TGF-beta -- an excellent servant but a bad master

ABSTRACT: The transforming growth factor (TGF-beta) family of growth factors controls an immense number of cellular responses and figures prominently in development and homeostasis of most human tissues. Work over the past decades has revealed significant insight into the TGF-beta signal transduction network, such as activation of serine/threonine receptors through ligand binding, activation of SMAD proteins through phosphorylation, regulation of target genes expression in association with DNA-binding partners and regulation of SMAD activity and degradation. Disruption of the TGF-beta pathway has been implicated in many human diseases, including solid and hematopoietic tumors. As a potent inhibitor of cell proliferation, TGF-beta acts as a tumor suppressor; however in tumor cells, TGF-beta looses anti-proliferative response and become an oncogenic factor. This article reviews current understanding of TGF-beta signaling and different mechanisms that lead to its impairment in various solid tumors and hematological malignancies.     

Performance of a clinical decision support system and of clinical pharmacists in preventing drug–drug interactions on a geriatric ward

Background Drug–drug interactions (DDIs) can lead to adverse drug events and compromise patient safety. Two common approaches to reduce these interactions in hospital practice are the use of clinical decision support systems and interventions by clinical pharmacists. Objective To compare the performance of both approaches with the main objective of learning from one approach to improve the other. Setting Acute geriatric ward in a university hospital. Methods Prospective single-centre, cohort study of patients admitted to the geriatric ward. An independent pharmacist compared the clinical decision support alerts with the DDIs identified by clinical pharmacists and evaluated their interventions. Contextual factors used by the clinical pharmacists for evaluation of the clinical relevance were analysed. Adverse drug events related to DDIs were investigated and the causality was evaluated by a clinical pharmacologist based on validated criteria. Main outcome measure Number of alerts, interventions and the acceptance rates. Results Fifty patients followed by the clinical pharmacists, were included. The clinical pharmacists identified 240 DDIs (median of 3.5 per patient) and advised a therapy change for 16 of which 13 (81.2 %) were accepted and three (18.8 %) were not. The decision support system generated only six alerts of which none were accepted by the physicians. Thirty-seven adverse drug events were identified for 29 patients that could be related to 55 DDIs. For two interactions the causality was evaluated as certain, for 31 as likely, for ten as possible and for 12 as unlikely. Mainly intermediate level interactions were related to adverse drug events. Contextual factors taken into account by the clinical pharmacists for evaluation of the interactions were blood pressure, international normalised ratio, heart rate, potassium level and glycemia. Additionally, the clinical pharmacists looked at individual administration intervals and drug sequence to determine the clinical relevance of the interactions. Conclusion Clinical pharmacists performed better than the decision support system mainly because the system screened only for high level DDIs and because of the low specificity of the alerts. This specificity can be increased by including contextual factors into the logic and by defining appropriate screening intervals that take into account the sequence in which the drugs are given.     

Disentangling Desire and Arousal: A Classificatory Conundrum

A controversial proposal to collapse sexual disorders of desire and arousal is forthcoming in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) (DSM-5). Yet, no study has attempted to empirically distinguish these disorders by using explicit criteria to recruit and compare distinct groups of low desire and arousal sufferers. The goal of the current study was to test the feasibility of finding medically healthy men and women meeting clearly operationalized DSM-IV-TR criteria for disorders of desire and/or arousal and compare them to matched controls. To assess operational criteria, participants completed a comprehensive telephone screening interview assessing DSM-IV-TR and DSM-5 criteria, as well as standardized self-report measures of sexual functioning. The use of operationalized DSM-IV-TR criteria to recruit participants led to the exclusion of over 75 % of those reporting sexual difficulties, with the primary reason for exclusion being failure to meet at least one central diagnostic criterion. The application of the DSM-5 criteria was even more restrictive and led to the exclusion of all but four men and one woman using the original four-symptom criteria, and four men and five women using the revised three-symptom criteria. Cluster analyses supported the distinction between desire and genital arousal difficulties, and suggest that different groups with distinct clusters of symptoms may exist, two of which are consistent with the DSM-5 criteria. Overall, results highlight the need for revisions to the diagnostic criteria, which, as they stand, do not capture the full range of many people’s sexual difficulties.     

Melanoma genetics: the other side

Although melanoma has traditionally been regarded as a uniformly fatal malignancy, personalized treatment of this cancer relies on the recognition of its genetic heterogeneity and our ability to pharmacologically target these specific and recurrent changes. Recent advances in the treatment of melanoma have come from the understanding that melanoma is a large family of molecularly distinct diseases. Advances in melanoma genetics and new molecular technology, such as whole-exome and whole-genome sequencing, have lead to unprecedented progress in understanding the key oncogenes and signaling pathways involved in the pathogenesis and progression of melanoma. In addition, we have gained an appreciation for the complexity of such a system with numerous points of cross talk, which has partially impeded our current therapeutic strategies in patients with advanced melanoma. In this review, we focus on the novel discoveries in melanoma genetics and the potential for therapeutic options.