Rumination in PTSD as well as in Traumatized and Non-Traumatized Depressed Patients: A Cross-Sectional Clinical Study

Background: Although rumination is a key process in the onset and maintenance of depressive symptoms and a powerful predictor of persistent posttraumatic stress disorder (PTSD), little is known about the differences and similarities of rumination in these conditions. Previous research has not always differentiated between rumination and intrusive images. Aims: We sought to systematically evaluate rumination and to gather more information about the content and associated emotions in three patient groups (PTSD, and depressed with and without trauma; n = 65). Furthermore, we examined the interaction between rumination and another predominant intrusive cognition, intrusive image. Method: A multi-method assessment for rumination, including a rumination questionnaire and a rumination log (kept for one week), was employed. Results: Rumination was found to be complex and composed of subcomponents that are similar across the diagnostic groups. Rumination rarely stopped intrusive images and it made the participants feel worse. There were, however, also important differences: in PTSD, rumination always or often triggered intrusive images and the traumatized individuals (PTSD and depressed with trauma) ruminated more than non-traumatized depressed patients. Conclusions: The results corroborate the assumption of rumination being a transdiagnostic process, with similarities but also with important differences across diagnostic groups. Moreover, the findings support recent research on the intricate relationship between different types of intrusive cognition

p21-Activated Kinase 3 (PAK3) Is an AP-1 Regulated Gene Contributing to Actin Organisation and Migration of Transformed Fibroblasts

Activating Protein 1 (AP-1) plays a vital role in cell proliferation, differentiation and apoptosis. While de-regulation of AP-1 has been linked to many cancers, little is known regarding its downstream transcriptional targets that associate with cellular transformation. Previous studies identified PAK3, a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigate AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 expression in cJun/AP-1 over-expressing cells associated with a significant increase in PAK3 promoter activation. This increased promoter activity was lost when a single putative Jun binding site, which can bind AP-1 directly both in vitro and in vivo, was mutated. Further, inhibition of PAK3 using siRNA showed a regression in the cell morphology, migratory potential and actin organisation associated with AP-1 transformed cells. Our study is a first to describe a role for AP-1 in regulating PAK3 expression and suggest that PAK3 is an AP-1 target required for actin organization and migration observed in transformed cells

Deep, noninvasive imaging and surgical guidance of submillimeter tumors using targeted M13-stabilized single-walled carbon nanotubes

Highly sensitive detection of small, deep tumors for early diagnosis and surgical interventions remains a challenge for conventional imaging modalities. Second-window near-infrared light (NIR2, 950–1,400 nm) is promising for in vivo fluorescence imaging due to deep tissue penetration and low tissue autofluorescence. With their intrinsic fluorescence in the NIR2 regime and lack of photobleaching, single-walled carbon nanotubes (SWNTs) are potentially attractive contrast agents to detect tumors. Here, targeted M13 virus-stabilized SWNTs are used to visualize deep, disseminated tumors in vivo. This targeted nanoprobe, which uses M13 to stably display both tumor-targeting peptides and an SWNT imaging probe, demonstrates excellent tumor-to-background uptake and exhibits higher signal-to-noise performance compared with visible and near-infrared (NIR1) dyes for delineating tumor nodules. Detection and excision of tumors by a gynecological surgeon improved with SWNT image guidance and led to the identification of submillimeter tumors. Collectively, these findings demonstrate the promise of targeted SWNT nanoprobes for noninvasive disease monitoring and guided surgery.National Institutes of Health (U.S.). Center for Nanotechnology Excellence (Grant U54-CA119349-04)National Institutes of Health (U.S.). Center for Nanotechnology Excellence (Grant U54-CA151884)David H. Koch Institute for Integrative Cancer Research at MIT. Frontier Research Program (Kathy and Curt Marble Cancer Research Fund)National Institute of Environmental Health Sciences (Grant P30-ES002109)Marie D. & Pierre Casimir-Lambert FundAmar G. Bose Research Gran

The Priority Battle Over Returned and Repossessed Goods

Article 9 of the Uniform Commercial Code (the Code) governs secured transactions in personal property and fixtures.\u27 When more than one creditor has a security right in the same piece of collateral, the Article 9 rules of priority determine the order in which each creditor may satisfy his claim. The creditor with the highest priority rank gets paid first, and, if his claim exceeds the amount of the proceeds, junior creditors take nothing. Consequently, creditors want to determine their priority rights in collateral before extending credit. If one creditor determines that another creditor will have priority over its security interest, then it may wish to require substitute collateral or to increase the interest rate for the loan. Priority rules should be uniform and readily determinable so that creditors can allocate their risks in extending credit and adjust the terms of the credit accordingly. Because of disagreement among the courts, however, the priority rules governing interests in returned or repossessed goods are neither uniform nor readily determinable. The split among the courts centers on whether, under Section 9-306(5) of the Code, a perfected inventory financer subordinates an unperfected chattel paper financer The following example illustrates a typical situation in which priority conflicts arise

