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Background: Methylation of HIN-1 is associated with poor outcomes in patients with ovarian clear cell carcinoma (OCCC), which is regarded to be an aggressive, chemo-resistant histological subtype. This study aimed to evaluate whether 5-aza-2-deoxycytidine (5-aza-2-dC) can reverse methylation of the HIN-1 gene to restore chemo-sensitivity of OCCC and the possible mechanism.Methods: In vitro flow cytometric analysis and evaluation of caspase-3/7 activity of paclitaxel-sensitive and resistant OCCC cell lines were performed. Methylation status and expression changes of HIN-1 in the OCCC cell lines treated with 5-aza-2-dC were evaluated, and immunohistochemical staining of HIN-1 in OCCC tissues was performed. In vivo tumor growth with or without 5-aza-2-dC treatment was analyzed, and Western blotting of AKT-mTOR signaling-related molecules was performed.Results: G2-M phase arrest was absent in paclitaxel-resistant OCCC cells after treatment with the cytotoxic drug. The caspase activities of the chemo-resistant OCCC cells were lower than those of the chemo-sensitive OCCC cells when treated with paclitaxel. Methylation of HIN-1 was noted in paclitaxel-resistant OCCC cell lines and cancerous tissues. 5-aza-2-dC reversed the methylation of HIN-1, re-activated the expression of HIN-1, and then suppressed the in vivo tumor growth of paclitaxel-resistant OCCC cells. Immunoblotting revealed that phospho-AKT473 and phospho-mTOR were significantly increased in HIN-1-methylated paclitaxel-resistant OCCC cell lines. However, the expressions of phospho-AKT at Ser473 and Thr308 and phospho-mTOR decreased in the OCCC cells with a high expression of HIN-1.Conclusions: Demethylating agents can restore the HIN-1 expression in paclitaxel-resistant OCCC cells through the HIN-1-AKT-mTOR signaling pathway to inhibit tumor growth. [ABSTRACT FROM AUTHOR]

Background: The liver is the most common target organ in the metastasis of colorectal cancer (CRC). Synchronous liver metastases may confer a poorer prognosis than metachronous metastases, and genetic alterations and an inflammatory response have also been associated with a poor prognosis in cases of a liver metastasis arising from CRC. However, few studies have examined the relationship between KRAS mutations and inflammatory status in CRC, especially with respect to liver metastases. Methods: The effect of the activated mitogen-activated protein kinase pathway and another protein involved in inflammation, C-reactive protein, in liver metastases were examined. We aimed to determine the impact of the CRP-specific single nucleotide polymorphism (SNP) rs7553007 in liver metastasis on the CRC-specific survival (CSS) of patients after colorectal liver metastasectomy. Results: We found no significant differences in genotype distributions and allele frequencies at the CRP SNP rs7553007 between CRC patients with liver metastasis and the control group. CSS rates were low in the subgroup of patients with synchronous metastasis with the A-allele (A/A and A/G) at rs7553007 or mutated KRAS/BRAF in liver metastatic specimens. Furthermore, the CRP SNP rs7553007 (hazard ratio [HR] = 1.101; 95% confidence interval [CI] = 1.011–1.200; P = 0.027) and KRAS/BRAF mutations (HR = 2.377; 95% CI = 1.293–4.368; P = 0.005) remained predictive for the CSS of CRC patients with synchronous liver metastasis in multivariate analysis. Conclusions: Both the CRP SNP rs7553007 and KRAS/BRAF mutations were independent prognostic factors for CRC patients with synchronous liver metastasis. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the predominant gastrointestinal malignancy and the leading cause of cancer death. The identification of genes related to CRC is important for the development of successful therapies and earlier diagnosis.Methods: Molecular analysis of feces was evaluated as a potential method for CRC detection. Expression of a predicted protein with unknown function, KIAA0247, was found in feces evaluated using specific quantitative real-time polymerase chain reaction. Its cellular function was then analyzed using immunofluorescent staining and the changes in the cell cycle in response to 5-fluorouracil (5-FU) were assessed.Results: Gastrointestinal tissues and peripheral blood lymphocytes ubiquitously expressed KIAA0247. 56 CRC patients fell into two group categories according to fecal KIAA0247 mRNA expression levels. The group with higher fecal KIAA0247 (n=22; ≥0.4897) had a significantly greater five-year overall survival rate than the group with lower fecal KIAA0247 (n = 30; <0.4897) (66.0 ± 11.6%; p=0.035, log-rank test). Fecal expression of KIAA0247 inversely related to CRC tumor size (Kendall's tau-b=-0.202; p=0.047). Immunofluorescent staining revealed that the cytoplasm of CRC cells evenly expresses KIAA0247 without 5-FU treatment, and KIAA0247 accumulates in the nucleus after 40 μM 5-FU treatment. In HCT116 p53(-/-) cells, which lack p53 cell cycle control, the proportion of cells in the G2/M phase was larger (13%) in KIAA0247-silent cells than in the respective shLuc control (10%) and KIAA0247-overexpressing cells (7%) after the addition of low dose (40 μM) 5-FU. Expression of three cyclin genes (cyclin A2, cyclin B1, and cyclin B2) also downregulated in the cells overexpressing KIAA0247.Conclusions: This is the first description of a linkage between KIAA0247 and CRC. The study's data demonstrate overexpression of KIAA0247 associates with 5-FU therapeutic benefits, and also identify the clinical significance of fecal KIAA0247 in CRC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most prevalent malignant diseases worldwide. Recurrence is associated with the poor survival of patients with CRC. Targeted therapy and precision medicine for recurrent CRC may improve the clinical outcome. Therefore, finding biomarkers that can detect CRC early, assess its prognosis and survival, and predict its treatment response is key to improving the clinical prognosis. The aim of this study was to assess CRC recurrence by analyzing molecular differences using postoperative specimens. Whole-exome sequencing was first used to evaluate the molecular differences in CRC tissues from patients with recurrent disease, and the results were then verified with tissue array methods. The regulation of single nucleotide polymorphisms (SNPs) in long noncoding regions of interest was analyzed in the presence of target microRNAs (miRs) using luciferase assays. The results demonstrated that in patients with recurrent CRC, the G allele was mainly detected at the rs28382740 SNP in the 3'-untranslated region of the X-linked inhibitor of apoptosis (XIAP)-encoding gene. From the tissue arrays, 60% (3/5) of patients with the G allele of the rs28382740 SNP were diagnosed with CRC recurrence, whilst only 10% (1/10) of patients without the G allele had recurrent CRC (P=0.077). Furthermore, XIAP levels were high in non-CRC (50%; 2/4) and CRC (75%; 3/4) tissues of patients with recurrent disease and CRC (54.5%; 6/11) tissues of patients without recurrent disease. However, but only 9.1% (1/11) of non-CRC tissues of nonrecurrent patients had significantly high XIAP expression levels (P=0.022). Using a luciferase assay, it was demonstrated that miR-24s (miR-24-1-5p and miR-24-2-5p) targeting the rs28382740 SNP reduced XIAP levels in CRC cells with rs28382740 SNP genotype G. These results indicate that apoptosis-related proteins, such as XIAP, may be therapeutic targets or biomarkers for tumor development. The data from the present study support an inhibitory effect of miR-24s on XIAP expression. However, this inhibitory potency depends on the rs28382740 SNP genotype and may alleviate CRC progression by regulating the expression of XIAP., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Tian et al.)

