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hemoglobin switching

Sarinthip Preedagasamzin, Tiwaporn Nualkaew, Tanjitti Pongrujikorn, Natini Jinawath, Ryszard Kole, Suthat Fucharoen, Natee Jearawiriyapaisarn, Saovaros Svasti
Repair of a splicing defect of β-globin pre-mRNA harboring hemoglobin E (HbE) mutation was successfully accomplished in erythroid cells from patients with β-thalassemia/HbE disorder by a synthetic splice-switching oligonucleotide (SSO). However, its application is limited by short-term effectiveness and requirement of lifelong periodic administration of SSO, especially for chronic diseases like thalassemias. Here, we engineered lentiviral vectors that stably express U7 small nuclear RNA (U7 snRNA) carrying the splice-switching sequence of the SSO that restores correct splicing of βE -globin pre-mRNA and achieves a long-term therapeutic effect...
March 14, 2018: Biochemical and Biophysical Research Communications
Chan-Hee Jung, Eun-Jung Rhee, Won-Young Lee, Kyung Wan Min, Vyankatesh K Shivane, Aravind R Sosale, Hak Chul Jang, Choon Hee Chung, Il Seong Nam-Goong
We investigated the long-term efficacy and safety of gemigliptin and the efficacy and safety of gemigliptin treatment after once daily treatment with sitagliptin 100 mg, in patient with type 2 diabetes. This study was a 28-week, extension of a 24-week, randomized, double-blind, parallel study of gemigliptin or sitagliptin, added to ongoing metformin therapy. After randomized to sitagliptin 100 mg qd(S), gemigliptin 25 mg bid (G1), or gemigliptin 50 mg qd(G2) groups and completing treatment of 24 weeks, 118 patients switched from gemigliptin 25 mg bid to 50 mg qd(G1/G2), 111 patients continued gemigliptin 50 mg qd(G2/G2), and 106 patients switched from sitagliptin 100 mg qd to gemigliptin 50 mg qd(S/G2)...
February 13, 2018: Diabetes, Obesity & Metabolism
Samuel Lessard, Mélissa Beaudoin, Stuart H Orkin, Daniel E Bauer, Guillaume Lettre
In humans, fetal erythropoiesis takes place in the liver whereas adult erythropoiesis occurs in the bone marrow. Fetal and adult erythroid cells are not only produced at different sites, but are also distinguished by their respective transcriptional program. In particular, whereas fetal erythroid cells express γ-globin chains to produce fetal hemoglobin (HbF), adult cells express β-globin chains to generate adult hemoglobin. Understanding the transcriptional regulation of the fetal-to-adult hemoglobin switch is clinically important as re-activation of HbF production in adult erythroid cells would represent a promising therapy for the hemoglobin disorders sickle cell disease and β-thalassemia...
February 8, 2018: Human Molecular Genetics
Mohammad Hamid, Sanaz Ershadi Oskouei, Gholamreza Shariati, Esmaeil Babaei, Hamid Galehdari, Alihossein Saberi, Alireza Sedaghat
BACKGROUND: Any mutation in the Krüppel-like factor 1 (KLF1) gene may interfere with its proper related function in the erythropoiesis process and lead to alterations in proper activation of its downstream protein through globin switching, which results in an increase in fetal hemoglobin (HbF). This study aimed to investigate whether KLF1 mutation can associate with high level of HbF in individuals with increased fetal hemoglobin referred for screening of hemoglobinopathies in south of Iran...
February 7, 2018: Journal of Pediatric Hematology/oncology
Jing Zhao, Mengjun Xue, Dorota Gudanis, Hanna Gracz, Gerhard H Findenegg, Zofia Gdaniec, Stefan Franzen
Dehaloperoxidase-hemoglobin is the first hemoglobin identified with biologically-relevant oxidative functions, which include peroxidase, peroxygenase and oxidase activities. Herein we report a study of the protein backbone dynamics of DHP using heteronuclear NMR relaxation methods and molecular dynamics (MD) simulations to address the role of protein dynamics in switching from one function to another. The results show that DHP's backbone helical regions and turns have average order parameters of S2 = 0...
January 12, 2018: Journal of Inorganic Biochemistry
Ting Duan, Chenchen Shi, Jing Zhou, Xiao Lv, Yongli Li, Yiping Luo
This study aimed to test the hypothesis that the aerial survival of the northern snakehead is involved not only with suprabranchial chamber respiration but also with physiological regulations. The aerial survival time and oxygen consumption rate (VO2) were determined in snakeheads with either normal or injured suprabranchial organs. Some hematological and biochemical parameters were assessed during aerial exposure. The results showed that resting VO2 decreased when switching from water to air in both the control and the suprabranchial organ-injured fish, with decreases of 22...
