Factors related to swallowing oral phase

Introduction: Efficacy of swallowing oral phase is often impaired in dysphagic patients and may impact on pharyngeal stage, meal consumption, nutritional status and quality of life. However, factors related to oral phase of swallowing have been little studied. Matherial & Methods: Thirty-nine adult patients with dysphagia of different etiology were enrolled. FEES and the Test of Mastication and Swallowing Solids (TOMASS) were performed. The Penetration-Aspiration scale, the Yale Pharyngeal Residue Severity Rating Scale and the Dysphagia Outcome and Severity Scale (DOSS) were used to assess the FEES. Tongue strength was assessed using the Iowa Oral Performance Instrument. Patients completed the Eating Assessment Tool-10. The time the patients needed to consume a meal, the Functional Oral Intake Scale score and the body mass index (BMI) were recorded. Correlations between the TOMASS and other variables were studied using Spearman\u2019s correlation coefficient. TOMASS scores were compared between patients with complete denture and those with partial edentulism through Mann-Whitney test. Results: The number of discrete bites correlated only with the BMI (r=-0.38; p=0.01). Statistically significant correlations were found between the number of masticatory cycles and tongue strength (r=-0.47; p<0.01), pharyngeal residue (r=0.42; p<0.01), DOSS (r=-0.38; p=0.01). The total time of the TOMASS correlated with tongue strength (r=-0.45; p<0.01), pharyngeal residue (r=0.48; p<0.01), time needed to consume a meal (r=0.41; p=0.01) and DOSS (r=-0.36; p=0.02). A significant difference was found between patients with complete denture and patients with partial edentulism for the number of masticatory cycles (p=0.02) and total time (p=0.03). Conclusions: Swallowing oral phase seems to correlate with tongue strength, denture, pharyngeal residue, overall dysphagia severity, duration of meals and BMI. Further studies involving a larger sample size are necessary to confirm present data

Three new Alpha1-Antitrypsin deficiency variants help to define a C-Terminal region regulating conformational change and polymerization

Alpha1-antitrypsin (AAT) deficiency is a hereditary disorder associated with reduced AAT plasma levels, predisposing adults to pulmonary emphysema. The most common genetic AAT variants found in patients are the mildly deficient S and the severely deficient Z alleles, but several other pathogenic rare alleles have been reported. While the plasma AAT deficiency is a common trait of the disease, only a few AAT variants, including the prototypic Z AAT and some rare variants, form cytotoxic polymers in the endoplasmic reticulum of hepatocytes and predispose to liver disease. Here we report the identification of three new rare AAT variants associated to reduced plasma levels and characterize their molecular behaviour in cellular models. The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AAT, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AAT reactive loop and through effects on core packing. In conclusion, the new AAT deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant. The new mutations cluster structurally, thus defining a region of the AAT molecule critical for regulating its conformational state

<b><i>Topoisomerase 1</i></b> Promoter Variants and Benefit from Irinotecan in Metastatic Colorectal Cancer Patients

Objective: Topoisomerase 1 (topo-1) is an important target for the treatment of metastatic colorectal cancer (CRC). The aim of the present study was to evaluate the correlation between topo-1 single-nucleotide polymorphisms (SNPs) and clinical outcome in metastatic CRC (mCRC) patients. Methods: With the use of specific software (PROMO 3.0), we performed an in silico analysis of topo-1 promoter SNPs; the rs6072249 and rs34282819 SNPs were included in the study. DNA was extracted from 105 mCRC patients treated with FOLFIRI ± bevacizumab in the first line. SNP genotyping was performed by real-time PCR. Genotypes were correlated with clinical parameters (objective response rate, progression-free survival, and overall survival). Results: No single genotype was significantly associated with clinical variables. The G allelic variant of rs6072249 topo-1 SNP is responsible for GC factor and X-box-binding protein transcription factor binding. The same allelic variant showed a nonsignificant trend toward a shorter progression-free survival (GG, 7.5 months; other genotypes, 9.3 months; HR 1.823, 95% CI 0.8904-3.734; p = 0.1). Conclusion: Further analyses are needed to confirm that the topo-1 SNP rs6072249 and transcription factor interaction could be a part of tools to predict clinical outcome in mCRC patients treated with irinotecan-based regimens

k cl co transport plays an important role in normal and β thalassemic erythropoiesis