Background: It is unclear whether hydroxymethylglutaryl-CoA reductase inhibitor (statin) therapy decreases the risk of mortality and cardiovascular disease (CVD) in patients undergoing peritoneal dialysis (PD)., Methods: We performed a literature search of PubMed, Cochrane Library, Embase, and other databases for research publications up to June 2022. The outcomes of interest were fatal and nonfatal CVDs, all-cause mortality, and changes in the biochemical profiles. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled and synthesized using a random-effects model. The certainty of the evidence was determined using Grading of Recommendations, Assessment, Development, and Evaluation., Results: Nine studies, including 2,933 patients undergoing PD, were included. Among them, three studies, including 2,099 patients, reported all-cause mortality, and three, including 1,571 patients, reported CVDs. In these patients, pooling results of two observational studies (very low-certainty evidence) showed that statin therapy significantly reduced CVDs (HR = 0.67; 95% CI = 0.54-0.84; p = 0.0004). Moreover, statin therapy was associated with significantly reduced low-density lipoprotein cholesterol, total cholesterol, and C-reactive protein levels (very low certainty of evidence). However, the effects of statin therapy on triglyceride, high-density lipoprotein, and albumin levels were not statistically significant., Conclusion: Although statin therapy was associated with significantly reduced low-density lipoprotein cholesterol, total cholesterol, and C-reactive protein levels, the probable beneficial effect of statins on CVD risk in patients undergoing PD could not be concluded firmly. Additional high-quality studies are required to assess the potential beneficial effects of statin therapy in PD patients., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Aim: To clarify the importance of HbA1c reduction and antidiabetic drug use in preventing major adverse cardiovascular events (MACE) for patients with type 2 diabetes (T2D)., Materials and Methods: We conducted an updated systematic review of contemporary large randomized controlled trials assessing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk in adult T2D patients. Mixed-effects meta-regression was performed to examine the associations of HbA1c reduction with subsequent risk of macrovascular and microvascular events. We evaluated the potential mediating role of HbA1c reduction in the relationship between antidiabetic drugs and MACE., Results: Eighteen placebo-controlled trials comprising 155 610 participants were included. The effects of treatment differed among antidiabetic drug classes for most adverse outcomes with high heterogeneity (I 2 : 63.7%-95.8%). Mean HbA1c reduction was lowest with dipeptidyl peptidase-4 inhibitors (0.30%), followed by sodium-glucose co-transporter-2 inhibitors (0.46%), and was highest with glucagon-like peptide-1 receptor agonists (0.58%) and thiazolidinediones (0.60%). Lower relative risks of MACE were significantly associated with larger reductions in achieved HbA1c (β -0.3182; 95% CI: -0.5366 to -0.0998; P = .0043), even after adjusting for drug classes. When considering HbA1c lowering as a mediator to be controlled, beneficial effects owing to specific antidiabetic treatment for MACE were not observed (χ 2  = 1.4494; P = .6940). The proportion mediated by HbA1c reduction was 50.0%-63.5% for these antidiabetic agents., Conclusions: The main benefits of antidiabetic agents might result from the reduction in blood sugar levels and are generally independent of drugs used. Risk reduction in MACE was proportional to the magnitude of HbA1c decrease conferred by antidiabetic agents with less hypoglycaemic hazard., (© 2022 John Wiley & Sons Ltd.)

Background/purpose: Previously we had identified concurrent genes, which highlighted the interplay between copy number variation (CNV) and differential gene expression (GE) for Han Chinese breast cancers. The merit of the approach is to discovery biomarkers not identifiable by conventional GE only data, for which phenotype-correlation or gene variability is the criteria of gene selection., Materials and Methods: Thirty-one comparative genomic hybridization (CGH) and 83 GE microarrays were performed, with 29 breast cancers assayed from both platforms. Potential targets were revealed by Genomic Identification of Significant Targets in Cancer (GISTIC) from CGH arrays. Concurrent genes and genes with significant GISTIC scores were used to derive the extended concurrent genes signature, which was consensus from leading edge analysis across all studies and a supervised partial least square (PLS) regression predictive model of disease-free survival was constructed., Results: There were 1584 concurrent genes from 29 samples with both CGH and GE microarrays. Enriched concurrent genes sets for disease-free survival were identified independently from 83 GE arrays and another one with Han Chinese origin as well as three studies of Western origin. For five studies with disease-free survival follow up, prognostic discrepancy was observed between predicted high-risk and low-risk group patients., Conclusion: We concluded that through parallel analyses of CGH and GE microarrays, the proposed extended concurrent gene expression signature can identify biomarkers with prognostic values., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Aims: Impaired renal function (IRF) prevails in patients with acute heart failure. The study aimed to investigate the prevalence of on-admission IRF and its association with short-term and long-term mortalities in patients hospitalized for HF with reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) left ventricular ejection fraction (LVEF)., Methods: Patients hospitalized for acute heart failure were enrolled and stratified by LVEF into three phenotypes as HFpEF (≥50%), HFmrEF (40-49%), and HFrEF (<40%). IRF was defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73m 2 on admission. National Death Registry was linked for the identification of mortality., Results: Of 2613 patients enrolled, 673 (25.7%) had HFrEF, 367 (14.0%) had HFmrEF, and 1573 (60.1%) had HFpEF, whereas IRF was prevalent among 63.7, 68.6, and 67.5% of them, respectively. IRF significantly correlated with higher long-term mortality in each phenotype of HF. However, IRF was associated with 90-day and 1-year mortality in subjects with HFrEF and HFmrEF, but not HFpEF. After accounting for age, gender, hypertension, diabetes, coronary artery disease, atrial fibrillation, stroke, serum sodium, de novo heart failure, date of enrolment, and systolic blood pressure <90 mmHg or use of inotropic agents, IRF remained related to 5-year mortality in patients with HFrEF (hazard ratio and 95% confidence interval: 1.346, 1.034-1.751), HFmrEF (2.210, 1.435-3.404), and HFpEF (1.493, 1.237-1.801)., Conclusions: On-admission IRF was independently predictive of long-term mortality in patients hospitalized for HF, irrespective of HF phenotypes. Furthermore, IRF was also associated with short-term mortality in HFrEF and HFmrEF, but not in HFpEF., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Inflammatory bowel disease (IBD) is associated with dysbiosis and intestinal barrier dysfunction, as indicated by epithelial hyperpermeability and high levels of mucosal-associated bacteria. Changes in gut microbiota may be correlated with IBD pathogenesis. Additionally, microbe-based treatments could mitigate clinical IBD symptoms. Plasmon-activated water (PAW) is known to have an anti-inflammatory potential. In this work, we studied the association between the anti-inflammatory ability of PAW and intestinal microbes, thereby improving IBD treatment. We examined the PAW-induced changes in the colonic immune activity and microbiota of mice by immunohistochemistry and next generation sequencing, determined whether drinking PAW can mitigate IBD induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) and dysbiosis through mice animal models. The effects of specific probiotic species on mice with TNBS-induced IBD were also investigated. Experimental results indicated that PAW could change the local inflammation in the intestinal microenvironment. Moreover, the abundance of Akkermansia spp. was degraded in the TNBS-treated mice but elevated in the PAW-drinking mice. Daily rectal injection of Akkermansia muciniphila , a potential probiotic species in Akkermansia spp., also improved the health of the mice. Correspondingly, both PAW consumption and increasing the intestinal abundance of Akkermansia muciniphila can mitigate IBD in mice. These findings indicate that increasing the abundance of Akkermansia muciniphila in the gut through PAW consumption or other methods may mitigate IBD in mice with clinically significant IBD.

