875 research outputs found
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
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
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
In situ detection of unexpected patterns of mutant p53 gene expression in non-small cell lung cancers
RASSF1A and the Taxol Response in Ovarian Cancer
The RASSF1A tumor suppressor gene is frequently inactivated by promoter methylation in human tumors. The RASSF1A protein forms an endogenous complex with tubulin and promotes the stabilization of microtubules. Loss of RASSF1A expression sensitizes cells to microtubule destabilizing stimuli. We have observed a strong correlation between the loss of RASSF1A expression and the development of Taxol resistance in primary ovarian cancer samples. Thus, we sought to determine if RASSF1A levels could dictate the response to Taxol and whether an epigenetic therapy approach might be able to reverse the Taxol resistant phenotype of RASSF1A negative ovarian tumor cells. We found that knocking down RASSF1A expression in an ovarian cancer cell line inhibited Taxol-mediated apoptosis and promoted cell survival during Taxol treatment. Moreover, using a combination of small molecule inhibitors of DNA Methyl Transferase enzymes, we were able restore RASSF1A expression and Taxol sensitivity. This identifies a role for RASSF1A in modulating the tumor response to Taxol and provides proof of principal for the use of epigenetic therapy to overcome Taxol resistance
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
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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
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
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