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González-Ortega, I., S. Alberich-Mesa, E. Echeburúa, M. Bernardo, B. Cabrera, S. Amoretti, A. Lobo, et al. "Social cognition as a mediator between cognitive reserve and psychosocial functioning in patients with first episode psychosis." European Psychiatry 64, S1 (April 2021): S163. http://dx.doi.org/10.1192/j.eurpsy.2021.436.
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IntroductionSocial cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear.ObjectivesThe aim of the study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years.MethodsThe sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis.ResultsAt baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (−10.215 to −0.337) and (−4.731 to −0.605) respectively).ConclusionsCognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.DisclosureThis work was supported by the Carlos III Institute of Health and European Fund for Regional Development (PI08/1213, PI11/ 01977, PI14/01900, PI08/01026, PI11/02831, PI14/01621, PI08/1161, PI16/ 00359, PI16/01164, PI18/00805), the Basque Foundation for He
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Mohandas, Arunesh, Heddy Zola, Simon Barry, and Doreen Krumbiegel. "Peptidase inhibitor 16 identifies a unique subset of memory T helper cells with hyperproliferative and proinflammatory properties (IRC8P.477)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 190.5. http://dx.doi.org/10.4049/jimmunol.192.supp.190.5.
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Abstract T helper (Th) cells play a major role in protecting the body against pathogens. Any imbalance in Th cell subsets could lead to autoimmune and inflammatory diseases. Peptidase inhibitor 16 (PI16), also known as prostate secretory protein of 94 amino acid - binding protein, was recently discovered to be expressed on memory regulatory T cells. This study investigates the expression and function of PI16 on Th cells. In healthy adults, 5-25% of CD4+ Th cells express PI16 with over 90% showing a memory phenotype. PI16+ Th cells have an increased expression of chemokine receptors CCR4 and CCR6 compared with PI16- Th cells. Transwell migration assays showed that more PI16+ Th cells migrated towards the CCR4 and CCR6 ligands (CCL17 and CCL20) compared with PI16- Th cells. After 7 day stimulation using CD3 / CD28 beads, PI16+ Th cells produce more IL-17A and less IFN-g compared with PI16- Th cells. PI16+ Th cells also have a higher expression of ROR-gt compared to PI16- Th cells. Furthermore, in comparison to PI16- Th cells, PI16+ Th cells have an increased proliferative potential and are less responsive to suppression by Treg. The memory phenotype of PI16+ Th cells, the high expression of Th17-like chemokine receptors, increased ROR-gt expression and high production of IL-17A suggest an active role of PI16+ Th cells at the site of infection or inflammation. Further studies are ongoing to understand the functional role of PI16 on Th cells in autoimmune and inflammatory diseases.
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Singhmar, Pooja, Ronnie The Phong Trinh, Jiacheng Ma, XiaoJiao Huo, Bo Peng, Cobi J. Heijnen, and Annemieke Kavelaars. "The fibroblast-derived protein PI16 controls neuropathic pain." Proceedings of the National Academy of Sciences 117, no. 10 (February 20, 2020): 5463–71. http://dx.doi.org/10.1073/pnas.1913444117.
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Chronic pain is a major clinical problem of which the mechanisms are incompletely understood. Here, we describe the concept that PI16, a protein of unknown function mainly produced by fibroblasts, controls neuropathic pain. The spared nerve injury (SNI) model of neuropathic pain increases PI16 protein levels in fibroblasts in dorsal root ganglia (DRG) meninges and in the epi/perineurium of the sciatic nerve. We did not detect PI16 expression in neurons or glia in spinal cord, DRG, and nerve. Mice deficient in PI16 are protected against neuropathic pain. In vitro, PI16 promotes transendothelial leukocyte migration. In vivo, Pi16−/− mice show reduced endothelial barrier permeability, lower leukocyte infiltration and reduced activation of the endothelial barrier regulator MLCK, and reduced phosphorylation of its substrate MLC2 in response to SNI. In summary, our findings support a model in which PI16 promotes neuropathic pain by mediating a cross-talk between fibroblasts and the endothelial barrier leading to barrier opening, cellular influx, and increased pain. Its key role in neuropathic pain and its limited cellular and tissue distribution makes PI16 an attractive target for pain management.
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Lin, S., X. Gu, F. Wang, and W. Tan. "POS0002 PI16 REPRESSES FOXP3 EXPRESSION IN T REGULATORY CELLS AND EXACERBATES AUTOIMMUNE ARTHRITIS VIA INHIBITING THE K48-LINKED POLYUBIQUITIN DEGRADATION OF BMI-1." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 203.2–203. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2756.
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Background:Regulatory T cells (Tregs) play an essential role in maintaining self-tolerance and immune homeostasis. Abnormalities in the quantity or function of Treg cells are believed in RA patients, contributing to the inability to suppress autoimmunity and proinflammatory cytokines. Forkhead box P3 (Foxp3) is a crucial transcription factor for the development and differentiation of Tregs. How Tregs lose Foxp3 expression under inflammatory milieu remains largely unknown. Peptidase inhibitor 16 (PI16) is a member of the CAP (Cysteine-rich secretory proteins, Antigen 5, and Pathogenesis-related 1) protein family and its function are largely poor understood. In a genome-wide expression profiling study for identifying human Foxp3 target genes revealed PI16 was expressed on the cell surface of >80% of resting human CD25+ Foxp3+ Tregs. In the inflamed joint of juvenile idiopathic arthritis revealed a low number of PI16+ Tregs but high number of Th17 cells. However, little is known the function role of PI16 on Tregs or on RA development.Objectives:To investigate the role of peptidase inhibitor 16 (PI16) on the key T regulatory (Tregs) cells transcription factor Foxp3 expression and on the development of autoimmune arthritis.Methods:The expression of PI16 in blood, synovial fluid, inflamed joints were examined in Rheumatoid arthritis (RA) patients and in arthritic mice. Arthritis symptom, histological features and Foxp3 expression in PI16 transgenic (PI16Tg) arthritic mice were examined. Posttranslational mechanisms on PI16-mediated Foxp3 expression were analyzed. The specific role PI16 on Foxp3 expression was validated in conditional knockout (KO) mice.Results:The expression of PI16 was significantly increased in PBMC, serum, synovial tissue from RA patients or arthritic mice compared with controls. PI16Tg arthritic mice exhibited obvious inflammation, synovial hyperplasia and articular cartilage destruction in the joints compared with those in wild-type mice (WT) arthritic mice.Foxp3 is downregulated in splenic T cells and synovial tissue from PI16Tg arthritic mice. Naïve T cells derived from PI16Tg arthritic mice showed the decreased capacity to differentiate into Tregs. Polycomb-group (PcG) proteins complex molecule of Bmi-1 was significant increase in Tregs and joint tissue from PI16Tg arthritic mice. A direct interaction between 1-95AA domains of PI16 and 169 and 436 domains of Bmi-1 in Tregs promoter was observed. The binding of PI16 with Bmi-1 in the Foxp3 promoter inhibit the K48-linked polyubiquitin degradation of Bmi-1 at lysine site 72 and 153 region, which prompts the repressive histone modification of H3K27me3 and H2AK119ub, and inhibits the active histone modification of H3K4me3. Furthermore, conditional knockout of PI16 in Tregs retarded Foxp3 loss and blunted disease progression in experimental arthritis.Conclusion:PI16 represses Foxp3 expression by mediating histone modification via inhibiting K48-linked polyubiquitin degradation of Bmi-1 in Foxp3 promoter, contributing to disease progression in arthritic mice.Disclosure of Interests:None declared.
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Chen, De-jian, and Da-peng Li. "A Potential miRNA-mRNA Network for Dementia and Hernia Crosstalk." BioMed Research International 2021 (July 23, 2021): 1–14. http://dx.doi.org/10.1155/2021/4324068.
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Background. It has been reported that there may be a potential link between hernia and dementia. However, the exact mechanisms of their association have not been established. This study is aimed at constructing miRNA-mRNA networks to elucidate on the potential link between dementia and hernia. Methods. Gene expression profiles for dementia, herniation, and skeletal muscle were downloaded from the GEO database after which differentially expressed mRNAs and miRNAs were obtained. In addition, fascia tissue samples were obtained during surgery. A total of 41 patients were recruited in this study, and expression levels of candidate genes were examined using quantitative RT-PCR. Luciferase reporter gene assays were used to identify potential miRNA-mRNA regulatory pathways. Results. Differentially expressed mRNAs and miRNAs were screened. A potential miRNA-mRNA network revealing the crosstalk mechanism between herniation and dementia was identified. Single cell analysis revealed that PI16 was highly enriched in adipose tissues, skeletal muscles, and in the skin. GSEA enrichment analysis showed that PI16 is involved in adipose metabolism, muscle functions, and energy metabolism. In clinical samples, PI16 was found to be upregulated in hernia, while miR-4451 was found to be downregulated. The luciferase reporter gene assay revealed that downregulation of circulating miR-4451 may be responsible for the upregulated PI16 expression in hernia sacs. Conclusions. We constructed an miRNA-mRNA network that shows the potential association between dementia and hernia. We also found that miR-4451 regulates the PI16 expression, which may be a key target and biomarker for hernia pathogenesis and dementia crosstalk.
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GROSE, RANDALL H., DEBORAH J. MILLARD, CHRIS MAVRANGELOS, SIMON C. BARRY, HEDDY ZOLA, IAN C. NICHOLSON, WENG TARNG CHAM, CHRISTINA A. BOROS, and DOREEN KRUMBIEGEL. "Comparison of Blood and Synovial Fluid Th17 and Novel Peptidase Inhibitor 16 Treg Cell Subsets in Juvenile Idiopathic Arthritis." Journal of Rheumatology 39, no. 10 (August 15, 2012): 2021–31. http://dx.doi.org/10.3899/jrheum.111421.
