Citations

Abstract Family history is a strong predictor of colorectal cancer risk; however, a diagnosis of colorectal cancer among first-degree relatives has not been systematically investigated as a function of the colorectal cancer molecular subtypes related to tumor microsatellite instability (MSI) status. We investigated whether the observable familial colorectal cancer risks differed according to tumor MSI subtypes, stratified as MSI-High (>30% instability), MSI-Low (<30% instability), and MSS (no instability). Data from 3,143 population-based colorectal cancer cases from five institutions were assessed for family history according to the Amsterdam criteria and the Bethesda guidelines, age at diagnosis, sex, tumor location, and MSI status. The distribution of patient characteristics by MSI status was compared using polytomous logistic regression. Overall, 2.8% colorectal cancer cases met the Amsterdam criteria and 37% met the Bethesda guidelines. There were 14% MSI-High, 13% MSI-Low, and 73% MSS colorectal cancers. MSI-High (P < 0.0001) and MSI-Low tumors (P = 0.01) were more proximally located than MSS tumors. MSI-High tumors were more common among females (P < 0.001). The highest proportion of MSI-High tumors occurred in cases <40 years of age whereas the age-dependent distribution of MSI-Low tumors was unchanged. MSI-High tumors showed a statistically significant association with increasing numbers of first-degree relatives with colorectal cancer (P = 0.002); this association disappeared, however, when MSI-High cases meeting Amsterdam criteria were removed from the analysis. MSI-Low tumors did not show a similar association with family history of colorectal cancer. Familial risk associated with MSI-High tumors is primarily driven by the Amsterdam-criteria patients. MSI-Low tumors may represent a distinct subtype of colorectal cancer with respect to certain epidemiologic variables studied here. (Cancer Epidemiol Biomarkers Prev 2009;18(3):967–75)

The Wnt/β-catenin pathway exhibits distinct and developmental stage-specific roles during cardiogenesis. However, little is known about the molecular mechanisms of Wnt/β-catenin signaling in the establishment of cardiac left-right (LR) asymmetry. Using zebrafish as an animal model, we show here that Wnt/β-catenin signaling is differentially required in cardiac LR patterning. At an early stage, during asymmetric signal generation,Wnt/β-catenin signaling is necessary for Kupffer's vesicle development and for the regulation of both heart and visceral laterality. At a later stage, during asymmetric signal propagation, excessive Wnt/β-catenin signaling inhibits the transmission of asymmetric cues from the lateral plate mesoderm (LPM) to the cardiac field but not to the developing gut; as such, it only regulates heart laterality. Molecular analysis identifies Gata4 as the downstream target of Wnt/β-catenin signaling in the cardiac field that responds to the Wnt/β-catenin signaling and regulates the competence of the heart field to express left-sided genes. In summary, our results reveal a previously unexpected role of Wnt-Gata4 signaling in the control of asymmetric signal propagation from the LPM to the cardiac field.

Tendons are frequently injured by direct trauma. Tendon adhesions were a common sequel of tendon repair and are one of the most challenging problems in hand surgery. The concept of “controlled motion” gradually replaced “total immobilization” in the treatment of flexor tendon injuries and today represents a standard of care for all primary repaired flexor tendon injury. Use of controlled motion splints during the early stages of stages of tendon recovery in crease tendon gliding. However, how best to achieve passive motion and the effect of passive motion on tendon gliding have remained controversial subjects. Based on a series of recent experiments, the concept of “dynamic synergistic wrist motion splint” was established and evaluated. It was found that this synergistic wrist motion increases the tendon excursion due to eliminating the laxity and buckling of tendon in the regions between pulleys without introduce excessive amount of tension. The purpose of this study is to design and fabricate a dynamic splint based on this concept and define the nature coordinated motion between the wrist and finger joints due to the passive tension of the muscles in vivo. Parametric analysis will be conducted to achieve an optimum design with the consideration of anatomic constraints. Clinical trial of using such dynamic splint will be evaluated in the future.

Abstract Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.)

AbstractMicroRNAs (miRNA) can act as oncogenes or tumor suppressors and modulate the expression of approximately one third of all human genes. To test the hypothesis that adverse alleles in miRNA-related genes may increase the risk for esophageal cancer, we assessed the associations between esophageal cancer risk and 41 potentially functional single nucleotide polymorphisms (SNP) in 26 miRNA-related genes in a case-control study of 346 Caucasian esophageal cancer patients (85.5% with esophageal adenocarcinoma) and 346 frequency-matched (age, gender, and ethnicity) controls. Seven SNPs were significantly associated with esophageal cancer risk. The most notable finding was that the SNP rs6505162, which is located in the pre-mir423 region, was associated with a per-allele odds ratio of 0.64 [95% confidence interval (95% CI), 0.51-0.80; P for trend < 0.0001]. This association remained significant after we corrected for multiple comparisons. A common haplotype of the GEMIN4 gene was associated with a significantly reduced risk of esophageal cancer (odds ratio, 0.65; 95% CI, 0.42-0.99). We did a combined unfavorable genotype analysis to further evaluate the cumulative effects of the promising (risk associated) SNPs. In comparison with the low-risk group (fewer than three unfavorable genotypes), the medium-risk group (three unfavorable genotypes) had a 2.00-fold (95% CI, 1.31-3.08) increased risk and the high-risk group (more than three unfavorable genotypes) had a 3.14-fold (95% CI, 2.03-4.85) increased risk (P for trend < 0.0001). Results for the risk of esophageal adenocarcinoma were similar to the overall risk results. The present study provides the first evidence that miRNAs may affect esophageal cancer risk in general and that specific genetic variants in miRNA-related genes may affect esophageal cancer risk individually and jointly.

Background— Various dyssynchrony indexes derived from tissue velocity and strain imaging have been proposed to predict the effectiveness of cardiac resynchronization therapy (CRT). We sought to compare the effect of CRT on dyssynchrony indexes derived by tissue velocity and strain and to determine which baseline intraventricular dyssynchrony parameters correlate with improvement in left ventricular volume after CRT. Methods and Results— Echocardiography with tissue Doppler imaging was performed in 45 patients with systolic heart failure at baseline, 1 day after CRT, and a median of 6 months after CRT. We calculated septal–lateral delay and anteroseptal–posterior delay and standard deviation of time to peak systolic velocity in the 12 basal and mid-left ventricular segments (Tv-SD). The standard deviation for time to peak strain in the 12 basal and mid-left ventricular segments (Tε-SD) was calculated as a strain-derived dyssynchrony index. None of the tissue velocity–derived dyssynchrony indexes improved after CRT (septal–lateral delay, P =0.39; anteroseptal–posterior delay, P =0.46; Tv-SD, P =0.30), whereas Tε-SD decreased significantly after CRT ( P <0.001). Improvement in Tε-SD 1 day after CRT correlated with the reduction in end-systolic volume at follow-up ( r =0.66; P <0.001). Baseline Tε-SD demonstrated significant correlation with the reduction of end-systolic volume at follow-up ( r =0.57; P <0.001); however, baseline tissue velocity–derived dyssynchrony indexes failed to predict the effect of CRT. Conclusions— The strain-derived dyssynchrony index is a better measurement than the tissue velocity dyssynchrony index for monitoring changes in mechanical dyssynchrony after CRT and for predicting reduction in left ventricular volume after CRT.