To increase the survival span after dialysis in patients with end-stage renal disease (ESRD), identifying specific cancer risks is crucial in the cancer screening of these patients. The aim of this ...study was to investigate the risks of various cancers in an incident dialysis group in comparison with a non-dialysis group.
We conducted a nationwide cohort study by using data from the Taiwan National Health Insurance Research Database. Patients who initially received long-term dialysis between January 1997 and December 2004, were selected and defined as the dialysis group and were matched with the non-dialysis patients (control group) according to age, sex, and index year. Competing risk analysis was used to estimate cumulative incidence and subdistribution hazard ratios (SHRs) of the first cancer occurrence.
After consideration for the competing risk of mortality, the dialysis group showed a significantly higher 7-year cancer incidence rate than did the control group (6.4%; 95% confidence interval CI, 6.0%-6.7% vs 1.7%; 95% CI, 1.4%-2.1%; P <0.001).The modified Cox proportional hazard model revealed that the dialysis group had significantly association with increased risks for all cancers (SHR, 3.43; 95% CI, 3.02-3.88). The risk of cancers was dominated in younger and female patients. Specific cancer risks were significantly higher in the dialysis group particularly in the development of oral, colorectal, liver, blood, breast, renal, upper urinary tract, and bladder cancer than in the control group. Multivariable stratified analyses confirmed the association between long-term dialysis and cancer in all subgroups of patients.
Dialysis is associated with a higher risk of cancer in patients with ESRD. However, cancer screening in ESRD population should be a selective approach, based on individual patient health condition and life expectancy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
People with bipolar disorder have an elevated risk of mortality. This study evaluated associations between the use of mood stabilizers and the risks of all‐cause mortality, suicide, and ...natural mortality in a national cohort of people with bipolar disorder.
Methods
In this nationwide cohort study, we used data from January 1, 2000, to December 31, 2016, collected from Taiwan's National Health Insurance Research Database and included 25,787 patients with bipolar disorder. Of these patients, 4000 died during the study period (including 760 and 2947 from suicide and natural causes, respectively). Each standardized mortality ratio (SMR) was calculated as the ratio of observed mortality in the bipolar cohort to the number of expected deaths in the general population. Multivariable Cox proportional hazards regression with a time‐dependent model was performed to estimate the hazard ratio (HR) of each mood stabilizer with each mortality outcome.
Results
The SMRs of all‐cause mortality, suicide, and natural mortality in the bipolar disorder cohort were 5.26, 26.02, and 4.68, respectively. The use of mood stabilizers was significantly associated with decreased risks of all‐cause mortality (adjusted HR aHR = 0.58, p< 0.001), suicide (aHR = 0.60, p < 0.001), and natural mortality (aHR = 0.55, p < 0.001) within a 5‐year follow‐up period after index admission. Among the individual mood stabilizers, lithium was associated with the lowest risks of all‐cause mortality (aHR = 0.38, p < 0.001), suicide (aHR = 0.39, p < 0.001), and natural mortality (aHR = 0.37, p < 0.001).
Conclusion
In addition to having protective effects against suicide and all‐cause mortality, mood stabilizers also exert a substantial protective effect against natural mortality, with lithium associated with the lowest risk of mortality.
Gut bacterial β-D-glucuronidases (GUSs) catalyze the removal of glucuronic acid from liver-produced β-D-glucuronides. These reactions can have deleterious consequences when they reverse xenobiotic ...metabolism. The human gut contains hundreds of GUSs of variable sequences and structures. To understand how any particular bacterial GUS(s) contributes to global GUS activity and affects human health, the individual substrate preference(s) must be known. Herein, we report that representative GUSs vary in their ability to produce various xenobiotics from their respective glucuronides. To attempt to explain the distinct substrate preference, we solved the structure of a bacterial GUS complexed with coumarin-3-β-D-glucuronide. Comparisons of this structure with other GUS structures identified differences in loop 3 (or the α2-helix loop) and loop 5 at the aglycone-binding site, where differences in their conformations, hydrophobicities and flexibilities appear to underlie the distinct substrate preference(s) of the GUSs. Additional sequence, structural and functional analysis indicated that several groups of functionally related gut bacterial GUSs exist. Our results pinpoint opportunistic gut bacterial GUSs as those that cause xenobiotic-induced toxicity. We propose a structure-activity relationship that should allow both the prediction of the functional roles of GUSs and the design of selective inhibitors.
