Synuclein expression in the lizard Anolis carolinensis

The synuclein (syn) family comprises three proteins: alpha-, beta- and gamma-syns. In humans, they are involved in neurodegenerative diseases such as Parkinson's disease and in tumors. Members of the syn family were sequenced in representative species of all vertebrates and the comparative analysis of amino acid sequences suggests that syns are evolutionarily conserved, but information about their expression in vertebrate lineages is still scarce and completely lacking in reptiles. In this study, the expression of genes coding for alpha-, beta- and gamma-syns was analyzed in the green lizard Anolis carolinensis by semiquantitative RT-PCR and Western blot. Results demonstrate good expression levels of the three syns in the lizard nervous system, similarly to human syns. This, together with the high identity between lizard and human syns, suggests that these proteins fulfill evolutionarily conserved functions. However, differences between lizard and humans in the expression of syn variants (two different variants of gamma-syn were detected in A. carolinensis) and differences in some amino acids in key positions for the regulation of protein conformation and affinity for lipid and metal ions also suggest that these proteins may have acquired different functional specializations in the two lineages

Is type 2 diabetes really resolved after laparoscopic sleeve gastrectomy? Glucose variability studied by continuous glucose monitoring

The study was carried out on type 2 diabetic obese patients who underwent laparoscopic sleeve gastrectomy (LSG). Patients underwent regular glycemic controls throughout 3 years and all patients were defined cured from diabetes according to conventional criteria defined as normalization of fasting glucose levels and glycated hemoglobin in absence of antidiabetic therapy. After 3 years of follow-up, Continuous Glucose Monitoring (CGM) was performed in each patient to better clarify the remission of diabetes. In this study, we found that the diabetes resolution after LSG occurred in 40% of patients; in the other 60%, even if they showed a normal fasting glycemia and A1c, patients spent a lot of time in hyperglycemia. During the oral glucose tolerance test (OGTT), we found that 2 h postload glucose determinations revealed overt diabetes only in a small group of patients and might be insufficient to exclude the diagnosis of diabetes in the other patients who spent a lot of time in hyperglycemia, even if they showed a normal glycemia (<140 mg/dL) at 120 minutes OGTT. These interesting data could help clinicians to better individualize patients in which diabetes is not resolved and who could need more attention in order to prevent chronic complications of diabetes

Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism

Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pah(enu2) (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders

Malignant ventricular arrhythmias induction by programmed electrical stimulation of the right ventricular outflow tract only during type 1 brugada ECG maximization

OBJECTIVE: The role of electrophysiology study in Brugada syndrome (BS) sudden cardiac death risk stratification remains controversial and seems to depend on the phenotypic expression of the channelopathy. Ajmaline has a key role in the diagnosis of BS. We observed that programmed electrical stimulation (PES) of the right ventricular outflow tract (RVOT), only when type 1 BS ECG is unmasked by ajmaline administration, induces ventricular arrhythmias. CASE REPORT: We describe a case of ventricular fibrillation induction by PES of the RVOT when type 1 BS ECG is revealed by ajmaline, in a patient with a baseline dynamic intermittent type 1 and 2 BS ECG. CONCLUSIONS: The heterogeneous clinical presentations of BS are due to the underlying mechanisms. PES of the RVOT during positive ajmaline test maximizes the channelopathy and therefore sudden cardiac death risk-stratification in BS

Stem cell plasticity and dormancy in the development of cancer therapy resistance

Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drug-refractory cell populations, ultimately leading to therapy failure. The biological features of drug resistant cells are largely overlapping with those of cancer stem cells and include heterogeneity, plasticity, self-renewal ability, and tumor-initiating capacity. Moreover, drug resistance is usually characterized by a suppression of proliferation that can manifest as quiescence, dormancy, senescence, or proliferative slowdown. Alterations in key cellular pathways such as autophagy, unfolded protein response or redox signaling, as well as metabolic adaptations also contribute to the establishment of drug resistance, thus representing attractive therapeutic targets. Moreover, a complex interplay of drug resistant cells with the micro/macroenvironment and with the immune system plays a key role in dictating and maintaining the resistant phenotype. Recent studies have challenged traditional views of cancer drug resistance providing innovative perspectives, establishing new connections between drug resistant cells and their environment and indicating unexpected therapeutic strategies. In this review we discuss recent advancements in understanding the mechanisms underlying drug resistance and we report novel targeting agents able to overcome the drug resistant status, with particular focus on strategies directed against dormant cells. Research on drug resistant cancer cells will take us one step forward toward the development of novel treatment approaches and the improvement of relapse-free survival in solid and hematological cancer patients

Making the Communication of CCS more "human"

CCS communication has proven a tough challenge, particularly for the difficulty in raising interest for the technology, which is still unknown to the majority of the population, and for the complexity of conveying information about its potential for reducing emissions. In this paper we present a research based effort for bringing CCS nearer to people, through visual material developed taking into account emotional needs related to the technology. The production of a short introductory film on CCS is illustrated and its testing with a sample of 700 high school students

Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer

Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system

Synuclein expression in the lizard Anolis carolinensis

The synuclein (syn) family comprises three proteins: alpha-, beta- and gammasyn. In mammals alpha- and beta- syn are primarily expressed in the brain where they are localized in pre-synaptic terminals while gamma-syn is mainly expressed in the peripheral nervous system. In humans, syns are involved in neurodegenerative diseases with high social impact such as Parkinson’s disease and tumors. However, the normal cellular functions of the three syns have not yet been fully clarified. Members of the syn family were sequenced in representative species of all vertebrates and the comparative sequence analysis suggested that syns are evolutionary conserved, although several differences in the number of genes encoding syn proteins have been identified in different taxa. On this knowledge, non mammalian vertebrates may represent useful models to understand the evolution and the physiological role of these proteins. Our research focused on the evolution of syns with the aim of analyzing their molecular and cellular expression in the CNS of representative vertebrates. A first study was published on alpha-syn distribution in the CNS of the carp Cyprinus carpio, by using antibodies against human alpha-syn [1]. Results showed that alpha-syn proteins are expressed to different levels in the brain and spinal cord regions of the carp. Differently from mammals, neuronal expression was mainly localized in cholinergic cell populations. At intracellular level, alpha-syn expression was localized in neuronal perikarya,varicose axons and terminal varicosities, but never in the cell nucleus. Apart from the above differences, the comparison between carp and mammals also suggested similarities in the distribution at the level of definite cholinergic systems. Thus, alpha-syn possibly modulates similar molecular pathways in cholinergic systems of phylogenetically distant vertebrates as teleosts and mammals. Current model of our comparative analysis is the lizard Anolis carolinensis, given the availability of sequenced genome in this species. Three syn genes (snca, sncb and sncg) have been identified in the lizard and their expression was studied by RT-PCR and Western blot experiments. Preliminary results on syns expression in the CNS are here reported

Lung Cancer Organoids. The Rough Path to Personalized Medicine

Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalised therapeutic approach for lung cancer patients

Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells

To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1–4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven’t been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity