Outcomes and validity of risk stratification tools for endoscopic submucosal dissection of early gastric cancer in Western Australia.

Background And Aim: Endoscopic submucosal dissection (ESD) has become the treatment of choice for many superficial gastric neoplasms. Clinical outcomes are increasingly comparable between Japanese and Western series; however, data are lacking on the validity of risk stratification tools in Western cohorts. We aimed to evaluate clinical outcomes, explore risk stratification, and compare our data with published Western series.

mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes.

Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos.

Rab12 is a regulator of LRRK2 and its activation by damaged lysosomes.

Leucine-rich repeat kinase 2 (LRRK2) variants associated with Parkinson's disease (PD) and Crohn's disease lead to increased phosphorylation of its Rab substrates. While it has been recently shown that perturbations in cellular homeostasis including lysosomal damage can increase LRRK2 activity and localization to lysosomes, the molecular mechanisms by which LRRK2 activity is regulated have remained poorly defined. We performed a targeted siRNA screen to identify regulators of LRRK2 activity and identified Rab12 as a novel modulator of LRRK2-dependent phosphorylation of one of its substrates, Rab10.

A Fixable Fluorescence-Quenched Substrate for Quantitation of Lysosomal Glucocerebrosidase Activity in Both Live and Fixed Cells.

Fluorogenic substrates are emerging tools that enable studying enzymatic processes within their native cellular environments. However, fluorogenic substrates that function within live cells are generally incompatible with cellular fixation, preventing their tandem application with fundamental cell biology methods such as immunocytochemistry. Here we report a simple approach to enable the chemical fixation of a dark-to-light substrate, LysoFix-GBA, which enables quantification of glucocerebrosidase (GCase) activity in both live and fixed cells.

Functional genomics of OCTN2 variants informs protein-specific variant effect predictor for Carnitine Transporter Deficiency.

Genetic variants in , encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of . Interpretation of missense variants of uncertain significance (VUSs) is a major challenge.

Phenotypic Screening Using High-Content Imaging to Identify Lysosomal pH Modulators in a Neuronal Cell Model.

Lysosomes are intracellular organelles responsible for the degradation of diverse macromolecules in a cell. A highly acidic pH is required for the optimal functioning of lysosomal enzymes. Loss of lysosomal intralumenal acidity can disrupt cellular protein homeostasis and is linked to age-related diseases such as neurodegeneration.

Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy.

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer's disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and toxicity.

Genetically Encoded, pH-Sensitive mTFP1 Biosensor for Probing Lysosomal pH.

Lysosomes are important sites for macromolecular degradation, defined by an acidic lumenal pH of ∼4.5. To better understand lysosomal pH, we designed a novel, genetically encoded, fluorescent protein (FP)-based pH biosensor called Fluorescence Indicator REporting pH in Lysosomes (FIRE-pHLy).

Reimagining dots and dashes: Visualizing structure and function of organelles for high-content imaging analysis.

Organelles are responsible for biochemical and cellular processes that sustain life and their dysfunction causes diseases from cancer to neurodegeneration. While researchers are continuing to appreciate new roles of organelles in disease, the rapid development of specifically targeted fluorescent probes that report on the structure and function of organelles will be critical to accelerate drug discovery. Here, we highlight four organelles that collectively exemplify the progression of phenotypic discovery, starting with mitochondria, where many functional probes have been described, then continuing with lysosomes and Golgi and concluding with nascently described membraneless organelles.

Vedolizumab-induced acute pancreatitis: the first reported clinical case.

Drug-induced acute pancreatitis (DIAP) is a rare, but clinically significant diagnosis. Vedolizumab, an αβ integrin inhibitor, which was approved in 2015 for treatment of moderate to severe inflammatory bowel disease, is a well-tolerated medication with a favourable safety profile and minimal serious adverse events in premarketing clinical trials. We present the first reported case of acute pancreatitis directly attributable to vedolizumab.

Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans.

