Citations

The accumulation of somatic mutations, to which the cellular genome is permanently exposed, often leads to cancer. Analysis of any tumour shows that, besides the malignant cells, one finds other ‘supporting’ cells such as fibroblasts, immune cells of various types and even blood vessels. Together, these cells generate the microenvironment that enables the malignant cell population to grow and ultimately lead to disease. Therefore, understanding the dynamics of tumour growth and response to therapy is incomplete unless the interactions between the malignant cells and normal cells are investigated in the environment in which they take place. The complex interactions between cells in such an ecosystem result from the exchange of information in the form of cytokines- and adhesion-dependent interactions. Such processes impose costs and benefits to the participating cells that may be conveniently recast in the form of a game pay-off matrix. As a result, tumour progression and dynamics can be described in terms of evolutionary game theory (EGT), which provides a convenient framework in which to capture the frequency-dependent nature of ecosystem dynamics. Here, we provide a tutorial review of the central aspects of EGT, establishing a relation with the problem of cancer. Along the way, we also digress on fitness and of ways to compute it. Subsequently, we show how EGT can be applied to the study of the various manifestations and dynamics of multiple myeloma bone disease and its preceding condition known as monoclonal gammopathy of undetermined significance. We translate the complex biochemical signals into costs and benefits of different cell types, thus defining a game pay-off matrix. Then we use the well-known properties of the EGT equations to reduce the number of core parameters that characterize disease evolution. Finally, we provide an interpretation of these core parameters in terms of what their function is in the ecosystem we are describing and generate predictions on the type and timing of interventions that can alter the natural history of these two conditions.

Background: Strengthening of core hip, trunk, and abdominal muscles has been utilized with injury prevention and low back pain and has the potential to improve athletic performance. Hypothesis: During a side-bridge, trunk and thigh muscles on the ipsilateral weightbearing side would produce greater activation than their counterparts on the contralateral nonweightbearing side. Study Design: Descriptive laboratory study. Methods: Twelve females and 13 males participated. Electromyography (EMG) signals were gathered for 5 right-sided muscles (rectus abdominis [RA], external oblique [EO], longissimus thoracis [LT], lumbar multifidus [LM], and gluteus medius [GM]) during 3 repetitions of 4 side-bridging exercises (trunk-elevated side support [TESS], foot-elevated side support [FESS], clamshell, and rotational side-bridge [RSB]) performed bilaterally in random order using surface electrodes. EMG signals were normalized to peak activity in maximum voluntary isometric contraction (MVIC) trials and expressed as a percentage. Descriptive EMG data were calculated for EMG recruitment (% MVIC) and compared between right side up and right side down conditions and between exercises with 2-way repeated-measures analyses of variance at α = 0.05. Results: RSB created the most muscle activation in 3 of 4 recorded trunk muscles (RA, 43.9% MVIC; EO, 62.8 % MVIC; and LT, 41.3% MVIC). Activation of the GM exceeded 69% MVIC for TESS, FESS, and RSB. With the exception of the RA in RSB and LT in TESS, recruitment within muscles of the ipsilateral weightbearing trunk and thigh (% MVIC) was significantly greater than their counterparts on the nonweightbearing trunk and thigh for all muscles during the side-bridge exercise conditions. Conclusion: Muscle recruitment was greater within muscles of the ipsilateral weightbearing trunk and thigh for all examined muscles except RA during RSB and LT during TESS. Activation at or above 50% MVIC is needed for strengthening. Activation of the GM and EO meets these requirements. Clinical Relevance: Side-bridge exercises appear to provide strengthening benefits to core hip, trunk, and abdominal muscles on the ipsilateral weightbearing side.

Importance Direct transcutaneous resection has been a widely accepted standard for the removal of benign forehead lesions. In recent years, the endoscopic approach has become more prevalent because of its noninvasiveness. To date, only a few studies with limited case numbers have reported on this technique. We report our findings from one of the largest cohorts of patients undergoing tumor resection of the forehead via the endoscopic approach. Objectives To evaluate results of the endoscopic forehead approach for benign tumor excisions, to give a more nuanced insight into this procedure, and to discuss technical pearls and potential pitfalls from our experience. Design, Setting, and Participants Multicenter, retrospective case study at 2 university centers and 1 private practice among 36 patients aged 18 to 72 years (mean age, 44 years) who underwent the endoscopic forehead approach for benign tumor resections. Main Outcomes and Measures Symptoms at presentation, surgical procedure and duration, type of lesions, intraoperative and postoperative complications, recurrences, and patient satisfaction. Results In total, 34 patients had an asymptomatic forehead mass, while 2 patients reported discomfort and headache. Among all patients, complete tumor excision was achieved endoscopically. The mean operative time was 36 minutes. Histopathological examination revealed 18 lipomas, 13 osteomas, 2 dermoid cysts, and 1 bone fragment after previous rhinoplasty. In 2 patients, no specimen was submitted. No hematomas, infections, scalp numbness, contour irregularities, temporal branch paralysis, or tumor recurrences occurred. One patient had a prolonged area of alopecia, which resolved on its own. All patients attested to a high satisfaction rate. Conclusions and Relevance The endoscopic approach offers excellent aesthetic results and allows for safe tumor removal. It has proven to be an effective and minimally invasive alternative to the conventional open approach. Level of Evidence 4 .

Objectives/HypothesisApplication to otolaryngology–head and neck surgery residency is highly competitive, and the interview process strives to select qualified applicants with a high aptitude for the specialty. Commonly employed criteria for applicant selection have failed to show correlation with proficiency during residency training. We evaluate the correlation between the results of a surgical aptitude test administered to otolaryngology resident applicants and their performance during residency.Study DesignRetrospective study at an academic otolaryngology–head and neck surgery residency program.MethodsBetween 2007 and 2013, 224 resident applicants participated in a previously described surgical aptitude test administered at a microvascular surgical station. The composite score and attitudinal scores for 24 consecutive residents who matched at our institution were recorded, and their residency performance was analyzed by faculty survey on a five‐point scale. The composite and attitudinal scores were analyzed for correlation with residency performance score by regression analysis.ResultsTwenty‐four residents were evaluated for overall quality as a clinician by eight faculty members who were blinded to the results of surgical aptitude testing. The results of these surveys showed good inter‐rater reliability. Both the overall aptitude test scores and the subset attitudinal score showed reliability in predicting performance during residency training.ConclusionsThe goal of the residency selection process is to evaluate the candidate's potential for success in residency and beyond. The results of this study suggest that a simple‐to‐administer clinical skills test may have predictive value for success in residency and clinician quality.Level of Evidence4 Laryngoscope, 125:E57–E61, 2015

ABSTRACT HIV-1 utilizes the cellular protein LEDGF/p75 as a chromosome docking and integration cofactor. The LEDGF/p75 gene, PSIP1 , is a potential therapeutic target because, like CCR5, depletion of LEDGF/p75 is tolerated well by human CD4 + T cells, and knockout mice have normal immune systems. RNA interference (RNAi) has been useful for studying LEDGF/p75, but the potent cofactor activity of small protein residua can be confounding. Here, in human cells with utility for HIV research (293T and Jurkat), we used transcription activator-like effector nucleases (TALENs) to completely eradicate all LEDGF/p75 expression. We performed two kinds of PSIP1 knockouts: whole-gene deletion and deletion of the integrase binding domain (IBD)-encoding exons. HIV-1 integration was inhibited, and spreading viral replication was severely impaired in PSIP1 −/− Jurkat cells infected at high multiplicity. Furthermore, frameshifting the gene in the first coding exon with a single TALEN pair yielded trace LEDGF/p75 levels that were virologically active, affirming the cofactor's potency and the value of definitive gene or IBD exon segment deletion. Some recent studies have suggested that LEDGF/p75 may participate in HIV-1 assembly. However, we determined that assembly of infectious viral particles is normal in PSIP1 −/− cells. The potency of an allosteric integrase inhibitor, ALLINI-2, for rendering produced virions noninfectious was also unaffected by total eradication of cellular LEDGF/p75. We conclude that HIV-1 particle assembly and the main ALLINI mechanism are LEDGF/p75 independent. The block to HIV-1 propagation in PSIP1 −/− human CD4 + T cells raises the possibility of gene targeting PSIP1 combinatorially with CCR5 for HIV-1 cure. IMPORTANCE LEDGF/p75 dependence is universally conserved in the retroviral genus Lentivirus . Once inside the nucleus, lentiviral preintegration complexes are thought to attach to the chromosome when integrase binds to LEDGF/p75. This tethering process is largely responsible for the 2-fold preference for integration into active genes, but the cofactor's full role in the lentiviral life cycle is not yet clear. Effective knockdowns are difficult because even trace residua of this tightly chromatin-bound protein can support integration cofactor function. Here, in experimentally useful human cell lines, we used TALENs to definitively eradicate LEDGF/p75 by deleting either all of PSIP1 or the exons that code for the integrase binding domain. HIV-1 replication was severely impaired in these PSIP1 knockout cells. Experiments in these cells also excluded a role for LEDGF/p75 in HIV-1 assembly and showed that the main ALLINI mechanism is LEDGF/p75 independent. Site-specific gene targeting of PSIP1 may have therapeutic potential for HIV-1 disease.

Inducible gene expression, which requires chromatin remodeling on gene promoters, underlies the epigenetically inherited differentiation program of most immune cells. However, chromatin-mediated mechanisms that underlie these events in T regulatory cells remain to be fully characterized. Here, we report that inducibility of FOXP3, a key transcription factor for the development of T regulatory cells, depends upon Kruppel-like factor 10 (KLF10) interacting with two antagonistic histone-modifying systems. We utilized chromatin immunoprecipitation, genome-integrated reporter assays, and functional domain KLF10 mutant proteins, to characterize reciprocal interactions between this transcription factor and either the Sin3-histone deacetylase complex or the histone acetyltransferase, p300/CBP-associated factor (PCAF). We characterize a Sin3-interacting repressor domain on the NH2 terminus of KLF10, which works to limit the activating function of this transcription factor. Indeed, inactivation of this Sin3-interacting domain renders KLF10 able to physically associate with PCAF as to induce FOXP3 gene transcription. We show that this biochemical data derived from studying our genome-integrated reporter cell system are recapitulated in primary murine lymphocytes. Collectively, these results advance our understanding of how a single transcription factor, namely KLF10, functions as a toggle to integrate antagonistic signals regulating FOXP3 and, thus, immune activation.