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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common life-threatening malignances worldwide. CRC relapse markedly decreases the 5-year survival of patients following surgery. Aberrant expression of genes involved in pathways regulating the cell cycle, cell proliferation, or cell death are frequently reported in CRC tumorigenesis. We hypothesized that genes involved in CRC relapse might serve as prognostic indicators. We first evaluated the significance of gene sequences in the feces of patients with CRC relapse by consulting a public database. Tumorigenesis of target tissues was tested through tumor cell growth, cell cycle regulation, and chemotherapeutic efficacy. We found a highly significant correlation between CRC relapse and growth arrest-specific 2 (GAS2) gene expression. Based on cell models, the overexpressed GAS2 was associated with cellular growth rate, cell cycle regulation, and with chemotherapeutic sensitivity. Cell division was impaired by treating cells with 2-[4-(7-chloro-2-quinoxalinyloxy)phenoxy]-propionic acid (XK469), even when the cells were overexpressing GAS2. Thus, downregulation of GAS2 expression might control CRC relapse after curative resection. GAS2 could serve as a noninvasive marker from the feces of patients with prediagnosed CRC. Our findings suggest that GAS2 could have potential clinical applications for predicting early CRC relapse after radical resection, and that XK469 might impair tumor cell division by reducing GAS2 expression or blocking its cellular translocation. This will help in selecting the best therapeutic option, 5-fluorouracil in combination with XK469, for patients overexpressing GAS2 in CRC cells. Thus, GAS2 might act as a prognostic biomolecule and potential therapeutic target in patients with CRC relapse. [ABSTRACT FROM AUTHOR]

Objective: The hepatitis B virus (HBV)-polymerase region overlaps pre-S/S genes with high epitope density and plays an essential role in viral replication. We investigated whether genetic variation in the polymerase region determined long-term dynamics of viral load and the risk of hepatitis B progression in a population-based cohort study. Methods: We sequenced the HBV-polymerase region using baseline plasma from treatment-naïve individuals with HBV-DNA levels≥1000 copies/mL in a longitudinal viral-load study of participants with chronic HBV infection followed-up for 17 years, and obtained sequences from 575 participants (80% with HBV genotype Ba and 17% with Ce). Results: Patterns of viral sequence diversity across phases (i.e., immune-tolerant, immune-clearance, non/low replicative, and hepatitis B e antigen (HBeAg)-negative hepatitis phases) of HBV-infection, which were associated with viral and clinical features at baseline and during follow-up, were similar between HBV genotypes, despite greater diversity for genotype Ce vs. Ba. Irrespective of genotypes, however, HBeAg-negative participants had 1.5-to-2-fold higher levels of sequence diversity than HBeAg-positive participants (P<0.0001). Furthermore, levels of viral genetic divergence from the population consensus sequence, estimated by numbers of nucleotide substitutions, were inversely associated with long-term viral load even in HBeAg-negative participants. A mixed model developed through analysis of the entire HBV-polymerase region identified 153 viral load-associated single nucleotide polymorphisms in overall and 136 in HBeAg-negative participants, with distinct profiles between HBV genotypes. These polymorphisms were most evident at sites within or flanking T-cell epitopes. Seven polymorphisms revealed associations with both enhanced viral load and a more than 4-fold increased risk of hepatocellular carcinoma and/or liver cirrhosis. Conclusions: The data highlight a role of viral genetic divergence in the natural course of HBV-infection. Interindividual differences in the long-term dynamics of viral load is not only associated with accumulation of mutations in HBV-polymerase region, but differences in specific viral polymorphisms which differ between genotypes. [ABSTRACT FROM AUTHOR]

Background: The development and progression of colorectal cancer (CRC) involve a complex process of multiple genetic changes. Tumor suppressor p53 is capable of determining the fate of CRC cells. However, the role of a p53-inducible modulator, ribosomal protein S27-like (RPS27L), in CRC is unknown. Methods: Here, the differential expression of RPS27L was examined in the feces and colonic tissues of CRC patients, to explore its possible correlation with patient survival and to investigate the cellular mechanisms underlying their clinical outcomes. Eighty intermediate-stage CRC patients (42 at stage II and 38 at stage III) were divided into two groups according to their fecal RPS27L mRNA levels. The survival probabilities of the groups were estimated using the Kaplan–Meier method. The RPS27L protein in the colonic tissues of stage III patients with different prognoses was further examined immunohistochemically. RPS27L expression in LoVo cells was manipulated to examine the possible cellular responses in vitro. Results: Elevated RPS27L expression, in either feces or tissues, was related to a better prognosis. In vitro, RPS27L-expressing LoVo cells ceased DNA synthesis and apoptotic activity while the expression of their DNA repair molecules was upregulated. Conclusions: Elevated RPS27L may improve the prognoses of certain CRC patients by enhancing the DNA repair capacity of their colonic cells, and can be determined in feces. By integrating clinical, molecular, and cellular data, our study demonstrates that fecal RPS27L may be a useful index for predicting prognoses and guiding personalized therapeutic strategies, especially in patients with intermediate-stage CRC. [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: This study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA). Materials and methods: The promoter methylation statuses of 40 genes in primary ovarian carcinomas including 47 clear- and 63 non-clear-cell type tissues, 6 OCCA cell lines, 29 benign ovarian endometriotic cysts, and 31 normal controls were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The MS-MLPA results were correlated with clinicopathological features and outcomes of 47 OCCA patients. Functions of the target genes were further explored by Western Blot Analysis, apoptosis assay, and caspase-3/7 activity analysis.Results: Frequencies of methylated RASSF1A, CDH13, CACNA1A, HIN-1, and sFRP5 genes in OCCA tissues were significantly higher than those in non-OCCA cancerous tissues and benign endometriotic cysts. The expected OS for patients with methylated promoters of HIN-1 was significantly worse than those for patients without methylated HIN-1 (30% vs. 62%, p = 0.002). The HIN-1 gene was over-expressed in ES2 cells, a significant reduction in cell growth and induction of apoptosis, and increasing paclitaxel sensitivity by reducing phosphorylation of Akt were observed. Conclusions: Methylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in OCCA patients. Ectopic expression of the HIN-1 gene increased paclitaxel sensitivity which is partly through Akt pathway. [ABSTRACT FROM AUTHOR]

