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Reduced protein levels of SMARCB1 (also known as BAF47, INI1, SNF5) have long been observed in synovial sarcoma. Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in synovial sarcoma. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human synovial sarcoma cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, coincorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF subcomplexes that contained equal levels of SMARCB1 regardless of SS18 or SS18-SSX inclusion. In vivo , SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis. SIGNIFICANCE: The protein level of BAF component SMARCB1 is reduced in synovial sarcoma but plays a defining role, incorporating into PBAF and SS18-SSX-containing canonical BAF complexes. Reduced levels of SMARCB1 derive from whole-complex degradation of canonical BAF driven by SS18-SSX, with relative increases in the abundance of other BAF-family subtypes. See related commentary by Maxwell and Hargreaves, p. 2375 . This article is highlighted in the In This Issue feature, p. 2355 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: Patients who undergo surgical stabilization for impending or pathologic fractures secondary to metastasis are often treated with radiation therapy to the involved site. We sought to retrospectively analyze outcomes from single versus multifraction regimens of radiation therapy in this setting., Methods and Materials: From our institutional radiation database, we identified 87 patients between 2004 and 2016 who had an impending or pathologic fracture from metastatic disease and who underwent surgical fixation in conjunction with either neoadjuvant (within 5 weeks before surgery) or adjuvant (within 10 weeks after surgery) radiation therapy, representing 99 total treatment sites. Patients were included on the basis of intention to treat with bimodality therapy. Baseline patient characteristics were compared using 2-sided t tests and Fisher's exact tests. Cumulative incidence of local failure, reirradiation, and reoperation were calculated using the Fine-Gray method for competing risks. Freedom from complication was calculated using the Kaplan-Meier method., Results: Baseline characteristics between the single (n = 52) and multifraction (n = 47) cohorts were similar with the exception of higher rates of synchronous bony metastasis (83% vs 60%, P  = .01) and female patients (71% vs 43%, P  = .004) in the single fraction cohort. There was no significant difference in overall survival between treatment groups. After a median follow-up of 13 months, there was no significant difference in the single and multifraction cohorts, respectively, in the 1-year cumulative incidence rates of local failure (4% vs 7%, P  = .58), reirradiation (5% vs 4%, P  = .95), reoperation (4% vs 0%, P  = .30), or 1-year freedom from complication (90% vs 95%, P  = .40)., Conclusions: This is the first study comparing outcomes between single and multifraction radiation therapy in conjunction with surgical stabilization of an impending or pathologic fracture. We found no difference in outcomes between single and multifraction regimens in this setting. Given these findings, single fraction perioperative radiation therapy may be a viable treatment option in appropriately selected patients pending prospective validation of these findings., (© 2021 Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.)

Background: The purpose of the study was to identify genetic variants associated with rotator cuff disease by performing a genome-wide association study (GWAS) for shoulder impingement using the UK Biobank (UKB) cohort and then combining the GWAS data with a prior GWAS for rotator cuff tears. The loci identified by the GWAS and meta-analysis were examined for changes in expression following rotator cuff tearing using RNA sequencing., Methods: A GWAS was performed using data from UKB with 3864 cases of shoulder impingement. The summary statistics from shoulder impingement and a prior study on rotator cuff tears were combined in a meta-analysis. Also, the previous association of 2 single-nucleotide polymorphisms (SNPs) with shoulder impingement from a published GWAS using the UKB was tested. Rotator cuff tendon biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and differential gene expression was measured by RNA sequencing for genes with variants associated with rotator cuff tearing., Results: The shoulder impingement GWAS identified 4 new loci: LOC100506457, LSP1P3, LOC100506207, and MIS18BP1/LINC00871. Combining data with a prior GWAS for rotator cuff tears in a meta-analysis resulted in the identification of an additional 7 loci: SLC39A8/UBE2D3, C5orf63, ASTN2, STK24, FRMPD4, ACOT9/SAT1, and LINC00890/ALG13. Many of the identified loci have known biologic functions or prior associations with diseases, suggesting possible biologic pathways leading to rotator cuff disease. RNA sequencing experiments show that expression of STK24 increases whereas expression of SAT1 and UBE2D3 decreases following rotator cuff tearing. Two SNPs previously reported to show an association with shoulder impingement from a prior UKB GWAS were not validated in our study., Conclusion: This is the first GWAS for shoulder impingement in which new data from UKB enabled the identification of 4 loci showing a genetic association. A meta-analysis with a prior GWAS for rotator cuff tearing identified an additional 7 loci. The known biologic roles of many of the 11 loci suggest plausible biologic mechanisms underlying the etiology of rotator cuff disease. The risk alleles from each of the genetic loci can be used to assess the risk for rotator cuff disease in individual patients, enabling preventative or restorative actions via personalized medicine., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies., Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan., Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types., Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients., (© 2021 American Cancer Society.)

Clear cell sarcoma (CCS) is a deadly malignancy affecting adolescents and young adults. It is characterized by reciprocal translocations resulting in expression of the chimeric EWSR1-ATF1 or EWSR1-CREB1 fusion proteins, driving sarcomagenesis. Besides these characteristics, CCS has remained genomically uncharacterized. Copy number analysis of human CCSs showed frequent amplifications of the MITF locus and chromosomes 7 and 8. Few alterations were shared with Ewing sarcoma or desmoplastic, small round cell tumors, which are other EWSR1-rearranged tumors. Exome sequencing in mouse tumors generated by expression of EWSR1-ATF1 from the Rosa26 locus demonstrated no other repeated pathogenic variants. Additionally, we generated a new CCS mouse by Cre-loxP-induced chromosomal translocation between Ewsr1 and Atf1, resulting in copy number loss of chromosome 6 and chromosome 15 instability, including amplification of a portion syntenic to human chromosome 8, surrounding Myc. Additional experiments in the Rosa26 conditional model demonstrated that Mitf or Myc can contribute to sarcomagenesis. Copy number observations in human tumors and genetic experiments in mice rendered, for the first time to our knowledge, a functional landscape of the CCS genome. These data advance efforts to understand the biology of CCS using innovative models that will eventually allow us to validate preclinical therapies necessary to achieve longer and better survival for young patients with this disease.

Objective: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic., Methods: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus., Results: To date, 39 guidance statements have been approved by the task force. Those with similar recommendations were combined to form a total of 33 final guidance statements, all of which received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 5) or high consensus (n = 28)., Conclusion: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated., (© 2021, American College of Rheumatology.)

Sarcoma comprises a group of malignancies that includes over 100 individual disease entities. Type-specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasingly molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (© 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

The coronavirus disease-2019 (COVID-19) pandemic has changed the conduct of clinical trials. For studies with physical function and physical activity outcomes that require in-person participation, thoughtful approaches in transitioning to the remote research environment are critical. Here, we share our experiences in transitioning from in-person to remote assessments of physical function and activity during the pandemic and highlight key considerations for success. Details on the development of the remote assessment protocol, integration of a two-way video platform, and implementation of remote assessments are addressed. In particular, procedural challenges and considerations in transitioning and conducting remote assessments will be discussed in terms of efforts to maintain participant safety, maximize study efficiency, and sustain trial integrity. Plans for triangulation and analysis are also discussed. Although the role of telehealth platforms and research activities in remote settings are still growing, our experiences suggest that adopting remote assessment strategies are useful and convenient in assessing study outcomes during, and possibly even beyond, the current pandemic. Trial register and number: ClinicalTrials.gov [NCT03728257]., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ligand-induced endocytosis of the immune receptor FLAGELLIN SENSING2 (FLS2) is critical for maintaining its proper abundance in the plasma membrane (PM) to initiate and subsequently down regulate cellular immune responses to bacterial flagellin or flg22-peptide. The molecular components governing PM abundance of FLS2, however, remain mostly unknown. Here, we identified Arabidopsis (Arabidopsis thaliana) DYNAMIN-RELATED PROTEIN1A (DRP1A), a member of a plant-specific family of large dynamin GTPases, as a critical contributor to ligand-induced endocytosis of FLS2 and its physiological roles in flg22-signaling and immunity against Pseudomonas syringae pv. tomato DC3000 bacteria in leaves. Notably, drp1a single mutants displayed similar flg22-defects as those previously reported for mutants in another dynamin-related protein, DRP2B, that was previously shown to colocalize with DRP1A. Our study also uncovered synergistic roles of DRP1A and DRP2B in plant growth and development as drp1a drp2b double mutants exhibited severely stunted roots and cotyledons, as well as defective cell shape, cytokinesis, and seedling lethality. Furthermore, drp1a drp2b double mutants hyperaccumulated FLS2 in the PM prior to flg22-treatment and exhibited a block in ligand-induced endocytosis of FLS2, indicating combinatorial roles for DRP1A and DRP1B in governing PM abundance of FLS2. However, the increased steady-state PM accumulation of FLS2 in drp1a drp2b double mutants did not result in increased flg22 responses. We propose that DRP1A and DRP2B are important for the regulation of PM-associated levels of FLS2 necessary to attain signaling competency to initiate distinct flg22 responses, potentially through modulating the lipid environment in defined PM domains., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The etiology of rotator cuff tearing is likely multifactorial, including a potential genetic predisposition. The purpose of the study was to identify genetic variants associated with rotator cuff tearing utilizing the UK Biobank (UKB) cohort, confirm variants using a separate genetic database, and evaluate tissue expression of genes with associated variants following rotator cuff tearing using RNA sequencing., Methods: Genome-wide association study (GWAS): A GWAS was performed using data from UKB with 5701 cases of rotator cuff injury. RNA sequencing analyses: rotator cuff biopsies were obtained from 24 patients with full-thickness rotator cuff tears who underwent arthroscopic rotator cuff repair (cases) and 9 patients who underwent open reduction internal fixation for a proximal humerus fracture (controls). Total RNA was extracted and differential gene expression was measured by RNAseq for genes with variants associated with rotator cuff tearing., Results: The results of the UKB GWAS identified 3 loci that reached genome-wide statistical significance: 2 loci on chromosome 7 in GLCCI1 (rs4725069; P = 5.0E-09) and THSD7A (rs575224171; P = 5.3E-09), and 1 locus on chromosome 2 in ZNF804A (rs775583810; P = 3.9E-09). The association with rotator cuff injury of the GLCCI1 single-nucleotide polymorphism (SNP; rs4725069) was confirmed in the Kaiser Permanente Research Bank cohort (P = .008). Twenty previously reported SNPs in 12 genes were evaluated using summary statistics from the UKB GWAS, which confirmed 3 SNPs in TNC with rotator cuff injury (rs1138545, rs72758637, and rs7021589; all P < .0024). Of 17 genes with variants associated with rotator cuff injury (14 previously from literature plus 3 new genes from current UKB GWAS), TIMP2, Col5A1, TGFBR1, and TNC were upregulated (P < .001 for all) and THSD7A was downregulated (P = .005) in tears vs. controls in the RNA sequencing data set., Conclusion: The UKB GWAS has identified 3 novel loci associated with rotator cuff tearing (ZNF804A, GLCCI1, THSD7A). Expression of the THSD7A gene was significantly downregulated in rotator cuff tears vs. controls supporting a potential functional role. Three previously reported SNPs in the TNC gene were validated in the UKB GWAS, supporting a role for this gene in rotator cuff tearing. Finally, TIMP2, Col5A1, TGFBR1, and TNC genes were found to have significantly upregulated tissue expression in cases vs. controls supporting a biologic role in tearing for these genes., (Copyright © 2020 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Introduction: In light of the opioid overdose epidemic in the US and the necessity of developing training to conduct difficult conversations around opioid dependence, three case-based videos were created to demonstrate providers using motivational interviewing (MI) with patients who have opioid use disorder (OUD). These vignettes displayed a primary care provider interacting with a patient seeking opioids., Methods: Learners-including third-year medical and physician assistant (PA) students, and family medicine residents-viewed three videos set in a family medicine clinic and assessed clinician use of MI when interacting with patients with OUD. The patients were at different levels of acknowledging their need to change their opioid use behaviors and/or pursue treatment. Learners rated each video with an MI rating scale, and a facilitator debriefed strengths, weaknesses, and omissions regarding MI., Results: Medical and PA students, and resident family physicians provided 572 ratings. Analysis of variance of mean percent incorrect was lower in residents than in all groups combined, but failed to reach statistical significance (47% + 12.0 vs 53% + 15.0, p = .43)., Discussion: These case-based videos with MI ratings afforded students and residents the opportunity to assess clinician use of MI techniques with patients with OUD. The MI rating scale had clinical significance (residents scored +5 points and had more training) despite lacking statistical significance. These scenarios allowed learners to recognize how to use MI when having a difficult conversation with patients who misuse opioids. We envision individual use or use for group discussion., (© 2020 Spangler et al.)

