Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model.

Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aß deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.

Can We Accurately Predict the Quadruple Hamstring Graft Diameter From Preoperative Magnetic Resonance Imaging?

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction with a quadruple hamstring (QH) autograft is a widely utilized procedure with good outcomes. A graft diameter less than 8 mm, however, has been associated with higher revision rates. Accurately determining the diameter of the hamstring tendon preoperatively can help surgeons plan accordingly. PURPOSE/HYPOTHESIS: The purpose of our study was to determine whether QH graft size can be reliably predicted from preoperative magnetic resonance imaging (MRI) measurements. We hypothesized that we can achieve a high predicted QH graft size correlation with regard to preoperative and intraoperative measurements. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: We evaluated patients undergoing ACL reconstruction using QH autografts. At the time of surgery, the semitendinosus tendon (ST) and gracilis tendon (GT) were harvested and sized and then sized as a QH graft. Preoperative individual ST and GT sizes were determined from T2-weighted fat-saturated MRI at 3 cm above the joint line using correlating axial and coronal images. We then used a predictive chart to predict what the size of the QH graft would be and compared this with the actual measurements. Pearson correlation coefficients between predicted and actual graft sizes were calculated. RESULTS: The predicted GT graft size was within 0.5 mm of the actual size in 45 of 60 (75%) patients and within 1 mm of the actual graft size in 59 of 60 (98%) patients. The predicted GT graft size from MRI measurements correlated with the actual GT graft size (r = 0.62, P < .00001). The predicted ST graft size was within 0.5 mm of the actual size in 45 of 60 (75%) patients and within 1 mm of the actual graft size in 56 of 60 (93%) patients. The predicted ST graft size from MRI measurements correlated with the actual ST graft size (r = 0.71, P < .00001). The predicted QH graft size was within 0.5 mm of the actual size in 52 of 60 (87%) patients and within 1 mm of the actual graft size in 60 of 60 (100%) patients. The predicted QH graft size from MRI measurements correlated with the actual QH graft size (r = 0.81, P < .00001). CONCLUSION: The current technique can reliably predict the size of a QH graft within 1 mm of the final graft size.

BRD4 Profiling Identifies Critical Chronic Lymphocytic Leukemia Oncogenic Circuits and Reveals Sensitivity to PLX51107, a Novel Structurally Distinct BET Inhibitor.

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

RAF inhibitors that evade paradoxical MAPK pathway activation.

Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.

Extensile posterior approach to the ankle with detachment of the achilles tendon for oncologic indications.

BACKGROUND: We describe an extensile posterior approach to the ankle with detachment of the Achilles tendon for resection of extensive tumors involving the posterior ankle. To the best of our knowledge, this approach and its results have not been reported for oncologic indications. METHODS: The surgical technique involved detachment of the Achilles tendon, tumor resection and reconstruction of the Achilles tendon with anchor sutures, and was used in six patients. The diagnosis was pigmented villonodular synovitis (5) and chondroblastoma (1). RESULTS: At a mean of 6 (range, 2 to 10) years followup, all patients were free from tumor. All patients could walk an unlimited amount without any support. There were no problems with Achilles incompetence. The mean Musculoskeletal Tumor Society score was 97 ± 4.2% (range, 90 to 100) and the mean Achilles Tendon Total Rupture Score was 95 ± 5.7 (range, 87 to 100). One patient with screwed suture anchors had backing out of two anchors along with deep infection, requiring surgical debridement and anchor removal. One other patient had a post-traumatic small wound dehiscence which responded to local wound care. CONCLUSION: Excellent exposure, tumor control and patient function were achieved by this approach in a select group of patients. The surgical technique described in this report offers another alternative for an extensile posterior approach to the ankle and/or subtalar joints.

Athletic trainers' and physical therapists' perceptions of the effectiveness of psychological skills within sport injury rehabilitation programs.

CONTEXT: Psychological skills are alleged to augment sport-injury rehabilitation; however, implementation of mental imagery within rehabilitation programs is limited. OBJECTIVE: To examine attitudes of athletic trainers (ATs) and physical therapists (PTs) on the effectiveness of mental imagery, goal setting, and positive self-talk to improve rehabilitation adherence and recovery speed of injured athletes. DESIGN: The ATs and PTs were contacted via electronic or physical mailings to complete a single administration survey that measured their beliefs about the effectiveness of psychological skills for increasing adherence and recovery speed of injured athletes undergoing rehabilitation. SETTING: Professional member databases of the National Athletic Trainers' Association and the American Physical Therapy Association. PATIENTS OR OTHER PARTICIPANTS: Of the 1000 ATs and 1000 PTs who were selected randomly, 309 ATs (age = 34.18 +/- 8.32 years, years in profession = 10.67 +/- 7.34) and 356 PTs (age = 38.58 +/- 7.51 years, years in profession = 13.18 +/- 6.17) responded. MAIN OUTCOME MEASURE(S): The Attitudes About Imagery (AAI) survey measures attitudes about psychological skills for enhancing adherence and recovery speed of injured athletes. The AAI includes demographic questions and 15 items on a 7-point Likert scale measuring attitudes about the effectiveness of mental imagery, self-talk, goal setting, and pain control on rehabilitation adherence and recovery speed of injured athletes. Test-retest reliability ranged from .60 to .84 and Cronbach alphas ranged from .65 to .90. We calculated 1-way analyses of variance to determine whether differences existed in attitudes as a result of the professionals' education, training experience, and interest. RESULTS: Mean differences were found on attitudes about effectiveness of psychological skills for those who reported formal training and those who reported interest in receiving formal training (P < .05). In addition, ATs held more positive attitudes than PTs on 9 of 15 AAI items (P < .05). CONCLUSIONS: Overall, ATs and PTs held positive attitudes on the effectiveness of psychological skills to augment the rehabilitation process. Clinical implications regarding the use of mental skills are discussed.