Introduction: Coxsackievirus/adenovirus receptors (CARs) and desmoglein-2 (DSG2) are similar molecules to adenovirus-based vectors in the cell membrane. They have been found to be associated with lung epithelial cell tumorigenesis and can be useful markers in predicting survival outcome in lung adenocarcinoma (LUAD). Methods: A gene ontology enrichment analysis disclosed that DSG2 was highly correlated with CAR. Survival analysis was then performed on 262 samples from the Cancer Genome Atlas, forming "Stage 1A" or "Stage 1B". We therefore analyzed a tissue microarray (TMA) comprised of 108 lung samples and an immunohistochemical assay. Computer counting software was used to calculate the H-score of the immune intensity. Cox regression and Kaplan–Meier analyses were used to determine the prognostic value. Results: CAR and DSG2 genes are highly co-expressed in early stage LUAD and associated with significantly poorer survival (p = 0.0046). TMA also showed that CAR/DSG2 expressions were altered in lung cancer tissue. CAR in the TMA was correlated with proliferation, apoptosis, and epithelial–mesenchymal transition (EMT), while DSG2 was associated with proliferation only. The Kaplan–Meier survival analysis revealed that CAR, DSG2, or a co-expression of CAR/DSG2 was associated with poorer overall survival. Conclusions: The co-expression of CAR/DSG2 predicted a worse overall survival in LUAD. CAR combined with DSG2 expression can predict prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the association between survival outcome and the new grading system among advanced stage lung adenocarcinoma (LADC) (stages IIIA, IIIB and IV) patients who were diagnosed as LADC with a pathologic report according to a new grading system by the International Association for the Study of Lung Cancer (IASLC) pathology committee. The results indicate that the poorly differentiated group had a poorer prognosis in PFS, as did patients with wild-type EGFR who were treated with chemotherapy. No survival difference could be found among EGFR mutation patients. Older age and a lower body mass index also led to worse survival. Patients with poorly differentiated adenocarcinoma likewise had worse survival, especially compared to those with moderately differentiated adenocarcinoma. Our findings highlight that the therapeutic regimen should be adjusted for wild-type EGFR patients with poorly differentiated adenocarcinoma treated with chemotherapy to provide better outcomes. No survival difference could be seen among EGFR mutation patients. The impact of the new International Association for the Study of Lung Cancer pathology committee grading system for advanced lung adenocarcinoma (LADC) on survival is unclear, especially in Asian populations. In this study, we reviewed the prognostic outcomes of patients with late-stage disease according to the new grading system. We reviewed 136 LADC cases who underwent a small biopsy from 2007 to 2018. Tumors were classified according to the new grading system for LADC. Baseline characteristics (age, sex, smoking status, body mass index, and driver gene mutations) were analyzed. Kaplan–Meier and Cox regression analyses were used to determine correlations with the new grading system and prognosis. Patients with poorly differentiated adenocarcinoma were significantly correlated with a poor progression-free survival (PFS) (p = 0.013) but not overall survival (OS) (p = 0.154). Subgroup analysis showed that wild-type EGFR patients with poorly differentiated adenocarcinoma treated with chemotherapy had significantly worse PFS (p = 0.011). There was no significant difference in survival among the patients with epidermal growth factor receptor mutations who were treated with tyrosine kinase inhibitors. Patients aged >70 years and those with a BMI ≤ 25 kg/m2 and wild-type patients had significantly worse OS in both univariate (HR = 1.822, p = 0.006; HR = 2.250, p = 0.004; HR = 1.537, p = 0.046, respectively) and multivariate analyses (HR = 1.984, p = 0.002; HR = 2.383, p = 0.002; HR = 1.632, p = 0.028, respectively). Despite therapy, patients with poorly differentiated tumors still fared worse than those with better differentiated tumors. No differences were found among the EGFR mutations treated with TKI. Our findings highlight that the therapeutic regimen should be adjusted for EGFR Wild-type patients with poorly differentiated adenocarcinoma treated with chemotherapy to provide better outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The present study investigated the prognostic values for office brachial (OB), office central (OC), and ambulatory daytime brachial (AmDB) hypertension, as defined by a unifying threshold of 130/80 mmHg, and the incremental value of either OC or AmDB hypertension to OB hypertension. A total of 1219 community residents without receiving anti‐hypertensive treatment (671 men and 548 women, aged ≥ 30 years old) from central Taiwan and Kinmen islands had OB, OC, and AmDB blood pressure measurements during a cardiovascular survey conducted in 1992–1993. OB hypertension, OC hypertension, and AmDB hypertension were all defined in retrospect at the threshold of 130/80 mmHg. They were followed up for nonfatal and fatal cardiovascular events until December 31, 2017, by linking the baseline database to the National Health Insurance Research dataset and the National Death Registry. During a follow‐up of 25 612.5 person‐years (Average event‐free time: 21.0 years), there were 368 fatal and nonfatal cardiovascular events. In multivariable analyses, OB hypertension, OC hypertension, and AmDB hypertension had similar hazard ratios for cardiovascular events [2.03, 95% confidence interval: 1.47‐2.80]; 1.92 (1.47‐2.51); and 1.79 (1.41‐2.29), respectively. Using OB normotension as the reference, either the concordant OB and OC hypertension [2.24 (1.61‐3.12)], or the concordant OB and AmDB hypertension [2.52 (1.80‐3.54)] was significantly associated with cardiovascular events. Moreover, OB hypertension plus AmDB normotension was also significantly associated with increased risk for cardiovascular events. We concluded that OB hypertension, OC hypertension, and AmDB hypertension defined by a unifying threshold of 130/80 mmHg may provide similar estimates of long‐term risk for cardiovascular events. Cross‐classification analyses suggest that addition of OC hypertension or AmDB hypertension may improve the prognostic value of OB hypertension. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 R2 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 (R2 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 (R2 analog = 0.911). Furthermore, the change in PVR was with the highest explanatory power for total mortality of PAH patients (R2 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 [ABSTRACT FROM AUTHOR]

