Non-small cell lung cancer (NSCLC) has a 5-y survival rate of ∼16%, with most deaths associated with uncontrolled metastasis. We screened for stem cell identity-related genes preferentially expressed in a panel of cell lines with high versus low metastatic potential, derived from NSCLC tumors of Kras LA1/+ ;P53 R172HΔG/+ (KP) mice. The Musashi-2 (MSI2) protein, a regulator of mRNA translation, was consistently elevated in metastasis-competent cell lines. MSI2 was overexpressed in 123 human NSCLC tumor specimens versus normal lung, whereas higher expression was associated with disease progression in an independent set of matched normal/primary tumor/lymph node specimens. Depletion of MSI2 in multiple independent metastatic murine and human NSCLC cell lines reduced invasion and metastatic potential, independent of an effect on proliferation. MSI2 depletion significantly induced expression of proteins associated with epithelial identity, including tight junction proteins [claudin 3 (CLDN3), claudin 5 (CLDN5), and claudin 7 (CLDN7)] and down-regulated direct translational targets associated with epithelial-mesenchymal transition, including the TGF-β receptor 1 (TGFβR1), the small mothers against decapentaplegic homolog 3 (SMAD3), and the zinc finger proteins SNAI1 (SNAIL) and SNAI2 (SLUG). Overexpression of TGFβRI reversed the loss of invasion associated with MSI2 depletion, whereas overexpression of CLDN7 inhibited MSI2-dependent invasion. Unexpectedly, MSI2 depletion reduced E-cadherin expression, reflecting a mixed epithelialmesenchymal phenotype. Based on this work, we propose that MSI2 provides essential support for TGFβR1/SMAD3 signaling and contributes to invasive adenocarcinoma of the lung and may serve as a predictive biomarker of NSCLC aggressiveness.on-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the world (1). Approximately 7% of individuals born in the United States in 2013 will ultimately be diagnosed with lung cancer, and 160,000 die from this disease each year (1). The 5-y survival rate for lung cancer is around 16% of diagnosed cases (2). Much of the lethality of lung cancer is due to frequent diagnosis of the malignancy at the metastatic stage, when fundamental changes in tumor biology cause the disease to be refractory to many treatments. A better understanding of the biological processes that promote NSCLC metastasis promises to further improve clinical care of the patients. Kras LA1/+ ;P53 R172HΔG/+ (KP) mice provide a useful and wellvalidated model for the study of NSCLC metastasis. These mice combine a mutant p53 allele (p53 R175HΔG) with an activating KrasG12D allele (Kras LA1 ) (3), leading to development of adenocarcinomas resembling human NSCLC, which are often characterized by mutation of KRAS (∼30%) (4) and loss of TP53 (∼60%) (5). Many of the KP tumors metastasize to sites commonly seen in NSCLC patients (3). These features make the KP murine model a useful tool with which to evaluate factors that underlie NSCLC metastasis. Among the pathways activated...

Objective: To report the most up-to-date evidence on the effects of tumour necrosis factor (TNF)-alpha inhibition on cartilage with a focus on its clinical relevance. Design: A systematic review was performed by searching PubMed, Embase and Cochrane Library databases. Inclusion criteria were studies of any level of evidence published in peer-reviewed journals reporting clinical or preclinical results written in English. Relative data were extracted and critically analysed. PRISMA guidelines were applied, and risk of bias was assessed as well as the methodological quality of the included studies. Results: 13 studies were included after applying the inclusion and exclusion criteria. Three were in vitro human studies from osteoarthritis (OA) patients. Ten were animal modal studies including two in vitro studies, and eight in vivo studies. TNF-alpha inhibition in in vitro studies was generally reported beneficial due to the improved osteochondral viability, proliferation and chondrogenesis. In addition, TNFalpha inhibition was noted to be beneficial in promoting the natural repair of osteochondral lesions and has a chondroprotective effect in in vivo studies. Conclusion:Based on current evidence, TNF might have the potential to interfere with the healing process of chondral and osteochondral defects occurring naturally or in low inflammatory environment after a cartilage repair procedure. Therefore, the use of biological agents to inhibit its action in cartilage repair surgery could be beneficial, and this could translate into a promising therapy that improves the outcome of currently available cartilage procedures.

Periprosthetic joint infection in total knee arthroplasty is a significant complication that is a common reason for revision surgery. The current standard of care is two-stage revision surgery. There is however increasing evidence to support the use of single-stage revision surgery. We conducted a PRISMA systematic review of the current evidence on the use of single-stage revision for infected total knee arthroplasty. Four databases (PubMed, Embase, Science Direct, and Cochrane Library) were systematically screened for eligible studies. The risk bias of each study was identified using ROBINS-I tool, and the quality of evidence was assessed using the GRADE criteria. Sixteen articles were retained after applying the inclusion and exclusion criteria that evaluated 3645 knee single-stage revision surgeries. Our review reveals satisfactory outcomes for single-stage revision in the management of infected total knee arthroplasty. The reinfection rates in the studies included in our review varied however the majority reported low reinfection rates and good functional outcomes. Although strict patient selection criteria have yielded successful results, good results were also reported when these criteria were not applied. The greater use of risk factors in identifying patients likely to have a successful outcome needs to be balanced with the practical benefits of performing a single stage procedure in higher risk patients. Future large clinical randomized control trials are required to confirm our results.