Antidepressant-like effects of ethanolic extract of
(HE) mycelium enriched in erinacine A on depressive mice challenged by repeated restraint stress (RS) were examined. HE at 100, 200 or 400 mg/kg ...body weight/day was orally given to mice for four weeks. After two weeks of HE administration, all mice except the control group went through with 14 days of RS protocol. Stressed mice exhibited various behavioral alterations, such as extending immobility time in the tail suspension test (TST) and forced swimming test (FST), and increasing the number of entries in open arm (POAE) and the time spent in the open arm (PTOA). Moreover, the levels of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) were decreased in the stressed mice, while the levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased. These changes were significantly inverted by the administration of HE, especially at the dose of 200 or 400 mg/kg body weight/day. Additionally, HE was shown to activate the BDNF/TrkB/PI3K/Akt/GSK-3β pathways and block the NF-κB signals in mice. Taken together, erinacine A-enriched HE mycelium could reverse the depressive-like behavior caused by RS and was accompanied by the modulation of monoamine neurotransmitters as well as pro-inflammatory cytokines, and regulation of BDNF pathways. Therefore, erinacine A-enriched HE mycelium could be an attractive agent for the treatment of depressive disorders.
Head and neck squamous cell carcinomas (HNSCCs) are generally associated with tobacco consumption, alcohol abuse or both. Mucins (MUCs) are high‐molecular‐weight glycoproteins produced by many ...epithelial tissues. Many studies have indicated that MUCs play an important role in cancer metastasis. MUC6 expression has been observed in gastric and oncocytic phenotypes and plays an important role during cancer progression. We found that levels of MUC6 are lower in Asian HNCC patients and affect the disease‐free survival of HNCC patients. Next, we investigated the combined effect of MUC6 polymorphisms and exposure to environmental carcinogens on the susceptibility to and clinicopathological characteristics of HNCC. Three single‐nucleotide polymorphisms (SNPs) of MUC6 (rs7481521, rs6597947 and rs61869016) were analysed using real‐time PCR. After adjusting for other co‐variants, we found that carrying a CC genotype at MUC6 rs6597947 led to a lower risk of developing oral squamous cell carcinoma (OSCC) than wild‐type carriers among non‐betel‐quid chewers. Moreover, male oral cancer patients who carried the AA + CC genotype at MUC6 rs6597947 had a lower risk of lymph node metastasis than other genotypes, suggesting a significant functional compromise and decompensated disease. Therefore, our findings suggest that genetic variations in MUC6 may correlate to OSCC and indicate the progression in OSCC patients.
Cyanobacteria hold promise as a cell factory for producing biofuels and bio-derived chemicals, but genome engineering of cyanobacteria such as Synechococcus elongatus PCC 7942 poses challenges ...because of their oligoploidy nature and long-term instability of the introduced gene. CRISPR-Cas9 is a newly developed RNA-guided genome editing system, yet its application for cyanobacteria engineering has yet to be reported. Here we demonstrated that CRISPR-Cas9 system can effectively trigger programmable double strand break (DSB) at the chromosome of PCC 7942 and provoke cell death. With the co-transformation of template plasmid harboring the gene cassette and flanking homology arms, CRISPR-Cas9-mediated DSB enabled precise gene integration, ameliorated the homologous recombination efficiency and allowed the use of lower amount of template DNA and shorter homology arms. The CRISPR-Cas9-induced cell death imposed selective pressure and enhanced the chance of concomitant integration of gene cassettes into all chromosomes of PCC 7942, hence accelerating the process of obtaining homogeneous and stable recombinant strains. We further explored the feasibility of engineering cyanobacteria by CRISPR-Cas9-assisted simultaneous glgc knock-out and gltA/ppc knock-in, which improved the succinate titer to 435.0±35.0μg/L, an ≈11-fold increase when compared with that of the wild-type cells. These data altogether justify the use of CRISPR-Cas9 for genome engineering and manipulation of metabolic pathways in cyanobacteria.
