Compelling evidence has implicated the Wnt signaling pathway in the pathogenesis of colorectal cancer. We assessed the use of tag single nucleotide polymorphisms (tSNPs) in adenomatous polyposis coli ...(APC)/β-catenin (CTNNB1) genes to predict outcomes in patients with colorectal cancer. We selected and genotyped 10 tSNP to predict common variants across entire APC and CTNNB1 genes in 282 colorectal cancer patients. The associations of these tSNPs with distant metastasis-free survival and overall survival were evaluated by Kaplan-Meier analysis, Cox regression model, and survival tree analysis. The 5-year overall survival rate was 68.3%. Survival tree analysis identified a higher-order genetic interaction profile consisting of the APC rs565453, CTNNB1 2293303, and APC rs1816769 that was significantly associated with overall survival. The 5-year survival overall rates were 89.2%, 66.1%, and 58.8% for the low-, medium-, and high-risk genetic profiles, respectively (log-rank P = 0.001). After adjusting for possible confounders, including age, gender, carcinoembryonic antigen levels, tumor differentiation, stage, lymphovascular invasion, perineural invasion, and lymph node involvement, the genetic interaction profile remained significant. None of the studied SNPs were individually associated with distant metastasis-free survival and overall survival. Our results suggest that the genetic interaction profile among Wnt pathway SNPs might potentially increase the prognostic value in outcome prediction for colorectal cancer.
Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, ...we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.
Osteoporosis is a common comorbidity in non-cystic fibrosis (non-CF) bronchiectasis patients. We determined whether desaturation during 6-min walk test (6MWT) can be a predictor for osteoporosis ...risk.
This was a retrospective cross-sectional study. Sixty-six non-CF bronchiectasis patients were enrolled. Lung function, walking distance, the lowest oxygen saturation (SpO
), the fall in SpO
(ΔSpO
), and the distance-saturation product (DSP) were determined during the 6MWT. Desaturators (n = 45) were defined as those with ΔSpO
> 10% or the lowest SpO
< 88%. Bone mineral density (BMD) was determined through dual-energy X-ray absorptiometry. The severity of non-CF bronchiectasis was evaluated using high-resolution computed tomography.
Osteoporosis was evident in more desaturators (82%) than non-desaturators (43%, p < 0.01). BMD at the level of the femoral neck was significantly lower in desaturators than in non-desaturators (- 3.6 ± 1.1 vs. - 2.4 ± 0.9, p < 0.01). BMD was correlated positively with the lowest SpO
and negatively with ΔSpO
and severe exacerbations. In multivariate linear regression analysis, desaturation during 6MWT was the most significant predictive factor for osteoporosis (95% confidence interval - 1.60 to - 0.26, p = 0.01). Other risk factors included old age, low body mass index and severe exacerbation.
Exertional desaturation during the 6MWT was a significant predictive factor for osteoporosis in Asian non-CF bronchiectasis patients. The 6MWT may be useful in identifying the osteoporotic phenotype of non-CF bronchiectasis and increasing clinician awareness to promote early intervention.
Background
Conventional supine emergence and prone extubation from general endotracheal anesthesia (GEA) are associated with extubation-related adverse events (ERAEs). Given the minimally invasive ...nature of endoscopic retrograde cholangiopancreatography (ERCP) as well as the improved ventilation/perfusion matching and easier airway opening in the prone position, we aimed to assess the safety of prone emergence and extubation in patients undergoing ERCP under GEA.
Methods
Totally, 242 eligible patients were recruited and randomized into the supine extubation group (
n
= 121; supine group) and the prone extubation group (
n
= 121; prone group). The primary endpoint was the incidence of ERAEs during emergence, including hemodynamic fluctuations, coughing, stridor, and hypoxemia requiring airway maneuvers. The secondary endpoints included the incidence of monitoring disconnections, extubation time, recovery time, room exit time, and post-procedure sore throat.
Results
The incidence of ERAEs was significantly lower in the prone group compared with the supine group (8.3% vs 34.7%, OR = 0.17, 95% CI 0.18–0.56;
P
< 0.001). Moreover, the prone group demonstrated no monitoring disconnections, shorter extubation time and room exit time, faster recovery, and, lower frequency and milder sore throat after the procedure.
