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1.
PLoS One ; 15(4): e0232089, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32353060

RESUMO

BACKGROUND: We aimed to determine the optimal approach with endoscopic biliary drainage (EBD) and corticosteroid (CS) for the treatment of IgG4-related sclerosing cholangitis (ISC). METHODS: To evaluate the safety of EBD for treatment of biliary stricture caused by ISC, we assessed the risk of stent dislodgement and sought to determine the most appropriate time for stent removal. We also assessed the safety of treatment with CS alone for patients with obstructive jaundice, and the rate of and risk factors for biliary tract complications. RESULTS: Sixty-nine patients with ISC treated with CS were enrolled. Twenty-eight patients (40.6%) were treated with EBD for biliary stricture before CS initiation. Intentional stent removal was performed in thirteen (46.4%) after confirming CS-induced improvement. Eleven of thirteen patients (84.6%) underwent stent removal within 1 month after CS initiation and all their stent removals were safely carried out without early (within two weeks) recurrence of obstructive jaundice. Ten of twenty-eight patients (35.7%) experienced spontaneous stent dislodgement after CS initiation, and seven (70%) of them developed stent dislodgement two weeks to two months after CS initiation. Among forty-one patients treated with CS alone without EBD, 10 patients had obstructive jaundice at the time of CS initiation and all of them achieved clinical improvement without biliary tract infection. During the follow-up, three patients (4.3%), all of whom had undergone EBD, developed bile-duct stones, while none of those treated with CS alone developed bile-duct stones (p = 0.032). Long-term biliary stenting was a risk factor for bile-duct stones. CONCLUSIONS: Biliary stent removal should be carried out within 2 weeks after CS initiation if biliary stricture improves to prevent stent dislodgement. Obstructive jaundice can be treated safely with CS alone in patients without infection. Clinicians should be aware of the possibility of bile-duct stones in patients treated with EBD.

2.
Transl Oncol ; 13(7): 100777, 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32413834

RESUMO

Dendritic cell (DC)-based immunotherapies are believed to help eradicate residual tumor cells, including hepatocellular carcinoma (HCC). Here, we assessed the safety and clinical response to OK432-stimulated monocyte-derived DCs (MoDCs) in treating HCC after radiofrequency ablation (RFA). MoDCs were derived from 30 HCC patients in the presence of interleukin-4 and granulocyte-macrophage colony stimulating factor for 5 days and then cultured for 2 more days in the medium (basic protocol) or stimulated with OK432. On day 7, DCs were harvested and percutaneously injected into HCC tumors after RFA. We observed no grade 3 or 4 National Cancer Institute Common Toxicity Criteria adverse events. Kaplan-Meier analysis indicated that patients treated with RFA + OK432-stimulated DCs transfer had longer recurrence-free survival than those treated with RFA + basic-protocol DCs (median: 24.8 vs 13.0 months; P = .003). RFA with DC infusion can enhance various tumor-associated antigen (TAA)-specific T-cell responses. Additionally, the 5-year RFS rate for patients with significantly increased TAA-specific T-cell responses was much higher than for other patients (50.0% vs. 7.7%; P = .030). Our study provides useful information for development of HCC immunotherapies (trial registration: UMIN000001701).

3.
J Neurol Sci ; 414: 116813, 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32353608

RESUMO

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is an adult-onset, systemic disorder caused by mutations in the transthyretin (TTR) gene. As ATTRv amyloidosis is inherited in an autosomal dominant manner, family members of the patients are at risk of developing the disease. METHODS: With an objective of discussing recommendations on monitoring of family members for early diagnosis of ATTRv amyloidosis, we held a medical advisory board meeting in Tokyo, Japan, in October 2017. RESULTS: Our recommendations are summarized as follows: periodic follow-up genetic counseling should be offered to asymptomatic gene mutation carriers; follow-up assessments should be started when the carriers are still asymptomatic to test for amyloidosis onset, irrespective of TTR genotype and age at onset in the particular family. We suggest annual routine assessments and in-depth assessments every 3-5 years, with the frequency of these increased as required. Periodical monitoring of asymptomatic gene mutation carriers is crucial for attending physicians to detect early signs or symptoms of the disease and start disease-modifying therapy (DMT). CONCLUSIONS: The monitoring strategy for asymptomatic TTR gene mutation carriers should progress toward rapid diagnosis and early intervention with DMT. This approach may be more appropriate for countries with more resources.

