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Active surveillance (AS) is recommended as a management option for men with favorable-risk (low risk and favorable intermediate risk) prostate cancer; however, national rates remain low. The Michigan Urological Surgery Improvement Collaborative (MUSIC) established a quality improvement (QI) initiative in June 2014 to increase AS utilization. In this report, we analyze the rates of AS utilization over time in the state of Michigan (MUSIC) for men with favorable-risk prostate cancer and compare these to rates for other men diagnosed with favorable-risk prostate cancer in the USA outside the state of Michigan. While the variables that influence AS utilization were the same in both cohorts, we found that the AS utilization rates and the rate of increase were significantly higher in MUSIC. We conclude that the QI initiative started in MUSIC should serve as a roadmap to increasing AS use nationwide. PATIENT SUMMARY: Active surveillance (AS), which involves close monitoring with blood tests and scans, is recommended for management of favorable-risk prostate cancer to avoid or delay unnecessary treatment. Our results show that a quality improvement program in Michigan increased AS use for prostate cancer patients in the state. This program should be used to increase AS uptake throughout the USA.

Background Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. Methods Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). Results Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54–5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19–3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42–3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01–4.68, P = 0.04). Conclusions This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.

Ankylosing spondylitis (AS) is an inflammatory rheumatic disease in which the physical impact has been evaluated; however, the psychological consequences are less well explored. The primary aim of this review was to determine the effectiveness of group versus home-based exercises on psychological status of patients with AS.Six databases were searched until January 2020. Eligible studies were randomised controlled trials including group or home-based exercise interventions. Risk of bias (RoB) was evaluated using the Cochrane RoB 2.0 tool. Relative percentage difference (RPD) between groups and effect sizes were presented as standardised mean differences (SMDs) with 95% confidence intervals (CI).Five studies met the inclusion criteria (n = 240), outcomes of interest were depression, anxiety and mental health. Three studies were low-risk RoB, one study was high-risk RoB and one study there was 'some concerns' of bias. Group-based exercise was more effective than home-based exercise for improving depression at 6-week (RPD 18%) and 3-month (RPD 42%), anxiety (RPD 17%) and mental health (RPD 20%). Home-based exercise was more effective than control interventions for improving depression (RPD 33%). A meta-analysis demonstrated group-based exercises compared to home exercises, improved depression (SMD: -0.54; 95% CI: [-0.89; -0.18]; p = 0.003) and physical function (SMD: -0.49; 95% CI: [-0.84; -0.14]; p = 0.006).Supervised group-based demonstrated improvements in depression, anxiety and mental health compared to home-based exercise. Individualised home-based exercise is more effective than no intervention for improving depression in people with AS.

Patient characteristics of samples used for discovery and independent validation.

Top upstream regulators significantly enriched in PDAC vs PAT and PAT vs CP, as determined using IPA.

Patient characteristics of UoL serum sample cohorts.

Patient characteristics of samples included on TMAs histologically stained for TNC.

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research.Significance:Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.

Supplementary Material and Methods

XLS file, 27K, Deregulated genes known to promote carcinogenesis, tumor progression, or metastatic dissemination.

PDF file, 8K.

PDF file, 251K, Supplemental Figure S1 (a) Gene expression profiling of 131 clinical specimens for which we have staging information shows that overexpression of PTTG1 correlates with high tumor stage. (b) Association of increased PTTG1 expression with decreased probability of survival for 5-years. Dashed lines indicate 95% confidence intervals (c) Similarly, ECT2 overexpression is most prominent in high stage ccRCC tumors. (d) PTTG1 and ECT2 are coordinately overexpressed in primarily high stage tumors. (e) Cells completely deficient of ECT2 acquire a highly-branched and spindle-shaped morphology.

PDF file, 646K, Supplemental Figure S2. (a) SiRNA targeting PTTG1 achieved complete suppression of PTTG1 expression for at least 72 hours. (b) Immunofluorescent staining revealed abundant nuclear and cytoplasmic localization of PTTG1 in 786-O cells and suppression of PTTG1 expression upon treatment with targeted siRNA. (c) A 2-dimensional colony formation assay demonstrated that PTTG1 knockdown had little effect on anchorage-dependent growth rate. Crystal violet staining and microscopic imaging of these colonies further revealed that 786-O cells exhibit no major morphological differences following PTTG1 knockdown.

PDF file, 278K, Supplemental Figure S3. Direct targeting of ECT2 by siRNA results in a dose-dependent inhibition of ccRCC cell growth. (a) MTS proliferation assays showed a dose-dependent reduction in 786-O cell growth upon treatment with siRNA's targeting ECT2. (b) Depletion of ECT2 results in an accumulation of cells in G2/M phase. (c) Cells unable to complete cell division acquired a multinucleate phenotype, indicative of cytokinesis defects upon ECT2 knockdown.

PDF file, 27K, FISH Samples: Clinical Features and Maximum PTTG1 Copy Number. Interphase FISH analysis of ccRCC tumor touch preparations. FISH probe locations are shown in Figure 1a.

XLS file, 27K, Known Chromosome 5q Oncogenes.

Research methodology The case was written based on personal interviews with Jordan Boyes. Case overview/synopsis Boyes Group, a private real estate brokerage in Saskatoon, Saskatchewan, had been growing rapidly. Company founder Jordan Boyes needed to determine where to continue expanding. Saskatoon held great potential in home building, and he wondered if this would be a direction for his company. His real estate reputation was excellent, but he wondered if building homes would jeopardize his current relationships with local builders. He wanted to move fast, to avoid giving up market share to his competitors. Complexity academic level This case was designed for undergraduate and graduate classes in strategy.

