Arak city governmental employees' life span experiences of weakness of culture of work: A qualitative study

The weakness of the culture of work and the tendency of people in the society to work poorly and inadequate performance of their duties and responsibilities is one of the problems of human societies. The present study examined the life span experiences of individuals in this field. Methods: This study was performed qualitatively, using phenomenological methods. Participates were selected from the staff and managers of Arak city governmental agencies and organizations. 42 participants were selected by purposeful sampling. The method of data collection was semi-structured interview which was recorded and rewritten with the consent of the participants and was analyzed by colazzi method. Results: Data analysis resulted in the extraction of six main categories and several subcategories. The main categories included lack of organizational justice, change of intrinsic values of work, weakness of personality system, Weakness motivational system, Weakness socialization and poor growth of spirit of intellect. Conclusion: The present study, by describing the weakness of the culture of work, provided a new understanding of individuals’ experiences of this phenomenon. It also links the origins of such an event to the individual factors in addition to structural factors, which are mutually interconnected. Therefore, it is suggested that in order to change the culture of work and to achieve an excellent and progressive culture of work, at the same time, it is necessary to modify both middle-level and large-scale community structures and mechanisms, as well as to reinforce, educate, and change its individual and personal contexts

Human GM3 Synthase Attenuates Taxol-Triggered Apoptosis Associated with Downregulation of Caspase-3 in Ovarian Cancer Cells

BACKGROUND: Taxol (paclitaxel) inhibits proliferation and induces apoptosis in a variety of cancer cells, but it also upregulates cytoprotective proteins and/or pathways that compromise its therapeutic efficacy. MATERIALS AND METHOD: The roles of GM3 synthase (α2,3-sialyltransferase, ST3Gal V) in attenuating Taxol-induced apoptosis and triggering drug resistance were determined by cloning and overexpressing this enzyme in the SKOV3 human ovarian cancer cell line, treating SKOV3 and the transfectants (SKOV3/GS) with Taxol and determining apoptosis, cell survival, clonogenic ability, and caspase-3 activation. RESULTS: In this report, we demonstrated that Taxol treatment resulted in apoptosis which was associated with caspase-3 activation. Taxol treatment upregulated the expression of human GM3 synthase, an enzyme that transfers a sialic acid to lactosylceramide. Moreover, we cloned the full-length GM3 synthase gene and showed for the first time that forced expression of GM3 synthase attenuated Taxol-induced apoptosis and increased resistance to Taxol in SKOV3 cells. CONCLUSIONS: GM3 synthase overexpression inhibited Taxol-triggered caspase-3 activation, revealing that upregulation of GM3 synthase prevents apoptosis and hence reduces the efficacy of Taxol therapy

c-FLIP, a Novel Biomarker for Cancer Prognosis, Immunosuppression, Alzheimer’s Disease, Chronic Obstructive Pulmonary Disease (COPD), and a Rationale Therapeutic Target

Dysregulation of c-FLIP (cellular FADD-like IL-1β-converting enzyme inhibitory protein) has been shown in several diseases including cancer, Alzheimer’s disease, and chronic obstructive pulmonary disease (COPD). c-FLIP is a critical anti-cell death protein often overexpressed in tumors and hematological malignancies and its increased expression is often associated with a poor prognosis. c-FLIP frequently exists as long (c-FLIPL) and short (c-FLIPS) isoforms, regulates its anti-cell death functions through binding to FADD (FAS associated death domain protein), an adaptor protein known to activate caspases-8 and -10 and links c-FLIP to several cell death regulating complexes including the death-inducing signaling complex (DISC) formed by various death receptors. c-FLIP also plays a critical role in necroptosis and autophagy. Furthermore, c-FLIP is able to activate several pathways involved in cytoprotection, proliferation, and survival of cancer cells through various critical signaling proteins. Additionally, c-FLIP can inhibit cell death induced by several chemotherapeutics, anti-cancer small molecule inhibitors, and ionizing radiation. Moreover, c-FLIP plays major roles in aiding the survival of immunosuppressive tumor-promoting immune cells and functions in inflammation, Alzheimer’s disease (AD), and chronic obstructive pulmonary disease (COPD). Therefore, c-FLIP can serve as a versatile biomarker for cancer prognosis, a diagnostic marker for several diseases, and an effective therapeutic target. In this article, we review the functions of c-FLIP as an anti-apoptotic protein and negative prognostic factor in human cancers, and its roles in resistance to anticancer drugs, necroptosis and autophagy, immunosuppression, Alzheimer’s disease, and COPD

