Inflammatory bowel disease (IBD), which includes both ulcerative colitis and Crohn's disease, is a chronic relapsing inflammation of the gastrointestinal tract, and is difficult to treat. The ...pathophysiology of IBD is multifactorial and not completely understood, but genetic components, dysregulated immune responses, oxidative stress, and inflammatory mediators are known to be involved. Animal models of IBD can be chemically induced, and are used to study etiology and to evaluate potential treatments of IBD. Currently available IBD treatments can decrease the duration of active disease but because of their adverse effects, the search for novel therapeutic strategies that can restore intestinal homeostasis continues. This review summarizes and discusses what is currently known of the effects of amino acids on the reduction of inflammation, oxidative stress, and cell death in the gut when IBD is present. Recent studies in animal models have identified dietary amino acids that improve IBD, but amino acid supplementation may not be adequate to replace conventional therapy. The animal models used in dietary amino acid research in IBD are described.
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life‐threatening adverse reactions to drugs and psychological sequelae are also observed to follow the trauma of widespread ...epidermal necrolysis. To delineate the association between SJS and TEN, and psychiatric disorders, we conducted a retrospective population‐based cohort study by including 212 patients diagnosed with first‐time SJS or TEN in Taiwan between 2000 and 2013 and 669 population controls. Adjusted hazard ratios were calculated after adjusting for sex, age, comorbidity in the form of Charlson comorbidity index, and facility level of care. Overall, SJS or TEN was associated with an increased risk of developing psychiatric disorders including schizophrenia, major depressive disorder, mania, anxiety, and bipolar with an adjusted hazard ratio of 1.392 (95% CI, 1.192–1.625; p < 0.001). Particularly, the adjusted hazard ratios of psychiatric disorders were 1.290 (95% CI, 1.105–1.506; p < 0.001) for SJS and 1.855 (95% CI, 1.587–2.167; p < 0.001) for TEN.
Methionine is an aliphatic, sulfur-containing, essential amino acid, and a precursor of succinyl-CoA, homocysteine, cysteine, creatine, and carnitine. Recent research has demonstrated that methionine ...can regulate metabolic processes, the innate immune system, and digestive functioning in mammals. It also intervenes in lipid metabolism, activation of endogenous antioxidant enzymes such as methionine sulfoxide reductase A, and the biosynthesis of glutathione to counteract oxidative stress. In addition, methionine restriction prevents altered methionine/transmethylation metabolism, thereby decreasing DNA damage and carcinogenic processes and possibly preventing arterial, neuropsychiatric, and neurodegenerative diseases. This review focuses on the role of methionine in metabolism, oxidative stress, and related diseases.
Background & Aims
Transarterial chemoembolization (TACE) is a standard treatment for Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC), but the outcome varied. This study ...aimed to develop a model to predict the outcome of TACE in HCC patients.
Methods
Consecutive 570 treatment‐naïve BCLC stage B HCC patients undergoing TACE as the initial treatment from 2007 to 2016 were retrospectively enrolled. Factors associated with survival were analysed. Patients undergoing TACE from 2007 to 2011 constituted the training cohort (n = 293), while patients undergoing TACE from 2012 to 2016 constituted the validation cohort (n = 277). Homogeneity and corrected Akaike information criterion (AICc) were compared between each prognostic model.
Results
A total of 1796 TACE sessions were performed for the 570 patients during the median follow‐up period of 18.3 months. By multivariate analysis, beyond up‐to‐11 criteria (hazard ratio HR = 1.694, P < .001), alpha‐foetoprotein >200 ng/mL (HR = 1.771, P < .001) and albumin‐bilirubin (ALBI) grade 2 or 3 (HR = 1.817, P < .001) were independent predictors of overall survival (OS) in the training cohort. An ALBI‐TAE model based on the three independent predictors of OS from the training cohort was developed to classify HCC patients into four subgroups. The performance of the ALBI‐TAE model was superior to other prognostic models with lowest AICc values and highest homogeneity in both the training and validation datasets as well as the overall cohort.
Conclusions
Albumin‐bilirubin grade is an important factor associated with survival in BCLC stage B HCC patients undergoing TACE. ALBI‐TAE model can be applied to select patients who can get most benefit from TACE.
Background & Aims: This study investigated whether obesity, diabetes, and other metabolic factors are independently associated with hepatocellular carcinoma (HCC), stratified by hepatitis B virus ...(HBV) and hepatitis C virus (HCV) serostatus, and explored the possible joint influence of obesity/diabetes and HBV/HCV infections on the risk of HCC. Methods: A total of 23,820 residents in Taiwan were recruited and followed up for 14 years. All analyses were stratified by hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) at enrollment, and 218 subjects positive for both seromarkers were excluded. Incident HCC cases were identified via linkage to the national cancer registry. Multivariate-adjusted relative risk (RRa ) and 95% confidence interval (95% CI) were estimated using Cox proportional hazards models. Results: Extreme obesity (body mass index ≥30 kg/m2 ) was independently associated with a 4-fold risk of HCC (RRa , 4.13; 95% CI, 1.38–12.4) among anti-HCV–seropositive subjects and a 2-fold risk (RRa , 2.36; 95% CI, 0.91–6.17) in persons without HBV and HCV infections, after controlling for other metabolic components, but not in HBsAg-seropositive subjects (RRa , 1.36; 95% CI, 0.64–2.89). Diabetes was associated with HCC in all 3 groups, with the highest risk in those with HCV infection (RRa , 3.52; 95% CI, 1.29–9.24) and lowest in HBV carriers (RRa , 2.27; 95% CI, 1.10–4.66). We found more than 100-fold increased risk in HBV or HCV carriers with both obesity and diabetes, indicating synergistic effects of metabolic factors and hepatitis. Conclusions: The finding that both obesity and diabetes are predictors of HCC risk, possibly differently depending on HBV and HCV infection status, may shed some light in preventing HCC.
Purpose To construct a nomogram with the albumin-bilirubin (ALBI) grade to assess the long-term outcomes of patients with early-stage hepatocellular carcinoma (HCC) after radiofrequency ablation ...(RFA). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. We studied 622 treatment-naïve patients with HCC according to the Milan criteria who subsequently underwent RFA from 2002 to 2013. Baseline characteristics were collected to identify the risk factors for determination of poor overall survival after RFA. The multivariate Cox proportional hazards model based on significant prognostic factors of overall survival was used to construct the nomogram. Results After a median follow-up time of 35.7 months, 190 patients had died. The cumulative 5- and 10-year overall survival rates were 63.1% and 48.7%, respectively. Stratified according to ALBI grade, the cumulative 5- and 10-year survival rates were 80.0% and 67.9% for patients with grade 1, respectively, and 48.6% and 35.1% for those with grades 2-3, respectively (P < .001). Multivariate analysis results showed that patient age older than 65 years, a prothrombin time international normalized ratio greater than 1.1, α-fetoprotein level greater than 20 ng/mL, multiple tumors, and ALBI grade 2 or 3 were associated with overall mortality. A nomogram was developed on the basis of these five variables. Internal validation with 200 bootstrapped sample sets had a good concordance index of 0.770 (95% confidence interval: 0.633, 0.876). Conclusion This simple nomogram based on the ALBI grade offers personalized long-term survival data for patients with early-stage HCC who undergo RFA.
RSNA, 2017 Online supplemental material is available for this article.
Deoxynivalenol (DON) is one of the most common mycotoxins that contaminates food or feed and cause intestinal damage. Long‐chain n‐3 polyunsaturated fatty acids (PUFA) such as EPA and DHA exert ...beneficial effects on intestinal integrity in animal models and clinical trials. Necroptosis signaling pathway plays a critical role in intestinal cell injury. This study tested the hypothesis that EPA and DHA could alleviate DON‐induced injury to intestinal porcine epithelial cells through modulation of the necroptosis signaling pathway. Intestinal porcine epithelial cell 1 (IPEC‐1) cells were cultured with or without EPA or DHA (6.25‐25 μg/mL) in the presence or absence of 0.5 μg/mL DON for indicated time points. Cell viability, cell number, lactate dehydrogenase (LDH) activity, cell necrosis, transepithelial electrical resistance (TEER), fluorescein isothiocyanate‐labeled dextran 4kDa (FD4) flux, tight junction protein distribution, and protein abundance of necroptosis related signals were determined. EPA and DHA promoted cell growth indicated by higher cell viability and cell number, and inhibited cell injury indicated by lower LDH activity in the media. EPA and DHA also improved intestinal barrier function, indicated by higher TEER and lower permeability of FD4 flux as well as increased proportions of tight junction proteins located in the plasma membrane. Moreover, EPA and DHA decreased cell necrosis demonstrated by live cell imaging and transmission electron microscopy. Finally, EPA and DHA downregulated protein expressions of necroptosis related signals including tumor necrosis factor receptor (TNFR1), receptor interacting protein kinase 1 (RIP1), RIP3, phosphorylated mixed lineage kinase‐like protein (MLKL), phosphoglycerate mutase family 5 (PGAM5), dynamin‐related protein 1 (Drp1), and high mobility group box‐1 protein (HMGB1). EPA and DHA also inhibited protein expression of caspase‐3 and caspase‐8. These results suggest that EPA and DHA prevent DON‐induced intestinal cell injury and enhance barrier function, which is associated with inhibition of the necroptosis signaling pathway.
With the progression of molecular techniques, the detection of circulating plasma DNA (cpDNA) is clinically feasible. However, the role of the cpDNA levels in gastric cancer is not well understood. ...This study assessed the mutational profile in primary tumors and clarified the clinical utility of quantitative and qualitative cpDNA alterations in 277 patients with advanced gastric cancer. The concentrations of cpDNA were measured by TaqMan qPCR, and 68 mutations in 8 genes were studied for cpDNA mutations. The median cpDNA concentrations in patients with stages I, II, and III gastric cancer were 3979, 3390 and 4278 copies/mL, respectively, and increased to 11,380 copies/mL in patients with Stage IV gastric cancer (p < 0.001). Among the 35 patients harboring cpDNA mutations, Stage IV patients (100%) were more likely to display high cpDNA levels than were Stage I (33.3%), II (75%) and III patients (66.7%) (p = 0.037). Patients displaying high cpDNA levels were more likely to experience peritoneal recurrence and exhibited significantly lower 5‐year overall survival rates (39.2% vs. 45.8%, p = 0.039) than did patients displaying low cpDNA levels. Only for late stage (Stages III or IV) gastric cancer, patients harboring cpDNA mutations were more likely to experience vascular invasion (20% vs. 2.4%, p = 0.036) and exhibited a lower 5‐year overall survival rate than did those lacking cpDNA mutations (5.6% vs. 31.5%, p = 0.028). High cpDNA levels are associated with peritoneal recurrence and poor prognosis in patients with advanced gastric cancer; harboring cpDNA mutations is associated with poor prognosis among patients with late stage gastric cancer.
What's new?
Patients whose gastric cancer returns despite curative surgery tend to suffer poor prognosis. According to the authors of this study; however, it may be possible to catch recurrent disease before it reaches advanced stages using circulating plasma (cp) DNA, a blood‐based biomarker. In advanced gastric cancer patients, cpDNA levels were associated with tumor recurrence and initial recurrence pattern, with high cpDNA levels signaling an increased likelihood of peritoneal recurrence versus locoregional or distant recurrence. Primary tumor mutations in cpDNA were linked to reductions in 5‐year survival, suggesting that cpDNA mutational status can predict poor prognosis in late‐stage disease.
