Artículos de revistas: "ITGB3"

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Antosik, Paweł, Michal Jeseta, Wiesława Kranc, Adrian Chachuła, Artur Bryja, Joanna Budna, Sylwia Ciesiółka et al. "Expression of integrins and GDF9 mRNAs is associated with ovarian follicle size and donor puberty status in pigs". Medycyna Weterynaryjna 72, n.º 12 (2016): 750–54. http://dx.doi.org/10.21521/mw.5601.

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Ovarian folliculogenesis and oogenesis has a significant impact on embryo growth and development in preimplantation stages. Although both processes are widely understood in several species of mammals, including pigs, the factors influencing the proper maturation capability of oocytes, as well as the developmental competence of the surrounding somatic granulosa cells (GCs) and cumulus cells (CCs), are still not entirely known. This study aimed to investigate the expression of growth differentiation factor 9 (GDF9) and integrins (ITGB1, ITGB2, ITGB3 and ITGB4) in porcine oocytes isolated from follicles of various size and donors characterized by different puberty status. The relative abundance of GDF9, ITGB1, ITGB2, ITGB3, and ITGB4 mRNAs in porcine oocytes isolated from medium follicles of cycling sows (MFCS), small follicles of juvenile gilts (SFJG), and small follicles of cycling sows (SFCS) was assessed by an RT-qPCR assay. We found an increased expression of GDF9 in oocytes isolated from the small follicles of juvenile gilts as compared to the other two groups (P<0.001). A significant down-regulation of ITGB1 and ITGB2 oocyte mRNAs collected from medium follicles of cycling sows was observed (P<0.05 and P<0.001, respectively). The ITGB3 mRNA expression was significantly decreased in oocytes isolated from small follicles of juvenile gilts (P<0.001), whereas a lower expression of ITGB4 in oocytes from both medium follicles (cycling sows) and small follicles (juvenile gilts) was observed. In conclusion, GDF9 may be recognized as the main factor regulating follicle growth at early stages of folliculogenesis. The expression of ITGBs is significantly regulated by the puberty status of donor pigs, and different follicular sizes may play a subordinate role in integrin expression during in vivo follicle development in pigs.

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Massuto, Dana A., Eric C. Kneese, Gregory A. Johnson, Robert C. Burghardt, R. Neil Hooper, Nancy H. Ing y Laurie A. Jaeger. "Transforming growth factor beta (TGFB) signaling is activated during porcine implantation: proposed role for latency-associated peptide interactions with integrins at the conceptus–maternal interface". REPRODUCTION 139, n.º 2 (febrero de 2010): 465–78. http://dx.doi.org/10.1530/rep-09-0447.

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The process of implantation is mediated by a complex network of signaling and adhesive factors. In the pig, latent and active transforming growth factor beta (TGFB), TGFB receptors (TGFBR), and integrins (ITGs) are present during the peri-implantation period. TGFB signals via TGFBR and activates downstream effector SMAD proteins 2 and 3 (p-SMAD2/3). Latency-associated peptide (LAP), part of the latent TGFB complex, is known to bind to ITG heterodimers and activate TGFB. We hypothesize that active TGFBs and TGFBRs along with LAP and ITGs functionally interact at the conceptus–maternal interface to mediate events essential for conceptus development and attachment in pigs. Uteri and conceptuses from days 10, 12, 16, 20, and 24 pregnant gilts were immunostained for TGFB, LAP, and ITG subunits (ITGAV, ITGB1, ITGB3, ITGB5, ITGB6, and ITGB8). Activation of TGFBRs was evaluated by the presence of phosphorylated downstream effector SMAD2/3. Binding of LAP to ITGs was also evaluated using porcine trophectoderm cells. Abundant active TGFB was detected at the apical surfaces of epithelia at the conceptus–maternal interface, and p-SMAD2/3 was detected at both conceptus attachment and nonattachment sites during implantation. Separate aggregates of LAP, ITGB1, ITGB5, and later ITGB3 were detected at the porcine conceptus–maternal interface, and binding of LAP to ITGs on apical surfaces was demonstrated. Results suggest that functional LAP–ITG adhesion complexes support conceptus attachment and promote TGFB activation leading to TGFB interaction with TGFBR supporting events of porcine implantation.

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Stenhouse, Claire, Charis O. Hogg y Cheryl J. Ashworth. "Association of foetal size and sex with porcine foeto-maternal interface integrin expression". Reproduction 157, n.º 4 (abril de 2019): 317–28. http://dx.doi.org/10.1530/rep-18-0520.

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Integrins regulate adhesion at the foeto-maternal interface by interacting with secreted phosphoprotein 1 (SPP1) and fibronectin (FN). It is hypothesised that impaired foetal growth of ‘runt’ piglets is linked to altered integrin signalling at the foeto-maternal interface. Placental and endometrial samples associated with the lightest and closest to mean litter weight (CTMLW) (gestational day (GD18, 30, 45, 60 and 90), of both sex (GD30, 45, 60 and 90) (n = 5–8 litters/GD), Large White × Landrace conceptuses or foetuses were obtained. The mRNA expression of the integrin subunits (ITG) ITGA2, ITGAV, ITGB1, ITGB3, ITGB5, ITGB6, ITGB8, SPP1 and FN was quantified by qPCR. Temporal changes in mRNA expression were observed, with different profiles in the two tissues. Endometrial ITGB1 (P ≤ 0.05, GD45) and SPP1 (P ≤ 0.05, all GD combined and GD60) expression was decreased in samples supplying the lightest compared to the CTMLW foetuses. Placentas supplying female foetuses had decreased expression of ITGB6 (GD45, P ≤ 0.05) and FN (GD90, P ≤ 0.05) compared to those supplying male foetuses. Endometrial samples supplying females had increased ITGB3 (P ≤ 0.05, GD60) and FN (P ≤ 0.05, GD30) expression and decreased SPP1 (P ≤ 0.05, GD60) expression compared to male foetuses. Correlations between mean within-gilt mRNA expression and percentage prenatal survival, number of live foetuses or conceptuses and percentage male foetuses were observed. This study has highlighted novel and dynamic associations between foetal size, sex and integrin subunit mRNA expression at the porcine foeto-maternal interface. Further studies should be performed to improve the understanding of the mechanisms behind these novel findings.

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Park, Hye Jin, Ji Eun Park, Hyun Lee, Seong Jae Kim, Jung Im Yun, Minseok Kim, Kyu Hyun Park y Seung Tae Lee. "Integrins functioning in uterine endometrial stromal and epithelial cells in estrus". Reproduction 153, n.º 3 (marzo de 2017): 351–60. http://dx.doi.org/10.1530/rep-16-0516.

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Here, as a basic study in the construction of a non-cellular niche that supports artificial organization of three-dimensional endometrial tissue, we defined the types of integrin heterodimers that are expressed transcriptionally, translationally and functionally in endometrial stromal (ES) and endometrial epithelial (EE) cells isolated from the mouse uterus in estrus. Gene and protein expression of integrin subunits were analyzed at the transcriptional and translational level by real-time PCR and fluorescent immunoassay, respectively. Moreover, the functionality of integrin heterodimers was confirmed by attachment and antibody inhibition assays. Itga2, Itga5, Itga6, Itga9, Itgav, Itgb1, Itgb3 and Itgb5 in ES cells, and Itga2, Itga5, Itga6, Itga7, Itga9, Itgav, Itgb1, Itgb3, Itgb4, Itgb5 and Itga6 and in EE cells showed significantly higher transcriptional levels than the other integrin subunits. Furthermore, translational expression of the total integrin α and β subunit genes that showed increased transcription was determined in ES and EE cells. ES cells showed significantly increased adhesion to collagen I, fibronectin and vitronectin, and functional blocking of integrin α2, α5 or αV significantly inhibited adhesion to these molecules. Moreover, EE cells showed significantly increased adhesion to collagen I, fibronectin, laminin and vitronectin, and functional blocking of integrin α2, α5, α6 or αV significantly inhibited adhesion to these molecules. Accordingly, we confirmed that integrin α2β1, α5β1, αVβ1, αVβ3 and/or αVβ5, and integrin α2β1, α5β1, α6β1 and/or α6β4, αVβ1, αVβ3 and/or αVβ5, actively function on the surface of ES and EE cells from mouse uterus in estrus phase, respectively.

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Cockburn, Jessica G., Douglas S. Richardson, Taranjit S. Gujral y Lois M. Mulligan. "RET-Mediated Cell Adhesion and Migration Require Multiple Integrin Subunits". Journal of Clinical Endocrinology & Metabolism 95, n.º 11 (1 de noviembre de 2010): E342—E346. http://dx.doi.org/10.1210/jc.2010-0771.

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Context: The RET receptor tyrosine kinase is an important mediator of several human diseases, most notably of neuroendocrine cancers. These diseases are characterized by aberrant cell migration, a process tightly regulated by integrins. Objective: Our goals were to investigate the role of integrins in RET-mediated migration in two neoplastic cell models: the neural-derived cell line SH-SY5Y, and the papillary thyroid carcinoma cell line TPC-1. We also evaluated whether multiple integrin subunits have a role in RET-mediated cell migration. Design: We evaluated the expression and activation of integrins in response to RET activation using standard cell adhesion and migration (wound-healing) assays. We examined focal adhesion formation, using integrin-paxillin coimmunoprecipitations and immunofluorescence, as an indicator of integrin activity. Results: Our data indicate that β1 integrin (ITGB1) is expressed in both SH-SY5Y and TPC-1 cell lines and that these cells adhere strongly to matrices preferentially associated with ITGB1. We showed that RET can activate ITGB1, and that RET-induced cell adhesion and migration require ITGB1. Furthermore, we showed that β3 integrin (ITGB3) also plays a role in RET-mediated cell adhesion and migration in vitro and ITGB3 expression correlates with RET-mediated invasion in a mouse tumor xenograft model, suggesting that RET mediates the activity of multiple integrin subunits. Conclusions: Our data are the first to show that multiple integrin subunits contribute to cell adhesion and migration downstream of RET, suggesting that coordinated signaling through these pathways is important for cell interactions with the microenvironment during tumor invasion and progression.

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He, Dongmei, Hong Zeng, Jingfei Chen, Lan Xiao, Yuhao Zhao y Nenghui Liu. "H19 regulates trophoblastic spheroid adhesion by competitively binding to let-7". Reproduction 157, n.º 5 (mayo de 2019): 423–30. http://dx.doi.org/10.1530/rep-18-0339.