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Objective.Early recognition and treatment of juvenile idiopathic arthritis (JIA) can prevent joint damage and minimize side effects of medication. The balance between proinflammatory and antiinflammatory mechanisms is known to be important in JIA, and we therefore investigated T cell subsets including Th cells, autoaggressive Th17 cells, and regulatory T cells (Treg), including a novel Treg subset in peripheral blood (PB) and synovial fluid (SF) of patients with JIA.Methods.Fifty children with JIA were enrolled in our study. Frequency, phenotype, and function of T lymphocytes in PB and SF were characterized using flow cytometry. Migration capabilities of PB and SF cells were compared.Results.Synovial T cells showed different phenotype and function compared with PB T cells, with an increased proportion of memory T cells, expression of CCR4, CCR5, CXCR3, interleukin 23R, and an increased ratio of Th17 to Treg. Although Treg were increased in SF compared with the PB, we found a significant decrease in the numbers of peptidase inhibitor 16 (PI16)+ Treg in active joints compared with peripheral blood. Coexpression of CCR4 and CCR6 was reduced on PI16+ Treg in PB and SF of patients with JIA compared with healthy children, however the ability of these cells to migrate toward their ligands was unaffected.Conclusion.This is a comprehensive characterization of novel PI16+ Treg and Th17 cells in matched blood and synovial fluid samples of patients with JIA. Despite an increased number of Treg within the inflamed joint, lower numbers of PI16+ Treg but high numbers of Th17 cells might contribute to the inability to control disease.
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Fukuta, Yoshimichi, Mary Jeanie Telebanco-Yanoria, Nagao Hayashi, Seiji Yanagihara, Catherine Wanjiku Machungo, and Daigo Makihara. "Pathogenicities of Rice Blast (Pyricularia oryzae Cavara) Isolates From Kenya." Plant Disease 103, no. 12 (December 2019): 3181–88. http://dx.doi.org/10.1094/pdis-04-19-0870-re.
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A total of 99 isolates of rice blast (Pyricularia oryzae Cavara) were collected from 2010 to 2015 from four regions in Kenya: Kirinyaga County and Embu County, Kisumu County, Tana River County, and Mombasa County. The pathogenicities of these isolates were clarified based on the reaction patterns of Lijiangxintuanheigu and differential varieties (DVs) targeting 23 resistance genes. The frequency of virulent isolates was high for DVs for Pib, Pia, Pii, Pi3, Pi5(t), Pik-s, Pik-m, Pi1, Pik-h, Pik, Pik-p, Pi7(t), Pi19(t), and Pi20(t); low for DVs for Pish, Pi9(t), Piz-5, and Piz-t; and intermediate for the remaining DVs for Pit, Piz, Pita-2, Pita, and Pi12(t). These blast isolates were classified into three cluster groups: Ia, Ib, and II. The frequencies of virulent isolates to DVs for Pit, Pii, Pik-m, Pi1, Pik-h, Pik, Pik-p, Pi7(t), Piz, and Pi12(t) differed markedly between clusters I and II, and those of DVs for Pib, Pit, Pia, Pi3, Pita-2, Pita, and Pi20(t) differed between Ia and Ib. The frequencies of cluster groups in the four geographical regions were different. A total of 62 races were found, with 19 blast isolates categorized into one race (U63-i7-k177-z00-ta003), whereas the other races included only some isolates in each.
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Wang, Pusen, Zhongyi Jiang, Xueni Liu, Kanru Yu, Chunguang Wang, Hao Li, and Lin Zhong. "PI16 attenuates response to sorafenib and represents a predictive biomarker in hepatocellular carcinoma." Cancer Medicine 9, no. 19 (August 10, 2020): 6972–83. http://dx.doi.org/10.1002/cam4.3331.
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Gibbs, Gerard M., Kim Roelants, and Moira K. O'Bryan. "The CAP Superfamily: Cysteine-Rich Secretory Proteins, Antigen 5, and Pathogenesis-Related 1 Proteins—Roles in Reproduction, Cancer, and Immune Defense." Endocrine Reviews 29, no. 7 (December 1, 2008): 865–97. http://dx.doi.org/10.1210/er.2008-0032.
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Abstract The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily members are found in a remarkable range of organisms spanning each of the animal kingdoms. Within humans and mice, there are 31 and 33 individual family members, respectively, and although many are poorly characterized, the majority show a notable expression bias to the reproductive tract and immune tissues or are deregulated in cancers. CAP superfamily proteins are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumor suppressor or prooncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilization. This review describes mammalian CAP superfamily gene expression profiles, phylogenetic relationships, protein structural properties, and biological functions, and it draws into focus their potential role in health and disease. The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. We conclude that overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters target specificity and, therefore, the biological consequences.
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Kawasaki-Tanaka, A., N. Hayashi, S. Yanagihara, and Y. Fukuta. "Diversity and Distribution of Rice Blast (Pyricularia oryzae Cavara) Races in Japan." Plant Disease 100, no. 4 (April 2016): 816–23. http://dx.doi.org/10.1094/pdis-04-15-0442-re.
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In total, 310 rice blast (Pyricularia oryzae Cavara) isolates from Japan showed wide variation in virulence. Virulence on rice (Oryza sativa L.) differential varieties (DV) harboring resistance genes Pish, Pia, Pii, Pi3, Pi5(t), Pik-s, and Pi19(t) ranged from 82.9 to 100.0%. In contrast, virulence on DV possessing Pib, Pit, Pik-m, Pi1, Pik-h, Pik, Pik-p, Pi7(t), Pi9(t), Piz, Piz-5, Piz-t, Pita-2, Pita, Pi12(t), and Pi20(t) ranged from 0 to 21.6%. Cluster analysis using the reaction patterns of the DV classified isolates into three groups: I, virulent to Pik, Pik-h, Pik-p, Pik-m, Pi1, and Pi7(t); IIa, avirulent to the preceding 6 genes and virulent to Pia, Pii, Pi3, and Pi5(t); and IIb, avirulent to all 10 genes. Group I was limited to northern Japan and group IIb to central Japan, while group IIa was distributed throughout Japan. We estimate that group IIa represents the original population and that groups I and IIb arose from it through minor changes in pathogenicity. We classified these isolates into 123 races by a new designation system and conclude that the rice blast races in Japan are less diverse than previously thought.
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Nicholson, Ian C., Christos Mavrangelos, Daniel R. G. Bird, Suzanne Bresatz-Atkins, Nicola G. Eastaff-Leung, Randall H. Grose, Batjargal Gundsambuu, et al. "PI16 is expressed by a subset of human memory Treg with enhanced migration to CCL17 and CCL20." Cellular Immunology 275, no. 1-2 (January 2012): 12–18. http://dx.doi.org/10.1016/j.cellimm.2012.04.002.
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Olivera-Valle, I., M. C. Latorre, M. Calvo, B. Gaspar, C. Gómez-Oro, A. Collazos, A. Breton, et al. "Vaginal neutrophils eliminate sperm by trogocytosis." Human Reproduction 35, no. 11 (October 4, 2020): 2567–78. http://dx.doi.org/10.1093/humrep/deaa198.
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Abstract STUDY QUESTION What is the vaginal polymorphonuclear (PMN) spermicidal mechanism to reduce the excess of sperm? SUMMARY ANSWER We show that PMNs are very efficient at killing sperm by a trogocytosis-dependent spermicidal activity independent of neutrophil extracellular traps (NETs). WHAT IS KNOWN ALREADY Trogocytosis has been described as an active membrane exchange between immune cells with a regulatory purpose. Recently, trogocytosis has been reported as a mechanism which PMNs use to kill tumour cells or Trichomonas vaginalis. STUDY DESIGN, SIZE, DURATION We used in vivo murine models and human ex vivo sperm and PMNs to investigate the early PMN–sperm response. PARTICIPANTS/MATERIALS, SETTING, METHODS We set up a live/dead sperm detection system in the presence of PMNs to investigate in vivo and ex vivo PMN-spermicidal activity by confocal microscopy, flow cytometry and computer-assisted sperm analysis (SCA). MAIN RESULTS AND THE ROLE OF CHANCE We revealed that PMNs are highly efficient at killing sperm by way of a NETs-independent, contact-dependent and serine proteases-dependent engulfment mechanism. PMNs ‘bite’ sperm and quickly reduce sperm motility (within 5 min) and viability (within 20 min) after contact. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION This study was conducted using murine models and healthy human blood PMNs; whether it is relevant to human vaginal PMNs or to cases of infertility is unknown. WIDER IMPLICATIONS OF THE FINDINGS Vaginal PMNs attack and immobilize excess sperm in the vagina by trogocytosis because sperm are exogenous and may carry pathogens. Furthermore, this mechanism of sperm regulation has low mucosal impact and avoids an exacerbated inflammatory response that could lead to mucosal damage or infertility. STUDY FUNDING/COMPETING INTEREST(S) This work was partially supported by Ministry of Economy and Competitiveness ISCIII-FIS grants, PI16/00050, and PI19/00078, co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’ and IiSGM intramural grant II-PI-MRC-2017. M.R. holds a Miguel Servet II contract (CPII14/00009). M.C.L. holds IiSGM intramural contract. There are no competing interests.
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Hazell, Georgina, Jack E. Teasdale, Graciela Sala-Newby, Andrew C. Newby, and Stephen J. White. "Shear stress and inflammation modulate the expression of Peptidase Inhibitor 16 (PI16) in human coronary artery endothelial cells (HCAECs)." Atherosclerosis 237, no. 2 (December 2014): e8-e9. http://dx.doi.org/10.1016/j.atherosclerosis.2014.10.056.
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Nguyet, Nguyen T. M., Hoang H. Long, Nguyen B. Ngoc, Nguyen T. Nhai, Nguyen T. T. Thuy, Nagao Hayashi, and Yoshimichi Fukuta. "Diversity and Distribution of Rice Blast (Pyricularia oryzae Cavara) Races in Vietnam." Plant Disease 104, no. 2 (February 2020): 381–87. http://dx.doi.org/10.1094/pdis-05-19-1008-re.
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A total of 239 isolates of blast (Pyricularia oryzae Cavara) collected from northern and central Vietnam showed a wide variation in pathogenicity based on the reaction patterns to 25 differential varieties (DVs) harboring 23 resistance genes and susceptible cultivar Lijiangxintuanheigu (LTH). The frequencies of isolates virulent toward DVs for Pish, Pik-m, Pi1, Pik-h, Pik, Pik-p, Pi7(t), Pi9(t), Piz-5, Pita-2, and Pita were low, but they were high for DVs for Pib, Pit, Pia, Pii, Pi3, Pi5(t), Pik-s, Piz, Piz-t, Pi12(t), Pi19(t), and Pi20(t). Isolates were classified into three cluster groups Ia, Ib, and II based on reaction patterns to DVs and LTH. The frequencies of isolates virulent toward 11 DVs for Pik-m, Pi1, Pik-h, Pik, Pik-p, Pi7(t), Pi9(t), Piz, Piz-5, Pita-2, and Pita in cluster II and DV for Piz-t were higher and lower than those of Ia and Ib, respectively. The frequencies to DVs for Pii, Pi3, Pi5(t), and Piz-t were different between clusters Ia and Ib. Clusters Ia and Ib were distributed with similar frequencies in the northeast, north central, and south central coast regions, but the frequencies among three cluster groups in the Red River Delta and northwest regions were different. This means that the blast races in these two regions were different from the others. Overall, the blast isolates were categorized into 153 races. Among them, 26 were selected as a set of standard differential blast isolates for characterizing 23 resistance genes and developing a differential system in Vietnam.
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Gaikwad, Avinash S., Jinghua Hu, David G. Chapple, and Moira K. O’Bryan. "The functions of CAP superfamily proteins in mammalian fertility and disease." Human Reproduction Update 26, no. 5 (May 7, 2020): 689–723. http://dx.doi.org/10.1093/humupd/dmaa016.
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Abstract BACKGROUND Members of the cysteine-rich secretory proteins (CRISPS), antigen 5 (Ag5) and pathogenesis-related 1 (Pr-1) (CAP) superfamily of proteins are found across the bacterial, fungal, plant and animal kingdoms. Although many CAP superfamily proteins remain poorly characterized, over the past decade evidence has accumulated, which provides insights into the functional roles of these proteins in various processes, including fertilization, immune defence and subversion, pathogen virulence, venom toxicology and cancer biology. OBJECTIVE AND RATIONALE The aim of this article is to summarize the current state of knowledge on CAP superfamily proteins in mammalian fertility, organismal homeostasis and disease pathogenesis. SEARCH METHODS The scientific literature search was undertaken via PubMed database on all articles published prior to November 2019. Search terms were based on following keywords: ‘CAP superfamily’, ‘CRISP’, ‘Cysteine-rich secretory proteins’, ‘Antigen 5’, ‘Pathogenesis-related 1’, ‘male fertility’, ‘CAP and CTL domain containing’, ‘CRISPLD1’, ‘CRISPLD2’, ‘bacterial SCP’, ‘ion channel regulator’, ‘CatSper’, ‘PI15’, ‘PI16’, ‘CLEC’, ‘PRY proteins’, ‘ASP proteins’, ‘spermatogenesis’, ‘epididymal maturation’, ‘capacitation’ and ‘snake CRISP’. In addition to that, reference lists of primary and review article were reviewed for additional relevant publications. OUTCOMES In this review, we discuss the breadth of knowledge on CAP superfamily proteins with regards to their protein structure, biological functions and emerging significance in reproduction, health and disease. We discuss the evolution of CAP superfamily proteins from their otherwise unembellished prokaryotic predecessors into the multi-domain and neofunctionalized members found in eukaryotic organisms today. At least in part because of the rapid evolution of these proteins, many inconsistencies in nomenclature exist within the literature. As such, and in part through the use of a maximum likelihood phylogenetic analysis of the vertebrate CRISP subfamily, we have attempted to clarify this confusion, thus allowing for a comparison of orthologous protein function between species. This framework also allows the prediction of functional relevance between species based on sequence and structural conservation. WIDER IMPLICATIONS This review generates a picture of critical roles for CAP proteins in ion channel regulation, sterol and lipid binding and protease inhibition, and as ligands involved in the induction of multiple cellular processes.
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Díaz-García, César, Sonia Herraiz, Esperanza Such, María del Mar Andrés, Eva Villamón, Empar Mayordomo-Aranda, José V. Cervera, Miguel A. Sanz, and Antonio Pellicer. "Dexamethasone does not prevent malignant cell reintroduction in leukemia patients undergoing ovarian transplant: risk assessment of leukemic cell transmission by a xenograft model." Human Reproduction 34, no. 8 (July 24, 2019): 1485–93. http://dx.doi.org/10.1093/humrep/dez115.
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Abstract STUDY QUESTION Does dexamethasone (DXM) incubation avoid the reintroduction of leukemic malignant cells after ovarian tissue retransplantation in vivo? SUMMARY ANSWER DXM incubation prior to retransplantation of ovarian tissue does not prevent reintroduction of leukemic cells. WHAT IS KNOWN ALREADY Retransplantation of cryopreserved ovarian cortex from patients diagnosed with acute lymphoblastic leukemia (ALL) involves a risk of reintroducing malignant cells. DXM treatment is effective at inducing leukemic cell death in vitro. STUDY DESIGN, SIZE, DURATION This was an experimental study where ovarian cortex fragments from patients with ALL were randomly allocated to incubation with or without DXM (n = 11/group) and grafted to 22 immunodeficient mice for 6 months. In a parallel experiment, 22 immunodeficient mice were injected i.p. with varying amounts of RCH-ACV ALL cells (human leukemia cell line) and maintained for 4 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Cryopreserved ovarian fragments from patients with ALL were exposed in vitro to 0.4 μM DXM or basal media (control) prior to xenograft into ovariectomized severe combined immunodeficiency (SCID) mice (experiment 1). After 6 months of monitoring, leukemia cell contamination was assessed in ovarian grafts and mouse organs by histology, PCR (presence of mouse mtDNA and absence of p53 were together considered a negative result for the presence of human cells) and detection of immunoglobulin monoclonality and specific ALL markers if present in the patient. In experiment 2, a series of 22 immunodeficient female mice was injected with specific doses of the leukemia cell line RCH-ACV (103 − 5 × 106, n = 4/group) to assess the engraftment competence of the SCID model. MAIN RESULTS AND THE ROLE OF CHANCE ALL metastatic cells were detected, by PCR, in five DXM-treated and one control human ovarian tissue graft as well as in a control mouse liver, although malignant cell infiltration was not detected by histology in any sample after 6 months. In total, minimal residual disease was present in three DXM-treated and three control mice. RCH-ACV cells were detected in liver and spleen samples after the injection of as little as 103 cells, although only animals receiving 5 × 106 cells developed clinical signs of disease and metastases. LIMITATIONS, REASONS FOR CAUTION This is an experimental study where the malignant potential of leukemic cells contained in human ovarian tissues has been assessed in immunodeficient mice. WIDER IMPLICATIONS OF THE FINDINGS These results indicate that DXM incubation prior to retransplantation of ovarian tissue does not prevent reintroduction of leukemic cells. Therefore, caution should be taken in retransplanting ovarian tissue from patients with leukemia until safer systems are developed, as leukemic cells present in ovarian grafts were able to survive, proliferate and migrate after cryopreservation and xenograft. STUDY FUNDING/COMPETING INTEREST(S) Funded by the Regional Valencian Ministry of Education (PROMETEO/2018/137) and by the Spanish Ministry of Economy and Competitiveness (PI16/FIS PI16/01664 and PTQ-16-08222 for S.H. participation). There are no competing interests.
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Xangsayasane, Phetmanyseng, Chanthakone Boualaphanh, Chay Bounphanousay, Viengphone Bounphanousay, Phatsalakone Manivong, Singty Voradeth, Phoumi Inthapanya, et al. "Genetic Variation of Rice Blast (Pyricularia oryzae) Isolates in Laos." Plant Health Progress 21, no. 4 (January 1, 2020): 248–55. http://dx.doi.org/10.1094/php-05-20-0041-rs.
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The pathogenicity of 192 blast isolates collected from regions across the whole of Laos from 2007 to 2009 showed a wide variation in terms of the frequencies of virulence toward differential varieties (DVs) and the susceptible control cultivar Lijiangxintuanheigu. High frequencies of virulence (>50%) were found in the reactions of DVs for Pit, Pia, Pi3, Pi5(t), Pik-s, Piz-t, Pi19(t), and Pi20(t); intermediate values (from 10 to 50%) were found in DVs for Pib, Pii, Pik-m, Pi1, Pik-h, Pik, Pik-p, Pi7(t), Piz-5, Pita (two lines), Pita-2 (two lines), and Pi12(t); and low frequencies (<10%) were found in DVs for Pish, Piz, and Pi9(t). The blast isolates were classified into three cluster groups: Ia and Ib (low virulence) and II (high virulence), based on the patterns of reaction to them. The blast isolates in cluster group Ia were dominant in rainfed lowland areas, those in Ib were dominant in irrigated lowland areas, and those in II were dominant in upland areas. Cluster groups Ia, Ib, and II were dominant in the Southern, Central, and Northern regions, respectively. Blast races in Laos were distributed according to ecosystems for rice cultivation and geographical regions from south to north with different virulence. These isolates were categorized into 156 races, and the numbers of blast isolates were few in each race. A total of 15 representative isolates were selected from among them as standard differential blast isolates, to develop a differential system.
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Khan, M. A. I., M. A. Ali, M. A. Monsur, A. Kawasaki-Tanaka, N. Hayashi, S. Yanagihara, M. Obara, M. A. T. Mia, M. A. Latif, and Y. Fukuta. "Diversity and Distribution of Rice Blast (Pyricularia oryzae Cavara) Races in Bangladesh." Plant Disease 100, no. 10 (October 2016): 2025–33. http://dx.doi.org/10.1094/pdis-12-15-1486-re.
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The pathogenicity of 331 blast isolates (Pyricularia oryzae Cavara) collected from different regions and ecosystems for rice cultivation in Bangladesh was evaluated by compatibility on 23 differential varieties (DV), each harboring a single blast resistance gene, and susceptible ‘Lijiangxintuanheigu’ (LTH). A wide variation in virulence was found among the isolates, and 267 races were classified using a new designation system. Virulence of blast isolates against DV carrying the resistance genes Pia, Pib, Pit, Pik-s, Piz-t, Pi12(t), Pi19(t), and Pi20(t), as well as avirulence against those carrying Pish, Pi9, Pita-2, and Pita, was distributed widely in Bangladesh. Cluster analysis of the compatibility data on the DV initially classified the isolates into groups I and II. The virulence spectra of the two groups differed mainly according to the reactions of the DV to Pii, Pi3, Pi5(t), Pik-m, Pi1, Pik-h, Pik, Pik-p, and Pi7(t). Group I isolates were distributed mainly in rainfed lowlands, whereas group II isolates were found mainly in irrigated lowlands; however, there were no critical differences in geographic distribution of the blast isolates. In total, 26 isolates, which could be used to identify the 23 resistance genes of the DV on the basis of their reaction patterns, were selected as a set of standard differential blast isolates. To our knowledge, this is the first clear demonstration of the diversity and differentiation of blast races in Bangladesh. This information will be used to develop a durable blast protection system in that country.
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Kadarmideen, H. N., and G. Mazzoni. "Transcriptomics–genomics data integration and expression quantitative trait loci analyses in oocyte donors and embryo recipients for improving invitro production of dairy cattle embryos." Reproduction, Fertility and Development 31, no. 1 (2019): 55. http://dx.doi.org/10.1071/rd18338.
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In this paper we first provide a brief review of main results from our previously published studies on genome-wide gene expression (transcriptomics) in donor and recipient cattle used in invitro production (IVP) of embryos and embryo transfer (ET). Then, we present novel results from applying integrative systems genomics and biological analyses where transcriptomics data are combined with genomic data in both donor and recipient cattle to map expression quantitative trait loci (eQTLs). The eQTLs are genetic markers that can regulate or control the expression of genes in the entire genome, via complex molecular mechanisms, and thus can act as a powerful tool for genomic and gene-assisted selection. We identified significant eQTLs potentially controlling the expression of 13 candidate genes for donor cow quality (IVP parameters; e.g. cyclin B1 (CCNB1), outer dense fiber of sperm tails 2 like (ODF2L)) and 19 candidate genes for recipient cows quality (endometrial receptivity; e.g. ER membrane protein complex subunit 9 (EMC9), mannosidase beta (MANBA), peptidase inhibitor 16 (PI16)). Annotation and colocation of detected eQTLs show that some of the eQTLs are in the same genomic regions previously reported as QTLs for reproduction-related traits. However, eQTLs and the candidate genes identified should be further validated in larger populations before implementation as genetic markers or used in genomic selection for improving IVP and ET performance.
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Tyznik, Aaron J., Nihan Kara, Mirko Corselli, Noel L. Warner, Alan M. Stall, Joe Trotter, and Suraj Saksena. "Evaluation of activation and homing markers on regulatory T cells using a modular flow cytometry approach on the BD FACSLyric™ flow cytometer." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 120.25. http://dx.doi.org/10.4049/jimmunol.200.supp.120.25.
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Abstract Advancements in cell analysis capabilities have significantly expanded our understanding of the complexity of immunological systems. As the need for deeper analysis has increased, many laboratories have employed a set of lineage markers to define a cell population, followed by the addition of unique markers specific to their biological question. Utilizing regulatory T cells (Treg) as a model population, we describe the design of an 8-color backbone panel on a 12-Color BD FACSLyric™ flow cytometer that can be supplemented with 4 drop-in markers (colors) to characterize two critical facets of Treg biology: activation and homing. Intelligent panel design enabled identification of human naïve and activated Treg cells utilizing established Treg markers (CD3, CD4, CD25, CD127, FoxP3, CD45RA). CD15s and CD161 were included in the 8-color backbone panel to identify functionally suppressive effector and/or pro-inflammatory cytokine secreting Tregs. Importantly, addition of a 4-color drop-in activation panel (PI16, CD147, CD39 and HLA-DR) or a 4-color drop-in homing panel (CCR4, CCR6, CXCR3 and CD31) did not impact resolution of the backbone Treg population(s), while providing new and interesting insights into Treg biology. We highlight the utility of a modular panel design approach that provides an efficient, scalable, and standardized solution for complex analysis of essentially any cell population of interest.
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Wu, Shan, Jing Xu, Guang Li, and Xi Jin. "Integrating Radiosensitivity Gene Signature Improves Glioma Outcome and Radiotherapy Response Prediction." Medicina 58, no. 10 (September 22, 2022): 1327. http://dx.doi.org/10.3390/medicina58101327.
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Response to radiotherapy (RT) in gliomas varies widely between patients. It is necessary to identify glioma-associated radiosensitivity gene signatures for clinically stratifying patients who will benefit from adjuvant radiotherapy after glioma surgery. Methods: Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) glioma patient datasets were used to validate the predictive potential of two published biomarkers, the radiosensitivity index (RSI) and 31-gene signature (31-GS). To adjust these markers for the characteristics of glioma, we integrated four new glioma-associated radiosensitivity predictive indexes based on RSI and 31-GS by the Cox analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. A receiver operating characteristic (ROC) curve, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used to compare the radiosensitivity predictive ability of these six gene signatures. Subgroup analysis was used to evaluate the discriminative capacity of those gene signatures in identifying radiosensitive patients, and a nomogram was built to improve the histological grading system. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were used to explore related biological processes. Results: We validated and compared the predictive potential of two published predictive indexes. The AUC area of 31-GS was higher than that of RSI. Based on the RSI and 31-GS, we integrated four new glioma-associated radiosensitivity predictive indexes—PI10, PI12, PI31 and PI41. Among them, a 12-gene radiosensitivity predictive index (PI12) showed the most promising predictive performance and discriminative capacity. Examination of a nomogram created from clinical features and PI12 revealed that its predictive capacity was superior to the traditional WHO classification system. (C-index: 0.842 vs. 0.787, p ≤ 2.2 × 10−16) The GO analysis and GSEA showed that tumors with a high PI12 score correlated with various aspects of the malignancy of glioma. Conclusions: The glioma-associated radiosensitivity gene signature PI12 is a promising radiosensitivity predictive biomarker for guiding effective personalized radiotherapy for gliomas.
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Ivancic, Melanie M., Leigh W. Anson, Perry J. Pickhardt, Bryant Megna, Bryan D. Pooler, Linda Clipson, Mark Reichelderfer, Michael R. Sussman, and William F. Dove. "Conserved serum protein biomarkers associated with growing early colorectal adenomas." Proceedings of the National Academy of Sciences 116, no. 17 (April 10, 2019): 8471–80. http://dx.doi.org/10.1073/pnas.1813212116.
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A major challenge for the reduction of colon cancer is to detect patients carrying high-risk premalignant adenomas with minimally invasive testing. As one step, we have addressed the feasibility of detecting protein signals in the serum of patients carrying an adenoma as small as 6–9 mm in maximum linear dimension. Serum protein biomarkers, discovered in two animal models of early colonic adenomagenesis, were studied in patients using quantitative mass-spectrometric assays. One cohort included patients bearing adenomas known to be growing on the basis of longitudinal computed tomographic colonography. The other cohort, screened by optical colonoscopy, included both patients free of adenomas and patients bearing adenomas whose risk status was judged by histopathology. The markers F5, ITIH4, LRG1, and VTN were each elevated both in this patient study and in the studies of the Pirc rat model. The quantitative study in the Pirc rat model had demonstrated that the elevated level of each of these markers is correlated with the number of colonic adenomas. However, the levels of these markers in patients were not significantly correlated with the total adenoma volume. Postpolypectomy blood samples demonstrated that the elevated levels of these four conserved markers persisted after polypectomy. Two additional serum markers rapidly renormalized after polypectomy: growth-associated CRP levels were enhanced only with high-risk adenomas, while PI16 levels, not associated with growth, were reduced regardless of risk status. We discuss biological hypotheses to account for these observations, and ways for these signals to contribute to the prevention of colon cancer.
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Hernández-Breijo, B., C. Plasencia, C. García-Hoz, C. Sobrino, V. Navarro-Compán, A. Martínez-Feito, I. Nieto-Gañán, et al. "FRI0582 GM-CSF PRODUCED BY CD4+ T CELLS AS A MARKER OF CLINICAL REMISSION IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TNF INHIBITORS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 895.2–895. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1338.
