Two novel mutations of Wiskott–Aldrich syndrome: the molecular prediction of interaction between the mutated WASP L101P with WASP-interacting protein by molecular modeling

AbstractWiskott–Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and increased susceptibility of infections, with mutations of the WAS gene being responsible for WAS and X-linked thrombocytopenia. Herein, two novel mutations of WAS at T336C on exon 3, and at 1326–1329, a G deletion on exon 10, resulting in L101P missense mutation and frameshift mutation 444 stop, respectively, are reported. The affected patients with either mutation showed severe suppression of WAS protein (WASP) levels, T cell proliferation, and CFSE-labeled T cells division. Because WASP L101 have not shown direct nuclear Overhauser effect (NOE) contact with the WASP-interacting protein (WIP) in NMR spectroscopy, molecular modeling was performed to evaluate the molecular effect of WASP P101 to WIP peptide. It is presumed that P101 induced a conformational change in the Q99 residue of WASP and made the side chain of Q99 move away from the WIP peptide, resulting in disruption of the hydrogen bond between Q99 WASP and Y475 WIP. A possible model for the molecular pathogenesis of WAS has been proposed by analyzing the interactions of WASP and WIP using a molecular modeling study

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1

Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40-60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions

CT and MR Imaging of the Buccal Space: Normal Anatomy and Abnormalities

The buccal space is an anatomical compartment lying anterior to the masticator space and lateral to the buccinator muscle. Since the major purpose of imaging is to define the likely anatomic origin and also the extent of a given lesion, thorough knowledge of the normal anatomy of the buccal space is essential, and this knowledge can aid the physician in narrowing down the list of possible maladies on the differential diagnosis. We illustrate here in this paper the important anatomic landmarks and typical pathologic conditions of the buccal space such as the developmental lesions and the neoplastic lesions. Knowledge of the expected pathologic conditions is useful for the radiologist when interpreting facial CT and MR images

Background 18F-FDG uptake in positron emission mammography (PEM): Correlation with mammographic density and background parenchymal enhancement in breast MRI

AbstractWe aimed to determine whether background 18F-FDG uptake in positron emission mammography (PEM) was related to mammographic density or background parenchymal enhancement in breast MRI.MethodsWe studied a total of 52 patients (mean age, 50.9 years, 26 premenopausal, 26 postmenopausal) with newly diagnosed breast cancer who underwent 18F-FDG PEM (positron emission mammography), conventional mammography and breast MRI. The background mean 18F-FDG uptake value on PEM was obtained by drawing a user-defined region of interest (ROI) in a normal area of the contralateral breast. We reviewed the mammography retrospectively for overall breast density of contralateral breast according to the four-point scale (grade 1–4) of the Breast Imaging Reporting and Data System (BI-RADS) classification. The background parenchymal enhancement of breast MRI was classified as minimal, mild, moderate, or marked. All imaging findings were interpreted by two readers in consensus without knowledge of image findings of other modalities.ResultsMultiple linear regression analysis revealed a significant correlation between background 18F-FDG uptake on PEM and mammographic density after adjustment for age and menopausal status (P<0.01), but not between background 18F-FDG uptake on PEM and background parenchymal enhancement on MRI.ConclusionBackground 18F-FDG uptake on PEM significantly increases as mammographic density increases. Background parenchymal enhancement in breast MRI was not an independent predictor of the background 18F-FDG uptake on PEM unlike mammographic density

Unmasking intra-tumoral heterogeneity and clonal evolution in NF1-MPNST

Sarcomas are highly aggressive cancers that have a high propensity for metastasis, fail to respond to conventional therapies, and carry a poor 5-year survival rate. This is particularly true for patients with neurofibromatosis type 1 (NF1), in which 8%-13% of affected individuals will develop a malignant peripheral nerve sheath tumor (MPNST). Despite continued research, no effective therapies have emerged from recent clinical trials based on preclinical work. One explanation for these failures could be the lack of attention to intra-tumoral heterogeneity. Prior studies have relied on a single sample from these tumors, which may not be representative of all subclones present within the tumor. In the current study, samples were taken from three distinct areas within a single tumor from a patient with an NF1-MPNST. Whole exome sequencing, RNA sequencing, and copy number analysis were performed on each sample. A blood sample was obtained as a germline DNA control. Distinct mutational signatures were identified in different areas of the tumor as well as significant differences in gene expression among the spatially distinct areas, leading to an understanding of the clonal evolution within this patient. These data suggest that multi-regional sampling may be important for driver gene identification and biomarker development in the future

Superparamagnetic Iron Oxide Nanoparticles Coated with Galactose-Carrying Polymer for Hepatocyte Targeting