Background: The prognostic value of chronic obstructive pulmonary disease (COPD) as a comorbidity in heart failure has been well documented. However, the role of pulmonary function indices in patients with heart failure and preserved ejection fraction (HFpEF) remains to be elucidated. Methods: Subjects with HFpEF received pulmonary function tests and echocardiogram. Total lung capacity (TLC), residual volume (RV), forced expiratory flow rate between 25% and 75% of vital capacity (FEF25-75), forced expiratory volume in the 1st second (FEV1), forced vital capacity (FVC), and vital capacity (VC) were measured. Echocardiographic indices, including pulmonary artery systolic pressure (PASP), the ratio of early ventricular filling flow velocity to the septal mitral annulus tissue velocity (E/e'), and left ventricular mass (LVM), were recorded. National Death Registry was linked for the identification of mortality. Results: A total of 1194 patients (72.4±13.2 years, 59% men) were enrolled. PASP, E/e' and LVM were associated with either obstructive (RV/TLC, FEV1 and FEF25-75) or restrictive (VC and TLC) ventilatory indices. During a mean follow-up of 23.0±12.8 months, 182 patients died. Subjects with COPD had a lower survival rate than those without COPD. While VC, FVC, RV/TLC, and FEV1 were all independently associated with all-cause mortality in patients without COPD, only FEF25-75 was predictive of outcomes in those with COPD. Conclusions: The abnormalities of pulmonary function were related to the cardiac hemodynamics in patients with HFpEF. In addition, these ventilatory indices were independently associated with long-term mortality, especially in those without COPD. [ABSTRACT FROM AUTHOR]

• Genes from stools have molecular significance with CRC tumorgenesis. • SCFAs, the metabolites of microbiota, can suppress CRC tumorigenesis. • Relationship between colonic genes, gut microbiota, or their metabolites is significant. • Changes of PLAC8 and butyrate-producing organisms were found in stools of CRC patients. • Butyrate can reduce the CRC formation through regulating PLAC8 expression. 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. [ABSTRACT FROM AUTHOR]

Background: Heart failure with mid-range ejection fraction (HFmrEF) has been proposed as a new phenotype of heart failure. We therefore investigated the pulsatile hemodynamic characteristics and outcomes in patients with HFmrEF, in comparison with those with reduced (HFrEF) or preserved (HFpEF) ejection fraction. Methods: The study was composed of two cohorts of patients hospitalized due to acute heart failure. Pulsatile hemodynamic measures, including carotid-femoral pulse wave velocity (cf-PWV), carotid pulse pressure (cPP), amplitude of the backward pressure wave (Pb) and carotid augmentation index (cAIx), were recorded on admission and before discharge in Cohort A (n = 230, mean age 69.9 ±15.4 years), and long-term follow-up was performed in Cohort B (n = 2677, mean age 76.3 ± 33.4 years). Results: In Cohort A, patients with HFmrEF had persistently greater cf-PWV, cPP, Pb, and cAI than those with HFrEF, both on admission and before discharge. In contrast, patients with HFmrEF and HFpEF had similar pulsatile hemodynamic characteristics. In cohort B, patients with HFmrEF and HFrEF had similar three-year mortality rates and both were significantly higher than that in patients with HFpEF (both P values < 0.05). Conclusions: Patients with HFmrEF were characterized by a worse left ventricular systolic function than patients with HFpEF and excessive wave reflections than patients with HFrEF. Future studies are required to confirm that the unfavorable ventriculo-arterial coupling in HFmrEF might play a role in the pathogenesis of high long-term mortality in these patients. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide. The poor specificity and sensitivity of the fecal occult blood test has prompted the development of CRC-related genetic markers for CRC screening and treatment. Gene expression profiles in stool specimens are effective, sensitive and clinically applicable. Herein, a novel advantage of using cells shed from the colon is presented for cost-effective CRC screening. Molecular panels were generated through a series of leave-one-out cross-validation and discriminant analyses. A logistic regression model following reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry was used to validate a specific panel for CRC prediction. The panel, consisting of ubiquitin-conjugating enzyme E2 N (UBE2N), inosine monophosphate dehydrogenase 1 (IMPDH1), dynein cytoplasmic 1 light intermediate chain 1 (DYNC1LI1) and phospholipase A and acyltransferase 2 (HRASLS2), accurately recognized patients with CRC and could thus be further investigated as a potential prognostic and predictive biomarker for CRC. UBE2N, IMPDH1 and DYNC1LI1 expression levels were upregulated and HRASLS2 expression was downregulated in CRC tissues. The predictive power of the panel was 96.6% [95% confidence interval (CI), 88.1-99.6%] sensitivity and 89.7% (95% CI, 72.6-97.8%) specificity at a predicted cut-off value at 0.540, suggesting that this four-gene panel testing of stool specimens can faithfully mirror the state of the colon. On the whole, the present study demonstrates that screening for CRC or cancer detection in stool specimens collected non-invasively does not require the inclusion of an excessive number of genes, and colonic defects can be identified via the detection of an aberrant protein in the mucosa or submucosa. [ABSTRACT FROM AUTHOR]

