Clinical features and predictive biomarkers for bladder cancer in patients with type 2 diabetes presenting with haematuria.

AIMS: To identify clinical features and protein biomarkers associated with bladder cancer (BC) in individuals with type 2 diabetes mellitus presenting with haematuria. MATERIALS AND METHODS: Data collected from the Haematuria Biomarker (HaBio) study was used in this analysis. A matched sub-cohort of patients with type 2 diabetes and patients without diabetes was created based on age, sex, and BC diagnosis, using approximately a 1:2 fixed ratio. Randox Biochip Array Technology and ELISA were applied for measurement of 66 candidate serum and urine protein biomarkers. Hazard ratios and 95% confidence intervals were estimated by chi-squared and Wilcoxon rank sum test for clinical features and candidate protein biomarkers. Diagnostic protein biomarker models were identified using Lasso-based binominal regression analysis. RESULTS: There was no difference in BC grade, stage, and severity between individuals with type 2 diabetes and matched controls. Incidence of chronic kidney disease (CKD) was significantly higher in patients with type 2 diabetes (p = 0.008), and CKD was significantly associated with BC in patients with type 2 diabetes (p = 0.032). A biomarker model, incorporating two serum (monocyte chemoattractant protein 1 and vascular endothelial growth factor) and three urine (interleukin 6, cytokeratin 18, and cytokeratin 8) proteins, predicted incidence of BC with an Area Under the Curve (AUC) of 0.84 in individuals with type 2 diabetes. In people without diabetes, the AUC was 0.66. CONCLUSIONS: We demonstrate the potential clinical utility of a biomarker panel, which includes proteins related to BC pathogenesis and type 2 diabetes, for monitoring risk of BC in patients with type 2 diabetes. Earlier urology referral of patients with type 2 diabetes will improve outcomes for these patients. TRIAL REGISTRATION: http://www.isrctn.com/ISRCTN25823942.

Thrombomodulin Expression in Bladder Cancer Tissue and Its Association with Prognosis and Patient Survival.

BACKGROUND: Decreased expression of thrombomodulin (TM) in bladder cancer tissue has been shown to be associated with cell proliferation, increased malignancy and a poor prognosis. The aim of this study was to investigate the immunoexpression of TM in bladder tissue cores by immunohistochemistry (IHC) and the relationship between TM score and patient survival for the following pathologies: transitional cell papillary carcinoma (TCPC), transitional cell carcinoma (non-papillary) (TCC), squamous cell carcinoma (SCC), adenocarcinoma, and sarcoma. TM immunoexpression was also evaluated in normal adjacent bladder tissue cores. METHODS: TM immunoexpression was assessed in n=185 formalin-fixed paraffin-embedded (FFPE) bladder tissue cores from n=98 patients by IHC. Tissue cores included TCPC (n=29), TCC (n=85), SCC (n=21), adenocarcinoma (n=12), sarcoma (n=4), and normal tissue cores (n=34). RESULTS: TM immunoexpression scores are stronger in TCPC, TCC and SCC bladder cancer tissue cores with respect to adenocarcinoma and sarcoma (mean TM immunoexpression scores: 3.04, 2.57, 2.55, 1.55 and 1.19, respectively) (Kruskal-Wallis p<0.001). TM immunoexpression scores significantly decreased in bladder cancer tissue cores across both stage (p<0.001) and grade (p<0.001) (Kruskal-Wallis). Survival data were available for n=45 bladder cancer patients (mean follow-up of 34 months). Applying a TM immunoexpression cut-off score of 3.0 demonstrated that patients with bladder cancer who had a TM immunoexpression score <3.0 had lower survival rates (median survival 23.5 months). In contrast, patients with TM immunoexpression scores ≥3.0 had longer survival rates (median survival 40 months) (log-rank; p=0.045). CONCLUSION: TM immunoexpression in bladder cancer tissue may be a clinically relevant predictor of tumor progression and survival. Low expression of TM in bladder cancer biopsies or in recurrent bladder cancer may be indicative of a poor prognosis. TM immunoexpression could be used to guide clinical decision making.

Clinical Parameters Are More Likely to Be Associated with Thyroid Hormone Levels than with Thyrotropin Levels: A Systematic Review and Meta-Analysis.

Background: Though the functional states of other endocrine systems are not defined on the basis of levels of controlling hormones, the assessment of thyroid function is based on levels of the controlling hormone thyrotropin (TSH). We, therefore, addressed the question as to whether levels of thyroid hormones [free thyroxine (fT4), total triiodothyronine (TT3)/free triiodothyronine (fT3)], or TSH levels, within and beyond the reference ranges, provide the better guide to the range of clinical parameters associated with thyroid status. Methods: A PubMed/MEDLINE search of studies up to October 2019, examining associations of levels of thyroid hormones and TSH, taken simultaneously in the same individuals, with clinical parameters was performed. We analyzed atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia, frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes. Studies were assessed for quality by using a modified Newcastle-Ottawa score. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. A meta-analysis of the associations was performed to determine the relative likelihood of fT4, TT3/fT3, and TSH levels that are associated with the clinical parameters. Results: We identified 58 suitable articles and a total of 1880 associations. In general, clinical parameters were associated with thyroid hormone levels significantly more often than with TSH levels-the converse was not true for any of the clinical parameters. In the 1880 considered associations, fT4 levels were significantly associated with clinical parameters in 50% of analyses. The respective frequencies for TT3/fT3 and TSH levels were 53% and 23% (p < 0.0001 for both fT4 and TT3/fT3 vs. TSH). The fT4 and TT3/fT3 levels were comparably associated with clinical parameters (p = 0.71). More sophisticated statistical analyses, however, indicated that the associations with TT3/fT3 were not as robust as the associations with fT4. Conclusions: Thyroid hormones levels, and in particular fT4 levels, seem to have stronger associations with clinical parameters than do TSH levels. Associations of clinical parameters with TSH levels can be explained by the strong negative population correlation between thyroid hormones and TSH. Clinical and research components of thyroidology currently based on the measurement of the thyroid state by reference to TSH levels warrant reconsideration.

Application of a New Multiplexed Array for Rapid, Sensitive, Simultaneous and Quantitative Assessment of Spliced and Unspliced XBP1.

BACKGROUND: IRE1α-mediated unconventional splicing of XBP1 is emerging as a biomarker in several disease states and is indicative of activation of the unfolded protein response sensor IRE1. Splicing of XBP1 mRNA results in the translation of two distinct XBP1 protein isoforms (XBP1s and XBP1u) which, due to post-translational regulation, do not correlate with mRNA levels. As both XBP1 isoforms are implicated in pathogenic or disease progression mechanisms there is a need for a reliable, clinically applicable method to detect them. METHODS: A multiplexed isoform-specific XBP1 array utilising Biochip array technology (BAT™) was assessed for specificity and suitability when using cell protein lysates. The array was applied to RIPA protein lysates from several relevant pre-clinical models with an aim to quantify XBP1 isoforms in comparison with RT-PCR or immunoblot reference methods. RESULTS: A novel reliable, specific and sensitive XBP1 biochip was successfully utilised in pre-clinical research. Application of this biochip to detect XBP1 splicing at the protein level in relevant breast cancer models, under basal conditions as well as pharmacological inhibition and paclitaxel induction, confirmed the findings of previous studies. The biochip was also applied to non-adherent cells and used to quantify changes in the XBP1 isoforms upon activation of the NLRP3 inflammasome. CONCLUSIONS: The XBP1 biochip enables isoform specific quantification of protein level changes upon activation and inhibition of IRE1α RNase activity, using a routine clinical methodology. As such it provides a research tool and potential clinical tool with a quantified, simultaneous, rapid output that is not available from any other published method.

A novel multiplex-protein array for serum diagnostics of colorectal cancer: impact of pre-analytical storage conditions.

INTRODUCTION: Biomarker discovery studies seldom report on pre-analytical effects. We used a novel multiplex protein biochip for colorectal cancer screening to investigate effects of different storage temperatures and repeated freeze-thaw cycles. METHODS: This biochip, composed of CEA, IL-8, VEGF, M-CSF, S100A11, C3adesArg, CD26, and CRP, was applied to twenty highly standardized preserved serum samples. RESULTS: Aliquot comparison of long-term storage at -80°C (n=20) versus -170°C (n=20) did not show significant differences for any of the eight markers. In contrast, three freeze-thaw cycles (3 × 20 aliquots) detected changes in the serum level for all markers (p<0.05) but S100A11 and CD26: levels of CEA, IL-8, C3adesArg, and CRP increased, while VEGF and M-CSF levels decreased. However, applying diagnostic thresholds for CEA, IL-8, and CRP revealed that freeze-thaw cycles did not affect diagnostic performance. In contrast, analysis of samples stored at -80°C compared to -170°C failed to detect one out of three detectable malignancies. CONCLUSION: We conclude that three freeze-thaw cycles modulated serum marker levels significantly, but do not compromise biochip diagnostic performance. For our marker panel, serum preservation at -80°C seems comparable to -170°C; however, storage at -80°C could lead to misdiagnosis. Our findings emphasize the need for standardized sample collection, processing, storage, and reporting.

Improving physician clinical documentation quality: evaluating two self-efficacy-based training programs.

BACKGROUND: Clinical documentation is critical to health care quality and cost. The generally poor quality of such documentation has been well recognized, yet medical students, residents, and physicians receive little or no training in it. When clinical documentation quality (CDQ) training for residents and/or physicians is provided, it excludes key constructs of self-efficacy: vicarious learning (e.g., peer demonstration) and mastery (i.e., practice). CDQ training that incorporates these key self-efficacy constructs is more resource intensive. If such training could be shown to be more effective at enhancing clinician performance, it would support the investment of the additional resources required by health care systems and residency training programs. PURPOSES: The aim of this study was to test the impact of CDQ training on clinician self-efficacy and performance and the relative efficacy of intervention designs employing two versus all four self-efficacy constructs. METHODOLOGY/APPROACH: Ninety-one internal medicine residents at a major academic medical center in the northeastern United States were assigned to one of two self-efficacy-based training groups or a control group, with CDQ and clinical documentation self-efficacy measured before and after the interventions. A structural equation model (AMOS) allowed for testing the six hypotheses in the context of the whole study, and findings were cross-validated using traditional regression. FINDINGS: Although both interventions increased CDQ, the training designed to include all four self-efficacy constructs had a significantly greater impact on improving CDQ. It also increased self-efficacy. PRACTICE IMPLICATIONS: CDQ may be significantly improved and sustained by (a) training physicians in clinical documentation and (b) employing all four self-efficacy constructs in such training designs.

A novel multiplex-protein array for serum diagnostics of colon cancer: a case-control study.

BACKGROUND: More than 1.2 million new cases of colorectal cancer are reported each year worldwide. Despite actual screening programs, about 50% of the patients are diagnosed at advanced tumor stages presenting poor prognosis. Innovative screening tools could aid the detection at early stages and allow curative treatment interventions. METHODS: A nine target multiplex serum protein biochip was generated and evaluated using a training- and validation-set of 317 highly standardized, liquid nitrogen preserved serum samples comprising controls, adenomas, and colon cancers. RESULTS: Serum levels of CEA, IL-8, VEGF, S100A11, MCSF, C3adesArg, CD26, and CRP showed significant differences between cases and controls. The largest areas under the receiver operating characteristics curve were observed for CEA, IL-8, and CRP. At threshold levels yielding 90% specificity, sensitivities for CEA, IL-8 and CRP were 26%, 22%, and 17%, respectively. The most promising marker combinations were CEA + IL-8 reaching 37% sensitivity at 83% specificity and CEA + CRP with 35% sensitivity at 81% specificity. In an independent validation set CEA + IL-8 reached 47% sensitivity at 86% specificity while CEA + CRP obtained 39% sensitivity at 86% specificity. Early carcinomas were detected with 33% sensitivity for CEA + IL-8 and 28% for CEA + CRP. CONCLUSIONS: Apart from CEA, IL-8, and CRP, the screening value of additional blood markers and the potential advantage of combining serum biochip testing with fecal occult blood testing needs to be studied. Multiplex biochip array technology utilizing serum samples offers an innovative approach to colorectal cancer screening.

Reduced plasma levels of P-selectin and L-selectin in a pilot study from Alzheimer disease: relationship with neuro-degeneration.

Neurodegenerative processes associated with Alzheimer's disease (AD) are accompanied by reactive astrogliosis and microglia activation and a role for chronic inflammation in the brain degeneration of these patients has been suggested. Moreover impaired immune functions in AD brains might also influence the disease's progression. Therefore, it is of interest to further characterized inflammatory molecules in the peripheral blood of patients with AD and its relationship with cognitive decline. A complex picture emerged in this pilot study and IL-8, IFN-gamma, MCP-1 and VEGF levels were increased in AD. Levels of P-selectin and L-selectin were decreased in AD and lowest in AD patients with highest cognitive decline. Our findings suggest that these molecules may induce alterations of endothelial regulation and influence neurodegenerative processes of AD.

An analysis of the interactions between individual comorbidities and their treatments--implications for guidelines and polypharmacy.

BACKGROUND: With aging there is an increase in frailty and chronic disease leading to a potential increase in medication use. Most clinical trials have excluded old, frail individuals and have failed to take into account the effects of outcome interaction. METHODS AND RESULTS: In this article we provide a mathematical model demonstrating that comorbidities, including old age, interact with therapies, reducing their effectiveness. CONCLUSION: These findings question the validity of single disease guidelines in old persons or in persons with multiple chronic diseases.