Citations

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention.

The role of venous stasis syndrome (VSS) mechanisms (i.e. venous outflow obstruction [VOO] and venous valvular incompetence [VVI]) on quality of life (QoL) and activities of daily living (ADL) is unknown. The objective of this study was to test the hypotheses that venous thromboembolism (VTE),VSS,VOO and VVI are associated with reduced QoL and ADL. This study is a follow-up of an incident VTE case-control study nested within a population-based inception cohort of residents from Olmsted County, MN, USA, between 1966 and 1990. The study comprised 232 Olmsted County residents with a first lifetime VTE and 133 residents without VTE. Methods included a questionnaire and physical examination for VSS; vascular laboratory testing for VOO and VVI; assessment of QoL by SF36 and of ADL by pertinent sections from the Older Americans Resources and Services (OARS) and Arthritis Impact Measurement Scales (AIMS2) questionnaires. Of the 365 study participants, 232 (64%), 161 (44%), 43 (12%) and 136 (37%) had VTE, VSS, VOO and VVI, respectively. Prior VTE was associated with reduced ADL and increased pain, VSS with reduced physical QoL and increased pain, and VOO with reduced physical QoL and ADL.VVI was not associated with QoL or ADL. In conclusion,VSS and VOO are associated with worse physical QoL and increased pain. VOO and VTE are associated with impaired ADL. We hypothesize that rapid clearance of venous outflow obstruction in individuals with acute VTE will improve their QoL and ADL.

Purpose To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). Patients and Methods Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [ CLIA ] –certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. Results In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. Conclusion It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.

Neointimal hyperplasia contributes to failure of hemodialysis arteriovenous fistulas (AVFs). Increased expression of matrix metalloproteinase (MMP)-9 occurs in AVFs, and MMP-9 is implicated in neointimal hyperplasia and vascular injury. Recent studies demonstrate that MMP-9, by degrading N-cadherin, leads to increased expression of β-catenin and β-catenin-dependent proliferation of smooth muscle cells. The present study examined this pathway in the venous limb of a murine AVF model. Western analyses demonstrate that, in this model, there is diminished expression of N-cadherin accompanied by increased expression of β-catenin, c-Myc, and proliferating cell nuclear antigen (PCNA). By immunohistochemistry, β-catenin and c-Myc localized to proliferating smooth muscle cells in the venous limb of the AVF. Increased expression of β-catenin was accompanied by augmented expression of phosphorylated (p)-glycogen synthase kinase (GSK)-3β, GSK-3β, and integrin-linked kinase. The administration of doxycycline suppressed MMP-9 expression but did not reduce venous histological injury in the AVF, or increase AVF patency assessed 6 wk after its creation. Doxycycline did not influence expression of β-catenin, c-Myc, GSK-3β, or integrin-linked kinase. Thus, in this vascular injury model, the upregulation of β-catenin cannot be readily attributed to MMP-9 upregulation; increased β-catenin expression may reflect either the upregulation of p-GSK-3β, GSK-3β, or integrin-linked kinase. This study provides the first exploration of β-catenin in an AVF, demonstrating substantial upregulation of this mitogenic signaling molecule and uncovering possible mechanisms that may account for such upregulation.

Abstract A critical problem in the treatment of malignant gliomas is the extensive infiltration of individual tumor cells into adjacent brain tissues. This invasive phenotype severely limits all current therapies, and to date, no treatment is available to control the spread of this disease. Members of the tumor necrosis factor (TNF) ligand superfamily and their cognate receptors regulate various cellular responses including proliferation, migration, differentiation, and apoptosis. Specifically, the TNFRSF19/TROY gene encodes a type I cell surface receptor that is expressed on migrating or proliferating progenitor cells of the hippocampus, thalamus, and cerebral cortex. Here, we show that levels of TROY mRNA expression directly correlate with increasing glial tumor grade. Among malignant gliomas, TROY expression correlates inversely with overall patient survival. In addition, we show that TROY overexpression in glioma cells activates Rac1 signaling in a Pyk2-dependent manner to drive glioma cell invasion and migration. Pyk2 coimmunoprecipitates with the TROY receptor, and depletion of Pyk2 expression by short hairpin RNA interference oligonucleotides inhibits TROY-induced Rac1 activation and subsequent cellular migration. These findings position aberrant expression and/or signaling by TROY as a contributor, and possibly as a driver, of the malignant dispersion of glioma cells. Mol Cancer Res; 8(11); 1558–67. ©2010 AACR.

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.

