Stemness Features in Liver Cancer

Heterogeneity is a cardinal hallmark of cancer, including primary liver cancer (PLC), and occurs at different layers including putative cell-of-origin. Current evidence suggests that within cellular subpopulations in PLC there are stem-like cells, the cancer stem cells (CSCs). The CSC concept has been recently proposed as an explanation of such intra-tumor heterogeneity. According to this model, CSCs are responsible for tumor initiation, recurrence, metastasis as well as drug-resistance. However, although the CSC hypothesis is intriguing and supported by a large number of experimental studies, there are still open questions regarding the origin of putative CSCs. Since chemo-resistance and recurrence represent major issues in PLC treatment, the development of new therapeutic strategies is needed, for which a good understanding of tumor behavior and in particular of CSCs biology is an imperative prerequisite. In this review we summarize the regulatory pathways that support CSC features in PLC. Moreover, we highlight the key features of hepatic CSC, in terms of enhanced drug-resistance, increased metastatic potential and metabolic rearrangement. Knowledge of the molecular mechanisms underlying CSC biology may provide novel options for PLC combination therapies

Sacrospinous Ligament Suspension With Transobturator Mesh Versus Sacral Colpopexy For Genital Prolapse

To compare the safety and efficacy of abdominal sacral colpopexy and sacrospinous ligament suspension with the use of vaginal mesh for apical prolapse. METHOD: This retrospective study was conducted from 2005 to 2012 and included 89 women with apical prolapse who underwent surgery. Assessments included pre- and postoperative Pelvic Organ Prolapse Quantification (POP-Q) stage. Rates of objective cure and immediate/late complications were compared. RESULTS: In total, 41 of the 89 women underwent sacrospinous ligament suspension, and 48 of the women underwent abdominal sacral colpopexy. A total of 40.4% of the women had vault prolapse (p=0.9361). Most of them had no complications (93.2%) (p=0.9418). Approximately 30% of the women had late complications; local pain was the main symptom and was found only in women who underwent the abdominal procedure (25.6%) (p=0.001). Only the women who were submitted to the vaginal procedure had mesh exposure (18.4%). The objective success rate and the rate of anterior vaginal prolapse (p=0.2970) were similar for both techniques. CONCLUSION: Sacrospinous ligament suspension was as effective and had a similar objective success rate as abdominal sacral colpopexy for the treatment of apical prolapse. Sacrospinous ligament suspension performed with the use of vaginal mesh in the anterior compartment was effective in preventing anterior vaginal prolapse after surgery.71948749

Environmental Impact of Dietary Choices: Role of the Mediterranean and Other Dietary Patterns in an Italian Cohort

Background: Current scientific literature suggests healthy dietary patterns may have less environmental impact than current consumption patterns, but most of the studies rely on theoretical modeling. The aim of this study was to assess the impact on resources (land, water, and energy) use and greenhouse gas (GHG) emissions of healthy dietary patterns in a sample of Italian adults. Methods: Participants (n = 1806) were recruited through random sampling in the city of Catania, southern Italy. Dietary consumption was assessed through a validated food frequency questionnaire (FFQ); dietary patterns were calculated through dietary scores. The specific environmental footprints of food item production/processing were obtained from various available life-cycle assessments; a sustainability score was created based on the impact of the four environmental components calculated. Results: The contribution of major food groups to the environmental footprint showed that animal products (dairy, egg, meat, and fish) represented more than half of the impact on GHG emissions and energy requirements; meat products were the stronger contributors to GHG emissions and water use, while dairy products to energy use, and cereals to land use. All patterns investigated, with the exception of the Dietary Approach to Stop Hypertension (DASH), were linearly associated with the sustainability score. Among the components, higher adherence to the Mediterranean diet and Alternate Diet Quality Index (AHEI) was associated with lower GHG emissions, dietary quality index-international (DQI-I) with land use, while Nordic diet with land and water use. Conclusions: In conclusion, the adoption of healthy dietary patterns involves less use of natural resources and GHG emissions, representing eco-friendlier options in Italian adults

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma : An Overview of Current Perspectives

Cholangiocarcinoma (CCA) is a deadly tumor without an effective therapy. Unique metabolic and bioenergetics features are important hallmarks of tumor cells. Metabolic plasticity allows cancer cells to survive in poor nutrient environments and maximize cell growth by sustaining survival, proliferation, and metastasis. In recent years, an increasing number of studies have shown that specific signaling networks contribute to malignant tumor onset by reprogramming metabolic traits. Several evidences demonstrate that numerous metabolic mediators represent key-players of CCA progression by regulating many signaling pathways. Besides the well-known Warburg effect, several other different pathways involving carbohydrates, proteins, lipids, and nucleic acids metabolism are altered in CCA. The goal of this review is to highlight the main metabolic processes involved in the cholangio-carcinogeneis that might be considered as potential novel druggable candidates for this disease

Macrophage MerTK promotes profibrogenic cross-talk with hepatic stellate cells via soluble mediators