Our goal is to develop the functionalized superparamagnetic iron oxide nanoparticles (SPIONs) demonstrating the capacities to be delivered in liver specifically and to be dispersed in physiological environment stably. For this purpose, SPIONs were coated with polyvinylbenzyl-O-β-D-galactopyranosyl-D-gluconamide (PVLA) having galactose moieties to be recognized by asialoglycoprotein receptors (ASGP-R) on hepatocytes. For use as a control, we also prepared SPIONs coordinated with 2-pyrrolidone. The sizes, size distribution, structure, and coating of the nanoparticles were characterized by transmission electron microscopy (TEM), electrophoretic light scattering spectrophotometer (ELS), X-ray diffractometer (XRD), and Fourier transform infrared (FT-IR), respectively. Intracellular uptake of the PVLA-coated SPIONs was visualized by confocal laser scanning microscopy, and their hepatocyte-specific delivery was also investigated through magnetic resonance (MR) images of rat liver. MRI experimental results indicated that the PVLA-coated SPIONs possess the more specific accumulation property in liver compared with control, which suggests their potential utility as liver-targeting MRI contrast agent

Associations among Organochlorine Pesticides, Methanobacteriales, and Obesity in Korean Women

BACKGROUND: Although Methanobacteriales in the gut has recently been linked to obesity, no study has examined the hypothesis that waist circumference, a marker of visceral obesity, are positively associated with Methanobacteriales in the general population. Since Methanobacteriales increase in a petroleum-contaminated environment to biodegrade petroleum as one way of autopurification, we also hypothesized that high body burden of highly lipophilic petroleum-based chemicals like organochlorine pesticides (OCPs) is associated with higher levels of Methanobacteriales in the gut. METHODOLOGY/PRINCIPAL FINDINGS: Among 83 Korean women who visited a community health service center for a routine health checkup, quantitative real-time PCR (qPCR) based on 16S rDNA was used to quantify Methanobacteriales in feces. Nine OCPs were measured in both serum and feces of 16 subjects. Methanobacteriales were detected in 32.5% (27/83 women). Both BMI and waist circumference among women with Methanobacteriales were significantly higher than in women without Methanobacteriales (P = 0.04 and P = 0.01, respectively). Also, Methanobacteriales levels in feces were positively associated with BMI and waist circumference (r = +0.23 and P = 0.03 for both). Furthermore, there were significant correlations between feces Methanobacteriales levels and serum concentrations of most OCPs, including with cis-nonachlor (r = +0.53, P<0.05), oxychlordane (r = +0.46, P<0.1), and trans-nonachlor (r = +0.43, P<0.1). Despite high correlations of serum and feces concentrations of most OCPs, feces OCP concentrations were not clearly associated with feces Methanobacteriales levels. CONCLUSION/SIGNIFICANCE: In this cross-sectional study, the levels of Methanobacteriales in the human gut were associated with higher body weight and waist circumference. In addition, serum OCP concentrations were positively correlated with levels of Methanobacteriales. There may be a meaningful link among body burden of OCP, Methanobacteriales in the gut, and obesity in the general population

Recurred pneumocephalus in a head trauma patient following positive pressure mask ventilation during induction of anesthesia -A case report-

Pneumocephalus is a condition which usually results from head trauma. It has been known that iatrogenic pneumocephalus can occur as a complication of positive pressure mask ventilation during induction of anesthesia or ventilatory care for head trauma patients. We report a case of mask ventilation during anesthesia induction in a 50-year-old male patient with head trauma. Initial pneumocephalus associated with cerebrospinal fluid leakage was diagnosed immediate following head injury involving facial sinuses. He was managed with emergent lumbar drainage and supportive care. Pneumocephalus recurred following positive pressure mask ventilation (PPMV) during anesthesia induction for surgery on the right arm. Recurred pneumocephalus was managed with high flow oxygen and supportive care. Anesthesiologists should be aware of pneumocephalus as a potential complication of PPMV in head trauma patients, even after resolution of previous pneumocephalus

Planalto barrosão

O concelho de Montalegre, situado no planalto Barrosão, é uma das regiões mais remotas e isoladas de Portugal Continental. É um território com baixa densidade populacional, em que cerca de um quarto da superfície do concelho se situa dentro do Parque Nacional da Peneda Gerês, a elevada altitude. É sobre este circunstancialismo geográfico, que permitiu preservar uma ruralidade vincada, que recai a representação fotográfica de paisagem do Planalto do Barroso. É uma representação da paisagem como uma construção cultural e pretende questionar as fronteiras de uma paisagem protegida e como se relaciona com questões de identidade e património.Montalegre, in the Northeast of Portugal, is one of the most remote and isolated areas of the country. The region is an important part of a National Park, the Peneda Geres, located at high altitude and with a very low level of human occupation. This geographic aspect, that led to the preservation and observation of a strong rurality, allowed a photographic representation of the landscape in Barroso´s Plateaus. It’s a photographic representation of the landscape as a cultural construction, questioning the frontiers of a protected landscape and how it relates to heritage and identity