Vector integration and fate in the hemophilia dog liver multiple years after AAV-FVIII gene transfer.

Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity.

Metabolically Active Zones Involving Fatty Acid Elongation Delineated by DESI-MSI Correlate with Pathological and Prognostic Features of Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer deaths. Despite recent advances, five-year survival rates remain largely unchanged. Desorption electrospray ionization mass spectrometry imaging (DESI) is an emerging nondestructive metabolomics-based method that retains the spatial orientation of small-molecule profiles on tissue sections, which may be validated by 'gold standard' histopathology.

The utility of image-enhanced endoscopy and Lugol's for the assessment of esophageal squamous carcinoma.

Video 1This is a case of a patient with esophageal squamous cell carcinoma who underwent endoscopic submucosal dissection and subsequent esophagectomy. The endoscopic findings using imaged endoscopy, magnification, and Lugol's are demonstrated. There is a demonstration of endoscopic and pathological correlation in addition to the emphasis on a patient-centered multidisciplinary approach to esophageal neoplasia and the diagnostic utility of endoscopic submucosal dissection.

Surgical practice patterns and outcomes in T2 and T3 gallbladder cancer: a population-based study.

Background: The extent of resection required in advanced gallbladder cancer is controversial. We aimed to describe the management and outcomes in patients with resected stage T2 and T3 gallbladder cancer.

Methods: In this population-based study, all T2 and T3 gallbladder cancer cases from Jan.

Genetic diversity in alveolar soft part sarcoma: A subset contain variant fusion genes, highlighting broader molecular kinship with other MiT family tumors.

Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis. The disease-defining molecular event characterizing the diagnosis of ASPS is the ASPSCR1-TFE3 fusion gene. Following identification of an index case of ASPS with a novel TFE3 fusion partner, we performed a retrospective review to determine whether this represents an isolated event.

Epigenetic modification of intestinal smooth muscle cell phenotype during proliferation.

Inflammation causes proliferation of intestinal smooth muscle cells (ISMC), contributing to a thickened intestinal wall and to stricture formation in Crohn's disease. Proliferation of ISMC in vitro and in vivo caused decreased expression of marker proteins, but the underlying cause is unclear. Since epigenetic change is important in other systems, we used immunocytochemistry, immunoblotting, and quantitative PCR to examine epigenetic modification in cell lines from rat colon at low passage or after extended growth to evaluate phenotype.

Do Lower-Risk Thyroid Cancer Patients Who Live in Regions with More Aggressive Treatments Have Better Outcomes?

Background: The management of differentiated thyroid cancer has traditionally consisted of total thyroidectomy with or without adjuvant radioactive iodine. However, in the last two decades, this approach has been challenged, with the consideration of more conservative approaches such as less radical surgery and deferring adjuvant treatment, especially in lower-risk patients. The objective of this study was to consider the effectiveness of current treatment options by comparing the survival outcomes from different geographic regions with different treatment philosophies.

Differential roles of RET isoforms in medullary and papillary thyroid carcinomas.

The RET receptor tyrosine kinase mediates cell proliferation, survival and migration in embryogenesis and is implicated in the transformation and tumour progression in multiple cancers. RET is frequently mutated and constitutively activated in familial and sporadic thyroid carcinomas. As a result of alternative splicing, RET is expressed as two protein isoforms, RET9 and RET51, which differ in their unique C-terminal amino acids.

Liver-specific knockout of arginase-1 leads to a profound phenotype similar to inducible whole body arginase-1 deficiency.

Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype.

A human gut ecosystem protects against C. difficile disease by targeting TcdA.

Background: A defined Microbial Ecosystem Therapeutic (MET-1, or "RePOOPulate") derived from the feces of a healthy volunteer can cure recurrent C. difficile infection (rCDI) in humans. The mechanisms of action whereby healthy microbiota protect against rCDI remain unclear.

Administration of defined microbiota is protective in a murine Salmonella infection model.

Salmonella typhimurium is a major cause of diarrhea and causes significant morbidity and mortality worldwide, and perturbations of the gut microbiota are known to increase susceptibility to enteric infections. The purpose of this study was to investigate whether a Microbial Ecosystem Therapeutic (MET-1) consisting of 33 bacterial strains, isolated from human stool and previously used to cure patients with recurrent Clostridium difficile infection, could also protect against S. typhimurium disease.

Long-term correction of Sandhoff disease following intravenous delivery of rAAV9 to mouse neonates.

G(M2) gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb(-/-)) of the G(M2) gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or -LacZ and monitored for serum β-hexosaminidase activity, motor function, and survival.

Clinical features distinguish eosinophilic and reflux-induced esophagitis.

Background And Objectives: Diagnosing eosinophilic esophagitis (EoE) depends on intraepithelial eosinophil count of ≥15 eosinophils per high-power field (HPF); however, differentiating EoE from gastroesophageal reflux disease (GERD) continues to be a challenge because no true "criterion standard" criteria exist. Identifying clinical and endoscopic characteristics that distinguish EoE could provide a more comprehensive diagnostic strategy than the present criteria. The aim of the study was to determine symptoms and signs that can be used to distinguish EoE from reflux esophagitis.

Atopic and non-atopic eosinophilic oesophagitis are distinguished by immunoglobulin E-bearing intraepithelial mast cells.

Aims: Eosinophilic oesophagitis (EoE) occurs in atopic individuals and features eosinophils and mast cells, but differences in the inflammatory cell density between the epithelium and lamina propria (LP) are not fully understood. The aim of this study was to determine if numbers of eosinophils, B lymphocytes and immunoglobulin E (IgE)-bearing mast cells are increased in the mucosa of EoE patients with and without concurrent atopy.

Methods And Results: Oesophageal biopsies containing ≥ 4 high-power fields (HPF) of epithelium and LP were identified for normal (n = 9), gastroesophageal reflux disease (GERD) (n = 5) and EoE (n = 25) patients.

Brain-gut interactions increase peripheral nociceptive signaling in mice with postinfectious irritable bowel syndrome.

Background & Aims: To investigate the peripheral sensory effects of repeated stress in patients with postinfectious irritable bowel syndrome (IBS), we tested whether stress following self-limiting bacterial colitis increases colonic dorsal root ganglia (DRG) nociceptive signaling.

Methods: C57BL/6 mice were infected with Citrobacter rodentium. Stress was induced using a 9-day water avoidance paradigm (days 21-30 after infection).

Antigen presentation and MHC class II expression by human esophageal epithelial cells: role in eosinophilic esophagitis.

Professional antigen-presenting cells (APCs) play a crucial role in initiating immune responses. Under pathological conditions, epithelial cells at mucosal surfaces act as nonprofessional APCs, thereby regulating immune responses at the site of exposure. Epithelial cells in the esophagus may contribute to the pathogenesis of eosinophilic esophagitis (EoE) by presenting antigens on the major histocompatibility complex (MHC) class II.

Citrobacter rodentium colitis evokes post-infectious hyperexcitability of mouse nociceptive colonic dorsal root ganglion neurons.

To investigate the possible contribution of peripheral sensory mechanisms to abdominal pain following infectious colitis, we examined whether the Citrobacter rodentium mouse model of human E. coli infection caused hyperexcitability of nociceptive colonic dorsal root ganglion (DRG) neurons and whether these changes persisted following recovery from infection. Mice were gavaged with C.

Undifferentiated pancreatic carcinoma with osteoclast-like giant cells: report of a case with osteochondroid differentiation.

We report a case of an undifferentiated pancreatic carcinoma with osteoclast-like giant cells with focal osteochondroid differentiation in a 66-year-old man, who presented with painless jaundice, pruritus, and weight loss. Imaging studies revealed an inhomogeneous mass in the head of the pancreas. A pylorus preserving pancreaticoduodenectomy was performed.