Citations

Background: Low-intensity pulsed ultrasound (LIPUS), as a safe biophysiotherapy, can enhance bone-tendon (B-T) healing in vivo and induce osteogenic or chondrogenic differentiation of mesenchymal stromal cells in vitro. This study aimed to determine whether LIPUS can improve the efficacy of transplanted mesenchymal stromal cells on B-T healing. Hypothesis: LIPUS can induce lineage-specific differentiation of transplanted adipose-derived stromal cells (ASCs) at the B-T healing site, thus resulting in superior healing quality when compared with LIPUS or ASCs alone. Study Design: Controlled laboratory study. Methods: A total of 112 mature rabbits with partial patellectomy in the hindlimb were randomly assigned into mock sonication without ASCs (control), ultrasonication without ASCs (LIPUS), mock sonication with ASCs (ASCs), and ultrasonication with ASCs (LIPUS + ASCs). The treatment time of the mock sonication or ultrasonication was 20 minutes per day. Autologous ASCs were transplanted to the healing site by fibrin glue during the operation, and LIPUS was delivered daily starting at postoperative day 3 until euthanasia. The patella–patellar tendon junctions were postoperatively harvested at 8 and 16 weeks for radiological, histological, and mechanical evaluations. Additionally, 9 animals were used for ASC tracking with mCherry protein. Results: Radiologically, there was more new bone formation and remodeling in the LIPUS + ASCs group as compared with the other groups. Synchrotron radiation micro–computed tomography showed that the LIPUS + ASCs group significantly increased bone volume fraction, trabecular thickness, and trabecular number at the healing site as compared with the other groups at postoperative 8 weeks ( P < .05 for all). Histologically, immunohistochemical staining confirmed that the transplanted mCherry-ASCs can differentiate into osteoblasts and fibrochondrocytic-like cells. Meanwhile, as compared with the other groups, the LIPUS + ASCs group showed more formation and maturity of the fibrocartilage layer and new bone at postoperative weeks 8 and 16 ( P < .05 for all). Biomechanically, the LIPUS + ASCs group showed significantly higher failure load and stiffness versus the other groups at postoperative weeks 8 and 16 ( P < .05 for all). Conclusion: Autologous ASC transplantation stimulated with LIPUS can result in superior B-T healing quality when compared with LIPUS or ASCs alone. Clinical Relevance: This study demonstrates the effectiveness of using ASC transplantation stimulated with LIPUS for B-T healing and provides a foundation for future clinical studies.

Suppression of ZEB1 through miR-200 expression or HDAC inhibition with mocetinostat sensitizes resistant KRAS mutant lung cancers to MEK inhibition.

Background: Achilles tendon tears are potentially career-ending injuries for professional athletes. For players in the National Football League (NFL), return requires not only surgery and extensive rehabilitation but also the ability to compete in a market with limited positions that annually introduces new recruits. Purpose/Hypothesis: We authors sought to evaluate factors related to return to play (RTP) and changes in performance following a primary Achilles tear. Our hypothesis was that “skilled” position players and those drafted in later rounds would return at a lower rate as compared with “unskilled” position players and higher draft-round players. Study Design: Case-control study; Level of evidence, 3. Methods: From a previously established database, 80 NFL players were identified as having primary Achilles tendon tears between the 2009 and 2014 seasons. RTP was defined as playing in a regular season or postseason game following injury. Probability of RTP was modeled as a function of time after injury in Kaplan-Meier analysis with demographic variables assessed via generalized linear models. Twelve players (15%) experienced a subsequent Achilles tendon tear during or after the study period and were included in the overall RTP rate but were excluded from performance analyses owing to the confounding effects of an ipsilateral retear or contralateral tear. Results: The overall RTP rate was 61.3%. Age, number of prior seasons, position type, or draft round status did not significantly affect RTP when evaluated with Kaplan-Meier analysis. In the season before their injury, players who did RTP played in a significantly greater number of regular season games (13.7) compared with players who did not RTP (8.71) ( P = .011). Players who did not RTP exhibited a significant decrease in performance in the season preceding injury (12.7 regular season games played 2 seasons preinjury vs 8.71 regular season games played 1 season prior preinjury;, P = .019). Players who returned did not display a significant change in the number of games played or started in seasons following injury when >1 season after return was evaluated. Conclusion: Rate of RTP following primary Achilles tendon tears may be lower than previously published. However, for those able to return, performance only in the season immediately following injury appears to be affected; players return to preinjury levels if given the opportunity to play >1 season after injury.

Abstract An ultimate goal of precision medicine in lung cancer treatment is to restore patient health with maximized quality of life (QOL). Results from Mayo Clinic studies show that a significant improvement in fatigue, dyspnea, and pain scales could lead to better overall QOL. Although treatments and guidelines for clinical implementation to alleviate these key symptoms are available, few cancer patients receive adequate therapy, mostly because of limitations in current care delivery systems and unclear clinicians’ roles. For optimal care of lung cancer survivors in different subpopulations, three barriers must be overcome: physicians’ lack of knowledge, unwarranted practice variation, and uncertainty regarding care provider roles. Appropriate culturally adapted, tested and validated tools for QOL measures must be developed, rather than directly translating existing tools between different languages and across cultures or diverse subpopulations. Finally, lack of sensitive, adequate, and relevant tools in measuring health-related QOL (HRQOL) has long been an issue for effective data collection, demanding a global consensus on a set of core components that reflect the needs of all critical parties for the best cure and care, supporting patients to achieve optimal HRQOL.

Abstract The oncolytic reovirus (RV) has demonstrated clinical efficacy and minimal toxicity in a variety of cancers, including multiple myeloma (MM). MM is a malignancy of plasma cells that is considered treatable but incurable because of the 90% relapse rate that is primarily from drug resistance. The systemic nature of MM and the antitumor immunosuppression by its tumor microenvironment presents an ongoing therapeutic challenge. In the present study, we demonstrate that RV synergizes with the standard-of-care MM drug bortezomib (BTZ) and, importantly, enhances its therapeutic potential in therapy-resistant human MM cell lines in vitro. Using the syngeneic Vk*MYC BTZ-resistant immunocompetent transplantable MM murine model, we also demonstrate that mice harboring BTZ-insensitive MM tumors respond to the RV/BTZ combination treatment in terms of decreased tumor burden and improved overall survival (P &lt; .00001). We demonstrate that BTZ augments RV replication in tumor-associated endothelial cells and myeloma cells, leading to enhanced viral delivery and thereby stimulating cytokine release, immune activity, apoptosis, and reduction of the MM-associated immune suppression. We conclude that combined RV/BTZ is an attractive therapeutic strategy with no safety signals for the treatment of MM.

HIV-1 infections usually start at a mucosal surface after sexual contact. Creating a barrier of protection at these mucosal sites may be a good strategy for to protect against HIV-1 infections. While HIV-1 enters at mucosa, most vaccines are not delivered here. Most are instead injected into the muscle, a site well distant and functionally different than mucosal tissues. This study tested if delivering HIV vaccines at mucosa or in the muscle makes a difference in the quality, quantity, and location of immune responses against the virus. These data suggest that there are indeed advantages to educating the immune system at mucosal sites with an HIV-1 vaccine.