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Acute Pancreatitis: Genetic Risk and Clinical Implications.

Acute pancreatitis (AP) is one of the most common gastroenterological indications for emergency admittance and hospitalization. Gallstones, alcohol consumption or the presence of additional initiating factors give rise to a disease with a diverse clinical appearance and a hard-to predict course of progression. One major challenge in the treatment of AP patients is the early identification of patients at risk for the development of systemic complications and organ failure. In addition, 20%-30% of patients with a first episode of AP later experience progress to recurrent or chronic disease. Comp

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… In chronic pancreatitis patients a low lipase activity in serum does not rule out the presence of an acute episode, as glandular atrophy and exocrine insufficiency may prevent high lipase activity levels. … Other genetically determined disease mechanisms include mutations in lipase genes like the carboxyl ester lipase ( CEL ) or pancreatic lipase ( PNLIP ) [ 74 , 75 ]. …

A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank.

BACKGROUND & AIMS: The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis. METHODS: We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n = 1,703) and confirming

Genetic polymorphisms associated with fatty liver disease and fibrosis in HIV positive patients receiving combined antiretroviral therapy (cART).

Hepatic steatosis can occur with any antiretroviral therapy (cART). Although single nucleotide polymorphisms (SNPs) have been identified to predispose to alcoholic and non-alcoholic fatty liver disease, their role for treatment-associated steatosis in HIV-positive patients remains unclear. We determined the frequency of PNPLA3 (rs738409), CSPG3/NCAN (rs2228603), GCKR (rs780094), PPP1R3B (rs4240624), TM6SF (rs8542926), LYPLAL1 (rs12137855) and MBOAT7 (rs626283) by RT-PCR in 117 HIV-positive patients on cART and stratified participants based on their "controlled attenuation parameter" (CAP) into

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards

Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysi

Clinical and genetic analysis of lipid storage myopathies.

Causative genes have been identified only in four types of lipid storage myopathies (LSMs): SLC22A5 for primary carnitine deficiency (PCD); ETFA, ETFB, and ETFDH for multiple acyl-coenzyme A dehydrogenation deficiency (MADD); PNPLA2 for neutral lipid storage disease with myopathy (NLSDM); and ABHD5 for neutral lipid storage disease with ichthyosis. However, the frequency of these LSMs has not been determined. We found mutations in only 9 of 37 LSM patients (24%): 3 in SLC22A5; 4 in MADD-associated genes; and 2 in PNPLA2. This low frequency suggests the existence of other causative genes. Muscl

Malnutrition and cachexia in ovarian cancer patients: pathophysiology and management.

In ovarian cancer patients the poor nutritional status and cachexia are caused by the metabolic effects of the enlarging tumor masses and bowel obstruction. These patients may have a high resting energy expenditure due to increase in Cori cycle activity, glucose and triglyceride-fatty acid cycling and gluconeogenesis. Biochemical mediators of cachexia include cytokines, such as tumor necrosis factor and interleukin-6, and tumor-produced catabolic factors, such as lipid-mobilizing factor, proteolysis-inducing factor, and anemia-inducing factor. Mechanisms involved in the pathogenesis of obstruc

A brief clinical genetics review: stepwise diagnostic processes of a monogenic disorder-hypertriglyceridemia.

The completion of the Human Genome Project and tremendous advances in automated high-throughput genetic analysis technologies have enabled explosive progress in the field of genetics, which resulted in countless discoveries of novel genes and pathways. Many phenotype- or disease-associated single nucleotide polymorphisms (SNPs) with a high statistical significance have been identified through numerous genome-wide association studies (GWAS), and various polygenic risk scoring (PRS) schemes have been proposed to identify individuals with a high risk for a certain trait or disorder. Meanwhile, me

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… Familial Lipoprotein Lipase Deficiency, Apo C-II Deficiency, and Hepatic Lipase Deficiency. McGraw-Hill Medical; 2016. 58. Dawson A, Kanukuntla A, Kata P, et al. Pseudohyponatremia Leading to a Fatal Outcome in a Patient With Familial Hypertriglyceridemia. … A novel method for measuring human lipoprotein lipase and hepatic lipase activities in postheparin plasma. J Lipid Res 2008;49:1431-7. 10.1194/jlr.M700528-JLR200 78. Neuger L, Vilaró S, Lopez-Iglesias C, et al. Effects of heparin on the uptake of lipoprotein lipase in rat liver. …

Ezabenlimab and induction chemotherapy followed by adaptive chemoradiotherapy in patients with stage 3 squamous cell anal carcinoma (INTERACT-ION): an open-label, single-arm, phase 2 trial.

BACKGROUND: The standard of care for patients with locally advanced squamous cell anal carcinoma (SCAC) is concurrent chemoradiotherapy; how … [23%]), neutropenia (two [15%]), and diarrhoea (two [15%]) during concurrent chemoradiotherapy; and lipase increase, CMV colitis, and lichen planus (one [3%] each) during maintenance. Serious adverse events occurred in 20 (36%) patients; the most common were diarrhoea, nausea, and neutropenia during induction (two [4%] each). Seven (13%) of 55 patients d …

Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor rece … 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fat …

Rogaratinib in patients with advanced cancers selected by FGFR mRNA expression: a phase 1 dose-escalation and dose-expansion study.