4.
Hepatol Res ; 2020 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-32307874

RESUMO

AIM: Most patients with advanced hepatocellular carcinoma (HCC) have underlying chronic liver disease, which potentially deteriorated the liver functional reserve that often affects the patients' clinical course. We investigated and compared the changes in liver functional reserve during lenvatinib or sorafenib therapy in patients with advanced HCC. METHODS: We prospectively collected medical information about patients with advanced HCC with a Child-Pugh score of 5-7 to compare the liver functional reserve during treatment in those who were treated with lenvatinib or sorafenib. We also evaluated the effect of the change in the liver functional reserve on patients' outcome. Moreover, we analyzed the contributing factors for maintaining the liver functional reserve during treatment. RESULTS: Patients were treated with lenvatinib (n = 45) or sorafenib (n = 157). Forty-five patients in the lenvatinib group and 135 patients in the sorafenib group were selected through a propensity score matching analysis. More patients treated with lenvatinib had a Child-Pugh score that was maintained or improved after 4 and 12 weeks compared with those treated with sorafenib (P = 0.048, P = 0.036, respectively). Lenvatinib was identified as one of the variables that was associated with maintaining Child-Pugh scores. Multivariate analysis revealed that a worsened Child-Pugh score after 4 weeks was an independent unfavorable predictive factor for overall survival. CONCLUSIONS: More patients treated with lenvatinib for advanced HCC maintained their liver functional reserves compared with those treated with sorafenib. Maintaining the liver functional reserve contributed to better outcomes for patients with advanced HCC.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32169577

RESUMO

BACKGROUND & AIMS: Sorafenib is a multireceptor tyrosine kinase inhibitor that can prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Although most HCC patients who receive sorafenib ultimately show disease progression, it still is unclear whether and how HCC cells acquire chemoresistance during sorafenib treatment in human beings. METHODS: We analyzed surgically resected HCC tissues from a patient who received sorafenib for prevention of HCC recurrence after surgery (Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial) and established patient-derived HCC cells. Whole-exome sequence analysis was performed to detect mutations in sorafenib-resistant clones. We examined 30 advanced HCC cases immunohistochemically and 140 HCC cases enrolled in the Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial using microarray analysis to evaluate the association of CIC status with sorafenib treatment response. RESULTS: We found a CIC mutation in recurrent HCC specimens after sorafenib. CIC encodes Capicua, a general sensor of receptor tyrosine kinase signaling. HCC cells established from the recurrent tumor specimen showed chemoresistance to sorafenib in vitro and in vivo. Established sorafenib-resistant Huh1 and Huh7 cell lines showed reduced expression of Capicua without mutations. Immunohistochemical analysis showed that HCC patients with low Capicua expression showed poor overall survival. Microarray analysis showed that the CIC gene signature could predict the preventive effect of adjuvant sorafenib treatment on HCC recurrence. Intriguingly, although CIC knockdown induced sorafenib resistance in HCC cell lines, regorafenib suppressed growth of sorafenib-resistant, Capicua-inactivated HCC cells and inhibited extracellular signal-regulated kinase phosphorylation. CONCLUSIONS: Evaluation of Capicua status may be pivotal to predict response to sorafenib, and regorafenib treatment could be effective to treat HCC with functional Capicua impairment.

6.
Nat Commun ; 11(1): 1557, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214089

RESUMO

The telomerase reverse transcriptase is upregulated in the majority of human cancers and contributes directly to cell transformation. Here we report that hTERT is phosphorylated at threonine 249 during mitosis by the serine/threonine kinase CDK1. Clinicopathological analyses reveal that phosphorylation of hTERT at threonine 249 occurs more frequently in aggressive cancers. Using CRISPR/Cas9 genome editing, we introduce substitution mutations at threonine 249 in the endogenous hTERT locus and find that phosphorylation of threonine 249 is necessary for hTERT-mediated RNA dependent RNA polymerase (RdRP) activity but dispensable for reverse transcriptase and terminal transferase activities. Cap Analysis of Gene Expression (CAGE) demonstrates that hTERT phosphorylation at 249 regulates the expression of specific genes that are necessary for cancer cell proliferation and tumor formation. These observations indicate that phosphorylation at threonine 249 regulates hTERT RdRP and contributes to cancer progression in a telomere independent manner.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32180251

RESUMO

BACKGROUND AND AIM: Single-nucleotide polymorphisms (SNPs) of the interleukin-28B (IL-28B) gene are associated with the effectiveness of interferon therapy for chronic hepatitis C infection. Whether the IL-28B genotype affects the course of treatment and the outcomes of patients with advanced hepatocellular carcinoma (HCC) is unknown. METHODS: We detected the IL-28B SNP (rs8099917) using TaqMan PreDesigned SNP Genotyping Assays to assess the effects of the IL-28B genotype on treatment efficacy and prognosis of patients with advanced HCC treated with hepatic arterial infusion chemotherapy (HAIC) between September 2003 and January 2015. RESULTS: The study included 154 patients who received HAIC to treat advanced HCC, among which 27 (17.5%) had the minor genotype, IL-28B rs8099917 TG or GG, and the others had the major genotype, IL-28B rs8099917 TT. The objective response rates of patients with the minor or major genotype were 51.9% and 29.1% (P = 0.022), respectively. Multivariate analysis revealed that the minor genotype remained associated with the response to HAIC (odds ratio, 2.620; P = 0.026). The median overall survival of patients with major or minor genotypes was 14.1 and 16.9 months, respectively, and the overall survival of patients with the major genotype was significantly shorter than that of patients with the minor genotype (P = 0.027). Multivariate analysis revealed that the major genotype was an independent, unfavorable prognostic factor (hazard ratio, 1.720; P = 0.024). Consistent results were obtained in selected populations after propensity score matching analysis. CONCLUSIONS: The IL-28B SNP (rs8099917) will serve as a useful predictor of the outcomes of patients with advanced HCC treated with HAIC.

8.
Amyloid ; : 1-10, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32131641

RESUMO

Introduction: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated.Methods: Patients received either patisiran 0.3 mg/kg (n = 148) or placebo (n = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL.Results: At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares [LS] mean difference: -21.1; p = 1.10 × 10-10; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2; p = 1.4 × 10-12), EuroQoL-visual analog scale (LS mean difference: 9.5; p=.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0; p = 4.07 × 10-16) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: -7.5; p=.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation.Conclusion: The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.

9.
J Gastroenterol ; 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32124081

RESUMO

BACKGROUND: The interaction between T-cells/fatty acids involved in non-alcoholic fatty liver disease (NAFLD) and liver fibrosis progression is poorly understood. In this study, we conducted a comprehensive analysis of T-cell profiles of NAFLD patients to better understand their relationship with fatty acids and relevance to liver fibrosis. METHODS: We analyzed the differences in T-cell profiles of peripheral blood mononuclear cells (PBMCs) between 40 NAFLD patients and 5 healthy volunteers (HVs), and their relationship with liver fibrosis stage or progression. Moreover, we analyzed the relationship between T-cell profiles and fatty acid compositions in vivo, and changes in T-cell profiles after treatment with fatty acids in vitro. RESULTS: T-cell profiles of NAFLD patients were different from those of HVs. The CD25+CD45+CD4+ T-cell frequency was increased in NAFLD patients with high liver fibrosis stage and progression, and this indicated immune activation. Despite such a state of immune activation, the PD1+CD4+ T-cell frequency was decreased in the same patients group. The PD1+CD4+ T-cell frequency had a significantly negative correlation with the serum fatty acid composition ratio C16:1n7/C16:0. Moreover, the PD1+CD4+ T-cell frequency was significantly decreased by in vitro treatment with fatty acids. In addition, its rate of frequency change was significantly different between C16:0 and C16:1n7 and decreased by artificially increasing the C16:1n7/C16:0 ratio. CONCLUSIONS: The analysis of PBMCs in NAFLD patients showed that T-cell profiles were different from those of HVs. And, it suggested that fatty acids modified T-cell profiles and were involved in liver fibrosis in NAFLD patients.

10.
Sci Rep ; 10(1): 4021, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132566

RESUMO

α-Fetoprotein (AFP) is considered a good target for immunotherapy strategies against hepatocellular carcinoma (HCC); however, no immunodominant AFP-derived MHC class II-restricted helper T-lymphocyte (HTL) epitope has been reported. Therefore, we identified novel AFP-derived HTL epitopes possessing high immunogenicity. HTL epitopes were predicted using the online service, and peptides were subsequently synthesized. Four newly synthesized peptides showed positive reactivity in >20% patients on ELISPOT using peripheral blood mononuclear cells (PBMCs). Among these, the highest rate was shown by AFP1 (MKWVESIFLIFLLNFTESRT), which also showed the highest positive rate in cell proliferation assays. Binding assays demonstrated that AFP1 had strong binding properties toward MHC molecules. Further, blocking assays performed using an anti-HLA-DR antibody showed that immune response decreased, confirming the binding of AFP1 to HLA-DR molecules. Furthermore, the survival rates of patients with stages II-IV HCC indicated that T cell response against AFP1 led to significantly greater survival that of patients without T cell response. When evaluating immune response against AFP1 before and after HCC treatment, an increase in the frequency of peptide-specific T cells was observed after treatment in patients with HLA-DRB1*1502, *0405, and *0901 alleles. In conclusion, the identified epitopes may be useful for immunotherapy strategies against HCC.

11.
J Obstet Gynaecol Res ; 46(5): 787-790, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32077184

RESUMO

Amyloidosis of the uterine cervix is rare. A 35-year-old pregnant woman underwent a cervical biopsy and was found to have amyloid deposits. The results of liquid chromatography-tandem mass spectrometry revealed that these deposits mainly consisted of immunoglobulin light chain (kappa chain). After undergoing several examinations, the patient was diagnosed with localized amyloidosis, without systemic or secondary amyloidosis. She underwent a normal delivery without disease exacerbation. The possible presence of systemic and secondary amyloidosis must be evaluated carefully during the diagnosis of localized cervical amyloidosis.

12.
World J Gastroenterol ; 26(3): 353-365, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31988594

RESUMO

BACKGROUND: Programmed cell death-1 (PD-1) inhibitor has been indicated for many types of malignancies. However, these inhibitors also cause immune-related adverse events. Hepatobiliary disorder is a phenotype of immune-related adverse event affecting 0%-4.5% of patients treated with PD-1 inhibitors. Recent studies have reported PD-1 inhibitor-related sclerosing cholangitis (SC); however, the associated clinical and pathological features are unclear. AIM: To evaluate the clinical and pathological features of PD-1 inhibitor-related SC through a systematic review of the literature. METHODS: The review, conducted using electronic databases in PubMed, was restricted to the period from January 2014 to September 2019 and focused on case reports/series on PD-1 inhibitor-related SC published in English. We scanned the references of the selected literature to identify any further relevant studies. Six cases previously studied by us, including three that have not yet been published, were included in this review. RESULTS: Thirty-one PD-1 inhibitor-related SC cases were evaluated. Median age of patients was 67 years (range, 43-89), with a male to female ratio of 21:10. The main disease requiring PD-1 inhibitor treatment was non-small cell lung cancer. Agents that caused PD-1 inhibitor-related SC were nivolumab (19 cases), pembrolizumab (10 cases), avelumab (1 case), and durvalumab (1 case). The median number of cycles until PD-1 inhibitor-related SC onset was 5.5 (range, 1-27). Abdominal pain or discomfort (35.5%, 11/31) was the most frequent symptom. Blood serum tests identified liver dysfunction with a notable increase in biliary tract enzymes relative to hepatic enzymes, and a normal level of serum immunoglobulin G4. Biliary dilation without obstruction (76.9%, 20/26), diffuse hypertrophy of the extrahepatic biliary tract (90.5%, 19/21), and multiple strictures of the intrahepatic biliary tract (30.4%, 7/23) were noted. In 11/23 (47.8%) cases, pathological examination indicated that CD8+ T cells were the dominant inflammatory cells in the bile duct or peribiliary tract. Although corticosteroids were mainly used for PD inhibitor-related SC treatment, the response rate was 11.5% (3/26). CONCLUSION: Some clinical and pathological features of PD-1 inhibitor-related SC were revealed. To establish diagnostic criteria for PD-1 inhibitor-related SC, more cases need to be evaluated.

