The MUC gene family: Their role in diagnosis and early detection of pancreatic cancer

The early diagnosis of pancreatic cancer, as well as distinguishing between chronic pancreatitis and malignant pancreatic disease, remains still a clinical problem. Presently, there is no specific tumor marker for diagnosing pancreatic cancer. Mucin-associated marker like CA 19-9 are the most widely available pancreatic cancer tumor marker, but its value as a screening marker is limited by its reduced specificity. Mucins (MUCs) are heavily glycosylated, high molecular weight glycoproteins with an aberrant expression profile in various malignancies. This review considers briefly the potential use of the mucin expression pattern in diagnosis of pancreatic neoplasm. The overview will point out the present knowledge about changes in the mucin gene expression in pancreatic intraepithelial neoplasia (PanINs) as precursor lesions and in pancreatic adenocarcinoma, compared to normal pancreas and chronic pancreatitis and the potential role for differentiating chronic pancreatitis from pancreatic cancer. Furthermore, the potential use of MUCs in the diagnosis and differentiation of intraductal papillary-mucinous neoplasm's (IPMNs) will be discussed

Risk stratification tools for branch-duct intraductal papillary mucinous neoplasms of the pancreas

Prediction models have been built to improve the correct identification of high‐risk IPMNs and thus the selection of patients for surgery. However, there are currently no tools to recommend the best IPMN surveillance strategy and to distinguish those who might not warrant surveillance at all

Pancreatic exocrine insufficiency after bariatric surgery

Morbid obesity is a lifelong disease, and all patients require complementary follow-up including nutritional surveillance by a multidisciplinary team after bariatric procedures. Pancreatic exocrine insufficiency (PEI) refers to an insufficient secretion of pancreatic enzymes and/or sodium bicarbonate. PEI is a known multifactorial complication after upper gastrointestinal surgery, and might constitute an important clinical problem due to the large number of bariatric surgical procedures in the world. Symptoms of PEI often overlap with sequelae of gastric bypass, making the diagnosis difficult. Steatorrhea, weight loss, maldigestion and malabsorption are pathognomonic for both clinical conditions. Altered anatomy after bypass surgery can make the diagnostic process even more difficult. Fecal elastase-1 (FE1) is a useful diagnostic test. PEI should be considered in all patients after bariatric surgery with prolonged gastrointestinal complaints that are suggestive of maldigestion and/or malabsorption. Appropriate pancreatic enzyme replacement therapy should be part of the treatment algorithm in patients with confirmed PEI or symptoms suggestive of this complication

Dynamics of Bacteriorhodopsin in the Dark‐Adapted State from Solution NMR

To achieve efficient proton pumping in the light-driven proton pump bacteriorhodopsin, the protein must be tightly coupled to the retinal to rapidly convert retinal isomerization into protein structural rearrangements. Methyl group dynamics of bR embedded in lipid nanodiscs were determined in the dark-adapted state, and were found to be mostly well-ordered at the cytosolic side. Methyl groups in the M145A mutant of bR, which displays only 10% residual proton pumping activity, are less well ordered suggesting a link between side chain dynamics on the cytosolic side of the bR cavity and proton pumping activity. In addition, slow conformational exchange, attributed to low frequency motions of aromatic rings, was indirectly observed for residues on the extracellular side of the bR cavity. This may be related to reorganization of the water network. These observations provide a detailed picture of previously undescribed equilibrium dynamics on different time scales for ground-state bR

Ascl1 Balances Neuronal versus Ependymal Fate in the Spinal Cord Central Canal

Generation of neuronal types at the right time, location, and number is essential for building a functional nervous system. Significant progress has been reached in understanding the mechanisms that govern neuronal diversity. Cerebrospinal fluid-contacting neurons (CSF-cNs), an intriguing spinal cord central canal population, are produced during advanced developmental stages, simultaneous with glial and ependymal cells. It is unknown how CSF-cNs are specified after the neurogenesis-to-gliogenesis switch. Here, we identify delayed Ascl1 expression in mouse spinal progenitors during the gliogenic phase as key in CSF-cN differentiation. With fate mappings and time-controlled deletions, we demonstrate that CSF-cNs derive from Ascl1-expressing cells and that Ascl1 triggers late neurogenesis in the amniote spinal cord. Ascl1 abrogation transforms prospective CSF-cN progenitors into ependymocytes. These results demonstrate that late spinal progenitors have the potential to produce neurons and that Ascl1 initiates CSF-cN differentiation, controlling the precise neuronal and nonneuronal composition of the spinal central canal.Fil: Di Bella, Daniela Jesica. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Instituto Leloir; ArgentinaFil: Carcagno, Abel Luis. Fundación Instituto Leloir; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bartolomeu, M. Lucía. Fundación Instituto Leloir; ArgentinaFil: Pardi, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Löhr, Heiko. University of Cologne; AlemaniaFil: Siegel, Nicole. Fundación Instituto Leloir; ArgentinaFil: Hammerschmidt, Matthias. University of Cologne; AlemaniaFil: Marin Burgin, Antonia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Lanuza, Guillermo Marcos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación Instituto Leloir; Argentin

