The mediating role of processing speed in the relationship between depressive symptoms and cognitive function in multiple sclerosis

Introduction: Although disorders of mood and cognition are frequently observed in multiple sclerosis, their relationship remains unclear. We aimed to investigate whether this mood–cognition relationship is mediated by inefficient processing speed, a deficit typically associated with mood symptomatology in the psychiatric literature and a common deficit observed in multiple sclerosis patients. Method: In this study, comprehensive cognitive data and self-reported mood data were retrospectively analyzed from 349 patients with relapsing remitting multiple sclerosis. We performed a bootstrapping analysis to examine whether processing speed provided an indirect means by which depressive symptoms influenced cognitive functioning, specifically memory and executive function. Results: We observed that processing speed mediated the relationship between depressive symptoms and measures of memory and executive function. Interestingly, exploratory analyses revealed that this mediational role of processing speed was specific to MS patients who were younger, had a lower disability level, and had fewer years since MS diagnosis. Conclusions: Together, these findings have implications for mood and cognitive intervention with multiple sclerosis patients.     

Phenotypic drug screening and target validation for improved personalized therapy reveal the complexity of phenotype-genotype correlations in clear cell renal cell carcinoma

ObjectivesNovel personalized therapeutic approaches are urgently needed for patients with metastatic clear cell renal cell carcinoma (ccRCC).Methods and materialsWe combined the development of a primary patient-derived ccRCC cell line with a phenotypic drug screen consisting of 101 approved anticancer compounds.ResultsWe identified the MNNG HOS transforming gene (MET)-anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitor crizotinib as the top hit of our drug screen, whereas compounds targeting the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) pathway showed no or only minor in vitro activity. Among the known major crizotinib targets MET, ALK, and ROS-1, only MET was expressed in our ccRCC cell line. Subsequent sequence analysis revealed a heterozygous R988C mutation of the MET gene and a VHL deletion in both the primary tumor and the tumor-derived ccRCC cell line. However, we were unable to show an activation of MET and, further, MET knockdown did not result in increased apoptosis or cytotoxicity. Therefore, our results suggest that MET R988C does not function as a major oncogenic driver mutation but rather represents a sequence variant. However, we provide evidence that the cytotoxic effect of crizotinib in our cell line model correlates with its ability to inhibit P-glycoprotein (ABCB1)-associated transport functions.ConclusionsOur study shows that a phenotypic screen of a patient-derived tumor cell line can identify compounds with antitumor activity but with an unexpected mode of action. Our results underscore that target validation and phenotype-genotype correlations remain a major experimental challenge. The implications of our findings for a personalized management of patients with cancer are discussed.     

Diagnostic Performance of Self-Assessment for Constipation in Patients With Long-Term Opioid Treatment

Constipation is a prevalent comorbidity affecting ∼50% of patients with long-term opioid therapy. In clinical routine different diagnostic instruments are in use to identify patients under risk. The aim of this study was to assess the diagnostic performance of an 11-item Likert scale for constipation used as a self-assessment in opioid-treated patients.This trial was conducted as a retrospective cohort study in Berlin, Germany. Patients with long-term opioid therapy treated in 2 university-affiliated outpatient pain facilities at the Charité hospital were included from January 2013 to August 2013. Constipation was rated in a self-assessment using a numeric rating scale from 0 to 10 (Con-NRS) and compared with results from a structured assessment based on ROME-III criteria.Altogether, 171 patients were included. Incidence of constipation was 49% of patients. The receiver-operating characteristic of Con-NRS achieved an area under the curve of 0.814 (AUC 95% confidence interval 0.748–0.880, P < 0.001). Con-NRS ≥ 1 achieved sensitivity and specificity of 79.7% and 77.2%, respectively. The positive predictive value and the negative predictive value were 70.3% and 81.6%, respectively.Overall diagnostic performance of a concise 11-item Likert scale for constipation was moderate. Although patients with long-term opioid therapy are familiar with numeric rating scales, a significant number of patients with constipation were not identified. The instrument may be additionally useful to facilitate individualized therapeutic decision making and to control therapeutic success when measured repetitively.