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LAL deficiency

Ryan W Himes, Sarah E Barlow, Kevin Bove, Norma M Quintanilla, Rachel Sheridan, Rohit Kohli
Lysosomal acid lipase deficiency (LAL-D) is a classic lysosomal storage disorder characterized by accumulation of cholesteryl ester and triglyceride. Although it is associated with progressive liver injury, fibrosis, and end-stage liver disease in children and adolescents, LAL-D frequently presents with nonspecific signs that overlap substantially with other, more common, chronic conditions like nonalcoholic fatty liver disease (NAFLD), metabolic syndrome, and certain inherited dyslipidemias. We present 2 children with NAFLD who achieved clinically significant weight reduction through healthy eating and exercise, but who failed to have the anticipated improvements in aminotransferases and γ-glutamyl transferase...
September 13, 2016: Pediatrics
Shruti Lal, Mahsa Zarei, Saswati N Chand, Emanuela Dylgjeri, Nicole C Mambelli-Lisboa, Michael J Pishvaian, Charles J Yeo, Jordan M Winter, Jonathan R Brody
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, in part, because of the lack of effective targeted therapeutic options. MK-1775 (also known as AZD1775), a mitotic inhibitor, has been demonstrated to enhance the anti-tumor effects of DNA damaging agents such as gemcitabine. We evaluated the efficacy of MK-1775 alone or in combination with DNA damaging agents (MMC or oxaliplatin) in PDA cell lines that are either DNA repair proficient (DDR-P) or deficient (DDR-D). PDA cell lines PL11, Hs 766T and Capan-1 harboring naturally selected mutations in DNA repair genes FANCC, FANCG and BRCA2 respectively, were less sensitive to MK-1775 as compared to two out of four representative DDR-P (MIA PaCa2 and PANC-1) cell lines...
2016: Scientific Reports
Anu Gupta, Sudesh Prabhakar, Manish Modi, Sanjay K Bhadada, Mani Kalaivani, Vivek Lal, Dheeraj Khurana
BACKGROUND AND AIMS: Vitamin D deficiency is a common problem in stroke survivors. Observational studies have reported an association of low vitamin D levels with greater stroke severity, poststroke mortality and functional disability. Randomised clinical trials are lacking. We sought to assess the effect of calcium and vitamin D supplementation in ischaemic stroke survivors with vitamin D deficiency/insufficiency on disability/mortality outcomes. METHODS: In this randomised controlled open-label trial, 73 patients of acute ischaemic stroke were screened for serum 25 hydroxy Vitamin D (25(OH)D) levels...
September 2016: International Journal of Clinical Practice
Ting Zhao, Cong Yan, Hong Du
Bone marrow mesenchymal stem cells (MSCs) are an important participant in the tumor microenvironment, in which they promote tumor growth and progression. Here we report for the first time that depletion of lysosomal acid lipase (LAL) in MSCs impairs their abilities to stimulate tumor growth and metastasis both in allogeneic and syngeneic mouse models. Reduced cell viability was observed in LAL-deficient (lal-/-) MSCs, which was a result of both increased apoptosis and decreased proliferation due to cell cycle arrest...
August 12, 2016: Oncotarget
Ting Zhao, Xinchun Ding, Hong Du, Cong Yan
Lysosomal acid lipase (LAL), a key enzyme in the metabolic pathway of neutral lipids, has a close connection with inflammation and tumor progression. One major manifestation in LAL-deficient (Lipa(-/-)) mice is an increase of tumor growth and metastasis associated with expansion of myeloid-derived suppressor cells. In the lung, LAL is highly expressed in alveolar type II epithelial cells. To assess how LAL in lung epithelial cells plays a role in this inflammation-related pathogenic process, lung alveolar type II epithelial cell-specific expression of human LAL (hLAL) in Lipa(-/-) mice was established by crossbreeding of CCSP-driven rtTA transgene and (TetO)7-CMV-hLAL transgene into Lipa(-/-) mice (CCSP-Tg/KO)...
August 2016: American Journal of Pathology
Barbara Sjouke, Joep C Defesche, Janine S E de Randamie, Albert Wiegman, Sigrid W Fouchier, G Kees Hovingh
BACKGROUND AND AIMS: We recently identified lysosomal acid lipase (LAL) deficiency, a recessive disease caused by mutations in LIPA, in 3 patients with a clinical diagnosis of familial hypercholesterolemia (FH). We aimed to determine the prevalence of LIPA mutations among individuals with a clinical FH diagnosis. METHODS: In 276 patients with phenotypic FH, in whom no genetic basis for their phenotype was found, LIPA was sequenced. All variants were assessed for pathogenicity using a literature search and in silico prediction models...