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Integrin β3 (ITGB3), which is the target gene of the miRNA let-7 that can be antagonized by long noncoding RNA (lncRNA) H19, is well known to have a critical role in endometrium receptivity. However, the regulation of ITGB3 in cell–cell or cell–extracellular matrix adhesion and invasion for the maintenance of early pregnancy remains unknown. This study aimed to explore the role of the H19/let-7/ITGB3 axis in regulating trophoblastic spheroid adhesion and in vitro invasion ability using the HTR-8/SVneo cell line and to investigate the expression levels of lncRNA H19 and ITGB3 in human products of conception. The in vitro knockdown of H19 resulted in decreased expression of ITGB3 at the mRNA and protein levels and reduced the adhesion and invasion ability. In the embryonic chorion tissue of spontaneous abortion (SA), the expressions of H19 and ITGB3 at both the mRNA and protein levels decreased. The results of quantitative RT-PCR, Western blot analysis, dual-luciferase report gene and functional miRNA let-7 rescue experiments, adhesion assay and in vitro transwell invasion assay confirmed that H19 regulated trophoblastic spheroid adhesion with endometrial stromal cells through the H19/let-7/ITGB3 axis, thereby providing an improved understanding of the molecular mechanism of SA.

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Al-Shahrour, Fatima, Kimberly A. Hartwell, Lisa P. Chu, Jaras Marcus, Rishi V. Puram, Alexandre Puissant, Kevin Callahan et al. "In Vivo RNA Interference Screening Identifies a Leukemia-Specific Dependence on Integrin Beta 3 Signaling". Blood 118, n.º 21 (18 de noviembre de 2011): 758. http://dx.doi.org/10.1182/blood.v118.21.758.758.

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Abstract Abstract 758 Primary leukemia stem cells (LSCs) reside in an in vivo microenvironment that supports the growth and survival of malignant cells. Despite the increasing understanding of the importance of niche interactions and primary cell biology in leukemia, many studies continue to focus on cell autonomous processes in artificial model systems. The majority of strategies to-date that attempt to define therapeutic targets in leukemia have relied on screening cell lines in culture; new strategies should incorporate the use of primary disease within a physiologic niche. Using a primary murine MLL-AF9 acute myeloid leukemia (AML) model highly enriched for LSCs, we performed an in vivo short hairpin RNA (shRNA) screen to identify novel genes that are essential for leukemia growth and survival. LSCs infected with pools of shRNA lentivirus were transplanted and grown in recipient mice for 2 weeks, after which bone marrow and spleen cells were isolated. Massively parallel sequencing of infected LSCs isolated before and after transplant was used to quantify the changes in shRNA representation over time. Our in vivo screens were highly sensitive, robust, and reproducible and identified a number of positive controls including genes required for MLL-AF9 transformation (Ctnnb1, Mef2c, Ccna1), genes universally required for cell survival (Ube2j2, Utp18), and genes required in other AML models (Myb, Pbx1, Hmgb3). In our primary and validation screens, multiple shRNAs targeting Integrin Beta 3 (Itgb3) were consistently depleted by more than 20-fold over two weeks in vivo. Follow up studies using RNA interference (RNAi) and Itgb3−/− mice identified Itgb3 as essential for murine leukemia cells growth and transformation in vivo, and loss of Itgb3 conferred a statistically significant survival advantage to recipient mice. Importantly, neither Itgb3 knockdown or genetic loss impaired normal hematopoietic stem and progenitor cell (HSPC) function in 16 week multilineage reconstitution assays. We further identified Itgav as the heterodimeric partner of Itgb3 in our model, and found that knockdown of Itgav inhibited leukemia cell growth in vivo. Consistent the therapeutic aims or our study, flow cytometry on primary human AML samples revealed ITGAV/ITGB3 heterodimer expression. To functionally assess the importance of gene expression in a human system, we performed another RNAi screen on M9 leukemia cells, primary human cord blood CD34+ cells transduced with MLL-ENL that are capable of growing in vitro or in a xenotransplant model in vivo. We found that ITGB3 loss inhibited M9 cell growth in vivo, but not in vitro, consistent with the importance of ITGB3 in a physiologic microenvironment. We explored the signaling pathways downstream of Itgb3 using an additional in vivo, unbiased shRNA screen and identified Syk as a critical mediator of Itgb3 activity in leukemia. Syk knockdown by RNAi inhibited leukemia cell growth in vivo; downregulation of Itgb3 expression resulted in decreased levels of Syk phosphorylation; and expression of an activated form of Syk, TEL-SYK, rescued the effects of Itgb3 knockdown on leukemia cell growth in vivo. To understand cellular processes controlled by Itgb3, we performed gene expression studies and found that, in leukemia cells, Itgb3 knockdown induced differentiation and inhibited multiple previously published LSC transcriptional programs. We confirmed these results using primary leukemia cell histology and a model system of leukemia differentiation. Finally, addition of a small molecule Syk inhibitor, R406, to primary cells co-cultured with bone marrow stroma caused a dose-dependent decrease in leukemia cell growth. Our results establish the significance of the Itgb3 signaling pathway, including Syk, as a potential therapeutic target in AML, and demonstrate the utility of in vivo RNA interference screens. Disclosures: Armstrong: Epizyme: Consultancy.

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Zhai, Jun, Gui-Dong Yao, Jing-Yuan Wang, Qing-Ling Yang, Liang Wu, Zi-Yin Chang y Ying-Pu Sun. "Metformin Regulates Key MicroRNAs to Improve Endometrial Receptivity Through Increasing Implantation Marker Gene Expression in Patients with PCOS Undergoing IVF/ICSI". Reproductive Sciences 26, n.º 11 (1 de enero de 2019): 1439–48. http://dx.doi.org/10.1177/1933719118820466.

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To some extent, the use of metformin may improve endometrial receptivity and pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection. However, the mechanism is not well-known. The endometrium of metformin-treated group (metformin-treated patients with PCOS) and the control group (non-metformin-treated patients with PCOS) were analyzed for the expression of homeobox A10 (HOXA10) and integrin beta-3 (ITGB3) and differential micro RNA (miRNA) expression profiles. On this basis, miRDB and Target Scan databases were used to predict and screen out that miR-491-3p and miR-1910-3p may target HOXA10 and ITGB3. Furthermore, we verified the effects of metformin on the expression of HOXA10 and ITGB3, and regulatory effects of miR-1910-3p and miR-491-3p on HOXA10 and ITGB3 using Ishikawa cell line. Metformin induced a significant dose-dependent upregulation of HOXA10 and ITGB3. The results from the microarray analyses showed there were 40 differentially expressed miRNAs between the 2 groups. Among them, miR-1910-3p and miR-491-3p were the 2 significantly downregulated miRNAs. Bioinformatics prediction indicated that HOXA10 and ITGB3 are potential target genes for miR-1910-3p and miR-491-3p. In Ishikawa cells transfected with miR-491-3p mimics, the expression of HOXA10 and ITGB3 on both messenger RNA (mRNA) and protein level were lower than those in control group ( P < .001). Also, the expression of HOXA10 mRNA and protein was lower in Ishikawa cells transfected with miR-1910-3p mimics ( P < .001). However, no significant changes in ITGB3 levels were observed in cells transfected with miR-1910-3p mimics ( P > .05). Metformin likely improves endometrial receptivity through downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 in the endometrium of PCOS women.

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Salama, Yousef, Andries Hendrik Heida, Kazuaki Yokoyama, Satoshi Takahashi, Koichi Hattori y Beate Heissig. "The EGFL7-ITGB3-KLF2 axis enhances survival of multiple myeloma in preclinical models". Blood Advances 4, n.º 6 (19 de marzo de 2020): 1021–37. http://dx.doi.org/10.1182/bloodadvances.2019001002.

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Abstract Angiogenic factors play a key role in multiple myeloma (MM) growth, relapse, and drug resistance. Here we show that malignant plasma cells (cell lines and patient-derived MM cells) express angiocrine factor EGF like-7 (EGFL7) mRNA and protein. MM cells both produced EGFL7 and expressed the functional EGFL7 receptor integrin β 3 (ITGB3), resulting in ITGB3 phosphorylation and focal adhesion kinase activation. Overexpression of ITGB3 or EGFL7 enhanced MM cell adhesion and proliferation. Intriguingly, ITGB3 overexpression upregulated the transcription factor Krüppel-like factor 2 (KLF2), which further enhanced EGFL7 transcription in MM cells, thereby establishing an EGFL7-ITGB3-KLF2-EGFL7 amplification loop that supports MM cell survival and proliferation. EGFL7 expression was found in certain plasma cells of patients with refractory MM and of patients at primary diagnosis. NOD.CB17-Prkdc<scid>/J mice transplanted with MM cells showed elevated human plasma EGFL7 levels. EGFL7 knockdown in patient-derived MM cells and treatment with neutralizing antibodies against EGFL7 inhibited MM cell growth in vitro and in vivo. We demonstrate that the standard-of-care MM drug bortezomib upregulates EGFL7, ITGB3, and KLF2 expression in MM cells. Inhibition of EGFL7 signaling in synergy with BTZ may provide a novel strategy for inhibiting MM cell proliferation.

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Burghardt, Robert C., James R. Burghardt, James D. Taylor, Adele T. Reeder, Bar T. Nguen, Thomas E. Spencer, Kayla J. Bayless y Greg A. Johnson. "Enhanced focal adhesion assembly reflects increased mechanosensation and mechanotransduction at maternal–conceptus interface and uterine wall during ovine pregnancy". REPRODUCTION 137, n.º 3 (marzo de 2009): 567–82. http://dx.doi.org/10.1530/rep-08-0304.

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The integrity of the fetal–maternal interface is critical for proper fetal nourishment during pregnancy. Integrins are important adhesion molecules present at the interface during implantation; however,in vivoevidence for integrin activation and focal adhesion formation at the maternal–conceptus interface is limited. We hypothesized that focal adhesion assembly in uterine luminal epithelium (LE) and conceptus trophectoderm (Tr) results from integrin binding of extracellular matrix (ECM) at this interface to provide increased tensile forces and signaling to coordinate utero-placental development. An ovine model of unilateral pregnancy was used to evaluate mechanotransduction events leading to focal adhesion assembly at the maternal–conceptus interface and within the uterine wall. Animals were hysterectomized on days 40, 80, or 120 of pregnancy, and uteri immunostained for integrins (ITGAV, ITGA4, ITGA5, ITGB1, ITGB3, and ITGB5), ECM proteins (SPP1, LGALS15, fibronectin (FN), and vitronectin (VTN)), cytoskeletal molecules (ACTN and TLN1), and a signal generator (PTK2). Focal adhesion assembly in myometrium and stroma was also studied to provide a frame of reference for mechanical stretch of the uterine wall. Large focal adhesions containing aggregates of ITGAV, ITGA4, ITGA5, ITGB1, ITGB5, ACTN, and PTK2 were detected in interplacentomal uterine LE and Tr of gravid but not non-gravid uterine horns and increased during pregnancy. SPP1 and LGALS15, but not FN or VTN, were present along LE and Tr interfaces in both uterine horns. These data support the idea that focal adhesion assembly at the maternal–conceptus interface reflects adaptation to increasing forces caused by the growing fetus. Cooperative binding of multiple integrins to SPP1 deposited at the maternal–conceptus interface forms an adhesive mosaic to maintain a tight connection between uterine and placental surfaces along regions of epitheliochorial placentation in sheep.

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Albalushi, Talal, Shoaib AlZadjali, Hamood AlHaddabi, J. David Dennison, Salam Alkindi, Shanmugaonkar Muralitharan, Tadao Arinami y Anil Pathare. "A Novel Mutation (Q694X) in the ITGB3 Gene Causing Glanzmann’s Thrombasthenia from the Sultanate of Oman". Blood 112, n.º 11 (16 de noviembre de 2008): 4540. http://dx.doi.org/10.1182/blood.v112.11.4540.4540.

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Abstract Background : Glanzmann Thrombasthenia (GT) results from mutations in the genes ITGA2B and ITGB3, located on chromosome 17q21–23 which encodes the platelet glycoprotein αIIbβ3 complex, namely GPIIb (αIIb) and GPIIIa (β3), the fibrinogen receptors on platelets, which play an important role in platelet aggregation. Patients with GT can require frequent hospitalization and can be a burden on the nation’s health resources. The possibility that GT could be cured by gene replacement therapy makes it essential to study the molecular basis of the GT patients in a particular family or kindred. Objectives : Our aim was to identify the underlying mutations responsible for GT in Omani patients in order to establish a strategy for genetic counseling and carrier detection to prevent the occurrence of the homozygous state by prenatal diagnosis. Methods: GT was diagnosed in a 17 year old Omani female at the Sultan Qaboos University Hospital. The diagnosis of GT was based on clinical features, platelet aggregometry and biochemical studies. Platelet surface expression of GPIIb/IIIa was also studied by flowcytometry. Molecular studies performed at Medical Genetics Department, Tsukuba University, Japan, include DNA sequencing of all exons and exon-intron junctions of ITGA2B and ITGB3 of the two genes by the ABI 3100 Genetic Analyzer®. [Applied Biosystems, Foster City, CA, USA]. Genomic DNA was also analyzed by Illumina Human-1 Bead Chip Illumina® (Illumina Inc., San Diego, CA, USA) to exclude the whole region of the two genes that could produce an apparent homozygous state. Results : We have identified a novel nonsense causative mutation (Q694X) by sequencing the ITGB3 gene. [Figure 1a & b]. In addition, sequencing ITGB3 gene also revealed 2 SNPs (rs 3809863; IVS14+9C/T, rs 3809865; 3383T/A). The Micro-Array assay using Illumina Human-1 Bead chip excluded the possibility of deletion of these genes in chromosome 17 in this patient. Summary/Conclusion: A stop codon was found in exon 13 of ITGB3 gene causing the translated protein to be abnormally shortened. It is hypothesized that the altered form of ITGB3 gene is both extremely unstable and rapidly degraded after its biosynthesis, leading to a loss of function of the protein. Further RNA expression studies, transfection tests and cDNA sequencing are ongoing to elucidate the molecular mechanisms responsible for GT. Fig. 1 a] Structure of αIIbβ3 complex. The blue box indicates the position of the nonsense mutation in ITGB3 gene, which is clearly before the transmembrane (Red Box) AA sequence. 1 b] Electropherogram showing a nonsense mutation in exon 13 of ITGB3. Fig. 1. a] Structure of αIIbβ3 complex. The blue box indicates the position of the nonsense mutation in ITGB3 gene, which is clearly before the transmembrane (Red Box) AA sequence. 1 b] Electropherogram showing a nonsense mutation in exon 13 of ITGB3.

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Sanmukh, Swapnil Ganesh, Nilton José dos Santos, Caroline Nascimento Barquilha, Maira Smaniotto Cucielo, Márcio de Carvalho, Patricia Pintor dos Reis, Flávia Karina Delella, Hernandes F. Carvalho y Sérgio Luis Felisbino. "Bacteriophages M13 and T4 Increase the Expression of Anchorage-Dependent Survival Pathway Genes and Down Regulate Androgen Receptor Expression in LNCaP Prostate Cell Line". Viruses 13, n.º 9 (2 de septiembre de 2021): 1754. http://dx.doi.org/10.3390/v13091754.

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Wild-type or engineered bacteriophages have been reported as therapeutic agents in the treatment of several types of diseases, including cancer. They might be used either as naked phages or as carriers of antitumor molecules. Here, we evaluate the role of bacteriophages M13 and T4 in modulating the expression of genes related to cell adhesion, growth, and survival in the androgen-responsive LNCaP prostatic adenocarcinoma-derived epithelial cell line. LNCaP cells were exposed to either bacteriophage M13 or T4 at a concentration of 1 × 105 pfu/mL, 1 × 106 pfu/mL, and 1 × 107 pfu/mL for 24, 48, and 72 h. After exposure, cells were processed for general morphology, cell viability assay, and gene expression analyses. Neither M13 nor T4 exposure altered cellular morphology, but both decreased the MTT reduction capacity of LNCaP cells at different times of treatment. In addition, genes AKT, ITGA5, ITGB1, ITGB3, ITGB5, MAPK3, and PI3K were significantly up-regulated, whilst the genes AR, HSPB1, ITGAV, and PGC1A were down-regulated. Our results show that bacteriophage M13 and T4 interact with LNCaP cells and effectively promote gene expression changes related to anchorage-dependent survival and androgen signaling. In conclusion, phage therapy may increase the response of PCa treatment with PI3K/AKT pathway inhibitors.

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Golovchenko, Oleg V., Irina V. Ponomarenko y Mikhail I. Churnosov. "The rs5918 polymorphism in the ITGB3 gene increases the risk for preeclampsia in pregnant women with fetal growth retardation". Gynecology 23, n.º 4 (22 de septiembre de 2021): 330–34. http://dx.doi.org/10.26442/20795696.2021.4.200863.

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Aim. To assess the relationship of rs5918 ITGB3, rs1126643 ITGA2 and rs5985 F13A1 polymorphic loci with the risk for preeclampsia (PE) in pregnant women with fetal growth retardation (FGR). Materials and methods. The study included 272 pregnant women, of which 76 had a combination of PE and FGR and 196 had FGR. In the studied groups, genetic testing was carried out for three polymorphic loci of candidate genes for hereditary thrombophilia (rs5918 ITGB3, rs1126643 ITGA2, and rs5985 F13A1). Results. The rs5918 genetic variant in the ITGB3 gene is associated with the development of PE in pregnant women with FGR: C allele of rs5918 ITGB3 increases the risk for this complication of pregnancy by 1,8 times (OR 1.761.77, p0.036, pperm0.038). The rs5918 polymorphism determines an increase in the affinity of DNA motifs for seven transcription factors (BDP1, ELF1, IRF, NRSF, Pax-5, Sp1, and Zfx), is a missense mutation and causes the Leu59Pro amino acid substitution in the 3 subunit of integrin, is multidirectionally associated with the expression of five genes (EFCAB13, TBKBP1, NPEPPS, MRPL45P2, THCAT158) and alternative splicing of two genes (EFCAB13, MRPL45P2), is located in the region of functionally important DNA regions (promoters and enhancers) in cell cultures and organs which are pathogenetically important for the formation of PE and FGR. Conclusion. The rs5918 polymorphism in the ITGB3 gene increases the risk for PE in pregnant women with FGR.

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Al-Asadi, Mazin Gh, Marcos Castellanos, Sean T. May, Nigel H. Russell, Claire H. Seedhouse y Monica Pallis. "Molecular Signature of Dormancy in CD34+CD38- Acute Myeloid Leukaemia Cells". Blood 128, n.º 22 (2 de diciembre de 2016): 1660. http://dx.doi.org/10.1182/blood.v128.22.1660.1660.

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Abstract Chemotherapy drugs tend to spare cells in a state of dormancy (G0 phase of the cell cycle). Relapse of acute myeloid leukaemia (AML) is likely in part due to dormant cells evading remission-induction chemotherapy. Dormant AML cells have been identified in the bone marrow endosteal region which is characterised by an excess of TGFβ1 and a shortage of nutrients. We developed and characterized an in-vitro model of AML cell dormancy by exploiting these features. Following preliminary investigation of several cell lines, the CD34+CD38- line TF1a was selected for in depth investigation. TF1a cells showed 72% inhibition of proliferation (p<0.001), with features of dormancy, in response to 72 hours TGFβ1+mTOR inhibitor treatment (mTOR pathway inhibition mimics major effects of nutrient scarcity).This treatment caused loss of Ki-67, as well as upregulating ALDH and CD34 and causing nuclear translocation of FOXO3a. In contrast to conventional serum-withdrawal assays for dormancy, the treatment had no impact on cell viability, assessed by Annexin V assay. Nor did the treatment lead to cell differentiation, assessed by CD11b staining and morphology. Using whole human genome expression microarray and by intersecting differentially regulated genes in dormancy-induced TF1a cells in comparison to their proliferating (untreated) counterparts, we identified 240 genes which are significantly up-regulated >2 fold including genes involved in stemness, chemoresistance and tumour suppressor genes in addition to genes involved in canonical cell cycle regulation. There was striking upregulation of genes involved in adhesion and migration: raised expression levels of SPP1 (the gene coding for osteopontin), ITGB3, ITGB4, ITGA3 and CD44 in dormant cells were confirmed by real-time PCR. The most upregulated gene was SPP1/osteopontin (16 fold). Immunocytochemistry of biopsy material from AML patients confirmed high levels of osteopontin in the cytoplasm of blasts near the paratrabecular bone marrow. Osteopontin and other genes identified in this model, including well-characterised genes (e.g. CD44, CD47, CD123, ABBC3 and CDKN2B) as well as little-known ones (e.g. PTPRU, ITGB3 and BTG2), are potential therapeutic targets in dormant AML cells. Disclosures No relevant conflicts of interest to declare.

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Sandrock-Lang, Kirstin, Johannes Oldenburg, Verena Wiegering, Susan Halimeh, Sentot Santoso, Karin Kurnik, Lars Fischer et al. "Characterisation of patients with Glanzmann thrombasthenia and identification of 17 novel mutations". Thrombosis and Haemostasis 113, n.º 04 (julio de 2015): 782–91. http://dx.doi.org/10.1160/th14-05-0479.

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SummaryGlanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients’ bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT by sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected.

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Frank, James W., Heewon Seo, Robert C. Burghardt, Kayla J. Bayless y Greg A. Johnson. "ITGAV (alpha v integrins) bind SPP1 (osteopontin) to support trophoblast cell adhesion". Reproduction 153, n.º 5 (mayo de 2017): 695–706. http://dx.doi.org/10.1530/rep-17-0043.

