High-resolution anorectal manometry in children with functional constipation with or without fecal incontinence

Background: High-resolution anorectal manometry (HR-ARM) is expected to be better than conventional manometry. Our aim was to characterize HR-ARM pressures in children with functional constipation (FC), with or without fecal incontinence (FI). Methods: Children with diagnosis of FC, with or without FI, according to Rome-IV criteria, were enrolled. All patients underwent HR-ARM using 24-channel water-perfused catheter. Results: Twenty-nine consecutive children (M/F: 21/8; mean age ± SD: 9.5 ± 3.1 years; range 4-15), of whom 21 affected by FC without FI (mean age ± SD: 9.3 ± 3.23 years) and 8 affected by FC with FI (mean age ± SD: 10.2 ± 3.08 years), were enrolled. No significant differences were found regard to gender and age. The analysis of HR-ARM 3D plots demonstrated asymmetry of the anal canal, with higher pressures in distal halves. Comparing pressures between the two groups, we found lower values in FC with FI than in FC without FI group, with a statistically significance for maximum and mean resting pressures (P =.032 and P =.008, respectively). When evaluating our study population respect to asymptomatic children, we found lower resting pressures, lower maximum squeeze pressure, and higher rectoanal inhibitory reflex (RAIR) values. Conclusions: Our data demonstrate that HR-ARM pressures at rest and during squeezing in FC with FI children are lower than FC without FI subjects, particularly in anteroposterior quadrants. Compared to children without lower gastrointestinal symptoms, children with FC with or without FI show lower pressures and higher values of RAIR

Recent insights into Histone Acetyltransferase-1: biological function and involvement in pathogenesis

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Role of non-acid gastro-esophageal reflux in children with respiratory symptoms

Objectives: Respiratory symptoms are a possible atypical clinical picture of gastro-esophageal reflux disease (GERD). However, a significant number of patients with GERD-related respiratory symptoms do not report improvement despite aggressive acid-suppressive therapy. Some of these refractory casesmay be due to the recently appreciated entity of non-acid or weakly acidic reflux. The aim of our study is to assess the pH-impedance features of GER inducing airway symptoms, compared with GER inducing typical gastro-intestinal (GI) symptoms. Methods: We prospectively enrolled infants and children with GERD-related respiratory symptoms from January 2015 to December 2015. Age-and sex-matched patients with GERD-related GI symptoms were enrolled as comparison group. The overall number, the acidity pattern, and the height of reflux episodes were compared between the two groups. Results: Forty patients (M/F: 20/20; mean age: 58.3 months) were enrolled in the study group and 40 in the comparison group. The mean acid exposure index was 7.9% within the study group and 15.9% within the comparison group (p:0.026). Children with respiratory symptoms versus children with GI symptoms had a mean of 40.8 acid reflux episodes versus 62.4 (p:0.001), a mean of 2.2 weakly acid reflux episodes versus 20.1 (p:0.002), and a mean of 22.1 weakly alkaline reflux episodes versus 10.2 (P < 0.001). Separate analysis of both infants and children was performed. Conclusions: The main finding of this prospective, controlled study is that children >1 year with GERD-related respiratory symptoms showed a significantly higher number of weakly alkaline refluxes than children with GERD-related GI symptoms. This supports the hypothesis that respiratory symptoms are less related to acidity than GI symptoms

Recent insights into Histone Acetyltransferase-1: biological function and involvement in pathogenesis

Acetylation of histone and non-histone proteins is a post-translational modification mostly associated with activation of gene transcription. The first histone acetyltransferase (HAT) identified as modifying newly synthesized histone H4 in yeast was a type B HAT named HAT1. Although it was the first HAT to be discovered, HAT1 remains one of the most poorly studied enzymes in its class. In addition to its well-established role in the cytoplasm, recent findings have revealed new and intriguing aspects of the function of HAT1 in the nucleus. Several studies have described its involvement in regulating different pathways associated with a wide range of diseases, including cancer. This review focuses on our current understanding of HAT1, highlighting its importance in regulating chromatin replication and gene expression. This previously unknown role for HAT1 opens up novel scenarios in which further studies will be required to better understand its function

