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Mucolipidosis II and III/ (I-cell disease and pseudo-Hurler polydystrophy) N-acetyl-glucosaminyl-l-phosphotransferase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Mucolipidosis II and III reflect multiple deficiencies of many lysosomal hydrolases that require post-translational processing to form the recognition site that permits their cellular uptake. The fundamental defect is in N-acetylglucosaminyl-l-phosphotransferase (GlcNAc phosphotransferase) (Figure 83.2) [1]. The lysosomal enzyme substrates for this enzyme are glycoproteins containing reactive mannose molecules, and in the reaction a GlcNAc phosphate is linked to the mannose; a subsequent phosphodiesterase reaction cleaves off the GlcNAc, leaving the mannose phosphate recognition site. Patients with I-cell disease, or mucolipidosis II, have complete deficiency of this enzyme, while patients with mucolipidosis III have varying amounts of residual activity of the enzyme. Variable patterns of clinical phenotype in mucolipidosis III reflect the considerable variation in enzyme activity as well as its effect on so very many lysosomal enzymes. The extent of the phenotypic variability has doubtless not yet been defined. Leroy and colleagues [2, 3] gave the disease its name I-cell disease, the I indicating inclusions.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Differential diagnosis: stippling may be a feature of many disorders, which include chondrodysplasia punctata (p. 272); warfarin embryopathy (p. 294); fetal exposure to hydantoin and alcohol; trisomy 18 (p. 586); trisomy 21. CHILD syndrome: an acronym for Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects, a very rare condition which shows unilateral involvement with joint contractures, limb hypoplasia and a wide range of organ malformations (cardiac, genitourinary, endocrine, cerebral); Zellweger syndrome (p. 301); mucolipidosis type 2 (I-cell disease) (p. 381); GM gangliosidosis type 1 – findings are similar to I-cell disease and it is also a storage disorder; Cornelia de Lange syndrome (p. 454); Sjogren syndrome; multiple sulphatase deficiency, a recessive condition caused by mutations in the sulphatase-modifying factor-1 gene (SUMF1), responsible for the activation of all the sulphatase enzymes in the cell. Smith-Lemli-Opitz syndrome – caused by a defect in the enzyme 3 beta-hydroxysterol-delta 7-reductase; this converts 7-dehydrocholesterol to cholesterol (gene DHCR7). This more complex syndrome has characteristic facial traits (bitemporal narrowing, ptosis, broad nasal bridge, short nasal root, anteverted nares, micrognathia), cleft palate, brain anomalies (microcephaly, agenesis of the corpus callo-sum, holoprosencephaly), and anomalies of genital, cardiovascular and gastrointestinal systems. Skeletal anomalies include rhizomelia, postaxial polydactyly, syndactyly of second and third toes and short, proximally placed thumbs.
Cytokines and Alveolar Type II Cells
Published in Jason Kelley, Cytokines of the Lung, 2022
The epithelial lining of the alveolus is composed of two types of cells: the alveolar type I cell and the alveolar type II cell. The alveolar type I cell is a flattened, membranous epithelial cell that is believed to be structured for gas exchange. However, very little is known about the cell biology of the type I cell because this cell cannot be isolated and studied in vitro. In contrast, the alveolar type II cell can be isolated, and its cell biology, biochemistry, and molecular biology have been studied in primary culture and in organ culture. A distinctive morphological characteristic of the type II cell is its organelle, the lamellar body, the storage form of intracellular surfactant (Williams, 1977, 1978). On histopathological examination of rodent lung sections, the alveolar type II cell is characteristically located in the comer of the alveolus. These morphological and topographical characteristics of the alveolar type II cell have led to its designation by a variety of other names, including alveolar type 2 cell, granular pneumocyte, great alveolar cell, type II pneumocyte, and giant comer cell. The major functions of the alveolar type II cell include the synthesis, storage, secretion, and uptake of pulmonary surface active material, proliferation and differentiation into type I cells during lung growth and development and after lung injury, and transepithelial solute transport. Other less well-studied functions of the alveolar type II cell include the production of eicosanoids, interferonlike proteins, and major histocompatibility complex (MHC) class II proteins; basement membrane synthesis; and xenobiotic metabolism. Although the cell biology, biochemistry, and molecular biology of the alveolar type II cell and its role in pulmonary surfactant metabolism have been studied extensively over the past decade, alveolar type II cell production of and interaction with various cytokines have been less well characterized. Therefore, for the purposes of this review, the definition of cytokines has been expanded to include not only those secreted extracellular signaling proteins that affect closely adjacent cells in an autocrine or paracrine fashion (Kelly, 1990), but also the circulating endocrine hormones. This review focuses on the effects of cytokines on the major alveolar type II cell functions and discusses alveolar type II cell production of and interaction with cytokines.