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Background:According to the EULAR recommendations, the therapeutic target in patients with RA should be remission (REM). However, no more than 50% of the patients treated with TNF inhibitors (TNFi) attains this outcome. Previous investigations suggested the peripheral blood mononuclear cells (PBMC) as markers associated with the TNFi treatment success1,2. Granulocyte-monocyte colony-stimulating factor (GM-CSF) plays a relevant role in the pathogenesis of rheumatoid arthritis (RA) because it promotes the macrophage differentiation, survival and activation3.Objectives:To analyse the intracellular cytokine production by PBMC and its association with REM attainment after 6 months (m) of TNFi treatment in patients with RA.Methods:This was a prospective bi-center pilot study including 36 patients with RA. PBMC were isolated from patients at baseline and after 6m of treatment with TNFi and cryopreserved until studied. Intracellular cytokine production by PBMC was stimulated in the presence of 2µg/mL brefeldin as follow: monocytes were stimulated with 20ng/mL LPS during 4h; and simultaneously lymphocytes were stimulated with 50ng/mL phorbol 12-myristate 13-acetate (PMA) and 750ng/mL ionomycin during 4h at 37°C. To identify IL-10-producing B cells, PBMC were pre-incubated with 3µg/mL of CpG oligonucleotide during 20h at 37°C prior to stimulation in presence of 2µmol/L monensin. Intracellular cytokine production (TNFα, IL6, GM-CSF, IL10) by the different cell subsets (monocytes, CD4+and CD8+T cells, naïve and memory B cells) was analysed by flow-cytometry. Clinical activity at baseline and after 6m was assessed by DAS28. REM was defined as DAS28≤2.6 at 6m. The association between REM and the change in cytokine production (Δ, 6m-0m) by each PBMC subset was analysed through univariable and multivariable logistic regression models.Results:Seventy-eight percent of the patients were female. After 6m of TNFi treatment, 47% patients attained REM. Univariable analyses was performed to investigate the association between REM and the baseline variables. Male sex (OR: 12.6; 95% CI: 1.35-117.57; p=0.03) and having lower baseline DAS28 (OR: 0.4; 95% CI: 0.19-0.85; p=0.02) were independently associated with attaining REM after 6m of TNFi. In the multivariable analysis, only being male (OR: 19.7; 95% CI: 1.4-273.9; p=0.03) remained independently associated with REM after 6m of treatment. Therefore, further analyses were adjusted by sex. Decreased production of GM-CSF by CD4+T cells percentage was found after 6m of TNFi treatment in REM patients (0m: 6.07%; 6m: 3.87%; p=0.007) while no-REM patients did not show differences with the baseline (0m: 3.70%; 6m: 3.75%; p=0.9). The decrease was significantly associated with attaining REM (OR: 0.56; 95% CI: 0.33-0.95; p: 0.03). No significant association was found between any other analysed intracellular cytokine produced by the different PBMC subsets and REM.Conclusion:GM-CSF intracellular production by CD4+T cells was significantly decreased by TNFi treatment only in patients who attained REM. Therefore, our results suggest that GM-CSF production by CD4+T cells may be a useful marker of REM to TNFi in RA.References:[1] Sobrino C, et al. Ann Rheum Dis. 2019; 78 (S2): A1665.[2] Hernández-Breijo B, et al. Ann Rheum Dis. 2019; 78 (S2): A711.[3] Avci AB, et al. Clin Exp Rheumatol. 2016; 34 (S98), 39-44.Figure. 1:Association between the change in intracellular cytokine production (Δ, 6m-0m) by each PBMC subset and REM. Adjusted logistic regression analyses were performed for each cytokine.Acknowledgments:ISCIII (PI16/00474; PI16/01092)Disclosure of Interests:Borja Hernández-Breijo: None declared, Chamaida Plasencia: None declared, Carlota García-Hoz: None declared, Cristina Sobrino: None declared, Victoria Navarro-Compán Consultant of: Abbvie, Lilly, Novartis, Pfizer, UCB, Speakers bureau: AbbVie, MSD, Lilly, Novartis, Pfizer, UCB, ANA MARTÍNEZ-FEITO: None declared, Israel Nieto-Gañán: None declared, Paloma Lapuente-Suanzes: None declared, Javier Bachiller-Corral: None declared, Gemma Bonilla: None declared, Cristina Pijoan Moratalla: None declared, Garbiñe Roy: None declared, Mónica Vázquez Díaz: None declared, Alejandro Balsa Grant/research support from: BMS, Roche, Consultant of: AbbVie, Gilead, Lilly, Pfizer, UCB, Sanofi, Sandoz, Speakers bureau: AbbVie, Lilly, Sanofi, Novartis, Pfizer, UCB, Roche, Nordic, Sandoz, Luisa María Villar: None declared, DORA PASCUAL-SALCEDO Grant/research support from: Pfizer, Novartis & Progenika, Speakers bureau: Pfizer, Merck, Novartis, Takeda, Menarini & Grifols, Eulalia Rodríguez-Martín: None declared
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Hernández-Breijo, B., E. Rodríguez-Martín, C. García-Hoz, V. Navarro-Compán, C. Sobrino, A. Martínez-Feito, I. Nieto-Gañán, et al. "POS0623 CYTOKINE PRODUCTION BY BLOOD LYMPHOCYTES DEFINES A PROFILE ASSOCIATED WITH NON-REMISSION IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH TNF INHIBITORS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 549.2–550. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2361.
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Background:In clinical practice no more than 50% of the patients treated with TNF inhibitors (TNFi) achieve remission (REM). Previous investigations suggested that peripheral blood mononuclear cells (PBMC) may be markers associated with the TNFi treatment success1.Objectives:This study aims to analyse the intracellular cytokine production by PBMC and its association with REM achievement after 6 months (m) of TNFi treatment in patients with RA.Methods:This was a prospective study including 62 patients with RA starting the 1st TNFi. PBMC were isolated from patients at baseline and after 6m of treatment with TNFi and cryopreserved until studied. In vitro stimulation and intracellular cytokine production by PBMC was performed as follow: in the presence of 2µg/mL brefeldin and 2µmol/L monensin monocytes were stimulated with 20ng/mL LPS during 4h whereas lymphocytes were stimulated with 50ng/mL phorbol 12-myristate 13-acetate and 750ng/mL ionomycin for 4h at 37°C. To identify IL10-producing B cells, PBMC were pre-incubated with 3µg/mL of CpG oligonucleotide during 20h at 37°C prior to stimulation. Intracellular cytokine production (TNFα, IL6, GM-CSF, IL10) by the different cell subsets (monocytes, CD4+ and CD8+ T cells, naïve and memory B cells) was analysed by flow-cytometry. Clinical activity at baseline and after 6m was assessed by DAS28-ESR. REM was defined as DAS28≤2.6 at 6m. The association between cytokine production by each PBMC subset and REM was analysed through univariable and multivariable logistic regression models. Receiving operating curve (ROC) analysis was used to select the optimal ratio of cytokine production associated with REM status.Results:After 6m of TNFi treatment, 30 (48%) patients achieved REM. No significant differences between REM and non-REM groups were observed for patients’ characteristics at baseline except for DAS28, which was lower in the REM group (non-REM: 5.4±0.9; REM: 4.3±0.9; p<0.0001) (Table 1). Therefore, further analyses were adjusted by baseline DAS28. A lower ratio between calculated with the IL10 and TNFα production by B cells and by CD4+ T cells (IL10 B/TNF CD4) at 6m was found for non-REM patients (non-REM: 0.31 vs REM: 0.54; p=0.007). Based on a ROC analysis, we found that a (IL10 B/TNF CD4)<0.54 at 6 m was significantly associated with a higher probability of non-REM at 6 months (OR: 5.0; 95% CI: 1.1-21.7) (Figure 1).Table 1.Baseline predictors of reduction of disease activity at 12 months from start of abatacept. Linear regression.Baseline patients’ characteristicsTotal patients (n=62)DAS28>2.6(n=32; 52%)DAS28≤2.6(n=30; 48%)p-valueAge (years)53±1253±1352±100.8Female55 (89)30 (94)25 (83)0.2Disease duration (years)8 (4-11)8 (4-12)7 (3-11)0.7RF positive49 (79)23 (72)26 (87)0.1ACPA positive54 (87)26 (81)28 (93)0.2Smoking habit (n=55)0.2Non-smokers26 (47)16 (55)10 (38) Smoker29 (53)13 (45)16 (51)Body mass index (kg/m2)25.9±5.625.8±5.726.0±5.60.9DAS284.9±1.05.4±0.94.3±0.9<0.0001Concomitant csDMARDs60 (97)32 (100)28 (93)0.3MTX [±OD]46 (74)26 (81)20 (67)0.3Only OD14 (23)6 (19)8 (26)0.3Prednisone36 (58)19 (59)17 (57)0.9Conclusion:Our results show that the proinflammatory IL10 B/TNF CD4 ratio is associated with non-REM status. It could be useful to analyse the success of TNFi treatment in patients with RA.References:[1]Rodríguez-Martín E, et al. Front Immunol. 2020; 11: 1913.Acknowledgements:ISCIII (PI16/00474; PI16/01092)Disclosure of Interests:Borja Hernández-Breijo: None declared, Eulalia Rodríguez-Martín: None declared, Carlota García-Hoz: None declared, Victoria Navarro-Compán Speakers bureau: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer and UCB, Grant/research support from: Abbvie, Janssen, Lilly, MSD, Novartis, Pfizer and UCB, Cristina Sobrino: None declared, ANA MARTÍNEZ-FEITO: None declared, Israel Nieto-Gañán: None declared, Javier Bachiller-Corral Speakers bureau: Abbvie, MSD, BMS and Roche, Grant/research support from: Pfizer, Paloma Lapuente-Suanzes: None declared, Gemma Bonilla: None declared, Cristina Pijoán-Moratalla: None declared, Mónica Vázquez: None declared, Alejandro Balsa Speakers bureau: Abbvie, BMS, Nordic, Novartis, Pfizer, Sandoz, Sanofi, Roche and UCB, DORA PASCUAL-SALCEDO: None declared, Luisa María Villar: None declared, Chamaida Plasencia Speakers bureau: AbbVie, Lilly, Novartis, Pfizer, Sanofi, Biogen and UCB
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Somervaille, Tim, Olga Salamero, Pau Montesinos, Christophe Willekens, Jose Antonio Perez Simon, Arnaud Pigneux, Christian Recher, et al. "Safety, Phamacokinetics (PK), Pharmacodynamics (PD) and Preliminary Activity in Acute Leukemia of Ory-1001, a First-in-Class Inhibitor of Lysine-Specific Histone Demethylase 1A (LSD1/KDM1A): Initial Results from a First-in-Human Phase 1 Study." Blood 128, no. 22 (December 2, 2016): 4060. http://dx.doi.org/10.1182/blood.v128.22.4060.4060.