Theoretical basis The case learning objectives and discussion questions relate very closely to several theories related to branding, including brand positioning, brand growth, brand management, customer value proposition, brand matrix and brand identity. Research methodology The information provided in this case was gathered by the author through personal interviews and email exchanges with Jordan Boyes, managing broker and owner of Boyes Group Realty Inc. Secondary research was also conducted to gather relevant academic materials, as well as industry and competitor information. Case overview/synopsis Jordan Boyes opened Boyes Group Realty Inc. in 2015 after working as a Realtor® at another private realty firm in Saskatoon, Saskatchewan for several years. They offered buying and selling services in the areas of commercial, residential and farm real estate. Over the past five years, they had experienced strong sales numbers and growth in the number of new agents joining the company. However, Boyes saw untapped potential in the marketplace and wanted to develop a brand strategy that took the best advantage of brand extension opportunities to drive the continued growth of his company. Complexity academic level This case is suitable at the undergraduate level for a branding course, marketing strategy course or services marketing course. The case is best used to apply the concept of developing brand identity and making strategic decisions in a service-based organization.

Background miRNAs are promising biomarkers in oncology as their small size makes them less susceptible to degradation than mRNA in FFPE tissue. We aimed to derive a hypoxia-associated miRNA signature for bladder cancer. Methods Taqman miRNA array cards identified miRNA seed genes induced under hypoxia in bladder cancer cell lines. A signature was derived using feature selection methods in a TCGA BLCA training data set. miRNA expression data were generated for 190 tumours from the BCON Phase 3 trial and used for independent validation. Results A 14-miRNA hypoxia signature was derived, which was prognostic for poorer overall survival in the TCGA BLCA cohort (n = 403, p = 0.001). Univariable analysis showed that the miRNA signature predicted an overall survival benefit from having carbogen–nicotinamide with radiotherapy (HR = 0.30, 95% CI 0.094–0.95, p = 0.030) and performed similarly to a 24-gene mRNA signature (HR = 0.47, 95% CI 0.24–0.92, p = 0.025). Combining the signatures improved performance (HR = 0.26, 95% CI 0.08–0.82, p = 0.014) with borderline significance for an interaction test (p = 0.065). The interaction test was significant for local relapse-free survival LRFS (p = 0.033). Conclusion A 14-miRNA hypoxia signature can be used with an mRNA hypoxia signature to identify bladder cancer patients benefitting most from having carbogen and nicotinamide with radiotherapy.

Tumour hypoxia status provides prognostic information and predicts response to hypoxia‑modifying treatments. A previous study by our group derived a 24‑gene signature to assess hypoxia in bladder cancer. The objectives of the present study were to compare platforms for generating signature scores, identify cut‑off values for prospective studies, assess intra‑tumour heterogeneity and confirm hypoxia relevance. Briefly, RNA was extracted from prospectively collected diagnostic biopsies of muscle invasive bladder cancer (51 patients), and gene expression was measured using customised Taqman Low Density Array (TLDA) cards, NanoString and Clariom S arrays. Cross‑platform transferability of the gene signature was assessed using regression and concordance analysis. The cut‑off values were the cohort median expression values. Intra‑ and inter‑tumour variability were determined in a retrospective patient cohort (n=51) with multiple blocks (2‑18) from the same tumour. To demonstrate relevance, bladder cancer cell lines were exposed to hypoxia (0.1% oxygen, 24 h), and extracted RNA was run on custom TLDA cards. Hypoxia scores (HS) values showed good agreement between platforms: Clariom S vs. TLDA (r=0.72, P0.0001; concordance 73%); Clariom S vs. NanoString (r=0.84, P0.0001; 78%); TLDA vs. NanoString (r=0.80, P0.0001; 78%). Cut‑off values were 0.047 (TLDA), 7.328 (NanoString) and 6.667 (Clariom S). Intra‑tumour heterogeneity in gene expression and HS (coefficient of variation 3.9%) was less than inter‑tumour (7.9%) variability. HS values were higher in bladder cancer cells exposed to hypoxia compared with normoxia (P0.02). In conclusion, the present study revealed that application of the 24‑gene bladder cancer hypoxia signature was platform agnostic, cut‑off values determined prospectively can be used in a clinical trial, intra‑tumour heterogeneity was low and the signature was sensitive to changes in oxygen levels

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. Significance: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.

Glaucoma is a complex neurodegenerative disease resulting in progressive optic neuropathy and is a leading cause of irreversible blindness worldwide. Primary open angle glaucoma (POAG) is the predominant form affecting 65.5 million people globally. Despite the prevalence of POAG and the identification of over 120 glaucoma related genetic loci, the underlaying molecular mechanisms are still poorly understood. The transforming growth factor beta (TGF-β) signalling pathway is implicated in the molecular pathology of POAG. To gain a better understanding of the role TGF-β2 plays in the glaucomatous changes to the molecular pathology in the trabecular meshwork, we employed RNA-Seq to delineate the TGF-β2 induced changes in the transcriptome of normal primary human trabecular meshwork cells (HTM). We identified a significant number of differentially expressed genes and associated pathways that contribute to the pathogenesis of POAG. The differentially expressed genes were predominantly enriched in ECM regulation, TGF-β signalling, proliferation/apoptosis, inflammation/wound healing, MAPK signalling, oxidative stress and RHO signalling. Canonical pathway analysis confirmed the enrichment of RhoA signalling, inflammatory-related processes, ECM and cytoskeletal organisation in HTM cells in response to TGF-β2. We also identified novel genes and pathways that were affected after TGF-β2 treatment in the HTM, suggesting additional pathways are activated, including Nrf2, PI3K-Akt, MAPK and HIPPO signalling pathways. The identification and characterisation of TGF-β2 dependent differentially expressed genes and pathways in HTM cells is essential to understand the patho-physiology of glaucoma and to develop new therapeutic agents.