BackgroundColorectal cancer (CRC) is a major worldwide health problem due to its high prevalence and mortality rate. T-cell intracellular antigen 1 (TIA1) is an important tumor suppressor involved in many aspects of carcinogenesis and cancer development. How TIA1 expression is regulated during CRC development remains to be carefully elucidated.MethodsIn CRC tissue sample pairs, TIA1 protein and mRNA levels were monitored by Western blot and qRT-PCR, respectively. Combining meta-analysis and miRNA target prediction software, we could predict microRNAs that targeted TIA1. Next, three CRC cell lines (SW480, Caco2 and HT29) were used to demonstrate the direct targeting of TIA1 by miR-19a. In addition, we investigated the biological effects of TIA1 inhibition by miR-19a both in vitro by CCK-8, EdU, Transwell, Ki67 immunofluorescence and Colony formation assays and in vivo by a xenograft mice model.ResultsIn colorectal cancer (CRC), we found that TIA1 protein, but not its mRNA, was downregulated. We predicted that TIA1 was a target of miR-19a and validated that miR-19a binded directly to the 3’-UTR of TIA1 mRNA. miR-19a could promote cell proliferation and migration in CRC cells and accelerated tumor growth in xenograft mice by targeting TIA1.ConclusionsThis study highlights an oncomiR role for miR-19a in regulating TIA1 in CRC and suggests that miR-19a may be a novel molecular therapeutic target for CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0625-8) contains supplementary material, which is available to authorized users.
Polymorphisms in CYP2C9 and VKORC1 have been shown to be associated with warfarin dose requirements and could be used to predict warfarin dose. We conducted a prospective study in which warfarin dose was prescribed based on CYP2C9 and VKORC1 polymorphisms in 108 Han-Chinese patients without prior warfarin treatments. Using the genotype-based dosing, 83% of patients reached stable, therapeutic international normalized ratio (INR) within 2 weeks of treatment initiation and none of the patients developed clinical bleeding or thromboembolic event. Ten percent (11) of patients with INR > 4 and no clinical bleeding were detected during this study. At 12 weeks, 69% of the patients' maintenance doses matched the prediction. Dosing algorithms incorporating genetic factors, age, and body surface area were developed, which could explain up to 62% of the total variation (R(2) of 0.62). This study demonstrated that pharmacogenetics-based dosing could improve time to stable, therapeutic INR, reduce adverse events, and achieve high sensitivity.
The use of a transanal drainage tube in anterior resection for rectal cancer may be a simple, safe, and effective means of preventing or reducing the occurrence of anastomotic leakage and bleeding. A larger-scale single or multi-center prospective randomized study or a meta-analysis including similar studies is necessary for further elucidation of this issue.
Background Appendectomy is considered the first treatment choice for appendicitis. However, controversy exists since conservative therapy is associated with fewer complications than appendectomy for patients with acute appendicitis (AA). This meta-analysis aimed to compare the outcomes between conservative therapy and appendectomy in the management of adult AA. Methods A literature search was performed to screen eligible clinical studies. Subgroup analyses of the uncomplicated population, complicated population and mixed population of randomized clinical trials were subsequently performed. Clinical outcomes included the overall effective rate of treatment, complication rate, relapse rate (reoperation rate) and overall length of stay (LOS). Results Eleven trials totalling 2751 patients (conservative = 1463, appendectomy = 1288) were analysed. Patients receiving conservative treatment had a lower overall effective rate (OR: 0.11 ~ 0.17) and complication rate (OR: 0.21 ~ 0.51). The conservative group had a higher reoperation rate (5.6, 95% CI: 3.1% ~ 10.2%) than the appendectomy group (OR: 9.58 ~ 14.29). Conservative treatment was associated with a shorter overall length of stay (0.47 day, 95% CI: 0.45 ~ 0.5 day) than appendectomy. Conclusions For both uncomplicated and complicated adult AA, non-operative management with antibiotics was associated with significantly fewer complications and a shorter length of stay but a lower effective rate and higher relapse rate.
ObjectiveCongenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited.Design and methodsOne hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees.ResultsOur results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands.ConclusionsMost cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.
Disorders of sexual development (DSD) are rare congenital conditions in which chromosomal, gonadal, or anatomical sex is atypical. Currently, less than 20% of patients receive an accurate genetic diagnosis. Targeted next-generation sequencing, consisting of 33 candidate genes and 47 genes involved in sexual differentiation and development, was performed on 70 46, XY DSD patients. Functional assays were performed to evaluate the expression and transcriptional activity of one reported and nine novel mutations of NR5A1. In total, 113 mutations, including 86 novel and 27 reported sites in 40 genes, were identified in 52 patients. Among them, 37 mutations from 19 genes were first identified in 46, XY DSD patients, including EGF, LHX9, and CST9. Nine patients displayed biallelic mutations, 12 had mutations in sex chromosome genes and 14 had monoallelic mutations in NR5A1, BMP4, and WT1. Higher frequency mutations were identified in AR, SRD5A2, and NR5A1. Six missense, one frameshift, and one three-nucleotide deletion mutations of NR5A1 were shown to impair the transactivation ability with an altered nuclear aggregation of p.T29K and p.N44del variants. Multiple genetic mutations were identified in 33 of the 70 patients. The targeted sequencing panel provides an efficient method for the etiological diagnosis of 46, XY DSD patients and expands the candidate genes and inherited patterns.
Introduction: A subset of regulatory B cells in humans and mice has been defined functionally by their ability to produce interleukin (IL)-10. We characterized IL-10-producing B (B10) cells in myasthenia gravis (MG) patients and correlated them with disease activity and responsiveness to rituximab therapy. Methods: Frequencies of B10 cells from MG patients and healthy controls were monitored by fluorescenceactivated cell sorting (FACS). Results: MG patients had fewer B10 cells than controls, which was associated with more severe disease status. Moreover, patients who responded well to rituximab therapy exhibited rapid repopulation of B10 cells, whereas in patients who did not respond well to rituximab, B10 cell repopulation was delayed. The kinetics of B10 cells were related to the responsiveness to rituximab in MG. Conclusions: We have characterized a specific subset of B10 cells in MG patients which may serve as a marker for disease activity and responsiveness to immune therapy.
BackgroundColorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood.MethodsIn CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR’s 3’-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun’s occupancy on the C17orf91 promoter.ResultsWe observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3’-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22.ConclusionsOur findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0751-3) contains supplementary material, which is available to authorized users.
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