Behaviour of a Geogrid Reinforced Embankment over Waste Material

The paper deals with the monitoring of a geogrid reinforced embankment, 5.0 m high and 600 m long, built to contain additional waste material in the municipal landfill in Modena (Northern Italy). The embankment was founded directly over the waste already placed in the landfill, consisting of\u27 compressible and dishomogeneus material, varying from solid urban waste to muddy industrial material. The geotechnical parameters assumed to characterize the fill soil and the waste material of the foundation soil are described. The settlements of the embankment and the forces and strains in the geogrids were monitored from the beginning of the construction until some months later. The instrumentation used in order to perform this control is described. The actual results are compared with those obtained from the design model and with other field tests concerning geogrid reinforced structures

Murine colon organoids as a novel model to study Trypanosoma cruzi infection and interactions with the intestinal epithelium

Chagas disease (CD) is a life-threatening illness caused by the parasite Trypanosoma cruzi (T. cruzi). With around seven million people infected worldwide and over 50,000 deaths per year, CD is a major public health issue in Latin America. The main route of transmission to humans is through a triatomine bug (vector-borne), but congenital and oral transmission have also been reported. The acute phase of CD presents mild symptoms but may develop into a long-lasting chronic illness, characterized by severely impaired cardiac, digestive, and neurological functions. The intestinal tissue appears to have a key role during oral transmission and chronic infection of CD. In this immune-privileged reservoir, dormant/quiescent parasites have been suggested to contribute to disease persistence, infection relapse, and treatment failure. However, the interaction between the intestinal epithelium and T. cruzi has not been examined in depth, in part, due to the lack of in vitro models that approximate to the biological and structural complexity of this tissue. Therefore, to understand the role played by the intestinal tissue during transmission and chronic infection, physiological models resembling the organ complexity are needed. Here we addressed this issue by establishing and characterizing adult stem cell-derived colonoid infection models that are clinically relevant for CD. 3D and 2D systems of murine intestinal organoids infected with T. cruzi Dm28c (a highly virulent strain associated with oral outbreaks) were analyzed at different time points by confocal microscopy. T. cruzi was able to invade and replicate in intestinal epithelial primary cells grown as intact organoids (3D) and monolayers (2D). The permissiveness to pathogen infection differed markedly between organoids and cell lines (primate and intestinal human cell lines). So far, this represents the first evidence of the potential that these cellular systems offer for the study of host-pathogen interactions and the discovery of effective anti-chagasic drugs.Agencia Nacional de Investigación e InnovaciónPasteur NetworkFOCEM (MERCOSUR Structural Convergence Fund

Modeling host-parasite interaction in chagas disease with murine intestinal organoids

Chagas disease (CD) is a potentially life-threatening illness caused by the parasite Trypanosoma cruzi (T. cruzi). With around seven million people infected worldwide and over 10,000 deaths per year, CD is a major public health issue in Latin America. The main route of transmission to humans is through a triatomine bug (vector-borne) and, to a minor extent, by blood transfusion, organ transplantation, laboratory accidents, congenitally and orally (food-borne). The acute phase of CD presents mild symptoms. If left untreated, it develops into a long-lasting chronic illness, characterized by severely impaired cardiac, digestive, and neurological functions. The intestinal tissue appears to have a key role during oral transmission and chronic infection of CD. In these immune-privileged reservoirs, dormant/quiescent parasites have been suggested to contribute to disease persistence, infection relapse, and treatment failure. However, the interaction between the intestinal epithelium and T. cruzi has not been examined in depth, in part, due to the lack of in vitro models resembling the biological and structural complexity of this organ. Therefore, to understand the pathophysiological role played by the intestinal tissue during transmission and chronic infection, we evaluated the progression of T. cruzi infection of murine colon organoids. In order to model CD, 3D and 2D systems of murine intestinal organoids were infected with T. cruzi Dm28c, a strain that has been associated with high virulence and oral outbreaks. At different time points, the presence and load of parasites in the organoids, as well as the host cell morphology were evaluated by confocal microscopy, and compared to those obtained with a classical infection model (Vero cells). We show that the parasite invades and replicates in intestinal epithelial primary cells grown as intact organoids (3D) and monolayers (2D). The permissiveness to pathogen infection differed markedly between the primary and the tumoral (Vero) cells. So far, this represents the first evidence of the potential of these nearly physiological cellular systems to study host-pathogen interaction for CD and/or for the future evaluation of anti-chagasic drugs.Agencia Nacional de Investigación e Innovación (ANII)FOCEM (MERCOSUR Structural Convergence Fund