13.
Cardiovasc Pathol ; 46: 107191, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31927216

RESUMO

Pericardial amyloidosis is a rare cause of pericardial effusion. Here, we report a case of recurrent pericardial effusion because of pericardial amyloid deposition. The patient was a man in his 40s admitted for pulmonary embolism. During hospitalization, arterial fibrillation and cardiac tamponade were observed, and an initial pericardial puncture was performed. Thereafter, pericardial puncture was repeated nine times over the next two years. Cytological examination of the pericardial effusion suggested malignant mesothelioma. Afterward, pericardial fenestration and partial resection were performed. Intraoperatively, a thickened pericardium and hemorrhagic pericardial effusion were noted. Histologically, the surface of the pericardium was covered by an eosinophilic amorphous material. Congo red and DYLON stains, electron microscopy, and immunohistochemical findings revealed localized amyloidosis composed of an immunoglobulin lambda light chain. Although the patient did not receive further treatment for 5 years postoperatively, his renal and cardiac functions remained within normal limits. Based on these findings, the patient was diagnosed with localized amyloidosis. So far, hemorrhagic pericardial effusion has been reported in few cases with systemic amyloidosis. Because localized immunoglobulin light-chain-derived (AL) amyloidosis may progress to systemic disease (although it is a very rare occurrence), long-term follow-up is necessary to detect recurrence or progression to a systemic form.

14.
Sci Rep ; 10(1): 815, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31965018

RESUMO

Hyperuricemia drives the development of nonalcoholic fatty liver disease (NAFLD). Pharmacological inhibition of xanthine oxidase (XO), a rate-limiting enzyme for uric acid (UA) production, has been demonstrated to improve hepatic steatosis in diet-induced obese mice. However, it remains unclear whether inhibition of XO improves nonalcoholic steatohepatitis (NASH), a more advanced form of NAFLD, in terms of both liver inflammation and fibrosis. Here, we investigated the effects of febuxostat and allopurinol, two XO inhibitors clinically used for gout, on a mouse model of NASH. Furthermore, we conducted a single-arm, open-label intervention study with febuxostat for NAFLD patients with hyperuricemia. Despite a similar hypouricemic effect of the XO inhibitors on blood UA level, febuxostat, but not allopurinol, significantly decreased hepatic XO activity and UA levels in the NASH model mice. These reductions in hepatic XO activity and UA levels were accompanied by attenuation of insulin resistance, lipid peroxidation, and classically activated M1-like macrophage accumulation in the liver. Furthermore, in NAFLD patients with hyperuricemia, treatment with febuxostat for 24 weeks decreased the serum UA level, accompanied by reductions in the serum levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase. XO may represent a promising therapeutic target in NAFLD/NASH, especially in patients with hyperuricemia.

15.
Amyloid ; 27(1): 25-35, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31615282

RESUMO

Amyloidosis is an extremely rare event in rats. In this study, we report that lipopolysaccharide binding protein (LBP) is the most likely amyloidogenic protein in rat mammary amyloidosis. Histologically, corpora amylacea (CA) and stromal amyloid (SA) were observed in rat mammary glands, and needle-shaped amyloid (NA) was also observed on the surface or gap of CA and SA. Following surveillance in aged rats, NA was observed in 62% of mammary tumours, 25% of male mammary glands and 83% of female mammary glands. Proteomic analysis showed that lactadherin was a major constitutive protein of CA and SA, and both were positive following immunohistochemistry with anti-lactadherin antibodies. In the same analysis, LBP was detected as a prime candidate protein in NA, and NA was positive following immunohistochemistry and immunoelectron microscopy with anti-LBP antibody. Furthermore, synthetic peptides derived from rat LBP formed amyloid fibrils in vitro. Overall, these results provide evidence that LBP is an amyloid precursor protein of NA in rat mammary glands.

