Citations

Left ventricular assist devices (LVADs) are systems for mechanical support for patients with end-stage heart failure. Preoperative, postoperative and comprehensive followup with transthoracic echocardiography has a major role in LVAD patient management. In this paper, we will present briefly the hemodynamics of axial-flow LVAD, the rationale, and available data for a complete and organized echocardiographic assessment in these patients including preoperative assessment, postoperative and long-term evaluation.

Abstract Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism. Mol Cancer Ther; 10(1); 117–25. ©2011 AACR.

Abstract The contribution of emphysema to lung cancer risk has been recognized, but the effect size needs to be further defined. In this study, 565 primary lung cancer cases were enrolled though a prospective lung cancer cohort at Mayo Clinic, and 450 controls were smokers participating in a lung cancer screening study in the same institution using spiral computed tomography (CT). Cases and controls were frequency matched on age, gender, race, smoking status, and residential region. CT imaging using standard protocol at the time of lung cancer diagnosis (case) or during the study (control) was assessed for emphysema by visual scoring CT analysis as a percentage of lung tissue destroyed. The clinical definition of emphysema was the diagnosis recorded in the medical documentation. Using multiple logistic regression models, emphysema (≥5% on CT) was found to be associated with a 3.8-fold increased lung cancer risk in Caucasians, with higher risk in subgroups of younger (<65 years old, OR = 4.64), heavy smokers (≥40 pack-years, OR = 4.46), and small-cell lung cancer (OR = 5.62). When using >0% or ≥10% emphysema on CT, lung cancer risk was 2.79-fold or 3.33-fold higher than controls. Compared with CT evaluation (using criterion ≥5%), the sensitivity, specificity, positive and negative predictive values, and the accuracy of the clinical diagnosis for emphysema in controls were 19%, 98%, 73%, 84%, and 83%, respectively. These results imply that an accurate evaluation of emphysema could help reliably identify individuals at greater risk of lung cancer among smokers. Cancer Prev Res; 4(1); 43–50. ©2010 AACR.

Background— Respiratory dependence of tricuspid regurgitation (TR), a long-held concept suggested by murmur variation, remains unproven and of unclear mechanisms. Methods and Results— In 41 patients with mild or greater TR (median age, 67 years), we performed triple Doppler echocardiographic quantification (TR severity, right ventricular, and right atrial quantification) with simultaneous respirometer recording of respiratory phases. Expiration to inspiration changes (median) affected TR peak velocity (−40 cm/s; 25th to 75th percentile, −60 to −30 cm/s), duration (−12 milliseconds; 25th to 75th percentile, −45 to 2 milliseconds), and time-velocity integral (−17 cm; 25th to 75th percentile, −23.4 to −10 cm; all P <0.001), consistent with decreased TR driving force. Nevertheless, inspiratory TR augmentation was demonstrated by increased effective regurgitant orifice (0.21 cm 2 ; 25th to 75th percentile, 0.09 to 0.34 cm 2 ) and volume (18 mL per beat; 25th to 75th percentile, 10 to 25 mL per beat; all P <0.001) infrequently detected clinically (2 of 41, 5). As a result of reduced TR driving force, regurgitant volume increased less than effective regurgitant orifice (120 [25th to 75th percentile, 78.6 to 169] versus 169 [ 25th to 75th percentile, 12.9 to 226.1]; P <0.001). During inspiration, right ventricular area increased (diastolic, 27.8 [25th to 75th percentile, 22.6 to 36.3] versus 26.5 [21.1 to 31.9]; P <0.0001) with widening of right ventricular shape (length-to-width ratio, 1.6 [ 25th to 75th percentile, 1.37 to 1.95] versus 1.7 [1.46 to 2.1]; P <0.0001), increased systolic annular diameter ( P =0.003), valve tenting height ( P <0.0001) and area ( P <0.0001), and reduced valvular-to-annular ratio ( P =0.006). Effective regurgitant orifice during inspiration was independently determined by inspiratory valvular-to-annular ratio ( P =0.026) and inspiratory change in right ventricular length-to-width ratio ( P =0.008) and valve tenting area ( P =0.015). Conclusions— TR is dynamic with almost universal respiratory changes of large magnitude and complex pathophysiology. During inspiration, a large increase in effective regurgitant orifice causes, despite a decline in regurgitant gradient, a notable increase in regurgitant volume. Effective regurgitant orifice changes are independently linked to inspiratory annular enlargement (decreased valvular coverage) and to inspiratory right ventricular shape widening with increased valvular tenting. These novel physiological insights into TR respiratory dependence underscore right-side heart plasticity and are important for clinical TR severity evaluation.

Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis.

SummaryClinical trials often include binary end points. In some cases, no successes are observed and the usual large sample estimates of relative risk are undefined. The paper proposes an estimator for relative risk based on the median unbiased estimator. The relative risk estimator proposed is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and an SAS macro is available to perform the necessary calculations. An on-going randomized clinical trial motivated the development of the estimator and is used to illustrate the approach.

Abstract A common variant on chromosomal region 15q24-25.1, marked by rs1051730, was found to be associated with lung cancer risk. Here, we attempted to confirm the second variant on 15q24-25.1 in several large sporadic lung cancer populations and determined what percentage of additional risk for lung cancer is due to the genetic effect of the second variant. SNPs rs1051730 and rs481134 were genotyped in 2,818 lung cancer cases and 2,766 controls from four populations. Joint analysis of these two variants (rs1051730 and rs481134) on 15q24-25.1 identified three major haplotypes (G_T, A_C, and G_C) and provided stronger evidence for association of 15q24-25.1 with lung cancer (P = 9.72 × 10−9). These two variants represent three levels of risk associated with lung cancer. The most common haplotype G_T is neutral; the haplotype A_C is associated with increased risk for lung cancer with 5.0% higher frequency in cases than in controls [P = 1.68 × 10−7; odds ratio (OR), 1.24; 95% confidence interval (95% CI), 1.14–1.35]; whereas the haplotype G_C is associated with reduced risk for lung cancer with 4.4% lower frequency in cases than in controls (P = 7.39 × 10−7; OR, 0.80; 95% CI, 0.73–0.87). We further showed that these two genetic variants on 15q24-25.1 independently influence lung cancer risk (rs1051730: P = 4.42 × 10−11; OR, 1.60; 95% CI, 1.46–1.74; rs481134: P = 7.01 × 10−4; OR, 0.81; 95% CI, 0.72–0.92). The second variant on 15q24-25.1, marked by rs481134, explains an additional 13.2% of population attributable risk for lung cancer. Cancer Res; 70(8); 3128–35. ©2010 AACR.

Abstract Background: Genetic factors play important roles in lung cancer susceptibility. In this study, we replicated the association of 5p15.33 and 6p21.33 with familial lung cancer. Taking into account the previously identified genetic susceptibility variants on 6q23-25/RGS17 and 15q24-25.1, we further determined the cumulative association of these four genetic regions and the population attributable risk percent of familial lung cancer they account for. Methods: One hundred ninety-four case patients and 219 cancer-free control subjects from the Genetic Epidemiology of Lung Cancer Consortium were used for the association analysis. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Single nucleotide polymorphisms (SNP) on chromosomal regions 5p15.33, 6p21.33, 6q23-25/RGS17, and 15q24-25.1 were assessed for their associations with familial lung cancer. The cumulative association of the four chromosomal regions with familial lung cancer was evaluated with the use of a linear logistic model. Population attributable risk percent was calculated for each SNP using risk ratio. Results: SNP rs31489 showed the strongest evidence of familial lung cancer association on 5p15.33 (P = 2 × 10−4; odds ratio, 0.57; 95% confidence interval, 0.42-0.77), whereas rs3117582 showed a weak association on 6p21.33 (P = 0.09; odds ratio, 1.47; 95% confidence interval, 0.94-2.31). Analysis of a combination of SNPs from the four regions provided a stronger cumulative association with familial lung cancer (P = 6.70 × 10−6) than any individual SNPs. The risk of lung cancer was increased to 3- to 11-fold among those subjects who had at least one copy of risk allele at each region compared with subjects without any of the risk factors. These four genetic regions contribute to a total of 34.6% of familial lung cancer in smokers. Conclusions: The SNPs in four chromosomal regions have a cumulative and significant association with familial lung cancer and account for about one-third of the population attributable risk for familial lung cancer. Cancer Epidemiol Biomarkers Prev; 19(2); 517–24