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Abstract In preclinical studies, LSD1 inhibitors derived from tranylcypromine were active in acute myeloid leukemia models, particularly in the MLL-translocated subtype. We now report the safety, PK and PD properties of ORY-1001 (a potent and selective inhibitor of LSD1) in a multicenter phase I study (EUDRACT nº 2013-002447-29). The primary objective was to assess safety and tolerability in relapsed or refractory acute leukemia (RR-AL). Secondary objectives were to a) characterize PK, b) to monitor a panel of surrogate PD markers for target engagement and c) assess clinical response. Patients ≥16yr with RR-AL, ECOG PS ≤2 and life expectancy >8wk were eligible. ORY-1001 was administered orally once daily in a 28 day cycle (5d ON/2d OFF x4wk). Plasma ORY-1001 levels were analyzed by HPLC-MS/MS. Blood leukocyte expression of candidate differentiation PD biomarkers was determined by qRT-PCR. Twenty-seven subjects (mean age 66.5, range 40-81; gender 19 M/8F) were recruited into the dose escalation phase (26 - RR-AML; 1 - RR-ALL). Mean time since initial diagnosis was 12.6 months and since last treatment was 2.1 months. Twenty patients completed cycle 1, 9 started cycle 2 with 3 completions and 3 started and completed cycle 3. The most frequent ADR was thrombocytopenia (7 events, 5 subjects). Twenty-two subjects experienced 32 SAEs of which two (Cohort 8 - 220 µg/m2/d) were considered possibly related to ORY-1001: grade 5 lobar pneumonia and grade 3 febrile neutropenia (in combination with grade 2 fatigue and grade 2 erythema multiforme). These were considered dose limiting toxicities. Consequently the recommended dose for the extension phase was established at 140 μg/m2/d. At the end of the dose escalation phase, 358 treatment emergent AEs were reported. The most frequent were asthenia (16 events, 12 subjects), febrile neutropenia (15 events, 13 subjects), constipation (12 events, 9 subjects) and peripheral oedema (11 events, 8 subjects). ORY-1001 plasma concentration increased with dose across cohorts. At 140 µg/m2/d (recommended dose) on d1 mean±SD Cmax was 13.1±7.2 and mean±SD AUC (0-24h) was 181.7±61.3pg.hr/mL. On d5 mean±SD Cmax was 42.2±27 and mean±SD AUC (0-24h) 723.3±341.5pg.hr/mL. PD biomarker response varied due to differences in disease genetics and circulating blast percentages. Nevertheless select biomarkers demonstrated time and dose dependent response profiles in individual patients. For example, PI16 (peptidase inhibitor 16; or CRISP-9) levels were induced in cohort 7 (140 µg/m2/d). Maximum PI16 induction was seen at 18hr on d1, pre-dose levels remained high on d5 and were sustained through the OFF period until pre-dose on d8. An extension cohort of 14 patients (mean age 57; range 30-78, gender 8M/6F) with specific RR-AML subtypes predicted to be more sensitive based upon preclinical studies, was also enrolled (AML MLL-translocated n=10; acute erythroleukemia/M6 n=4). At data cut-off (31 July 2016), 131 AEs and 27 SAEs have been reported. Eight SAEs were considered related to treatment, including a differentiation syndrome in two patients. PK and PD analyses are ongoing. For response assessment, 14 patients were evaluable. Objective responses were seen in 5/14 patients (36%): two patients with t(9;11) exhibited stable disease and three a partial response (one MLL after 3 cycles, and two M6). Importantly, there was evidence of morphologic blast differentiation in blood and/or BM in 9/14 patients (5 MLL and 4 M6). In summary, ORY-1001 at the recommended dose is well tolerated and promotes blast cell differentiation in 64% of patients. This, together with the partial responses observed, suggest that LSD1 inhibition may be a possible therapy for some AML patients. Disclosures Somervaille: Novartis: Consultancy, Honoraria; Imago Biosciences: Consultancy. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Molinero:Oryzon Genomics: Employment, Equity Ownership. Mascaro:Oryzon Genomics: Employment. Maes:Oryzon Genomics: Employment, Equity Ownership.
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Bischoff, Allison, Yaqing Zhang, Wei Yan, Kristee Brown, Wenting Du, and Marina Pasca di Magliano. "Abstract C049: WT1+ cancer-associated fibroblasts promote pancreatic cancer growth." Cancer Research 82, no. 22_Supplement (November 15, 2022): C049. http://dx.doi.org/10.1158/1538-7445.panca22-c049.
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Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by dense, fibro-inflammatory stroma that is established in early pathogenesis. Cancer-associated fibroblasts (CAFs) make up a significant proportion of the tumor microenvironment and represent a heterogeneous cell population that play both tumor-promoting and tumor-restricting roles. Despite their dramatic expansion in PDA pathogenesis, it is still unclear what cells in the normal pancreas give rise to these CAFs. Lineage-tracing experiments have previously identified pancreatic stellate cells, mesothelial, and tissue-resident fibroblasts as progenitors to subsets of CAFs. In this research, we firstly pulse-labeled cells expressing the mesothelial and fibroblast marker Wilms tumor 1 (WT1) in the normal pancreas of WT1CreERT;R26tdTomato mice and used an orthotopic model of PDA to trace their contribution to the PDA tumor microenvironment. We found WT1+ cells in the normal pancreas expanded to comprise a significant proportion of PDA CAFs according to immunofluorescence. Based upon single-cell RNA-sequencing (scRNA-seq), these WT1+ precursors represent an endogenous pancreatic fibroblast population similar to previously characterized universal adventitial fibroblasts (Pi16+, Dpp4+). To determine the role of WT1 in established PDA, we labeled WT1+ cells following orthotopic tumor implantation into WT1CreERT;R26tdTomato mice, and scRNA-seq analysis revealed that both inflammatory CAFs (iCAFs) and myofibroblastic CAFs (MyCAFs) express WT1. Notably, iCAFs had higher relative expression of WT1+. Additionally, we depleted WT1+ cells with diphtheria toxin from orthotopic tumors established in WT1CreERT;R26tdTomato/iDTR mice. We found depletion of WT1+ cells reduced orthotopic tumor growth, and depleted fibroblasts from the PDA tumor microenvironment. These findings implicate WT1 as a promising lineage tracing marker for a subset of pancreatic fibroblasts and demonstrates a pro-tumorigenic role of WT1+ fibroblasts in PDA. Citation Format: Allison Bischoff, Yaqing Zhang, Wei Yan, Kristee Brown, Wenting Du, Marina Pasca di Magliano. WT1+ cancer-associated fibroblasts promote pancreatic cancer growth [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C049.
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Ibáñez, Mariam, Alexander Neef, Carmen Martínez-Losada, Esperanza Such, Desiree Company, Marta Llop, Josefina Serrano, et al. "Clonal Hematopoiesis Landscape in Patients with De Novo Acute Myeloid Leukemia By Deep Sequencing." Blood 128, no. 22 (December 2, 2016): 598. http://dx.doi.org/10.1182/blood.v128.22.598.598.
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Abstract Purpose: Acute myeloid leukemia (AML) is associated with progressive accumulation of genetic alterations in hematopoietic progenitors. Massive sequencing allows inference of the clonal architecture of hematologic malignancies, by determining the presence of subclones, their genetic composition and evolution. The objective of the present study was to determine the spectrum of mutations present at relapse and define the proportion of cellular clones and the genetic architecture of the evolution of patients with de novo AML. Methods: Paired samples (diagnostic/relapse) of 44 patients of the University Hospital La Fe with de novo AML and treated with consecutive PETHEMA schemes were studied. The samples were provided by the Biobanco La Fe. The median age was 59 years (range 17 - 89); 21M/13F; 17 patients with normal karyotype; 14 patients with FLT3-ITD positive and 9 with mutations in NPM1. Using an amplicon panel (Ampliseq, Life Technologies) for deep sequencing (10.000x) with an Ion Torrent Proton, the complete coding regions of the following genes were sequenced, BCOR, BRAF, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, GNAS, LUC7L2, NF1, PHF6, PTPN11, RAD21, RPS14, SF1, SF3A1, SMC3, SPARC, SRSF2, STAG2 and ZRSR2, as well as, the hotspot regions of ASXL1, MPL, NPM1, JAK2, KRAS, NRAS, TET2, U2AF1, KIT, IDH1, RUNX1, IDH2, SETBP1, TP53, WT1, CBL, SF3B1 and FLT3. Primary bioinformatic analysis was performed using an in-house protocol and variants were selected based on VAF ≥ 1%, its absence in the healthy population (UCSC Common SNPs; MAF < 0.01) and its putative effect on the protein. Results: At least one alteration was detected in 98% of patients, (n = 43). At a mean sequencing depth of 8967x, in total, 249 mutations were detected with an average of 3.3 mutations per patient and sample (range 0 - 8). Comparing the two time points, we noted that 45% of the mutations were present at both moments, with rather similar VAF values. However, 24% were acquired during progression while 31% went missing at the time of relapse. Regarding the mutated genes analyzed at diagnosis, in 8 of 44 patients one single gene clone was detected, in 26 two subclones and in 10 three or more subclones. In addition, two different patterns of clonal evolution were detected. In model 1 the dominant founder clone persisted at relapse (n = 32, 71%), occasionally acquiring new changes, either in the same clone (n = 5) or in a new subclone (n = 17). In model 2 the founder clone was displaced at relapse by new subclones (n = 12, 29%), probably due to selective pressure through competition between subclones or as a consequence of the chemotherapy. Furthermore, the clonal hematopoiesis models did not show an association with clinical variables or prognostic impact on OS or EFS (P = 0.317; P = 0.12, respectively). Conclusions: AML cells can acquire additional mutations at relapse. Some of those may contribute to the clonal selection responsible for disease progression. Two models of clonal evolution were observed: model 1, where the dominant founder clone persists during relapse, and, model 2, where the founder clone is displaced by new cell subclones, displaying, both models, a similar impact on outcome. Financed by the Spanish Foundation of Hematology (FEHH), PI12/01047, RD12/0036/0014, PIE13/00046, PI13/01640, PI13/02837, PT13/0010/0026, PI14/01649, ACOMP2015/0335 and PROMETEOII/2015/study/025. Disclosures No relevant conflicts of interest to declare.