BACKGROUND: The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR ge … ommon grade 3-4 adverse events were fatigue (in 11 [9%] of 126 patients) and asymptomatic increased lipase (in 10 [8%]). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury [NSCLC], hypoglycaemia [other solid tumours], retinopathy [urot …

Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial.

BACKGROUND: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is a … de 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more t …

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of … ost frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (2 …

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial.

BACKGROUND: We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients … eatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group. INTERPRETATION: Despite early study termination, in a preplanned subgroup analys …

Ivacaftor treatment of cystic fibrosis in children aged 12 to <24 months and with a CFTR gating mutation (ARRIVAL): a phase 3 single-arm study.

BACKGROUND: Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutation … increased and concentrations of immunoreactive trypsinogen had decreased from baseline. Mean serum lipase and amylase were raised at baseline and rapidly decreased after treatment was started. INTERPRETATION: Ivacaftor was generally safe and well tolerated in children aged 12 to <24 months for up to 24 weeks and was associated with rapid and sustained …

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study.

BACKGROUND: Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with ch … eks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) pati …

Causes, clinical findings and therapeutic options in chylomicronemia syndrome, a special form of hypertriglyceridemia.

The prevalence of hypertriglyceridemia has been increasing worldwide. Attention is drawn to the fact that the frequency of a special hypertriglyceridemia entity, named chylomicronemia syndrome, is variable among its different forms. The monogenic form, termed familial chylomicronemia syndrome, is rare, occuring in 1 in every 1 million persons. On the other hand, the prevalence of the polygenic form of chylomicronemia syndrome is around 1:600. On the basis of the genetical alterations, other factors, such as obesity, alcohol consumption, uncontrolled diabetes mellitus and certain drugs may sign

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… Lipoprotein lipase (LPL) plays a key role in lipid metabolism. Apolipoprotein (apo) C2 serves as an activator of the enzyme, while lipase maturation factor-1 (LMF1) plays a role in the formation of the proper structure of LPL and regulates its expression. … Péterfy M Lipase maturation factor 1: a lipase chaperone involved in lipid metabolism Biochim Biophys Acta 2012 1821 5 790 794 10.1016/j.bbalip.2011.10.006 22063272 PMC3288453 10. …

The WWOX gene modulates high-density lipoprotein and lipid metabolism.

BACKGROUND: Low levels of high-density lipoprotein (HDL) cholesterol constitutes a major risk factor for atherosclerosis. Recent studies from our group reported a genetic association between the WW domain-containing oxidoreductase (WWOX) gene and HDL cholesterol levels. Here, through next-generation resequencing, in vivo functional studies and gene microarray analyses, we investigated the role of WWOX in HDL and lipid metabolism. METHODS AND RESULTS: Using next-generation resequencing of the WWOX region, we first identified 8 variants significantly associated and perfectly segregating with th

Тип перегонки 1 диабет через ось эндоканнабиноидома-микробиота: системная биологическая перспектива.

Тип 1 диабет (T1D) давно признан аутоиммунным заболеванием на основе Т. Вместе с тем все больше фактов свидетельствует об участии в его развитии факторов, связанных с метаболизмом, подстрекательством и кишечной микробиотой. Эндоканнабиноидная система (ЭКС), являющаяся одним из ключевых регуляторов иммунного и метаболического гомеостаза, все чаще привлекается к аутоиммунной патофизиологии, в частности благодаря ее взаимодействию с кишечными метаболитами. В этой гипотетической статье подчеркивается необходимость пересмотра патофизиологии Т1D путем интеграции дисфункции ЭКС, кишечного дисбиоза и

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… The ECS comprises endocannabinoids (primarily anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), their associated receptors (CB1, CB2, TRPV1, GPR55), and metabolic enzymes such as fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and diacylglycerol lipase (DAGL) ( 6 , 22 ). … Diacylglycerol lipase (DAGL), responsible for 2-AG synthesis, and monoacylglycerol lipase (MAGL), responsible for its degradation, are dynamically regulated by both inflammatory cytokines and microbial metabolites. …

Acute portal vein thrombosis in a 59-year-old male with JAK2 V617F mutation.

Portal vein thrombosis is an uncommon finding that typically arises in the context of cirrhosis. In the acute setting, it may present with abdominal pain, portal hypertension, ascites, gastrointestinal bleeding, or mesenteric ischemia. Local risk factors that predispose its formation include: cirrhosis, hepatocellular carcinoma, pancreatitis, and intraabdominal infection. Systemic factors, including hypercoagulable states and sepsis, also pose an increased risk. JAK2 V617F positive myeloproliferative disorders are associated with systemic prothrombotic states and are a less frequently identifi

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… However, serum amylase and lipase were within normal limits decreasing suspicion for pancreatitis as the primary cause. A multidisciplinary approach was implemented to identify the etiology of the patient's condition, and appropriate therapy was administered. … Serum amylase and lipase were within normal limits. Due to acute abdominal symptoms, the initial study performed was contrast CT with 300 mg intravenous iopromide (Ultravist, Bayer Pharmaceuticals, Berlin, Germany) of the abdomen and pelvis. …