Mutations in TAX1BP3 Cause Dilated Cardiomyopathy with Septo‐Optic Dysplasia

We describe a Bedouin family with a novel autosomal recessive syndrome characterized by dilated cardiomyopathy and septo‐optic dysplasia. Genetic analysis revealed a homozygous missense mutation in TAX1BP3, which encodes a small PDZ domain containing protein implicated in regulation of the Wnt/β‐catenin signaling pathway, as the causative mutation. The mutation affects a conserved residue located at the core of TAX1BP3 binding pocket and is predicted to impair the nature of a crucial hydrophobic patch, thereby interrupting the structure and stability of the protein, and its ability to interact with other proteins. TAX1BP3 is highly expressed in heart and brain and consistent with the clinical findings observed in our patients; a knockdown of TAX1BP3 causes elongation defects, enlarged pericard, and enlarged head structures in zebrafish embryos. Thus, we describe a new genetic disorder that expands the monogenic cardiomyopathy disease spectrum and suggests that TAX1BP3 is essential for heart and brain development.     

The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway

Aim:

(−)-Epigallocatechin-3-gallate (EGCG) is one of the most abundant polyphenols in green tea with strong antioxidant activity and various therapeutic effects. In this study, we investigated the anti-fibrotic effects of EGCG and underlying mechanisms in bile duct-ligated (BDL) rats and a liver fibrosis model in vitro.

Methods:

BDL rats were treated with EGCG (25 mg·kg⁻¹·d⁻¹, po) for 14 d, and then the serum, bile and liver samples were collected. Liver fibrosis was assessed by serum, urine and bile biochemistry analyses and morphological studies of liver tissues. TGF-β1-stimulated human hepatic stellate LX-2 cells were used as a liver fibrosis model in vitro. The expression of liver fibrogenic genes and signaling proteins in the PI3K/Akt/Smad pathway was examined using Western blotting and/or real-time PCR.

Results:

In BDL rats, EGCG treatment significantly ameliorates liver necrosis, inflammation and fibrosis, and suppressed expression of the genes associated with liver inflammation and fibrogenesis, including TNF-α, IL-1β, TGF-β1, MMP-9, α-SMA, and COL1A1. In LX-2 cells, application of EGCG (10, 25 μmol/L) dose-dependently suppressed TGF-β1-stimulated expression of COL1A1, MMP-2, MMP-9, TGF-β1, TIMP1, and α-SMA. Furthermore, EGCG significantly suppressed the phosphorylation of Smad2/3 and Akt in the livers of BDL rats and in TGF-β1-stimulated LX-2 cells. Application of {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, a specific inhibitor of PI3K, produced similar effects as EGCG did in TGF-β1-stimulated LX-2 cells, but co-application of EGCG and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 did not produce additive effects.

Conclusion:

EGCG exerts anti-fibrotic effects in BDL rats and TGF-β1-stimulated LX-2 cells in vitro via inhibiting the PI3K/Akt/Smad pathway.     

Comprehensive profiling of novel microRNA-9 targets and a tumor suppressor role of microRNA-9 via targeting IGF2BP1 in hepatocellular carcinoma

MicroRNA-9 (miR-9) dysregulation is implicated in a variety of human malignancies including hepatocellular carcinoma (HCC), but its role remains contradictory. In this study, we explored the expression and methylation status of miR-9 in HCC samples, as well as the tumor-related functions of miR-9 in vitro. Bioinformatics analysis, array-based RNA expression profile, and literature retrieval were used to identify miR-9 targets in HCC. The potential downstream candidates were then validated by luciferase reporter assay, real-time quantitative PCR, and western blot or enzyme linked immunosorbent assay (ELISA). The expression status and clinicopathologic significances of miR-9 target genes in clinical samples were further explored. The results showed that miR-9 was frequently downregulated in primary HCC. Its silencing was largely contributed by a high frequency (42.5%) of mir-9-1 hypermethylation, which was correlated with bigger tumor size (P = 0.0234). In vitro functional studies revealed that miR-9 restoration retarded HCC cell proliferation and migration. IL-6, AP3B1, TC10, ONECUT2, IGF2BP1, MYO1D, and ANXA2 were confirmed to be miR-9 targets in HCC. Among them, ONECUT2, IGF2BP1, and ANXA2 were confirmed to be aberrantly upregulated in HCC. Moreover, upregulation of ONECUT2, IGF2BP1, and IL-6 were significantly associated with poor post-surgery prognosis (P = 0.0458, P = 0.0037 and P = 0.0461, respectively). Mechanically, miR-9 plays a tumor suppressive role partially through a functional miR-9/IGF2BP1/AKT&ERK axis. Our study suggests that miR-9 functions as a tumor suppressor in HCC progression by inhibiting a series of target genes, including the newly validated miR-9/IGF2BP1/AKT&ERK axis, thus providing potential therapeutic targets and novel prognostic biomarkers for HCC patients.     

Involvement of Ras GTPase-activating protein SH3 domain-binding protein 1 in the epithelial-to-mesenchymal transition-induced metastasis of breast cancer cells via the Smad signaling pathway

In situ models of epithelial-to-mesenchymal transition (EMT)-induced carcinoma develop into metastatic carcinoma, which is associated with drug resistance and disease recurrence in human breast cancer. Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1), an essential Ras mediator, has been implicated in cancer development, including cell growth, motility, invasion and apoptosis. Here, we demonstrated that the upregulation of G3BP1 activates the EMT in breast cancer cells. Silencing Smads almost completely blocked this G3BP1-induced EMT, suggesting that this process depends on the Smad signaling pathway. We also found that G3BP1 interacted with the Smad complex. Based on these results, we proposed that G3BP1 might act as a novel co-factor of Smads by regulating their phosphorylation status. Moreover, knockdown of G3BP1 suppressed the mesenchymal phenotype of MDA-MB-231 cells in vitro and suppressed tumor growth and lung metastasis of 4T1 cells in vivo. Our findings identified a novel function of G3BP1 in the progression of breast cancer via activation of the EMT, indicating that G3BP1 might represent a potential therapeutic target for metastatic human breast cancer.     

Clinical outcomes of community pharmacy services: A systematic review and meta‐analysis

Community pharmacy services (CPS) have been shown to be positive in many disease management and patient care programs, but clinical outcomes were followed by process indicators and methodological flaws in previous researches made it difficult to prove the effectiveness of clinical outcomes of CPS. Therefore, this study attempted to review the clinical outcomes of CPS. Interventions included are provision of medication review, patient education, adherence assessment, health/lifestyle advice, physical assessment, monitoring, prescribing, or adjusting and administering therapy from community pharmacists. By searching for key words like community pharmacists, pharmaceutical services, clinical outcomes in MEDLINE and EMBASE and manually searching (up to June 2017), 1910 studies investigating the clinical outcomes of CPS were obtained. After screening the titles, abstracts and full texts for relevancy, 52 researches with controlled groups were included and assessed for methodological quality. Finally, 25 studies were selected for the meta‐analysis based on their common endpoints: systolic blood pressure, diastolic blood pressure and glycosylated haemoglobin. The Cochrane tool was used to assess the risk of bias. Chi‐square and I‐square tests were performed to assess heterogeneity, and the weighted mean differences were estimated using random effect models. Of the 52 articles, 47 studies demonstrated that CPS had positive clinical outcomes, 3 studies showed mixed outcomes and 2 studies revealed no effects. In the meta‐analysis, intervention groups displayed greater reductions in systolic BP (95% CI: ?8.198–2.356), diastolic BP (95% CI: ?3.648–0.645) and HbA1c (95% CI: ?0.905–0.224) than usual care groups. CPS have positive clinical outcomes, particularly significant reductions in systolic BP, diastolic BP and HbA1c. It was difficult to find out which intervention(s) of CPS directly led to certain changes and influence of CPS might be underestimated for only three common surrogate endpoints. More researches should be conducted with sufficient data.     

Painful Hip Arthroplasty: What Should We Find? Diagnostic Approach and Results

IntroductionIdentifying the source of pain is paramount for determining appropriate treatment and ensuring successful outcome in terms of management and relief of pain. The difficulty is that each surgeon has his or her own way of seeing the problem, and there is no consensus for the evaluation of these patients. The study hypothesis was that it is possible to find the cause of the pain in most cases.Patients and methodsAll patients consulting for unexplained painful hip arthroplasty were included and followed a decision tree to assess the cause of the pain. The primary endpoint was the final diagnosis. Secondary endpoints were subgroup comparison between main causes and assessment of risk factors.ResultsTwo hundred one hips of 194 patients were included as unexplained painful hip arthroplasty 6 months postoperatively. Final diagnoses comprised periarticular pain in 53 cases (26.4%): 40 cases of trochanteric bursitis, 5 of iliopsoas tendinitis, 5 of abductor deficiency, 1 of ischial tuberosity tendinitis, and 2 of heterotopic ossification; projected pain in 49 (24.4%): 45 cases of back pain with or without neuropathy, 3 of knee osteoarthritis, and 1 of metabolic neuropathy; wear in 40 (19.9%), in the polyethylene liner; loosening in 20 (10.0%): loosening of the femoral component in 8 and that of the cup in 12; material problems in 17 (8.5%): trunnionosis in 13 and metallosis in metal-on-metal implants in 4; no diagnosis in 7 hips (3.5%); infection in 6 (3.0%), all chronic; instability without real dislocation in 3 (1.5%); misplacement in 3 (1.5%), all for leg-length discrepancy; fracture in 2 (1.0%): 1 of greater trochanter and 1 of ilio-ischiopubic ramus; complex regional pain syndrome in 1 (0.5%).DiscussionTo our knowledge, this is the first study on the causes of painful hip arthroplasty in clinical practice, whether leading to revision or not. A systematic approach, including physical examination, radiographic assessment and laboratory studies, is needed to find the cause of the pain. It is important to understand the pain so that it can be treated appropriately. Revision surgery can sometimes help—but the worst thing is to make the patient worse.Level of Evidencelevel 4, retrospective study.     

Prediction of inflammatory responses induced by biomaterials in contact with human blood using protein fingerprint from plasma

Inappropriate complement activation is often responsible for incompatibility reactions that occur when biomaterials are used. Complement activation is therefore a criterion included in legislation regarding biomaterials testing. However, no consensus is yet available regarding appropriate complement-activation-related test parameters. We examined protein adsorption in plasma and complement activation/cytokine release in whole blood incubated with well-characterized polymers. Strong correlations were found between the ratio of C4 to its inhibitor C4BP and generation of 10 (mainly pro-inflammatory) cytokines, including IL-17, IFN-γ, and IL-6. The levels of complement activation products correlated weakly (C3a) or not at all (C5a, sC5b-9), confirming their poor predictive values. We have demonstrated a direct correlation between downstream biological effects and the proteins initially adhering to an artificial surface after contact with blood. Consequently, we propose the C4/C4BP ratio as a robust, predictor of biocompatibility with superior specificity and sensitivity over the current gold standard.     

Postural Orthostatic Tachycardia Syndrome: JACC Focus Seminar

Postural orthostatic tachycardia syndrome (POTS), the most common form of orthostatic intolerance in young people, affects approximately 500,000 people in the United States alone, typically young women at the peak of their education and the beginning of their working lives. This is a heterogeneous disorder, the pathophysiology and mechanisms of which are not well understood. There are multiple contributing factors and numerous potential mimics. This review details the most current views on the potential causes, comorbid conditions, proposed subtypes, differential diagnoses, evaluations, and treatment of POTS from cardiological and neurological perspectives.