Citations

Abstract Background: Telomeres, the ends of chromosomes, are critical for maintaining genomic stability and grow shorter with age. Shortened telomeres in pancreatic tissue play a key role in the pathogenesis of pancreatic cancer, and shorter telomeres in peripheral blood leukocytes (PBL) have been associated with increased risk for several cancer types. We hypothesized that shorter blood telomeres are associated with higher risk for pancreatic cancer. Methods: Telomere length was measured in PBLs using quantitative real-time PCR in 499 cases with pancreatic cancer and 963 cancer-free controls from the Mayo Clinic. ORs and confidence intervals (CI) were computed using logistic generalized additive models (GAM) adjusting for multiple variables. Results: In multivariable adjusted models, we observed a significant nonlinear association between telomere length in peripheral blood samples and the risk for pancreatic cancer. Risk was lower among those with longer telomeres compared with shorter telomeres across a range from the 1st percentile to 90th percentile of telomere length. There was also some evidence for higher risk among those with telomeres in the longest extreme. Conclusions: Short telomeres in peripheral blood are associated with an increased risk for pancreatic cancer across most of the distribution of length, but extremely long telomeres may also be associated with higher risk. Impact: Although the temporality of this relationship is unknown, telomere length may be useful as either a marker of pancreatic cancer risk or of the presence of undetected pancreatic cancer. If telomere shortening precedes cancer incidence, interventions to preserve telomere length may be an effective strategy to prevent pancreatic cancer. Cancer Epidemiol Biomarkers Prev; 21(11); 2095–100. ©2012 AACR.

Background— Type 2 long QT syndrome involves mutations in the human ether a-go-go–related gene ( hERG or KCNH2 ). T421M, an S1 domain mutation in the Kv11.1 channel protein, was identified in a resuscitated patient. We assessed its biophysical, protein trafficking, and pharmacological mechanisms in adult rat ventricular myocytes. Methods and Results— Isolated adult rat ventricular myocytes were infected with wild-type (WT)–Kv11.1– and T421M-Kv11.1–expressing adenovirus and analyzed with the use of patch clamp, Western blot, and confocal imaging techniques. Expression of WT-Kv11.1 or T421M-Kv11.1 produced peak tail current ( I Kv11.1 ) of 8.78±1.18 and 1.91±0.22 pA/pF, respectively. Loss of mutant I Kv11.1 resulted from (1) a partially trafficking-deficient channel protein with reduced cell surface expression and (2) altered channel gating with a positive shift in the voltage dependence of activation and altered kinetics of activation and deactivation. Coexpression of WT+T421M-Kv11.1 resulted in heterotetrameric channels that remained partially trafficking deficient with only a minimal increase in peak I Kv11.1 density, whereas the voltage dependence of channel gating became WT-like. In the adult rat ventricular myocyte model, both WT-Kv11.1 and T421M-Kv11.1 channels responded to β-adrenergic stimulation by increasing I Kv11.1 . Conclusions— The T421M-Kv11.1 mutation caused a loss of I Kv11.1 through interactions of abnormal protein trafficking and channel gating. Furthermore, for coexpressed WT+T421M-Kv11.1 channels, different dominant-negative interactions govern protein trafficking and ion channel gating, and these are likely to be reflected in the clinical phenotype. Our results also show that WT and mutant Kv11.1 channels responded to β-adrenergic stimulation.

Background and Purpose— Minorities in the United States have less access to healthcare system resources, especially preventative treatments. We sought to determine whether racial and sex disparities existed in the treatment of unruptured intracranial aneurysms. Methods— Using the Nationwide Inpatient Sample, hospitalizations for clipping and coiling of intracranial aneurysms from 2001 to 2009 were identified by cross-matching International Classification of Diseases, 9th Revision codes for diagnosis of unruptured aneurysm and subarachnoid hemorrhage (SAH) with procedure codes for clipping or coiling of cerebral aneurysms. Demographic information analyzed included age (<50, 50–64, 65–79, and ≥80 years), race (white, black, Hispanic, Asian/Pacific Islander), sex, income quartile, primary payer (Medicare, Medicaid, private insurance, self-pay, no charge, other), and Charlson comorbidity index. Results— When compared with patients treated for SAH, those treated for unruptured intracranial aneurysm were significantly more likely to be women (75.0% versus 69.0%; P <0.0001). In all, 9.7% of patients receiving treatment for SAH were self-payers versus 3.0% of patients being treated for unruptured intracranial aneurysm ( P <0.0001). In all, 62.2% of patients receiving treatment for SAH were white compared with 76.4% of patients being treated for unruptured intracranial aneurysm ( P <0.0001). There was a higher proportion of black, Hispanic, and Asian patients in the SAH treatment group when compared with the unruptured aneurysm treatment group ( P <0.0001 for all groups). Conclusions— When compared with patients undergoing treatment for SAH, patients undergoing surgical and endovascular treatment for unruptured intracranial aneurysm are generally from higher socioeconomic strata and are more likely to be insured, women, and white. Future studies are needed to determine the underlying causes and solutions for this disparity.

Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13–null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.