Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates.Comment: 49 pages, 2 figures, 2 tables, 10 supplementary figures, 13 supplementary table

Analysis of the Prevalence and Severity of Dysregulated Bone Mineral Homeostasis in Nondialyzed Chronic Kidney Disease Patients

Abstract Background Progressive loss of kidney function in chronic kidney disease (CKD) leads to altered mineral homeostasis, reflected by the imbalance in calcium and phosphorus, and has been associated with progression of renal failure. Aims The aim of this study was to investigate CKD-mineral bone disorder (CKD-MBD)-associated candidate variables and its relationship with parathyroid hormone (PTH), as well as to quantify the prevalence of CKD-associated mineral disturbances in nondialyzed CKD patients. Materials and Methods This cross-sectional analytical study included 124 CKD patients and 157 control participants. Blood samples were analyzed for serum total calcium, phosphorus, PTH, electrolytes, and other hematological/hemodynamic parameters by standard methods. Suitable descriptive statistics was used for different variables. Results The 124 patients had a mean age of 50.2 ± 7.8 years with male to female ratio of 1.58; majority of patients had stage 3 CKD (40.32%), and the most common comorbid conditions were diabetes mellitus (n = 78 [62.9%]) and hypertension (n = 63 [50.8%]). A high prevalence of mineral metabolite abnormalities was observed in a patient cohort; overall prevalence of hyperparathyroidism was found in 57.25% patients, hypocalcemia in 61.29%, and hyperphosphatemia in 82.25% patients. Prevalence of abnormal homeostasis (with regard to total calcium, phosphate, and PTH) increased progressively with the severity of disease (analysis of variance; p &lt; 0.05). Significant differences in the mean values of total calcium, phosphorus, alkaline phosphatase, and PTH were seen compared with healthy participants (p &lt; 0.0001). Furthermore, there was a significant positive correlation between serum PTH with serum phosphorous (R 2: 0.33; p &lt; 0.0001), serum creatinine (R 2: 0.084; p &lt; 0.0259), serum potassium (R 2: 0.068; p &lt; 0.0467), and a significant negative correlation with serum total calcium (R 2: 0.37; p &lt; 0.0001). Conclusions CKD patients are at risk of or may already have developed secondary hyperparathyroidism apparent from PTH-linked derangements in mineral metabolism in predialysis CKD patients. These abnormalities start in early stages of CKD and worsen with disease progression. This accentuates the significance of early recognition of mineral bone disorder, understanding its pathophysiological consequences and scheduling necessary interventions/management strategies to protect the CKD patients from a plethora of complications.</jats:p

Analysis of Prediagnostic Circulating Levels of Gonadotropins and Androgens with Risk of Epithelial Ovarian Cancer

Abstract Background Prevailing experimental and epidemiological evidence supports the role of circulating endogenous sex steroid hormones in the pathogenesis of ovarian carcinogenesis by dysregulation of cell differentiation, proliferation, and apoptosis but is scarce and inconclusive. Objectives This article evaluates the role of circulating levels of gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]) and androgens (testosterone, dehydroepiandrosterone-sulfate [DHEA-S]) for the risk of epithelial ovarian cancer in a case–control approach using samples collected in advance of clinical diagnosis. Materials and Methods A total of 100 epithelial ovarian cancer (EOC) patients and 100 healthy female controls were consequently enrolled in this hospital-based case–control study. Serum FSH, LH, testosterone, and DHEA-S were measured based on the principle of electrochemiluminescence immunoassay. Suitable descriptive statistics were used for different variables. Results Median values of FSH (58.9 vs. 45.5 IU/L, p = 0.02) and DHEA-S (163.43 vs. 142.2 ug/dL, p = 0.03) were significantly high in EOC patients compared with controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH and DHEA-S concentrations, and the results revealed that the highest third tertile of FSH (&gt; 72.6 IU/L; OR = 3.0, confidence interval [CI] = 1.24–7.29, p trend = 0.04) and DHEA-S (&gt; 194.2 ug/dL; OR = 3.8, CI = 1.26–11.61, p trend = 0.03) were significantly associated with increased risk of ovarian cancer in postmenopausal and premenopausal women, respectively. The statistically significant trend observed for FSH in postmenopausal women, remained only for the subgroup with menopause duration greater than 10 years (OR = 5.9, CI = 1.33–26.66, p trend = 0.04). FSH and DHEA-S concentrations and ovarian cancer risk were internally consistent with groups defined by oral contraceptive pill use, hormone replacement therapy, and smoking. However, no evidence was found for the association between serum LH and testosterone level with the occurrence of ovarian tumorigenesis. Conclusion Prediagnostic circulating concentration of FSH and DHEA-S unveiled a significant positive association with augmented risk of EOC, thus might serve as a predictive marker for the susceptibility to ovarian carcinogenesis and should be added in the screening profile of EOC for early recognition and scheduling necessary interventions/management strategies.</jats:p