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Poza, María, Rafael Colmenares, Alba González, Noemi Alvarez, Gonzalo Carreño Gomez-Tarragona, Esther Onecha, María Teresa Cedena, et al. "Differences in the Mutational Landscape of Myeloid Malignancies (acute myeloid leukemia, myelodysplastic syndrome and myeloproliferative neoplasm) and Their Clinical Impact." Blood 136, Supplement 1 (November 5, 2020): 41–42. http://dx.doi.org/10.1182/blood-2020-141534.
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Introduction: Myeloid malignancies are clonal disorders of hematopoietic stem cells and include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Common biological markers have been described in the molecular pathogenesis, including gene mutations in splicing factors, epigenetic modifiers, transcription factors, signal pathways and tumor suppressors. These mechanisms have been associated with MDS and MPN progression to AML. Objectives: The main objective of this study is to identify differences in the mutational landscape of myeloid malignancies and describe mutation frequencies of genes and functional pathways in each neoplasm, as well as determine their clinical impact. Methods: This study involved a retrospective analysis of 430 patients with AML (209), MDS (106) and Philadelphia negative MPN (86) diagnosed in the Hospital Universitario 12 de Octubre (Spain). They were analyzed by a next generation sequencing (NGS)- panel for myeloid malignancies. The panel include 32 genes: CALR, ASXL1, EZH2, PHF6, DNMT3A 2, TET2, IDH1, IDH2, KDM6A, KMT2A, SF1, SF3A1, SF3B1, SRSF2, U2AF1, ZRSR2, PRPF40B, EPOR, FLT3, JAK2, KIT, SH2B3, MPL, CBL, HRAS, NRAS, KRAS, ETV6, RUNX1, VHL, TP53, PTEN. In addition, there were included 29 patients diagnosed with benign pathology that were referred to rule out MPN or congenital polyglobulia. Results: In the analyzed cohort we obtained a larger number of mutations in the more aggressive malignancies, AML and MDS. Mutations in epigenetic modifiers and signal pathways were the most frequent detected (31% and 24% respectively). The epigenetic modifiers were notably affected in AML (78%) and MDS (60.4%), whereas signal pathways were mutated more frequently in MPN (70.9%). Transcription factors, tumor suppressors and splicing factors mutations were more detected in AML and MDS (40%, 32%, 44% and 22%, 13%, 32% respectively). The mutation landscape obtained by genes was: Signal pathways: FLT3, NRAS, KIT, KRAS y SH2B3 were specially detected in AML (25%, 11%, 6%, 5% and 4% respectively). JAK2, CALR and MPL in MPN (38%, 15% and 6% respectively). Transcription factors: RUNX1, ETV6, PHF6, CEBPA and WT1 mutations were regularly observed in AML (21%, 6%, 6%, 6% and 5% respectively), and GATA1 in SMD (3.8%). Tumor suppressors: TP53 was particularly affected in AML (21%) and MDS (11%). Epigenetic modifiers: TET2 was notably mutated in MDS (32%), whereas ASXL1, DNMT3A, IDH2, IDH1 and EZH2 were in AML (21%, 21%, 17% 16% and 8% respectively). Splicing factors: SF3B1 was more frequently detected in MDS (18%) than AML (7%), whereas ZRSR2 presented a similar frequency in both pathologies (around 8%). U2AF1 was most commonly mutated in MPN (9%). SRSF2 was specially mutated in AML (23%). SF3A1 was altered in around 1%, similar in all three malignancies. With regard to survival studies, the presence of mutations in splicing factors (primarily in U2AF1) and its absence in signal pathways conferred an adverse outcome for overall survival (OS) in MPN. In MDS, gene mutations in tumor suppressors (especially TP53), U2AF1 splicing factor and EZH2 epigenetic modifier were associated with poor outcome. In our series of AML, gene mutations in tumor suppressors and TP53 were related to unfavorable prognosis in OS. Conclusion: The largest number of mutations and affected genes observed in AML suggest that leukemic transformation of MDS and MPN is conditioned by acquisition of new mutations. We observed different frequencies of mutations between AML, MDS and MPN that could guide the diagnostic and identify new targets of treatment. Further, some mutations have demonstrated differential prognostic impact. An extension of this study and the design of an algorithm with mutation data to elucidate a more accurate molecular prognosis will be presented at the meeting. This work has been financed thanks to the grant PI16/01225, PI 19/01518 and PI19/00730 from the Instituto de Salud Carlos III (Ministerio de Economia, Industria y Competititvidad) and cofinanced by the European Development Fund. Figure 1. Mutations detected (%) in AML, MDS and MPN classified by function. Table 1. Median overall survival of patients with MPN, MDS and AML according to gene state (mutated or not). Figure Disclosures No relevant conflicts of interest to declare.
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Alias, Norsyuhada, Mu’adz Ahmad Mazian, Abu Bakar Salleh, Mahiran Basri, and Raja Noor Zaliha Raja Abd Rahman. "Molecular Cloning and Optimization for High Level Expression of Cold-Adapted Serine Protease from Antarctic Yeast Glaciozyma antarctica PI12." Enzyme Research 2014 (June 30, 2014): 1–20. http://dx.doi.org/10.1155/2014/197938.
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Psychrophilic basidiomycete yeast, Glaciozyma antarctica strain PI12, was shown to be a protease-producer. Isolation of the PI12 protease gene from genomic and mRNA sequences allowed determination of 19 exons and 18 introns. Full-length cDNA of PI12 protease gene was amplified by rapid amplification of cDNA ends (RACE) strategy with an open reading frame (ORF) of 2892 bp, coded for 963 amino acids. PI12 protease showed low homology with the subtilisin-like protease from fungus Rhodosporidium toruloides (42% identity) and no homology to other psychrophilic proteases. The gene encoding mature PI12 protease was cloned into Pichia pastoris expression vector, pPIC9, and positioned under the induction of methanol-alcohol oxidase (AOX) promoter. The recombinant PI12 protease was efficiently secreted into the culture medium driven by the Saccharomyces cerevisiae α-factor signal sequence. The highest protease production (28.3 U/ml) was obtained from P. pastoris GS115 host (GpPro2) at 20°C after 72 hours of postinduction time with 0.5% (v/v) of methanol inducer. The expressed protein was detected by SDS-PAGE and activity staining with a molecular weight of 99 kDa.
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Harmawanto, Agung Gagah, Yosef Cahyo Setianto Poernomo, and Sigit Winarto. "PERENCANAAN ALTERNATIF GEOMETRIK DAN METODE PELAKSANAAN RUAS JALAN NGRAHO – NGAWI STA.14+500 - STA.19+500." Jurnal Manajemen Teknologi & Teknik Sipil 2, no. 2 (November 6, 2019): 179. http://dx.doi.org/10.30737/jurmateks.v2i2.510.
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Ngraho - Ngawi Sta. 14 + 500 – Sta. 19 + 500 highway is a collector connecting Bojonegoro to Ngawi Due to high traffic density, a road geometric Development is in need. The objective of this final project is to plan a good alternative geometric design-safe, comfortable, and easy to access. The required data were of topographic map and the road geometric design was based on the “Tata Cara Perencanaan Geometrik Jalan Antar Kota” General Works Standart No. 038/TBM/1997. The calculations result in Class 2 – lane collector road with one lane of 3 m wide having 8 turns, twists PI1 Spiral-Spiral, PI2 Spiral-Circle-Spiral, PI3 Spiral-Circle-Spiral, PI4 Spiral-Circle-Spiral, PI5 Spiral-Circle-Spiral, PI6 Spiral-Circle-Spiral, PI7 Spiral-Circle-Spiral, and turn PI8 Spiral-Spiral shape PPV PPV 1 concave and 2 convex, concave 3 PPV.Jalan provinsi ruas Ngraho – Ngawi Sta. 14+500 – Sta. 19+500 adalah jalan kolektor yang menghubungkan kota Bojonegoro - Ngawi. Karena lalu lintasnya padat, maka perlu diadakan peningkatan geometrik jalan. Dalam laporan akhir ini penulis membuat perencanaan alternatif desain geometrik jalan yang baik-aman,nyaman, dan mudah diakses oleh pengguna jalan. Data yang digunakan adalah peta topografi dan perencanaan desain geometrik jalan berpedoman oleh “Tata Cara Perencanaan Geometrik Jalan Antar Kota” Standar Bina Marga No.038/TBM/1997. Dari perhitungan diperoleh hasil sebagai berikut: kelas jalan kolektor dengan 2 lajur 1 jalur dan memiliki lebar 3 m, 8 tikungan, tikungan PI1Spiral-Spiral, PI2 Spiral-Circle-Spiral, PI3 Spiral-Circle-Spiral, PI4 Spiral-Circle-Spiral, PI5 Spiral-Circle-Spiral, PI6 Spiral-Circle-Spiral, PI7 Spiral-Circle-Spiral,dan tikunganPI8 Spiral-Spiralbentuk PPV 1 cekung dan PPV 2 cembung, PPV 3 cekung.