The Signature Center Initiative for the Cure of Glioblastoma

poster abstractGlioblastoma multiforme (GBM, World Health Organization/WHO grade IV) is the most common form of brain cancer in the central nervous system. Although conventional treatment-surgery, radiation, and temozolomide-is somewhat effective in adults, overall survival is still < 15 months. In pediatric patients, morbidity due to GBM is the highest among all pediatric cancers. In the context of brain cancers, new and existing therapeutics typically fail due to heterogeneity of genetic mutations within tumors, and because biologically effective doses of drug cannot be delivered to the primary site and invasive perimeter of the tumor due to the blood brain barrier. The Signature Center Initiative to Cure GBM is a funding mechanism that supports a research portal to foster investigations of the Brain Tumor Working Group for development of effective treatments for the eradication of GBM. The overall mission of the Signature Center Initiative is to: 1. Interrogate the molecular mechanisms of GBM biology and develop interventions that result in improved duration and quality of life for our patients. 2. Stimulate consistent and productive exchange of ideas between clinicians and basic scientists while employing bench-to-bedside and bedside-to-bench strategies to generate and prioritize scientific questions. 3. Provide infrastructure and mentorship needed to successfully compete for external funding. 4. Engage the community through patient advocacy to positively impact brain cancer patient outcomes and enhance philanthropic initiatives. The Brain Tumor Working Group brings together scientists committed to engaging in a team-based approach to study GBM biology. Infrastructure required to advance in vivo humanized intracranial tumor models, drug delivery, target validation, and development of new therapeutic strategies are in place. Additionally a patient sample pipeline to obtain, analyze, and distribute primary patient GBM specimens from the operating room to the research laboratory has been established. In year one of funding, over $70,000 in pilot project funding derived from the Signature Center Initiative and private donations has been distributed to the membership. The Brain Tumor Working Group meets in both small and large group formats to strategize experimental design and grant submissions. A network of basic scientists and clinicians has been developed that provides an effective forum for addressing clinically relevant questions related to GBM. A team-based approach, scientific expertise, and continued development of infrastructure provide our membership with a critical foundation to obtain new knowledge related to understanding how GBM cells evade therapy. In the future, this information can be applied to development of effective treatments that will cure GBM

4-(4-Chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH) targets mRNA of the c-FLIP variants and induces apoptosis in MCF-7 human breast cancer cells

Cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor for the tumor necrosis factor-related apoptosis-inducing ligand TRAIL and in drug resistance in human malignancies. c-FLIP is an antagonist of caspases-8 and -10, which inhibits apoptosis and is expressed as long (c-FLIPL) and short (c-FLIPS) splice forms. c-FLIP is often overexpressed in various human cancers, including breast cancer. Several studies have shown that silencing c-FLIP by specific siRNAs sensitizes cancer cells to TRAIL and anticancer agents. However, systemic use of siRNA as a therapeutic agent is not practical at present. In order to reduce or inhibit c-FLIP expression, small molecules are needed to allow targeting c-FLIP without inhibiting caspases-8 and -10. We used a small molecule inhibitor of c-FLIP, 4-(4-chloro-2-methylphenoxy)-N-hydroxybutanamide (CMH), and show that CMH, but not its inactive analog, downregulated c-FLIPL and c-FLIPS mRNA and protein levels, caused poly(ADP-ribose) polymerase (PARP) degradation, reduced cell survival, and induced apoptosis in MCF-7 breast cancer cells. These results revealed that c-FLIP is a critical apoptosis regulator that can serve as a target for small molecule inhibitors that downregulate its expression and serve as effective targeted therapeutics against breast cancer cells

Emerging targets for glioblastoma stem cell therapy

Glioblastoma multiforme (GBM), designated as World Health Organization (WHO) grade IV astrocytoma, is a lethal and therapy-resistant brain cancer comprised of several tumor cell subpopulations, including GBM stem cells (GSCs) which are believed to contribute to tumor recurrence following initial response to therapies. Emerging evidence demonstrates that GBM tumors are initiated from GSCs. The development and use of novel therapies including small molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of GSCs, immunotherapy, and non-coding microRNAs may provide better means of treating GBM. Identification and characterization of GSC-specific signaling pathways would be necessary to identify specific therapeutic targets which may lead to the development of more efficient therapies selectively targeting GSCs. Several signaling pathways including mTOR, AKT, maternal embryonic leucine zipper kinase (MELK), NOTCH1 and Wnt/β-catenin as well as expression of cancer stem cell markers CD133, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain GSC properties. Moreover, the data published in the Cancer Genome Atlas (TCGA) specifically demonstrated the activated PI3K/AKT/mTOR pathway in GBM tumorigenesis. Studying such pathways may help to understand GSC biology and lead to the development of potential therapeutic interventions to render them more sensitive to chemotherapy and radiation therapy. Furthemore, recent demonstration of dedifferentiation of GBM cell lines into CSC-like cells prove that any successful therapeutic agent or combination of drugs for GBM therapy must eliminate not only GSCs, but the differentiated GBM cells and the entire bulk of tumor cells

Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs

AbstractCancer stem cells (CSCs) or cancer initiating cells (CICs) maintain self-renewal and multilineage differentiation properties of various tumors, as well as the cellular heterogeneity consisting of several subpopulations within tumors. CSCs display the malignant phenotype, self-renewal ability, altered genomic stability, specific epigenetic signature, and most of the time can be phenotyped by cell surface markers (e.g., CD133, CD24, and CD44). Numerous studies support the concept that non-stem cancer cells (non-CSCs) are sensitive to cancer therapy while CSCs are relatively resistant to treatment. In glioblastoma stem cells (GSCs), there is clonal heterogeneity at the genetic level with distinct tumorigenic potential, and defined GSC marker expression resulting from clonal evolution which is likely to influence disease progression and response to treatment. Another level of complexity in glioblastoma multiforme (GBM) tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs, and the potential for non-GSCs to revert (dedifferentiate) to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell population. Moreover, exposure of the differentiated GBM cells to therapeutic doses of temozolomide (TMZ) or ionizing radiation (IR) increases the GSC pool both in vitro and in vivo. This review describes various subtypes of GBM, discusses the evolution of CSC models and epigenetic plasticity, as well as interconversion between GSCs and differentiated non-GSCs, and offers strategies to potentially eliminate GSCs

DNA Repair Defects in Sarcomas

DNA repair pathway is considered to be one of the most important mechanisms that protect cells from intrinsic and extrinsic stresses. It has been established that DNA repair activity has a crucial role in the way that cancer cells respond to treatment. Sarcomas are a group of tumors with mesenchymal origin in which their association with DNA repair aberrations has been reported in numerous studies. Special attention has been focused on exploiting these alterations to improve the patient’s overall survival and overcome drug resistance in cancer. While there is a large degree of heterogeneity among different types of sarcomas, DNA repair alteration is found to be a common defect in the majority of patients. In this chapter, we will introduce and review some of the most important dysregulated components involved in the DNA repair system, and discuss their association with tumorigenesis, cancer aggressiveness, drug resistance, and overall prognosis in the patients with sarcomas

Vascular and Cardiac Adult Stem Cell Therapy Center

poster abstractThe mission of the Vascular and Cardiac Adult Stem Cell Therapy Center (VC-CAST) is the discovery and clinical translation of therapies involving transplantation of adult stem cells into patients with debilitating diseases. To accomplish this, VC-CAST fosters multidisciplinary research collaborations that address both biology of adult stem cells that are readily available, and the translation of their study from the laboratory into clinical trials. The use of such cells is highly feasible, and not ethically controversial, as they are derived from readily-available tissues such as fat and bone marrow. Since its inception, VC-CAST projects have been multidisciplinary, involving multiple clinical as well as basic departments of the School of Medicine. VC-CAST projects are also collaborative, with most of the projects having one or more industrial partners. A key partnership has also been established by the creation of the Veterans Affairs Center for Regenerative Medicine (VACRM) at the Roudebush VA Medical Center in Indianapolis, which will provide a unique referral site focusing on research and implementation of first-in-human trials in the fields of poor circulation, arthritis, wound healing, diabetes, and emphysema. Given the focus of VC-CAST researchers on translation, the center is active in pursuit of intellectual property that is critical to building corporate engagement and thus the enablement of translation to clinical trials. Signature center funding has allowed IUPUI investigators to try high-risk, high-reward ideas, which could not otherwise be funded readily, via either NIH or venture-capital methods. Most of these experiments are still ongoing, but have already led to discoveries of potentially critical significance to patients. The novelty of some of these discoveries promises to attract new funding, as well as to provide bases for potential licensing revenues and startup opportunities. This poster will highlight several of these projects, representative of center activities in their collaborative, multidisciplinary and translational and potentially commercializable aspects. Some key projects are as follows: • Based on recent completion of the Phase I/II clinical trial, “Stem cell Angiogenesis to promote limb salVagE (SAVE), a new randomized Phase III clinical trial testing the use of one’s own bone marrow-derived stem cells to save legs from amputation has been initiated, with Dr. Murphy as the national PI. • Adipose Stem Cells for Peripheral Arterial Disease. • Endometrial Regenerative Cells for Peripheral Arterial Disease. • Adipose Stem Cells for treatment of Heart Attack and prevention of Heart Failure. • Adipose Stem Cells for Emphysema and other Lung Diseases • Adipose Stem Cells for Prevention and Treatment of Diabetes • Isolation and Characterization of Endothelial and Mesenchymal Stem Cells from Term Human Placenta. • Isolation and Characterization of Endothelial Colony Forming Cells (ECFCs) from Human Adult Blood Vessel

Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC