Financial Support Models: A Case for Use of Financial Navigators in the Oncology Setting.

BACKGROUND: Financial toxicity causes significant psychological and practical distress for patients and can affect their ability and willingness to undertake optimal treatment. Although different models of financial support are typically available to patients undergoing cancer treatments, not all models can offer equal amounts of support and effective solutions, particularly to those patients at the highest levels of risk for this toxicity. OBJECTIVES: This article discusses the two most prevalent models available to healthcare institutions to provide financial support (financial counseling and financial advocacy) and makes recommendations for implementation of a more comprehensive, proactive financial navigation model. METHODS: This article reviews current and emerging financial support models. FINDINGS: Financial toxicity is on the rise, and the financial navigation model shows promise in decreasing the number of patients experiencing financial hardship.

1-(sulfonyl)-5-(arylsulfonyl)indoline as activators of the tumor cell specific M2 isoform of pyruvate kinase.

Cancer cells preferentially use glycolysis rather than oxidative phosphorylation for their rapid growth. They consume large amount of glucose to produce lactate even when oxygen is abundant, a phenomenon known as the Warburg effect. This metabolic change originates from a shift in the expression of alternative spliced isoforms of the glycolytic enzyme pyruvate kinase (PK), from PKM1 to PKM2. While PKM1 is constitutively active, PKM2 is switched from an inactive dimer form to an active tetramer form by small molecule activators. The prevalence of PKM2 in cancer cells relative to the prevalence of PKM1 in many normal cells, suggests a therapeutic strategy whereby activation of PKM2 may counter the abnormal cellular metabolism in cancer cells, and consequently decreased cellular proliferation. Herein we describe the discovery and optimization of a series of PKM2 activators derived from the 2-((2,3-dihydrobenzo[b][1,4] dioxin-6-yl)thio)-1-(2-methyl-1-(methylsulfonyl)indolin-5-yl) ethanone scaffold. The synthesis, SAR analysis, enzyme active site docking, enzymatic reaction kinetics, selectivity and pharmaceutical properties are discussed.

Inaccuracy in Legionella tests of building water systems due to sample holding time.

Most Legionella culture tests are performed on building water samples that have been shipped to analytical laboratories for analysis. Significant (≥ 1 log10 unit) changes in results were observed in 52% of held samples (6 h or longer, ambient temperature) drawn from building water systems in a 42-sample initial survey. It was not practical to use the spread plate protocol for on-site "t = 0" cultures in a larger, more diverse survey of thousands of building water systems. Two thousand four hundred twenty-one (2421) building water samples were split for on-site analysis using a field culture protocol and then also cultured after overnight shipment to the lab for analysis with the standardized spread plate method. Legionella test results from building water system samples are usually interpreted as ≥ a numerical detection or action limit. Therefore, binary statistical analyses were calculated by setting t = 0 culture results to "true". Overall in this survey, 10.4% of water samples sent to the laboratory for analysis returned either false-positive or false-negative results. The overall positive predictive value of results was poor (36%). Most (83%) false-positive results were returned from utility water systems. Most (74%) false-negative results were returned from potable water systems. These inaccuracies have serious implications in regard to interpretation and use of Legionella test results. The overall negative predictive value of results was excellent (99%) and also it was good (92%) for results from a polymerase chain reaction (PCR) assay that can be therefore used as a negative screening method.

Developing predictive models of health literacy.

INTRODUCTION: Low health literacy (LHL) remains a formidable barrier to improving health care quality and outcomes. Given the lack of precision of single demographic characteristics to predict health literacy, and the administrative burden and inability of existing health literacy measures to estimate health literacy at a population level, LHL is largely unaddressed in public health and clinical practice. To help overcome these limitations, we developed two models to estimate health literacy. METHODS: We analyzed data from the 2003 National Assessment of Adult Literacy (NAAL), using linear regression to predict mean health literacy scores and probit regression to predict the probability of an individual having 'above basic' proficiency. Predictors included gender, age, race/ethnicity, educational attainment, poverty status, marital status, language spoken in the home, metropolitan statistical area (MSA) and length of time in U.S. RESULTS: All variables except MSA were statistically significant, with lower educational attainment being the strongest predictor. Our linear regression model and the probit model accounted for about 30% and 21% of the variance in health literacy scores, respectively, nearly twice as much as the variance accounted for by either education or poverty alone. CONCLUSIONS: Multivariable models permit a more accurate estimation of health literacy than single predictors. Further, such models can be applied to readily available administrative or census data to produce estimates of average health literacy and identify communities that would benefit most from appropriate, targeted interventions in the clinical setting to address poor quality care and outcomes related to LHL.

Synthesis and biological investigation of new 4''-malonyl tethered derivatives of erythromycin and clarithromycin.

A new approach to 4''-substituted derivatives of erythromycin and clarithromycin was developed by converting them into corresponding 4''-malonic monoesters. Subsequent carbodiimide coupling with alcohols and amines provided new macrolide derivatives that are capable of binding to 50S ribosomal subunits and inhibiting protein synthesis in cell-free system.

Schizosaccharomyces pombe replication protein Cdc45/Sna41 requires Hsk1/Cdc7 and Rad4/Cut5 for chromatin binding.

Cdc45 is a conserved protein required for firing of replication origins and processive DNA replication. We used an in situ chromatin-binding assay to determine factors required for fission yeast Cdc45p chromatin binding. Assembly of the pre-replicative complex is essential for Cdc45p chromatin binding, but pre-replicative complex assembly occurs independently of Cdc45p. Fission yeast Cdc45p associates with MCM proteins in asynchronously growing cells and cells arrested in S phase by hydroxyurea, but not in cells arrested at the G2/M transition. Both hsk1+ (the fission yeast CDC7 homologue) and rad4+/ cut5+ (the fission yeast DPB11 homologue) are required for Cdc45p chromatin binding. Cdc45p also remains chromatin-bound in mutants that fail to recover from replication arrest. In summary, Cdc45p chromatin binding requires an intact pre-replicative complex as well as signaling from both the Dbf4-dependent kinase and cyclin-dependent kinases.

VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism.

Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis, but the mechanisms by which VEGF differentially regulates these processes have been elusive. Here we describe a regulatory loop by which VEGF controls survival of haematopoietic stem cells (HSCs). We observed a reduction in survival, colony formation and in vivo repopulation rates of HSCs after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in HSC survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis.

ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo.

The angiopoietin family of secreted factors is functionally defined by the C-terminal fibrinogen (FBN)-like domain, which mediates binding to the Tie2 receptor and thereby facilitates a cascade of events ultimately regulating blood vessel formation. By screening expressed sequence tag data bases for homologies to a consensus FBN-like motive, we have identified ANGPTL3, a liver-specific, secreted factor consisting of an N-terminal coiled-coil domain and the C-terminal FBN-like domain. Co-immunoprecipitation experiments, however, failed to detect binding of ANGPTL3 to the Tie2 receptor. A molecular model of the FBN-like domain of ANGPTL3 was generated and predicted potential binding to integrins. This hypothesis was experimentally confirmed by the finding that recombinant ANGPTL3 bound to alpha(v)beta(3) and induced integrin alpha(v)beta(3)-dependent haptotactic endothelial cell adhesion and migration and stimulated signal transduction pathways characteristic for integrin activation, including phosphorylation of Akt, mitogen-activated protein kinase, and focal adhesion kinase. When tested in the rat corneal assay, ANGPTL3 strongly induced angiogenesis with comparable magnitude as observed for vascular endothelial growth factor-A. Moreover, the C-terminal FBN-like domain alone was sufficient to induce endothelial cell adhesion and in vivo angiogenesis. Taken together, our data demonstrate that ANGPTL3 is the first member of the angiopoietin-like family of secreted factors binding to integrin alpha(v)beta(3) and suggest a possible role in the regulation of angiogenesis.