Conclusions
For patients undergoing ERCP under GEA, compared with supine, prone emergence, and extubation had remarkably lower rates of EAREs and better recovery, and can maintain continuous monitoring and improve efficiency.
Graphical abstract
This study aims to investigate dietary and nutritional biochemistry profiles of attention-deficit/hyperactivity disorder (ADHD) and to explore their potential relationship by path analysis. We ...enrolled 216 children with ADHD and 216 age-, height- and gender-matched controls from 31 elementary schools in Taiwan. Dietary intake of the participants was assessed using a food frequency questionnaire (FFQ). Fasting blood samples were collected to determine the serum levels of multiple nutritional markers. Moreover, we employed a structural equation model (SEM) to link diet, nutritional markers and ADHD. Compared to healthy control, ADHD children had significantly lower serum levels of vitamin B12, folate, vitamin B6, ferritin concentration, and monounsaturated fatty acids (MUFA), but higher levels of serum saturated fatty acids (SFA), n-6/n-3 fatty acid ratio, and inorganic phosphorous concentration. Children with ADHD had more intake of nutrient-poor foods such as high sugar and high fat foods, and had less intake of vegetable, fruit, protein-rich foods than their counterpart. SEM analysis showed that the poor nutritional biochemistry profiles linked the association between unhealthy dietary patterns and ADHD. In conclusion, an unhealthy dietary pattern may be a predecessor of the poor nutritional biochemistry status, and managing diet and nutrition conditions should be considered to improve ADHD symptoms in children.
•PANC1 and invasive PANC1-I5, as a model system toinvestigate the metastatic mechanism•88 proteins are differentially expressed between PANC1-I5 and PANC1 cells•galectin-1 is one of the potential ...players in modulating pancreatic cancer metastasis
Cancer metastasis is the major cause of death in pancreatic cancer. We have established a pair of pancreatic ductal adenocarcinoma cell line, PANC1 and invasive PANC1-I5, as a model system toinvestigate the metastatic mechanism as well as potential therapeutic targets in pancreatic cancer. We used proteomic analysis based on two-dimensional differential gel electrophoresis (2D-DIGE) and matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry (MALDI-TOF MS) to examine the global protein expression alterations between PANC1 and PANC1-I5. Proteomic study revealed that 88 proteins are differentially expressed between PANC1-I5 and PANC1 cells, and further functional evaluations through protein expression validation, gene knockout, migration and invasion analysis revealed that galectin-1 is one of the potential players in modulating pancreatic cancer metastasis. To conclude, we have identified numerous proteins might be associated with pancreatic cancer invasiveness in the pancreatic cancer model.
Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and ...dementia; however, the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice.
All ApoE-TR mice exposed to CUMS at 3 months old recovered from a depression-like state by the age of 12 months. Of note, ApoE4-TR mice, unlike age-matched ApoE3-TR mice, displayed impaired spatial cognitive abilities, loss of GABAergic neurons, decreased expression of Reelin, PSD95, SYN and Fyn, and reduced phosphorylation of NMDAR2B and CREB.
These results suggest that early-life stress may mediate cognitive impairment in middle-age ApoE4-TR mice through sustained reduction of GABAergic neurons and Reelin expression, which might further diminish the activation of the Fyn/NMDAR2B signaling pathway.
A major cause of failure in chemotherapy is drug resistance of cancer cells. Exosomes have been introduced to spread chemoresistance through delivering miRNAs. However, a systematic evaluation of the ...exosomal miRNA expression profiles responsible for chemoresistance is still lacking. In the present study, miRNA signature differentially expressed in exosomes derived from adriamycin-resistant (A/exo) and parental breast cancer cells (S/exo) were analyzed by microarray and the results were confirmed by PCR. A total of 309 miRNAs were increased and 66 miRNAs were decreased significantly in A/exo compared with S/exo. Specifically, 52 novel miRNAs with increased expression levels >16.0-fold in A/exo were identified. After prediction of target genes for 13 of 52 selected novel miRNAs, pathway analysis, gene ontology (GO) terms, and protein-protein interactions (PPIs) were constructed. The results implied that these selected exosomal miRNAs inhibited target genes involved in transcriptional misregulation in cancer, MAPK, and Wnt signaling pathways. Functional enrichment analysis demonstrated that the target genes were mainly responsible for protein phosphorylation, transcription regulation, molecular binding, and kinase activity. In summary, the current bioinformatics study of exosomal miRNAs may offer a new understanding into mechanisms of chemoresistance, which is helpful to find potential exosomal miRNAs to overcome drug insensitivity in future breast cancer treatment.