H22954, a long non-coding RNA, inhibits glucose uptake in leukemia cells in a GLUT10-dependent manner
Published in Hematology, 2022
Yujia Bai, Bibo Ye, Tianyu Li, Rongrong Wang, Xiaofei Qi
As a novel lncRNA, H22954 inhibited the development and progression of AML both in vitro and in vivo. In the present study, we found that lactic acid production was inhibited in K562 cells culture medium with H22954 overexpression, resulting in lower glucose uptake in these cells. Similar results were observed in NB4 cells. In SHI-I cells, supportive results were also observed when H22954 was knocked down. According to the qRT-PCR results, the expression of pyruvate kinase M (PKM) and lactate dehydrogenase A (LDHA), two key molecules in aerobic glycolysis [16,17], showed no significant or consistent changes in K562 or SHI-I cells with H22954 overexpression or knockdown (Supplement Figure S2), implying that H22954 regulated ‘aerobic glycolysis’ in leukemia cells depends on glucose uptake.
Current and emerging pharmacotherapy for Gaucher disease in pediatric populations
Published in Expert Opinion on Pharmacotherapy, 2021
Richard Sam, Emory Ryan, Emily Daykin, Ellen Sidransky
In 1964, Christian de Duve first suggested that lysosomal storage diseases might be treated by enzyme replacement. Dr. Roscoe O. Brady, having discovered that deficient GCase led to the development of GD, first proposed a strategy to replace the missing enzyme by supplementing deficient enzyme [70,71]. The proof-of-concept of ERT was initially established in vitro in the monogenic disorder I-cell disease [72]. However, implementing ERTs for patients with GD1 required the production of purified, concentrated enzyme from human origins. Over three decades, the development of ERTs focused on assessing the efficacy of placenta-derived GCase, alglucerase, and then finally recombinant GCase, or imiglucerase. The recombinant protein, generated using Chinese hamster ovary (CHO) cells in the mid-1990s, continues to serve as the most widely used GCase in clinics globally. Several other forms of the recombinant enzyme, including taliglucerase and velaglucerase alpha, which are produced in plant cells and human fibrosarcoma lines, respectively, subsequently received approval and are used to treat GD [73,74] (Table 2). The enzyme preparations are all administered intravenously. Some patients receive infusions at clinics, hospitals, or at home through either self-administration or administration by visiting nurses.
Trial watch: intratumoral immunotherapy
Published in OncoImmunology, 2021
Juliette Humeau, Julie Le Naour, Lorenzo Galluzzi, Guido Kroemer, Jonathan G. Pol
Therapeutic cancer vaccines are designed to prime an adaptive immunity against neoplastic cells.257,258 They rely on providing an abundant source of tumor-specific antigens (TSAs) or tumor-associated antigens (TAAs) in order to favor their capture and (cross-) presentation to T cells by endogenous DCs. This strategy has the advantage to stimulate a cellular immune response that is highly specific to malignant entities. Cancer vaccines exist in different forms: i) cell lysates, ii) purified antigens, iii) recombinant DNA, RNA, or viruses encoding antigenic determinants, or iv) DCs presenting antigens.259–260 In this dynamic, some efforts are being made for the design of bioinformatics algorithms predicting the binding of antigen epitopes to major histocompatibility complex molecules.261 A proteogenomic approach combining mass spectrometry and RNA sequencing has also been developed for the identification of tumor antigens, including aberrantly expressed TSAs, which remained undetected with previous methods.262,263