Etiology and Pathogenesis of Epithelial Ovarian Cancer

Ovarian cancer is complex disease composed of different histological grades and types. However, the underlying molecular mechanisms involved in the development of different phenotypes remain largely unknown. Epidemiological studies identified multiple exogenous and endogenous risk factors for ovarian cancer development. Among them, an inflammatory stromal microenvironment seems to play a critical role in the initiation of the disease. The interaction between such a microenvironment, genetic polymorphisms, and different epithelial components such as endosalpingiosis, endometriosis, and ovarian inclusion cyst in the ovarian cortex may induce different genetic changes identified in the epithelial component of different histological types of ovarian tumors. Genetic studies on different histological grades and types provide insight into the pathogenetic pathways for the development of different disease phenotypes. However, the link between all these genetic changes and the etiological factors remains to be established

An RNA Interference Lethality Screen of the Human Druggable Genome to Identify Molecular Vulnerabilities in Epithelial Ovarian Cancer

Targeted therapies have been used to combat many tumor types; however, few have effectively improved the overall survival in women with epithelial ovarian cancer, begging for a better understanding of this deadly disease and identification of essential drivers of tumorigenesis that can be targeted effectively. Therefore, we used a loss-of-function screening approach to help identify molecular vulnerabilities that may represent key points of therapeutic intervention. We employed an unbiased high-throughput lethality screen using a 24,088 siRNA library targeting over 6,000 druggable genes and studied their effects on growth and/or survival of epithelial ovarian cancer (EOC) cell lines. The top 300 “hits” affecting the viability of A1847 cells were rescreened across additional EOC cell lines and non-tumorigenic, human immortalized ovarian epithelial cell lines. Fifty-three gene candidates were found to exhibit effects in all tumorigenic cell lines tested. Extensive validation of these hits refined the list to four high quality candidates (HSPA5, NDC80, NUF2, and PTN). Mechanistic studies show that silencing of three genes leads to increased apoptosis, while HSPA5 silencing appears to alter cell growth through G1 cell cycle arrest. Furthermore, two independent gene expression studies show that NDC80, NUF2 and PTN were significantly aberrantly overexpressed in serous adenocarcinomas. Overall, our functional genomics results integrated with the genomics data provide an important unbiased avenue towards the identification of prospective therapeutic targets for drug discovery, which is an urgent and unmet clinical need for ovarian cancer

Weekly vs. Every-3-Week Paclitaxel and Carboplatin for Ovarian Cancer

BACKGROUND A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab. METHODS We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival. RESULTS A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%). CONCLUSIONS Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer

curatedOvarianData: clinically annotated data for the ovarian cancer transcriptome

This article introduces a manually curated data collection for gene expression meta-analysis of patients with ovarian cancer and software for reproducible preparation of similar databases. This resource provides uniformly prepared microarray data for 2970 patients from 23 studies with curated and documented clinical metadata. It allows users to efficiently identify studies and patient subgroups of interest for analysis and to perform meta-analysis immediately without the challenges posed by harmonizing heterogeneous microarray technologies, study designs, expression data processing methods and clinical data formats. We confirm that the recently proposed biomarker CXCL12 is associated with patient survival, independently of stage and optimal surgical debulking, which was possible only through meta-analysis owing to insufficient sample sizes of the individual studies. The database is implemented as the curatedOvarianData Bioconductor package for the R statistical computing language, providing a comprehensive and flexible resource for clinically oriented investigation of the ovarian cancer transcriptome. The package and pipeline for producing it are available from http://bcb.dfci.harvard.edu/ovariancancer. Database URL: http://bcb.dfci.harvard.edu/ovariancance

CL100 expression is down-regulated in advanced epithelial ovarian cancer and its re-expression decreases its malignant potential

Although early stage ovarian cancer can be effectively treated with surgery and chemotherapy, the majority of cases present with advanced disease, which remains essentially incurable. Unfortunately, little is known about the genes important for the development and progression of this disease. In this study, the expression of 68 phosphatases was determined in immortalized ovarian epithelial cells (IOSE) and compared to ovarian cancer cell lines. CL100, a dual specificity phosphatase, displayed 10-25-fold higher expression in normal compared to malignant ovarian cell lines. Immunohistochemical staining of normal ovaries and 68 ovarian cancer specimens confirmed this differential expression. Re-expression of CL100 in ovarian cancer cells decreased adherent and non-adherent cell growth and induced phenotypic changes including loss of filopodia and lamellipodia with an associated decrease in cell motility. Induced expression of CL100 in ovarian cancer cells suppressed intraperitoneal tumor growth in nude mice. These results show for the first time that CL100 expression is altered in human ovarian cancer, that CL100 expression changes cell morphology and motility, and that it suppresses intraperitoneal growth of human ovarian epithelial cancer. These data suggest that down-regulation of CL100 may play a role in the progression of human ovarian cancer