Staphylococcal Enterotoxin B-Induced MicroRNA-155 Targets SOCS1 To Promote Acute Inflammatory Lung Injury

Staphylococcal enterotoxin B (SEB) causes food poisoning in humans. It is considered a biological weapon, and inhalation can trigger lung injury and sometimes respiratory failure. Being a superantigen, SEB initiates an exaggerated inflammatory response. While the role of microRNAs (miRNAs) in immune cell activation is getting increasing recognition, their role in the regulation of inflammatory disease induced by SEB has not been studied. In this investigation, we demonstrate that exposure to SEB by inhalation results in acute inflammatory lung injury accompanied by an altered miRNA expression profile in lung-infiltrating cells. Among the miRNAs that were significantly elevated, miR-155 was the most overexpressed. Interestingly, miR-155^−/− mice were protected from SEB-mediated inflammation and lung injury. Further studies revealed a functional link between SEB-induced miR-155 and proinflammatory cytokine gamma interferon (IFN-γ). Through the use of bioinformatics tools, suppressor of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ, was identified as a potential target of miR-155. While miR-155^−/− mice displayed increased expression of Socs1, the overexpression of miR-155 led to its suppression, thereby enhancing IFN-γ levels. Additionally, the inhibition of miR-155 resulted in restored Socs1expression. Together, our data demonstrate an important role for miR-155 in promoting SEB-mediated inflammation in the lungs through Socs1 suppression and suggest that miR-155 may be an important target in preventing SEB-mediated inflammation and tissue injury.     

The influence of scaffold material on chondrocytes under inflammatory conditions

Cartilage tissue engineering aims to repair damaged cartilage tissue in arthritic joints. As arthritic joints have significantly higher levels of pro-inflammatory cytokines (such as IL-1β and TNFα that cause cartilage destruction, it is critical to engineer stable cartilage in an inflammatory environment. Biomaterial scaffolds constitute an important component of the microenvironment for chondrocytes in engineered cartilage. However, it remains unclear how the scaffold material influences the response of chondrocytes seeded in these scaffolds under inflammatory stimuli. Here we have compared the responses of articular chondrocytes seeded within three different polymeric scaffolding materials (silk, collagen and polylactic acid (PLA)) to IL-1β and TNFα. These scaffolds have different physical characteristics and yielded significant differences in the expression of genes associated with cartilage matrix production and degradation, cell adhesion and cell death. The silk and collagen scaffolds released pro-inflammatory cytokines faster and had higher uptake water abilities than PLA scaffolds. Correspondingly, chondrocytes cultured in silk and collagen scaffolds maintained higher levels of cartilage matrix than those in PLA, suggesting that these biophysical properties of scaffolds may regulate gene expression and the response to inflammatory stimuli in chondrocytes. Based on this study we conclude that selecting the proper scaffold material will aid in the engineering of more stable cartilage tissues for cartilage repair, and that silk and collagen are better scaffolds in terms of supporting the stability of three-dimensional cartilage under inflammatory conditions.     

Molecular targeted therapy in ovarian cancer: what is on the horizon?

Over the past two decades, empirical optimization of cytotoxic chemotherapy combinations and surgical debulking procedures have improved outcomes and survival in epithelial ovarian cancer. Yet, this disease remains the fifth leading cause of cancer-related deaths in the US, as cure rates seem to have reached a plateau at approximately 20% with conventional chemotherapy. Novel high-throughput genomic and proteomic analyses have improved the molecular understanding of ovarian carcinogenesis, thereby providing a vast array of new potential drug targets with complex signalling interactions. In order to yield the most significant impact on disease outcome, it is necessary to carefully select, and subsequently target, the driving molecular pathway(s) within a tumour or tumour subtype, which are most likely to correspond to high-frequency mutations and genomic aberrations. The identification of biomarkers predictive of response to targeted therapy is essential to avoid poor responses to potentially useful drugs in unselected trial populations. With some promising, albeit early, phase III data on the angiogenesis inhibitor bevacizumab, exciting new opportunities lie ahead with the ultimate goal of personalizing therapies to individual tumour profiles.     

Effect of trans-cinnamaldehyde on reducing resistance to environmental stresses in Cronobacter sakazakii

Cronobacter sakazakii is an emerging foodborne pathogen transmitted exclusively through contaminated infant formula (IFM), and associated with life-threatening infections in infants. C. sakazakii has the ability to tolerate a variety of environmental stress conditions, including heat stress, acidity, high osmotic pressure, and desiccation. In this study, we investigated the efficacy of a subinhibitory concentration (750?μM) of trans-cinnamaldehyde (TC), an ingredient in cinnamon, for reducing C. sakazakii's tolerance to these environmental stresses. Three strains of TC-treated C. sakazakii were separately subjected to high temperature (50°C, 55°C, and 60°C), acidic pH (3.3), high osmotic pressure (a(w) 0.81), and desiccation. TC (750?μM) substantially (p?相似文献   

Genetic variations at microRNA and processing genes and risk of oral cancer

Genetic variations at microRNA and microRNA processing genes are known to confer risk of cancer in different populations. Here, we studied variations at eight microRNA (miRNA) and four miRNA processing genes in 452 controls and 451 oral cancer patients by TaqMan genotyping assays. Variant allele-containing genotypes at mir-196a2 and variant allele homozygous genotype at Ran increased the risk of cancer significantly [adjusted odds ratio (OR) (95 % confidence interval (CI))?=?1.3 (1–1.7) and 2.3 (1.1–4.6), respectively]. Conversely, variant allele-containing genotypes at mir-34b and variant allele homozygous genotype at Gemin3 reduced the risk of cancer significantly [adjusted OR (95 % CI)?=?0.7 (0.5–0.9) and 0.6 (0.4–1), respectively]. Cumulative risk was also increased by three times with increase in the number of risk alleles at these four loci. In tobacco stratified analysis, variant allele homozygous genotypes at mir-29a and Ran increased [adjusted OR (95 % CI)?=?1.5 (1–2.3) and 3 (1.1-8.4) respectively], while variant allele-containing genotypes at mir-34b decreased [adjusted OR (95 % CI)?=?0.6 (0.4–0.9)] the risk of cancer significantly. Thus, genetic variation at miRNA and processing genes altered the risk of oral cancer in this population thereby corroborating studies in other populations. However, it is necessary to validate this result in different Indian sub populations with larger sample sizes and examine the effect of these variations in tumour tissues to explain the mechanism of risk alteration.     

Dilated SMV in Colon Cancer—Is There any Significance

Objective  

Changes in splanchnic circulation have been seen in patients with colorectal cancer. We have previously reported that the inferior mesenteric vein is dilated in rectal cancer. We wanted to assess whether the superior mesenteric vein (SMV) is dilated in right-sided colon cancer.     

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group

Background

Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I–III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported.

Methods

Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non–low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan–Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%–94.0%) and 95.6% (95% CI, 90.8%–100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%–100.0%) and 97.6% (95% CI, 90.0%–100.0%), respectively. Twenty-six patients with non–low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%–100.0%) and 95.8% (95% CI, 87.7%–100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%–88.8%).

Conclusions

Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non–low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.     

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors.Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models.Results Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively.Conclusion A clinical trial may be justified to further investigate the utility of IAP inhibitors.Subject terms: Ovarian cancer, Chemotherapy