Objective: To provide clinical guidance to rheumatology providers who treat children with pediatric rheumatic disease (PRD) in the context of the coronavirus disease 2019 (COVID-19) pandemic., Methods: The task force, consisting of 7 pediatric rheumatologists, 2 pediatric infectious disease physicians, 1 adult rheumatologist, and 1 pediatric nurse practitioner, was convened on May 21, 2020. Clinical questions and subsequent guidance statements were drafted based on a review of the queries posed by the patients as well as the families and healthcare providers of children with PRD. An evidence report was generated and disseminated to task force members to assist with 3 rounds of asynchronous, anonymous voting by email using a modified Delphi approach. Voting was completed using a 9-point numeric scoring system with predefined levels of agreement (categorized as disagreement, uncertainty, or agreement, with median scores of 1-3, 4-6, and 7-9, respectively) and consensus (categorized as low, moderate, or high). To be approved as a guidance statement, median vote ratings were required to fall into the highest tertile for agreement, with either moderate or high levels of consensus., Results: The task force drafted 33 guidance statements, which were voted upon during the second and third rounds of voting. Of these 33 statements, all received median vote ratings within the highest tertile of agreement and were associated with either moderate consensus (n = 6) or high consensus (n = 27). Statements with similar recommendations were combined, resulting in 27 final guidance statements., Conclusion: These guidance statements have been generated based on review of the available literature, indicating that children with PRD do not appear to be at increased risk for susceptibility to SARS-CoV-2 infection. This guidance is presented as a "living document," recognizing that the literature on COVID-19 is rapidly evolving, with future updates anticipated., (© 2020, American College of Rheumatology.)

High pulmonary blood pressure contributes to exercise-induced pulmonary hemorrhage. The objective of this study was to use bioimpedance spectroscopy to assess body fluid compartment volumes under 3 conditions in 6 racehorses: i) Pre- and post-supramaximal treadmill exercise (control); ii) Exercise 4 hours after furosemide (0.5 mg/kg body weight, IV); iii) Exercise, removal of ~14 L of blood and subsequent reinfusion of the blood. Statistical analysis used linear mixed effects models. Body compartment volumes did not change during the control runs. Total body water (TBW) ( P = 0.007, P = 0.007), extracellular fluid (ECF) ( P = 0.003, P = 0.003), and intracellular fluid (ICF) volumes ( P = 0.04, P = 0.04) decreased pre- and post-exercise following furosemide administration. The ICF trended to decrease ( P = 0.07) after slow removal of blood. Blood reinfusion increased TBW ( P = 0.02, P = 0.02) and ICF ( P = 0.005, P = 0.005) pre- and post-exercise., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)

Epigenetic regulation is critical to physiological control of development, cell fate, cell proliferation, genomic integrity and, fundamentally, transcriptional regulation. This epigenetic control occurs at multiple levels including through DNA methylation, histone modification, nucleosome remodelling and modulation of the 3D chromatin structure. Alterations in genes that encode chromatin regulators are common among mesenchymal neoplasms, a collection of more than 160 tumour types including over 60 malignant variants (sarcomas) that have unique and varied genetic, biological and clinical characteristics. Herein, we review those sarcomas in which chromatin pathway alterations drive disease biology. Specifically, we emphasize examples of dysregulation of each level of epigenetic control though mechanisms that include alterations in metabolic enzymes that regulate DNA methylation and histone post-translational modifications, mutations in histone genes, subunit loss or fusions in chromatin remodelling and modifying complexes, and disruption of higher-order chromatin structure. Epigenetic mechanisms of tumorigenesis have been implicated in mesenchymal tumours ranging from chondroblastoma and giant cell tumour of bone to chondrosarcoma, malignant peripheral nerve sheath tumour, synovial sarcoma, epithelioid sarcoma and Ewing sarcoma - all diseases that present in a younger patient population than most cancers. Finally, we review current and potential future approaches for the development of sarcoma therapies based on this emerging understanding of chromatin dysregulation.

