection for patients with hilar cholangiocarcinoma: original data and meta-analysis.

BACKGROUND/AIMS: To evaluate the effect of vascular resection (VR) in surgical management of hilar cholangiocarcinoma (HCCA), this report did a clinical analysis and conducted a systematic review, combined other studies, based on meta-analysis. METHODOLOGY: Two hundred and thirty eight HCCA patients underwent hepatectomy in the Eastern Hepatobiliary Surgery Hospital. Binary logistic regression analysis was performed to investigate the potentially complications associated factors. Kaplan-Meier test was employed to compare the long-term survival of patients in four groups (RO + PVR-free, RO + PVR, R1 and R2). Meta-analysis was performed with RevMan 4.3.2 software. RESULTS: The results suggested that hepatectomy and HAR were important negative factors from complications (P < 0.01). Compared with patients in other groups, survival of patients in RO + PVR group was worse than RO + PVR-free group, better than R2 group and similar to R1 group with P = 0.001, 0.047 and 0.606 respectively. The results of meta-analysis suggested patients who underwent VR had higher complications rate and mortality rate than patients who did not. Moreover, patients with vascular resection had lower long-term survival rate. CONCLUSIONS: VR used to be considered effective to the patients with vascular invasion. However our study suggest that the surgical decision of undergoing VR should be made cautiously, since VR could diminish the survival time in some cases.

Effects of visual-motor combined response ability training on cognitive function and brain plasticity mechanism in different populations: a study protocol for a single-center, open-label, controlled clinical trial.

UNSTRUCTURED: Background: Cognitive impairment is one of the major diseases facing the aging society. The progressive decline of cognitive function will lead to the decline or even loss of life, work and social ability. Exercise and behavioral stimulation can increase neurotransmitters in the brain and improve overall health and cognitive function. Reactivity training can mobilize neuromuscular function and induce changes in brain plasticity, which may effectively improve cognitive dysfunction and delay the occurrence and development of Alzheimer's disease, but the evidence of its effectiveness is still limited. Methods: This study is a single-center, open-label, controlled clinical trial. Seventy-eight participants will be recruited for the study, including an equal number of athletes, average healthy college students, and average older adults in the community. Subjects will receive two weeks of visual-motor response training. The primary outcome of this study was to assess the imaging difference of functional magnetic resonance imaging (fMRI) at 2 weeks. Secondary outcomes are acousto-optic response time, Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), Mini-mental State Examination (MMSE), Activity of Daily Living Scale (ADL), Subjective Cognitive Decline Questionnaire-9 (SCD-Q9), 10-word memory test and safety. Results: The study was approved by the Shanghai Clinical Research Ethics Committee on January 2, 2024 (ethical reference: SECCR/2023-162-01). As of February 31, 2024, we have recruited 53 participants. We expect to complete recruitment in April 2024 and expect to complete the collection and analysis of study data in July 2024. Discussion: The purpose of this study is to compare improvements in brain perceptual motor functional characteristics and cognitive levels in different populations by response ability training, and to explore the efficacy and safety of exercise-based non- pharmacological therapies in improving cognitive function. Other potential benefits include understanding the functional differences and perceptual characteristics of the brain's perceptual-motor system between athletes and the general population, and exploring the adaptability of the brain for acquiring skills during training in competitive sports, thus providing an evidence base for early sports talent development and broader youth development. Trial registration: Chinese Clinical Trial Registry ID: ChiCTR2400079602. Registered 8 Jan 2024, Available at: www.chictr.org.cn/showproj.html?proj=215669 Abbreviations: AD=Alzheimer's disease (AD), DMC=data Monitoring Committee, fMRI=functional magnetic resonance imaging.

Postpartum depression and autoimmune disease: a bidirectional Mendelian randomization study.

Purpose: The rising prevalence of postpartum depression (PPD) is harmful to women and families. While there is a growing body of evidence suggesting an association between PPD and autoimmune diseases (ADs), the direction of causality remains uncertain. Therefore, Mendelian randomization (MR) study was employed to investigate the potential causal relationship between the two. Methods: This study utilized large-scale genome-wide association study genetic pooled data from two major databases: the IEU OpenGWAS project and the FinnGen databases. The causal analysis methods used inverse variance weighting (IVW). The weighted median, MR-Egger method, MR-PRESSO test, and the leave-one-out sensitivity test have been used to examine the results' robustness, heterogeneity, and horizontal pleiotropy. Results: A total of 23 ADs were investigated in this study. In the IVW model, the MR study showed that PPD increased the risk of type 1 diabetes (OR , = 1.15 (1.05-1.26),p<0.01),Hashimoto's thyroiditis((OR) = 1.21 (1.09-1.34),p<0.0001),encephalitis((OR) = 1.66 (1.06-2.60),p<0.05). Reverse analysis showed that ADs could not genetically PPD. There was no significant heterogeneity or horizontal pleiotropy bias in this result. Conclusion: Our study suggests that PPD is a risk factor for type 1 diabetes, Hashimoto's thyroiditis, and encephalitis from a gene perspective, while ADs are not a risk factor for PPD. This finding may provide new insights into prevention and intervention strategies for ADs according to PPD patients.