No abstract

Tumor necrosis factor-alpha (TNF-α) plays an important pathogenic role in cardiac hypertrophy and heart failure (HF); however, anti-TNF is paradoxically negative in clinical trials and even worsens HF, indicating a possible protective role of TNF-α in HF. TNF-α exists in transmembrane (tmTNF-α) and soluble (sTNF-α) forms. Herein, we found that TNF receptor 1 (TNFR1) knockout (KO) or knockdown (KD) by short hairpin RNA or small interfering RNA (siRNA) significantly alleviated cardiac hypertrophy, heart dysfunction, fibrosis, and inflammation with increased tmTNF-α expression, whereas TNFR2 KO or KD exacerbated the pathological phenomena with increased sTNF-α secretion in transverse aortic constriction (TAC)- and isoproterenol (ISO)-induced cardiac hypertrophy in vivo and in vitro, respectively, indicating the beneficial effects of TNFR2 associated with tmTNF-α. Suppressing TNF-α converting enzyme by TNF-α Protease Inhibitor-1 (TAPI-1) to increase endogenous tmTNF-α expression significantly alleviated TAC-induced cardiac hypertrophy. Importantly, direct addition of exogenous tmTNF-α into cardiomyocytes in vitro significantly reduced ISO-induced cardiac hypertrophy and transcription of the pro-inflammatory cytokines and induced proliferation. The beneficial effects of tmTNF-α were completely blocked by TNFR2 KD in H9C2 cells and TNFR2 KO in primary myocardial cells. Furthermore, we demonstrated that tmTNF-α displayed antihypertrophic and anti-inflammatory effects by activating the AKT pathway and inhibiting the nuclear factor (NF)-κB pathway via TNFR2. Our data suggest that tmTNF-α exerts cardioprotective effects via TNFR2. Specific targeting of tmTNF-α processing, rather than anti-TNF therapy, may be more useful for the treatment of hypertrophy and HF.

Transmembrane TNF-α (tmTNF-α) and secretory TNF-α (sTNF-α) display opposite effects in septic shock. Reducing tmTNF-α shedding can offset the detrimental effects of sTNF-α and increase the beneficial effect of tmTNF-α. We previously developed a monoclonal antibody that is specific for tmTNF-α and does not cross-react with sTNF-α. In this study, we show that this antibody can specifically suppress tmTNF-α shedding by competing with a TNF-α converting enzyme that cleaves the tmTNF-α ectodomain to release sTNF-α. This tmTNF-α antibody significantly inhibited LPS-induced secretion of interleukin (IL)-1β, IL-6, interferon-β, and nitric oxide by monocytes/macrophages, and protected mice from septic shock induced by lipopolysaccharide (LPS) or cecal ligation and puncture, while reducing the bacterial load. The mechanism associated with the protective effect of this tmTNF-α antibody involved promotion of LPS-induced toll-like receptor 4 (TLR4) internalization and degradation by recruiting Triad3A to TLR4. Moreover, the tmTNF-α antibody inhibited LPS-induced activation of nuclear factor-κB and interferon regulatory factor 3 pathways by upregulating expression of A20 and monocyte chemotactic protein-induced protein 1. Similarly, treatment of macrophages with exogenous tmTNF-α suppressed LPS/TLR4 signaling and release of proinflammatory cytokines, indicating that increased levels of tmTNF-α promoted by the antibody contributed to its inhibitory effect. Thus, use of this tmTNF-α antibody for specific suppression of tmTNF-α shedding may be a promising strategy to treat septic shock.

Background. Epithelial ovarian cancer (EOC) is a heterogeneous disease, which has been recently classified into four molecular subtypes, of which the mesenchymal subtype exhibited the worst prognosis. We aimed to identify a microRNA- (miRNA-) based signature by incorporating the molecular modalities involved in the mesenchymal subtype for risk stratification, which would allow the identification of patients who might benefit from more rigorous treatments. Method. We characterized the regulatory mechanisms underlying the mesenchymal subtype using network analyses integrating gene and miRNA expression profiles from The Cancer Genome Atlas (TCGA) cohort to identify a miRNA signature for prognosis prediction. Results. We identified four miRNAs as the master regulators of the mesenchymal subtype and developed a risk score model. The 4-miRNA signature significantly predicted overall survival (OS) and progression-free survival (PFS) in discovery (p=0.004 and p=0.04) and two independent public datasets (GSE73582: OS, HR: 2.26 (1.26-4.05), p=0.005, PFS, HR: 2.03 (1.34-3.09), p<0.001; GSE25204: OS, HR: 3.07 (1.73-5.46), p<0.001, PFS, HR: 2.59 (1.72-3.88), p<0.001). Moreover, in multivariate analyses, the miRNA signature maintained as an independent prognostic predictor and achieved superior efficiency compared to the currently used clinical factors. Conclusions. In conclusion, our network analysis identified a 4-miRNA signature which has prognostic value superior to currently reported clinical covariates. This signature warrants further testing and validation for use in clinical practice.

Columnar cell variant of papillary thyroid carcinoma (CCV-PTC) is an unusual neoplasm, the clinical behavior of which mainly depends on the encapsulation or infiltration. Patients with extensive extrathyroidal extension usually have an aggressive biological behavior. This study confirmed that beta-human chorionic gonadotropin (β-hCG) secreting invasive CCV-PTC has good prognosis comparing with a cohort of follicular cell differentiated thyroid carcinoma. On the contrary, positive immunoreaction with β-hCG was proved in three anaplastic thyroid carcinoma patients showing aggressive clinical courses. The clinicopathologic characteristics of CCV-PTC and the paraneoplastic syndromes in follicular cell differentiated thyroid carcinoma were further summarized using literature review.