16.
J Cardiol ; 75(1): 12-19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31324572

RESUMO

BACKGROUND: The diagnosis of wild-type transthyretin cardiac amyloidosis (ATTRwt) is frequently missed or delayed because of the limited specificity of manifestations. We investigated the utility of combined assessment of high-sensitivity cardiac troponin T (hs-cTnT) measurement and 99mTc-pyrophosphate (99mTc-PYP) scintigraphy as diagnostic modalities in ATTRwt. METHODS: We divided 39 consecutive ATTRwt patients into two groups depending on whether serum hs-cTnT measurement and 99mTc-PYP scintigraphy were adopted as diagnostic tools: group A patients (n=8) who were diagnosed before the introduction of these two tools and group B patients (n=31) who were diagnosed after the introduction of the two tools. We retrospectively evaluated the two groups. RESULTS: Diagnostic yield was higher in group B than in group A (1.2 vs. 5.4 ATTRwt patients per 1000 hospitalized patients, p<0.01). Group B patients presented broad clinical features that were different from group A patients with classical characteristics. Atrial fibrillation was more frequent (12.5% vs. 58.1%, p=0.044) and inter-ventricular septum (IVS) thickness and relative wall thickness (RWT) were smaller in group B patients than in group A patients (IVS thickness: 16.1±2.4mm vs. 13.6±2.8mm, p=0.023; RWT: 0.71±0.11mm vs. 0.58±0.13mm, p=0.014). Furthermore, left ventricular hypertrophy (LVH) (IVS thickness ≥15mm) was more frequent in patients in group A than in patients in group B (87.5% vs. 33.3%, p=0.013). No significant difference was observed in the mean value of left ventricular ejection fraction (LVEF), whereas the dispersion of LVEF was high in group B (interquartile range: 47-58% vs. 39-57%). CONCLUSIONS: An integrated approach consisting of hs-cTnT measurement and 99mTc-PYP scintigraphy significantly increases the diagnostic rate of ATTRwt and has a high potential to identify ATTRwt patients with a variety of clinical phenotypes.

17.
Hepatol Commun ; 3(12): 1687-1703, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31832575

RESUMO

The circadian rhythm of the liver plays an important role in maintaining its metabolic homeostasis. We performed comprehensive expression analysis of microRNAs (miRNAs) using TaqMan polymerase chain reaction of liver biopsy tissues to identify the miRNAs that are significantly up-regulated in advanced chronic hepatitis C (CHC). We found miR-10a regulated various liver metabolism genes and was markedly up-regulated by hepatitis C virus infection and poor nutritional conditions. The expression of miR-10a was rhythmic and down-regulated the expression of the circadian rhythm gene brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1) by directly suppressing the expression of RA receptor-related orphan receptor alpha (RORA). Overexpression of miR-10a in hepatocytes blunted circadian rhythm of Bmal1 and inhibited the expression of lipid synthesis genes (sterol regulatory element binding protein [SREBP]1, fatty acid synthase [FASN], and SREBP2), gluconeogenesis (peroxisome proliferator-activated receptor gamma coactivator 1 alpha [PGC1α]), protein synthesis (mammalian target of rapamycin [mTOR] and ribosomal protein S6 kinase [S6K]) and bile acid synthesis (liver receptor homolog 1 [LRH1]). The expression of Bmal1 was significantly correlated with the expression of mitochondrial biogenesis-related genes and reduced Bmal1 was associated with increased serum alanine aminotransferase levels and progression of liver fibrosis in CHC. Thus, impaired circadian rhythm expression of Bmal1 by miR-10a disturbs metabolic adaptations, leading to liver damage, and is closely associated with the exacerbation of abnormal liver metabolism in patients with advanced CHC. In patients with hepatitis C-related liver cirrhosis, liver tissue miR-10a levels were significantly associated with hepatic reserve, fibrosis markers, esophageal varix complications, and hepatitis C-related hepatocellular carcinoma recurrence. Conclusion: MiRNA-10a is involved in abnormal liver metabolism in cirrhotic liver through down-regulation of the expression of the circadian rhythm gene Bmal1. Therefore, miR-10a is a possible useful biomarker for estimating the prognosis of liver cirrhosis.

18.
BMC Gastroenterol ; 19(1): 217, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842768

RESUMO

BACKGROUND: Portal vein thrombosis (PVT) is a common complication of cirrhosis. However, in patients with PVT and cirrhosis, there is no clear evidence supporting effective treatment modalities. In this study, we examined the effectiveness and safety of anticoagulation therapy using danaparoid sodium for PVT in patients with cirrhosis. METHODS: This retrospective study assessed 52 cirrhotic patients with PVT treated with danaparoid sodium for 2 weeks between November 2008 and September 2018. The primary outcome measure was the post-treatment status of PVT assessed by reduction in thrombus volume and safety of the therapeutic intervention. PVT status was evaluated with contrast-enhanced computed tomography (CECT). All patients received 1250 units of danaparoid sodium twice daily by intravenous injection for 14 days. Patients on antithrombin III (AT-III) combination therapy were additionally administered 1500 units of AT-III on days 1-5 and days 8-12. Effectiveness was evaluated by CECT from between days 13 and 18. The secondary outcome measure was the prognosis of PVT. RESULTS: All patients showed reduction in PVT volume without complications. Return of plasma AT-III level to > 70% during the treatment period contributes to ≥75% reduction of PVT volume. The prognosis in PVT patients depends on hepatic reserve capacity. When limited to Child-Pugh B and C liver cirrhosis patients, a ≥ 75% reduction of PVT volume improved the prognosis. CONCLUSIONS: Danaparoid sodium-based anticoagulation therapy was effective and safe for PVT in patients with cirrhosis. Return of plasma AT-III level to the normal range during the treatment period contributes to reduction of PVT volume. A reduction of ≥75% in PVT volume may improve the prognosis of Child-Pugh B and C decompensated cirrhosis patients with PVT.


Assuntos
Anticoagulantes/uso terapêutico , Sulfatos de Condroitina/uso terapêutico , Dermatan Sulfato/uso terapêutico , Heparitina Sulfato/uso terapêutico , Cirrose Hepática/complicações , Veia Porta , Trombose Venosa/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Trombose Venosa/etiologia
19.
Genome Biol ; 20(1): 252, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767028

RESUMO

BACKGROUND: Recent metagenomic analyses have revealed dysbiosis of the gut microbiota of ulcerative colitis (UC) patients. However, the impacts of this dysbiosis are not fully understood, particularly at the strain level. RESULTS: We perform whole-genome shotgun sequencing of fecal DNA extracts from 13 healthy donors and 16 UC and 8 Crohn's disease (CD) patients. The microbiota of UC and CD patients is taxonomically and functionally divergent from that of healthy donors, with E. faecium being the most differentially abundant species between the two microbial communities. Transplantation of feces from UC or CD patients into Il10-/- mice promotes pathological inflammation and cytokine expression in the mouse colon, although distinct cytokine expression profiles are observed between UC and CD. Unlike isolates derived from healthy donors, E. faecium isolates from the feces of UC patients, along with E. faecium strain ATCC 19434, promotes colitis and colonic cytokine expression. Inflammatory E. faecium strains, including ATCC 19434 and a UC-derived strain, cluster separately from commercially available probiotic strains based on whole-genome shotgun sequencing analysis. The presence of E. faecium in fecal samples is associated with large disease extent and the need for multiple medications in UC patients. CONCLUSIONS: E. faecium strains derived from UC patients display an inflammatory genotype that causes colitis.

20.
Neurology ; 93(17): e1587-e1596, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31511348

RESUMO

OBJECTIVE: To elucidate the clinical characteristics of acquired ATTR amyloidosis after domino liver transplantation (DLT) with liver grafts explanted from patients with hereditary variant ATTR (ATTRv) amyloidosis. METHODS: We evaluated the presence of amyloid deposits and clinical symptoms in 30 recipients of domino liver transplants (24 men and 6 women) who underwent DLT with liver grafts explanted from patients with ATTRv amyloidosis. We analyzed symptoms and measures of 7 cases of symptomatic acquired ATTR amyloidosis and compared those with 30 patients with ATTRv amyloidosis who were the domino liver donors. We also reviewed the literature on case studies of acquired ATTR amyloidosis. RESULTS: We found amyloid deposition in 13 of our 30 domino liver recipients. A Kaplan-Meier analysis estimated that the median time from DLT to the first detection of amyloid was 8.5 years. In the literature review, the mean time was 7.3 years, with a wide range of 0.5-13 years. Our 7 symptomatic cases and the literature cases with acquired ATTR amyloidosis presented with clinical features that differed from patients with ATTRv amyloidosis who were the domino liver donors. Patients with acquired ATTR amyloidosis showed markedly milder autonomic disturbance, which is one of the main symptoms of ATTRv amyloidosis. CONCLUSIONS: Careful monitoring is required for DLT recipients of ATTRv liver grafts because the time from DLT to disease onset has a wide range and the clinical picture of these DLT recipients is distinct from that of liver donors.


Assuntos
Amiloidose/etiologia , Transplante de Fígado , Complicações Pós-Operatórias , Adolescente , Adulto , Feminino , Humanos , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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