Notch signaling in serous ovarian cancer

Ovarian cancer is the most lethal of all gynecologic malignancies because women commonly present with advanced stage disease and develop chemotherapy refractory tumors. While cytoreductive surgery followed by platinum based chemotherapy are initially effective, ovarian tumors have a high propensity to recur highlighting the distinct need for novel therapeutics to improve outcomes for affected women. The Notch signaling pathway plays an established role in embryologic development and deregulation of this signaling cascade has been linked to many cancers. Recent genomic profiling of serous ovarian carcinoma revealed that Notch pathway alterations are among the most prevalent detected genomic changes. A growing body of scientific literature has confirmed heightened Notch signaling activity in ovarian carcinoma, and has utilized in vitro and in vivo models to suggest that targeting this pathway with gamma secretase inhibitors (GSIs) leads to anti-tumor effects. While it is currently unknown if Notch pathway inhibition can offer clinical benefit to women with ovarian cancer, several GSIs are currently in phase I and II trials across many disease sites including ovary. This review will provide background on Notch pathway function and will focus on the pre-clinical literature that links altered Notch signaling to ovarian cancer progression

Serum 25-Hydroxyvitamin D Levels Among Boston Trainee Doctors in Winter

As indoor workers, trainee doctors may be at risk for inadequate vitamin D. All trainee doctors (residents) in a Boston pediatric training program (residency) were invited to complete a survey, and undergo testing for serum 25-hydroxyvitamin D [25(OH)D], PTH, and calcium during a 3-week period in March 2010. We examined the association between resident characteristics and serum 25(OH)D using Chi2 and Kruskal-Wallis test and multivariable linear and logistic regression. Of the 119 residents, 102 (86%) participated. Although the mean serum 25(OH)D level was 67 nmol/L (±26), 25 (25%) had a level <50 nmol/L and 3 (3%) residents had levels <25 nmol/L. In the multivariable model, factors associated with 25(OH)D levels were: female sex (β 12.7, 95% CI 3.6, 21.7), white race (β 21.7, 95% CI 11.7, 31.7), travel to more equatorial latitudes during the past 3 months (β 6.3, 95% CI 2.0, 10.5) and higher daily intake of vitamin D (β 1.1, 95% CI 0.04, 2.1). Although one in four residents in our study had a serum 25(OH)D <50 nmol/L, all of them would have been missed using current Centers for Medicare and Medicaid Services (CMS) screening guidelines. The use of traditional risk factors appears insufficient to identify low vitamin D in indoor workers at northern latitudes

The Role of Para-Aortic Lymphadenectomy in the Surgical Staging of Women with Intermediate and High-Risk Endometrial Adenocarcinomas

Objectives:. To characterize clinical outcomes in patients with intermediate or high-risk endometrial carcinoma who underwent surgical staging with or without para-aortic lymphadenectomy. Methods:. This is a retrospective cohort study of patients with intermediate or high-risk endometrial adenocarcinoma who underwent surgical staging with (PPALN group) or without (PLN) para-aortic lymphadenectomy. Data were collected, Kaplan-Meier curves were generated, and univariate and multivariate analyses performed to compare differences in adjuvant therapy, disease recurrence, disease-free survival (DFS), and overall survival (OS). Results. 118 patients were included in the PPALN group and 139 in the PLN group. Patients in the PPALN group were more likely to receive adjuvant vaginal brachytherapy (25.4% versus 11.5%, OR = 2.5, P = 0.03) and less likely to receive adjuvant multimodal combination therapy (17.81% versus 28.8%, OR = 0.28, P = 0.002). DFS was improved in the PLN group as compared to PPALN (80% versus 62%, P = 0.02). OS was equivalent (P = 0.93). Patients in the PPALN group who had less than 10 para-aortic nodes removed were twice as likely to recur than patients who had 10 or more para-aortic nodes or patients in the PLN group (HR 2.08, CI 1.20–3.60, P = 0.009). Conclusions:. Patients in the PLN group were more likely to receive multimodal adjuvant therapy and had better DFS than the PPALN group. Pelvic lymphadenectomy followed by adjuvant radiation and chemotherapy may represent an effective treatment option for patients with intermediate or high-risk disease. If systematic para-aortic lymphadenectomy is performed and less than 10 para-aortic lymph nodes are obtained, multimodality adjuvant therapy should be considered to improve DFS

Inhibition of Notch Signaling in Combination with Paclitaxel Reduces Platinum-Resistant Ovarian Tumor Growth

Introduction: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p < 0.05), as well as in one of three platinum-sensitive tumors (p = 0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting. Conclusion: Inhibiting the Notch signaling cascade with a GSI reduces primary human xenograft growth in vivo. GSI synergized with conventional cytotoxic chemotherapy only in the platinum-resistant OvCa models with single agent paclitaxel. These findings suggest inhibition of the Notch pathway in concert with taxane therapy may hold promise for treatment of platinum-resistant OvCa

Monitoring Motor Fluctuations in Patients With Parkinson’s Disease Using Wearable Sensors