Background and Objectives Cell volume changes are hallmarks of both cell maturation and apoptosis, and are paralleled by modulation of membrane ion transport pathways. We evaluated the possible role of K-Cl co-transport (KCC) in both normal and β-thalassemic erythropoiesis in vitro . Design and Methods We studied the effects of the KCC inhibitor, DIOA, on cell proliferation and differentiation, on expression of KCC mRNA and polypeptides, and on expression of cell cycle and apoptosis genes in in vitro liquid-cultures of CD34+ cells from normal and β-thalassemic subjects. Results β-thalassemic erythroid precursors showed increased abundance of KCC1-3 mRNA and of KCC polypeptides in late erythropoiesis. DIOA markedly modified the composition of normal erythroid precursors, promoting differentiation and arrest at the polychromatic erythroblast stage and resulting in a precursor distribution profile similar to that of untreated β-thalassemic cells. DIOA up-regulated cyclin-D mRNA levels in late erythropoiesis in both cell models, paralleling changes in the percentage of S-phase-cells. Caspase-3 activity in late erythropoiesis declined to similar degrees in both cell models. DIOA did not modify caspase-3 or -8 mRNA levels. Interpretation and Conclusions Ineffective erythropoiesis of in vitro cultured β-thalassemic cells is likely related to impaired cell maturation. KCC activity appears to contribute to erythroid cell growth during late erythropoiesis

Primary tumor sidedness and benefit from FOLFOXIRI plus bevacizumab as initial therapy for metastatic colorectal cancer. Retrospective analysis of the TRIBE trial by GONO

Right-sided metastatic colorectal cancer (mCRC) patients have poor prognosis and achieve limited benefit from first-line doublets plus a targeted agent. In this unplanned analysis of the TRIBE study, we investigated the prognostic and predictive impact of primary tumor sidedness in mCRC patients and the differential impact of the intensification of the chemotherapy in subgroups defined according to both primary tumor sidedness and RAS and BRAF mutational status

Met-activating genetically improved chimeric factor-1 promotes angiogenesis and hypertrophy in adult myogenesis

BACKGROUND: Myogenic progenitor cells (activated satellite cells) are able to express both HGF and its receptor cMet. After muscle injury, HGF-Met stimulation promotes activation and primary division of satellite cells. MAGIC-F1 (Met-Activating Genetically Improved Chimeric Factor-1) is an engineered protein that contains two human Met-binding domains that promotes muscle hypertrophy. MAGIC-F1 protects myogenic precursors against apoptosis and increases their fusion ability enhancing muscle differentiation. Hemizygous and homozygous Magic-F1 transgenic mice displayed constitutive muscle hypertrophy. METHODS: Here we describe microarray analysis on Magic-F1 myogenic progenitor cells showing an altered gene signatures on muscular hypertrophy and angiogenesis compared to wild-type cells. In addition, we performed a functional analysis on Magic-F1+/+ transgenic mice versus controls using treadmill test. RESULTS: We demonstrated that Magic-F1+/+ mice display an increase in muscle mass and cross-sectional area leading to an improvement in running performance. Moreover, the presence of MAGIC-F1 affected positively the vascular network, increasing the vessel number in fast twitch fibers. Finally, the gene expression profile analysis of Magic-F1+/+ satellite cells evidenced transcriptomic changes in genes involved in the control of muscle growth, development and vascularisation. CONCLUSION: We showed that MAGIC -F1-induced muscle hypertrophy affects positively vascular network, increasing vessel number in fast twitch fibers. This was due to unique features of mammalian skeletal muscle and its remarkable ability to adapt promptly to different physiological demands by modulating the gene expression profile in myogenic progenitors

Guide cells support muscle regeneration and affect neuro-muscular junction organization

Muscular regeneration is a complex biological process that occurs during acute injury and chronic degeneration, implicating several cell types. One of the earliest events of muscle regeneration is the inflammatory response, followed by the activation and differentiation of muscle progenitor cells. However, the process of novel neuromuscular junction formation during muscle regeneration is still largely unexplored. Here, we identify by single-cell RNA sequencing and isolate a subset of vessel-associated cells able to improve myogenic differentiation. We termed them 'guide' cells because of their remarkable ability to improve myogenesis without fusing with the newly formed fibers. In vitro, these cells showed a marked mobility and ability to contact the forming myotubes. We found that these cells are characterized by CD44 and CD34 surface markers and the expression of Ng2 and Ncam2. In addition, in a murine model of acute muscle injury and regeneration, injection of guide cells correlated with increased numbers of newly formed neuromuscular junctions. Thus, we propose that guide cells modulate de novo generation of neuromuscular junctions in regenerating myofibers. Further studies are necessary to investigate the origin of those cells and the extent to which they are required for terminal specification of regenerating myofibers

Identification of Isoform 2 Acid-Sensing Ion Channel Inhibitors as Tool Compounds for Target Validation Studies in CNS

Acid-sensing ion channels (ASICs) are a family of ion channels permeable to cations and largely responsible for the onset of acid-evoked ion currents both in neurons and in different types of cancer cells, thus representing a potential target for drug discovery. Owing to the limited attention ASIC2 has received so far, an exploratory program was initiated to identify ASIC2 inhibitors using diminazene, a known pan-ASIC inhibitor, as a chemical starting point for structural elaboration. The performed exploration enabled the identification of a novel series of ASIC2 inhibitors. In particular, compound 2u is a brain penetrant ASIC2 inhibitor endowed with an optimal pharmacokinetic profile. This compound may represent a useful tool to validate in animal models in vivo the role of ASIC2 in different neurodegenerative central nervous system pathologies