C. elegans cdf-1 was identified in a genetic screen for regulators of Ras-mediated signaling. CDF-1 is a cation diffusion facilitator protein that is structurally and functionally similar to vertebrate ZnT-1. These proteins have an evolutionarily conserved function as positive regulators of the Ras pathway, and the Ras pathway has an evolutionarily conserved ability to respond to CDF proteins. CDF proteins regulate Ras-mediated signaling by promoting Zn(2+) efflux and reducing the concentration of cytosolic Zn(2+), and cytosolic Zn(2+) negatively regulates Ras-mediated signaling. Physiological concentrations of Zn(2+) cause a significant inhibition of Ras-mediated signaling. These findings suggest that Zn(2+) negatively regulates a conserved element of the signaling pathway and that Zn(2+) regulation is important for maintaining the inactive state of the Ras pathway.

Skin cancers are the most common malignancies in solid organ transplant recipients (SOTR). A case-observational, retrospective study was performed to determine the efficacy of low-dose capecitabine in the secondary prevention of skin cancers in SOTRs treated at a single institution. SOTRs with recurrent squamous cell carcinoma (SCC) and/or basal cell carcinoma (BCC) were given low-dose capecitabine 1 g/m(2) daily, days 1-14 of a 21-d treatment cycle. Skin surveillance was performed by dermatologists every 1-3 months. Cumulative incidence rates of SCC, BCC, and actinic keratosis (AK) before and after treatment were scored and statistically compared for each patient using a non-parametric Wilcoxon signed rank test. Fifteen patients (13 men and two women) with a median age of 57 yr (range 40-73) were treated. Incidence rates as measured by mean number of events per month declined by 0.33 for SCC, 0.04 for BCC, and 2.45 for AK (p < 0.05). The most common grade 3 and 4 toxicities included fatigue (40.0%), hand-foot syndrome (20.0%), and diarrhea (20.0%). The discontinuation rate at one yr was approximately 33.3%. We conclude that oral capecitabine significantly decreases the incidence rates of recurrent SCC, BCC, and AK in SOTRs and is associated with manageable toxicity.

The Ras-extracellular signal-regulated kinase (ERK) cascade is a critical intracellular signaling pathway that regulates growth, survival, and differentiation. Previous work established that Ras-GTP binds to, and facilitates the activation of, the protein kinase Raf-1. Recently, it was demonstrated that the cation diffusion facilitator (CDF) proteins are involved in Ras-ERK signaling by use of a Caenorhabditis elegans genetic screen that identified suppressors of activated Ras. In the current work, we demonstrate that CDF proteins may function downstream of Ras, but upstream of Raf-1 in Xenopus oocytes. We also show that the C. elegans protein CDF-1 and its mammalian homologue ZnT-1 bind to the amino-terminal regulatory portion of Raf-1 and promote the biological and enzymatic activity of Raf-1. Furthermore, we show that Zn 2؉ inhibits Raf-1 binding to ZnT-1. We propose a model in which CDF protein binding facilitates Raf-1 activation.The Raf-1 protein kinase plays an important role in signal transduction in eukaryotic cells (1-3). Raf-1 is a member of a multigene family that includes A-Raf and B-Raf. Raf family members regulate cell proliferation and differentiation, and are also involved in the pathogenesis of many forms of human cancer. A recent study found that mutations in B-Raf are present in 66% of human melanomas, highlighting the importance of this gene family (4).When active, Raf-1 phosphorylates and activates MEK1, 1 a protein threonine and tyrosine kinase that, in turn, phosphorylates and activates the mitogen-activated protein kinase (MAPK) family members ERK1 and -2 (hereafter called ERK) (5-7). Raf-1 activation is a highly complex and incompletely understood process. Although the three-dimensional x-ray crystallographic structure of Raf-1 has not been solved, a widely accepted model is that that amino-terminal portion of Raf-1 folds over the carboxyl-terminal half to inhibit its kinase activity (8). 14-3-3 dimers may stabilize the inactive conformation of Raf-1 by interacting simultaneously with phosphoserine 259 and phosphoserine 621 of inactive Raf-1 (9 -13). Inactive Raf-1 is also bound to several heat shock proteins that may prevent the proteasome-mediated degradation of Raf-1 and facilitate its cytoplasmic localization (14, 15).The Ras family of small GTPases plays a key role in the activation of . When bound to GTP, Ras binds to two domains on Raf-1, the Ras-binding domain comprising amino acids 51-131, and the cysteine-rich domain (CRD) comprising amino acids 139 -184 (19 -21). Recently, Morrison's group demonstrated that protein phosphatase 2A dephosphorylates phosphoserine 259 of Raf-1 to release 14-3-3 and promote Ras-GTP binding to the CRD in growth factor-stimulated cells (22). By binding to Raf-1, Ras also promotes the plasma membrane localization of Raf-1. Therefore, Ras-GTP facilitates Raf-1 translocation and activation. However, Ras-GTP is not sufficient in most cases to fully activate Raf-1. First, several phosphorylation events occur at the plasma membrane, which facilitate activ...

Objective IBM(R) Watson for Oncology (WfO) is a clinical decision-support system (CDSS) that provides evidence-informed therapeutic options to cancer-treating clinicians. A panel of experienced oncologists compared CDSS treatment options to treatment decisions made by clinicians to characterize the quality of CDSS therapeutic options and decisions made in practice. Methods This study included patients treated between 1/2017 and 7/2018 for breast, colon, lung, and rectal cancers at Bumrungrad International Hospital (BIH), Thailand. Treatments selected by clinicians were paired with therapeutic options presented by the CDSS and coded to mask the origin of options presented. The panel rated the acceptability of each treatment in the pair by consensus, with acceptability defined as compliant with BIH’s institutional practices. Descriptive statistics characterized the study population and treatment-decision evaluations by cancer type and stage. Results Nearly 60% (187) of 313 treatment pairs for breast, lung, colon, and rectal cancers were identical or equally acceptable, with 70% (219) of WfO therapeutic options identical to, or acceptable alternatives to, BIH therapy. In 30% of cases (94), 1 or both treatment options were rated as unacceptable. Of 32 cases where both WfO and BIH options were acceptable, WfO was preferred in 18 cases and BIH in 14 cases. Colorectal cancers exhibited the highest proportion of identical or equally acceptable treatments; stage IV cancers demonstrated the lowest. Conclusion This study demonstrates that a system designed in the US to support, rather than replace, cancer-treating clinicians provides therapeutic options which are generally consistent with recommendations from oncologists outside the US.