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]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the incidence of thyroid cancer is increasing, improvements in treatment have resulted in more patients being confirmed to have a second primary cancer. However, studies on potential biomarkers for predicting the risk of second primary malignancy are extremely limited. Therefore, our objective was to establish molecular biomarkers for the risk prediction of second primary malignancy using routinely collected formalin-fixed paraffin-embedded tissue specimens. Our results suggest that the deficient mismatch repair phenotype, the expression of pRb, and the lack of CDK4 or CDK6 are significantly associated with co-occurrence of nonthyroid malignancy. The predictive value of these immunohistochemical profiles for the co-occurrence of nonthyroid malignancy was also assessed. The combined evaluation of a four-biomarker signature model may provide the most important predictive innovation. Our study proposes the first tissue-based screening tool for risk stratification and further active surveillance in patients with thyroid cancer. 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. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the association of fasting insulin and glucose levels with hepatocellular carcinoma (HCC) risk in a case–cohort study within a cohort (1989–2006) of 2903 male government employees chronically infected with hepatitis B virus (HBV) in Taiwan. Insulin, glucose and HBV-related factors were assayed in baseline plasma among 124 HCC cases and a random subcohort of 1084 of the total cohort. After adjustment for demographics and HBV-related factors, including viral load and genotype, the HCC risk was higher for the highest [>6.10 μU/ml, hazard ratio (HR) = 2.36, 95% confidence interval (CI): 1.43–3.90] and lowest (<2.75 μU/ml, HR = 1.57, 95% CI: 0.96–2.58) categories of insulin, compared with insulin of 2.75–4.10 μU/ml. The dose–response relationship between insulin and HCC varied by follow-up time, with stronger association for the HCC cases that occurred ≥8 years after baseline (P for trend <0.0001). The effect of higher insulin on HCC risk remained after adjustment for other metabolic factors, and was fairly consistent across strata of age, body mass index, and HBV genotypic variants. However, it was more profound among those with viral load <4.39 log10 copies/ml at recruitment (>6.10 μU/ml, HR = 6.15, 95% CI: 2.48–15.22). Higher insulin was also associated with an increased risk for cirrhosis diagnosed by ultrasonography and elevated alanine aminotransferase. No association with either cirrhosis or HCC was noted for glucose or diabetes after adjusting for insulin. In conclusion, elevated insulin levels are an independent risk factor for HCC among HBV carriers, especially for those with lower viral load. [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]

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. [ABSTRACT FROM AUTHOR]

