Analyzing patterns of staining in immunohistochemical studies: application to a study of prostate cancer recurrence.

BACKGROUND: Immunohistochemical studies use antibodies to stain tissues with the goal of quantifying protein expression. However, protein expression is often heterogeneous resulting in variable degrees and patterns of staining. This problem is particularly acute in prostate cancer, where tumors are infiltrative and heterogeneous in nature. In this article, we introduce analytic approaches that explicitly consider both the frequency and intensity of tissue staining. METHODS: Compositional data analysis is a technique used to analyze vectors of unit-sum proportions, such as those obtained from soil sample studies or species abundance surveys. We summarized specimen staining patterns by the proportion of cells staining at mild, moderate, and intense levels and used compositional data analysis to summarize and compare the resulting staining profiles. RESULTS: In a study of Syndecan-1 staining patterns among 44 localized prostate cancer cases with Gleason score 7 disease, compositional data analysis did not detect a statistically significant difference between the staining patterns in recurrent (n = 22) versus nonrecurrent (n = 22) patients. Results indicated only modest increases in the proportion of cells staining at a moderate intensity in the recurrent group. In contrast, an analysis that compared quantitative scores across groups indicated a (borderline) significant increase in staining in the recurrent group (P = 0.05, t test). CONCLUSIONS: Compositional data analysis offers a novel analytic approach for immunohistochemical studies, providing greater insight into differences in staining patterns between groups, but possibly lower statistical power than existing, score-based methods. When appropriate, we recommend conducting a compositional data analysis in addition to a standard score-based analysis.     

Identification of RAD51–BRCA2 Inhibitors Using N-Acylhydrazone-Based Dynamic Combinatorial Chemistry

RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51–BRCA2 protein–protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further ¹⁹F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors.     

Mast cells and tumour angiogenesis: new insight from experimental carcinogenesis

Histopathologic examination and clinical observations of solid and haematological malignancies indicates mast cells as key host cells in the tumour infiltrate, with important consequence on tumour-associated angiogenesis and tumour growth. Data suggest indeed that tumour-infiltrating mast cells may exert a prominent function in the angiogenic "switch", which is essential for the progression of early tumours. The experimental approach has substantially increased our understanding of the role of tumour-infiltrating mast cells in the process of angiogenesis that accompanies tumour development. This review will focus on the crucial contribution of mast cells in promoting tumour neovascularization as it emerges from the most recent observations of experimental carcinogenesis in in vivo and in vitro models.     

Correlation of catheterized and clean catch urine protein/creatinine ratios in preeclampsia evaluation

OBJECTIVE: To examine whether clean catch urine specimens correlate with catheterized specimens for determination of protein/creatinine ratios in pregnant women being evaluated for preeclampsia. METHODS: Sixty pregnant women who were at least at 20 weeks of gestation were enrolled. Patients with ruptured membranes, vaginal bleeding, or urinary tract infections were excluded. Midstream clean catch urine specimens were collected. Catheterized specimens were then collected and used for clinical management. The specimens were analyzed for protein, creatinine, urinalysis, and culture. Based on sample size calculations, 60 participants were needed to detect a correlation of 0.90 with 80% power and alpha=0.05. RESULTS: Mean gestational age at enrollment was 35.9 weeks (range 23.1-41.7 weeks). Median (range) clean catch and catheterized protein/creatinine ratios were 0.204 (0.089-3.465) and 0.181 (0.067-3.335), respectively, with a correlation coefficient of 0.897 (P<.001). When results were categorized by degree of proteinuria using a cutoff of 0.3, sensitivity and specificity of the clean catch protein/creatinine ratios were 95.2% and 97.4%. When using a more conservative cutoff of 0.19, sensitivity and specificity of the clean catch protein/creatinine ratios were 96.4% and 75.0%. CONCLUSION: Clean catch and catheterized urine specimens correlate well in women with suspected preeclampsia. Routine catheterization of pregnant women is not necessary in the evaluation of preeclampsia.     

Mit Kiffen aufhören. Die Bereitschaft zur Verhaltensänderung bei Cannabisgebrauchenden in der Schweiz

Summary Quitting hash. The readiness for behaviour change among cannabis users in Switzerland. Objectives: The study aims to identify factors that are associated with the willingness of adolescents and young adults to modify their cannabis use. It is hypothesized that frequency of use, cannabis-related problems and age of onset are associated with their willingness to change. Methods: In 2004, a survey on cannabis use was conducted among 13 to 29 year-olds living in Switzerland. Of the 5025 participants 593 had taken cannabis during the past six months. They were then asked about their willingness to change. Three groups of users were compared: those not willing to change, those considering change, and those determined to change. Pearson Chi-square-tests and logistic regressions were performed to test the hypotheses. Results: Experience of problems motivates users to start thinking about changing their behavior. Frequent use and early onset are associated with young people not making the transition from considering changing behavior to resolving to do so. Conclusions: The need to perceive problematic use as a first step towards change and the inhibiting effect of dependencerelated factors on the transition from consideration to determination calls for tailored intervention approaches that are matched to the willingness to change. Eingereicht: 10. Dezember 2005; überarbeitet: 13. September 2006; Angenommen: 6. M?rz 2007     

Risk of Death in Comorbidity Subgroups of Hospitalized COVID-19 Patients Inferred by Routine Laboratory Markers of Systemic Inflammation on Admission: A Retrospective Study

Our study objective was to construct models using 20 routine laboratory parameters on admission to predict disease severity and mortality risk in a group of 254 hospitalized COVID-19 patients. Considering the influence of confounding factors in this single-center study, we also retrospectively assessed the correlations between the risk of death and the routine laboratory parameters within individual comorbidity subgroups. In multivariate regression models and by ROC curve analysis, a model of three routine laboratory parameters (AUC 0.85; 95% CI: 0.79–0.91) and a model of six laboratory factors (AUC 0.86; 95% CI: 0.81–0.91) were able to predict severity and mortality of COVID-19, respectively, compared with any other individual parameter. Hierarchical cluster analysis showed that inflammatory laboratory markers grouped together in three distinct clusters including positive correlations: WBC with NEU, NEU with neutrophil-to-lymphocyte ratio (NLR), NEU with systemic immune-inflammation index (SII), NLR with SII and platelet-to-lymphocyte ratio (PLR) with SII. When analyzing the routine laboratory parameters in the subgroups of comorbidities, the risk of death was associated with a common set of laboratory markers of systemic inflammation. Our results have shown that a panel of several routine laboratory parameters recorded on admission could be helpful for early evaluation of the risk of disease severity and mortality in COVID-19 patients. Inflammatory markers for mortality risk were similar in the subgroups of comorbidities, suggesting the limited effect of confounding factors in predicting COVID-19 mortality at admission.     

Sarcopenia in Parkinson Disease: Comparison of Different Criteria and Association With Disease Severity

Objectives

In Parkinson disease (PD), sarcopenia may represent the common downstream pathway that from motor and nonmotor symptoms leads to the progressive loss of resilience, frailty, and disability. Here we (1) assessed the prevalence of sarcopenia in older adults with PD using 3 different criteria, testing their agreement, and (2) evaluated the association between PD severity and sarcopenia.