Faculty Bibliography

Metastasis remains a leading cause of cancer mortality due to the lack of specific inhibitors against this complex process. To identify compounds selectively targeting the metastatic state, we used the perinucleolar compartment (PNC), a complex nuclear structure associated with metastatic behaviors of cancer cells, as a phenotypic marker for a high-content screen of over 140,000 structurally diverse compounds. Metarrestin, obtained through optimization of a screening hit, disassembles PNCs in multiple cancer cell lines, inhibits invasion in vitro, suppresses metastatic development in three mouse models of human cancer, and extends survival of mice in a metastatic pancreatic cancer xenograft model with no organ toxicity or discernable adverse effects. Metarrestin disrupts the nucleolar structure and inhibits RNA polymerase (Pol) I transcription, at least in part by interacting with the translation elongation factor eEF1A2. Thus, metarrestin represents a potential therapeutic approach for the treatment of metastatic cancer.

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10-10) pQTLs in 38 (43%) of blood proteins tested. Most pQTL SNPs were novel with low overlap to eQTL SNPs. The pQTL SNPs explained >10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group.

AIMS/OBJECTIVE:Calcimimetics are effective in reducing parathyroid hormone (PTH) levels in patients with secondary hyperparathyroidism, but variability in dose response has been noted. We examined SNP Arg990Gly of the calcium-sensing receptor as a possible cause. MATERIALS & METHODS/METHODS:We performed a dose-response study with cinacalcet on 23 hemodialysis patients (with PTH >300 pg/ml). Intact (i)PTH levels were measured at baseline and over time post-dose; 17 patients had iPTH measured at 24 h post-dose (60 mg). Arg990Gly status was established by sequencing a section from exon 7 of the CaSR gene. RESULTS:Only 33% of patients homozygous for the arginine allele showed an iPTH suppression of at least 5% of baseline at 24 h, while 88% of patients with one or two glycine alleles achieved this target (p < 0.05). CONCLUSION/CONCLUSIONS:We conclude that Arg990Gly influences the response to calcimimetics in patients with secondary hyperparathyroidism with an odds ratio of 2.6. This corresponds with in vitro data testing the effect of calcimimetic agent R-568 in HEK-293 cells transfected with the two alleles of Arg990Gly: HEK-293 cells expressing glycine-type CaSR were more sensitive to R-568 than arginine-type CaSR (p = 0.0001).

BACKGROUND: In patients with congestive heart failure (CHF), continuous diuretic therapy may result in acute renal insufficiency (ARI). This study examines factors contributing to this complication. METHODS: We analyzed clinical data from 318 consecutive patients who were hospitalized for CHF. All were treated with diuretics and had echocardiography performed within 4 days of hospitalization. Systolic left ventricular (LV) dysfunction is defined as an ejection fraction less than 50%, and diastolic LV dysfunction, as an ejection fraction of 50% or greater in the presence of LV hypertrophy and a reversed E/A ratio. RESULTS: ARI, defined as a 25% increase in serum creatinine level, occurred in 110 patients (35%) after diuretic therapy. Risk factors for ARI on univariate analyses were older age, higher baseline serum creatinine level, lower baseline serum sodium level, lower mean arterial pressure (MAP) during diuretic therapy, and greater doses and longer duration of diuretic therapy. In multivariate analyses, ARI occurred more frequently in patients with systolic (40%) than diastolic dysfunction (28%). The use of digoxin in patients with systolic LV dysfunction was observed to decrease the risk for ARI by 61%, independent of other agents used for the treatment of patients with CHF. CONCLUSION: Age, baseline renal function and serum sodium concentration, MAP, and intensity of diuretic therapy can identify individuals at risk for ARI while receiving diuretic therapy for CHF. This complication is observed more often in individuals with systolic dysfunction, and its risk may be decreased with the use of digoxin.

OBJECTIVE: To investigate factors associated with receipt of colorectal cancer (CRC) screening among urban senior Chinese-Americans. METHODS: Two hundred three men and women from three senior centers completed a questionnaire that included sections on demographics, fecal occult blood testing (FOBT) and sigmoidoscopy use, and potential barriers to screening. RESULTS: Receipt of a FOBT within the prior 12 months (37.9% of sample) was associated with fewer years of US residency, lower level of worries or fears of test results, and higher level of perceived susceptibility to CRC. Receipt of a flexible sigmoidoscopy within the past 5 years (22.2% of sample) was associated with higher levels of education, lower levels of worries or fears of test results, and higher level of perceived susceptibility of CRC. CONCLUSIONS: Intervention programs may target these areas to facilitate CRC screening in Chinese-Americans so that national goals can be met for all Americans.