Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon, and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT, and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway—involving AKT, CREB, Bcl-xL, survivin, and Bcl-2—downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that shRNA knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl play complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

• Mer tyrosine kinase is aberrantly expressed in ;30% of pediatric pre-B-ALL patients, including most patients with an E2A-PBX1 translocation.• Mer inhibition decreased B-ALL cell survival signal transduction, caused chemosensitization, and prolonged survival in a xenograft model.Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications. (Blood. 2013;122(9):1599-1609

Background:Research has found that injury rates in football are higher in competition than during practice. However, there is little research on the association between injury rates and type of football practices and how these specific rates compare with those in competitions.Purpose:This study utilized data from the National Collegiate Athletic Association Injury Surveillance System (NCAA ISS) to describe men’s collegiate football practice injuries (academic years 2004-2005 to 2008-2009) in 4 event types: competitions, scrimmages, regular practices, and walkthroughs.Study Design:Descriptive epidemiological study.Methods:Football data during the 2004-2005 to 2008-2009 academic years were analyzed. Annually, an average of 60 men’s football programs provided data (9.7% of all universities sponsoring football). Injury rates per 1000 athlete-exposures (AEs), injury rate ratios (RRs), 95% CIs, and injury proportions were reported.Results:The NCAA ISS captured 18,075 football injuries. Most injuries were reported in regular practices (55.9%), followed by competitions (38.8%), scrimmages (4.4%), and walkthroughs (0.8%). Most AEs were reported in regular practices (77.6%), followed by walkthroughs (11.5%), competitions (8.6%), and scrimmages (2.3%). The highest injury rate was found in competitions (36.94/1000 AEs), followed by scrimmages (15.7/1000 AEs), regular practices (5.9/1000 AEs), and walkthroughs (0.6/1000 AEs). These rates were all significantly different from one another. Distributions of injury location and diagnoses were similar across all 4 event types, with most injuries occurring at the lower extremity (56.0%) and consisting of sprains and strains (50.6%). However, injury mechanisms varied. The proportion of injuries due to player contact was greatest in scrimmages (66.8%), followed by regular practices (48.5%) and walkthroughs (34.9%); in contrast, the proportion of injuries due to noncontact/overuse was greatest in walkthroughs (41.7%), followed by regular practices (35.6%) and scrimmages (21.9%).Conclusion:Injury rates were the highest in competitions but then varied by the type of practice event, with higher practice injury rates reported in scrimmage. In addition, greater proportions of injuries were reported in regular practices, and greater proportions of exposures were reported in regular practices and walkthroughs. Efforts to minimize injury in all types of practice events are essential to mitigating injury incidence related to both contact and noncontact.

Practice concussion rates are highest during fully padded practices, preseason practices, and scrimmages, suggesting that the nature, focus, and intensity of football practices affect concussion risk. In addition, coaching staff should continue to closely monitor player safety during scrimmages. Meanwhile, future surveillance should examine whether removing scrimmages, particularly those that are not fully padded, will meaningfully reduce the incidence and rate of concussions.

Repetitive microtrauma from overhead hitting in volleyball generates forces on the inferior capsule of the shoulder joint that may cause inferior capsular laxity and subsequent failure of the humeral side of the axillary pouch portion of the inferior glenohumeral ligament.