Improvement in treatment abandonment in pediatric patients with cancer in Guatemala.

BACKGROUND: Treatment refusal and abandonment are major causes of treatment failure for children with cancer in low- and middle-income countries (LMICs), like Guatemala. This study identified risk factors for and described the intervention that decreased abandonment. METHODS: This was a retrospective study of Guatemalan children (0-18 years) with cancer treated at the Unidad Nacional de Oncología Pediátrica (UNOP), 2001-2008, using the Pediatric Oncology Network Database. Treatment refusal was a failure to begin treatment and treatment abandonment was a lapse of 4 weeks or longer in treatment. The impact of medicina integral, a multidisciplinary psychosocial intervention team at UNOP was evaluated. Cox proportional hazards analysis identified the effect of demographic and clinical factors on abandonment. Kaplan-Meier analysis estimated the survival. RESULTS: Of 1,789 patients, 21% refused or abandoned treatment. Abandonment decreased from 27% in 2001 to 7% in 2008 following the implementation of medicina integral. Factors associated with increased risk of refusal and abandonment: greater distance to the centre (P < 0.001), younger age (P = 0.017) and earlier year of diagnosis (P < 0.001). Indigenous race/ethnicity (P = 0.002) was associated with increased risk of abandonment alone. Abandonment correlated with decreased overall survival: 0.57 ± 0.02 (survival ± standard error) for those who completed therapy versus 0.06 ± 0.02 for those who abandoned treatment (P < 0.001) at 8.3 years. CONCLUSION: This study identified distance, age, year of diagnosis and indigenous race/ethnicity as risk factors for abandonment. A multidisciplinary intervention reduced abandonment and can be replicated in other LMICs.

Epidemiology of Bacteremia in Previously Healthy Febrile Infants: A Follow-up Study.

OBJECTIVE: Describe the etiology of bacteremia among a geographically diverse sample of previously well infants with fever admitted for general pediatric care and to characterize demographic and clinical characteristics of infants with bacteremia according to bacterial etiology. We hypothesized that the epidemiology of bacteremia in febrile infants from a geographically diverse cohort would show similar results to smaller or single-center cohorts previously reported. METHODS: This was a retrospective review of positive, pathogenic blood cultures in previously healthy, febrile infants≤90 days old admitted to a general unit. In total, there were 17 participating sites from diverse geographic regions of the United States. Cultures were included if the results were positive for bacteria, obtained from an infant 90 days old or younger with a temperature≥38.0°C, analyzed using an automated detection system, and treated as pathogenic. RESULTS: Escherichia coli was the most prevalent species, followed by group B Streptococcus, Streptococcus viridans, and Staphylococcus aureus. Among the most prevalent bacteria, there was no association between gender and species (Ps>.05). Age at presentation was associated only with Streptococcus pneumoniae. There were no cases of Listeria monocytogenes. CONCLUSIONS: Our study confirms the data from smaller or single-center studies and suggests that the management of febrile well-appearing infants should change to reflect the current epidemiology of bacteremia. Further research is needed into the role of lumbar puncture, as well as the role of Listeria and Enterococcus species in infantile bacteremia.

Ajuba LIM proteins are negative regulators of the Hippo signaling pathway.

The mammalian Ajuba LIM proteins (Ajuba, LIMD1, and WTIP) are adaptor proteins that exhibit the potential to communicate cell adhesive events with nuclear responses to remodel epithelia. Determining their role in vivo, however, has been challenging due to overlapping tissue expression and functional redundancy. Thus, we turned to Drosophila, where a single gene, CG11063 or djub, exists. Drosophila lacking the djub gene or depleted of dJub by RNA interference identify djub as an essential gene for development and a novel regulator of epithelial organ size as a component of the conserved Hippo (Hpo) pathway, which has been implicated in both tissue size control and cancer development. djub-deficient tissues were small and had decreased cell numbers as a result of increased apoptosis and decreased proliferation, due to downregulation of DIAP1 and cyclin E. This phenocopies tissues deficient for Yorkie (Yki), the downstream target of the Hippo pathway. djub genetically interacts with the Hippo pathway, and epistasis suggests that djub lies downstream of hpo. In mammalian and Drosophila cells, Ajuba LIM proteins/dJub interact with LATS/Warts (Wts) and WW45/Sav to inhibit phosphorylation of YAP/Yki. This work describes a novel role for the Ajuba LIM proteins as negative regulators of the Hippo signaling pathway.

Polychaetoid controls patterning by modulating adhesion in the Drosophila pupal retina.

Correct cellular patterning is central to tissue morphogenesis, but the role of epithelial junctions in this process is not well-understood. The Drosophila pupal eye provides a sensitive and accessible model for testing the role of junction-associated proteins in cells that undergo dynamic and coordinated movements during development. Mutations in polychaetoid (pyd), the Drosophila homologue of Zonula Occludens-1, are characterized by two phenotypes visible in the adult fly: increased sensory bristle number and the formation of a rough eye produced by poorly arranged ommatidia. We found that Pyd was localized to the adherens junction in cells of the developing pupal retina. Reducing Pyd function in the pupal eye resulted in mis-patterning of the interommatidial cells and a failure to consistently switch cone cell contacts from an anterior-posterior to an equatorial-polar orientation. Levels of Roughest, DE-Cadherin and several other adherens junction-associated proteins were increased at the membrane when Pyd protein was reduced. Further, both over-expression and mutations in several junction-associated proteins greatly enhanced the patterning defects caused by reduction of Pyd. Our results suggest that Pyd modulates adherens junction strength and Roughest-mediated preferential cell adhesion.

The Drosophila CD2AP/CIN85 orthologue Cindr regulates junctions and cytoskeleton dynamics during tissue patterning.

Developing tissues require cells to undergo intricate processes to shift into appropriate niches. This requires a functional connection between adhesion-mediating events at the cell surface and a cytoskeletal reorganization to permit directed movement. A small number of proteins are proposed to link these processes. Here, we identify one candidate, Cindr, the sole Drosophila melanogaster member of the CD2AP/CIN85 family (this family has been previously implicated in a variety of processes). Using D. melanogaster retina, we demonstrate that Cindr links cell surface junctions (E-cadherin) and adhesion (Roughest) with multiple components of the actin cytoskeleton. Reducing cindr activity leads to defects in local cell movement and, consequently, tissue patterning and cell death. Cindr activity is required for normal localization of Drosophila E-cadherin and Roughest, and we show additional physical and functional links to multiple components of the actin cytoskeleton, including the actin-capping proteins capping protein alpha and capping protein beta. Together, these data demonstrate that Cindr is involved in dynamic cell rearrangement in an emerging epithelium.