Duodenal gangliocytic paraganglioma, a rare entity among GEP-NET: a case report with immunohistochemical and molecular study

Gastroenteropancreatic neuroendocrine tumors are the most incident neuroendocrine tumors. In the new WHO classification (2010) the embryological derivation of each neoplastic entity is one of the most important parameters. Gangliocytic Paraganglioma is a tumor originating in the hindgut, a rare neoplasm, generally affecting the second portion of the duodenum, the majority of which are benign. Cases of gangliocytic paraganglioma with local metastasis or local recurrence have also been reported. We describe a GP in a 48-year-old caucasian male with an unusual site (4th portion of duodenum) and an interesting immunohistochemical and molecular pattern. In particular, we examined the expression of some neuroendocrine markers and a marker of neuronal differentiation, NeuroD1, whose expression can help to better understand the nature of this neoplasia. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/372095916109680

Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles

Colon cancer is one of the leading causes of cancer-related death worldwide and the therapy with 5-fluorouracil (5-FU) is mainly limited due to resistance. Recently, we have demonstrated that nucleolar stress upon 5-FU treatment leads to the activation of ribosome-free rpL3 (L3) as proapoptotic factor. In this study, we analyzed L3 expression profile in colon cancer tissues and demonstrated that L3 mRNA amount decreased with malignant progression and the intensity of its expression was inversely related to tumor grade and Bcl-2/Bax ratio. With the aim to develop a combined therapy of 5-FU plus plasmid encoding L3 (pL3), we firstly assessed the potentiation of the cytotoxic effect of 5-FU on colon cancer cells by L3. Next, 10 μM 5-FU and 2 μg of pL3 were encapsulated in biocompatible nanoparticles (NPs) chemically conjugated with HA to achieve active tumor-targeting ability in CD44 overexpressing cancer cells. We showed the specific intracellular accumulation of NPs in cells and a sustained release for 5-FU and L3. Analysis of cytotoxicity and apoptotic induction potential of combined NPs clearly showed that the 5-FU plus L3 were more effective in inducing apoptosis than 5-FU or L3 alone. Furthermore, we show that the cancer-specific chemosensitizer effect of combined NPs may be dependent on L3 ability to affect 5-FU efflux by controlling P-gp (P-glycoprotein) expression. These results led us to propose a novel combined therapy with the use of 5-FU plus L3 in order to establish individualized therapy by examining L3 profiles in tumors to yield a better clinical outcomes

A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype

Mutations in the diastrophic dysplasia sulfate transporter (DTDST or SLC26A2) cause a family of recessively inherited chondrodysplasias including, in order of decreasing severity, achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia. The gene encodes a widely distributed sulfate/chloride antiporter of the cell membrane whose function is crucial for the uptake of inorganic sulfate, which is needed for proteoglycan sulfation. To provide new insights in the pathogenetic mechanisms leading to skeletal and connective tissue dysplasia and to obtain an in vivo model for therapeutic approaches to DTD, we generated a Dtdst knock-in mouse with a partial loss of function of the sulfate transporter. In addition, the intronic neomycine cassette in the mutant allele contributed to the hypomorphic phenotype by inducing abnormal splicing. Homozygous mutant mice were characterized by growth retardation, skeletal dysplasia and joint contractures, thereby recapitulating essential aspects of the DTD phenotype in man. The skeletal phenotype included reduced toluidine blue staining of cartilage, chondrocytes of irregular size, delay in the formation of the secondary ossification center and osteoporosis of long bones. Impaired sulfate uptake was demonstrated in chondrocytes, osteoblasts and fibroblasts. In spite of the generalized nature of the sulfate uptake defect, significant proteoglycan undersulfation was detected only in cartilage. Chondrocyte proliferation and apoptosis studies suggested that reduced proliferation and/or lack of terminal chondrocyte differentiation might contribute to reduced bone growth. The similarity with human DTD makes this mouse strain a useful model to explore pathogenetic and therapeutic aspects of DTDST-related disorder

Issues related to typological fragility curves derivation starting from observed seismic damage