Hypertension-related death is the leading cause of mortality worldwide, making blood pressure (BP) control an important issue. Salt substitute is a non-pharmaceutical strategy to improve hypertension control. The goal of this study was to evaluate the effect of salt substitute on BP and cardiovascular disease. The authors searched the Cochrane Library and PubMed databases through March 2022, and assessed the risk-of-bias for included studies by the Cochrane risk-of-bias tool. Twenty-three randomized controlled trials with 32073 patients were included in our systematic review. A meta-analysis with random effects was performed to analyze the effects of salt substitute on systolic and diastolic BP, 24-h urinary sodium and potassium, and cardiovascular and all-cause mortality. In the random-effects model, participants consuming salt substitute showed significant reduction in systolic BP (mean difference (MD) -4.80 mmHg, 95% confidence interval (CI) -6.12 to -3.48, P < 0.0001) and diastolic BP (MD -1.48 mmHg, 95% CI -2.06 to -0.90, P < 0.0001) compared with participants consuming normal salt. In the urine electrolyte analysis, the salt substitute group had significant reduction in 24-h urine sodium (MD -22.96 mmol/24-h, P = 0.0001) and significant elevation in 24-h urine potassium (MD 14.41 mmol/24-h, P < 0.0001). Of the five studies with mortality outcome data, salt substitute significantly reduced all-cause mortality (hazard ratio 0.88, P = 0.0003). In conclusion, our analyses showed that salt substitute has a strong effect on lowering BP and reducing all-cause mortality. By modifying the daily diet with salt substitute, the authors can improve BP control by using this non-pharmaceutical management., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

The chromosome segregation 1‑like (CSE1L) protein, which regulates cellular mitosis and apoptosis, was previously found to be overexpressed in colorectal cancer (CRC) cells harboring mutations. Therefore, regulating CSE1L expression may confer chemotherapeutic effects against CRC. The gut microflora can regulate gene expression in colonic cells. In particular, metabolites produced by the gut microflora, including the short‑chain fatty acid butyrate, have been shown to reduce CRC risk. Butyrates may exert antioncogenic potential in CRC cells by modulating p53 expression. The present study evaluated the association between CSE1L expression and butyrate treatment from two non‑transformed colon cell lines (CCD‑18Co and FHC) and six CRC cell lines (LS 174T, HCT116 p53 +/+ , HCT116 p53 ‑/‑ , Caco‑2, SW480 and SW620). Lentiviral knockdown of CSE1L and p53, reverse transcription‑quantitative PCR (CSE1L, c‑Myc and p53), western blotting [CSE1L, p53, cyclin (CCN) A2, CCNB2 and CCND1], wound healing assay (cell migration), flow cytometry (cell cycle analysis) and immunofluorescence staining (CSE1L and tubulin) were adopted to verify the effects of butyrate on CSE1L‑expressing CRC cells. The butyrate‑producing gut bacteria Butyricicoccus pullicaecorum was administered to mice with 1,2‑dimethylhydrazine‑induced colon tumors before the measurement of CSE1L expression. The effects of B. pullicaecorum on CSE1L expression were then assessed by immunohistochemical staining for CSE1L and p53 in tissues from CRC‑bearing mice. Non‑cancerous colon cells with the R273H p53 mutation or CRC cells haboring p53 mutations were found to exhibit significantly higher CSE1L expression levels. CSE1L knockdown in HCT116 p53 ‑/‑ cells resulted in G 1 ‑and G 2 /M‑phase cell cycle arrest. Furthermore, in HCT116 p53 ‑/‑ cells, CSE1L expression was already high at interphase, increased at prophase, peaked during metaphase before declining at cytokinesis but remained relatively high compared with that in HCT116 expressing wild‑type p53. Significantly decreased expression levels of CSE1L were also observed in HCT116 p53 ‑/‑ cells that were treated with butyrate for 24 h. In addition, the migration of HCT116 p53 ‑/‑ cells was significantly decreased after CSE1L knockdown or butyrate treatment. Tumors with more intense nuclear p53 staining and weaker CSE1L staining were found in mice bearing DMH/DSS‑induced CRC that were administered with B. pullicaecorum . Taken together, the results indicated that butyrate can impair CSE1L‑induced tumorigenic potential. In conclusion, butyrate‑producing microbes, such as B. pullicaecorum , may reverse the genetic distortion caused by p53 mutations in CRC by regulating CSE1L expression levels.

Background: The aim of the study was to enhance colorectal cancer prognostication by integrating single nucleotide polymorphism (SNP) and gene expression (GE) microarrays for genomic and transcriptional alteration detection; genes with concurrent gains and losses were used to develop a prognostic signature., Methods: The discovery dataset comprised 32 Taiwanese colorectal cancer patients, of which 31 were assayed for GE and copy number variations (CNVs) with Illumina Human HT-12 BeadChip v4.0 and Omni 25 BeadChip v1.1. Concurrent gains and losses were declared if coherent manners were observed between GE and SNP arrays. Concurrent genes were also identified in The Cancer Genome Atlas Project (TCGA) as the secondary discovery dataset (n = 345)., Results: The "universal" concurrent genes, which were the combination of z-transformed correlation coefficients, contained 4022 genes. Candidate genes were evaluated within each of the 10 public domain microarray datasets, and 1655 (2000 probe sets) were prognostic in at least one study. Consensus across all datasets was used to build a risk predictive model, while distinct relapse-free/overall survival patterns between defined risk groups were observed among four out of five training datasets. The predictive accuracy of recurrence, metastasis, or death was between 61 and 86% (cross-validation area under the receiver operating characteristic (ROC) curve: 0.548-0.833) from five independent validation studies., Conclusion: The colorectal cancer concurrent gene signature is prognostic in terms of recurrence, metastasis, or mortality among 1746 patients. Genes with coherent patterns between genomic and transcriptional contexts are more likely to provide prognostication for colorectal cancer., (© 2022. The Author(s).)

Use of prebiotics is a growing topic in healthcare. A lightweight molecule and water-soluble fiber ingredient, longish glucomannan hydrolysates (LGH), has been developed to improve the intestinal mucosal barrier and confer gut health benefits. This study aims to investigate the implications of continuous LGH intervening in intestinal epithelium integrity and protective immunity against chemical dextran sodium sulfate (DSS)-induced colitis. Twelve male BALB/c mice were randomly arranged into four groups. The LGH/DSS group had results in bodyweight variance, epithelial cell density, and aberrancy score as good as the LGH group, and both were equivalent to the control group. LGH consumption effectively protects the distal intestinal epithelium by activating innate T lymphocytes. Meanwhile, T-cell subsets in subepithelial interspersion take a bystander role in these microenvironmental alterations. Under this stress, the cluster of differentiation 3 (CD3) + T cells infiltrate the epithelium, while CD4 + T cells inversely appear in submucosal large lymphoid aggregates/isolated lymphoid follicles (ILFs) in which significant CD3 + , CD4 + , and CD8 + T-cell populations agglomerate. Moreover, forkhead box P3 (Foxp3) and interleukin 17 (IL-17) are observed in these ILFs. Agglomerated CD4 + T-cell lineages may have roles with proinflammatory T helper 17 cells and anti-inflammatory regulatory T cells in balancing responses to intraluminal antigens. Collectively, LGH administration may function in immune modulation to protect against DSS-induced inflammation.

Objective: We tested the osteoblastic differentiation effects caused by physical stimulation such as hydrostatic pressure using placenta-derived multipotent cells., Materials and Methods: The placenta-derived multipotent cells (PDMCs) were treated with osteogenic medium to induce PDMCs differentiation into osteoblast-like cells. The induced PDMCs were stimulated using hydrostatic pressure at a magnitude of 30 kPa for 1 h/day for up to 12 days. The calcium deposition monitored by Alizarin Red staining and the calcium content of each experimental group were quantified., Results: The results demonstrated both the calcium deposition and concentration were elevated through hydrostatic pressure stimulation. Moreover, in order to indicate of PDMC osteodifferentiation, RT-qPCR analysis were performed and mRNA expression of osteoblast differentiation markers (type I collagen, alkaline phosphatase, RUNX2, and BGLAP), the bone morphogenetic protein family (BMP1-7) and BMP receptors (BMPR1A, BMPR1B, and BMPR2) were examined. Among them, the mRNA levels of RUNX2, COL1A1, BMP1, BMP3, and BMPR1A increased significantly in the hydrostatic-pressure-stimulated groups, whereas BGLAP, ALP, BMP2, BMP6, BMPR1B, and BMPR2 exhibited a slight upregulation between the control and experimental groups, indicating the specific signal route induced by hydrostatic pressure on PDMCs., Conclusion: Our results revealed the beneficial effects of stem cells stimulated using hydrostatic pressure, which could enhance calcium deposition considerably and facilitate osteodifferentiation, and the results may be applied to tissue regeneration in the near future., Competing Interests: Declaration of competing interest All authors declare they have no conflicts of interest of this manuscript., (Copyright © 2022. Published by Elsevier B.V.)

Little is known about genes that induce stem cells differentiation into astrocytes. We previously described that heat shock protein 27 (HSP27) downregulation is directly related to neural differentiation under chemical induction in placenta-derived multipotent stem cells (PDMCs). Using this neural differentiation cell model, we cross-compared transcriptomic and proteomic data and selected 26 candidate genes with the same expression trends in both omics analyses. Those genes were further compared with a transcriptomic database derived from Alzheimer's disease (AD). Eighteen out of 26 candidates showed opposite expression trends between our data and the AD database. The mRNA and protein expression levels of those candidates showed downregulation of HSP27, S100 calcium-binding protein A16 (S100A16) and two other genes in our neural differentiation cell model. Silencing these four genes with various combinations showed that co-silencing HSP27 and S100A16 has stronger effects than other combinations for astrocyte differentiation. The induced astrocyte showed typical astrocytic star-shape and developed with ramified, stringy and filamentous processes as well as differentiated endfoot structures. Also, some of them connected with each other and formed continuous network. Immunofluorescence quantification of various neural markers indicated that HSP27 and S100A16 downregulation mainly drive PDMCs differentiation into astrocytes. Immunofluorescence and confocal microscopic images showed the classical star-like shape morphology and co-expression of crucial astrocyte markers in induced astrocytes, while electrophysiology and Ca 2+ influx examination further confirmed their functional characteristics. In conclusion, co-silencing of S100A16 and HSP27 without chemical induction leads to PDMCs differentiation into functional astrocytes., (© 2022. The Author(s).)

Pancreatic adenocarcinoma (PAC) is the 8th leading cause of cancer-related deaths in Taiwan, and its incidence is increasing. The development of PAC involves successive accumulation of multiple genetic alterations. Understanding the molecular pathogenesis and heterogeneity of PAC may facilitate personalized treatment for PAC and identify therapeutic agents. We performed tumor-only next-generation sequencing (NGS) with targeted panels to explore the molecular changes underlying PAC patients in Taiwan. The Ion Torrent Oncomine Comprehensive Panel (OCP) was used for PAC metastatic lesions, and more PAC samples were sequenced with the Ion AmpliSeq Cancer Hot Spot (CHP) v2 panel. Five formalin-fixed paraffin-embedded (FFPE) metastatic PAC specimens were successfully assayed with OCP, and KRAS was the most prevalent alteration, which might contraindicate the use of anti-EGFR therapy. One PAC patient harbored a FGFR2 p. C382R mutation, which might benefit from FGFR tyrosine kinase inhibitors. An additional 38 samples assayed with CHP v2 showed 100 hotspot variants, collapsing to 54 COSMID IDs. The most frequently mutated genes were TP53 , KRAS , and PDGFRA (29, 23, 10 hotspot variants), impacting 11, 23, and 10 PAC patients. Highly pathogenic variants, including COSM22413 ( PDGFRA , FATHMM predicted score: 0.88), COSM520, COSM521, and COSM518 ( KRAS , FATHMM predicted score: 0.98), were reported. By using NGS with targeted panels, somatic mutations with therapeutic potential were identified. The combination of clinical and genetic information is useful for decision making and precise selection of targeted medicine.

Background: Facilitating the childbirth process is a global issue. Many strategies have been developed to cope with labor pain and improve the delivery experience and satisfaction of pregnant women. The results of different types of medical intervention on women's expectant pain have been varied. Therefore, this systematic review was aimed at summarizing the body of evidence regarding the effects of various non-pharmacological coping strategies for reducing labor pain., Methods: The review was conducted according to guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We systematically searched the articles published between 1989 and 2020 in six electronic databases: PubMed, MEDLINE, CINAHL, WOS, PsycARTICLES, and Airiti Library, and the reference lists of the Clinical Trial Registry. Twenty studies were identified, with eight eligible studies included in the Bayesian network meta-analysis., Results: Eight studies with 713 participants were included in the meta-analysis with nine different non-pharmacological strategies for reducing labor pain. The traditional meta-analysis demonstrated that the non-pharmacological coping strategies were effective in reducing labor pain. Of these interventional strategies, the ranking probabilities analysis of the network meta-analysis suggested that the Bonapace Method may be the most effective strategy in reducing labor pain, followed by acupressure., Conclusions: Non-pharmacological coping strategies can reduce labor pain while maintaining an effective and satisfactory delivery experience. This systematic review, by synthesizing the body of evidence, demonstrated that non-pharmacological coping strategies are effective in reducing labor pain. Furthermore, as demonstrated in the network meta-analysis, the Bonapace Method, modulating birth pain by involving the father, is the most effective non-pharmacological intervention for reducing labor pain., Competing Interests: The authors have declared that no competing interests exist.

Periodontal disease (PD) is one of the most prevalent disorders globally and is strongly associated with many other diseases. Inflammatory bowel disease (IBD), an inflammatory condition of the colon and the small intestine, is reported to be associated with PD through undetermined mechanisms. We analyzed taxonomic assignment files from the Crohn's Disease Viral and Microbial Metagenome Project (PRJEB3206). The abundance of Porphyromonadaceae in fecal samples was significantly different between patients with Crohn's disease and control volunteers. Dextran sulfate sodium was used to induce colitis in mice to reveal the effect of this periodontopathic pathogen in vivo. After intrarectal implantation of Porphyromonas gingivalis ( Pg )-the primary pathogen causing PD-the disease activity index score, colonic epithelial loss, and inflammatory cell infiltration were intensified. In addition, tumor necrosis factor-α and interleukin-6 showed the highest levels in Pg- infected colons. This revealed the importance of Pg in the exacerbation of IBD. Thus, simultaneous treatment of PD should be considered for people with IBD. Moreover, implantation of Pg in the rectum worsened the clinical symptoms of colitis in mice. Because Pg participates in the pathogenesis of IBD, reducing the chances of it entering the intestine might prevent the worsening of this disorder.