Gut microbes influence tumor development and progression in the intestines and may provide a novel paradigm for the treatment of colorectal cancer (CRC). Gut dysbiosis may be associated with the development and progression of CRC. Identifying the interactions between the colonic tract and gut microbiota may provide novel information relevant to CRC prevention. The present study examined the effects of butyrate-producing Butyricicoccus pullicaecorum (B. pullicaecorum) on mice with 1,2-dimethylhydrazine (DMH)-induced CRC and the microbial metabolite of B. pullicaecorum on CRC cells. Immunohistochemical staining of the mouse colon tissues and reverse transcription PCR of CRC cells were used to determine the protein and mRNA expression levels of the short-chain fatty acid (SCFA) transporter solute carrier family 5 member 8 (SLC5A8) and G-protein-coupled receptor 43 (GPR43). In CRC-bearing mice fed B. pullicaecorum, DMH-induced CRC regressed, body weight increased and serum carcinoembryonic antigen levels decreased. Notably, SLC5A8 and GPR43 were diffusely and moderately to strongly expressed in the neoplastic epithelial cells and underlying muscularis propria in the colons of the mice. In conclusion, administration of B. pullicaecorum or its metabolites improved the clinical outcome of CRC by activating the SCFA transporter and/or receptor. These results indicated that B. pullicaecorum was a probiotic with anti-CRC potential. [ABSTRACT FROM AUTHOR]

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 (χ2-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. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disorder with a pathogenesis involving the interleukin-23/interleukin-17 axis. Salvianolic acid B exerts several pharmacological effects, such as antioxidation, anti-inflammation, and antitumor effects. The anti-psoriatic effects of salvianolic acid B have not been reported. In this study, we aimed to determine the optimum vehicle for salvianolic acid B, investigate its therapeutic effect on psoriatic-like skin conditions, and explore its underlying mechanisms of action. BALB/c mice were administered topical imiquimod to induce psoriasis-like skin and were then randomly assigned to control, vehicle control, salvianolic acid B in vehicles, and 0.25% desoximetasone ointment treatment groups. Barrier function, cytokine expression, histology assessment, and disease severity were evaluated. The results showed that salvianolic acid B-containing microemulsion alleviated disease severity, reduced acanthosis, and inhibited interleukin-23/interleukin-17 (IL-23/IL-17) cytokines, epidermal proliferation, and increased skin hydration. Our study suggests that salvianolic acid B represents a possible new therapeutic drug for the treatment of psoriasis. In addition, such formulation could obtain high therapeutic efficacy in addition to providing sufficient hydration for dry skin. [ABSTRACT FROM AUTHOR]

The interplay between copy number variation (CNV) and differential gene expression may be able to shed light on molecular process underlying breast cancer and lead to the discovery of cancer-related genes. In the current study, genes concurrently identified in array comparative genomic hybridization (CGH) and gene expression microarrays were used to derive gene signatures for Han Chinese breast cancers. We performed 23 array CGHs and 81 gene expression microarrays in breast cancer samples from Taiwanese women. Genes with coherent patterns of both CNV and differential gene expression were identified from the 21 samples assayed using both platforms. We used these genes to derive signatures associated with clinical ER and HER2 status and disease-free survival. Distributions of signature genes were strongly associated with chromosomal location: chromosome 16 for ER and 17 for HER2. A breast cancer risk predictive model was built based on the first supervised principal component from 16 genes (RCAN3, MCOLN2, DENND2D, RWDD3, ZMYM6, CAPZA1, GPR18, WARS2, TRIM45, SCRN1, CSNK1E, HBXIP, CSDE1, MRPL20, IKZF1, and COL20A1), and distinct survival patterns were observed between the high- and low-risk groups from the combined dataset of 408 microarrays. The risk score was significantly higher in breast cancer patients with recurrence, metastasis, or mortality than in relapse-free individuals (0.241 versus 0, P<0.001). The concurrent gene risk predictive model remained discriminative across distinct clinical ER and HER2 statuses in subgroup analysis. Prognostic comparisons with published gene expression signatures showed a better discerning ability of concurrent genes, many of which were rarely identifiable if expression data were pre-selected by phenotype correlations or variability of individual genes. We conclude that parallel analysis of CGH and microarray data, in conjunction with known gene expression patterns, can be used to identify biomarkers with prognostic values in breast cancer. [ABSTRACT FROM AUTHOR]