OBJECTIVES: The objective of this study was to examine factors that are associated with aggression that is responsive versus refractory to individualized optimization of stimulant monotherapy among children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children who were aged 6 to 13 years and had ADHD, either oppositional defiant disorder or conduct disorder, significant aggressive behavior, and a history of insufficient response to stimulants completed an open stimulant monotherapy optimization protocol. Stimulant titration with weekly assessments of behavior and tolerability identified an optimal regimen for each child. Families also received behavioral therapy. Parents completed the Retrospective-Modified Overt Aggression Scale (R-MOAS) at each visit. Children were classified as having stimulant-refractory aggression on the basis of R-MOAS ratings and clinician judgment. Differences that pertained to treatment, demographic, and psychopathology between groups with stimulant monotherapy–responsive and –refractory aggression were evaluated. RESULTS: Aggression among 32 (49.3%) of 65 children was reduced sufficiently after stimulant dosage adjustment and behavioral therapy to preclude adjunctive medication. Those who responded to stimulant monotherapy were more likely to benefit from the protocol's methylphenidate preparation (once-daily, triphasic release), showed a trend for lower average dosages, and received fewer behavioral therapy sessions than did children with stimulant-refractory aggression. Boys, especially those with higher ratings of baseline aggression and of depressive and manic symptoms, more often exhibited stimulant-refractory aggression. CONCLUSIONS: Among children whose aggressive behavior develops in the context of ADHD and of oppositional defiant disorder or conduct disorder, and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well-monitored titration of stimulant monotherapy often culminates in reduced aggression that averts the need for additional agents.

Background— After repair of aortic coarctation, patients may develop restenosis, aneurysms, and pseudoaneurysms at the site of prior repair. We assessed the outcomes of late reintervention on the descending aorta after aortic coarctation repair. Methods and Results— From March 1954 to July 2008, 130 patients had operations or endovascular procedures on the descending aorta after previous coarctation repair. We excluded patients who had complex left-sided cardiac lesions or interrupted aortic arch. Mean age at reintervention was 32±24 years and 28% were female. The interval between coarctation repair and reintervention was 17±13 years. Seventy-four percent of patients had hypertension. Reasons for reintervention were restenosis (n=122 [94%]), aneurysm (n=4 [3%]), and pseudoaneurysm (n=4 [3%]). Ninety-five patients (73%) underwent operative procedures including an extra-anatomic conduit (n=41), patch repair (n=32), interposition graft (n=14), end–end anastomosis (n=6), and subclavian flap (n=2). Thirty-five patients underwent endovascular treatment (balloon dilatation, n=22 or stenting, n=13). There was no early mortality. In the surgical group, 5 patients required early reoperation for bleeding and 5 patients had early vocal cord paralysis. One patient in the endovascular group had aortic rupture at the time of intervention requiring urgent operation. Survival was 97% at 10 years. At 5 years, freedom from a second repeat procedure on the descending aorta was 96% in the surgical group and 72% in the endovascular group ( P <0.001). Five years after reintervention, fewer patients required treatment for hypertension (57% versus 74% , P <0.001) and a median of 1 antihypertensive medication was prescribed compared with a median of 2 medications preintervention. Conclusions— Operative and endovascular management of recoarctation can be performed safely with good late outcomes.

Abstract The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype–phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes.

Background— Proposed advantages to the Ross procedure included presumed increased freedom from reoperation and simpler reoperation for pulmonary conduit replacement if needed. It is increasingly apparent, however, that reoperations are frequent after the Ross procedure and that when required, they may be more complex than previously thought. Methods and Results— Between September 1991 and August 2008, 56 patients underwent reoperation at our institution after a Ross procedure performed by ourselves (n=13) or elsewhere (n=43). Median age at first reoperation at our institution was 26 years (range 1 to 69 years). The 4 most common indications for reoperation were isolated autograft (neoaortic) regurgitation in 11 cases (20), isolated pulmonary conduit regurgitation/stenosis in 9 (16), combined autograft regurgitation/dilatation in 8 (14), and combined autograft regurgitation and pulmonary conduit regurgitation/stenosis in 6 (11). A total of 144 procedures were performed in these 56 patients during first reoperation at our institution. The autograft valve required replacement in 21 cases (38) and aortic root replacement in 21 (38), with ascending aortic/arch reconstruction in 13 (23) and mitral valve surgery in 5 (9). The pulmonary valve was replaced in 33 cases (59) and the tricuspid valve was repaired/replaced in 10 (18). Early mortality was 1.8 (1 of 56 patients), and morbidity included 6 patients with respiratory failure and 3 who required postcardiotomy extracorporeal membrane oxygenation. There were 4 late deaths during the median follow-up of 8 months (range 1 to 179 months). Conclusions— A broad spectrum of complex reoperations may be required after the Ross procedure. Patients and family members considering the procedure should be informed of the potential for associated morbidity should reoperation be necessary.