Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation

Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene and a major cause of intellectual disability in females. No cure exists for RTT. We previously reported that the behavioural phenotype and brain mitochondria dysfunction are widely rescued by a single intracerebroventricular injection of the bacterial toxin CNF1 in a RTT mouse model carrying a truncating mutation of the MeCP2 gene (MeCP2-308 mice). Given the heterogeneity of MECP2 mutations in RTT patients, we tested the CNF1 therapeutic efficacy in a mouse model carrying a null mutation (MeCP2-Bird mice). CNF1 selectively rescued cognitive defects, without improving other RTT-related behavioural alterations, and restored brain mitochondrial respiratory chain complex activity in MeCP2-Bird mice. To shed light on the molecular mechanisms underlying the differential CNF1 effects on the behavioural phenotype, we compared treatment effects on relevant signalling cascades in the brain of the two RTT models. CNF1 provided a significant boost of the mTOR activation in MeCP2-308 hippocampus, which was not observed in the MeCP2-Bird model, possibly explaining the differential effects of CNF1. These results demonstrate that CNF1 efficacy depends on the mutation beared by MeCP2-mutated mice, stressing the need of testing potential therapeutic approaches across RTT models.     

Influence of a High-Impact Multidimensional Rehabilitation Program on the Gut Microbiota of Patients with Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative inflammatory condition mediated by autoreactive immune processes. Due to its potential to influence host immunity and gut-brain communication, the gut microbiota has been suggested to be involved in the onset and progression of MS. To date, there is no definitive cure for MS, and rehabilitation programs are of the utmost importance, especially in the later stages. However, only a few people generally participate due to poor support, knowledge, and motivation, and no information is available on gut microbiota changes. Herein we evaluated the potential of a brief high-impact multidimensional rehabilitation program (B-HIPE) in a leisure environment to affect the gut microbiota, mitigate MS symptoms and improve quality of life. B-HIPE resulted in modulation of the MS-typical dysbiosis, with reduced levels of pathobionts and the replenishment of beneficial short-chain fatty acid producers. This partial recovery of a eubiotic profile could help counteract the inflammatory tone typically observed in MS, as supported by reduced circulating lipopolysaccharide levels and decreased populations of pro-inflammatory lymphocytes. Improved physical performance and fatigue relief were also found. Our findings pave the way for integrating clinical practice with holistic approaches to mitigate MS symptoms and improve patients’ quality of life.     

Is Handedness Recognition Automatic? A Study Using a Simon-Like Paradigm.

The authors used a modified Simon task (J. R. Simon, 1969) to assess the automatic recognition of handedness. Participants responded to the color of a circle in the center of the photograph of a right or a left hand, displayed in the center of the computer screen. A regular Simon effect was found for back views, whereas a reverse Simon effect was found for palm views. This pattern of results was found when the forearm was present (Experiment 2), when 1 finger at a time was rendered invisible (Experiment 3), and when the hands were connected to a body image (Experiment 4). When the hands were cut at the wrist, no effect emerged (Experiment 1). These findings suggest an automatic encoding of the relative position of the hand in relation to the body (imaginary or real) rather than the automatic encoding of handedness. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

AdipoRon and Other Adiponectin Receptor Agonists as Potential Candidates in Cancer Treatments

The high mortality rate together with an ever-growing number of annual cases have defined neoplastic disorders as “the real 21st-century disease”. Its dubious distinction also results from conventional therapy failure, which has made cancer an orphan disease. Therefore, innovative and alternative therapeutic strategies are mandatory. The ability to leverage human naturally occurring anti-tumor defenses has always represented a fascinating perspective, and the immuno blockage approval in cancer treatment represents in timeline the latest success. As a multifunctional organ, adipose tissue releases a large amount of adipokines having both carcinogenic and antitumor properties. The negative correlation between serum levels and risk for developing malignancies, as well as the huge number of existing preclinical studies, have identified adiponectin as a potential anticancer adipokine. Nevertheless, its usage in clinical has constantly clashed with the inability to reproduce a mimic synthetic compound. Between 2011 and 2013, two distinct adiponectin receptor agonists were recognized, opening new scenarios even in cancer. Here, we review the first orally active adiponectin receptor agonists AdipoRon, from the discovery to the anticancer evidence. Including our latest findings in osteosarcoma models, we summarize AdipoRon and other existing agonists state-of-art, questioning about the feasibility assessment of this strategy in cancer treatment.     

The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory?

Non-clear cell renal cell carcinomas are a miscellaneous group of tumors that include different histological subtypes, each one characterized by peculiarity in terms of genetic alteration, clinical behavior, prognosis, and treatment response. Because of their low incidence and poor enrollment in clinical trials, alongside their heterogeneity, additional efforts are required to better unveil the pathogenetic mechanisms and, consequently, to improve the treatment algorithm. Nowadays, tyrosine kinase inhibitors, mTOR and MET inhibitors, and even cisplatin-based chemotherapy and immunotherapy are potential weapons that are still under evaluation in this setting. Various biomarkers have been evaluated for detecting progression and monitoring renal cell carcinoma, but more studies are necessary to improve this field. In this review, we provide an overview on the molecular characteristics of this group of tumors and the recently published trials, giving an insight into what might become the future therapeutic standard in this complex world of non-clear cell kidney cancers.     

Circulating Tumor DNA Testing for Homology Recombination Repair Genes in Prostate Cancer: From the Lab to the Clinic

Approximately 23% of metastatic castration-resistant prostate cancers (mCRPC) harbor deleterious aberrations in DNA repair genes. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) therapy has shown improvements in overall survival in patients with mCRPC who harbor somatic and/or germline alterations of homology recombination repair (HRR) genes. Peripheral blood samples are typically used for the germline mutation analysis test using the DNA extracted from peripheral blood leucocytes. Somatic alterations can be assessed by extracting DNA from a tumor tissue sample or using circulating tumor DNA (ctDNA) extracted from a plasma sample. Each of these genetic tests has its own benefits and limitations. The main advantages compared to the tissue test are that liquid biopsy is a non-invasive and easily repeatable test with the value of better representing tumor heterogeneity than primary biopsy and of capturing changes and/or resistance mutations in the genetic tumor profile during disease progression. Furthermore, ctDNA can inform about mutation status and guide treatment options in patients with mCRPC. Clinical validation and test implementation into routine clinical practice are currently very limited. In this review, we discuss the state of the art of the ctDNA test in prostate cancer compared to blood and tissue testing. We also illustrate the ctDNA testing workflow, the available techniques for ctDNA extraction, sequencing, and analysis, describing advantages and limits of each techniques.     

N‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable,Selective Melatonin Receptor Ligands

The class of N‐(anilinoethyl)amides includes melatonin receptor ligands with varied subtype selectivity and intrinsic activity. One of these ligands, the MT₂‐selective partial agonist UCM765 (N‐{2‐[(3‐methoxyphenyl)phenylamino]ethyl}acetamide), had evidenced hypnotic effects in rodents at doses ≥40 mg kg^?1 (s.c.), in spite of its sub‐nanomolar affinity for human melatonin receptors. Supposing that its low in vivo potency could be due, at least in part, to metabolic liability in rat liver, UCM765 was incubated with rat liver S9 fraction and rat, mouse, or human microsomes, and the major metabolites were identified by LC–MS, synthesized, and in vitro tested for their affinity toward MT₁ and MT₂ receptors. The obtained information was exploited to design novel analogues of UCM765 that are more resistant to in vitro oxidative degradation, while maintaining a similar binding profile. The analogue UCM924 (N‐{2‐[(3‐bromophenyl)‐(4‐fluorophenyl)amino]ethyl}acetamide) displayed a binding profile similar to that of UCM765 on cloned human receptors (MT₂‐selective partial agonist) and a significantly longer half‐life in the presence of rat liver S9 fraction.     

Design of novel three-phase PCL/TZ–HA biomaterials for use in bone regeneration applications

The design of bioactive scaffold materials able to guide cellular processes involved in new-tissue genesis is key determinant in bone tissue engineering. The aim of this study was the design and characterization of novel multi-phase biomaterials to be processed for the fabrication of 3D porous scaffolds able to provide a temporary biocompatible substrate for mesenchymal stem cells (MSCs) adhesion, proliferation and osteogenic differentiation. The biomaterials were prepared by blending poly(ε-caprolactone) (PCL) with thermoplastic zein (TZ), a thermoplastic material obtained by de novo thermoplasticization of zein. Furthermore, to bioactivate the scaffolds, microparticles of osteoconductive hydroxyapatite (HA) were dispersed within the organic phases. Results demonstrated that materials and formulations strongly affected the micro-structural properties and hydrophilicity of the scaffolds and, therefore, had a pivotal role in guiding cell/scaffold interaction. In particular, if compared to neat PCL, PCL–HA composite and PCL/TZ blend, the three-phase PCL/TZ–HA showed improved MSCs adhesion, proliferation and osteogenic differentiation capability, thus demonstrating potential for bone regeneration.     

Influence of O contamination and Au cluster properties on the structural features of Si nanowires

Silicon nanowires (Si NWs) are the emerging nanostructures for future nanodevices. In this work we have prepared them by electron beam evaporation (EBE) through the vapor-liquid-solid (VLS) mechanism. We discuss the growth of epitaxial NWs by EBE and the possibility to control their orientation and length by changing the experimental conditions. Moreover, the effects of the surface contamination and of the Au cluster preparation on the NWs structural properties and density will be discussed. We demonstrate that any O contamination has to be avoided since just a very thin native SiO₂ layer stops ad-atom diffusion on the surface and inhibits the NWs growth. Au cluster preparation has a determinant role too: by varying the procedure for their formation, it is possible to change NWs density and length. In particular, we observed that by evaporating Au on the heated substrate, the droplets active to promote NW growth are immediately formed and a faster growth process starts. The growth rate is about a factor of 4 times higher than in the sample where the Au is evaporated at room temperature and the cluster formed after a subsequent thermal annealing. On the contrary, the slower process allows the atom arrangement and ordering in an epitaxial manner, and a precise control of NW orientation can be achieved.