Background: Although the cause of rotator cuff tearing is likely multifactorial and a genetic predisposition has been proposed, the biochemical basis remains unknown., Purpose: To determine gene expression profiles in torn rotator cuff tendon tissue through use of RNA sequencing., Study Design: Controlled laboratory study., Methods: The supraspinatus tendon edge was biopsied in 24 patients undergoing arthroscopic rotator cuff repair for full-thickness supraspinatus rotator cuff tears. The supraspinatus tendon was also biopsied in 9 patients undergoing open reduction and internal fixation for a proximal humeral fracture (controls). Total RNA was extracted and sequenced. Differential gene expression was analyzed between the tear and control groups, and a secondary analysis was conducted between groups defined by an unbiased clustering., Results: Tear and control transcriptomes demonstrated significant differential expression in more than 3000 genes. The identified differential genes were highlighted in pathways involved in inflammation in control patients and extracellular matrix generation in patients with tears. Secondary analysis using unsupervised and thus unbiased hierarchical clustering revealed 2 clusters (c2 and c3). Cluster c3 contained smaller ( P < .001) and less retracted ( P = .018) tears (ie, tears earlier in the progression of rotator cuff disease) with increased expression of hypoxia target genes. Cluster c2 contained larger, more retracted tears (ie, tears further in the progression of rotator cuff disease) with increased expression of endothelial cell markers and chronic inflammation target genes. Tears in c2 had significantly worse healing rates compared with tears in c3 (0% vs 89%; P = .007)., Conclusion: Smaller, less retracted tears had increased expression of hypoxia target genes and improved healing, whereas larger, more retracted tears were associated with endothelial cell markers and worse healing. Thus, hypoxia may be the inciting event for tear development, whereas with tear enlargement, a chronic, inflammatory, angiogenic process may predominate., Clinical Relevance: Identification of differential gene expression in rotator cuff tears may be a reliable tool to predict repair healing in the future., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study received support from the LS Peery Foundation Discovery Program in Musculoskeletal Restoration. R.Z.T. has received consulting fees from Zimmer Biomet, Cayenne Medical, Wright Medical, and DePuy; royalties from Wright Medical, Shoulder Innovations, Zimmer Biomet, and Springer; hospitality payments from Wright Medical; and has stock in Conextions, INTRAFUSE, Genesis, and KATOR. P.N.C. has received educational support from Tornier and Active Medical, consulting fees from DePuy and Arthrex, and royalties from DePuy. K.B.J. has received research support from Pfizer. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2020.)

Background: Clinical workup and treatment guidelines have been published by the National Comprehensive Cancer Network (NCCN) to ensure patients are treated uniformly and appropriately. This study sought to retrospectively review patients with a new diagnosis of sarcoma who were treated in a National Cancer Institute (NCI) designated center and determine compliance rates with guidelines for sarcoma., Aim: To evaluate our compliance of NCCN sarcoma guidelines at a major NCI designated center and to report instances of deviation that could be used for future studies to improve patient care., Methods: Data was collected retrospectively as an internal review and quality assessment of 35 newly diagnosed and treated patients. Demographic data were recorded and information concerning whether patients had appropriate imaging, biopsy and management. Variables of interest were expressed as raw numbers and percentages., Results: Primary site imaging was obtained in 100% of cases. Chest and full-body imaging were obtained in 97% and 100% of indicated cases, respectively. Tissue was obtained preoperatively in 97% of cases. Imaging was reviewed at multidisciplinary Treatment Planning Conference (TPC) in 97% of cases. Pathology was reviewed in 94% of cases in TPC. Both tumor, node, metastasis staging and plan of care were reviewed in 100% of cases in TPC. Treatment guidelines were followed in 94% of cases reviewed., Conclusion: This study evaluated the workup and treatment provided by a single NCI designated sarcoma service to a series of patients with pathologies defined with the NCCN sarcoma treatment guidelines. Although adherence to NCCN was reported to be very high future prospective studies are required to investigate whether NCCN guidelines impact patient outcomes., Competing Interests: Conflict-of-interest statement: All authors declare no conflicts-of-interest related to this article., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS) lack specific molecular underpinnings, show high rates of metastasis, and display limited responsiveness to current therapies, making them challenging cancers both to treat and to study. It has been noted that MFS and UPS frequently lose function of the tumor suppressor genes RB1 and TP53 In this issue of Cancer Research , Li and colleagues demonstrate that proliferation in RB1- and TP53-deficient MFS and UPS depends on SKP2; inhibiting SKP2 with the neddylation inhibitor, pevonedistat, halts tumor growth in a panel of patient-derived xenografts. This renders the oncogenic protein SKP2 a promising therapeutic target. See related article by Li et al., p. 2461 ., (©2020 American Association for Cancer Research.)

Background: Health care costs and utilization for those with an intellectual or developmental disability (IDD) have been shown to be higher than the general population., Objective: To investigate the services that contribute to higher costs and utilization among noninstitutionalized children with an IDD., Design: Matched case-control secondary analysis of the 2000-2017 Medical Expenditure Panel Survey. Pediatric (age 0-21) patients with an IDD were matched to non-IDD subjects. Health care utilization and costs were evaluated with zero-inflated negative binomial regressions and generalized linear models, respectively., Measures: Outcome measures included high-acuity health care utilization [ie, emergency department (ED) visits and hospital admissions], and cost outcomes for total spending, ED use, hospitalization, medications, office visits, home health, and physical therapy., Results: There was no statistical difference in utilization of EDs among the 2 groups though subjects with an IDD showed more hospitalizations than their matched cohort (incidence rate ratios=1.63, P=0.00). Total health care spending was higher among patients with an IDD (coefficient=$5831, P=0.00). Pediatric spending was higher in all measures except for ED. The biggest discrepancies in spending were seen in home health (coefficient=$2558, P=0.00) and outpatient visits (coefficient=$1180, P=0.00)., Conclusions: Pediatric patients with an IDD had higher health care spending and utilization than non-IDD subjects in all categories except for ED use.

