ABSTRACT
The Rho family GTPases Rho, Rac, and Cdc42 have emerged as key players in cancer metastasis, due to their essential roles in regulating cell division and actin cytoskeletal rearrangements; and thus, cell growth, migration/invasion, polarity, and adhesion. This review will focus on the close homologs Rac and Cdc42, which have been established as drivers of metastasis and therapy resistance in multiple cancer types. Rac and Cdc42 are often dysregulated in cancer due to hyperactivation by guanine nucleotide exchange factors (GEFs), belonging to both the diffuse B-cell lymphoma (Dbl) and dedicator of cytokinesis (DOCK) families. Rac/Cdc42 GEFs are activated by a myriad of oncogenic cell surface receptors, such as growth factor receptors, G-protein coupled receptors, cytokine receptors, and integrins; consequently, a number of Rac/Cdc42 GEFs have been implicated in metastatic cancer. Hence, inhibiting GEF-mediated Rac/Cdc42 activation represents a promising strategy for targeted metastatic cancer therapy. Herein, we focus on the role of oncogenic Rac/Cdc42 GEFs and discuss the recent advancements in the development of Rac and Cdc42 GEF-interacting inhibitors as targeted therapy for metastatic cancer, as well as their potential for overcoming cancer therapy resistance.
ABSTRACT
The FAMACHA© system is used for targeted selective treatment (TST) of small ruminants for the control of haemonchosis. The aim of this study was to evaluate the sensitivity and specificity of this system in growing lambs. Between 2015 and 2016, lambs aged 60-210â¯days on two sheep farms were evaluated at 15-day intervals using the FAMACHA© system (F1-F5), with analysis of hematocrit (Ht), counting of eggs per gram of feces, and larval culture. The sensitivity and specificity of the system were calculated according to two criteria: criterion 1, lambs classified as F4 or F5 were considered anemic (positive test) and those classified as F1, F2, or F3 were considered not anemic (negative test); and criterion 2, lambs classified as F3, F4, or F5 were considered anemic (positive test) and those classified as F1 and F2 were considered not anemic (negative test). Three gold standard Ht cutoff values were used to diagnose anemia, i.e., ≤22%, ≤18%, and ≤15%. In total, 1591 assessments were analyzed. The highest percentage of larvae in the fecal cultures was for Haemonchus spp., with an average of 78.5%. The sensitivity values found when F3 lambs were considered anemic were 13.9%, 30.8%, and 66.7%, respectively, for Ht cutoff values of ≤22%, ≤18%, and ≤15%. When F3 lambs were excluded, the maximum sensitivity was 14.9% and the specificity was 100% for all degrees of anemia using criterion 1. The FAMACHA© system had low sensitivity in growing lambs and should not be used alone for control of haemonchosis in young animals.