January 22, 2018: Biology Open
Mark Peyrot, Darlene Dreon, Vivien Zraick, Brett Cross, Meng H Tan
INTRODUCTION: A basal-bolus insulin regimen is needed to achieve glycated hemoglobin A1c (HbA1c) below 7.0% in people with type 1 (T1D) or type 2 (T2D) diabetes who have significant loss of beta-cell function. Nonadherence to therapy is common and negatively affects the ability to reach treatment goals. We examined patient assessment of a new, wearable mealtime insulin-delivery system (patch) relative to their current mealtime insulin-delivery system (syringe, pen, or pump). The patch is designed to deliver only boluses of fast-acting insulin (no basal insulin), mechanically controlled by the patient...
January 11, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
E A Akam, R D Utterback, J R Marcero, H A Dailey, E Tomat
The iron metabolism of malignant cells, which is altered to ensure higher acquisition and utilization, motivates the investigation of iron chelation strategies in cancer treatment. In a prochelation approach aimed at increasing intracellular specificity, disulfide reduction/activation switches are incorporated on iron-binding scaffolds resulting in intracellularly activated scavengers. Herein, this strategy is applied to several tridentate donor sets including thiosemicarbazones, aroylhydrazones and semicarbazones...
January 4, 2018: Journal of Inorganic Biochemistry
Shaloo Gupta, Hongwei Wang, Neil Skolnik, Liyue Tong, Ryan M Liebert, Lulu K Lee, Peter Stella, Anna Cali, Ronald Preblick
INTRODUCTION: Usage patterns and effectiveness of a longer-acting formulation of insulin glargine at a strength of 300 units per milliliter (Gla-300) have not been studied in real-world clinical practice. This study evaluated differences in dosing and clinical outcomes before and after Gla-300 treatment initiation in patients with type 2 diabetes starting or switching to treatment with Gla-300 to assess whether the benefits observed in clinical trials translate into real-world settings...
January 8, 2018: Advances in Therapy
Laura J Norton, Alister P W Funnell, Jon Burdach, Beeke Wienert, Ryo Kurita, Yukio Nakamura, Sjaak Philipsen, Richard C M Pearson, Kate G R Quinlan, Merlin Crossley
Genes encoding the human β-like hemoglobin proteins undergo a developmental switch from fetal γ-globin to adult β-globin expression around the time of birth. β-hemoglobinopathies, such as sickle-cell disease and β-thalassemia, result from mutations affecting the adult β-globin gene. The only treatment options currently available carry significant adverse effects. Analyses of heritable variations in fetal hemoglobin (HbF) levels have provided evidence that reactivation of the silenced fetal γ-globin genes in adult erythroid cells is a promising therapy...
April 25, 2017: Blood Advances
Anabelle Cloutier, Stéfane Lebel, Frédéric Hould, François Julien, Simon Marceau, Léonie Bouvet, Serge Simard, Laurent Biertho
BACKGROUND: Biliopancreatic diversion with duodenal switch (BPD-DS) is one of the most effective bariatric surgeries, in terms of weight loss and remission of co-morbidities. It is however associated with a significant risk of protein and nutritional deficiency, as well as gastrointestinal side effects. OBJECTIVES: To assess the effect of increasing the strict alimentary limb on weight loss, nutritional deficiency and quality of life, compared with standard BPD-DS...
January 2018: Surgery for Obesity and related Diseases: Official Journal of the American Society for Bariatric Surgery
Rebecca Ortolano, Melissa Forouhar, Anne Warwick, David Harper
Congenital dyserythropoetic anemias (CDA) represent a heterogeneous group of inherited red cell disorders resulting in ineffective erythropoiesis. Several CDA variants have been identified. KLF1 is a transcription factor required for cell division in erythroid differentiation and maturation, and the switch from fetal to adult hemoglobin. Mutations in KLF1 gene can result in a wide range of phenotypes. This case illustrates the E325K mutation in KLF1 presenting with severe anemia in infancy, persistently elevated fetal hemoglobin, and progressive improvement with age...
December 1, 2017: Journal of Pediatric Hematology/oncology
Amanda L Richards, Heather L Howie, Linda M Kapp, Jeanne E Hendrickson, James C Zimring, Krystalyn E Hudson
Autoimmune hemolytic anemia (AIHA) results from breakdown of humoral tolerance to RBC antigens. Past analyses of B-cell receptor transgenic (BCR-Tg) mice that recognize RBC autoantigens led to a paradigm in which autoreactive conventional B-2 B cells are deleted whereas extramedullary B-1 B cells escape deletion due to lack of exposure to RBCs. However, BCR-Tg mice utilized to shape the current paradigm were unable to undergo receptor editing or class-switching. Given the importance of receptor editing as mechanism to tolerize autoreactive B cells during central tolerance, we hypothesized that expansion of autoreactive B-1 B cells is a consequence of the inability of the autoreactive BCR to receptor edit...
2017: Frontiers in Immunology
Neelam Lohani, Nupur Bhargava, Anjana Munshi, Sivaprakash Ramalingam
β-hemoglobin disorders, such as β-thalassemia and sickle cell anemia are among the most prevalent inherited genetic disorders worldwide. These disorders are caused by mutations in the gene encoding hemoglobin-β (HBB), a vital protein found in red blood cells (RBCs) that carries oxygen from lungs to all parts of the human body. As a consequence, there has been an enduring interest in this field in formulating therapeutic strategies for the treatment of these diseases. Currently, there is no cure available for hemoglobin disorders, although, some patients have been treated with bone marrow transplantation, whose scope is limited because of the difficulty in finding a histocompatible donor and also due to transplant-associated clinical complications that can arise during the treatment...
November 20, 2017: Journal of Cellular Physiology
Angela Fago, Kim Rohlfing, Elin E Petersen, Agnieszka Jendroszek, Thorsten Burmester
Agnathans have a globin repertoire that markedly differs from that of jawed (gnathostome) vertebrates. The sea lamprey (Petromyzon marinus) harbors at least 18 hemoglobin, two myoglobin, two globin X, and one cytoglobin genes. However, agnathan hemoglobins and myoglobins are not orthologous to their cognates in jawed vertebrates. Thus, blood-based O2 transport and muscle-based O2 storage proteins emerged twice in vertebrates from a tissue-globin ancestor. Notably, the sea lamprey displays three switches in hemoglobin expression in its life cycle, analogous to hemoglobin switching in vertebrates...
February 2018: Biochimica et Biophysica Acta
Nicola Gianotti, Andrea Poli, Silvia Nozza, Laura Galli, Nadia Galizzi, Marco Ripa, Marco Merli, Alessia Carbone, Vincenzo Spagnuolo, Adriano Lazzarin, Antonella Castagna
BACKGROUND: Switch strategies based on rilpivirine/tenofovir/emtricitabine or on an integrase inhibitor (InSTI) plus tenofovir/emtricitabine have never been compared in randomized clinical trials. The main aim of the study was to investigate the durability of these two switch regimens in virologically suppressed, HIV-infected patients. METHODS: Retrospective analysis of patients who started rilpivirine or an InSTI (both with tenofovir and emtricitabine) with <50 HIV-RNA copies/mL and had at least one HIV-RNA assessed while receiving the study regimen...
November 16, 2017: BMC Infectious Diseases
Shuaiying Cui, James Douglas Engel
Reactivation of fetal hemoglobin (HbF) in adult hematopoietic cells has the potential for great clinical benefit in patients bearing deleterious mutations in the β-globin gene, such as β-thalassemia and sickle cell disease (SCD), since increasing the production of HbF can compensate for underproduction of β-globin chains (in β-thalassemia) and it can also disrupt sickle hemoglobin polymerization (in SCD). Thus for the past few decades, concerted efforts have been made to identify an effective way to induce the synthesis of HbF in adult erythroid cells for potential therapeutic relief from the effects of these β-globinopathies...
2017: Advances in Experimental Medicine and Biology
Michel Fischbach, Elke Wühl, Sylvie C Meyer Reigner, Zoe Morgan, Franz Schaefer
BACKGROUND AND OBJECTIVES: The study was conducted to identify a conversion factor for switching from previous erythropoiesis-stimulating agents (ESAs) to continuous erythropoietin receptor activator-methoxy polyethylene glycol-epoetin beta (C.E.R.A.) and to document the efficacy and long-term safety of C.E.R.A. in pediatric patients with anemia of CKD undergoing hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this open-label, multicenter study, patients aged 6-17 years, with stable chronic anemia of CKD, undergoing hemodialysis received C...
January 6, 2018: Clinical Journal of the American Society of Nephrology: CJASN
Mayuko Oita, Hideaki Miyoshi, Kota Ono, Akinobu Nakamura, Kyu Yong Cho, Hiroshi Nomoto, Kohei Yamamoto, Kazuno Omori, Naoki Manda, Yoshio Kurihara, Shin Aoki, Tatsuya Atsumi
We compared treatment satisfaction between daily dipeptidyl peptidase-4 (DPP-4) inhibitors and a weekly DPP-4 inhibitor in patients with type 2 diabetes. The study was a 12-week, open-label, randomized, multicenter, controlled trial. Participants were Japanese patients with type 2 diabetes who had received daily DPP-4 inhibitors for more than 3 months. Patients were randomly assigned to a treatment cohort: (1) a group that continued taking daily DPP-4 inhibitors (daily group); or (2) a group that switched from daily DPP-4 inhibitors to a weekly DPP-4 inhibitor, trelagliptin (weekly group)...
October 31, 2017: Endocrine Journal
Joyce A Lloyd
Many experimental models have been used to study erythropoiesis. Even prior to the advent of the genetic manipulation of animal models, erythropoiesis was examined in the mouse, chicken, sheep, goat, and rabbit, among other vertebrates. Erythroid cell lines derived from human blood cancers were also very useful, as they could be genetically manipulated more easily than whole animals. Genetic models in the mouse, zebrafish, and frog have provided a plethora of information advancing our understanding of erythropoiesis, and remain gold standards in the field for studies of hemoglobin switching, and experiments to study authentic blood cell development...
2018: Methods in Molecular Biology
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