T-plastin, a cytoskeletal protein with important function in axonal growth, acts as a modifier of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a common inherited disorder characterized by neurodegeneration of α-motor neurons. SMA is caused by mutation and/or deletion of the SMN1 gene that encodes the survival of motor neuron protein (SMN). Homozygous SMN1 deletion in unaffected persons is a rare event suggesting that the SMA phenotype is modified by other factors. The microarray expression analysis of the SMA discordant families revealed for the first time, a transcript that encodes for a cytoskeletal protein, namely T-plastin, to be the most up-regulated gene in asymptomatic vs. symptomatic SMN1-deleted sibs. A closer look to a possible involvement of T-plastin in SMA pathophysiology revealed exciting observations. First, T-plastin was found to be expressed at high levels in spinal cord and muscle of fetal and adult tissues by semi-quantitative PCR, an observation that provides a strong evidence for T-plastin implication in neuronal differentiation and neuromuscular maturation. Moreover, T-plastin associates with SMN as shown by Co-IP experiments, but this interaction, as demonstrated by in vitro binding assay, is mediated by another so far unknown protein. Second, T-plastin and SMN were found by immunofluorescence to co-localize along the axons, at branch points and at the growth cones in neurite-like extensions in differentiated PC12 cells. Interestingly, the T-plastin protein amount was found to be up-regulated in differentiated PC12 cells under NGF stimulation, an observation that might propose a possible function for T-plastin as substrate for signalling molecules. Moreover, under NGF stimulation, the affinity of T-plastin for SMN increased up to 50% suggesting that a transient complex might occur during neuronal differentiation that contributes to a specific role during this biological process. Third, the effect of T-plastin loss/overexpression in differentiated PC12 cells (cells presenting either shorter neurites when T-plastin was depleted or longer neurites when T-plastin was overexpressed) hints to a perturbation in the axon growth, guidance (and perhaps branching) due to the involvement of T-plastin in F-actin filament formation and stabilization. Interestingly, by in vitro experiments it has been observed that in differentiated PC12 cells expressing low amount of SMN protein, but overexpressing T-plastin, the length of the neurites was rescued at least in part by higher T-plastin levels. This suggests that a higher amount of T-plastin protein might help the growth cone structures to reach their target (the muscle in case of motor neurons). While all analyzed unaffected SMN1-deleted sibs expressed T-plastin in both peripheral blood and EBV-transformed lymphoblastoid cell lines, only 6.5% of the control population expressed T-plastin. In classical SMA patients, T-plastin was highly expressed in 5.9%, medium in 7.4% and very weak in 13.4%. Finally, 8% patients without SMN1 mutations expressed T-plastin. These data suggest that T-plastin expression in leukocytes happens as a rare event in humans and its expression in blood significantly correlates with an SMA protection. Nevertheless, not all blood-T-plastin-expressing SMN1-deleted individuals are SMA protected, which suggest a potential differential regulation in the spinal cord.The answer to the question by which mechanism T-plastin is expressed in unaffected sibs with homozygous absence of SMN1 gene or in control population and classical SMA patients, was not found. No correlation between the T-plastin expression and any mutation or DNA variation in the T-plastin coding region, promoter, 3'UTR or intron 1 was observed. Moreover, epigenetic analysis of the T-plastin regulatory region (promoter-first exon-first intron) revealed no differences in DNA modification level. These observations together with the haplotype analysis of two blocks described within the T-plastin genomic region in both SMA discordant families and control population, strongly suggest that likely a trans- rather than a cis-acting factor is responsible for the differential expression between SMA discordant sibs or between SMA discordant families and control population. In hope to find additional modifying genes or factors that are able to regulate T-plastin expression, a genome-wide scan analysis was performed in 42 SMA discordant families. Regions on chromosomes 3q, 7p, 16p and 22q, respectively, are suggestive for linkage and require further investigations, however, none of these reached a significant LOD score. Taken together, the discovery of the T-plastin protein as a modulator of the SMA phenotype provides the opportunity to identify novel regulatory mechanisms that may act specifically in motor neurons from asymptomatic sibs with SMN1 homozygous deletion

Project Management Information System: the Role and the Issues of Implementation

We are coping more and more with the project and project management in day by day life. Even if some activities are the similarly with common organization actions, the life cycle project activities request more information and more actions. So it is necessary to have some tools, methods and rules to manage a large amount of information which must be disseminated to numerous stakeholders. This need could be solved by project management information systems (PMIS). PMIS is a complex one, with various components which are depending on type of project, type of organization etc. The latest evolution of information and communication technology was favorable to our research field. Therefore, there are different tools to support the structure, automation and efficiency of PMIS. Moreover from several years it is spread the following notions: web-based project management, project management office, enterprise project management. So, we can see the fast evolution of this field. But, our paper will bring general ideas relating to project management information systems, like definition of PMIS, the project life cycle and the information needed of each stage, various tools to support the PMIS procedures. The characteristics, tools, trends will be our future research.project management, project management life cycle, project management information system, project management software

Pancreatic Cancer, Leptin, and Chemoresistance: Current Challenges

Pancreatic cancer (PC) remains a leading cause of cancer-related deaths. Currently, conventional chemotherapies have showed only limited benefits for PC patients. Main factors affecting PC treatment failures are due to late detection, lack of early symptoms and biomarkers, and the development of desmoplasia and chemoresistance. Various mechanisms have been implicated in PC chemoresistance that includes stem cells, epigenetic changes, and alteration of signaling pathways, among others. Obesity is a modifiable factor for PC risk, which is characterized by high levels of the adipokine leptin that is a proinflammatory, proangiogenic, survival factor that affects chemotherapy effectiveness. Here, we will discuss on the mechanisms of PC chemoresistance and the influence of obesity and leptin signaling. Furthermore, the potential use of nontoxic leptin antagonists as a novel sensitization strategy for PC chemotherapeutics will also be discussed

Aberrant STYK1 expression in ovarian cancer tissues and cell lines

<p>Abstract</p> <p>Background</p> <p>Overexpression of <it>STYK1</it>, a putative serine/threonine and tyrosine receptor protein kinase has been shown to confer tumorigenicity and metastatic potential to normal cells injected into nude mice. Mutation of a tyrosine residue in the catalytic STYK1 domain attenuates the tumorigenic potential of tumor cells <it>in vivo</it>, collectively, suggesting an oncogenic role for STYK1.</p> <p>Methods</p> <p>To investigate the role of STYK1 expression in ovarian cancer, a panel of normal, benign, and ovarian cancer tissues was evaluated for STYK1 immunoreactivity using STYK1 antibodies. In addition, mRNA levels were measured by reverse transcription PCR and real-time PCR of estrogen receptors, GPR30 and STYK1 following treatment of ovarian cell lines with estrogen or G1, a GPR30 agonist, as well as western analysis.</p> <p>Results</p> <p>Our data showed higher expression of STYK1 in cancer tissues versus normal or benign. Only normal or benign, and one cancer tissue were STYK1-negative. Moreover, benign and ovarian cancer cell lines expressed <it>STYK1 </it>as determined by RT-PCR. Estradiol treatment of these cells resulted in up- and down-regulation of <it>STYK1 </it>despite estrogen receptor status; whereas G-1, a GPR30-specific agonist, increased STYK1 mRNA levels higher than that of estradiol.</p> <p>Conclusion</p> <p>We conclude that <it>STYK1 </it>is expressed in ovarian cancer and is regulated by estrogen through a GPR30 hormone-signaling pathway, to the exclusion of estrogen receptor-alpha.</p

Endometrial carcinoma with ectopic human chorionic gonadotropin expression

• Aggressive course and treatment resistance characterize ectopic human chorionic gonadotropin. • Recurrence of endometrial cancer with ectopic hCG was treated with brachytherapy and EMACO. • The serum hCG level can serve as a marker in tumors with ectopic hCG expression

Emerging Biomarkers and Clinical Implications in Endometrial Carcinoma

Endometrial cancer (EmCa) is the most common type of gynecological cancer. EmCa is the fourth most common cancer in the United States, which has been linked to increased incidence of obesity. EmCa can be classified into two main types: Type I and Type II, which include the major histological subtypes. Type I EmCa is hormonally driven, less aggressive, and has a more favorable prognosis. In contrast, Type II EmCa grows independently of hormonal signals, is more aggressive, and generally has an unfavorable prognosis. Various tumor biomarkers [i.e., tumor suppressor p53, hypoxia-inducible factor 1-alpha (HIF1-α), human epidermal growth factor receptor 2 (HER2/neu), and vascular endothelial growth factor (VEGF)] have been identified in EmCa. Biomarkers of treatment effectiveness involve immunosuppressive factors targeted by microRNA (miRNA)-based therapy. However, there are no reliable biomarker tests for early detection of EmCa and treatment effectiveness. A potential new biomarker is Notch, Interleukin-1, leptin crosstalk outcome (NILCO) that could affect the progression of Type II EmCa. NILCO expression in EmCa might be dependent on patient’s obesity status. This chapter presents updated information on these, and other potential emerging biomarkers for EmCa, and discusses current challenges and clinical implications on this area of research

Applying of multivariate analysis to study the correlation of mercury and other trace elements distribution in soil from a city from NW Romania

The mercury (Hg) concentrations were evaluated in soils and perennial plants from four districts of Baia Mare city, a historical mining and ore processing center from NW Romania. The results showed that in 24% of the analysed soil samples the mercury concentrations exceeded the guideline value of 1.0 mg kg'1, established by the Romanian Legislation, while the median concentration was 0.70 mg kg'1, bellow the guideline values, but higher than the normal values for soil and the mean or median concentration in soils from other cities all over the world. In the perennial plants, the median concentration was 0.22 mg kg'1, value that exceed the maximum level of Hg (0.10 mg kg'1) established by European Directive 2002/32/EC for animal feed in order to prevent its transfer and further accumulation in the higher levels of food chain. Poor correlations were found between Hg and other elements such as As, Cd, Cu, Pb and Zn known as pollutants resulted from non-ferrous smelting activities, probably due to the different physicochemical properties of Hg that lead to a different dispersion patter compared to other metals emitted by the two smelters

Chemotherapy Used to Halt Lower GI Bleeding in a Rare Case of Metastatic Choriocarcinoma to the GI Tract

Choriocarcinoma, a nonseminomatous germ cell tumor, is a rare type of testicular malignancy that tends to occur in young males. It is, however, exceedingly rare for choriocarcinoma to involve the GI tract. In this article, we present a rare case of a 31-year-old male, diagnosed with choriocarcinoma of the left testes, along with several metastases to distant sites. The patient presented with headaches and severe lower GI bleeding due to metastases to the GI tract, which was eventually controlled with systemic chemotherapy, while requiring several units of packed RBCs during his admission to the hospital. An extensive literature review found very few cases of the occurrence of GI bleeding as a consequence of choriocarcinoma due to metastases to the GI tract