This paper presents the results of a pilot study to assess the feasibility of using accelerometer data to estimate the severity of symptoms and motor complications in patients with Parkinson’s disease. A support vector machine (SVM) classifier was implemented to estimate the severity of tremor, bradykinesia and dyskinesia from accelerometer data features. SVM-based estimates were compared with clinical scores derived via visual inspection of video recordings taken while patients performed a series of standardized motor tasks. The analysis of the video recordings was performed by clinicians trained in the use of scales for the assessment of the severity of Parkinsonian symptoms and motor complications. Results derived from the accelerometer time series were analyzed to assess the effect on the estimation of clinical scores of the duration of the window utilized to derive segments (to eventually compute data features) from the accelerometer data, the use of different SVM kernels and misclassification cost values, and the use of data features derived from different motor tasks. Results were also analyzed to assess which combinations of data features carried enough information to reliably assess the severity of symptoms andmotor complications.Combinations of data features were compared taking into consideration the computational cost associated with estimating each data feature on the nodes of a body sensor network and the effect of using such data features on the reliability of SVM-based estimates of the severity of Parkinsonian symptoms and motor complications.Engineering and Applied Science

A Neural Dissociation Within Language: Evidence that the Mental Dictionary is Part of Declarative Memory, and that Grammatical Rules are Processed by the Procedural System

Language comprises a lexicon for storing words and a grammar for generating rule-governed forms. Evidence is presented that the lexicon is part of a temporal-parietalhnedial-temporal “declarative memory” system and that granlmatical rules are processed by a frontamasal-ganglia “procedural” system. Patients produced past tenses of regular and novel verbs (looked and plagged), which require an -ed-suffixation rule, and irregular verbs (dug), which are retrieved from memory. Word-finding difficulties in posterior aphasia, and the general declarative memory impairment in Alzheimer's disease, led to more errors with irregular than regular and novel verbs. Grammatical difficulties in anterior aphasia, and the general impairment of procedures in Parkinson's disease, led to the opposite pattern. In contrast to the Parkinson's patients, who showed suppressed motor activity and rule use, Huntington's disease patients showed excess motor activity and rule use, underscoring a role for the basal ganglia in grammatical processing.Psycholog

Palliative gastrostomy in the setting of voluminous ascites

Objective: We report the indications, methods, and complications of percutaneous gastrostomy/gastrojejunostomy (G/GJ) in patients with voluminous ascites. Methods: Following institutional review board approval, 69 patients (14 male, 55 female, mean age 58±12 years, range 32–89 years) who underwent percutaneous G/GJ with paracentesis were identified from a prospectively acquired database. Electronic medical record data extracted included diagnosis, method of G/GJ insertion, clinical course, and complications, which were graded by The Society of Interventional Radiology (SIR) criteria. Statistics were performed using Graphpad Instat. Results: Sixty-six G and three GJ catheters were placed in 62 patients with malignant and 7 patients with benign disease; 47 procedures were conducted using fluoroscopy and 22 using computed tomography (CT; 10 patients had failed fluoroscopy). Sixty-six patients had 1980±1371 mL (range, 20–5000 mL) ascites drained (more in males, p=0.01) 0.8±1.6 days (range, 0–5 days) prior to placement. Forty-one patients had significantly less ascites (1895±1426 mL; range, 100–5400 mL) drained after G/GJ (p>0.0.5). Mean survival after insertion was 43±57 days (range, 1–252 days) among 38 patients for whom data were available. Fifty-six patients had a mean postprocedure hospital stay of 8.6±8.4 days (range, 0–45 days); 3 were outpatients and 10 patients died in the hospital. Successful gastropexy was confirmed on subsequent cross-sectional imaging in 22 of 25 patients. There were 25 tube maintenance issues that included catheter displacement and leakage, one patient experienced hemorrhage, and there were two deaths. All except one patient had satisfactory gastrostomy function. Conclusion: Effective G/GJ placement is possible in most patients with voluminous ascites provided ascites is drained and gastrocutaneous fistula formation occurs. Caution is advised; placement is generally for fragile terminal patients, and fluoroscopy or CT guidance is required

Beneficial effect of human anti-amyloid-β active immunization on neurite morphology and tau pathology

Anti-amyloid-β immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-β-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-β active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 µm) were more abnormal than those far from plaques (i.e. beyond 50 µm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-β immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-β immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-β immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's diseas

The Cortical Signature of Alzheimer's Disease: Regionally Specific Cortical Thinning Relates to Symptom Severity in Very Mild to Mild AD Dementia and is Detectable in Asymptomatic Amyloid-Positive Individuals

Alzheimer's disease (AD) is associated with neurodegeneration in vulnerable limbic and heteromodal regions of the cerebral cortex, detectable in vivo using magnetic resonance imaging. It is not clear whether abnormalities of cortical anatomy in AD can be reliably measured across different subject samples, how closely they track symptoms, and whether they are detectable prior to symptoms. An exploratory map of cortical thinning in mild AD was used to define regions of interest that were applied in a hypothesis-driven fashion to other subject samples. Results demonstrate a reliably quantifiable in vivo signature of abnormal cortical anatomy in AD, which parallels known regional vulnerability to AD neuropathology. Thinning in vulnerable cortical regions relates to symptom severity even in the earliest stages of clinical symptoms. Furthermore, subtle thinning is present in asymptomatic older controls with brain amyloid binding as detected with amyloid imaging. The reliability and clinical validity of AD-related cortical thinning suggests potential utility as an imaging biomarker. This “disease signature” approach to cortical morphometry, in which disease effects are mapped across the cortical mantle and then used to define ROIs for hypothesis-driven analyses, may provide a powerful methodological framework for studies of neuropsychiatric diseases.Psycholog