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https://www.readbyqxmd.com/read/29920486/use-of-gene-expression-analysis-for-discrimination-of-primary-and-secondary-adenocarcinoma-of-the-liver
#1
Holger G Hass, Ulrich Vogel, Michael Scheurlen, Jürgen Jobst
BACKGROUND: Due to late diagnosis and resistance to chemotherapy, most patients with cholangiocarcinoma have an unfavorable prognosis. Despite the use of immunohistochemistry (IHC) in clinical routine, differentiation between intrahepatic cholangiocarcinoma (ICC) and secondary adenocarcinomas of the liver is frequently not clear, leading to false diagnosis and treatment decisions. METHODS: Oligonucleotide microarrays (Affymetrix Hu133A©) were used for gene expression analysis of ICC (n = 11) and secondary adenocarcinomas (colorectal metastases; n = 6)...
June 19, 2018: Oncology
https://www.readbyqxmd.com/read/29898395/pogz-is-required-for-silencing-mouse-embryonic-%C3%AE-like-hemoglobin-and-human-fetal-hemoglobin-expression
#2
Bjorg Gudmundsdottir, Kristbjorn O Gudmundsson, Kimberly D Klarmann, Satyendra K Singh, Lei Sun, Shweta Singh, Yang Du, Vincenzo Coppola, Luke Stockwin, Nhu Nguyen, Lino Tessarollo, Leifur Thorsteinsson, Olafur E Sigurjonsson, Sveinn Gudmundsson, Thorunn Rafnar, John F Tisdale, Jonathan R Keller
Fetal globin genes are transcriptionally silenced during embryogenesis through hemoglobin switching. Strategies to derepress fetal globin expression in the adult could alleviate symptoms in sickle cell disease and β-thalassemia. We identified a zinc-finger protein, pogo transposable element with zinc-finger domain (POGZ), expressed in hematopoietic progenitor cells. Targeted deletion of Pogz in adult hematopoietic cells in vivo results in persistence of embryonic β-like globin expression without affecting erythroid development...
June 12, 2018: Cell Reports
https://www.readbyqxmd.com/read/29884740/metformin-induces-foxo3-dependent-fetal-hemoglobin-production-in-human-primary-erythroid-cells
#3
Yankai Zhang, Alireza Paikari, Pavel Sumazin, Carly C Ginter Summarell, Jacy R Crosby, Eric Boerwinkle, Mitchell J Weiss, Vivien A Sheehan
Induction of red blood cell fetal hemoglobin (HbF, α2γ2) ameliorates the pathophysiology of sickle cell disease (SCD) by reducing the concentration of sickle hemoglobin (HbS, α2βS 2) to inhibit its polymerization. Hydroxyurea (HU), the only FDA-approved drug for SCD, acts in part by inducing HbF, but is not fully effective, reflecting the need for new therapies. Whole exome sequence analysis of rare genetic variants in SCD patients identified FOXO3 as a candidate regulator of RBC HbF. We validated these genomic findings through loss and gain of function studies in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation...
June 8, 2018: Blood
https://www.readbyqxmd.com/read/29879141/a-survey-of-genetic-fetal-haemoglobin-modifiers-in-nigerian-patients-with-sickle-cell-anaemia
#4
Titilope A Adeyemo, Oyesola O Ojewunmi, Idat A Oyetunji, Helen Rooks, David C Rees, Adebola O Akinsulie, Alani S Akanmu, Swee Lay Thein, Stephan Menzel
Genetic variants at three quantitative trait loci (QTL) for fetal haemoglobin (HbF), BCL11A, HBS1L-MYB and the β-globin gene cluster, have attracted interest as potential targets of therapeutic strategies for HbF reactivation in sickle cell anaemia (SCA). We carried out the first systematic evaluation of critical single nucleotide polymorphisms at these disease modifier loci in Nigerian patients with SCA. Common variants for BCL11A and HBS1L-MYB were strongly associated with HbF levels. At both loci, secondary association signals were detected, illustrating the mapping resolution attainable in this population...
2018: PloS One
https://www.readbyqxmd.com/read/29791856/activation-of-the-arterial-program-drives-development-of-definitive-hemogenic-endothelium-with-lymphoid-potential
#5
Mi Ae Park, Akhilesh Kumar, Ho Sun Jung, Gene Uenishi, Oleg V Moskvin, James A Thomson, Igor I Slukvin
Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment of blood diseases and immunotherapies. In the embryo, lymphoid progenitors and hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries but not veins. Here, we show that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhanced the formation of arterial-type HE expressing DLL4 and CXCR4...