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Attachment of the conceptus trophoblast (Tr) to the uterine luminal epithelium (LE) is critical for successful implantation. This study determined whether alpha v (av) integrins (ITGAV) directly mediate porcine trophoblast cell adhesion to secreted phosphoprotein 1 (SPP1, also known as osteopontin (OPN)) and examined the temporal/spatial expression of ITGAV, beta 3 (b3, ITGB3) and beta 6 (b6, ITGB6) integrin subunits, and SPP1, at the uterine–placental interface of pigs. Knockdown ofITGAVin porcine Tr (pTr2) cells by siRNA reduced pTr2 attachment to SPP1.In situhybridization confirmed the presence ofITGAV,ITGB3andITGB6mRNAs in uterine LE and conceptus Tr between Days 9 and 60 of gestation, with no change in the magnitude of expression over the course of pregnancy. Exogenous E2 or P4 did not affectITGAV,ITGB3andITGB6mRNA expression in the uteri of ovariectomized gilts. Immunofluorescence identified ITGAV, ITGB3 and SPP1 proteins in large aggregates at the uterine LE-placental Tr/chorion interface on Day 25, but aggregates were no longer observed by Day 50 of gestation. These results are the first to directly demonstrate that pTr2 cells engage ITGAV-containing integrin receptors to adhere to SPP1 and suggest that mechanical forces generated by tethering elongating conceptuses to uterine LE leads to assembly of focal adhesions containing ITGAV and SPP1; however, as placentation progresses, subsequent folding/interdigitation at the uterine–placental interface disperses mechanical forces resulting in the loss of focal adhesions.

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Bohanes, Pierre Oliver, Dongyun Yang, Fotios Loupakis, Melissa Janae Labonte, Armin Gerger, Yan Ning, Takeru Wakatsuki et al. "Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer." Journal of Clinical Oncology 30, n.º 15_suppl (20 de mayo de 2012): 3604. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.3604.

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3604 Background: Integrins are key elements in cancer biology regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Recent evidence showing that integrins are critical in cancer dormancy suggests that their differential expression or activity may be responsible for tumor recurrence. Moving from the hypothesis that integrins could have different effects in stage II and III colon cancer, we tested as a primary endpoint whether a comprehensive panel of germline single nucleotide polymorphisms (SNPs) in integrin genes could predict stage-specific time to tumor recurrence (TTR) in stage II and III colon cancer patients. Methods: A total of 234 patients, 105 high-risk stage II and 129 stage III, treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. The median follow-up time was 4.4 years. Whole blood samples were analyzed for 22 germline SNPs in integrin genes using PCR-RFLP or direct DNA-sequencing. Results: In the multivariate analysis,stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (HR=4.027, 95%CI 1.556-10.421, p=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, HR 95%CI 1.194-3.269, p=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases, both ITGB1 rs2298141 (HR=1.909, 95%CI 1.054-3.459, p=0.033) and ITGA4 rs7562325 (HR=0.227, 95%CI 0.064-0.804, p=0.022) were associated with TTR. The latter showed a significant interaction between stages (p=0.048). Conclusions: This study identifies germline polymorphisms in integrin genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data strengthen the role of tumor dormancy in early colon cancer and may help to select subgroups of patients who may benefit from integrin-targeted treatments.

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18

Morais, Sara, Jorge Oliveira, Catarina Lau, Mónica Pereira, Marta Gonçalves, Catarina Monteiro, Ana Rita Gonçalves et al. "αIIbβ3 variants in ten families with autosomal dominant macrothrombocytopenia: Expanding the mutational and clinical spectrum". PLOS ONE 15, n.º 12 (4 de diciembre de 2020): e0235136. http://dx.doi.org/10.1371/journal.pone.0235136.

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Background Rare pathogenic variants in either the ITGA2B or ITGB3 genes have been linked to autosomal dominant macrothrombocytopenia associated with abnormal platelet production and function, deserving the designation of Glanzmann Thrombasthenia-Like Syndrome (GTLS) or ITGA2B/ITGB3-related thrombocytopenia. Objectives To describe a series of patients with familial macrothrombocytopenia and decreased expression of αIIbβ3 integrin due to defects in the ITGA2B or ITGB3 genes. Methods We reviewed the clinical and laboratory records of 10 Portuguese families with GTLS (33 patients and 11 unaffected relatives), including the functional and genetic defects. Results Patients had absent to moderate bleeding, macrothrombocytopenia, low αIIbβ3 expression, impaired platelet aggregation/ATP release to physiological agonists and low expression of activation-induced binding sites on αIIbβ3 (PAC-1) and receptor-induced binding sites on its ligand (bound fibrinogen), upon stimulation with TRAP-6 and ADP. Evidence for constitutive αIIbβ3 activation, occurred in 2 out of 9 patients from 8 families studied, but also in 2 out of 12 healthy controls. We identified 7 missense variants: 3 in ITGA2B (5 families), and 4 in ITGB3 (5 families). Three variants (αIIb: p.Arg1026Trp and p.Arg1026Gln and β3: p.Asp749His) were previously reported. The remaining (αIIb: p.Gly1007Val and β3: p.Thr746Pro, p.His748Pro and p.Arg760Cys) are new, expanding the αIIbβ3 defects associated with GTLS. The integration of the clinical and laboratory data allowed the identification of two GTLS subgroups, with distinct disease severity. Conclusions Previously reported ITGA2B and ITGB3 variants related to thrombocytopenia were clustered in a confined region of the membrane-proximal cytoplasmic domains, the inner membrane clasp. For the first time, variants are reported at the outer membrane clasp, at the transmembrane domain of αIIb, and at the membrane distal cytoplasmic domains of β3. This is the largest single-center series of inherited macrothrombocytopenia associated with αIIbβ3 variants published to date.

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Wang, Li, Ya Jing Tan, Min Wang, Yi Fei Chen y Xin Yan Li. "DNA Methylation Inhibitor 5-Aza-2′-Deoxycytidine Modulates Endometrial Receptivity Through Upregulating HOXA10 Expression". Reproductive Sciences 26, n.º 6 (6 de diciembre de 2018): 839–46. http://dx.doi.org/10.1177/1933719118815575.

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Endometrial receptivity is a critical factor for embryo implantation. A decrease in endometrial homeobox A10 (HOXA10) expression is associated with hypermethylation of its promoter and lower endometrial receptivity in animals and humans. 5-Aza-2′-deoxycytidine (AZA) is a DNA methyltransferase inhibitor. However, whether demethylation of the HOXA10 gene could increase the receptivity of the human endometrium remains unknown. Homeobox A10 promoter methylation was analyzed using bisulfite genomic sequencing polymerase chain reaction. Quantitative real time polymerase chain reaction and Western blotting were used to analyze the expression of HOXA10 and its downstream target genes (integrin subunit β 3 [ITGB3] and insulin growth factor binding protein 1 [IGFBP1]) in Ishikawa cells treated with or without AZA for 24 hours. Their protein expression was analyzed with or without HOXA10 siRNA treatment. The effect of AZA on embryo implantation was examined using a Jeg-3 spheroid-endometrial cell attachment assay. The percentage of methylated CpG islands in the HOXA10 promoter was 72.0% without AZA treatment. However, it was 38% and 35% in the 1 and 10 μM AZA treatment groups, respectively. 5-Aza-2′-deoxycytidine strongly induced the expression of HOXA10, ITGB3, and IGFBP1 messenger RNA and their protein expression. Homeobox A10 knockdown led to decreased expression of HOXA10, ITGB3, and IGFBP1, with or without AZA treatment. The attachment rate of Jeg-3 spheroids increased significantly from 82% (control) to 95% (AZA 1 μM) and 96% (AZA 10 μM) after AZA treatment. 5-Aza-2′-deoxycytidine could upregulate the expression of ITGB3 and IGFBP1 via HOXA10 upregulation, and upregulation of ITGB3 and IGFBP1 plays an important role in endometrial receptivity during implantation. 5-Aza-2′-deoxycytidine may improve endometrial receptivity by upregulating the expression of HOXA10.

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Ye, Pingjiang, Zhenjun Li, Huafeng Jiang y Tao Liu. "SNPs in MicroRNA-Binding Sites in the ITGB1 and ITGB3 3′-UTR Increase Colorectal Cancer Risk". Cell Biochemistry and Biophysics 70, n.º 1 (29 de abril de 2014): 601–7. http://dx.doi.org/10.1007/s12013-014-9962-z.

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21

Vashukova, Elena S., Andrey S. Glotov, Maria D. Kanaeva, Lubov B. Polushkina, Nadezhda A. Shabanova, Pavel F. Tatarsky, Elena N. Nosenko et al. "Analysis haemostatic system gene polymorphism in pregnant women without complications from Russia and Ukraine". Ecological genetics 9, n.º 1 (15 de marzo de 2011): 70–80. http://dx.doi.org/10.17816/ecogen9170-80.

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Polymorphism of F5 1691G>A, F2 20210G>A, FGB –455G>A, ITGB3 1565Т>С, PAI1 –675 5G>4G, MTHFR 677C>Т genes in pregnant women from Russia and Ukraine was studied by biochip methods. No differences in distribution of F5, F2 and ITGβ3 gene polymorphism were detected. Higher rates of –455G/A FGB and –675 5G/4G PAI1 genotypes in ukrainians compared to pregnant women from Russia were found. Also variable distribution of MTHFR gene polymorphism in women from different countries was registered. The complex approach based on the calculation of relative “score” as a sum of relevant genetic polymorphisms has detected somewhat elevated risk of trombophilia for pregnant women from Ukraine compared to this one from Russia.

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Owaidah, Tarek, Hala Abalkhail, Abdulrahman Al Musa, Hasan Mosmali, Albanyan Abdulmajeed, Abdullah Al Jefri, Randa alNounou, Hazzaa Al Zahrani y Mahasen Saleh. "Noval Mutation in Four Saudi Families with Glanzmann Thrombasthenia". Blood 118, n.º 21 (18 de noviembre de 2011): 1136. http://dx.doi.org/10.1182/blood.v118.21.1136.1136.

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Abstract Abstract 1136 Introduction: Glanzmann thrombasthenia (GT) is a rare autosomal recessive inherited bleeding disorder characterized by an impaired platelet aggregation and variable bleeding tendency. Inherited genetic mutations in integrin alpha IIb and beta3 (ITGA2B, ITGB3) result in a heterogeneity of the thrombasthenia phenotypes. It is phenotypically expressed in homozygotes or compound heterozygotes, given that 50% of normal aIIbb3 is sufficient to guarantee unimpaired platelet function that result in asymptomatic carriers. Defects in ITGB3 result in failure of binding of B3 and alpha IIb. These defects had been reported in Arabs (Iraqi Jews). We are reporting some results of Saudi GT genotype project. Materials & Methods: In this study, we analyzed the entire coding region ITGB3 gene using polymerase chain reaction (PCR) and direct sequencing with primers specifically designed to amplify the coding region of exon 1–15 and exon /Intron boundaries in a cohort of 51 GT patients diagnosed and treated in our institute. Results: Out of 51 cases from 20 families had mutational screening of the ITGB3 gene with the aim to detect the causative pathogenic mutations to enable the pre-symptomatic diagnosis in at risk family members. In this study we detect 1 novel germline mutation c.2190delC (p.Ser703fs) in exon 13. The mutation is predicted to result in premature stop codon and protein truncation. The mutation was detected in 6 patients in homozygous stat (3 males and 3 females). Three tested samples from the patients family members detected the mutation in heterozygous state and all of them were asymptomatic with normal PFA and Intact expression of Platelet Glycoprotiens CD41(Gpllb), CD42a(GPIX), CD42b(GPlb), and CD61(Gpllla). All the GT patients with this mutation were type I GT with Prolonged PFA and complete absence of CD41(Gpllb) and CD61(Gpllla) glycoprotein. Conclusion: The result of this study represents the first Molecular analysis of ITGB3 gene in Saudi Arabia and displays the existence of novel pathogenic and possibly a founder effect in Saudi families. Disclosures: No relevant conflicts of interest to declare.

