Pragmatics, Theory of Mind and executive functions in schizophrenia: Disentangling the puzzle using machine learning

OBJECTIVE:Schizophrenia is associated with a severe impairment in the communicative-pragmatic domain. Recent research has tried to disentangle the relationship between communicative impairment and other domains usually impaired in schizophrenia, i.e. Theory of Mind (ToM) and cognitive functions. However, the results are inconclusive and this relationship is still unclear. Machine learning (ML) provides novel opportunities for studying complex relationships among phenomena and representing causality among multiple variables. The present research explored the potential of applying ML, specifically Bayesian network (BNs) analysis, to characterize the relationship between cognitive, ToM and pragmatic abilities in individuals with schizophrenia and healthy controls, and to identify the cognitive and pragmatic abilities that are most informative in discriminating between schizophrenia and controls. METHODS:We provided a comprehensive assessment of different aspects of pragmatic performance, i.e. linguistic, extralinguistic, paralinguistic, contextual and conversational, ToM and cognitive functions, i.e. Executive Functions (EF)-selective attention, planning, inhibition, cognitive flexibility, working memory and speed processing-and general intelligence, in a sample of 32 individuals with schizophrenia and 35 controls. RESULTS:The results showed that the BNs classifier discriminated well between patients with schizophrenia and healthy controls. The network structure revealed that only pragmatic Linguistic ability directly influenced the classification of patients and controls, while diagnosis determined performance on ToM, Extralinguistic, Paralinguistic, Selective Attention, Planning, Inhibition and Cognitive Flexibility tasks. The model identified pragmatic, ToM and cognitive abilities as three distinct domains independent of one another. CONCLUSION:Taken together, our results confirmed the importance of considering pragmatic linguistic impairment as a core dysfunction in schizophrenia, and demonstrated the potential of applying BNs in investigating the relationship between pragmatic ability and cognition

Conservation of Paleontological Finds: the Restoration Materials of the “Problematica Verrucana”

The materials used in the historical restoration of a fossil collection named “Problematica Verrucana”, have been studied in order to contribute to the creation of a catalogue of restoration materials used in the past. Due to the complexity of the mixtures used with different purposes to restore fossil finds, an extractive technique has been employed in order to separate the compounds soluble in solvents with different polarities. Using this procedure several components, even when found in small amounts, have been identified. The chemical composition of the organic and inorganic compounds used in the restoration material has been determined using extractive procedure, FT-IR and 1H-NMR spectroscopies. A preliminary macroscopic characterisation and mineralogical and petrographical analyses have also been performed on the inorganic filling materials found in several samples. The different compositions of various materials used in the restoration of this fossil collection might be related to the particular conservative and esthetic functions of the product applied on the find

Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation

The loss of functional beta-cell mass in type 2 diabetes (T2D) is associated with molecular events that include beta-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several beta-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects beta-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in beta-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human beta-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the beta-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects beta-cells from apoptosis through a CRTC1-dependent mechanism

Magnetically Driven Bioreactors as new Tools in Drug Delivery

The pharmacological properties of many drugs can be improved by drug delivery systems able to drive therapeutic agents to target regions. The use of carriers, in fact, may reduce possible cytotoxic effects of drugs and increase their bioavailability at the site of action, thus improving the efficacy and the safety of treatments. Therefore, we have developed an erythrocyte-based drug delivery system (erythro-magneto-HA virosome), which has the potential to be magnetically guided to specific sites and to fuse with target cells. These engineered erythrocytes have demonstrated in previous work a very high in vitro capability to release anticancer drugs directly inside target cells. Because the erythro-magneto-HA virosomes (EMHVs) proved to be promising carriers, we decided to investigate in more details the effectiveness and safety of this erythrocyte-based drug delivery system. We evaluated the ability of the EMHVs to be specifically localized in vivo to desired sites by means of an external magnetic field and to protect an anticancer drug such as 5-Aza-2\u27-deoxycytidine from degradation. Additionally we have assessed the ability of the EMHVs to act as bioreactors and to convert the pro-drug 5-Aza-2\u27-deoxycytidine into an active drug. Finally, we have studied the interaction of the EMHVs with the host immune system. The pro-drug 5-Aza-2\u27-deoxycytidine has short half-life when systemically injected and needs to be phosphorylated to become an active drug. We found that when inside the engineered erythrocytes it is protected by degradation and is transformed in its active form thus becoming readily available for uptake by the targeted cells. Moreover, we have observed that the EMHVs used didn\u27t cause either a cell-mediated or a humoral immune response in host mice having the same haplotype of the donors. These findings suggest that erythro-magneto-HA virosomes are a safe and useful drug delivery system that may offer numerous advantages for several clinical application

Level of HER2/neu amplification in primary tumours and metastases in HER2-positive breast cancer and survival after trastuzumab therapy

Abstract Background The level of HER2/neu amplification may vary widely in breast cancers with HER2/neu alteration. The clinical significance of this phenomenon is still unclear. This study was aimed to explore the level of HER2/neu amplification in primary tumours and metastases in HER2-positive metastatic breast cancer (MBC) and its potential impact on survival after a trastuzumab-containing therapy. Methods We retrospectively identified MBC patients treated with a trastuzumab-containing therapy and performed dual-colour FISH on tumour samples from either primary tumour and/or metastasis in a central laboratory. Results We retrieved 110 tumour samples from 91 patients and included 79 tumour samples (primary = 56; metastasis = 23) from 63 patients in the final analysis. We found higher level of HER2/neu amplification in the metastases than in the primary tumours (median HER2/CEP17 ratio: 10.5 vs 7.0, respectively). In 69% of patients ( n = 16) with two tumour samples, the level of HER2/neu amplification was higher in the metastasis than in the paired primary tumour (median HER2/CEP17 ratio: 10.9 vs 8.3, respectively, p = 0.004). The incremental gain in level of HER2/neu amplification was associated with significantly shorter OS after trastuzumab-containing therapy ( p = 0.023, HR 1.014, CI95%: 1.002–1.025). Conclusions The level of HER2/neu amplification tends to increase from the primary tumour to the paired metastases in a significant proportion of patients with HER2-positive MBC. This phenomenon, although still not completely understood, could lead to a shorter OS after trastuzumab therapy

Synthesis and preliminary in vitro evaluation of DOTA-Tenatumomab conjugates for theranostic applications in tenascin expressing tumors

Tenatumomab is an anti-tenascin murine monoclonal antibody previously used in clinical trials for delivering radionuclides to tumors by both pre-targeting (biotinylated Tenatumomab within PAGRIT) and direct 131Iodine labeling approaches. Here we present the synthesis and in vitro characterization of three Tenatumomab conjugates to bifunctional chelating agents (NHS-DOTA, NCS-DOTA and NCS-DTPA). Results indicate ST8198AA1 (Tenatumomab-DOTAMA, derived by conjugation of NHS-DOTA), as the most promising candidate in terms of conjugation rate and yield, stability, antigen immunoreactivity and affinity. Labeling efficiency of the different chelators was investigated with a panel of cold metals indicating DOTAMA as the best chelator. Labeling of Tenatumomab-DOTAMA was then optimized with several metals and stability performed confirms suitability of this conjugate for further development. ST8198AA1 represents an improvement of the previous antibody forms because the labeling with radionuclides like 177Lu or 64Cu would allow theranostic applications in patients bearing tenascin expressing tumors

Antibody drug conjugates with hydroxamic acid cargos for histone deacetylase (HDAC) inhibition.

The bioconjugation of hydroxamic acids to antibodies has been made possible through a non-cleavable linker based on the p-mercaptobenzyl alcohol structure that releases hydroxamates in the cells

Pediatric tuberculosis in Italian children: Epidemiological and clinical data from the Italian register of pediatric tuberculosis

Tuberculosis (TB) is one of the leading causes of death worldwide. Over the last decades, TB has also emerged in the pediatric population. Epidemiologic data of childhood TB are still limited and there is an urgent need of more data on very large cohorts. A multicenter study was conducted in 27 pediatric hospitals, pediatric wards, and public health centers in Italy using a standardized form, covering the period of time between 1 January 2010 and 31 December 2012. Children with active TB, latent TB, and those recently exposed to TB or recently adopted/immigrated from a high TB incidence country were enrolled. Overall, 4234 children were included; 554 (13.1%) children had active TB, 594 (14.0%) latent TB and 3086 (72.9%) were uninfected. Among children with active TB, 481 (86.8%) patients had pulmonary TB. The treatment of active TB cases was known for 96.4% (n = 534) of the cases. Overall, 210 (39.3%) out of these 534 children were treated with three and 216 (40.4%) with four first-line drugs. Second-line drugs where used in 87 (16.3%) children with active TB. Drug-resistant strains of Mycobacterium tuberculosis were reported in 39 (7%) children. Improving the surveillance of childhood TB is important for public health care workers and pediatricians. A non-negligible proportion of children had drug-resistant TB and was treated with second-line drugs, most of which are off-label in the pediatric age. Future efforts should concentrate on improving active surveillance, diagnostic tools, and the availability of antitubercular pediatric formulations, also in low-endemic countries