Abstract from the Chinese Journal of Hypertension

Association of Methylenetetrahydrofolate Reductase Gene Polymorphisms With Hypertension and Homocysteine Levels in a Hui Ethnic Population of Yinchuan

https://ift.tt/2QIg0cc

Abstract from the Chinese Journal of Hypertension

Cardiac-Specific Overexpression of Heat Shock Protein 27 Activates Mitophagy and Alleviates Cardiac Aging

https://ift.tt/2E8o3s8

Resistant Hypertension: An Update

With the recent publication of the revised American Heart Association (AHA) Scientific Statement on Resistant Hypertension: Detection, Evaluation, and Management as well as other critical documents, major advances have been in our in how resistant hypertension (RHTN) and is defined, diagnosed, and best treated as well as our understanding of the pathophysiology of RHTN.¹ The new Scientific Statement is important in defining RHTN much more comprehensively than simply based on the blood pressure (BP) level and number of prescribed medications as it has been expanded to incorporate exclusion of common pseudocauses of treatment resistance, specifically inaccurate BP measurement, a prominent white-coat effect, undertreatment, and poor medication adherence. The new American College of Cardiology (ACC)/AHA hypertension guidelines are important in providing a preliminary estimate of the prevalence of RHTN based on the now lower recommended BP goal of 130/80 mm Hg.² The landmark PATHWAY-2 study adds importantly to our understanding of the pathophysiology of RHTN and provides compelling evidence for the most effective multiple-drug combination for treating RHTN, including especially, preferential use of spironolactone.³ This editorial serves to highlight these recent advances.

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Yellowish lesions in the oesophagus

Clinical presentation

A 51-year-old man, who had no previous disease, underwent a screening oesophagogastroduodenoscopy, which revealed multiple yellowish lesions in the middle thoracic oesophagus. All lesions were ≤3 mm in size and slightly elevated. Each lesion showed one or two white protrusions on the surface (figure 1). We observed that one lesion looked obviously different from the others and showed yellowish granular spots (figure 2). A biopsy was performed on a representative lesion among the slightly elevated yellowish lesions with white protrusions (figure 3). A biopsy was repeated on a lesion showing yellowish granular spots (figure 4). Blood tests which were examined on the same day, including triglyceride and cholesterol, were within normal limits. Figure 1

Slightly elevated yellowish lesions with white protrusions in the middle thoracic oesophagus.

Figure 2

A lesion showing yellowish granular spots in the middle thoracic oesophagus.

Question

What is the diagnosis?

https://ift.tt/2EkFl6u

SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer

Objective

To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6.

Design

We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo. SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo. Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novoby virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitroand in vivo.

Results

SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo. We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity.

Conclusions

SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6.

Accession numbers

The accession numbers for sequencing data are SRP111763 and SRP111797.

https://ift.tt/2RMM509

Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohns disease (ANDANTE I and II)

Objective

Neutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn's disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.

Design

Parallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up.

Results

247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn's Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis.

Conclusions

PF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development.

Trial registration number

NCT01287897 and NCT01345318.

https://ift.tt/2RCN56N

A trivalent HCV vaccine elicits broad and synergistic polyclonal antibody response in mice and rhesus monkey

Objective

Despite the development of highly effective direct-acting antivirals, a prophylactic vaccine is needed for eradicating HCV. A major hurdle of HCV vaccine development is to induce immunity against HCV with high genome diversity. We previously demonstrated that a soluble E2 (sE2) expressed from insect cells induces broadly neutralising antibodies (NAbs) and prevents HCV infection. The objective of this study is to develop a multivalent HCV vaccine to increase the antigenic coverage.

Design

We designed a trivalent vaccine containing sE2 from genotype 1a, 1b and 3a. Mice and rhesus macaques were immunised with monovalent or trivalent sE2 vaccine, and sera or purified immunoglobulin were assessed for neutralisation against a panel of cell culture-derived virion (HCVcc) of genotype 1–7 in cell culture. Splenocytes from the vaccinated macaques were assessed for HCV-specific T cell response.

Results

We showed that the trivalent vaccine elicited pangenotypic NAbs in mice, which neutralised HCVcc of all the seven genotypes more potently than the monovalent vaccine. Further analyses demonstrated that each sE2 component of this trivalent vaccine elicited unique spectrum of NAbs which acted synergistically to inhibit HCV infection. Finally, the trivalent vaccine triggered stronger and more uniform multigenotypic neutralising antibody response than the monovalent vaccine in rhesus macaques.

Conclusions

In summary, we developed a trivalent HCV vaccine that induces broad and synergistic-acting neutralising antibodies in mice and non-human primates.

https://ift.tt/2RCMRfX