Studies on the effect of air pollutions on kidney diseases are still limited.
We aimed to investigate the associations between particulate matter (PM) exposures and renal function among adults.
We ...recruited 21,656 adults as participants from 2007 to 2009. The Taiwanese Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to derive the estimated glomerular filtration rate (eGFR). Subjects with an eGFR lower than 60 mL/min/1.73 m
were defined as having chronic kidney disease (CKD). Land use regression (LUR) models were used to estimate individual exposures to PM with an aerodynamic diameter < 10 μm (PM
), coarse particles (PM
), fine particles (PM
), and PM
. Generalized linear and logistic regression models were used to estimate the associations between PM exposure and renal function.
An IQR increase in PM
(5.83 μg/m
) was negatively associated with eGFR by -0.69 (95% CI: -0.89, -0.48) mL/min/1.73 m
and positively associated with the prevalence of CKD with adjusted OR = 1.15 (95% CI: 1.07, 1.23). An IQR increase in PM
(6.59 μg/m
) was significantly associated with lower eGFR by -1.07 (95% CI: -1.32, -0.81) mL/min/1.73 m
and CKD with OR = 1.26 (95% CI: 1.15, 1.38). In contrast, neither outcome was significantly associated with PM
or PM
. Stratified analyses indicated that associations of CKD with both PM
and PM
were limited to participants < 65 years of age, and were stronger (for PM
) or limited to (PM
) women. Associations also appeared to be stronger in those without (vs. with) hypertension, and in normal versus overweight participants.
Exposure during the previous year to PM
and PM
, but not PM
or PM
, was associated with reduced renal function among Taiwanese adults.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
PurposeThis study's purpose is to propose an integrated model based on expectation-confirmation model (ECM), task-technology fit (TTF) model, and updated DeLone and McLean information system (IS) ...success model to examine whether quality factors and TTF as antecedents to physician beliefs can affect physicians' continuance intention of the cloud-based hospital information system (HIS) and performance impact.Design/methodology/approachSample data for this study were collected from physicians at five hospitals in Taiwan. A total of 500 questionnaires were distributed, and 305 (61.0 percent) usable questionnaires were analyzed using structural equation modeling in this study.FindingsThis study verified that physicians' perceived information quality, system quality, general technical support service quality, and cloud storage service quality all positively caused their PU, confirmation, and perceived TTF in the cloud-based HIS, which together explained their satisfaction with the system, and subsequently led to their continuance intention of the system and performance impact.Originality/valueFirst, IS-related and cloud-related quality factors are simultaneously taken into consideration within this study's research model, and empirical results reveal deep insights into quality evaluation in the field of physicians' cloud-based HIS continuance intention. Next, this study contributes to an understanding of TTF in explaining physicians' cloud-based HIS continuance intention that is difficult to explain with only their utilitarian perception of the system, and places emphasis upon physicians' perception of performance impact greatly driven by their perceived TTF and continuance intention of the system, thus the results can shed light on antecedents and outcome of physicians' cloud-based HIS continuance intention.
Aims
Immune check‐point inhibitors are known to cause immune‐mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab.
Methods and results
...Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second‐generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check‐point inhibitor (3 days–1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab‐treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab‐treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8+/CD4+ cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug‐induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis.
Conclusions
Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8+ lymphocytes and macrophages due to blockage of PD‐1–PD‐L1 interaction.
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer‐related deaths worldwide. Sarcomatoid HCC is a rare histological subtype of HCC with largely ...unclear clinical manifestations and outcomes. We evaluated the clinical manifestations and outcomes of patients with sarcomatoid HCC. We identified 5,047 patients with histologically proven HCC from the Cancer Registry Database (1996‐2016) of National Taiwan University Hospital. Among them, 40 patients with sarcomatoid HCC were identified from the pathology database of National Taiwan University Hospital. We included 160 patients with nonsarcomatoid HCC through propensity score matching according to sex, age, and Barcelona Clinic Liver Cancer stage. The majority of these patients with sarcomatoid HCC were men (75%); their median age was 58 years. Only 47.5% of the patients with sarcomatoid HCC presented with typical image patterns of HCC. The pathological grading of sarcomatoid HCC was more advanced compared with that of nonsarcomatoid HCC (42.5% vs. 23.8% in grade III and IV, P < 0.0001). The sarcomatoid group had significantly shorter median recurrence‐free (13.3 vs. 84.2 months, log‐rank P < 0.0001) and overall (8.3 vs. 69.3 months, log‐rank P < 0.0001) survival than did the nonsarcomatoid group. The results of the multivariable Cox proportional hazard model revealed histological sarcomatoid subtype as an independent factor for all‐cause mortality (hazard ratio HR, 6.47; 95% confidence interval CI, 3.12‐13.43; P < 0.0001) and tumor recurrence (HR, 4.08; 95% CI, 1.72‐9.66; P = 0.001). Conclusion: Compared with nonsarcomatoid HCC, sarcomatoid HCC was associated with more advanced histological grades and atypical image patterns. Histological sarcomatoid subtype is an independent predictor of tumor recurrence after curative treatment and all‐cause mortality in patients with HCC.