Synovial sarcoma, an uncommon cancer, typically affects young adults. Survival rates range from 36% to 76%, decreasing significantly when metastases are present. Synovial sarcomas form in soft tissues, often near bones, with about 10% demonstrating ossification in the tumor. The literature is inconclusive on whether the presence of ossification portends a worse prognosis. To this end, we analyzed our genetic mouse models of synovial sarcoma to determine the extent of ossification in the tumors and its relationship with morbidity. We noted higher ossification within our metastatic mouse model of synovial sarcoma. Not only did we observe ossification within the tumors at a frequency of 7%, but an even higher frequency, 72%, of bone reactivity was detected by radiography. An enrichment of bone development genes was associated with primary tumors, even in the absence of an ossification phenotype. In spite of the ossification being intricately linked with the metastatic model, the presence of ossification was not associated with a faster or worse morbidity in the mice. Our conclusion is that both metastasis and ossification are dependent on time, but that they are independent of one another.

Background: Patient satisfaction and reported outcomes are becoming increasingly important in determining the efficacy of clinical care. To date no study has evaluated the patient experience in the orthopedic oncology outpatient setting to determine which factors of the encounter are priorities to the patient., Aim: To evaluate what factors impact patient experience and report satisfaction in an outpatient orthopedic oncology clinic., Methods: Press Ganey ® patient surveys from a single outpatient orthopedic oncology clinic at a tertiary care setting were prospectively collected per routine medical care. All orthopedic oncology patients who were seen in clinic and received electronic survey were included. All survey responses were submitted within one month of clinic appointment. IRB approval was obtained to retrospectively collect survey responses from 2015 to 2016. Basic demographic data along with survey category responses were collected and statistically analyzed., Results: One hundred sixty-two patient surveys were collected. Average patient age was 54.4 years (SD = 16.2 years) and were comprised of 51.2% female and 48.4% male. 64.2% of patients were from in-state. Out of state residents were more likely to recommend both the practice and attending physician. The likelihood to recommend attending physician was positively associated with MD friendliness/courtesy (OR = 14.4, 95%CI: 2.5-84.3), MD confidence (OR = 48.2, 95%CI: 6.2-376.5), MD instructions follow-up care (OR = 2.5, 95%CI: 0.4-17.4), and sensitivity to needs (OR = 16.1, 95%CI: 1-262.5). Clinic operations performed well in the categories of courtesy of staff (76%) and cleanliness (75%) and less well in ease of getting on the phone (49%), information about delays (36%), and wait time (37%)., Conclusion: Orthopedic specialties can utilize information from this study to improve care from the patient perspective. Future studies may be directed at how to improve these areas of care which are most valued by the patient., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

We explored articulations of lesbian styles, fashions, and ways of dressing in mainstream fashion and media outlets within the United States during the twentieth and twenty-first centuries. Based upon our findings, we propose that there was trending ambivalence and multiple assemblages across space and time where the mainstream media did not necessarily perpetuate a single stereotypical or essentialist way of conceptualizing fashionable lesbians or lesbian fashions. However, we also noted across time a divide between representations of celebrity lesbians and the contemporary lived experience of ordinary lesbians. Though the press acknowledged this divide on occasion, they also established, circulated, and reinforced this difference. According to the press, while lesbians have been 'chic' since the 1990s-whether they embraced a butch or femme esthetic-the best way to be lesbian was to be rich, white, and fashionably dressed.

GRM4 , a GWAS-suspected tumor suppressor, is tested in a mouse model of osteosarcomagenesis as well as the putative oncogene it suppresses, IL23 . Both are expressed in and exert the bulk of their influence among tumor-infiltrating myeloid-derived antigen-presenting cells, rather than osteosarcoma cells. See related article by Kansara et al., p. 1511 ., (©2019 American Association for Cancer Research.)

Primary tumors of the sacrum are difficult to manage, as they often require morbid resections and complex reconstructions. In the case of tumors such as chordoma or chondrosarcoma, aggressive resections are often required to achieve appropriate margins (extending disease-free survival), followed by complex reconstructions. These reconstructions are aimed at restoring the pelvic ring and have traditionally resulted in a lumbosacral construct that utilizes structural allograft/autograft bone (fibula most commonly used) and more recently, reconstruction with 3D-printed custom sacral prostheses. While there are no reports of anatomical reconstruction using sacral allografts, extracorporeal radiation therapy (ECRT) and reimplantation provides a size and shape-matched irradiated autograft which avoids the cultural stigma, structural strength and graft-host concerns associated with allografts, as well as the high costs and time to production associated with custom 3D-printed implants. Here we present an illustrative case with technical notes, outlining the steps used at our center for ECRT. While early results with ECRT in the sacrum are promising, future larger studies should be carried out to help detect differences that may exist in long-term complications., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

In this study we report the development of a novel viral pathogen immunosensor technology based on the electrochemical modulation of the optical signal from a surface plasmon wave interacting with a redox dye reporter. The device is formed by incorporating a sandwich immunoassay onto the surface of a plasmonic device mounted in a micro-electrochemical flow cell, where it is functionalized with a monoclonal antibody aimed to a specific target pathogen antigen. Once the target antigen is bound to the surface, it promotes the capturing of a secondary polyclonal antibody that has been conjugated with a redox-active methylene blue dye. The methylene blue displays a reversible change in the complex refractive index throughout a reduction-oxidation transition, which generates an optical signal that can be electrochemically modulated and detected at high sensitivity. For proof-of-principle measurements, we have targeted the hemagglutinin protein from the H5N1 avian influenza A virus to demonstrate the capabilities of our device for detection and quantification of a critical influenza antigen. Our experimental results of the EC-SPR-based immunosensor under potential modulation showed a 300 pM limit of detection for the H5N1 antigen.