Characterization of Histone Acetyltransferase-1 in cancer cells

Introduction: Acetylation of histone and non-histone proteins is a post-translational modification mostly associated with activation of gene transcription. The first histone acetyltransferase (HAT) identified as modifying newly synthesized histone H4 at Lys5 and Lys12 was a type B HAT named HAT1. Although it was the first HAT to be discovered, it remains one of the most poorly studied enzymes in its class. In addition to its well-established role in the cytoplasm, recent findings have revealed new and intriguing aspects about the function of HAT1 in the nucleus. Purpose: Uncovering the non-canonical role of HAT1 first in DNA damage repair, then in chromatin assembly and chromatin maturation prompted in-depth investigations into the functional role of this protein in several biological processes. The involvement of HAT1 in regulating different pathways associated with a wide range of diseases, including cancer, and its contradictory role in carcinogenesis lead us to elucidate its role. Specifically, recent studies have shown that lower expression of HAT1 is associated with the pathogenesis of lung cancer 1, while in hepatocellular carcinoma, nasopharyngeal cancer, and pancreatic cancer 2–4 is highly expressed, acting as an oncogene, and linked to poor prognosis 4. Results and Conclusions: Immunoprecipitation experiment of overexpressed HAT1 combined with MS/MS analysis will be important to assess in which protein complexes HAT1 resides in breast cancer cell line. Moreover, genomics will be used for seeking possible molecular markers that can contribute at activating oncogenes or inactivating tumor suppressor genes. The main goal of this project is to understand HAT1 molecular mechanisms in cancer in order to develop novel strategy for cancer therapy. While efforts to identify molecules able to block its enzymatic activity are ongoing, the development of new compounds targeting one of its interactors could provide another entry point for HAT1 inhibition. REFERENCE

Conformational Response to Ligand Binding in Phosphomannomutase2: INSIGHTS INTO INBORN GLYCOSYLATION DISORDER

The most common glycosylation disorder is caused by mutations in the gene encoding phosphomannomutase2, producing a disease still without a cure. Phosphomannomutase2, a homodimer in which each chain is composed of two domains, requires a bisphosphate sugar (either mannose or glucose) as activator, opening a possible drug design path for therapeutic purposes. The crystal structure of human phosphomannomutase2, however, lacks bound substrate and a key active site loop. To speed up drug discovery, we present here the first structural model of a bisphosphate substrate bound to human phosphomannomutase2. Taking advantage of recent developments in all-atom simulation techniques in combination with limited and site-directed proteolysis, we demonstrated that α-glucose 1,6-bisphosphate can adopt two low energy orientations as required for catalysis. Upon ligand binding, the two domains come close, making the protein more compact, in analogy to the enzyme in the crystals from Leishmania mexicana. Moreover, proteolysis was also carried out on two common mutants, R141H and F119L. It was an unexpected finding that the mutant most frequently found in patients, R141H, although inactive, does bind α-glucose 1,6-bisphosphate and changes conformation

Enzymatic and Biological Characterization of Novel Sirtuin Modulators against Cancer

Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure-activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine.Sirtuins, a family of nicotinamide adenine dinucleotide (NAD(+))-dependent lysine deacetylases, are promising targets for anticancer treatment. Recently, we characterized a novel pan-sirtuin (SIRT) inhibitor, MC2494, displaying antiproliferative effects and able to induce death pathways in several human cancer cell lines and decrease tumor growth in vivo. Based on the chemical scaffold of MC2494, and by applying a structure-activity relationship approach, we developed a small library of derivative compounds and extensively analyzed their enzymatic action at cellular level as well as their ability to induce cell death. We also investigated the effect of MC2494 on regulation of cell cycle progression in different cancer cell lines. Our investigations indicated that chemical substitutions applied to MC2494 scaffold did not confer higher efficacy in terms of biological activity and SIRT1 inhibition, but carbethoxy-containing derivatives showed higher SIRT2 specificity. The carbethoxy derivative of MC2494 and its 2-methyl analog displayed the strongest enzymatic activity. Applied chemical modifications improved the enzymatic selectivity of these SIRT inhibitors. Additionally, the observed activity of MC2494 via cell cycle and apoptotic regulation and inhibition of cell migration supports the potential role of SIRTs as targets in tumorigenesis and makes SIRT-targeting molecules good candidates for novel pharmacological approaches in personalized medicine