Citations

Abstract Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.

We assessed the clinical results, radiographic outcomes and complications of patients undergoing total shoulder replacement (TSR) for osteoarthritis with concurrent repair of a full-thickness rotator cuff tear. Between 1996 and 2010, 45 of 932 patients (4.8%) undergoing TSR for osteoarthritis underwent rotator cuff repair. The final study group comprised 33 patients with a mean follow-up of 4.7 years (3 months to 13 years). Tears were classified into small (10), medium (14), large (9) or massive (0). On a scale of 1 to 5, pain decreased from a mean of 4.7 to 1.7 (p = < 0.0001), the mean forward elevation improved from 99° to 139° (p = < 0.0001), and the mean external rotation improved from 20° (0° to 75°) to 49° (20° to 80°) (p = < 0.0001). The improvement in elevation was greater in those with a small tear (p = 0.03). Radiographic evidence of instability developed in six patients with medium or large tears, indicating lack of rotator cuff healing. In all, six glenoid components, including one with instability, were radiologically at risk of loosening. Complications were noted in five patients, all with medium or large tears; four of these had symptomatic instability and one sustained a late peri-prosthetic fracture. Four patients (12%) required further surgery, three with instability and one with a peri-prosthetic humeral fracture.Consideration should be given to performing rotator cuff repair for stable shoulders during anatomical TSR, but reverse replacement should be considered for older, less active patients with larger tears.Cite this article: Bone Joint J 2014;96-B:224–8.

Background—Doppler-echocardiography provides quantitative imaging of systolic and diastolic left ventricular (LV) function, functional mitral regurgitation (FMR), and pulmonary hypertension (PH) in patients with LV systolic dysfunction. Whether PH is linked to survival independently of LV features and FMR in symptomatic and asymptomatic patients is unknown.Methods and Results—Patients with LV ejection fraction ≤40% and quantitative Doppler-echocardiography assessment of FMR and PH were studied. Patients were frequency matched for those with Doppler-echocardiography estimated pulmonary systolic pressure ≥45 mm Hg (n=692) and those without PH (n=692; pulmonary systolic pressure, <45 mm Hg) for age, sex, LV ejection fraction, and quantified FMR severity and analyzed for long-term survival after diagnosis. During follow-up (median, 8.9 years), 885 deaths (63.5%) occurred, with PH being associated with higher 5-year mortality: 51±2% versus 37±2%,P<0.001. In multivariate analysis, PH demonstrated increased mortality risk independent of age, sex, severity of diastolic and systolic LV dysfunction, FMR, comorbidities, and symptom (hazard ratio, 1.34; 95% confidence limit, 1.17–1.53;P<0.001). Subgroup analysis, stratified by symptoms, degree of FMR, and severity of LV dysfunction, demonstrated that PH was associated with excess mortality in all subgroups.Conclusions—In this large cohort of patients with LV systolic dysfunction, in whom FMR and LV characteristics were quantified and matched between those with and without PH, the presence of PH was an independent factor for excess mortality and not a surrogate for the severity of LV systolic dysfunction or FMR. In asymptomatic or symptomatic patients with or without FMR, PH is a critical marker for poor outcomes.

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ−/− mice) were generated using loxP/Cre technology. ePPARδ−/− mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium ( Z)-1-( N, N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ−/− mice ( P < 0.05). In ePPARδ−/− mouse aortas, phosphorylation of endothelial NO synthase at Ser1177 was significantly decreased ( P < 0.05). However, basal levels of cGMP were unexpectedly increased ( P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ−/− mice ( P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta ( P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ−/− mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.

ObjectivesTo review the natural history of occult head and neck malignancy presenting with facial pain and evaluate the risk factors, diagnostic workup, and management of facial pain in the setting of occult malignancy.Study DesignRetrospective chart review.SettingTertiary care center.Subjects and MethodsAll patients presenting from 1980 to 2010 with facial pain and a delayed diagnosis of a head and neck cancer were reviewed.ResultsThirty‐eight patients were included. Onset of pain was rapid or sudden in 94.7%, intermittent in 84.2%, and sharp in 86.8%. Facial nerve weakness was present in 15.8%. Five patients had a history of locoregional skin cancer, and 14% had a history of malignancy. Average delay to diagnosis was 18.4 months. On average, the suspicious lesion was identified on the second scan (mean, 2.1; range, 1‐4 scans). Diagnosis was suggested by magnetic resonance imaging in 54.8% and computed tomography in 38.7% of patients. The most common pathology was squamous cell carcinoma (39.5%), and the predominant location was the parotid gland (28.9%). Surgical resection (66%) was the most common intervention. In patients who received treatment and had clinical follow‐up available for review, 97.0% (32/33) reported symptomatic improvement.ConclusionsIn our series, sudden‐onset, intermittent, sharp facial pain without resolution or improvement was associated with occult malignancy and should be considered in the differential diagnosis for facial pain. Based on the high incidence of early negative imaging, consideration should be given to repeat imaging when there is concern for malignancy. Therapeutic interventions often result in improvement of facial pain.

SummaryObjectiveSeizures are currently defined by their electrographic features. However, neuronal networks are intrinsically dependent on neurotransmitters of which little is known regarding their periictal dynamics. Evidence supports adenosine as having a prominent role in seizure termination, as its administration can terminate and reduce seizures in animal models. Furthermore, microdialysis studies in humans suggest that adenosine is elevated periictally, but the relationship to the seizure is obscured by its temporal measurement limitations. Because electrochemical techniques can provide vastly superior temporal resolution, we test the hypothesis that extracellular adenosine concentrations rise during seizure termination in an animal model and humans using electrochemistry.MethodsWhite farm swine (n = 45) were used in an acute cortical model of epilepsy, and 10 human epilepsy patients were studied during intraoperative electrocorticography (ECoG). Wireless Instantaneous Neurotransmitter Concentration Sensor (WINCS)–based fast scan cyclic voltammetry (FSCV) and fixed potential amperometry were obtained utilizing an adenosine‐specific triangular waveform or biosensors, respectively.ResultsSimultaneousECoG and electrochemistry demonstrated an average adenosine increase of 260% compared to baseline, at 7.5 ± 16.9 s with amperometry (n = 75 events) and 2.6 ± 11.2 s withFSCV(n = 15 events) prior to electrographic seizure termination. In agreement with these animal data, adenosine elevation prior to seizure termination in a human patient utilizingFSCVwas also seen.SignificanceSimultaneousECoG and electrochemical recording supports the hypothesis that adenosine rises prior to seizure termination, suggesting that adenosine itself may be responsible for seizure termination. Future work using intraoperativeWINCS–basedFSCVrecording may help to elucidate the precise relationship between adenosine and seizure termination.