The UBA domain of conjugating enzyme Ubc1/Ube2K facilitates assembly of K48/K63‐branched ubiquitin chains

The assembly of a specific polymeric ubiquitin chain on a target protein is a key event in the regulation of numerous cellular processes. Yet, the mechanisms that govern the selective synthesis of particular polyubiquitin signals remain enigmatic. The homologous ubiquitin-conjugating (E2) enzymes Ubc1 (budding yeast) and Ube2K (mammals) exclusively generate polyubiquitin linked through lysine 48 (K48). Uniquely among E2 enzymes, Ubc1 and Ube2K harbor a ubiquitin-binding UBA domain with unknown function. We found that this UBA domain preferentially interacts with ubiquitin chains linked through lysine 63 (K63). Based on structural modeling, in vitro ubiquitination experiments, and NMR studies, we propose that the UBA domain aligns Ubc1 with K63-linked polyubiquitin and facilitates the selective assembly of K48/K63-branched ubiquitin conjugates. Genetic and proteomics experiments link the activity of the UBA domain, and hence the formation of this unusual ubiquitin chain topology, to the maintenance of cellular proteostasis.Deutsche Forschungsgemeinschaft (DFG) http://dx.doi.org/10.13039/501100001659Max‐Planck‐Gesellschaft (MPG) http://dx.doi.org/10.13039/501100004189Peer Reviewe

SOAT1: a suitable target for therapy in high-grade astrocytic glioma?

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages

SOAT1: A Suitable Target for Therapy in High-Grade Astrocytic Glioma?

Targeting molecular alterations as an effective treatment for isocitrate dehydrogenasewildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages

Recommendations from the United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis

In collaboration with United European Gastroenterology, the working group on 'Harmonizing diagnosis and treatment of chronic pancreatitis across Europe' (HaPanEU) developed European guidelines for the management of chronic pancreatitis using an evidence-based approach.Recommendations of multidisciplinary review groups based on systematic literature reviews to answer predefined clinical questions are summarised. Recommendations are graded using the Grading of Recommendations Assessment, Development and Evaluation system.Recommendations covered topics related to the clinical management of chronic pancreatitis: aetiology, diagnosis of chronic pancreatitis with imaging, diagnosis of pancreatic exocrine insufficiency, surgical therapy, medical therapy, endoscopic therapy, treatment of pancreatic pseudocysts, pancreatic pain, nutrition and malnutrition, diabetes mellitus and the natural course of the disease and quality of life.The HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research. This article summarises the HaPanEU recommendations and statements

Life-threatening intoxication with methylene bis(thiocyanate): clinical picture and pitfalls. A case report

BACKGROUND: Methylene bis(thiocyanate) (MBT) is a microbiocidal agent mainly used in industrial water cooling systems and paper mills as an inhibitor of algae, fungi, and bacteria. CASE PRESENTATION: We describe the first case of severe intoxication following inhalation of powder in an industrial worker. Profound cyanosis and respiratory failure caused by severe methemoglobinemia developed within several minutes. Despite immediate admission to the intensive care unit, where mechanical ventilation and hemodialysis for toxin elimination were initiated, multi-organ failure involving liver, kidneys, and lungs developed. While liver failure was leading, the patient was successfully treated with the MARS (molecular adsorbent recirculating system) procedure. CONCLUSION: Intoxication with MBT is a potentially life-threatening intoxication causing severe methemoglobinemia and multi-organ failure. Extracorporeal liver albumin dialysis (MARS) appears to be an effective treatment to allow recovery of hepatic function