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Islam, Md Rabiul, Tasnova Tasnim Nova, NAM Momenuzzaman, Sikder Nahidul Islam Rabbi, Ishrat Jahan, Thomas Binder, Mohammad Safiqul Islam, Abul Hasnat y Zabun Nahar. "Prevalence of CYP2C19 and ITGB3 polymorphisms among Bangladeshi patients who underwent percutaneous coronary intervention". SAGE Open Medicine 9 (enero de 2021): 205031212110422. http://dx.doi.org/10.1177/20503121211042209.

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Introduction: Antithrombotic agents are the basic therapeutic option for patients with arterial thrombosis who underwent percutaneous coronary intervention (PCI). In Bangladesh, aspirin and clopidogrel are frequently prescribed as antithrombotics or platelet inhibitors. Studies reported the genetic polymorphisms of CYP2C19*2, CYP2C19*17, and ITGB3 cause an alteration of the pharmacodynamic and pharmacokinetic profile of aspirin and clopidogrel. Therefore, we aimed to assess the prevalence of CYP2C19*2, CYP2C19*17, and ITGB3 polymorphisms among Bangladeshi patients with cardiovascular disease (CVD) who underwent PCI. Methods: Here we assessed a total of 1,000 CVD patients (male 782 and female 218) who underwent PCI and were treated with clopidogrel and/or aspirin. We performed genotyping of patients treated with clopidogrel and aspirin by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) methods. The PCR products of clopidogrel-treated patients were screened with agarose gel electrophoresis and then digested with SmaI and NsiI-HF for CYP2C19*2 and CYP2C19*17, respectively. We genotyped aspirin-treated patients with T-ARMS-PCR for missense rs5918 (PlA1/A1) polymorphism of the ITGB3 gene. Then we ran the digested PCR products on 2% agarose gel electrophoresis to detect the mentioned polymorphisms. Results: Among the clopidogrel-treated patients, we observed 64.1% polymorphism (hetero + mutant) of CYP2C19*2 (loss-of-function allele) and 22.7% (hetero + mutant) of CYP2C19*17 (gain-of-function allele). On the other hand, among the aspirin-treated patients, polymorphisms of ITGB3 were 84.1% homozygous (PlA1/A1), 15.6% heterozygous (PlA1/A2), and 0.3% mutant homozygous. Conclusion: In the present study, we observed a high prevalence of genetic polymorphisms of CYP2C19 and ITGB3 genes. Therefore, we recommend genotyping of CVD patients before prescribing clopidogrel or aspirin to prevent coagulation. Based on the genotyping study, the adjustment of doses or alternative generics might require to avoid therapeutic failure or toxicity in some cases.

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Sandrock-Lang, Kirstin, Johannes Oldenburg, Verena Wiegering, Susan Halimeh, Sentot Santoso, Karin Kurnik, Lars Fischer et al. "Characterization of Patients with Glanzmann Thrombasthenia and Identification of 17 Novel Mutations". Blood 124, n.º 21 (6 de diciembre de 2014): 1460. http://dx.doi.org/10.1182/blood.v124.21.1460.1460.

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Abstract Background: Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder. Platelets from patients with GT show quantitative and/or qualitative defects of the platelet membrane glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. On activated platelets the αIIbβ3 binds von fibrinogen and Willebrand factor which leads to platelet spreading and formation of platelet-platelet protein bridges. Patients: In this study, 18 patients with GT were investigated with molecular genetic analyses. The patients presented with bleeding symptoms such as epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Methods and Results: As cause of GT in the patients homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified through sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analyzed. In summary, 16 of 18 patients revealed 27 different mutations (ITGA2B: n = 17, ITGB3: n = 10). Of these mutations, 17 have not been published yet. Conclusion: In 16 patients mutations in ITGA2B or ITGB3 were identified as cause of GT. A total of 27 mutations including 17 novel missense, nonsense, frameshift and splice site mutations were detected. None of these mutations were present more than once in unrelated patients. In addition, 2 patients were without molecular genetic findings in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We hypothesize that these patients may harbour defects in a regulatory element affecting the transcription of these genes or there may exist other proteins important for the activation of the αIIbβ3 complex that could be affected. Disclosures No relevant conflicts of interest to declare.

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Muslimova, Elvira F., Tatyana Y. Rebrova, Sergey A. Afanasiev, Tatyana N. Sergienko y Aleksey N. Repin. "The association of ITGB3 gene and NOS3 gene with the severity of coronary artery disease with and without type 2 diabetes". Diabetes mellitus 19, n.º 4 (9 de septiembre de 2016): 302–8. http://dx.doi.org/10.14341/dm7875.

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Type 2 diabetes (T2DM) is one of the key predictors of coronary artery disease (CAD) and its complications. Currently, along with metabolic risk factors for CAD, much attention has been given to the study candidate genes, including platelet fibrinogen receptor gene ITGB3 and the gene NOS3 of endothelial NO-synthase type 3.Aim. To estimate the associations of T1565C ITGB3 and T-786C NOS3 polymorphisms with the clinical condition of russian patients from West Siberian region with concomitant development of coronary artery disease and type 2 diabetes.Materials and methods. The study included 237 CAD patients; 78 (32.9%) of them had T2DM. The genotyping was performed by allele-specific polymerase chain reaction. Comparison of quantitative variables between groups with different genotypes was done by Mann-Whitney U test or Kruskal-Wallis test. Comparison of discrete parameters was done by Pearson χ2 test or Fisher's exact test.Results. Genotype 786CC (NOS3) (p=0,039) and allele 1565C (ITGB3) (p=0,045) were less common in the group CAD+T2DM than in the group CAD without T2DM. But in the group CAD+T2DM the frequency of obesity was higher among carriers of 1565C allele than in homozygotes 1565TT (p=0,039), and carriers of 786C allele have the highest concentration of glucose compared to homozygous 786TT (p=0,018). Furthermore, 786C allele is associated with obesity in the group of patients without T2DM detected (p = 0,015).Conclusion. Carriage of 1565C (ITGB3) allele and 786C (NOS3) allele can be considered as predictors of adverse course of the disease at concomitant development of CAD and T2DM.

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Pronko, T. P., V. A. Snezhitskiy, O. V. Gorchakova, M. L. Gladkiy y A. V. Kapytski. "Clinical and genetic factors associated with the risk of recurrent ischemic events in patients with stable stenocardia". Regional blood circulation and microcirculation 20, n.º 3 (27 de septiembre de 2021): 18–27. http://dx.doi.org/10.24884/1682-6655-2021-20-3-18-27.

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The aim of the study was to assess the clinical and genetic factors associated with the risk of recurrent ischemic events in patients with stable stenocardia (SS). Materials and methods. A total of 100 patients with SS were examined and followed-up for 15.3±8.3 months. The patients were divided into subgroups (SG): SG1 (n=51) – persons without events, SG2 (n=49) persons with recurrent ischemic events (hospitalization due to the development of pain syndrome, re-stenting due to stent restenosis, myocardial infarction, cerebral infarction and death from cardiovascular causes), SGB (n=11) – persons with «major» recurrent ischemic events (re-stenting due to stent restenosis, myocardial infarction, cerebral infarction and death from cardiovascular causes) , SGG (n=89) – persons without «major» events. The obtained survey data (general clinical, aggregometry, polymor phism of genes of platelet fibrinogen receptor ITGB3 (T1565C), platelet collagen receptor ITGA2 (C807T), ADP platelet receptor P2RY12, H1/H2 (T744C)) were analyzed using the STATISTICA 10.0 software. Results. In SG2, men predominated (χ2 =9.2; p<0.01), past MI was more common (χ2 =4.8; p<0.05), more stents were implanted (2.4±1.9 versus 1.7±1.1, p<0.05), TRAP-test values were higher (p<0.05) compared to SG1. In SGB, greater number of stents were implanted (3.1±2.2 versus 1.61±1.57, p<0.05), the carriage of the TC genotype of the ITGB3 gene was more common, (p<0.05), a combination of gene mutations ITGB3 and P2RY12 was more common, (p<0.05) compared to SGG. A logistic regression equation was constructed, including the presence of diabetes mellitus, the number of platelets in the blood test, the ASPI-test values, the carriage of the 1565C allele of the ITGB3 gene, the number of stents implanted, which makes it possible to determine the likelihood of developing «major» recurrent ischemic events with a cut-off threshold LP₀=0.0965, with sensitivity – 81.82 %, specificity – 78.48 %, overall accuracy – 78.89 %. Conclusions. The factors associated with the development of recurrent ischemic events are: male sex, previous MI, a greater number of implanted stents, and high TRAP-test values. The factors associated with the development of recurrent «major» ischemic events are: a greater number of implanted stents, carriage of the TC genotype of the ITGB3 gene, carriage of a combination of mutations of the H1/H2 polymorphic locus of the P2RY12 gene and the T1565C polymorphic locus of the ITGB3 gene, diabetes mellitus, the number of platelets in blood test, ASPI-test values.

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Nurden, Alan T., Mathieu Fiore, Paquita Nurden y Xavier Pillois. "Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models". Blood 118, n.º 23 (1 de diciembre de 2011): 5996–6005. http://dx.doi.org/10.1182/blood-2011-07-365635.

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Abstract Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetype-inherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, αIIbβ3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for β3 has a wide tissue distribution when present as αvβ3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of β3-deficiency or nonfunction are being increasingly described.

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Zhang, Dan, Gufeng Xu, Runju Zhang, Yimin Zhu, Huijuan Gao, Caiyun Zhou, Jianzhong Sheng y Hefeng Huang. "Decreased expression of aquaporin 2 is associated with impaired endometrial receptivity in controlled ovarian stimulation". Reproduction, Fertility and Development 28, n.º 4 (2016): 499. http://dx.doi.org/10.1071/rd13397.

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Recently, there has been evidence of decreased implantation rates with in vitro fertilisation and embryo transfer due to controlled ovarian stimulation (COS). The aim of this study was to investigate the effect of COS on embryo implantation and the role of aquaporin 2 (AQP2). We recruited eight patients who underwent COS and 40 matched controls. Endometrial samples were collected on Day 4~8 after injection of human chorionic gonadotrophin in the COS group and in the mid-secretory phase in the control group. Human endometrial morphological changes after COS were examined and expression of AQP2, leukaemia inhibitory factor (LIF) and integrin B3 (ITGB3) were determined by quantitative polymerase chain reaction, western blotting and immunohistochemistry in human endometrium and Ishikawa cells. Attachment rates were obtained using the embryo attachment test. The results showed that endometrial epithelial cells from the COS group were disrupted and lacked pinopodes. Messenger RNA and protein levels of AQP2, LIF and ITGB3 decreased in endometrial samples from the COS group. Knockdown of AQP2 resulted in reduced expression of LIF and ITGB3 and reduced embryo attachment rates. In conclusion, impaired endometrial receptivity in patients who underwent COS is correlated with a decreased expression of AQP2.