Background and Aims: The high false-positive rate of the treadmill exercise test (TET) may lead to unnecessary invasive coronary angiography. We aimed to develop a machine learning-based algorithm to improve the diagnostic performance of TET., Methods: Study included 2325 patients who underwent TET and subsequent coronary angiography within one-year interval. The mean age was 58.7 (48.1-69.3) years, 1731 (74.5%) were male, 1858 (79.9%) had positive TET result, and 812 (34.9%) had obstructive coronary artery disease (≥70% stenosis in at least one vessel). The study population were randomly divided into training (70%) and testing (30%) groups for algorithm development. A total of 93 features, including exercise performance, hemodynamics and ST-segment changes were extracted from the TET results. Clinical features included comorbidity, smoking, height, weight, and Framingham risk score. Support vector machine, logistic regression, random forest, k-nearest neighbor and extreme gradient boosting machine learning algorithms were used to build the predictive models. The performance of each model was compared with that of conventional TET., Results: Four of the five models exhibited comparable diagnostic performance and were better than conventional TET. The random forest algorithm had an area under the curve (AUC) of 0.73. When used with clinical features, the AUC improved to 0.74. The major advantage of the algorithm is the reduction of the false-positive rate compared with conventional TET (55% vs. 76.3%, respectively), while maintaining comparable sensitivity (85%)., Conclusions: Using the information obtained from conventional TET, a more accurate diagnosis can be made by incorporating an artificial intelligence-based model., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Stem cell-based therapy has been evaluated in many different clinical trials for various diseases. This capability was applied in various neurodegenerative diseases, such as multiple sclerosis, which is characterized by demyelination, axonal injury, and neuronal loss. Dental pulp stem cells (DPSCs) are mesenchymal stem cells from the oral cavity that have been studied with potential application for the regeneration of different tissues. Heat shock protein 27 (HSP27) regulates neurogenesis in the process of neural differentiation of placenta multipotent stem cells. Here, we hypothesize that HSP27 expression is also critical for the neural differentiation of DPSCs. An evaluation of the possible role of HSP27 in the differentiation of DPSCs was performed using gene knockdown and neural immunofluorescent staining. We found that HSP27 played a role in the differentiation of DPSCs and that knockdown of HSP27 in DPSCs rendered cells to oligodendrocyte progenitors; i.e., small hairpin specific for HSP27 DPSCs exhibited NG2-positive immunoreactivity and gave rise to oligodendrocytes or type-2 astrocytes. This neural differentiation of DPSCs may have clinical significance in the treatment of patients with neurodegenerative diseases. In conclusion, our data provide an example of the oligodendrocyte differentiation of a DPSC model, which may be applied in human regenerative medicine., (© 2022 S. Karger AG, Basel.)

Background: In patients with atrial fibrillation (AF) and acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI), choosing the most appropriate antithrombotic treatment remains a dilemma. We aimed to compare the relative efficacy and safety outcomes of antithrombotic drugs in patients with AF after undergoing PCI or ACS., Methods: Randomized controlled trials were systematically searched on PubMed, EMBASE, and the Cochrane Library. Five studies (11,532 patients) were included in the network meta-analysis. Trial sequential analysis (TSA) was performed to assess the reliability and conclusiveness of the meta-analysis comparing the dual antithrombotic therapy strategies with the triple antithrombotic therapy strategy., Results: Compared with vitamin K antagonist + dual antiplatelet therapy, novel oral anticoagulant (NOAC) + P2Y12 inhibitor was associated with a significantly better trial-defined primary safety outcome (odds ratio: 0.53; 95% CI, 0.31-0.90) and the lowest probability of thrombolysis in myocardial infarction major bleeding and intracranial hemorrhage using the cumulative ranking technique. In patients omitting aspirin, TSA demonstrated conclusive evidence with significant decreases in all safety outcomes and inconclusive evidence with a nonsignificant increase in in-stent thrombosis (risk ratio: 1.32; TSA-adjusted 95% CI, 0.54-3.24) and myocardial infarction (risk ratio: 1.19; TSA-adjusted 95% CI, 0.84-1.68)., Conclusions: In patients with AF receiving PCI or with ACS, NOAC + P2Y12 inhibitor was associated with the lowest bleeding risk but resulted in a statistically nonsignificant, numerically greater risk for stent thrombosis and myocardial infarction, suggesting that triple antithrombotic therapy should still be an option for certain patients at a high risk of stent thrombosis or myocardial infarction., Competing Interests: Conflicts of interest: Dr. Chern-En Chiang, an editorial board member at Journal of the Chinese Medical Association, had no role in the peer-review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Background Glomerular hyperfiltration (GHF) is paradoxically associated with increased cardiovascular events in healthy individuals, but the pathogenesis remains unclear. We aim to investigate whether GHF is associated with mortality and whether decreased heart rate variability (HRV) is associated with GHF. Methods and Results We retrospectively analyzed 1615 participants (aged 66.1±17.3 years, 61.9% men) without prior cardiovascular events. The glomerular filtration rate was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. GHF was defined as glomerular filtration rate >the 95th percentile after stratification for age and sex, whereas normal filtration was defined as the 25th to 75th percentiles. HRV indexes, including time domain, frequency domain, and sample entropy, were measured using 24-hour ambulatory electrocardiography. Clinical outcomes were defined as all-cause mortality at 2 years. During a mean follow-up of 16.5±8.2 months, there were 117 deaths (7.2%). GHF was associated with a higher risk of death (hazard ratio and 95% CIs, 1.97 [1.15-3.37]). Reduced HRV indexes, including time domain, frequency domain, and sample entropy (odds ratio and 95% CIs, 0.79 [0.70-0.89]) were all independently associated with the presence of GHF after accounting for age, sex, mean heart rate, morbidities, and medications. In subgroup analysis, reduced HRV was more predictive of GHF in the young than the elderly. Mediation analysis revealed a significant mediation effect between HRV and GHF in addition to their respective detrimental effects on survival. Conclusions Reduced HRV was independently associated with the presence of GHF. Autonomic dysfunction may be involved in the pathogenesis of adverse outcomes of GHF in individuals without prior cardiovascular events.

In bladder cancer, urothelial carcinoma is the most common histologic subtype, accounting for more than 90% of cases. Pathogenic effects due to the dysbiosis of gut microbiota are localized not only in the colon, but also in regulating bladder cancer distally. Butyrate, a short-chain fatty acid produced by gut microbial metabolism, is mainly studied in colon diseases. Therefore, the resolution of the anti-cancer effects of butyrate-producing microbes on bladder urothelial cells and knowledge of the butyrate-responsive molecules must have clinical significance. Here, we demonstrate a correlation between urothelial cancer of the bladder and Butyricicoccus pullicaecorum . This butyrate-producing microbe or their metabolite, butyrate, mediated anti-cancer effects on bladder urothelial cells by regulating cell cycle, cell growth, apoptosis, and gene expression. For example, a tumor suppressor against urothelial cancer of the bladder, bladder cancer-associated protein, was induced in butyrate-treated HT1376 cells, a human urinary bladder cancer cell line. In conclusion, urothelial cancer of the bladder is a significant health problem. To improve the health of bladder urothelial cells, supplementation of B. pullicaecorum may be necessary and can further regulate butyrate-responsive molecular signatures.

Some patients with thyroid cancer develop a second primary cancer. Defining the characteristics of patients with double primary cancers (DPCs) is crucial and needs to be followed. In this study, we examine molecular profiles in DPC. We enrolled 71 patients who received thyroid cancer surgery, 26 with single thyroid cancer (STC), and 45 with DPC. A retrograde cohort was used to develop immunohistochemical expressions of mismatch repair (MMR) proteins and cell-cycle-related markers from tissue microarrays to produce an equation for predicting the occurrence of DPC. The multivariate logistic model of 67 randomly selected patients (24 with STC and 43 with DPC) identified that the expression of deficient MMR (dMMR) (odds ratio (OR), 10.34; 95% confidence interval (CI), 2.17-49.21) and pRb (OR, 62.71; 95% CI, 4.83-814.22) were significantly associated with a higher risk of DPC. In contrast, the expression of CDK4 (OR, 0.19; 95% CI, 0.04-0.99) and CDK6 (OR, 0.03; 95% CI, 0.002-0.44) was significantly associated with a lower risk of DPC. Collectively, dMMR, pRb, CDK4, and CDK6 have a sensitivity of 88.9% (95% CI, 75.1-95.8) and a specificity of 69.2% (95% CI, 48.1-84.9) for occurrence of DPC in all 71 patients. This is the first report to demonstrate the molecular differentiation of STC and DPC. Overall, the integral molecular profile performed excellent discrimination and denoted an exponential function to predict the probability of DPC.

Background: Hemodynamic assessment in patients with pulmonary arterial hypertension (PAH) is essential for risk stratification and pharmacological management. However, the prognostic value of the hemodynamic changes after treatment is less well established., Objectives: We investigated the prognostic impacts of the changes in hemodynamic indices, including mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), right atrial pressure (RAP), and cardiac output index (CI). We conducted this systematic review with meta-regression analysis on existing clinical trials., Methods: We searched and identified all relevant randomized controlled trials from multiple databases. An analogous R 2 index was used to quantify the proportion of variance explained by each predictor in the association with PAH patients' prognosis. A total of 21 trials and 3306 individuals were enrolled., Results: The changes in mPAP, PVR, RAP, and CI were all significantly associated with the change in 6MWD (∆6MWD). The change in mPAP was with the highest explanatory power for ∆6MWD (R 2 analog = 0.740). Additionally, the changes in mPAP, PVR, and CI were independently predictive of adverse clinical events. The change in mPAP had the highest explanatory power for the clinical events (R 2 analog = 0.911). Furthermore, the change in PVR was with the highest explanatory power for total mortality of PAH patients (R 2 analog = 0.612)., Conclusion: Hemodynamic changes after treatment, including mPAP, PVR, CI, and RAP, were significantly associated with adverse clinical events or mortality in treated PAH patients. It is recommended that further studies be conducted to evaluate the changes in hemodynamic indices to guide drug titration., Systematic Review Registration: PROSPERO CRD42019125157., (© 2021. The Author(s).)

Sepsis is a state of host immune response triggered by virus or bacterial infection, in which the extent of regional and systemic inflammation and companion counter-inflammatory reactions determines disease outcomes. Probiotics are known for the immunomodulatory effect on allergic disorders, but it is not clear whether the beneficiary effect extends to sepsis and increases survival. In this mouse model, we injected intraperitoneally lipopolysaccharides (LPS) to induce sepsis, and investigated whether the pretreatment of Lactobacillus rhamnosus GG (LGG) contributed to host survival and examined the alteration of the gut microbiota and blood cytokines/chemokines profile before sepsis induction. Four-week-old male BALB/c mice were divided into two groups: one group were fed daily with LGG as a dietary supplement for fourteen days, whereas the other group with sterile water. Before sepsis induction, some mice from each group were killed to collect stool in the intestine and blood for microbial metagenomic and cytokine/chemokine analyses, respectively, and the rest were monitored afterward for mortality. The relative abundance of several families in the gut microbiota after LGG treatment was altered as well as the ratio of Firmicutes/Bacteroidetes. In addition, several pro-inflammatory cytokines such as G-CSF, IL7, IL15, and MCP1 were lower in the LGG group than in the control group. The survival rate following LPS-induced sepsis improved with LGG treatment. Our results indicated that dietary supplement of probiotic LGG improved survival from LPS-induced sepsis, most likely through pre-septic changes in the gut microbial constituents by LGG with reciprocal alteration of host immune system to a less reactive state to incoming pathogens., Competing Interests: The authors declare that they have no conflict of interest., (© 2021 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Breast cancer intrinsic subtypes have been identified based on the transcription of a predefined gene expression (GE) profiles and algorithm (prediction analysis of microarray 50 gene set, PAM50). The present study compared molecular subtyping with oligonucleotide microarray and NanoString nCounter assay. A total of 109 Taiwanese breast cancers (24 with adjacent normal breast tissues) were assayed with Affymetrix Human Genome U133 plus 2.0 microarrays and 144 were assayed with the NanoString nCounter while 64 patients were assayed for both platforms. Subtyping with the nearest centroid (single sample prediction (SSP)) was performed, and 16 out of 24 (67%) matched normal breasts were categorized as the normal breast-like subtype. For 64 breast cancers assayed for both platforms, 41 (65%, one unclassified by microarray) were predicted with an identical subtype, resulting in a fair κ statistic of 0.60. Taking nCounter subtyping as the gold standard, prediction accuracy was 43% (3/7), 81% (13/16), 25% (5/20), and 100% (20/20) for basal-like, human epidermal growth factor receptor II (HER2)-enriched, luminal A and luminal B subtypes predicted from microarray GE profiles. Microarray identified more luminal B cases from luminal A subtype predicted by nCounter. It is not uncommon to use microarray for breast cancer molecular subtyping for research. Our study showed that fundamental discrepancy existed between distinct GE assays, and cross-platform equivalence should be carefully appraised when molecular subtyping was conducted with oligonucleotide microarray., (© 2021 The Author(s).)

The variability of blood pressure (BPV) has been suggested as a clinical indicator for cognitive dysfunction, yet the results from clinical studies are variable. This study investigated the relationship between BPV and the risk of cognitive decline or dementia. Bibliographic databases, including PubMed, Scopus, and Embase, were searched systematically for longitudinal cohort studies with BPV measurements and neuropsychological examinations or dementia diagnosis. A traditional meta-analysis with subgroup analysis, and a further dose-response meta-analysis were conducted. Twenty cohort studies with 7 924 168 persons were included in this review. The results showed that a higher systolic BPV (SBPV), when measured with the coefficient of variation (SBP-CV) or standard deviation (SBP-SD), was associated with a higher risk of all-cause dementia diagnosis but not incidence of cognitive decline on neuropsychological examinations. In subgroup analysis, the effect was more prominent when using BPV of shorter timeframes, during shorter follow-ups, or among the elderly aged more than 65 years. No dose-response relationship could be found. Our study suggested possible positive associations between SBPV and the risk of dementia. Further studies are required to validate these findings., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Mitochondria play essential roles in regulating cellular functions. Some drug treatments and molecular interventions have been reported to have off-target effects damaging mitochondria and causing severe side effects. The development of a database for the management of mitochondrial toxicity-related molecules and their targets is important for further analyses., Results: To correlate chemical, biological and mechanistic information on clinically relevant mitochondria-related toxicity, a comprehensive mitochondrial toxicity database (MitoTox) was developed. MitoTox is an electronic repository that integrates comprehensive information about mitochondria-related toxins and their targets. Information and data related to mitochondrial toxicity originate from various sources, including scientific journals and other electronic databases. These resources were manually verified and extracted into MitoTox. The database currently contains over 1400 small-molecule compounds, 870 mitochondrial targets, and more than 4100  mitochondrial toxin-target associations. Each MitoTox data record contains over 30 fields, including biochemical properties, therapeutic classification, target proteins, toxicological data, mechanistic information, clinical side effects, and references., Conclusions: MitoTox provides a fully searchable database with links to references and other databases. Potential applications of MitoTox include toxicity classification, prediction, reference and education. MitoTox is available online at http://www.mitotox.org ., (© 2021. The Author(s).)

Breast cancer is the most common female malignancy in Taiwan, while conventional clinical and pathological factors fail to provide full explanation for prognostic heterogeneity. The aim of the study was to evaluate the feasibility of targeted sequencing combined with concurrent genes signature to identify somatic mutations with clinical significance. The extended concurrent genes signature was based on the coherent patterns between genomic and transcriptional alterations. Targeted sequencing of 61 Taiwanese breast cancers revealed 1036 variants, including 76 pathogenic and 545 likely pathogenic variants based on the ACMG classification. The most frequently mutated genes were NOTCH , BRCA1 , AR , ERBB2 , FANCA , ATM , and BRCA2 and the most common pathogenic deletions were FGFR1 , ATM , and WT1 , while BRCA1 (rs1799965), FGFR2 (missense), and BRCA1 (rs1799949) were recurrent pathogenic SNPs. In addition, 38 breast cancers were predicted into 12 high-risk and 26 low-risk cases based on the extended concurrent genes signature, while the pathogenic PIK3CA variant (rs121913279) was significantly mutated between groups. Two deleterious SH3GLB2 mutations were further revealed by multivariate Cox's regression (hazard ratios: 29.4 and 16.1). In addition, we identified several significantly mutated or pathogenic variants associated with differentially expressed signature genes. The feasibility of targeted sequencing in combination with concurrent genes risk stratification was ascertained. Future study to validate clinical applicability and evaluate potential actionability for Taiwanese breast cancers should be initiated.

Background: Metastatic renal cell carcinoma (RCC) often develops resistance to first-line targeted therapy such as sunitinib. G-Protein-coupled estrogen receptor 1 (GPER1) agonist G-1 was recently reported to regulate RCC physiology but the role of G-1 in RCC tumorigenesis and sunitinib resistance remains largely unknown., Materials and Methods: Parental and sunitinib-resistant 786-O cells were treated with GPER1 agonist G-1, and quantitative phosphoproteomics was performed. Bioinformatic analyses and validations, including immunoblotting, cell migration, and cell cycle distribution, were performed., Results: G-1 repressed cell proliferation and migration in both parental and sunitinib-resistant 786-O cells. Phosphoproteomic signatures, including phosphoinositide 3-kinase and protein kinase B (PI3K-AKT) as well as other pathways, were up-regulated in sunitinib-resistant cells but application of G-1 reversed this effect. Among phosphoprotein candidates, activating transcription factor 2 (ATF2) Thr69/71 phosphorylation was antagonistically regulated by sunitinib resistance and G-1., Conclusion: Our results open up the possibility for managing RCC and sunitinib resistance by GPER1 agonist G-1 and its regulated pathways., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The aim of the study was to perform digital RNA counting to validate a gene expression signature for operable breast cancers initially treated with curative intention, and the risk of recurrence, distant metastasis, and mortality was predicted., Methods: Candidate genes were initially discovered from the coherent genomic and transcriptional alternations from microarrays, and the extended concurrent genes were used to build a risk stratification model from archived formalin-fixed paraffin-embedded (FFPE) tissues with the NanoString nCounter., Results: The extended concurrent genes signature was prognostic in 144 Taiwanese breast cancers (5-year relapse-free survival: 89.8 and 69.4% for low- and high-risk group, log-rank test: P = 0.004). Cross-platform comparability was evidenced from significant and positive correlations for most genes as well as equal covariance matrix across 64 patients assayed for both microarray and digital RNA counting., Discussion: Archived FFPE samples could be successfully assayed by the NanoString nCounter. The purposed signature was prognostic stratifying breast cancer patients into groups with distinct survival patterns, and clinical applicability of the residual risk model was proved.

Microcalcification is one of the most common radiological and pathological features of breast ductal carcinoma in situ (DCIS), and to a lesser extent, invasive ductal carcinoma. We evaluated messenger RNA (mRNA) transcriptional profiles associated with ectopic mammary mineralization. A total of 109 breast cancers were assayed with oligonucleotide microarrays. The associations of mRNA abundance with microcalcifications and relevant clinical features were evaluated. Microcalcifications were present in 86 (79%) patients by pathological examination, and 81 (94%) were with coexistent DCIS, while only 13 (57%) of 23 patients without microcalcification, the invasive diseases were accompanied with DCIS (χ 2 -test, P < 0.001). There were 69 genes with differential mRNA abundance between breast cancers with and without microcalcifications, and 11 were associated with high-grade (comedo) type DCIS. Enriched Gene Ontology categories included glycosaminoglycan and aminoglycan metabolic processes and protein ubiquitination, indicating an active secretory process. The intersection (18 genes) of microcalcificaion-associated and DCIS-associated genes provided the best predictive accuracy of 82% with Bayesian compound covariate predictor. Ten genes were further selected for prognostic index score construction, and five-year relapse free survival was 91% for low-risk and 83% for high-risk group (log-rank test, P = 0.10). Our study suggested that microcalcification is not only the earliest detectable radiological sign for mammography screening but the phenomenon itself may reflect the underling events during mammary carcinogenesis. Future studies to evaluate the prognostic significance of microcalcifications are warranted.

Background: The electromechanical activation time (EMAT) normalized by cardiac cycle length (%EMAT) and the third heart sound (S3) strength, as measured by automated acoustic cardiography, are predictive of postdischarge adverse events in patients with acute heart failure (AHF). The aim of this study was to evaluate whether the acoustic cardiography-guided management improves outcomes in patients with AHF when it is compared with the conventional therapy., Methods and Results: This prospective single-blind study randomized 225 patients with AHF (74.1 ± 14.5 years of age, 26.2% women, and left ventricular ejection fraction 38.4 ± 14.4%) before discharge to the EMAT-guided group (n = 114) with the postdischarge treatment goals to reduce %EMAT to < 15% and S3 < 5, and the symptom-guided group (n = 111) to adjust medications without knowledge of the results of acoustic cardiography. The primary endpoints were rehospitalization for heart failure and total mortality during 1-year follow-up. The 2 groups were well matched in age and predischarge %EMAT and S3 strength. After a mean follow-up period of 238.1 ± 140.8 days, a significant reduction in the primary endpoints was seen in the EMAT-guided group compared with the symptom-guided group (43 events vs 61 events, P = 0.0095). Kaplan-Meier curves demonstrated significant differences in the time to first event, favoring the EMAT-guided group in the total study population (n = 225, hazard ratio and 95% confidence interval: 0.61, 0.42-0.91, log-rank P = 0.0129), as well as in the prespecified subgroup of patients with predischarge %EMAT > 15% (n = 85; 0.32, 0.16-0.65, P = 0.0008)., Conclusions: In patients hospitalized due to AHF, EMAT-guided postdischarge management was superior to the conventional symptoms-driven therapy in terms of 1-year outcomes (ClinicalTrials.gov number NCT01298232)., (Copyright © 2019. Published by Elsevier Inc.)

Tumor metastasis or recurrence often occurs in patients with curative resection of colorectal cancer (CRC). Placental-specific 8 (PLAC8), which has increased expression in stool, may be associated with CRC recurrence. Insights into the role of PLAC8 in CRC recurrence and its clinical significance may support to develop strategies for preventing CRC recurrence and deterioration. Clinical tissues, cell and animal models were used to clarify the roles of PLAC8 in CRC tumorigenesis, invasion, and migration. Next-generation sequencing of 16S ribosomal DNA has been used to assess the gut microbiota in stool of CRC patients. We found that PLAC8 was upregulated in tissues from patients with late-stage CRC. In our in vitro studies, PLAC8 was dynamically regulated in mitotic cells. Overexpressed PLAC8 was nucleated at the centrosome during mitosis, and therefore, PLAC8 overexpression might increase cell growth and migration (all p  < 0.05). The tumorigenic and invasive effects of PLAC8 on CRC cells were also confirmed in a xenograft mouse model. We further identified reduced levels of two butyrate-producing organisms, Butyricicoccus and Prevotella spp., in stools from CRC patients. We found that butyrate downregulated PLAC8 expression and induced apoptosis in PLAC8 -overexpressing cells. Our data suggests that PLAC8 gene and protein expression and dysbiosis of gut microflora, especially in butyrate-producing microorganisms, may be indicators of CRC progression., Competing Interests: The authors have declared no conflict of interest., (© 2019 THE AUTHORS. Published by Elsevier BV on behalf of Cairo University.)

End-stage renal disease (ESRD) incidence in Taiwan is highest worldwide. This study analyzed the relationship between health resource use and patients on hemodialysis (HD) asking for medical help as well as the outcomes in Taiwan.This was a retrospective cohort study that analyzed the medical data of patients on dialysis, which were collected from the National Health Insurance Database of Taiwan for the period 2000 to 2010. The study sample was screened out, and new patients starting HD from 2001 to 2005 were considered.The daily distribution of patients with ESRD in the Monday, Wednesday, and Friday (MWF) and Tuesday, Thursday, and Saturday (TTS) groups who underwent emergent HD showed remarkable person-time on Monday and Tuesday, respectively. The disease (complication) distribution in the MWF group was higher than that in the TTS group, and the statistics of heart-failure-associated diseases were significantly different. Considering 5-year survival status, the mortality rate of patients with HD was 21.94% (255 of 1162), among which those with a history of cerebrovascular disease and diabetes were 68.63% and 72.16%, respectively.Long interdialytic intervals may induce emergency dialysis. Therefore, the frequency of emergent HD therapy has increased (thrice a week), as predicted in the current HD policy.

The etiology of early-onset hepatocellular carcinoma (HCC) among hepatitis B virus (HBV) carriers remains unclear. DNA methylation levels in peripheral leukocytes have been associated with different environmental exposures and immune or inflammatory response. We aimed to identify methylation signatures of peripheral leukocytes that could track hepatitis B progression to HCC, especially for early-onset HCC. We first performed an epigenome-wide association analysis on 48 matched case-control pairs in a nested case-control study within a 22-yr follow-up cohort of HBV carriers. Through this analysis we found that progression to early-onset HCC involved methylation variable positions across the genome, in which a substantial proportion displayed significant variation due to HBV viral load, chronic hepatitis status, and/or leukocyte subtype composition, and these associations were significantly enriched among genes in immune pathways. Methylation at probes cg00300879, cg06872964, and cg07080864, that are located within the proximal promoter of CNKSR1, IFI44L, and PENK, respectively, was validated by bisulfite pyrosequencing and findings were replicated in a case-sibling study of early-onset HCC (134 cases vs. 174 sibling controls). Furthermore, a high methylation score, constructed using the three probes, was predictive for the risk of early-onset HCC in two datasets (adjusted-odds ratios = 0.21-0.32, P ≤ 0.0206). This association was also observed for late-onset HCC (adjusted-odds ratio = 0.42-0.47, P ≤ 0.0194) in a nested case-control study (120 cases vs. 178 controls). In prospective analysis, change in the score was detected 5-9 yr before HCC onset. Blood-based methylation profiling provides new insights into the complexity of virus-host interaction underlying HBV-related HCC, holding promise for the disease risk management. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Numerous mechanical biomarkers derived from pulse wave analysis (PWA) have been proposed to predict cardiovascular outcomes. However, whether these biomarkers carry independent prognostic value and clinical utility beyond traditional cardiovascular risk factors hasn't been systematically evaluated. We aimed to investigate the additive utility of PWA-derived biomarkers in two independent population-based cohorts., Methods: PWA on central arterial pressure waveforms obtained from subjects without a prior history of cardiovascular diseases of two studies was conducted based on the wave transmission and reservoir-wave theory: firstly in the Kinmen study (1272 individuals, a median follow-up of 19.8years); and then in the Cardiovascular Disease Risk Factors Two-Township Study (2221 individuals, median follow-up of 10years). The incremental value of the biomarkers was evaluated by net reclassification index (NRI)., Results: In multivariate Cox analyses accounting for age, gender, body mass index, systolic blood pressure, fasting glucose, high-density- and low-density-lipoprotein cholesterol, and smoking, only systolic (SC) and diastolic rate constant (DC) of reservoir pressure could independently and consistently predict cardiovascular mortality in both cohorts and the combined cohort (SC: hazard ratio 1.18 [95% confidence interval 1.08-1.28, p<0.001; DC: 1.18 [1.09-1.28], p<0.001]. Risk prediction estimates in traditional risk prediction models were significantly more accurate when incorporating peak of reservoir pressure (NRI=0.049, p=0.0361), SC (NRI=0.043, p=0.0236) and DC (NRI=0.054, p=0.047)., Conclusions: Of all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: It has been proposed that 17-β-estradiol (E2) activates estrogen receptor and inhibits renal cell carcinoma (RCC) growth. In the present study we explored the role of E2 and ER in the regulation of RCC growth., Materials and Methods: The RCC cell line ACHN was treated by E2 combining with E2 antagonist Fulvestrant or ER knockdown, and cell growth was monitored. Quantitative phosphoproteomics was applied to study the E2 regulated non-genomic phosphorylation changes. Western blotting, immunofluorescence microscopy, and apoptosis assays were used for validation., Results: E2 induced ER-dependent growth inhibition in RCC cell lines. Quantitative phosphoproteomics revealed that E2 induced both apoptosis and autophagy. Cellular apoptosis was confirmed by altered mitochondrial membrane potential, and ER-dependent autophagosome formation was also found., Conclusion: Our data revealed the potential dual roles of E2 in regulating RCC growth via autophagy and apoptosis pathways., (Copyright© 2016, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.)

Several prognostic signatures have been identified for breast cancer. However, these signatures vary extensively in their gene compositions, and the poor concordance of the risk groups defined by the prognostic signatures hinders their clinical applicability. Breast cancer risk prediction was refined with a novel approach to finding concordant genes from leading edge analysis of prognostic signatures. Each signature was split into two gene sets, which contained either up-regulated or down-regulated genes, and leading edge analysis was performed within each array study for all up-/down-regulated gene sets of the same signature from all training datasets. Consensus of leading edge subsets among all training microarrays was used to synthesize a predictive model, which was then tested in independent studies by partial least squares regression. Only a small portion of six prognostic signatures (Amsterdam, Rotterdam, Genomic Grade Index, Recurrence Score, and Hu306 and PAM50 of intrinsic subtypes) was significantly enriched in the leading edge analysis in five training datasets (n = 2,380), and that the concordant leading edge subsets (43 genes) could identify the core signature genes that account for the enrichment signals providing prognostic power across all assayed samples. The proposed concordant leading edge algorithm was able to discriminate high-risk from low-risk patients in terms of relapse-free or distant metastasis-free survival in all training samples (hazard ratios: 1.84-2.20) and in three out of four independent studies (hazard ratios: 3.91-8.31). In some studies, the concordant leading edge subset remained a significant prognostic factor independent of clinical ER, HER2, and lymph node status. The present study provides a statistical framework for identifying core consensus across microarray studies with leading edge analysis, and a breast cancer risk predictive model was established.

Naphtho[1,2-b] furan-4,5-dione (NFD) was investigated for its anti-proliferation effect on human hepatocellular carcinoma (HCC), Hep3B, HepG(2), and Huh-7 cells. The effect of NFD on inhibiting proliferation and apoptosis was correlated with up-regulation of pro-apoptotic protein and down-regulation of pro-survival proteins. Remarkably, we found that NFD inhibited the nuclear translocation of NF-kappaB, likely accounting for the down-regulation of pro-survival Bcl-2 family. Furthermore, suppression of p38 MAPK activity by a specific inhibitor significantly rescued the cell proliferation inhibited by NFD. These findings suggest that signaling imbalance between p38 MAPK and NF-kappaB by NFD results in the proliferative inhibition and apoptosis of HCC tumor cells., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background/aims: We attempted to specifically quantify transcripts of faecal cytokeratin 19 (CK19) and ribosomal protein L19 (RPL19) RNA expression of colorectal cancer and clarify their correlation with clinicopathological parameters and survival in combination., Methodology: Solid fecal samples were collected and preserved before any treatment. Levels of faecal CK19 and RPL19 mRNA were measured using quantitative real-time PCR. An expression level higher than median value was defined as positive., Results: Between April 2001 and June 2007, 92 patients were recruited. The levels of both markers increased in a trend as stage. Young patients (< 67 years) were correlated with higher rate of CK19+ (p = 0.001), so were higher stages but with borderline significance (p = 0.051). CK19+ and RPL19+ were highly correlated mutually (p = 0.001). Neither CK19+ (p = 0.12) nor RPL19+ (p = 0.14) alone was a prognostic factor of disease-free interval. However, CK19+/RPL19+ was shown to be with worse prognosis (p = 0.037), but not an independent factor in multivariate analysis with stage., Conclusions: Both markers were significantly higher in the patients of metastatic disease. The use of two markers will recognize the high risk group better than the single marker usage, though not reaching independent status yet. Multi-target strategy assay is suggested for fecal RNA examination.