•CRISPR-Cas9 triggers programmable double strand break (DSB) and death in cyanobacteria PCC 7942.•CRISPR-Cas9-mediated DSB enables precise gene integration in PCC 7942.•CRISPR-Cas9-induced DSB improves homologous recombination efficiency.•CRISPR-Cas9 accelerates the process of obtaining homogenous recombinant strain.•CRISPR-Cas9 enables metabolic engineering of PCC 7942 for succinate production.
Aim: Atherosclerotic diseases are the leading cause of death worldwide. Longitudinal changes in carotid intima-media thickness (IMT) and plaque are being increasingly used as markers of ...atherosclerosis progression and may predict future cardiovascular events. This study aimed to investigate the predictors of carotid IMT and plaque progression in a Chinese population and to determine whether these predictors differ by gender.Methods: Segment-specific carotid IMT and plaque were measured in 712 stroke- and myocardial infarction-free subjects at baseline and after an average interval of 4.3±0.9 years. Multivariate linear regression and logistic regression analyses were conducted to investigate the predictive effect of age, gender, and cardiovascular risk factors on carotid IMT and plaque progression. Gender-specific analyses were also performed.Results: Overall, age and smoking were predictors of common carotid artery IMT progression (adjusted p＜0.001 and p=0.045, respectively). Age, hypertension, and use of antihypertensive medication were predictors of bifurcation IMT progression (adjusted p＜0.001, p=0.033, and p＜0.001, respectively). The use of antihypertensive medication was associated with less annual IMT progression in hypertensive subjects than in those who did not take medication, which was most prominent in the bifurcation segment. In addition, most predictors of IMT progression were identified in women in a gender-specific analysis. For plaque progression, age and gender were independent predictors.Conclusions: The predictors of carotid atherosclerosis progression were gender and segment specific. The detection and control of hypertension may prevent atherosclerosis progression, particularly in women.
It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and ...correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis.
The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic.
We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P = 0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P = 0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P = 0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P = 0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P = 0.007).
Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several studies suggest that glial scars pose as physical and chemical barriers that limit neurite regeneration after spinal cord injury (SCI). Evidences suggest that the activation of the ...PI3K/Akt/mTOR signaling pathway is involved in glial scar formation. Therefore, inhibition of the PI3K/Akt/mTOR pathway may beneficially attenuate glial scar formation after SCI. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) negatively regulates the PI3K/Akt/mTOR pathway. Therefore, we hypothesized that the overexpression of PTEN in the spinal cord will have beneficial effects after SCI. In the present study, we intrathecally injected a recombinant adenovirus carrying the pten gene (Ad-PTEN) to cause overexpression of PTEN in rats with contusion injured spinal cords. The results suggest overexpression of PTEN in spinal cord attenuated glial scar formation and led to improved locomotor function after SCI. Overexpression of PTEN following SCI attenuated gliosis, affected chondroitin sulfate proteoglycan expression, and improved axon regeneration into the lesion site. Furthermore, we suggest that the activation of the PI3K/Akt/mTOR pathway in astrocytes at 3days after SCI may be involved in glial scar formation. Because delayed treatment with Ad-PTEN enhanced motor function recovery more significantly than immediate treatment with Ad-PTEN after SCI, the results suggest that the best strategy to attenuate glial scar formation could be to introduce 3days after SCI. This study's findings thus have positive implications for patients who are unable to receive immediate medical attention after SCI.
•I.t. Ad vector overexpression of astrocytic PTEN in normal and injured spinal cord.•Overexpression of PTEN following SCI led to improved locomotor function after SCI.•Overexpression of PTEN following SCI attenuated the glial scar formation.•Activation of the PI3K/Akt/mTOR pathway may be involved in glial scar formation.
There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of ...pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG-recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). Inflation increases as the level of evidence supporting the pathogenic nature of the variant decreases. We observed up to 11.5% of genetic disorders with inflation in pathogenic variant sets and up to 92.3% for the variant set with conflicting interpretations. This improved to 7.7% and 57.7%, respectively, after filtering for disease-specific allele frequency. The patterns of inflation were replicated using public data from more than 138,000 genomes. The burden of rare variants was a main contributing factor of the observed inflation, indicating collective misclassified rare variants. We also analyzed the dynamics of re-classification of variant pathogenicity in ClinVar over time, which indicates progressive improvement in variant classification. The study shows that databases include a significant proportion of wrongly ascertained variants; however, it underscores the critical role of ClinVar to contrast claims and foster validation across submitters.
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