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Cochrane, Lynne E., Katherine E. Tansey, Michael Gill, Louise Gallagher y Richard J. L. Anney. "Lack of association between markers in the ITGA3, ITGAV, ITGA6 and ITGB3 and autism in an Irish sample". Autism Research 3, n.º 6 (diciembre de 2010): 342–44. http://dx.doi.org/10.1002/aur.157.

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Weiss, Lauren A., Carole Ober y Edwin H. Cook. "ITGB3 shows genetic and expression interaction with SLC6A4". Human Genetics 120, n.º 1 (24 de mayo de 2006): 93–100. http://dx.doi.org/10.1007/s00439-006-0196-z.

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Wei, Wei, Yang Yang, Jian Cai, Kai Cui, Rong xian Li, Huan Wang, Xiujuan Shang y Dong Wei. "MiR-30a-5p Suppresses Tumor Metastasis of Human Colorectal Cancer by Targeting ITGB3". Cellular Physiology and Biochemistry 39, n.º 3 (2016): 1165–76. http://dx.doi.org/10.1159/000447823.

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Aims: MicroRNAs (miRNAs) are dysregulated in a wide range of malignant diseases, confirming their crucial role in tumor metastasis. MiRNA-30a-5p, a member of the miR-30 family, has been implicated in many types of cancers, including colorectal cancer, a leading cause of death worldwide. Methods: qRT-PCR, Western blot, Transwell assay,luciferase reporter assay were performed in the present study. Results: In this study, miR-30a-5p was found to be significantly downregulated in human colorectal cancer tissue specimens and cell lines compared with non-cancerous tissues and cells. The overexpression of miR-30a-5p inhibited the migratory and invasive abilities of colorectal cancer cells and suppressed the epithelial-mesenchymal transition, a crucial process in metastasis. Bioinformatic algorithms and luciferase reporter assays revealed that integrin β3 (ITGB3) is a direct target of miR-30a-5p. Importantly, overexpression of ITGB3 in colorectal cancer cells rescued these cells from miR-30a-5p-mediated suppression of metastasis and restored the epithelial-mesenchymal transition. Conclusion: Taken together, our study provides the first evidence that miR-30a-5p suppresses colon cancer metastasis through the inhibition of ITGB3. Thus, targeting miR-30a-5p might serve as a promising therapeutic strategy for the treatment of colorectal cancer.

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Stremitzer, Stefan, Anna Sophie Berghoff, Nico Benjamin Volz, Wu Zhang, Dongyun Yang, Sebastian Stintzing, Yan Ning et al. "Influence of genetic variants of genes potentially associated with colorectal brain metastases on overall survival." Journal of Clinical Oncology 32, n.º 3_suppl (20 de enero de 2014): 487. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.487.

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487 Background: Brain metastases (BM) in colorectal cancer (CRC) are rare, developing in only 0.3-9% of the patients, and considered a late-stage manifestation of the disease. The aim of this study was to investigate whether genetic variants of genes involved in BM-related pathways, such as integrin, invasion- and adhesion-mediating, angiogenic and tumor suppressing pathways, are associated with outcome. Methods: Genomic DNA was extracted from formalin-fixed paraffin embedded resected BM from 70 patients with histologically proven CRC. Single nucleotide polymorphisms (SNP) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed by direct Sanger DNA sequencing and evaluated for association with overall survival (OS) from resection of BM. Only SNPs with an allele frequency of ≥ 10% were analyzed. Results: In univariate analysis, rs17577 (MMP9) and rs4642 (ITGB3) showed a significant difference in OS [(G/G 7.4 months, G/A 5.1 months; HR (95% CI) 1.83 (0.95-3.53), p = 0.0440) and (A/A 9.4 months, A/G 4.8 months, G/G 4.3 months; HR (95% CI) 0.81 (0.44-1.49) and 2.14 (0.98-4.67), p = 0.0354), respectively]. In multivariate analysis adjusted for baseline characteristics [primary tumor site (right colon, left colon, rectal), chemotherapy before BM (yes/no), BM location (supratentorial, infratentorial, both), Karnofsky performance status (<80, 80-100)], rs2236599 (KLF4), and rs10171481 (ITGAV) are significant in OS [(G/G 7.4 months, G/A or A/A 4.8 months; HR (95% CI) 3.19 (1.55-6.53), p = 0.0016) and (A/A 5.7 months, A/G 4.4 months, G/G 15.5 months; HR (95% CI) 0.61 (0.29-1.29) and 0.25 (0.10-0.60), p = 0.0082), respectively]. Conclusions: This study suggests for the first time a prognostic effect of the SNPs involved in the BM pathway. Further analyses are needed to confirm these findings.

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Chen, Nannan, Mu Qin, Qunlin Gong, Nan Xu, Yu Lin, Jiahong Wang y Pengxiang Zheng. "Construction of mRNA Regulatory Networks Reveals the Key Genes in Atrial Fibrillation". Computational and Mathematical Methods in Medicine 2021 (24 de mayo de 2021): 1–10. http://dx.doi.org/10.1155/2021/5527240.

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Atrial fibrillation (AF), the most familiar heart rhythm disorder, is a major cause of stroke in the world, whereas the mechanism behind AF remains largely unclear. In the current study, we used the RNA-seq method to identify 275 positively regulated mRNAs and 117 negatively regulated mRNAs in AF compared to healthy controls. Through bioinformatic analysis, it indicated that these distinctively expressed genes took part in regulating multiple AF-related biological processes and pathways, such as platelet aggregation, platelet activation, pri-miRNA transcription, and transforming growth factor-beta (TGF-β) receptor signaling pathway. Protein-protein interaction (PPI) network analysis identified ITGB5, SRC, ACTG1, ILK, ITGA2B, ITGB3, TUBB4B, CDK11A, PAFAH1B1, CDK11B, and TUBG1 as hub regulators in AF. Moreover, the quantitative real-time PCR (qRT-PCR) assay was conducted and revealed that these hub genes were remarkably overexpressed in AF samples compared to normal samples. We believed that this study would enrich the understanding of the pathogenesis of AF and enable further research on the pathogenesis of AF.

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Ying, Zuolin, Madeleine Duvic, Lisa Shiue, Timothy Langridge, Meghali Goswami y Xiao Ni. "Blood Transcriptional Profiling in Patients with Leukemic Cutaneous T-Cell Lymphoma on Extracorporeal Photopheresis Reveals the Integrin Signaling As the Top Pathway Associated with Clinical Response". Blood 126, n.º 23 (3 de diciembre de 2015): 3981. http://dx.doi.org/10.1182/blood.v126.23.3981.3981.

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Abstract Extracorporeal photopheresis (ECP) is an effective frontline therapy for patients with leukemic cutaneous T-cell lymphoma (L-CTCL), but the mechanisms of action are not fully understood. To elucidate molecular mechanisms underlying the efficacy of ECP, we used Agilent Whole Human Genome Microarrays to examine blood transcriptional profiles in L-CTCL patients after ECP therapy. Ten L-CTCL patients including 5 clinical responders and 5 non-responders were studied. Their peripheral blood was collected before ECP (baseline), at Day 2, and one month post-ECP. Total RNA extracted from peripheral blood mononuclear cells was assayed with Whole Human Genome Oligo Microarrays (4 × 44 K) (Agilent, Santa Clara, CA). The differentially expressed gene analysis (DGA) was done using the paired t-test with Benjamini- Hochberg correction (P value < 0.05) between post-ECP and baseline. The fold change of gene expression between post-ECP and baseline were calculated from the normalized values. Hierarchical clustering of differentially expressed genes was performed with the Pearson correlation. The DGA between responders and non-responders were cross-compared. Canonical biological pathways were identified using Ingenuity Pathway Analysis (IPA, Ingenuity Systems, Redwood City, CA). Differentially expressed gene profiles were different in responders from non-responders. As indicated in Figure 1, there were more genes differentially regulated in responders than in non-responders post-ECP at both Day 2 (549 genes in responders versus 66 genes in non-responders) and at one month (472 genes in responders versus 95 genes in non-responders). Among 472 differentially expressed genes in responders at one month post-ECP, almost twice as many genes (313) were down-regulated compared to up-regulated genes (159). The top down-regulated genes were IL-1β, EGR1, CCL3, CCL3L3, and CXCL2. The down-regulated genes were mainly related to functions of platelets, immune and/or stress responses, and chromatin remodeling. The upregulated genes were mainly related to functions of the nucleolus and included USP34, POLR3F, ZNF529, C22orf35, and BAT2D1. The ingenuity pathway analysis revealed that the top 5 pathways affected by ECP at one-month in responders were 1) integrin signaling; 2) granulocyte adhesion and diapedesis; 3) signaling by Rho Family GPTases; 4) agranulocytes (lymphocyte, monocyte and macrophage) adhesion and diapedesis; and 5) triggering receptor expressed on myeloid cells 1 (TREM1) signaling (Table 1). In contrast, these pathways and genes were less affected in non-responders. Of note, a comparison of all DGA results indicated that the responder group overlapped in the differentially expressed genes between Day 2 group (RD2) and one month group (RM1), but had few genes in common to the non-responder group (NM1). There were 94 genes consistently downregulated among RD2 and RM1 while only 6 genes were found in common between the RM1 and NM1 group. Similarly, 61 genes were consistently upregulated in group RD2 and RM1 while only 3 genes were found in common between the RM1 and NM1 group. In summary, the blood transcriptional profiling by this study identifies a signature of genes and pathways relevant to clinical response to ECP in L-CTCL patients. These findings expand our understanding of molecular mechanisms of ECP. Further validation of these genes and pathways is warranted in the future studies. Table 1. Top canonical pathways affected by ECP in L-CTCL patients responded to ECP at one-month Canonical Pathways Downregulated genes Upregulated genes Integrin Signaling 15/201 (7%) ITGA2B, MAP3K11, ITGA5, MYLK, ITGB3, MYL9, PARVB, AKT1, RHOB, CAPN1, ACTN4, CTTN, ARPC4, ACTN1, ITGB5 2/201 (1%) ITGB1, PPP1R12A Granulocyte Adhesion and Diapedesis 14/179 (8%) CSF3R, ICAM1, PPBP,ITGA5, CXCL5, SDC4, CCL3, ITGB3, GNAI2, CLDN5, CCL3L3, IL1B, CXCL1, CXCL2 1/179 (1%) ITGB1 Signaling by Rho Family GTPases 13/236 (6%) SEPT5, MAP3K11, ITGA5, MYLK, GNAZ, CDC42EP2, GNAI2, MYL9, GNG11, GNA15, RHOB, GNB2, ARPC4 3/236 (1%) ITGB1, DIAPH3, PPP1R12A Agranulocyte Adhesion and Diapedesis 13/190 (7%) ICAM1, PPBP, ITGA5, CXCL5, SDC4, CCL3, GNAI2, MYL9, CLDN5, CCL3L3, IL1B, CXCL1, CXCL2 1/190 (1%) ITGB1 TREM1 Signaling 7/76 (9%) ICAM1, AKT1, NLRP12, ITGA5, IL1B, CD83, CCL3 2/76 (3%) ITGB1, NLRC3 Figure 1. Differentially expressed genes post-ECP between responders and non-responders Figure 1. Differentially expressed genes post-ECP between responders and non-responders Disclosures Duvic: Therakos: Research Funding. Ni:Therakos: Research Funding.