Clarifying the mechanisms connecting neurofibrillary tangle (NFT) neurotoxicity to neuronal dysfunction in humans is likely to be pivotal for developing effective treatments for Alzheimer's disease (AD). To model the temporal progression of AD in humans, we used a collection of brains with controls and individuals from each Braak stage to quantitatively investigate the correlation between intraneuronal caspase activation or macroautophagy markers, NFT burden, and neuronal loss, in the dorsal raphe nucleus and locus coeruleus, the earliest vulnerable areas to NFT accumulation. We fit linear regressions with each count as outcomes, with Braak score and age as the predictors.

Outcomes of preoperative biliary drainage from a single tertiary center: Is there still a role for plastic stents?

Objectives: Preoperative biliary drainage (PBD) can relieve symptoms of cholestasis, but carries risk of procedural complications. Metal stents have wider lumens and longer patency, although plastic stents (PS) remain in use. We reviewed the outcomes after PBD in patients with cholestasis.

Sitaxsentan-induced acute severe hepatitis treated with glucocorticoid therapy.

Endothelin receptor antagonists are commonly used in the treatment of pulmonary hypertension. Sitaxsentan, a selective endothelin A receptor blocker, induces a mild transaminitis in approximately 3% to 5% of patients, but rarely an acute severe hepatitis. A case involving a 61-year-old female with sitaxsentan-induced acute severe liver failure is presented.

Update of cholangioscopy and biliary strictures.

Cholangioscopy remains another modality in the investigation of biliary strictures. At cholangioscopy, the "tumour vessel" sign is considered a specific sign for malignancy. Through its ability to not only visualise mucosa, but to take targeted biopsies, it has a greater accuracy, sensitivity and specificity for malignant strictures than endoscopic retrograde cholangiopancreatography guided cytopathological acquisition.

Hemobilia.

Hemobilia is an uncommon medical problem that presents in a varied fashion and is increasingly of iatrogenic origin. The diagnosis of hemobilia needs to be considered in patients presenting with upper gastrointestinal bleeding, particularly if they are jaundiced with abdominal pain in the setting of recent or previous percutaneous liver intervention or abdominal trauma. Multislice computed tomographic angiography is increasingly being used in the investigation, but transcatheter arterial embolization remains the cornerstone of managing those patients requiring intervention.

Screening for coeliac disease using anti-tissue transglutaminase antibody assays, and prevalence of the disease in an Australian community.

Objectives: To determine (i) the prevalence of positive results of anti-tissue transglutaminase (anti-tTG) antibody assays and coeliac disease (CD) in a rural Australian community; and (ii) whether confirmatory testing of a positive assay result with an alternative anti-tTG assay improved the positive predictive value of the test in population screening for CD.

Design: Retrospective analysis in December 2004 of stored serum samples taken in 1994-1995 from 3011 subjects in the Busselton Health Study follow-up. Assays for IgA and IgG anti-tTG antibodies were performed, and positive or equivocal samples were retested with a different commercial anti-tTG assay.

Predictive and protective factors associated with upper gastrointestinal bleeding after percutaneous coronary intervention: a case-control study.

Background: Hemorrhagic complications of acute coronary syndromes and percutaneous coronary intervention (PCI) are associated with increased mortality. Upper gastrointestinal (UGI) bleeding after PCI is a potential target for preventative strategies.

Objective: To evaluate the risk factors for UGI bleeding in a large cohort of contemporary PCI patients and assess the outcomes of medical and endoscopic management.

Computed tomographic colonography: prevalence, nature, and clinical significance of extracolonic findings in a community screening program.

Objective: Colorectal neoplasia screening by computed tomographic colonography (CTC) may lead to the detection of incidental extracolonic findings. We report the prevalence and clinical significance of extracolonic pathology found within a community-based CTC screening program and the cost of clinical follow-up and further investigation of these findings.

Methods: A total of 432 asymptomatic subjects at an average risk of colorectal neoplasia, aged 50-69, had screening by CTC using a low radiation dose protocol.