Citations

Abstract Cutaneous squamous cell carcinoma (SCC) occurs commonly and can metastasize. Identification of specific molecular aberrations and mechanisms underlying the development and progression of cutaneous SCC may lead to better prognostic and therapeutic approaches and more effective chemoprevention strategies. To identify genetic changes associated with early stages of cutaneous SCC development, we analyzed a series of 40 archived skin tissues ranging from normal skin to invasive SCC. Using high-resolution array-based comparative genomic hybridization, we identified deletions of a region on chromosome 10q harboring the INPP5A gene in 24% of examined SCC tumors. Subsequent validation by immunohistochemistry on an independent sample set of 71 SCC tissues showed reduced INPP5A protein levels in 72% of primary SCC tumors. Decrease in INPP5A protein levels seems to be an early event in SCC development, as it also is observed in 9 of 26 (35%) examined actinic keratoses, the earliest stage in SCC development. Importantly, further reduction of INPP5A levels is seen in a subset of SCC patients as the tumor progresses from primary to metastatic stage. The observed frequency and pattern of loss indicate that INPP5A, a negative regulator of inositol signaling, may play a role in development and progression of cutaneous SCC tumors. Cancer Prev Res; 3(10); 1277–83. ©2010 AACR.

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13–18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

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.

Purpose We performed a case-control genome-wide association study (GWAS) to identify single nucleotide polymorphisms (SNPs) associated with musculoskeletal adverse events (MS-AEs) in women treated with aromatase inhibitors (AIs) for early breast cancer. Patients and Methods A nested case-control design was used to select patients enrolled onto the MA.27 phase III trial comparing anastrozole with exemestane. Cases were matched to two controls and were defined as patients with grade 3 or 4 MS-AEs (according to the National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0) or those who discontinued treatment for any grade of MS-AE within the first 2 years. Genotyping was performed with the Illumina Human610-Quad BeadChip. Results The GWAS included 293 cases and 585 controls. A total of 551,358 SNPs were analyzed, followed by imputation and fine mapping of a region of interest on chromosome 14. Four SNPs on chromosome 14 had the lowest P values (2.23E-06 to 6.67E-07). T-cell leukemia 1A (TCL1A) was the gene closest (926-7000 bp) to the four SNPs. Functional genomic studies revealed that one of these SNPs (rs11849538) created an estrogen response element and that TCL1A expression was estrogen dependent, was associated with the variant SNP genotypes in estradiol-treated lymphoblastoid cells transfected with estrogen receptor alpha and was directly related to interleukin 17 receptor A (IL17RA) expression. Conclusion This GWAS identified SNPs associated with MS-AEs in women treated with AIs and with a gene (TCL1A) which, in turn, was related to a cytokine (IL17). These findings provide a focus for further research to identify patients at risk for MS-AEs and to explore the mechanisms for these adverse events.

OBJECTIVE: To determine the incidence of reading disability (RD) among children with and without research-identified attention-deficit/hyperactivity disorder (ADHD), separately according to gender, in a population-based birth cohort. METHOD: Subjects included all children born in 1976–1982 remaining in Rochester, Minnesota, after 5 years of age (n = 5718). Information from medical, school, and private tutorial records was abstracted. Cumulative incidence of RD, by any of 3 RD formulas, in children with and without ADHD and corresponding hazard ratios (HRs) were calculated separately according to gender. RESULTS: Cumulative incidence of RD by the age of 19 years was significantly higher in children with ADHD (51% in boys, 46.7% in girls) compared with those without ADHD (14.5% in boys, 7.7% in girls). Among children with ADHD, the risk for RD was similar in boys versus girls (HR: 1.0). However, among children without ADHD, boys were 2.0 times more likely than girls to meet RD criteria. Among girls, the HR for the risk for RD associated with ADHD (versus those without ADHD) was 8.1 (95% confidence interval: 5.7–11.5), which was significantly higher than the corresponding HR among boys (3.9 [95% confidence interval: 3.2–4.9]). CONCLUSIONS: The risk for RD is significantly greater among children with ADHD compared with those without ADHD. Among children with ADHD, the risk for RD is the same for boys and girls. However, among children without ADHD, boys are more at risk for RD than girls. Among girls, the magnitude of increased risk for RD associated with ADHD is nearly twice that among boys, because girls without ADHD are less likely to have RD than boys without ADHD.

Background and Purpose— Carotid artery stenosis causes up to 10% of all ischemic strokes. Carotid endarterectomy (CEA) was introduced as a treatment to prevent stroke in the early 1950s. Carotid stenting (CAS) was introduced as a treatment to prevent stroke in 1994. Methods— The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is a randomized trial with blinded end point adjudication. Symptomatic and asymptomatic patients were randomized to CAS or CEA. The primary end point was the composite of any stroke, myocardial infarction, or death during the periprocedural period and ipsilateral stroke thereafter, up to 4 years. Results— There was no significant difference in the rates of the primary end point between CAS and CEA (7.2% versus 6.8%; hazard ratio, 1.11; 95% CI, 0.81 to 1.51; P =0.51). Symptomatic status and sex did not modify the treatment effect, but an interaction with age and treatment was detected ( P =0.02). Outcomes were slightly better after CAS for patients aged <70 years and better after CEA for patients aged >70 years. The periprocedural end point did not differ for CAS and CEA, but there were differences in the components, CAS versus CEA (stroke 4.1% versus 2.3%, P =0.012; and myocardial infarction 1.1% versus 2.3%, P =0.032). Conclusions— In CREST, CAS and CEA had similar short- and longer-term outcomes. During the periprocedural period, there was higher risk of stroke with CAS and higher risk of myocardial infarction with CEA. Clinical Trial Registration— www.clinicaltrials.gov. Unique identifier: NCT00004732.