May 22, 2018: Cell Reports
https://www.readbyqxmd.com/read/29610478/natural-regulatory-mutations-elevate-the-fetal-globin-gene-via-disruption-of-bcl11a-or-zbtb7a-binding
#6
Gabriella E Martyn, Beeke Wienert, Lu Yang, Manan Shah, Laura J Norton, Jon Burdach, Ryo Kurita, Yukio Nakamura, Richard C M Pearson, Alister P W Funnell, Kate G R Quinlan, Merlin Crossley
β-hemoglobinopathies such as sickle cell disease (SCD) and β-thalassemia result from mutations in the adult HBB (β-globin) gene. Reactivating the developmentally silenced fetal HBG1 and HBG2 (γ-globin) genes is a therapeutic goal for treating SCD and β-thalassemia 1 . Some forms of hereditary persistence of fetal hemoglobin (HPFH), a rare benign condition in which individuals express the γ-globin gene throughout adulthood, are caused by point mutations in the γ-globin gene promoter at regions residing ~115 and 200 bp upstream of the transcription start site...
April 2018: Nature Genetics
https://www.readbyqxmd.com/read/29606353/direct-promoter-repression-by-bcl11a-controls-the-fetal-to-adult-hemoglobin-switch
#7
Nan Liu, Victoria V Hargreaves, Qian Zhu, Jesse V Kurland, Jiyoung Hong, Woojin Kim, Falak Sher, Claudio Macias-Trevino, Julia M Rogers, Ryo Kurita, Yukio Nakamura, Guo-Cheng Yuan, Daniel E Bauer, Jian Xu, Martha L Bulyk, Stuart H Orkin
Fetal hemoglobin (HbF, α2 γ2 ) level is genetically controlled and modifies severity of adult hemoglobin (HbA, α2 β2 ) disorders, sickle cell disease, and β-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from γ- to β- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence...
April 5, 2018: Cell
https://www.readbyqxmd.com/read/29581848/aberrant-expression-of-nkl-homeobox-gene-hlx-in-hodgkin-lymphoma
#8
Stefan Nagel, Claudia Pommerenke, Corinna Meyer, Maren Kaufmann, Roderick A F MacLeod, Hans G Drexler
NKL homeobox genes are basic regulators of cell and tissue differentiation, many acting as oncogenes in T-cell leukemia. Recently, we described an hematopoietic NKL-code comprising six particular NKL homeobox genes expressed in hematopoietic stem cells and lymphoid progenitors, unmasking their physiological roles in the development of these cell types. Hodgkin lymphoma (HL) is a B-cell malignancy showing aberrant activity of several developmental genes resulting in disturbed B-cell differentiation. To examine potential concordances in abnormal lymphoid differentiation of T- and B-cell malignancies we analyzed the expression of the hematopoietic NKL-code associated genes in HL, comprising HHEX, HLX, MSX1, NKX2-3, NKX3-1 and NKX6-3...
March 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29555644/biological-impact-of-%C3%AE-genes-%C3%AE-haplotypes-and-g6pd-activity-in-sickle-cell-anemia-at-baseline-and-with-hydroxyurea
#9
Françoise Bernaudin, Cécile Arnaud, Annie Kamdem, Isabelle Hau, Françoise Lelong, Ralph Epaud, Corinne Pondarré, Serge Pissard
Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major β-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, β haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Créteil pediatric cohort with available α-gene and β-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study...
March 27, 2018: Blood Advances
https://www.readbyqxmd.com/read/29469608/bcl11a-and-mdr1-expressions-have-prognostic-impact-in-patients-with-acute-myeloid-leukemia-treated-with-chemotherapy
#10
Guo Xutao, Shi PengCheng, Li Yin, Dong Huijuan, Wang Yan, Zheng Haiqing, Xu Bing
Acute myeloid leukemia (AML) is a heterogeneous malignant disease. Many different genetic factors can affect a patient's clinical outcome. AIM: The aim of this study was to assess the expression of BCL11A and MDR1 in AML patients, and its relation to clinical outcome. MATERIALS & METHODS: We grouped the 142 patients by the levels of BCL11A and MDR1 and identified three different subgroups: high BCL11A and high MDR1 (n = 47), low BCL11A and low MDR1 (n = 47) and high BCL11A alone or high MDR1 alone (n = 48)...
March 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29457528/quantitative-trait-loci-influencing-hb-f-levels-in-southern-thai-hb-e-hbb-c-79g-a-heterozygotes
#11
Aumpika Kesornsit, Nutjaree Jeenduang, Dararat Horpet, Thunyaluk Plyduang, Manit Nuinoon
Variation of fetal hemoglobin (Hb F) expression in heterozygous Hb E (HBB: c.79G>A) individuals is associated with several genetic modifiers and not well understood. This study was undertaken in order to determine the effect of single nucleotide polymorphisms (SNPs), including XmnI G γ (rs7482144), rs766432 on the BCL11A gene and rs9376074 on the HBS1L gene, on Hb F levels in Southern Thai heterozygous Hb E individuals. A total of 97 Southern Thai subjects carrying heterozygous Hb E were selected for the hematological study...
January 2018: Hemoglobin
https://www.readbyqxmd.com/read/29416785/predictors-of-lymphovascular-invasion-identified-from-pathological-factors-in-chinese-patients-with-breast-cancer
#12
Sandi Shen, Gaofang Xiao, Richang Du, Ningdong Hu, Xu Xia, Haibo Zhou
This study aimed to evaluate correlations between lymphovascular invasion (LVI) and the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki-67, CK5/6, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), E-cadherin, BCL11A and P53 in invasive breast cancer and to identify predictors of LVI based on these pathological factors. In all, 392 paraffin-embedded tissues from consecutive patients with primary operable invasive breast cancer were included...
January 5, 2018: Oncotarget
https://www.readbyqxmd.com/read/29389946/the-effect-of-histone-deacetylase-inhibitors-on-ahsp-expression
#13
Mohammad Ali Okhovat, Katayoun Ziari, Reza Ranjbaran, Negin Nikouyan
Alpha-hemoglobin stabilizing protein (AHSP) is a molecular chaperone that can reduce the damage caused by excess free α-globin to erythroid cells in patients with impaired β-globin chain synthesis. We assessed the effect of sodium phenylbutyrate and sodium valproate, two histone deacetylase inhibitors (HDIs) that are being studied for the treatment of hemoglobinopathies, on the expression of AHSP, BCL11A (all isoforms), γ-globin genes (HBG1/2), and some related transcription factors including GATA1, NFE2, EKLF, KLF4, and STAT3...
2018: PloS One
https://www.readbyqxmd.com/read/29325430/rapid-and-sensitive-assessment-of-globin-chains-for-gene-and-cell-therapy-of-hemoglobinopathies
#14
Constantinos C Loucari, Petros Patsali, Thamar B van Dijk, Coralea Stephanou, Panayiota Papasavva, Maria Zanti, Ryo Kurita, Yukio Nakamura, Soteroulla Christou, Maria Sitarou, Sjaak Philipsen, Carsten W Lederer, Marina Kleanthous
The β-hemoglobinopathies sickle cell anemia and β-thalassemia are the focus of many gene-therapy studies. A key disease parameter is the abundance of globin chains because it indicates the level of anemia, likely toxicity of excess or aberrant globins, and therapeutic potential of induced or exogenous β-like globins. Reversed-phase high-performance liquid chromatography (HPLC) allows versatile and inexpensive globin quantification, but commonly applied protocols suffer from long run times, high sample requirements, or inability to separate murine from human β-globin chains...
February 2018: Human Gene Therapy Methods
https://www.readbyqxmd.com/read/29296711/klf1-directly-activates-expression-of-the-novel-fetal-globin-repressor-zbtb7a-lrf-in-erythroid-cells
#15
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
https://www.readbyqxmd.com/read/29276718/a-nonhuman-primate-transplantation-model-to-evaluate-hematopoietic-stem-cell-gene-editing-strategies-for-%C3%AE-hemoglobinopathies
#16
Olivier Humbert, Christopher W Peterson, Zachary K Norgaard, Stefan Radtke, Hans-Peter Kiem
Reactivation of fetal hemoglobin (HbF) is a promising approach for the treatment of β-hemoglobinopathies and the targeting of genes involved in HbF regulation is under intensive investigation. Here, we established a nonhuman primate (NHP) transplantation model to evaluate hematopoietic stem cell (HSC)-based gene editing strategies aimed at reactivating HbF. We first characterized the transient HbF induction to autologous HSC transplantation in pigtailed macaques, which was comparable in duration and amplitude to that of human patients...
March 16, 2018: Molecular Therapy. Methods & Clinical Development
https://www.readbyqxmd.com/read/29227829/a-long-noncoding-rna-from-the-hbs1l-myb-intergenic-region-on-chr6q23-regulates-human-fetal-hemoglobin-expression
#17
Tasha A Morrison, Ibifiri Wilcox, Hong-Yuan Luo, John J Farrell, Ryo Kurita, Yukio Nakamura, George J Murphy, Shuaiying Cui, Martin H Steinberg, David H K Chui
The HBS1L-MYB intergenic region (chr6q23) regulates erythroid cell proliferation, maturation, and fetal hemoglobin (HbF) expression. An enhancer element within this locus, highlighted by a 3-bp deletion polymorphism (rs66650371), is known to interact with the promoter of the neighboring gene, MYB, to increase its expression, thereby regulating HbF production. RNA polymerase II binding and a 50-bp transcript from this enhancer region reported in ENCODE datasets suggested the presence of a long noncoding RNA (lncRNA)...
March 2018: Blood Cells, Molecules & Diseases
https://www.readbyqxmd.com/read/29205277/clinical-and-genetic-factors-are-associated-with-pain-and-hospitalisation-rates-in-sickle-cell-anaemia-in-cameroon
#18
Ambroise Wonkam, Khuthala Mnika, Valentina J Ngo Bitoungui, Bernard Chetcha Chemegni, Emile R Chimusa, Collet Dandara, Andre P Kengne
We aimed to investigate the clinical and genetic predictors of painful vaso-occlusive crises (VOC) in sickle cell disease (SCD) in Cameroon. Socio-demographics, clinical variables/events and haematological indices were acquired. Genotyping was performed for 40 variants in 17 pain-related genes, three fetal haemoglobin (HbF)-promoting loci, two kidney dysfunctions-related genes, and HBA1/HBA2 genes. Statistical models using regression frameworks were performed in R® . A total of 436 hydoxycarbamide- and opioid-naïve patients were studied; median age was 16 years...
January 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29193029/recent-progress-in-understanding-and-manipulating-haemoglobin-switching-for-the-haemoglobinopathies
#19
REVIEW
Divya S Vinjamur, Daniel E Bauer, Stuart H Orkin
The major β-haemoglobinopathies, sickle cell disease and β-thalassaemia, represent the most common monogenic disorders worldwide and a steadily increasing global disease burden. Allogeneic haematopoietic stem cell transplantation, the only curative therapy, is only applied to a small minority of patients. Common clinical management strategies act mainly downstream of the root causes of disease. The observation that elevated fetal haemoglobin expression ameliorates these disorders has motivated longstanding investigations into the mechanisms of haemoglobin switching...
March 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29186860/bcl11a-mrna-targeting-by-mir-210-a-possible-network-regulating-%C3%AE-globin-gene-expression
#20
Jessica Gasparello, Enrica Fabbri, Nicoletta Bianchi, Giulia Breveglieri, Cristina Zuccato, Monica Borgatti, Roberto Gambari, Alessia Finotti
The involvement of microRNAs in the control of repressors of human γ-globin gene transcription has been firmly demonstrated, as described for the miR-486-3p mediated down-regulation of BCL11A. On the other hand, we have reported that miR-210 is involved in erythroid differentiation and, possibly, in γ-globin gene up-regulation. In the present study, we have identified the coding sequence of BCL11A as a possible target of miR-210. The following results sustain this hypothesis: (a) interactions between miR-210 and the miR-210 BCL11A site were demonstrated by SPR-based biomolecular interaction analysis (BIA); (b) the miR-210 site of BCL11A is conserved through molecular evolution; (c) forced expression of miR-210 leads to decrease of BCL11A-XL and increase of γ-globin mRNA content in erythroid cells, including erythroid precursors isolated from β-thalassemia patients...
November 26, 2017: International Journal of Molecular Sciences
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