Histone deacetylases (HDACs) are promising targets for cancer therapy, although their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in the regulation of MDM2 acetylation at previously uncharacterized lysines. Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 ubiquitin ligase E3 (MULE). This mechanism further reveals a therapeutic connection between the MULE ubiquitin ligase function and tumor suppression. Specifically, we show that HDAC inhibitor treatment promotes the accumulation of MULE, which diminishes the t(X; 18) translocation-associated synovial sarcomagenesis by directly targeting the fusion product SS18-SSX for degradation. These results uncover a new HDAC2-dependent pathway that integrates reversible acetylation signaling to the anticancer ubiquitin response., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

YM155 is an anti-cancer therapy that has advanced into 11 different human clinical trials to treat various cancers. This apoptosis-inducing therapy indirectly affects the protein levels of survivin (gene: Birc5 ), but the molecular underpinnings of the mechanism remain largely unknown. Synovial sarcoma is a rare soft-tissue malignancy with high protein expression of survivin. We investigated whether YM155 would be a viable therapeutic option to treat synovial sarcoma. YM155 therapy was applied to human synovial sarcoma cell lines and to a genetically engineered mouse model of synovial sarcoma. We discovered that YM155 exhibited nanomolar potency against human synovial sarcoma cell lines and the treated mice with synovial sarcoma demonstrated a 50% reduction in tumor volume compared to control treated mice. We further investigated the mechanism of action of YM155 by looking at the change of lysine modifications of the histone tails that were within 250 base pairs of the Birc5 promoter. Using chromatin immunoprecipitation (ChIP)-qPCR, we discovered that the histone epigenetic marks of H3K27 for the Birc5 promoter changed upon YM155 treatment. H3K27me3 and H3K27ac increased, but the net result was decreased Birc5 /survivin expression. Furthermore, the combination of molecular events resulted in caspase 3/7/8 upregulation and death of the sarcoma cells.

The oral mucosa is one of the most rapidly dividing tissues in the body and serves as a barrier to physical and chemical insults from mastication, food, and microorganisms. Breakdown of this barrier can lead to significant morbidity and potentially life-threatening infections for patients. Determining the identity and organization of oral epithelial progenitor cells (OEPCs) is therefore paramount to understanding their roles in homeostasis and disease. Using lineage tracing and label retention experiments, we show that rapidly dividing OEPCs are located broadly within the basal layer of the mucosa throughout the oral cavity. Quantitative clonal analysis demonstrated that OEPCs undergo population-asymmetrical divisions following neutral drift dynamics and that they respond to chemotherapy-induced damage by altering daughter cell fates. Finally, using single-cell RNA-seq, we establish the basal layer population structure and propose a model that defines the organization of cells within the basal layer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Individuals with intellectual and/or developmental disabilities (IDD) tend to incur high health care costs. The Neurobehavior HOME Program (HOME) is an interdisciplinary program that cares for this population. This study will evaluate the health care costs and utilization of individuals during their first year of enrollment in HOME and identify factors associated with higher cost and utilization. Secondary analysis of claims data were used to identify cost and utilization. Generalized linear regression and negative binomial regression were used to calculate utilization and cost. The mean total cost of care during the initial year of enrollment (n=239) per individual was $11,095.87, with $4,640.83 attributed to inpatient care. Those with diabetes (p=0.01), epilepsy (p=0.02), or mood disorders (p=0.03) were more likely to be admitted to the hospital and utilize the emergency department. These findings will enable systems and payers to better construct health care delivery reforms for this high-need population.

Objective To describe the process of creating the Family Medicine Vital Signs blog, curated and edited by residents and faculty at the University of Utah Family Medicine Residency Program and to obtain feedback from participants regarding educational impact. Methods Each resident and faculty member contributes at least one blog post per year (with other invited authors), resulting in one post per week on the blog site. An editorial board composed of residents and faculty provides direction and editorial assistance for each post. Residency staff assist in providing authors with reminders and logistical support. A survey was conducted of blog contributors to understand their perceptions of the blog's educational value. Results The Family Medicine Vital Signs blog was started in July 2014, with 40% (n = 68) of the 170 posts provided by residents, 38.2% (n = 65) by faculty, and 21.8% (n = 37) by invited authors through June 2017. It has averaged nearly 100 unique readers per week and has had 15 posts republished in different venues. The participant survey demonstrated scores above the median-possible score, showing positive impact in support of the educational goals. Conclusion A residency blog provides a venue for educational instruction, supporting physician development of communication skills, community engagement, and advocacy.

Background: Phenylalanine hydroxylase (PAH) deficiency, otherwise known as phenylketonuria (PKU), is an inborn error of metabolism that requires treatment to be initiated in the newborn period and continued throughout life. Due to the challenges of treatment adherence and the resulting cumulative effects of high and labile blood phenylalanine, PKU exerts a significant burden of disease. Retrospective studies using large databases allow for unique perspectives on comorbidities associated with rare diseases. An evaluation of comorbidities across various organ systems is warranted to understand the disease burden in adult patients., Objectives: The aim of this insurance claim-based observational study was to assess the prevalence of comorbid conditions across various organ systems (e.g. dermatological, renal, respiratory, gastrointestinal, hematological, and others) among adult PKU patients compared with matched controls from the general population., Methods: This retrospective, case-controlled study selected patients from United States insurance claims databases from 1998 to 2014 using International Classification of Diseases, Ninth Revision (ICD-9) codes for diagnosis of PKU. The date of first diagnosis during the study period was index date and this was not necessarily the first time the patient was diagnosed with PKU. Cases were matched with a 1:5 ratio with general population (non-PKU controls) on age, sex, race, geographic location, duration of time in the database and insurance type. Prevalence and prevalence ratio (PR) calculations for comorbidities across various organ systems among adults (≥20 years old) with PKU were compared with the general population (non-PKU controls). The conditions were selected based on complications associated with PKU and feedback from clinicians treating PKU patients., Results: A total of 3691 PKU patients and 18,455 matched, non-PKU controls were selected, with an average age of 35 years. The mean healthcare costs incurred by the PKU patients during baseline, were approximately 4 times that of the controls ($4141 vs $1283; p < .0001). The prevalence rates of comorbidities across various organ systems during the follow-up period were significantly higher for those with PKU than in the control group. After adjusting for baseline characteristics, the adjusted prevalence ratios (PR) of 15 conditions studied (asthma, alopecia, urticaria, gallbladder disease, rhinitis, esophageal disorders, anemia, overweight, GERD, eczema, renal insufficiency, osteoporosis, gastritis/esophagitis and kidney calculus) were all above PR = 1.24 and significantly higher for the PKU cohort (p ≤ .001). The highest adjusted PR were for renal insufficiency with hypertension (PR [95% CI]: 2.20 [1.60-3.00]; p < .0001) and overweight (PR [95%CI]: 2.06 [1.85-2.30]; p < .0001)., Conclusions: The prevalence of selected comorbidities across several organ systems is significantly higher among PKU patients than for general population controls. Regular screening for common co-morbidities may be warranted as part of PKU management., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The prevalence of metastatic bone disease (MBD) grows each year as treatments improve. Little has been published about functional and pain outcomes in this group after surgery. Patient-Reported Outcomes Measurement Information System (PROMIS ® ) can collect information, in just minutes, about patient's physical, mental, and social health. This study evaluated PROMIS ® pain and functional scores in surgically treated patients with MBD., Methods: Basic demographics and PROMIS ® scores were recorded from a total of 13 patients at 9 periods of time over 6 months., Results: The average change in physical function at week 1 was -2.5 (standard deviation [SD] = 5.4), at 2 weeks 1.7 (SD = 7.6), after 4 weeks 6.9 (SD = 10), after 6 weeks 6.4 (SD = 10.9), after 10 weeks 15.3 (SD = 3.1), and after 3 months 8.6 (SD = 7.6). The average change in pain inference at week 1 was -1.2 (SD = 7.3), at 2 weeks -2.1 (SD = 9.5), after 4 weeks -12.6 (SD = 4.5), after 6 weeks -8.3 (SD = 10.2), after 10 weeks -16.6 (SD = 4.3), and after 3 months -11.4 (SD = 8.2)., Conclusions: PROMIS ® provides a feasible means to collect data in this population. Trends of improved function and decreased pain were seen after surgery. Continuing this study will hopefully elucidate more insight into the surgical treatment of MBD., (© 2018 Wiley Periodicals, Inc.)

Sarcoma is a rare tumor type that occurs most frequently in connective tissue. Despite its uncommon occurrence, sarcoma research has provided the means for groundbreaking research that has advanced our understanding of general cancer mechanisms. It is through sarcoma research that the pioneering efforts of cancer immunotherapy were explored, that we understand the inherent genetic nature of cancer mutations, and that we appreciate the subclassification of general cancer types to make more accurate prognoses. This review explores the brief history of sarcoma research and what sarcomas can still teach us about the future of cancer research, especially in regard to novel immunotherapy targets, the role of epigenetics in disease progression and chemoresistance, and the benefits of more focused clinical trials., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Nonadherence is currently an underrecognized and potentially modifiable obstacle to care in juvenile idiopathic arthritis (JIA). The purpose of our study was to design and implement a standardized approach to identifying adherence barriers for youth with JIA across 7 pediatric rheumatology clinics through the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) and to assess the frequency of adherence barriers in patients and their caregivers across treatment modalities., Methods: An iterative process using coproduction among parents and providers of patients with JIA was used to design the Barriers Assessment Tool to screen for adherence barriers across 4 treatment modalities (i.e., oral medications, injectable medications, infusions, and physical/occupational therapy). This tool was implemented in 7 rheumatology clinics across the United States and patient responses were collected for analysis., Results: Data were collected from 578 parents and 99 patients (n = 44 parent-child dyads). Seventy-seven percent (n = 444) of caregivers and 70% (n = 69) of patients reported at least 1 adherence barrier across all treatment components. The most commonly reported adherence barriers included worry about future consequences of therapy, pain, forgetting, side effects, and embarrassment related to the therapy. There was no significant difference between endorsement of barriers between parents and adolescents., Conclusion: Implementing a standardized tool assessing adherence barriers in the JIA population across multiple clinical settings is feasible. Systematic screening sheds light on the factors that make adherence difficult in JIA and identifies targets for future adherence interventions in clinical practice.