Background & Aims: Activation of Kupffer cells and recruitment of monocytes are key events in fibrogenesis. These cells release soluble mediators which induce the activation of hepatic stellate cells (HSCs), the main fibrogenic cell type within the liver. Mer tyrosine kinase (MerTK) signaling regulates multiple processes in macrophages and has been implicated in the pathogenesis of non-alcoholic steatohepatitis-related fibrosis. In this study, we explored if MerTK activation in macrophages influences the profibrogenic phenotype of HSCs. Methods: Macrophages were derived from THP-1 cells or differentiated from peripheral blood monocytes towards MerTK+/CD206+/CD163+/CD209- macrophages. The role of MerTK was assessed by pharmacologic and genetic inhibition. HSC migration was determined in Boyden chambers, viability was measured by the MTT assay, and proliferation was evaluated by the BrdU incorporation assay. Results: Gas-6 induced MerTK phosphorylation and Akt activation in macrophages, and these effects were inhibited by UNC569. During polarization, MerTK+/CD206+/CD163+/CD209- macrophages exhibited activation of STAT3, ERK1/2, p38 and increased expression of VEGF-A. Activation of MerTK in THP-1 macrophages induced a secretome which promoted a significant increase in migration, proliferation, viability and expression of profibrogenic factors in HSCs. Similarly, conditioned medium from MerTK+ macrophages induced a significant increase in cell migration, proliferation, STAT3 and p38 phosphorylation and upregulation of IL-8 expression in HSCs. Moreover, conditioned medium from Gas-6-stimulated Kupffer cells induced a significant increase in HSC proliferation. These effects were specifically related to MerTK expression and activity in macrophages, as indicated by pharmacologic inhibition and knockdown experiments. Conclusions: MerTK activation in macrophages modifies the secretome to promote profibrogenic features in HSCs, implicating this receptor in the pathogenesis of hepatic fibrosis. Lay summary: Fibrosis represents the process of scarring occurring in patients with chronic liver diseases. This process depends on production of scar tissue components by a specific cell type, named hepatic stellate cells, and is regulated by interaction with other cells. Herein, we show that activation of MerTK, a receptor present in a population of macrophages, causes the production of factors that act on hepatic stellate cells, increasing their ability to produce scar tissue

Frataxin participates to the hypoxia-induced response in tumors

Defective expression of frataxin is responsible for the degenerative disease Friedreich's ataxia. Frataxin is a protein required for cell survival since complete knockout is lethal. Frataxin protects tumor cells against oxidative stress and apoptosis but also acts as a tumor suppressor. The molecular bases of this apparent paradox are missing. We therefore sought to investigate the pathways through which frataxin enhances stress resistance in tumor cells. We found that frataxin expression is upregulated in several tumor cell lines in response to hypoxic stress, a condition often associated with tumor progression. Moreover, frataxin upregulation in response to hypoxia is dependent on hypoxia-inducible factors expression and modulates the activation of the tumor-suppressor p53. Importantly, we show for the first time that frataxin is in fact increased in human tumors in vivo. These results show that frataxin participates to the hypoxia-induced stress response in tumors, thus implying that modulation of its expression could have a critical role in tumor cell survival and/or progression

Olfactory groove meningioma: report of 99 cases surgically treated at the Catholic University School of Medicine, Rome

OBJECTIVE: We reviewed our series of olfactory groove meningiomas (OGMs) with the aim to relate the surgical approach with outcome and to define clinical and pathologic predictors of prognosis. METHODS: Ninety-nine patients who underwent 113 craniotomies at our Institution between 1984 and 2010 were entered this study. The relationship between surgical approach (bifrontal, fronto-orbito-basal, and pterional) and either tumor diameter, extent of tumor resection, complication rate, need of reoperation, and Karnofsky Performance Status (KPS) was analyzed. The impact of age ( 64 70 vs. > 70 years), sex, tumor diameter (< 6 vs. 65 6 cm), pre- and postoperative KPS (< 80 vs. 65 80), Simpson grade (I-II vs. III-IV), and World Health Organization (WHO) histologic grade (I vs. II-III) on survival was assessed. Kaplan-Meier survival curves were plotted and differences in survival between groups of patients were compared. A multivariate analysis adjusted for age, pre- and postoperative KPS, Simpson grade, tumor diameter, and WHO histologic grade also was performed. RESULTS: The fronto-orbito-basal approach (n = 22) allowed a significantly greater percentage of Simpson I-II removals than the bifrontal (n = 70) and pterional approach (n = 21) (P = 0.0354 and P = 0.0485, respectively). The risk of life-threatening complications trended to be lower in patients operated upon either via the fronto-orbito-basal and via the pterional approach than in those treated via the bifrontal approach. Retraction-related brain swelling did not occur in any case after the fronto-orbito-basal approach (P = 0.0384); however, this approach was associated with a greater rate of cerebrospinal fluid leak (P = 0.0011). Among prognostic factors, age 64 70 years (P = 0.0044), tumor diameter <6 cm (P = 0.0455), pre- and postoperative KPS 65 80 (both P < 0.0001), Simpson grade I-II (P = 0.0096), and WHO histologic grade I (P = 0.0112) were significantly associated with longer overall survival. Age (P = 0.0393) and WHO histologic grade (P = 0.0418) emerged as independent prognostic factors for overall survival on multivariate analysis. CONCLUSION: In the largest series of OGMs published to date, the bifrontal approach was associated with a greater risk of life-threatening complications compared with the lateral pterional and fronto-orbito-basal approaches. The fronto-orbito-basal approach provided greater chances of total tumor removal than the bifrontal and pterional approaches. Two independent factors for overall survival of patients with OGM were identified, namely age and WHO grade

A tale of two community networks program centers: Operationalizing and assessing CBPR principles and evaluating partnership outcomes

BACKGROUND: Community Networks Program (CNP) centers are required to use a community-based participatory research (CBPR) approach within their specific priority communities. Not all communities are the same and unique contextual factors and collaborators’ priorities shape each CBPR partnership. There are also established CBPR and community engagement (CE) principles shown to lead to quality CBPR in any community. However, operationalizing and assessing CBPR principles and partnership outcomes to understand the conditions and processes in CBPR that lead to achieving program and project level goals is relatively new in the science of CBPR. OBJECTIVES: We sought to describe the development of surveys on adherence to and implementation of CBPR/CE principles at two CNP centers and examine commonalities and differences in program- versus project-level CBPR evaluation. METHODS: A case study about the development and application of CBPR/CE principles for the Missouri CNP, Program for the Elimination of Cancer Disparities, and Minnesota CNP, Padres Informados/Jovenes Preparados, surveys was conducted to compare project versus program operationalization of principles. Survey participant demographics were provided by CNP. Specific domains found in CBPR/CE principles were identified and organized under an existing framework to establish a common ground. Operational definitions and the number of survey items were provided for each domain by CNP. CONCLUSION: There are distinct differences in operational definitions of CBPR/CE principles at the program and project levels of evaluation. However, commonalities support further research to develop standards for CBPR evaluation across partnerships and at the program and project levels

Experimental study of the collision 11Be + 64Zn around the Coulomb barrier

In this paper details of the experimental procedure and data analysis of the collision of 11Be+64Zn around the Coulomb barrier are described and discussed in the framework of different theoretical approaches. In a previous work [ A. Di Pietro et al. Phys. Rev. Lett. 105 022701 (2010)], the elastic scattering angular distribution of the collisions 9, 10Be+64Zn as well as the angular distribution for the quasielastic scattering and transfer/breakup cross sections for the 11Be+64Zn reaction were briefly reported. The suppression of the quasielastic angular distribution in the Coulomb-nuclear interference angular region observed in the collision of the 11Be halo nucleus with respect to the other two beryllium isotopes was interpreted as being caused by a long-range absorption owing to the long decay length of the 11Be wave function. In this paper, new continuum-discretized coupled-channel calculations of the 11Be+64Zn reaction are reported in the attempt to interpret the effect of coupling with the breakup channels on the measured cross sections. The calculations show that the observed suppression of the Coulomb-nuclear interference peak is caused by a combined effect of Coulomb and nuclear couplings to the breakup channels

Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells

<p>Abstract</p> <p>Background</p> <p>Pancreatic cancer is a complex genetic disorder that is characterized by rapid progression, invasiveness, resistance to treatment and high molecular heterogeneity. Various agents have been used in clinical trials showing only modest improvements with respect to gemcitabine-based chemotherapy, which continues to be the standard first-line treatment for this disease. However, owing to the overwhelming molecular alterations that have been reported in pancreatic cancer, there is increasing focus on targeting molecular pathways and networks, rather than individual genes or gene-products with a combination of novel chemotherapeutic agents.</p> <p>Methods</p> <p>Cells were transfected with small interfering RNAs (siRNAs) targeting the individual CK2 subunits. The CK2 protein expression levels were determined and the effect of its down-regulation on chemosensitization of pancreatic cancer cells was investigated.</p> <p>Results</p> <p>The present study examined the impact on cell death following depletion of the individual protein kinase CK2 catalytic subunits alone or in combination with gemcitabine and the molecular mechanisms by which this effect is achieved. Depletion of the CK2α or -α' subunits in combination with gemcitabine resulted in marked apoptotic and necrotic cell death in PANC-1 cells. We show that the mechanism of cell death is associated with deregulation of distinct survival signaling pathways. Cellular depletion of CK2α leads to phosphorylation and activation of MKK4/JNK while down-regulation of CK2α' exerts major effects on the PI3K/AKT pathway.</p> <p>Conclusions</p> <p>Results reported here show that the two catalytic subunits of CK2 contribute differently to enhance gemcitabine-induced cell death, the reduced level of CK2α' being the most effective and that simultaneous reduction in the expression of CK2 and other survival factors might be an effective therapeutic strategy for enhancing the sensitivity of human pancreatic cancer towards chemotherapeutic agents.</p