Translational Implications for Radiosensitizing Strategies in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current multimodal therapeutic strategies involve surgery, chemotherapy (CHT) and radiotherapy (RT), but despite the deeper knowledge of response mechanisms underpinning CHT treatment and the technological improvements that characterize RT, local failures and recurrence frequently occur. This review sums up the RMS classification and the management of RMS patients, with special attention to RT treatment and possible radiosensitizing strategies for RMS tumors. Indeed, RMS radioresistance is a clinical problem and further studies aimed at dissecting radioresistant molecular mechanisms are needed to identify specific targets to hit, thus improving RT-induced cytotoxicity.     

TMEM106B Acts as a Modifier of Cognitive and Motor Functions in Amyotrophic Lateral Sclerosis

The transmembrane protein 106B (TMEM106B) gene is a susceptibility factor and disease modifier of frontotemporal dementia, but few studies have investigated its role in amyotrophic lateral sclerosis. The aim of this work was to assess the impact of the TMEM106B rs1990622 (A–major risk allele; G–minor allele) on phenotypic variability of 865 patients with amyotrophic lateral sclerosis. Demographic and clinical features were compared according to genotypes by additive, dominant, and recessive genetic models. Bulbar onset was overrepresented among carriers of the AA risk genotype, together with enhanced upper motor neuron involvement and poorer functional status in patients harboring at least one major risk allele (A). In a subset of 195 patients, we found that the homozygotes for the minor allele (GG) showed lower scores at the Edinburgh Cognitive and Behavioral Amyotrophic Lateral Sclerosis Screen, indicating a more severe cognitive impairment, mainly involving the amyotrophic lateral sclerosis-specific cognitive functions and memory. Moreover, lower motor neuron burden predominated among patients with at least one minor allele (G). Overall, we found that TMEM106B is a disease modifier of amyotrophic lateral sclerosis, whose phenotypic effects encompass both sites of onset and functional status (major risk allele), motor functions (both major risk and minor alleles), and cognition (minor allele).     

Diet and Proteinuria: State of Art

Proteinuria is a broad term used to describe the pathological presence of proteins, including albumin, globulin, Bence-Jones protein, and mucoprotein in the urine. When persistent, proteinuria is a marker of kidney damage and represents a reliable predictor of the risk of progression of renal failure. Medical nutrition therapy is imperative for patients with proteinuria because it may slow the progression of renal disease. The aim of this review is to explore different nutritional approaches in the management of proteinuria and their influence on pathophysiological processes. As such, protein restriction is the main dietary intervention. Indeed, other management approaches are frequently used to reduce it regarding micro and macronutrients, but also the dietary style. Among these, the nutritional approach represents one of the most used and controversial interventions and the studies rarely take the form of randomized and controlled trials. With this work we aspire to analyze current clinical knowledge of how nutrition could influence proteinuria, potentially representing a useful tool in the management of proteinuric nephropathy.     

L-Carnitine Functionalization to Increase Skeletal Muscle Tropism of PLGA Nanoparticles

Muscular dystrophies are a group of rare genetic pathologies, encompassing a variety of clinical phenotypes and mechanisms of disease. Several compounds have been proposed to treat compromised muscles, but it is known that pharmacokinetics and pharmacodynamics problems could occur. To solve these issues, it has been suggested that nanocarriers could be used to allow controlled and targeted drug release. Therefore, the aim of this study was to prepare actively targeted poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) for the treatment of muscular pathologies. By taking advantage of the high affinity for carnitine of skeletal muscle cells due to the expression of Na⁺-coupled carnitine transporter (OCTN), NPs have been actively targeted via association to an amphiphilic derivative of L-carnitine. Furthermore, pentamidine, an old drug repurposed for its positive effects on myotonic dystrophy type I, was incorporated into NPs. We obtained monodispersed targeted NPs, with a mean diameter of about 100 nm and a negative zeta potential. To assess the targeting ability of the NPs, cell uptake studies were performed on C2C12 myoblasts and myotubes using confocal and transmission electron microscopy. The results showed an increased uptake of carnitine-functionalized NPs compared to nontargeted carriers in myotubes, which was probably due to the interaction with OCTN receptors occurring in large amounts in these differentiated muscle cells.     

Celiac Disease and Neurological Manifestations: From Gluten to Neuroinflammation

Celiac disease (CD) is a complex multi-organ disease with a high prevalence of extra-intestinal involvement, including neurological and psychiatric manifestations, such as cerebellar ataxia, peripheral neuropathy, epilepsy, headache, cognitive impairment, and depression. However, the mechanisms behind the neurological involvement in CD remain controversial. Recent evidence shows these can be related to gluten-mediated pathogenesis, including antibody cross-reaction, deposition of immune-complex, direct neurotoxicity, and in severe cases, vitamins or nutrients deficiency. Here, we have summarized new evidence related to gut microbiota and the so-called “gut-liver-brain axis” involved in CD-related neurological manifestations. Additionally, there has yet to be an agreement on whether serological or neurophysiological findings can effectively early diagnose and properly monitor CD-associated neurological involvement; notably, most of them can revert to normal with a rigorous gluten-free diet. Moving from a molecular level to a symptom-based approach, clinical, serological, and neurophysiology data might help to disentangle the many-faceted interactions between the gut and brain in CD. Eventually, the identification of multimodal biomarkers might help diagnose, monitor, and improve the quality of life of patients with “neuroCD”.     

Unraveling the Link between Interferon-α and Systemic Lupus Erythematosus: From the Molecular Mechanisms to Target Therapies

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with a wide range of clinical expressions. The kidney is often affected, usually within 5 years of the onset of SLE, and lupus nephropathy (LN) carries a high risk for increased morbidity. The clinical heterogeneity of the disease is accompanied by complex disturbances affecting the immune system with inflammation and tissue damage due to loss of tolerance to nuclear antigens and the deposition of immune complexes in tissues. Several studies have reported that in human SLE, there is an important role of the Type-I-interferons (INF) system suggested by the upregulation of INF-inducible genes observed in serial gene expression microarray studies. This review aims to describe the transduction pathways of Type-I-interferons, in particular INFα, and its immune-regulatory function in the pathogenesis of SLE and, in particular, in LN. In addition, recent novelties concerning biologic therapy in LN will be discussed.     

Cyclisation of Alkynyl Alcohols and Carboxylic Acids Mediated by N-Heterocyclic Carbene Copper(I) Complexes

The cyclisation of alkynyl alcohols and carboxylic acids in the presence of a [Cu(NHC)₂]X complex is reported. The reactions were carried out in technical grade toluene in the presence of air with a catalyst that is readily accessible. N-Heterocyclic carbenes are recognised for stabilising metal centres in a range of oxidation states, and this work further supports that NHCs can also be used as activation sites in air and moisture stable yet active catalysts.     

Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling

Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT₁ receptors and NADPH oxidase, and lower expression of AT₂, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.