Multiple genetic factors affecting the pharmacokinetic and pharmacodynamic processes of tacrolimus in Chinese myasthenia gravis patients.

PURPOSE: Tacrolimus is a novel effective immunosuppressant for myasthenia gravis (MG) patients. However, the narrow therapeutic window, and high inter- and intrapatient variation in bioavailability largely limited its clinical application. This article intended to find the SNPs influencing clinical outcome and discover the possible mechanisms. METHODS: Based on the tagSNPs genotyped by Improved Multiple Ligase Detection Reaction, Plink 1.07 was used to find the SNPs having close interaction to tacrolimus serum concentration, QMG score changes or even reasonable drug dose. Then we searched several databases to predict the possible miRNA binding rs15524 sequence. Based on the prediction, dual-luciferase reporter assay and miRNA transfection were used to discover the mechanism of how SNP rs15524 controls tacrolimus serum concentration through influencing CYP3A5 expression. RESULTS: In this article, we found multiple SNPs on CYP3A4, CYP3A5, FKBP1A, NFATC2 genes were predicted closely related to tacrolimus serum concentration, therapeutic effect which reflected by QMG score changes or even reasonable drug dose. After in silico miRNA selection, possible relationship between hsa-miR-500a and rs15524 was found. With the help of dual-luciferase reporter assay, wild-type rs15524 (T allele) was found having a stronger binding affinity for hsa-miR-500a. Higher expression of CYP3A5 may also led by lower hsa-miR-500a level. CONCLUSIONS: SNP rs15524 may control CYP3A5 expression by affecting the binding affinity between CYP3A5 3'UTR and hsa-miR-500a. Wild type (T allele) 3'UTR of CYP3A5 has stronger binding affinity to hsa-miR-500a and cause lower CYP3A5 expression and higher tacrolimus serum concentration.

MiR-15a contributes abnormal immune response in myasthenia gravis by targeting CXCL10.

MiR-15a is likely to be associated with autoimmunity. Here, we aimed to examine the expression of miR-15 cluster in PBMCs from myasthenia gravis (MG) patients and investigate the potential roles of miR-15a in MG. We found that the expression of all miR-15 cluster was decreased in MG, furthermore, miR-15a levels in ocular MG (oMG) were much lower, while CXCL10 production was increased in MG. We display that CXCL10 was a functional target gene of miR-15a in MG. Increasing miR-15a expression could reduce CXCL10 expression and alleviate the abnormal T cells activation in immune response, while decreasing miR-15a expression could activate immune response abnormally. Moreover, miR-15a expression was significantly decreased after stimulation, and prednisone treatment could upregulate miR-15a expression in steroid-responsive MG patients. Take together, our data suggest that decreased miR-15a expression facilitates proinflammatory cytokines production and contributes to immune response at least in part via regulating CXCL10 expression in MG.

Integrating Lipidomics and Transcriptomics Reveals the Crosstalk Between Oxidative Stress and Neuroinflammation in Central Nervous System Demyelination.

Multiple sclerosis (MS) is an incurable and progressive neurodegenerative disease that affects more than 2.5 million people worldwide and brings tremendous economic pressures to society. However, the pathophysiology of MS is still not fully elucidated, and there is no effective treatment. Demyelination is thought to be the primary pathophysiological alteration in MS, and our previous study found abnormal lipid metabolism in the demyelinated corpus callosum. Growing evidence indicates that central nervous system (CNS) demyelinating diseases never result from one independent factor, and the simultaneous participation of abnormal lipid metabolism, oxidative stress, and neuroinflammation could potentiate each other in the pathogenesis of MS. Therefore, a single omics analysis cannot provide a full description of any neurodegenerative disease. It has been demonstrated that oxidative stress and neuroinflammation are two reciprocal causative reasons for the progression of MS disease. However, the potential crosstalk between oxidative stress and neuroinflammation remains elusive so far. With an integrated analysis of targeted lipidomics and transcriptomics, our research presents the potential interaction between abnormalities of lipid metabolism, mitochondrial dysfunction, oxidative stress, and neuroinflammation in CNS demyelinating diseases. The findings of this paper may be used to identify possible targets for the therapy of CNS demyelinating diseases.

Primary intestinal extranodal natural killer/T-cell lymphoma, nasal type: A case report.

BACKGROUND: Primary intestinal extranodal natural killer/T-cell lymphoma, nasal type (PI-ENKTCL) is a rare non-Hodgkin's lymphoma (NHL) subtype, and its prognosis is extremely poor. Clinical characteristics of the disease are not obvious and easily misdiagnosed. In this case report, we describe a patient with PI-ENKTCL who presented with intermittent hematochezia. The advantages of positron emission tomography/computed tomography (PET-CT) as a useful diagnostic tool and the role of surgery as an important therapy are highlighted. CASE SUMMARY: A 45-year-old man, hospitalized due to intermittent hematochezia, underwent gastroscopy, colonoscopy, biopsy and CT, but no cause was found. Hence, we carried out a multidisciplinary team (MDT) discussion on the causes and treatment of this patient, and it was decided to perform PET-CT imaging with a MDT discussion of the results. PET-CT demonstrated a diagnosis of lymphoma and it was decided to surgically resect the lesion, and a R0 resection was successfully performed. Postoperative pathology showed negative resection margins, and examination of the lesion confirmed the diagnosis of PI-ENKTCL. After surgery, the patient underwent a follow-up period of 6 mo and received 6 cycles of gemcitabine, oxaliplatin and L-asparaginase. No recurrence or metastasis occurred. CONCLUSION: PI-ENKTCL is rare, and MDT discussion is required during diagnosis. PET-CT can be performed for imaging diagnosis. Treatment is based on surgical resection, and the best treatment regimen is determined according to postoperative pathological results to improve prognosis and to extend survival in patients.

Application of multiple Roux-en-Y hepaticojejunostomy reconstruction by formation of bile hilar duct lake in the operation of hilar cholangiocarcinoma.

BACKGROUND: Hilar cholangiocarcinoma is the most common malignant tumor of the extrahepatic bile duct. Until now, radical resection has been the most effective method for the long-term survival of patients with the disease. However, many problems have emerged in the field of hepatobiliary surgery for a long time, including complex surgical procedures, low resection rate, and postoperative complications. We have adopted the "multiple Roux-en-Y hepaticojejunostomy reconstruction by formation of a bile duct lake" technique in the treatment of hilar cholangiocarcinoma since 2008, and obtained satisfactory short- and long-term results. AIM: To examine the feasibility of the application of multiple Roux-en-Y hepaticojejunostomy reconstruction by formation of a bile duct lake in the operation of hilar cholangiocarcinoma. METHODS: A retrospective analysis was performed for the clinical data, surgical methods, and results of 76 patients with hilar cholangiocarcinoma who were treated with hilar bile duct lake-forming multiple Roux-en-Y hepaticojejunostomy reconstruction at Gansu Provincial Hospital. RESULTS: In all 76 cases, the operation was successful and no operative death occurred. The mean (range) operation time was 215.4 ± 53.5 min (124-678 min), and the amount of bleeding during the operation was 428.2 ± 63.8 mL (240-2200 mL). The overall 1-year survival rate was 78.9%, and the 3-year survival rate was 32.8%. CONCLUSION: The multiple Roux-en-Y hepaticojejunostomy reconstruction technique with formation of a bile duct lake is safe and effective for the surgical treatment of hilar cholangiocarcinoma.

Increased KIF21B expression is a potential prognostic biomarker in hepatocellular carcinoma.

BACKGROUND: The kinesin superfamily protein member KIF21B plays an important role in regulating mitotic progression; however, the function and mechanisms of KIF21B in cancer, particularly in hepatocellular carcinoma (HCC), are unknown. AIM: To explore the role of KIF21B in hepatocellular carcinoma and its effect on prognosis after hepatectomy. METHODS: First, data on the differential expression of KIF21B in patients with HCC from The Cancer Genome Atlas database was analyzed. Subsequently, the expression levels of KIF21B in HCC cell lines and hepatocytes were detected by reverse transcription-polymerase chain reaction, and its biological effect on BEL-7404 cells was evaluated by KIF21B knockdown. Immunohistochemical analysis was used to validate the differential expression of KIF21B in HCC tissues and adjacent normal tissues from 186 patients with HCC after hepatectomy. The Kaplan-Meier method was used to assess prognosis significance. RESULTS: KIF21B expression levels were significantly higher in HCC tissues than in corresponding adjacent normal tissues. The expression levels of KIF21B in four HCC cell lines were higher than that in normal liver cells. Functional experiments showed that KIF21B knockdown remarkably suppressed cell proliferation and induced apoptosis. Moreover, immunohistochemistry results are consistent with The Cancer Genome Atlas analysis, with KIF21B expression levels being increased in HCC tissues compared to adjacent normal tissues. Univariate and multivariate analyses revealed KIF21B as an independent risk factor for overall survival and disease-free survival in patients with HCC after hepatectomy. CONCLUSION: Taken together, our results provide evidence that KIF21B plays an important role in HCC progression and may be a potential diagnostic and prognostic marker for HCC.

Glial pathology in bipolar disorder: potential therapeutic implications.

Bipolar disorder (BD) is a chronic and severe mental disorder with recurrent episodes of mania and depression. In addition to neuronal alterations, accumulating evidences have revealed the importance of glial system in pathophysiology and phenotype of the illness. Postmortem studies have repeatedly demonstrated the alterations in glial cells and its functions in patients with BD. The activated microglia and inflammatory cytokines are proposed to be the potential biomarkers that may help to predict disease exacerbation in BD. On the other hand, anti-BD drugs have been shown to produce profound effects on glial activity, which not only contributes to the therapeutic efficacy, but may also provide a potential target for the drug development of BD. We will focus on the recent development of glial abnormalities and potential therapeutic benefits targeted to glial modulation in BD.