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Health and Economic Burdens of Diabetes and Its Complications
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Prior to developing type 2 diabetes, individuals tend to have a variable period during which they have impaired fasting glucose or impaired glucose tolerance.4 This state has been defined as prediabetes.4 This diagnosis is significant, as the International Diabetes Federation estimated in 2015 that there were approximately 318 million adults with impaired glucose tolerance worldwide, with a projected increase to 482 million by 2040.5 In addition, the annual progression rate from prediabetes to diabetes mellitus is estimated to be approximately 5%–10%.5 Older individuals and individuals with severe insulin resistance, low insulin secretion, and other diabetes risk factors are at even higher risk of progression to diabetes.5 Laboratory confirmation of the diagnosis includes 75-g oral glucose tolerance test with a fasting plasma glucose of 100–125 mg/dL, a 2-hour post-load plasma glucose from 140 to 199 mg/dL, or a hemoglobin A1c from 5.7% to 6.4%.4 Several other markers have been proposed to aid with the diagnosis of prediabetes. These include glycated hemoglobin; 1,5-anhydroglucitol; adiponectin; fetuin-A; certain amino acids, such as isoleucine, leucine, valine, and tyrosine; α-hydroxybutyrate; linoleoyl glycerophosphocholine; lipoprotein A; triglycerides and high-density lipoprotein; ceramide; ferritin and transferrin; mannose-binding lectin serine peptidase; thrombospondin-1; glycosylphosphatidyl-inositol specific phospholipase D1; acyl-carnitine; micro-RNAs; and certain inflammatory markers (i.e., c-reactive protein [CRP] and interleukin [IL]-6, plasminogen activator-inhibitor 1, IL-18, IL-1 receptor antagonist); and even white blood cell, fibrinogen, and hematologic indices.5
Next Generation Sequencing in a Case of Early Onset Hydrops: Closing the Loop on the Diagnostic Odyssey!
Published in Fetal and Pediatric Pathology, 2023
Priya Ranganath, Vineeth VS, Ikromi Rungsung, Ashwin Dalal, Shagun Aggarwal
Chromosomal microarray did not reveal any pathogenic copy number gain or loss. Whole exome sequencing showed a homozygous missense variant c.2023C > T (p. R675W) in exon 18 of the Phospholipase D1 (PLD1) gene (NM_002662.5). This variant is absent in population databases (ExAC, 1000G, gnomAD) and predicted to be disease causing by various in-silico prediction tools (SIFT, Polyphen2, Provean, LRT and Mutation Taster2). Sanger sequencing confirmed the parents as heterozygous for the variant. Three-dimensional molecular modeling using PyMOL showed disruption of hydrogen bond formation in the PLD1 protein with Arg675Trp variant compared to the wild type (Figure 3). Based on the above evidence, this variant is classified as pathogenic, as per the ACMG-AMP 2015 guidelines (PS1, PS3, PS4, PM1, PM2, PP3, PP4) (Figure 4).
Signaling mechanisms of the platelet glycoprotein Ib-IX complex
Published in Platelets, 2022
Yaping Zhang, Samuel M Ehrlich, Cheng Zhu, Xiaoping Du
GPIb-IX-mediated platelet activation signaling has two phases. The early-phase signal induced by ligand binding to GPIb-IX activates the ligand binding function of integrin αIIbβ3. The late-phase amplification signal is mainly mediated by the integrin outside-in signaling pathway and integrin-stimulated ITAM signaling. These two phases are reflected in the intracellular calcium elevation induced by VWF binding to GPIb-IX. Under shear stress, platelet adhesion to VWF is associated with two major peaks of calcium elevation; a small peak associated with GPIb-IX early signaling followed by a late, but more robust integrin-dependent peak [36]. Similar to other platelet agonist signaling pathways, GPIb-IX-mediated calcium elevation is mediated by IP3-dependent intracellular store release and requires phospholipase C (PLC), particularly PLCγ, which cleaves phospholipids to release IP3 [12,94]. Whereas the exact pathway of GPIb-IX specific PLC activation is not completely clear, SFK are clearly required and several of the above-described pathways as well as secondary release of platelet agonists can lead to activation of various PLC isoforms. Also, phospholipase D1 reportedly promotes GPIb-IX-mediated SFK and PLCγ activation [95].
Blockade of PLD1 potentiates the antitumor effects of bortezomib in multiple myeloma cells by inhibiting the mTOR/NF-κB signal pathway
Published in Hematology, 2020
Yanfang Wang, Fei Dong, Wei Wan, Zhenhao Zhang, Jing Wang, Hua Wang, Xiaoyan Ke
Phospholipase D1 (PLD1), an enzyme of the PLD superfamily, catalyzes the hydrolysis of phosphatidylcholine into phosphatidic acid (PA) and choline in response to various stimuli. PLD1 is known to participate in several cellular physical functions such as vesicular transport, endocytosis, cell cycle progression, and T cell receptor-mediated primary and secondary immune responses [7–9]. It is also implicated in a variety of human diseases ranging from viral infections to neurodegeneration and cancer [10–12]. PLD1 is highly expressed in multiple tumors including breast, colorectal, glioma, and prostate cancers [13]. An upregulated PLD1 is positively associated with angiogenesis, invasion, distant metastasis as well as drug resistance through activation of downstream signal pathways such as the mechanistic target of rapamycin (mTOR), Ras, and PI3K-NF-κB [14–17]. Therefore, inhibition or elimination of PLD1 activity may reduce tumor growth and metastasis. In addition, previous results suggested that PLD1 plays vital roles in cancer progression and it may be a potential therapeutic target [18].