In this study typological fragility curves are proposed with a macro-seismic approach. To this scope, a stock of 56.338 residential masonry buildings struck by L’Aquila 2009 seismic sequence is analyzed, whose AeDES forms are archived within Da.D.O. platform, that is a web-gis database collecting the observed seismic damage data related to buildings surveyed after several Italian earthquakes. Moreover, issues significantly influencing the fragility curves derivation are in depth discussed. In particular, a criterion for the buildings stock completion adding undamaged and not surveyed buildings is proposed, based on the distributions known of the residential building typologies. Comparisons highlight that the database completion affects the resulting fragility curves, and in particular for low damage levels. Furthermore, it is shown how the fundamental parameters estimation, by using the Maximum Likelihood Estimation (MLE) method, is conspicuously influenced by the PGA intervals number (nint), that is an issue often ignored when fragility curves are derived. The numerical investigations show that, although a non-monotonic trend is observed, the fundamental parameters tend to converge to the asymptotic values as the nint of PGA increases, and that they are markedly dispersed when nint is low

Seismic risk analysis on masonry buildings damaged by L’Aquila 2009 and Emilia 2012 earthquakes

Earthquakes in the recent past continue to provide more and more information on the seismic behavior of existing buildings and on the related economic losses. For the reason it is interesting to compare the damage of buildings stocks archived after earthquakes survey activities. In this paper a study of the damage occurred on masonry buildings after L’Aquila 2009 and Emilia 2012 earthquakes is carried out, by considering the data available in the web-gis Da.D.O platform. Firstly, fragility curves are illustrated and compared by considering the vulnerability classes of Da.D.O. (Class A, Class B and Class C1). Then, an approach is proposed in order to evaluate the total Expected Annual Loss (EALtot) and its contributions due to the several damage level (D1, …, D5). The preliminary obtained results show that, with reference to the two masonry buildings stocks considered, the higher contribution to the (EALtot) is given by the damage level D3, that may be considered as the life safety limit state. In the case analyzed, the corresponding EALD3 results almost equal to 1/3 of EALtot

Deletion of the mental retardation gene Gdi1 impairs associative memory and alters social behavior in mice

Non-specific mental retardation (NSMR) is a common human disorder characterized by mental handicap as the only clinical symptom. Among the recently identified MR genes is GDI1, which encodes αGdi, one of the proteins controlling the activity of the small GTPases of the Rab family in vesicle fusion and intracellular trafficking. We report the cognitive and behavioral characterization of mice carrying a deletion of Gdi1. The Gdi1-deficient mice are fertile and anatomically normal. They appear normal also in many tasks to assess spatial and episodic memory and emotional behavior. Gdi1-deficient mice are impaired in tasks requiring formation of short-term temporal associations, suggesting a defect in short-term memory. In addition, they show lowered aggression and altered social behavior. In mice, as in humans, lack of Gdi1 spares most central nervous system functions and preferentially impairs only a few forebrain functions required to form temporal associations. The general similarity to human mental retardation is striking, and suggests that the Gdi1 mutants may provide insights into the human defect and into the molecular mechanisms important for development of cognitive function

Typological seismic losses assessment by damaged masonry buildings after L’Aquila 2009 and Emilia 2012 earthquakes

In this paper a seismic risk analysis of masonry buildings based on damage data from the 2009 L'Aquila and 2012 Emilia earthquakes. The seismic vulnerability is described by fragility curves from which economic loss curves are derived for each representative typological class of masonry buildings. The information on the buildings was collected by the Italian Civil Protection Department with the AeDES form and available in the Observed Damage Database (D.a.D.O.). The reliability of the database considered, however, was improved by carrying out a process of estimating undamaged buildings from data from the 15th ISTAT census. Finally, for each damage level, according to EMS-98 scale, a procedure to derive the Expected Annual Loss is presented, so as to express its percentage contribution in the seismic risk assessment

Rewiring the T cell-suppressive cytokine landscape of the tumor microenvironment: a new frontier for precision anti-cancer therapy

T lymphocytes that infiltrate the tumor microenvironment (TME) often fail to function as effective anti-cancer agents. Within the TME, cell-to-cell inhibitory interactions play significant roles in dampening their anti-tumor activities. Recent studies have revealed that soluble factors released in the TME by immune and non-immune cells, as well as by tumor cells themselves, contribute to the exacerbation of T cell exhaustion. Our understanding of the cytokine landscape of the TME, their interrelationships, and their impact on cancer development is still at its early stages. In this review, we aim to shed light on Interleukin (IL) -6, IL-9, and IL-10, a small group of JAK/STAT signaling-dependent cytokines harboring T cell-suppressive effects in the TME and summarize their mechanisms of action. Additionally, we will explore how advancements in scientific research can help us overcoming the obstacles posed by cytokines that suppress T cells in tumors, with the ultimate objective of stimulating further investigations for the development of novel therapeutic strategies to counteract their tumor-promoting activities