The outermost layer of the eye, the cornea, is renewed continuously throughout life. Stem cells of the corneal epithelium reside in the limbus at the corneal periphery and ensure homeostasis of the central epithelium. However, in young mice, homeostasis relies on cells located in the basal layer of the central corneal epithelium. Here, we first studied corneal growth during the transition from newborn to adult and assessed Keratin 19 (Krt19) expression as a hallmark of corneal maturation. Next, we set out to identify a novel marker of murine corneal epithelial progenitor cells before, during and after maturation, and we found that Bmi1 is expressed in the basal epithelium of the central cornea and limbus. Furthermore, we demonstrated that Bmi1+ cells participated in tissue replenishment in the central cornea. These Bmi1+ cells did not maintain homeostasis of the cornea for more than 3 months, reflecting their status as progenitor rather than stem cells. Finally, after injury, Bmi1+ cells fueled homeostatic maintenance, whereas wound closure occurred via epithelial reorganization. Stem Cells 2018;36:562-573., (© AlphaMed Press 2018.)

Differentiation features in cancer cells are typically attributed to the cell of origin. In this issue of Cancer Cell, Drummond et al. demonstrate a transdifferentiation program apparent in rhabdomyosarcomas (cancers with skeletal muscle differentiation features) arising through cell fate reprogramming from a single oncogene activation in endothelial cell precursors., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Synovial sarcoma (SS) is an aggressive soft-tissue sarcoma that is often discovered during adolescence and young adulthood. Despite the name, synovial sarcoma does not typically arise from a synoviocyte but instead arises in close proximity to bones. Previous work demonstrated that mice expressing the characteristic SS18-SSX fusion oncogene in myogenic factor 5-expressing (Myf5-expressing) cells develop fully penetrant sarcomagenesis, suggesting skeletal muscle progenitor cell origin. However, Myf5 is not restricted to committed myoblasts in embryos but is also expressed in multipotent mesenchymal progenitors. Here, we demonstrated that human SS and mouse tumors arising from SS18-SSX expression in the embryonic, but not postnatal, Myf5 lineage share an anatomic location that is frequently adjacent to bone. Additionally, we showed that SS can originate from periosteal cells expressing SS18-SSX alone and from preosteoblasts expressing the fusion oncogene accompanied by the added stabilization of β-catenin, which is a common secondary change in SS. Expression and secretion of the osteoclastogenesis inhibitory factor osteoprotegerin enabled early growth of SS18-SSX2-transformed cells, indicating a paracrine link between the bone and synovial sarcomagenesis. These findings explain the skeletal contact frequently observed in human SS and may provide alternate means of enabling SS18-SSX-driven oncogenesis in cells as differentiated as preosteoblasts.

Synovial sarcoma (SS) is initiated by a t(X;18) chromosomal translocation and resultant SS18-SSX fusion oncogene. Only a few SS cell lines exist. None has been compared to its source tumor. In order to compare matched tumor and cell line pairs, we performed RNAseq on 3 tumor/cell line pairs from a genetically engineered mouse model of SS, as well as 2 pairs from human SS tumors. Transcriptomes of mouse tumors and derivative cell lines deviated significantly. Differentially expressed genes highlighted inflammatory infiltrates and metabolism. The same was found for the human tumor and cell line pairs. More was shared between different tumors than between any tumor and its cell line. Direct xenografting generated transcriptomes that more closely resembled the primary tumor than did its derivative cell line. SS tumor transcriptomes are powerfully impacted by the environment wherein they reside, especially with regard to immune interaction and metabolism.

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor CDKN2A , and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Pten fl/fl ;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. Mol Cancer Ther; 16(12); 2656-67. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be. Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, because it is normally generated by the laCL but not the liCL. Here, we show that epithelial-specific deletion of the transcription factor Islet1 (Isl1) is sufficient to drive formation of ectopic enamel by the liCL stem cells, and also that it leads to production of altered enamel on the labial surface. Molecular analyses of developing and adult incisors revealed that epithelial deletion of Isl1 affected multiple, major pathways: Bmp (bone morphogenetic protein), Hh (hedgehog), Fgf (fibroblast growth factor), and Notch signaling were upregulated and associated with liCL-generated ectopic enamel; on the labial side, upregulation of Bmp and Fgf signaling, and downregulation of Shh were associated with premature enamel formation. Transcriptome profiling studies identified a suite of differentially regulated genes in developing Isl1 mutant incisors. Our studies demonstrate that ISL1 plays a central role in proper patterning of stem cell-derived enamel in the incisor and indicate that this factor is an important upstream regulator of signaling pathways during tooth development and renewal. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of many axial and appendicular skeletal elements. Surprisingly, it is not known whether such tumors also form in endochondral elements of the craniofacial skeleton. Here, we carried out a retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Interestingly, nearly half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1f/f;Col2-CreER or Ext1f/f;Aggrecan-CreER mouse models of HME along the synchondrosis growth plates. Osteochondroma formation was preceded by phenotypic alteration of cells at the chondro-perichondrial boundary and was accompanied by ectopic expression of major cartilage matrix genes -collagen 2 and collagen X- within the growing ectopic masses. Because chondrogenesis requires bone morphogenetic protein (BMP) signaling, we asked whether osteochondroma formation could be blocked by a BMP signaling antagonist. Systemic administration with LDN-193189 effectively inhibited osteochondroma growth in conditional Ext1-mutant mice. In vitro studies with mouse embryo chondrogenic cells clarified the mechanisms of LDN-193189 action that turned out to include decreases in canonical BMP signaling pSMAD1/5/8 effectors but interestingly, concurrent increases in such anti-chondrogenic mechanisms as pERK1/2 and Chordin, Fgf9 and Fgf18 expression. Our study is the first to reveal that the cranial base can be affected in patients with HME and that osteochondroma formation is amenable to therapeutic drug intervention.