Selective internal radiation therapy (SIRT) is an effective treatment strategy for unresectable hepatocellular carcinoma (HCC) patients. However, the prognoses of patients with portal vein ...thrombosis, extra-hepatic metastases, or residual tumors remain poor when treated with SIRT alone. In these patients, sequential external beam radiotherapy (EBRT) may offer a chance of salvage. Here, we reported the clinical outcomes and the detailed dosimetry analysis of 22 patients treated with combination therapy.
Between October 2011 and May 2015, 22 consecutive patients who underwent EBRT after yttrium-90 (90Y) SIRT were included in this study. The post-SIRT 90Y bremsstrahlung SPECT/CT of each patient was transferred to dose distribution by adopting the local deposition hypothesis. The patient-specific 3-dimensional biological effective dose distribution of combined SIRT and EBRT was generated. The overall survival and safety were evaluated. The relationship between dosimetric parameters and liver toxicity was analyzed.
The mean administered activity of SIRT was 1.50 GBq (range: 0.5-2.8). The mean prescribed dose of EBRT was 42.3 Gy (range: 15-63) in 14 fractions (range: 5-15) and was targeted to the residual liver tumor in 12 patients (55%), portal vein thrombosis in 11 patients (50%), and perihilar lymphadenopathies in 4 patients (18%). The overall 1-, 2-, and 3-year survival rates were 59.8%, 47.9%, and 47.9%, respectively. Overall, 8 patients (36%) developed > grade 2 liver toxicities, and the Child-Pugh score prior to EBRT strongly affected the toxicity risk. A dosimetry analysis restricted to 18 Child-Pugh A/B patients showed that the V100 (The fraction of normal liver exposed to more than 100 Gy) to V140 significance differed between patients who did or did not experience hepatotoxicity. The V110 was the strongest predictor of hepatotoxicity (18.6±11.6% vs 29.5±5.8%; P = 0.030).
Combined therapy is feasible and safe if patients are carefully selected. Specifically, 3-dimensional dosimetry is crucial for the evaluation of efficacy and toxicity. The normal liver V100 to V140 values of the combined dose should be as low as possible to minimize the risk of liver toxicity.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The Bcl-2 family proteins are important regulators of type I programmed cell death apoptosis; however, their role in autophagic cell death (AuCD) or type II programmed cell death is still largely ...unknown. Here we report the cloning and characterization of a novel Bcl-2 homology domain 3 (BH3)-only protein, apolipoprotein L1 (apoL1), that, when overexpressed and accumulated intracellularly, induces AuCD in cells as characterized by the increasing formation of autophagic vacuoles and activating the translocation of LC3-II from the cytosol to the autophagic vacuoles. Wortmannin and 3-methyladenine, inhibitors of class III phosphatidylinostol 3-kinase and, subsequently, autophagy, blocked apoL1-induced AuCD. In addition, apoL1 failed to induce AuCD in autophagy-deficient ATG5-/- and ATG7-/- mouse embryonic fibroblast cells, suggesting that apoL1-induced cell death is indeed autophagy-dependent. Furthermore, a BH3 domain deletion construct of apoL1 failed to induce AuCD, demonstrating that apoL1 is a bona fide BH3-only pro-death protein. Moreover, we showed that apoL1 is inducible by p53 in p53-induced cell death and is a lipid-binding protein with high affinity for phosphatidic acid (PA) and cardiolipin (CL). Previously, it has been shown that PA directly interacted with mammalian target of rapamycin and positively regulated the ability of mammalian target of rapamycin to activate downstream effectors. In addition, CL has been shown to activate mitochondria-mediated apoptosis. Sequestering of PA and CL with apoL1 may alter the homeostasis between survival and death leading to AuCD. To our knowledge, this is the first BH3-only protein with lipid binding activity that, when overproduced intracellularly, induces AuCD.
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