August 2016: Atherosclerosis
S Sreekantam, I Nicklaus-Wollenteit, J Orr, K Sharif, S Vijay, P J McKiernan, S Santra
Late-onset LAL deficiency, previously referred to as cholesteryl ester storage disorder, is a rare lysosomal storage disorder characterized by accumulation of cholesteryl esters. It has a heterogeneous clinical phenotype including abdominal pain, poor growth, hyperlipidemia with vascular complications and hepatosplenomegaly. End-stage liver disease may occur, but there are few reports of successful LT. There are also concerns that systemic manifestations of the disease might persist post-LT. We report a case with excellent outcome eight yr following LT...
September 2016: Pediatric Transplantation
Lukas Grumet, Thomas O Eichmann, Ulrike Taschler, Kathrin A Zierler, Christina Leopold, Tarek Moustafa, Branislav Radovic, Matthias Romauch, Cong Yan, Hong Du, Guenter Haemmerle, Rudolf Zechner, Peter Fickert, Dagmar Kratky, Robert Zimmermann, Achim Lass
Lysosomal acid lipase (LAL) is essential for the clearance of endocytosed cholesteryl ester and triglyceride-rich chylomicron remnants. Humans and mice with defective or absent LAL activity accumulate large amounts of cholesteryl esters and triglycerides in multiple tissues. Although chylomicrons also contain retinyl esters (REs), a role of LAL in the clearance of endocytosed REs has not been reported. In this study, we found that murine LAL exhibits RE hydrolase activity. Pharmacological inhibition of LAL in the human hepatocyte cell line HepG2, incubated with chylomicrons, led to increased accumulation of REs in endosomal/lysosomal fractions...
August 19, 2016: Journal of Biological Chemistry
Mario Mastrangelo, Ingrid E Scheffer, Nuria C Bramswig, Lal D V Nair, Candace T Myers, Maria Lisa Dentici, Georg C Korenke, Kelly Schoch, Philippe M Campeau, Susan M White, Vandana Shashi, Sujay Kansagra, Anthonie J Van Essen, Vincenzo Leuzzi
KCNH1 mutations have been identified in patients with Zimmermann-Laband syndrome and Temple-Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres...
June 1, 2016: Epileptic Disorders: International Epilepsy Journal with Videotape
Hafiza Fizzah Riaz, Karmoon Lal, Saif Ullah, Nadeem Ahmad Bhatti, Waheed Ullah, Sajid Malik
Terminal transverse deficiency of forearm is a very rare limb malformation. Most of the cases have traumatic etiology and congenital presentation is less common. A series of six individuals with transverse deficiency through the hands is presented in this communication. The cases were congenital, morphologically similar and showed loss of four fingers, most often postaxial. The affected arm was reduced in size compared to the contralateral limb and there was distortion of palmer creases. All cases were sporadic and non-syndromic in nature...
March 2016: Pakistan Journal of Medical Sciences Quarterly
Manisha Yadav, Abhishek Kumar Singh, Harish Kumar, Geeta Rao, Bandana Chakravarti, Anagha Gurjar, Shalini Dogra, Sapana Kushwaha, Achchhe Lal Vishwakarma, Prem Narayan Yadav, Dipak Datta, Anil Kumar Tripathi, Naibedya Chattopadhyay, Arun Kumar Trivedi, Sabyasachi Sanyal
BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitor gefitinib (Iressa) is used for treating non-small cell lung cancer. Gefitinib also induces differentiation in acute myeloid leukemia (AML) cell lines and patient samples lacking EGFR by an unknown mechanism. Here we dissected the mechanism of gefitinib action responsible for its EGFR-independent effects. METHODS: Signaling events were analyzed by homogenous time-resolved fluorescence and immunoblotting...
October 2016: Biochimica et Biophysica Acta
Branislav Radović, Nemanja Vujić, Christina Leopold, Stefanie Schlager, Madeleine Goeritzer, Jay V Patankar, Melanie Korbelius, Dagmar Kolb, Julia Reindl, Martin Wegscheider, Tamara Tomin, Ruth Birner-Gruenberger, Matthias Schittmayer, Lukas Groschner, Christoph Magnes, Clemens Diwoky, Saša Frank, Ernst Steyrer, Hong Du, Wolfgang F Graier, Tobias Madl, Dagmar Kratky
AIMS/HYPOTHESIS: Lysosomal acid lipase (LAL) hydrolyses cholesteryl esters and triacylglycerols (TG) within lysosomes to mobilise NEFA and cholesterol. Since LAL-deficient (Lal (-/-) ) mice suffer from progressive loss of adipose tissue and severe accumulation of lipids in hepatic lysosomes, we hypothesised that LAL deficiency triggers alternative energy pathway(s). METHODS: We studied metabolic adaptations in Lal (-/-) mice. RESULTS: Despite loss of adipose tissue, Lal (-/-) mice show enhanced glucose clearance during insulin and glucose tolerance tests and have increased uptake of [(3)H]2-deoxy-D-glucose into skeletal muscle compared with wild-type mice...