•ALBI score differs significantly across the natural course of chronic HBV infection.•Patients with high ALBI score have a stronger PEG-IFN-α and NAs treatment response.•Patients with ALBI grade 2 ...have a persistently higher rate of HBeAg and HBsAg loss.•ALBI score is an independent predictor of sustained response achievement.
Recently, the role of albumin-bilirubin (ALBI) score in chronic hepatitis B (CHB) has not been well-understood. We aimed to investigate the association of ALBI score with natural history of chronic HBV infection and treatment response of CHB patients.
The ALBI score in a cohort of 849 individuals including 721 chronic HBV-infected patients naïve to anti-HBV treatment in different phases and 128 healthy controls were estimated. Additionally, the dynamic changes of ALBI score of 243 hepatitis B e antigen (HBeAg)-positive CHB patients treated with pegylated interferon-alpha (PEG-IFN-α) or nucleos(t)ide analogues (NAs) were tested for 72 weeks.
ALBI score differed among phases, with the highest score in HBeAg-positive CHB patients, followed by HBeAg-negative CHB patients, HBeAg-positive chronic HBV infection, and HBeAg-negative chronic HBV infection. Besides, CHB patients harbouring high baseline ALBI score exhibited a relatively stronger therapeutic response to PEG-IFN-α or NAs. Moreover, the rate of HBeAg and HBsAg loss in patients with ALBI grade 2 was persistently higher than that in patients with ALBI grade 1 throughout the course of treatment. Furthermore, ALBI score was an independent predictor of sustained response achievement. The combined use of ALBI score, HBeAg and ALT could enhance the predictive value of treatment response.
ALBI score differed significantly across the natural course of chronic HBV infection and was correlated with PEG-IFN-α and NAs treatment response in HBeAg-positive CHB patients, which suggested that ALBI score could be useful as an auxiliary clinical factor to determine the initiation of therapy and predict stronger antiviral treatment response.
The objective of the current study was to determine whether exposure to earthquake stress during pregnancy and infancy impacted on the risk of chronic adult health problems. All subjects were divided ...into three groups: the infant exposure group, the fetus exposure group, and the non‐exposure group. All subjects completed a standardized interview that included questions on demographic information, traumatic experiences during the earthquake, Anthropomorphic parameters such as body height, weight, and blood pressure were measured. Traumatic events in childhood and adulthood were assessed by the Childhood Trauma Questionnaire (CTQ) and Life Event Scale (LES), respectively. Totally1325 subjects were included; 399 subjects experienced the earthquake as fetuses, 374 subjects who experienced the earthquake as infants and 552 subjects did not experience the earthquake. The three groups were comparable in sociodemographic and baseline characteristics except age (Infant exposure vs Prenatal exposure vs No exposure = 39.5 ± 0.6 vs 38.5 ± 0.8 vs 37.5 ± 0.9, p < .001). Fetal and infant exposure to earthquakes was associated with elevated systolic blood pressure (both were + 3 mm Hg, p < .001). After adjustment for covariates, earthquake exposure in infants (odds ratio OR = 2.010, 95% confidence interval CI = 1.216 ~ 3.322) and fetuses (OR = 1.509, 95% CI = 1.014 ~ 2.248) was a significant and independent risk factor for hypertension. Earthquake expose in fetuses was a significant and independent risk factor for diabetes (OR = 2.307, 95% CI = 1.136 ~ 4.686). Earthquake exposure in infants and fetuses is a significant and independent risk factor for hypertension. Earthquake exposure in fetuses is significant and independent risk factor for diabetes.
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