Love’s askesis and fragility of human formation in Plato’s Symposium

Inspirado por Martha Nussbaum e tomando como referência a ideia formativa inerente à ascese amorosa, o artigo investiga o significado atribuído a Eros por Platão em O banquete. Primeiro, reconstruímos o discurso de Aristófanes, enfatizando o aspecto de dupla comédia da vida humana. Depois, analisamos o caráter formativo do discurso de Diotima em termos de um duplo ensinamento: o da sacerdotisa a Sócrates e o de Sócrates a nós. Em seguida, indicamos o quanto a dialética do amor, ao ter que responder à objeção de Alcibíades, conduz à mudança da postura de Sócrates à medida que a presença de Alcibíades o faz retornar ao mundo sensível. Por fim, destacamos a dimensão formativa da ascese do amor e da reversibilidade de papéis entre erasta e erômeno, amante e amado.Inspired by Martha Nussbaum and taking as its guideline the discussion on the formative idea inherent to the askesis of love, this paper investigates the meaning Plato attributes to Eros in the Symposium. First part reconstructs the speech from Aristophanes, emphasizing the double comedy of the human life. The second part summarizes the formative aspect of Diotima’s speech from the perspective of a double lesson: from the priestess to Socrates, and from him to ourselves. The third part tries to point out how much the dialectic of love, by having to respond to Alcibiades’ objection, is what leads to the change on Socrates’ posture, insofar as the presence of Alcibiades makes him to back into the sensible. Finally, the formative dimension of the askesis of love is highlighted, stressing how much it leads to the reversibility of roles between erasta and eromeno, between lover and beloved

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System

Context: Adrenal insufficiency (AI) is a life-threatening condition complicating heterogeneous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. Objective: This work aimed to describe the spectrum of drug-induced AI through adverse drug event reports received by the US Food and Drug Administration (FDA). Methods: A retrospective disproportionality analysis reporting trends of drug-induced AI was conducted on the FDA Adverse Event Reporting System (FAERS) (> 15 000 000 reports since 2004). AE reports were extracted from FAERS over the past 2 decades. Interventions included cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI, and signals of disproportionate reporting for drugs recorded in 10 or more cases as primary suspect. Results: We identified 8496 cases of AI: 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015 to 2020. We identified 56 compounds associated with substantial disproportionality: glucocorticoids (N = 1971), monoclonal antibodies (N = 1644, of which N = 1330 were associated with immune checkpoint inhibitors-ICIs), hormone therapy (N = 291), anti-infectives (N = 252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N = 169), and protein kinase inhibitors (N = 138). Cases of AI by glucocorticoids were stable in each 5-year period (22%-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010 to 2015 to 33% in 2015 to 2020. Conclusion: We provide a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for the urgent identification of predictive factors for drug-induced AI, and the establishment of screening and educational protocols for patients and caregivers

Regulation of miR-483-3p by the O-linked N-acetylglucosamine transferase links chemosensitivity to glucose metabolism in liver cancer cells

The miR-483-3p is upregulated in several tumors, including liver tumors, where it inhibits TP53-dependent apoptosis by targeting the pro-apoptotic gene BBC3/PUMA. The transcriptional regulation of the miR-483-3p could be driven by the β-catenin/USF1 complex, independently from its host gene IGF2, and we previously demonstrated that in HepG2 hepatoblastoma cells carrying wild-type TP53 the upregulation of the miR-483-3p overcomes the antitumoral effects of the tumor-suppressor miR-145-5p by a mechanism involving cellular glucose availability. Here we demonstrate that in HepG2 cells, the molecular link between glucose concentration and miR-483-3p expression entails the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which stabilizes the transcriptional complex at the miR-483 promoter. HepG2 cells showed reduced miR-483-3p expression and increased susceptibility to 5-fluorouracil (5-FU)-induced apoptosis in presence of the inhibitor of glycolysis 2-deoxy-D-glucose (2-DG). However, in vivo experiments showed that HepG2 cells with higher miR-483-3p expression were selected during tumor progression regardless of 5-FU treatment. Furthermore, treatment with 2-DG alone did not significantly reduce HepG2 xenograft load in immunodeficient mice. In conclusion, we show that in HepG2 cells glucose uptake increases the expression of the oncogenic miR-483-3p through the OGT pathway. This suggests that depletion of the miR-483-3p may be a valuable therapeutic approach in liver cancer patients, but the use of inhibitors of glycolysis to achieve this purpose could accelerate the selection of resistant neoplastic cell clones

Results and clinical interpretation of germline RET analysis in a series of patients with medullary thyroid carcinoma: The challenge of the variants of uncertain significance

Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively