Abundant copy-number loss of CYCLOPS and STOP genes in gastric adenocarcinoma

Background Gastric cancer, a leading cause of cancer death worldwide, has been little studied compared with other cancers that impose similar health burdens. Our goal is to assess genomic copy-number loss and the possible functional consequences and therapeutic implications thereof across a large series of gastric adenocarcinomas. Methods We used high-density single-nucleotide polymorphism microarrays to determine patterns of copy-number loss and allelic imbalance in 74 gastric adenocarcinomas. We investigated whether suppressor of tumorigenesis and/or proliferation (STOP) genes are associated with genomic copy-number loss. We also analyzed the extent to which copy-number loss affects Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS (CYCLOPS) genes–genes that may be attractive targets for therapeutic inhibition when partially deleted. Results The proportion of the genome subject to copy-number loss varies considerably from tumor to tumor, with a median of 5.5 %, and a mean of 12 % (range 0–58.5 %). On average, 91 STOP genes were subject to copy-number loss per tumor (median 35, range 0–452), and STOP genes tended to have lower copy-number compared with the rest of the genes. Furthermore, on average, 1.6 CYCLOPS genes per tumor were both subject to copy-number loss and downregulated, and 51.4 % of the tumors had at least one such gene. Conclusions The enrichment of STOP genes in regions of copy-number loss indicates that their deletion may contribute to gastric carcinogenesis. Furthermore, the presence of several deleted and downregulated CYCLOPS genes in some tumors suggests potential therapeutic targets in these tumors.Singapore. Ministry of Health (Duke-NUS Signature Research Programs)Singapore. Agency for Science, Technology and ResearchSingapore-MIT Allianc

MicroRNA-9 controls dendritic development by targeting REST

MicroRNAs (miRNAs) are conserved noncoding RNAs that function as posttranscriptional regulators of gene expression. miR-9 is one of the most abundant miRNAs in the brain. Although the function of miR-9 has been well characterized in neural progenitors, its role in dendritic and synaptic development remains largely unknown. In order to target miR-9 in vivo, we developed a transgenic miRNA sponge mouse line allowing conditional inactivation of the miR-9 family in a spatio-temporal-controlled manner. Using this novel approach, we found that miR-9 controls dendritic growth and synaptic transmission in vivo. Furthermore, we demonstrate that miR-9-mediated downregulation of the transcriptional repressor REST is essential for proper dendritic growth.Fil: Giusti, Sebastian Alejandro. Max Planck Institute of Psychiatry; AlemaniaFil: Vogl, Annette M.. Max Planck Institute of Psychiatry; AlemaniaFil: Brockmann, Marina M.. Max Planck Institute of Psychiatry; AlemaniaFil: Vercelli, Claudia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Rein, Martin L.. Max Planck Institute of Psychiatry; AlemaniaFil: Trümbach, Dietrich. Helmholtz Zentrum München; AlemaniaFil: Wurst, Wolfgang. Helmholtz Zentrum München; AlemaniaFil: Cazalla, Demian. University of Utah; Estados UnidosFil: Stein, Valentin. Universitaet Bonn; AlemaniaFil: Deussing, Jan M.. Max Planck Institute of Psychiatry; AlemaniaFil: Refojo, Damian. Max Planck Institute of Psychiatry; Alemani

Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma

Objective Hepatocellular carcinoma (HCC) is a heterogeneous disease with poor prognosis and limited methods for predicting patient survival. The nature of the immune cells that infiltrate tumours is known to impact clinical outcome. However, the molecular events that regulate this infiltration require further understanding. Here the ability of immune genes expressed in the tumour microenvironment to predict disease progression was investigated.MethodsUsing quantitative PCR, the expression of 14 immune genes in resected tumour tissues from 57 Singaporean patients was analysed. The nearest-template prediction method was used to derive and test a prognostic signature from this training cohort. The signature was then validated in an independent cohort of 98 patients from Hong Kong and Zurich. Intratumoural components expressing these critical immune genes were identified by in situ labelling. Regulation of these genes was analysed in vitro using the HCC cell line SNU-182.ResultsThe identified 14 immune-gene signature predicts patient survival in both the training cohort (p=0.0004 and HR=5.2) and the validation cohort (p=0.0051 and HR=2.5) irrespective of patient ethnicity and disease aetiology. Importantly, it predicts the survival of patients with early disease (stages I and II), for whom classical clinical parameters provide limited information. The lack of predictive power in late disease stages III and IV emphasises that a protective immune microenvironment has to be established early in order to impact disease progression significantly. This signature includes the chemokine genes CXCL10, CCL5 and CCL2, whose expression correlates with markers of T helper 1 (Th1), CD8(+) T and natural killer (NK) cells. Inflammatory cytokines (tumour necrosis factor α, interferon γ) and Toll-like receptor 3 ligands stimulate intratumoural production of these chemokines which drive tumour infiltration by T and NK cells, leading to enhanced cancer cell death.ConclusionA 14 immune-gene signature, which identifies molecular cues driving tumour infiltration by lymphocytes, accurately predicts survival of patients with HCC especially in early disease

Probing commitment in individuals with borderline personality disorder

Interpersonal problems are a core symptom of borderline personality disorder (BPD). In particular, patients with BPD exhibit a heightened sensitivity to cues of acceptance or rejection in their relationships. The current study investigated the psychological processes underpinning this heightened responsiveness. In a between-subjects design, we implemented a reactivity induction designed to trigger either acceptance or rejection of a partner in two separate groups, and measured the effects which this manipulation had upon 49 patients with BPD, as well as 52 control participants. The experimental paradigm required participants to repeatedly choose whether to coordinate with their partner on a decision-making task. When both players coordinate on the same option, both are rewarded. The experiment probed participants’ commitment to their partners: participants were sometimes presented with tempting opportunities to unilaterally defect from the coordination. The results show that participants in the BPD group were less committed than participants in the control group when exposed to the rejection manipulation

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

MicroRNA-224 Targets SMAD Family Member 4 to Promote Cell Proliferation and Negatively Influence Patient Survival

10.1371/journal.pone.0068744PLoS ONE87-POLN

Retroperitoneal liposarcomas: The experience of a tertiary Asian center

10.1186/1477-7819-9-12World Journal of Surgical Oncology9