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Corinaldesi, Giorgio y Christian Corinaldesi. "Glanzmann's Thrombasthenia Mutation of the Genes ITGA2B and ITGB3." Blood 114, n.º 22 (20 de noviembre de 2009): 2411. http://dx.doi.org/10.1182/blood.v114.22.2411.2411.

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Abstract Abstract 2411 Poster Board II-389 Glanzmann Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a life-long mucocutaneous bleeding tenedency and absence or severely reduced platelet aggregation in response to ADP, epinephrine, and collagen, but relatively normal in response to ristocetin, where the glycoprotein (GP) IIb/IIIa a calcium dependent heterodimer complex is deficient or present but dysfunctional. GPIIb 172kbp is composed of 30 exons and GPIIIa 65Kbp is composed of 15 exons, have their own separate genes on the long arm of chomosome 17 (17q21-32), specific genetic abnormalities of each GP include missense, non sense, splite site mutation, deletions and point mutation. Mutation abrogates ligand binding to the activate integrin to the adhesive protein: fibrinogen, vWF, fibronectin, vitronectin, CD40L and the platelet are unable to mediate outside-inside signaling promoting actin plymerization and cytoskeletal reorganization such as clot retraction, talin and kindlin protein activation. We have studied four patients with mutation of the gene encoding platelet GPIIb (ITGAIIB) exon 17 mutation 1750 C (cystein)-T (threonin) phenotype non sense R584X,the proband showed a platelet with 3%-10% a fibrinogen binding and GPIIb/IIIa receptors; exon 23 mutation 2333 A (alanin)-C (cystein) phenotype missense Q778P, produced truncated protein, cystein residue is ipermethylated with a reduction of adhesion <8% cystein is postulated to be critical for post translational processing of GPIIb; and the gene encoding platelet GPIIIa (ITGB3) exon 11 mutation 1813 G (glycin)-A (alanin) phenotype missense H306P,ifluencing the Ca2+ dependent stabilty of the GPIIb/IIIa complex to divalent cation chelation; exon 3 mutation 355 C (cystein)- T (threonin) phenotype missense R119W escluding at codon 355 leader sequence, producing a frame-shift and protein termination and a stop codon with a great abnormalities of GPIIb/IIIa heterodimer inter subunit surface interaction, and intracellular trafficking. The patients have all severe bleeding included epistaxis, petechiae, gum bleeding, and a high grade of relapsing, refractory bleeding often requiring the transfusion with HLA compatible platelet concentrats and/or administration of recombinant FVIIa. This study confirmed that the genetic mutation can be significatly associated with the frequency and severity of bleeding and these approach may be the future of the management of GT. Disclosures: No relevant conflicts of interest to declare.

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Nurden, Alan T. y Xavier Pillois. "ITGA2B and ITGB3 gene mutations associated with Glanzmann thrombasthenia". Platelets 29, n.º 1 (10 de noviembre de 2017): 98–101. http://dx.doi.org/10.1080/09537104.2017.1371291.

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Cerhan, James R., Stephen M. Ansell, Zachary S. Fredericksen, Neil E. Kay, Mark Liebow, Timothy G. Call, Ahmet Dogan et al. "Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma". Blood 110, n.º 13 (15 de diciembre de 2007): 4455–63. http://dx.doi.org/10.1182/blood-2007-05-088682.

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Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P ≤ .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P ≤ .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.

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Yang, Eu, Ye Shim, Heung Kim, Young Lim, Ho Im, Kyung-Nam Koh, Hyery Kim et al. "Genetic Confirmation and Identification of Novel Variants for Glanzmann Thrombasthenia and Other Inherited Platelet Function Disorders: A Study by the Korean Pediatric Hematology Oncology Group (KPHOG)". Genes 12, n.º 5 (6 de mayo de 2021): 693. http://dx.doi.org/10.3390/genes12050693.

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The diagnosis of inherited platelet function disorders (IPFDs) is challenging owing to the unavailability of essential testing methods, including light transmission aggregometry and flow cytometry, in several medical centers in Korea. This study, conducted by the Korean Pediatric Hematology Oncology Group from March 2017 to December 2020, aimed to identify the causative genetic variants of IPFDs in Korean patients using next-generation sequencing (NGS). Targeted exome sequencing, followed by whole-genome sequencing, was performed for diagnosing IPFDs. Of the 11 unrelated patients with suspected IPFDs enrolled in this study, 10 patients and 2 of their family members were diagnosed with Glanzmann thrombasthenia (GT). The variant c.1913+5G>T of ITGB3 was the most common, followed by c.2333A>C (p.Gln778Pro) of ITGB2B. Known variants of GT, including c.917A>C (p.His306Pro) of ITGB3 and c.2975del (p.Glu992Glyfs*), c.257T>C (p.Leu86Pro), and c.1750C>T (p.Arg584*) of ITGA2B, were identified. Four novel variants of GT, c.1451G>T (p.Gly484Val) and c.1595G>T (p.Cys532Phe) of ITGB3 and c.1184G>T (p.Gly395Val) and c.2390del (p.Gly797Valfs*29) of ITGA2B, were revealed. The remaining patient was diagnosed with platelet type bleeding disorder 18 and harbored two novel RASGRP2 variants, c.1479dup (p.Arg494Alafs*54) and c.813+1G>A. We demonstrated the successful application of NGS for the accurate and differential diagnosis of heterogeneous IPFDs.

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Nurden, Paquita, Jean-Claude Bordet, Xavier Pillois y Alan T. Nurden. "An intracytoplasmic β3 Leu718 deletion in a patient with a novel platelet phenotype". Blood Advances 1, n.º 8 (10 de marzo de 2017): 494–99. http://dx.doi.org/10.1182/bloodadvances.2016002808.

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Key Points A novel heterozygous ITGB3 Leu718del shows loss of synchronization between the intracytoplasmic tail of β3 with that of αIIb. Decreased activation of αIIbβ3 accompanies enlarged platelets that contain giant granules and give a poor aggregation response.

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Wu, Pancheng, Yanyu Wang, Yijun Wu, Ziqi Jia, Yang Song y Naixin Liang. "Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer". PeerJ 7 (20 de diciembre de 2019): e8299. http://dx.doi.org/10.7717/peerj.8299.

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Background Integrins play a crucial role in the regulation process of cell proliferation, migration, differentiation, tumor invasion and metastasis. ITGA11, ITGB4 and ITGB8 are three encoding genes of integrins family. Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances. However, their expression patterns and prognostic roles for patients with non-small cell lung cancer (NSCLC) have not been completely illustrated. Methods We investigated the expression patterns and prognostic values of ITGA11, ITGB4 and ITGB8 in patients with NSCLC through using a series of databases and various datasets, including ONCOMINE, GEPIA, HPA, TCGA and GEO datasets. Results We found that the expression levels of ITGA11 and ITGB4 were significantly upregulated in both LUAD and LUSC, while ITGB8 was obviously upregulated in LUSC. Additionally, higher expression level of ITGB4 revealed a worse OS in LUAD. Conclusion Our findings suggested that ITGA11 and ITGB4 might have the potential ability to act as diagnostic biomarkers for both LUAD and LUSC, while ITGB8 might serve as diagnostic biomarker for LUSC. Furthermore, ITGB4 could serve as a potential prognostic biomarker for LUAD.

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Muslimova, E. F., S. A. Afanasiev, T. Yu Rebrova, T. N. Sergienko y A. N. Repin. "Association of ITGB3, P2RY12, and CYP2C19 gene polymorphisms with platelet functional activity in patients with coronary heart disease during dual antiplatelet therapy". Terapevticheskii arkhiv 89, n.º 5 (15 de mayo de 2017): 74–78. http://dx.doi.org/10.17116/terarkh201789574-78.

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Aim. To assess the association of CYP2C19 G681A, P2RY12 H1/H2, and ITGB3 T1565C polymorphisms with the extent of platelet aggregation in patients with coronary heart disease (CHD) during antiplatelet therapy. Subjects and methods. 166 male patients with CHD, living in the Western Siberian Region, were examined. All the patients underwent a test for platelet aggregation induced by ADP (2.5 and 5.0 µm) and epinephrine (0.2 µm). Genotyping was performed using an allele-specific polymerase chain reaction technique. Results. The polymorphic variants of the P2RY12 and ITGB3 genes were ascertained to have no impact on the extent of platelet aggregation in patients receiving clopidogrel and acetylsalicylic acid. An association was found between CYP2C19 681A allele carriage and the increased extent of platelet aggregation induced by ADP. Conclusion. The carriage of the cytochrome P450 CYP2C19 681A allele rather than platelet receptor gene polymorphisms determines a risk for clopidogrel resistance in patients with CHD.

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Manakhov, K. M., D. S. Sarksyan, M. V. Dudarev, T. O. Tolstoluckaya, N. S. Ponomarenko y V. V. Maleev. "Molecular genetic characteristics of hemostasis in hemorrhagic fever with renal syndrome". Kazan medical journal 101, n.º 6 (14 de diciembre de 2020): 812–19. http://dx.doi.org/10.17816/kmj2020-812.

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Aim. To assess the predictive value of single-nucleotide polymorphisms of hemostasis and folate cycle genes in hemorrhagic fever with renal syndrome (HFRS). Methods. 43 patients undergoing HFRS were examined based on the Republican clinical infectious diseases hospital in Izhevsk. Toxic shock syndrome (TSS) in the decompensated phase, pulmonary edema in the alveolar phase, and acute kidney injury (AKI) at stage F [RIFLE criteria (risk, injury, failure, loss, end-stage renal disease)] were registered as complications. Molecular analysis of patients genomic DNA was performed after its isolation from peripheral blood cells. Genotyping was performed by using multiplex real-time PCR with conformationally restricted probes. Statistical analysis was performed by the licensed program SPSS 22.0; the significance level of difference between groups was determined using the nonparametric MannWhitney test (for quantitative variables) and the Fishers exact test (for qualitative variables). Results. The C/C genotype of the ITGB3:1565T/C gene (p=0.0278), and the C/C genotype of the MTHFR1298 A/C gene (p=0.0407) was less common in severe cases, while the G allele of FGB:455G/A gene (p=0.046) and the T allele of the ITGB3:1565T/C gene (p=0.0166) was more frequent. More frequent detection of the 5G/4G genotype of the PAI-1:675 5G/4G gene was found in the case of TSS (p=0.0433). Genotype C/C of the ITGB3:1565T/C gene (p=0.0145) and a combination of pathological genotypes A/C and C/C of the MTHFR1298A/C gene (p=0.0004) are less common in the development of AKI at stage F. Conclusion. The molecular genetic analysis makes it possible to identify patients with genotypes predisposing to a severe and complicated course of hemorrhagic fever with renal syndrome.

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Губина, М. А., В. Н. Бабенко, Д. Е. Иванощук, А. К. Шуряева, О. О. Латыева, И. Г. Соловьева, М. Н. Пономарева et al. "Полиморфизм геновc-fms, ITGB3, CCR2иDBHв популяциях староверов Тюмени и русских Новосибирска". Молекулярная биология 50, n.º 2 (2016): 246–54. http://dx.doi.org/10.7868/s0026898416010055.

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Reich, Daniela, Anne Kresinsky, Jörg P. Müller, Reinhard Bauer, Julia Kallenbach, Tina M. Schnoeder, Florian H. Heidel et al. "SHP1 regulates a STAT6–ITGB3 axis in FLT3ITD-positive AML cells". Leukemia 34, n.º 5 (13 de diciembre de 2019): 1444–49. http://dx.doi.org/10.1038/s41375-019-0676-5.

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Ma, D. Q., R. Rabionet, I. Konidari, J. Jaworski, H. N. Cukier, H. H. Wright, R. K. Abramson et al. "Association and gene-gene interaction of SLC6A4 and ITGB3 in autism". American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 153B, n.º 2 (8 de julio de 2009): 477–83. http://dx.doi.org/10.1002/ajmg.b.31003.

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Shang, Chao, Hui Zhang, Yan Guo, Yang Hong, Yunhui Liu y Yixue Xue. "MiR-320a down-regulation mediates bladder carcinoma invasion by targeting ITGB3". Molecular Biology Reports 41, n.º 4 (18 de enero de 2014): 2521–27. http://dx.doi.org/10.1007/s11033-014-3110-0.

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Xu, D., T. Li y R. Mu. "AB0095 EXPRESSION AND PATHOGENIC ROLES OF INTEGRIN FAMILY GENE IN SYSTEMIC SCLEROSIS". Annals of the Rheumatic Diseases 80, Suppl 1 (19 de mayo de 2021): 1076.2–1076. http://dx.doi.org/10.1136/annrheumdis-2021-eular.3646.

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Background:Emerging evidence have shown that some integrin members are associated with inflammation and fibrosis in systemic sclerosis (SSc) patients[1-2]. However, the expression patterns and pathogenic significance of the whole integrin family in SSc are still unclear.Objectives:This study aimed at evaluating the integrin family gene expression in skin lesion from SSc patients and exploring its potential pathogenic mechanism.Methods:We utilized the public datasets of SSc skin tissue from Gene Expression Omnibus (GEO) database to analyze the expression and clinical significance of integrin family genes in SSc. In addition, functional enrichment and pathway analysis were also conducted.Results:Compared with healthy controls, ITGA5, ITGA7, ITGA8, ITGB2, ITGB5, ITGAE and ITGB3BP were abnormally overexpressed in the skin of SSc. Further analysis indicated that ITGA5, ITGA7, ITGA8, ITGB2 and ITGB5 were positively correlated with modified Rodnan skin thickness score (mRSS), while ITGAE and ITGB3BP were negatively correlated with mRSS in SSc. Increased ITGB5 expression was associated with positive of anti-centromere antibody (ACA). Functional enrichment and pathway analysis showed that integrin members had multiple functions in SSc. Among them, ITGA5, ITGB2 and ITGB5 might synergistically promote SSc through affecting extracellular matrix (ECM) turn over, ECM-receptor interaction, focal adhesion and leukocyte trans-endothelial migration. ITGA5 and ITGB5 also affected angiogenesis and endothelial cell function. In addition, ITGA5 was uniquely enriched for actin organization, ITGB5 was uniquely enriched for TGF-β signaling, and ITGB2 was uniquely associated with immune cells activation.Conclusion:Our results implied that integrins, especially ITGA5, ITGB5, ITGB2 participated in the process of inflammation, vasculopathy and fibrosis in SSc. Together, they might render important therapeutic targets for SSc.References:[1]Brown M, O’Reilly S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin Exp Immunol. 2019;195(3):310-321.[2]Gerber, E.E., et al., Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature, 2013. 503(7474): p. 126-30.Disclosure of Interests:None declared

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Antonacopoulou, A., A. Argyriou, A. E. Kottorou, C. D. Scopa y H. P. Kalofonos. "Association of integrin beta-3 polymorphism and chronic oxaliplatin-induced peripheral neuropathy: Preliminary results". Journal of Clinical Oncology 27, n.º 15_suppl (20 de mayo de 2009): e15082-e15082. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15082.

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e15082 Background: Peripheral neuropathy (PN) is widely recognised among the major non-haematological dose- limiting toxicities of oxaliplatin (OXL) which is used to treat advanced or metastatic colorectal cancer (CRC). OXL induces two clinically distinct forms of PN. The acute transient syndrome and the chronic OXL-induced peripheral neuropathy (OXLIPN). The integrin beta-3 (ITGB3) polymorphism at residue 33 (L33P) has been previously associated with altered adhesion ability and ERK2 activation. Thus it may affect neuronal survival. The aim of the current study was to investigate the role of the ITGB3 polymorphism at residue 33 in the development of chronic OXLIPN. Methods: Thirty four patients with advanced CRC were genotyped. All patients, 22 males and 12 females had received adjuvant chemotherapy consisting of 12 courses of the formal FOLFOX-4 regimen. Following the discontinuation of treatment, 20 of the patients (58.8 %), developed OXLIPN, whereas the remaining 14 (41.2%) patients remained unaffected with normal peripheral nerve function. The grading of the OXLIPN severity was defined by Total Neuropathy scores, corresponding to the WHO grading scales 1–3 for chemotherapy-induced PN. Genotyping was performed using allele specific primers and sybr green in real time polymerase chain reactions. Statistics were performed using the SPSS for Windows (release 16.0). Results: Patients with normal peripheral nerve function OXLIPN were 14.3% homozygous for C, 28.6% heterozygous and 57.1% homozygous for T. The corresponding percentages for patients who developed OXLIPN did not differ significantly and were 5%, 25% and 70%, respectively. The majority of patients with mild OXLIPN were heterozygotes (50%, with 16.7% CC and 33.3% TT), whereas the majority of patients with moderate OXLIPN were homozygous for TT (85.7% with the remaining 14.3% being CT). Notably, the TT genotype was associated with increased OXLIPN compared to the genotypes containing the C allele (p= 0.046). Conclusions: The ITGB3 polymorphism at residue 33 appears to be unrelated to the development of OXLIPN but related to the grade of OXLIPN.Further study on this important clinical issue is warranted. No significant financial relationships to disclose.

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Sun, Boyang, Donglei Zhang, Huiyuan Li, Xueqing Dou y Renchi Yang. "Detection and Analysis of Gene Mutations in Patients with Glanzmann's Thrombasthenia". Blood 134, Supplement_1 (13 de noviembre de 2019): 2373. http://dx.doi.org/10.1182/blood-2019-129446.

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Background: Glanzmann thrombasthenia (GT) is a rare inherited disorder of bleeding, and it is characterized by the impaired or absent platelet aggregation to multiple physiologic agonists such as collagen, adenosine diphosphate (ADP), arachidonic acid(AA), but normal reaction to ristocetin. There is qualitative or quantitative defect in platelet integrin αIIbβ3(GPIIb/IIIa). Pathogenic variants of either αIIb or β3 unit could cause GT. The database of gene mutations is continuously updated on the Internet (http://www.hgmd.org); it totally lists 236 variants of ITGA2B gene and 170 variants of ITGB3 gene. Aim: To characterize the clinical manifestation and molecular basis of GT patients in China, and update the pathogenic variants database. Method: Clinical features are evaluated in 104 patients with GT. New generation sequencing was performed with a custom designed panel for the bleeding and platelet disease involving 76 genes, while ITGA2B and ITGB3 were enrolled. Result: The initial bleeding occurred before 1 age in most patients. Incidence of consanguinity is 12.5%. Symptoms lessened with age in about 30% patients. Female patients suffered more severe bleeding than male patients. Fifty different mutations were detected, among which 15 were novel. Most patients were compound heterozygotes and most mutations detected were missense mutations. Among 15 novel mutations, there were 7 missense mutations, 2 nonsense mutations, 2 splicing mutations, 4 frameshift mutations. Pathogenicity of all novel mutations were evaluated according to the standards and guidelines of ACMG. All variants detected were pathogenic or likely pathogenic. Furthermore, c.1750C>T [p.R584X] and c.2333A>C [p.Q778P] in ITGA2B were detected in 10 and 16 unrelated families, strongly suggesting a founder effect. Conclusion: Our study reports the largest cohort of GT in China, describing the clinical, laboratory and genetic characteristics of 104 patients. We found 15 novel pathogenic mutations in ITGA2B and ITGB3 causing GT. Theses novel findings expand the GT mutation spectrum. Disclosures No relevant conflicts of interest to declare.

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Valiulyte, Indre, Giedrius Steponaitis, Deimante Kardonaite, Arimantas Tamasauskas y Arunas Kazlauskas. "A SEMA3 Signaling Pathway-Based Multi-Biomarker for Prediction of Glioma Patient Survival". International Journal of Molecular Sciences 21, n.º 19 (7 de octubre de 2020): 7396. http://dx.doi.org/10.3390/ijms21197396.

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Glioma is a lethal central nervous system tumor with poor patient survival prognosis. Because of the molecular heterogeneity, it is a challenge to precisely determine the type of the tumor and to choose the most effective treatment. Therefore, novel biomarkers are essential to improve the diagnosis and prognosis of glioma tumors. Class 3 semaphorin proteins (SEMA3) play an important role in tumor biology. SEMA3 transduce their signals by using neuropilin and plexin receptors, which functionally interact with the vascular endothelial growth factor-mediated signaling pathways. Therefore, the aim of this study was to explore the potential of SEMA3 signaling molecules for prognosis of glioma patient survival. The quantitative real-time PCR method was used to evaluate mRNA expression of SEMA3(A-G), neuropilins (NRP1 and NRP2), plexins (PLXNA2 and PLXND1), cadherins (CDH1 and CDH2), integrins (ITGB1, ITGB3, ITGA5, and ITGAV), VEGFA and KDR genes in 59 II-IV grade glioma tissues. Seven genes significantly associated with patient overall survival were used for multi-biomarker construction, which showed 64%, 75%, and 68% of accuracy of predicting the survival of 1-, 2-, and 3-year glioma patients, respectively. The results suggest that the seven-gene signature could serve as a novel multi-biomarker for more accurate prognosis of a glioma patient’s outcome.

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