Emerging evidence has revealed that Nestin not only serves as a biomarker for multipotent stem cells, but also regulates cell proliferation and invasion in various tumors. However, the mechanistic contributions of Nestin to cancer pathogenesis are still unknown. In the present study, previously thought to reside exclusively in the cytoplasm, Nestin can also be found in the nucleus and participate in protecting tumor cells against cellular senescence. Specifically, we reveal that Nestin has a nuclear localization signal (aa318–aa347) at the downstream of rod domain. We then find nuclear Nestin could interact with lamin A/C. Mechanistic investigations demonstrate that Nestin depletion results in the activation of cyclin-dependent kinase 5 (Cdk5), which causes the phosphorylation of lamin A/C (mainly at S392 site) and its subsequent translocation to the cytoplasm for degradation. The findings establish a role for nuclear Nestin in tumor senescence, which involves its nucleus-localized form and interaction with lamin A/C.

ApoE has been reported to be associated with tumorigenesis and tumor progression. In this study, we explored the potential diagnostic and prognostic role of serum ApoE in breast cancer patients. Subject cohorts consisted of 152 normal healthy controls female and 257 breast cancer cases. Serum levels of ApoE were determined with turbidimetric immunoassay. The serum levels of ApoE were significantly elevated in breast cancer patients compared with normal healthy controls (45.82 ± 13.96 mg/L vs. 33.61 ± 6.44 mg/L, respectively, P < 0.0001) and also significantly associated with TNM stage and lymph nodes status (all P < 0.05). Area under receiver operating characteristic curve for serum ApoE discriminate breast cancer patients from controls was 0.786 with specificity of 0.974 and sensitivity of 0.541, the cut-off value of ApoE was 43.15 mg/L. Kaplan-Meier log rank analysis showed that the high serum ApoE group (serum ApoE ≥ 43.15 mg/L) had a poorer progression-free survival and overall survival compared with low serum ApoE group (serum ApoE < 43.15 mg/L) (all P < 0.05). In addition, univariate and multivariate Cox regression analysis displayed serum ApoE as an independent risk factor of breast cancer patients prognosis (all P < 0.05). Serum ApoE played a role as serological biomarkers that indicated diagnostic and prognostic evaluation in breast cancer patients.

Staphylococcus aureus (S. aureus) is the most common bacterium in sepsis and pneumonia involving gram-positive bacteria. Lipoteichoic acid (LTA) is a cell wall component of gram-positive bacteria. It is a potent inducer of inflammatory mediators in human dendritic cells, human pulmonary epithelial cells, and murine macrophages. However, the effect of LTA on human alveolar macrophages (AMs) which are the major effector cells in host defense against respiratory tract infections has hardly been studied. Statins have anti-inflammatory, immunomodulatory, antioxidative, anticoagulant, and antibacterial activities. These effects may be contributed to reduce the markers of systemic inflammation. Emerging retrospective studies have demonstrated that statin use decreased the mortality of pneumonia. However, the precise mechanisms responsible for these effects are unclear. The purpose of this study is to define the role of S. aureus LTA in human AMs and the effects of simvastatin (SV) on LTA-stimulated human AMs. The results showed that LTA induced tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), IL-8 mRNA expression, and suppressed IL-10 mRNA expression in human AMs. Simultaneously, LTA induced human AMs apoptosis. These effects were parallel with the up-regulation of the expression of NF-κB-P65 protein in the LTA-stimulated human AMs. The above effects of LTA on human AMs were inhibited significantly by SV. These data indicate that S. aureus LTA induces potent pro-inflammatory and pro-apoptotic effects on human AMs and statins exert anti-inflammatory effects by mediating inhibition of NF-κB activation and cytokine mRNA expression in human AMs. These results may explain, in part, the mechanisms responsible for favorable effects of statins on pneumonia.

Macrophages play an important role in inflammatory responses; however, miRNA-mediated repolarization of macrophages is essential for fulfilling this function. To clarify a series of changes at the RNA level in alveolar macrophages under normal and inflammatory conditions, bronchial alveolar lavage liquid (BALF) was collected from healthy volunteers or patients with pneumonia. This approach, which differs from that used in previously, provides more accurate information about the states of macrophages in different lung microenvironments. In this study, the density plots of macrophage subtypes (M1 and M2) in the BALF of healthy volunteers differed from that of the patients with pneumonia. The M2 subtype dominated in healthy volunteers and was rapidly repolarized to M1 in response to miRNA-mediated gene regulation. Differential miRNA expression in the two macrophage subtypes revealed lower expression of miR-155 and MIR-146a in patients with pneumonia compared with healthy volunteers; this may be related to inflammation and the use of anti-inflammatory drugs. We also found increased TNF-α and IL-6 expression at the RNA level, while macrophage galactose-type C-type lectin 1 (MGL-1) expression decreased with downregulation of miR-155 and miR-146a expression. These results indicate that the gene regulation mediated by miR-155 and miR-146a contributes to human alveolar macrophage phenotype repolarization, thus leading to an early switch from pro-inflammatory to anti-inflammatory cytokine production.

BACKGROUND Severe hyperthyroidism is a life-threatening exacerbation of thyrotoxicosis, characterized by high fever and multiorgan failure. The most common medical treatments are administration of antithyroid drugs and radioactive iodine, and thyroidectomy. In some patients, antithyroid therapy is limited due to serious adverse effects or failure to control disease progression. In some extreme cases, such as thyroid storm, conventional therapy alone does not yield effective and rapid improvement before the development of multiorgan failure. CASE SUMMARY This report describes a Chinese patient with severe hyperthyroidism accompanied by multiorgan failure, who was transferred to the medical intensive care unit of our hospital. The patient presented with palpitations, vomiting, diarrhea, and shortness of breath for a week. Laboratory tests showed elevation of thyroid hormones. Hepatic failure occurred with high aminotransferase levels and jaundice. Given her abnormal liver function and medication history, we could not exclude diagnosis of propylthiouracil-induced hepatic failure. Moreover, she also suffered from heart failure. Therapeutic plasma exchange (commonly known as TPE) and continuous renal replacement therapy (commonly known as CRRT) were used as life-saving therapy, which resulted in notable improvement of clinical symptoms and laboratory tests. CONCLUSION Combined TPE and CRRT are safe and effective for patients with hyperthyroidism and multiorgan failure.