Cancer‐associated fibroblasts (CAFs), a major component of the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC), play an important role in tumorigenesis, metastasis, and ...chemoresistance. Tumor‐derived small extracellular vesicles (sEVs), which mediate cell‐to‐cell communication between cancer cells and fibroblasts, are also critical for cancer progression and metastasis. However, it remains unclear how PDAC cell‐derived sEVs activate fibroblasts, which contributes to tumor progression. Here, we report that ezrin (EZR) expression in PDAC cell‐derived sEVs (sEV‐EZR) can activate fibroblasts, resulting in increased migration ability and high expression of α‐SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV‐EZR‐activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver in animal models. Conversely, fibroblasts treated with PDAC cell‐derived sEVs with EZR knockdown resulted in the reduced metastatic ability of PDAC. Mechanistically, we demonstrated that PDAC cell‐derived sEV‐EZR increases the STAT3 and YAP‐1 signaling pathways to induce fibroblast activation, and the activated fibroblasts promote PDAC cell proliferation, invasion, and liver metastasis. Inhibition of the STAT3 and YAP‐1 signaling pathways by gene knockdown can abrogate sEV‐EZR‐induced effects. These findings suggest that targeting the interaction between PDAC cell‐derived sEV‐EZR and fibroblasts is a potential therapeutic strategy for PDAC.
PDAC cell‐derived sEVs can activate fibroblasts through activating STAT3 and YAP‐1 signaling, resulting in increased migration ability and high expression of α‐SMA, PDGFRB, and high production of extracellular matrix in fibroblasts. Reciprocally, sEV‐EZR‐activated fibroblasts enhanced PDAC cell proliferation, invasion, and metastasis to the liver. Inhibition of the STAT3 and YAP‐1 signaling pathways can abrogate sEV‐EZR‐induced effects. Thus, targeting sEV‐EZR may contribute to improve adjuvant PDAC therapies.
KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and ...what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.
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•Pancreatic cells exhibit lower phosphofructokinase activity than other cell types•High glucose elevates O-GlcNAcylation and genomic alterations in pancreatic cells•Reduction of RNR activity leads to nucleotide pool imbalance and KRAS mutations•PFK activity alters the sensitivity to high-glucose-induced genomic effects
Most pancreatic ductal adenocarcinomas contain activated KRAS mutations required for cancer initiation and maintenance. Here, Hu et al. show that high glucose promotes O-GlcNAcylation on ribonucleotide reductase, leading to nucleotide pool imbalance and KRAS mutations preferentially in pancreatic cells.
We investigated the utility of transient elastography (TE) for diagnosing biliary atresia (BA) in cholestatic infants and predicting the outcome of BA. Forty‐eight cholestatic infants (9‐87 days of ...age) with direct bilirubin level >1 mg/dL were enrolled. Liver stiffness measurement (LSM) by TE was performed during the cholestasis workup, and 15 subjects were diagnosed as BA. We assessed liver histology using liver biopsies from 36 subjects and graded fibrosis status using the METAVIR score. BA infants had significantly higher LSM values and METAVIR scores than non‐BA cholestatic infants. A receiver operating characteristic (ROC) curve analysis showed that an LSM >7.7 kPa was predictive of BA among cholestatic infants (sensitivity = 80%; specificity = 97%; area under the curve AUC = 85.3%; P = 0.0001). Cholestatic infants with an LSM >7.7 kPa were more likely to be diagnosed with BA (odds ratio OR = 128; P < 0.001). Very early measurement of LSM after hepatoportoenterostomy (HPE) is associated with occurrence of thrombocytopenia, splenomegaly, and esophageal varices 6 months post‐HPE. Five of the BA subjects were awaiting or had received liver transplantation (LT), and they had a significantly higher LSM measured 1 week post‐HPE than that in the other BA subjects (26.0 vs. 10.8 kPa; P = 0.006). A Cox proportional analysis demonstrated that the need for LT was significantly higher in BA subjects with LSM >16 kPa measured 1 week post‐HPE than other BA subjects (hazard ratio HR = 10.16; P = 0.04). Conclusion: LSM assessment during the workup of cholestatic infants may facilitate the diagnosis of BA. LSM post‐HPE may predict complications and the need for early LT in infants with BA. (Hepatology 2018).
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes
. The clinical presentation of patients with different subtypes is often atypical, and ...responses to therapies such as immune checkpoint blockade vary widely
. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8
T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
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