August 2016: Diabetologia
Xing Lu, Swetha Parvathaneni, Xiao Ling Li, Ashish Lal, Sudha Sharma
Gene expression changes in the functional absence of a specific RecQ protein, and how that relates to disease outcomes including cancer predisposition and premature aging in RecQ helicase associated syndromes, are poorly understood. Here we describe detailed experimental strategy for identification of RECQ1-regulated transcriptome that led us to uncover a novel association of RECQ1 in regulation of cancer cell migration and invasion. We initiated a focused study to determine whether RECQ1, the most abundant RecQ protein in humans, alters gene expression and also investigated whether RECQ1 binds with G4 motifs predicted to form G-quadruplex structures in the target gene promoters...
October 1, 2016: Methods: a Companion to Methods in Enzymology
Eyal Shteyer, Rivka Villenchik, Mahmud Mahamid, Nidaa Nator, Rifaat Safadi
Fatty liver has become the most common liver disorder and is recognized as a major health burden in the Western world. The causes for disease progression are not fully elucidated but lysosomal impairment is suggested. Here we evaluate a possible role for lysosomal acid lipase (LAL) activity in liver disease. To study LAL levels in patients with microvesicular, idiopathic cirrhosis and nonalcoholic fatty liver disease (NAFLD). Medical records of patients with microvesicular steatosis, cryptogenic cirrhosis and NAFLD, diagnosed on the basis of liver biopsies, were included in the study...
2016: International Journal of Molecular Sciences
Amal Zaghloul, T A M A Al-Bukhari, Nada Bajuaifer, Maged Shalaby, H A Al-Pakistani, Saeed H Halawani, Shirin H Teama, Ghada A Wassif
BACKGROUND: Many formulas from red blood cell (RCB) indices are instructed to differentiate between iron deficiency anemia (IDA) and beta thalassemia trait. None had 100% Youden index. AIM OF THE WORK: To introduce two new formulas and evaluate them in the differentiation between IDA and beta thalassemia trait in adults Saudi (male and female; male; female) in the Makkah region. Furthermore, to evaluate the previous formulas in our population. METHODS: A total of 249 participants, 91 with IDA, 123 with beta thalassemia trait, and 35 healthy persons...
July 2016: Hematology (Amsterdam, Netherlands)
Girdhari Lal, Neeraja Kulkarni, Yumi Nakayama, Amit K Singh, Apoorva Sethi, Bryna E Burrell, C Colin Brinkman, Daiki Iwami, Tianshu Zhang, Thomas Hehlgans, Jonathan S Bromberg
B cells are known to control CD4T cell differentiation in secondary lymphoid tissues. We hypothesized that IL-10 expression by marginal zone precursor (MZP) regulatory B cells controls the differentiation and positioning of effector and regulatory T cells during tolerization. Costimulatory blockade with donor-specific transfusion (DST) and anti-CD40L mAb in C57BL/6 mice induced tolerance to allogeneic cardiac allograft. B cell depletion or IL-10 deficiency in B cells prevented tolerance, resulting in decreased follicular regulatory CD4(+) T cells (Tfr) and increased IL-21 expression by T follicular helper (Tfh) cells in the B cell and T cell zones...
February 2016: Immunology Letters
Sara Boenzi, Federica Deodato, Roberta Taurisano, Bianca Maria Goffredo, Cristiano Rizzo, Carlo Dionisi-Vici
Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time-consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO)...
March 2016: Journal of Lipid Research
Ting Zhao, Hong Du, Janice S Blum, Cong Yan
Lysosomal acid lipase (LAL) is a key enzyme controlling neutral lipid metabolic signaling in myeloid-derived suppressor cells (MDSCs). MDSCs from LAL-deficient (lal-/-) mice directly stimulate cancer cell proliferation. PPARγ ligand treatment inhibited lal-/- MDSCs stimulation of tumor cell growth and metastasis in vivo, and tumor cell proliferation and migration in vitro. In addition, PPARγ ligand treatment impaired lal-/- MDSCs transendothelial migration, and differentiation from lineage-negative cells...
January 12, 2016: Oncotarget
Francesco Baratta, Daniele Pastori, Licia Polimeni, Giulia Tozzi, Francesco Violi, Francesco Angelico, Maria Del Ben
Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental...
2015: International Journal of Molecular Sciences
Xuzhou Yan, Haoze Wang, Cory E Hauke, Timothy R Cook, Ming Wang, Manik Lal Saha, Zhixuan Zhou, Mingming Zhang, Xiaopeng Li, Feihe Huang, Peter J Stang
Materials that organize multiple functionally active sites, especially those with aggregation-induced emission (AIE) properties, are of growing interest due to their widespread applications. Despite promising early architectures, the fabrication and preparation of multiple AIEgens, such as multiple tetraphenylethylene (multi-TPE) units, in a single entity remain a big challenge due to the tedious covalent synthetic procedures often accompanying such preparations. Coordination-driven self-assembly is an alternative synthetic methodology with the potential to deliver multi-TPE architectures with light-emitting characteristics...
December 9, 2015: Journal of the American Chemical Society
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