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Del Can-Sanchez, Diego Jesús, Diego Jesus Del Can Sanchez, Antonio Jesús Martínez-Ortega, Alvaro Flores-Martínez, Eva Venegas-Moreno, María Elena Dios-Fuentes, Ainara Madrazo-Atutxa, et al. "Markers of Aggressiveness in Craniopharyngiomas." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A646. http://dx.doi.org/10.1210/jendso/bvab048.1317.
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Abstract Craniopharyngiomas (CP) are rare tumors that may be locally aggressive. The presence of functional estrogen receptors (ER) has been reported in CP and might be related to risk of recurrence. Our aim is to ascertain if the expression estrogen and progesterone receptor (PR) might be associated with to recurrence in CP. Material and Methods: Descriptive retrospective observational study of patients with confirmed histology of CP and tissue sample available admitted to Virgen Del Rocio University Hospital (Seville, Spain) from January 1967 to October 2020 were included. Estrogen and progesterone receptor expression was analyzed by Immunohistochemistry. Ki-67 levels were also analyzed. Two CP groups were considereded according to Ki67 levels: Group A (Ki67<10%) and group B (Ki67>10%). As all variables followed a non-parametric distribution, U Mann Whitney, Chi-Square, and Z-test with Benjamini-Hochberg correction were used when needed. Results: Our study population includes 80 patients (46 male and 34 female), with a median age at diagnosis of 34 years [10-50.00]. Twenty-six patients were under 18 years old (children) with a median age of 7 years [4.5-10.00], and 54 were adults (aged 18 and above) with a median age of 45 years [33-58.50]. Our data shows higher recurrence rates when Ki67 levels staining were higher than 10%: 8/14 (57.2%) in comparison with Ki67<10% (6/14, 42.9%, p=0.018). In children we found 6 samples with Ki67<10% and 6 samples with Ki67 >10%; recurrences were observed in 2/6 (33,3%) in the first group and in 6/6 (100%) in the second, respectively (p= 0,199). In adults, we found 9 and 3 patients for high and low Ki67 levels, respectively. Recurrences were observed in 4/9 (44,4%) in the group A and in 2/3 (66,7%) in the group B, respectively (p= 0,28). There were no differences between age groups. In patients with positive ER, we observed an increased rate of recurrence: 12/23 (52.17%) versus 2/13 (15,38%) in patients with negative ER stain but it was no significant. (p=0,21). No association between PR and recurrence was observed. Conclusions: In our series, patients with CP with high Ki67 levels are more likely to recur. No clear association between ER, PR expression and recurrence was observed. These findings support the use of Ki67 as a marker of recurrence in CP. Sources of Research Support: Spanish Ministry of Health, ISCIII co-funded with Fondos FEDER (PI16/00175) and Novartis Oncology Spain.
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Fernández-Ibarrondo, Lierni, Joan Gibert, Concepción Fernández-Rodríguez, Laura Camacho, Anna Angona, Marcio Andrade, Nieves Garcia-Gisbert, et al. "Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy." Blood 138, Supplement 1 (November 5, 2021): 3623. http://dx.doi.org/10.1182/blood-2021-150491.
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Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p<0.001), and displayed higher leukocyte count (p<0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.
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Garcia-Gisbert, Nieves, Brayan Merchan, Sara Garcia-Avila, Marta Salido, Concepción Fernández-Rodríguez, Joan Gibert, Lierni Fernández-Ibarrondo, et al. "Non-Invasive Genetic Profiling and Monitoring in Myelodysplastic Syndromes." Blood 138, Supplement 1 (November 5, 2021): 2599. http://dx.doi.org/10.1182/blood-2021-148297.
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Abstract Introduction. Myelodysplastic syndromes (MDS) are clonal heterogeneous disorders in which molecular studies and cytogenetics are essential for diagnosis, classification and prognosis. Cell-free DNA (cfDNA) analysis has been reported as a reliable non-invasive approach for detecting molecular abnormalities in MDS. However, there is limited information about cytogenetic alterations and monitoring in cfDNA from MDS patients. Objective. To assess and monitor the molecular and cytogenetic abnormalities by next generation sequencing (NGS) using cfDNA from patients with MDS. Patients and methods. Bone marrow (BM) aspirates and peripheral blood (PB) samples were collected from 70 newly diagnosed or treatment-naïve patients with MDS (Table). PB samples from 21 healthy controls were also studied. Molecular characterization was performed in paired samples of BM DNA and cfDNA by NGS in all patients. Libraries were prepared using a custom panel including 48 myeloid-associated genes and genomic regions localized at the most frequently altered chromosomes in MDS (QIAseq Custom DNA Panels, Qiagen) and sequenced using Illumina. 20/70 (28.6%) showed cytogenetic/FISH alterations at diagnosis, 2 of them with infrequent alterations in MDS, not covered by the panel (+14, del(9q)). 6 cases presented chromosome Y loss as a single alteration, not covered by the NGS panel. Copy number variant (CNV) analysis was performed by NGS to detect cytogenetic alterations in both cfDNA and BM, and confirmed by chromosomal microarrays (CMA) in BM DNA (CytoScan/OncoScan, ThermoFisher). Results. We obtained a median amount of cfDNA of 58.4 ng/ml in MDS patients that was significantly higher than that obtained in healthy controls (median 32.4 ng/ml, P=0.023). Sequencing of BM DNA and cfDNA showed a comparable mutational profile (187/201 mutations, 93.0% concordance). The most frequently mutated genes were TET2 (44.3%), SF3B1 (37.1%), ASXL1 (20.0%), DNMT3A (20.0%), SRSF2 (15.7%), ZRSR2 (12.9%) and U2AF1 (12.9%). A strong correlation was observed between the VAFs of BM DNA and cfDNA (r s=0.797, P<0.001). VAFs of SF3B1 mutations detected in cfDNA were significantly higher than VAFs in BM DNA (P=0.016). The analysis of cytogenetic alterations by NGS showed abnormalities in 10/70 MDS patients in both BM DNA and cfDNA. Interestingly, in a patient without analyzable metaphases in karyotype, del(20q) was found by NGS and confirmed by CMA. Overall, CMA and NGS were highly concordant to detect chromosomal aberrations although they do not reach the sensitivity achieved by karyotype/FISH (Figure 1). However, all cytogenetic aberrations detected by NGS in BM DNA were also detected in cfDNA. Molecular and cytogenetic alterations were monitored in sequential samples from 7 cases (median follow up: 13 months, range 10-30). We observed an excellent correlation between the VAF of mutations in BM DNA and ctDNA across multiple matched time points. A decrease in the VAF was detected in patients responding to therapy (either hypomethylating agents or chemotherapy), but not in non-responding patients (Figure 2). Of note, cfDNA analysis also showed cytogenetic evolution in 2 cases not responding to azacitidine (del(12p) and +21). From the two untreated patients, one acquired a subclonal del(7q) not detected by NGS and observed only in few metaphases, and the second patient showed a clonal expansion of the NF1 mutation at the time of AML transformation. Conclusions. Analysis of cfDNA allows the characterization and monitoring of molecular abnormalities in patients with MDS. Cytogenetic alterations were detectable in most cases by NGS in both BM DNA and cfDNA although with a lower detection rate than karyotype/FISH. Acknowledgements. ISCIII-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure/Table legends: Table. MDS patients included, classified by disease subtype. (SLD: single lineage dysplasia; MLD: multilineage dysplasia; RS: ring sideroblasts; EB: excess blasts; MDS-U: MDS-unclassifiable) Figure 1. Detection of cytogenetic alterations by conventional karyotype, FISH, CMA and NGS. Figure 2. Monitoring of molecular and cytogenetic alterations in 7 patients with MDS. 5 patients receiving treatment (3 azacitidine, 1 FLAG-IDA + HCT, 1 inhibitor of hypoxia-inducible factor (HIF)) and 2 untreated cases were included. BM VAF dynamics are shown with a dotted line and cfDNA dynamics are shown with a solid line. Figure 1 Figure 1. Disclosures Besses: Gilead: Research Funding. Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau.
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Cuenca, Ernesto J., Nieves García Gisbert, Ascensión M. de Los Reyes-García, Cristina Aroca, Lorena Martinez-Montesinos, Marcio Andrade, Sonia Aguila, et al. "Hydroxyurea Reduces Neutrophil Extracellular Trap Formation in Myeloproliferative Neoplasms." Blood 136, Supplement 1 (November 5, 2020): 20–21. http://dx.doi.org/10.1182/blood-2020-139368.
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Introduction: Ph-negative myeloproliferative neoplasms (MPNs) are a group of clonal stem-cell disorders with an elevated risk for thrombosis. Leukocytosis is a well-known risk factor for thrombosis. Neutrophils from MPN patients display features of activation. On stimulation, neutrophils produce neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of thrombosis. Myeloperoxidase-conjugated DNA levels (a specific NET marker) have been found increased in plasma of thrombotic MPN patients (Guy, A, ISTH 2019 OC 77.3). Ex vivo, activated neutrophils from JAK2V617F patients are primed to form NETs, diminishing under ruxolitinib treatment. Mice with conditional knock-in of JAK2V617F have increased NETs formation and thrombotic events. Inhibition of JAK/STAT signaling by ruxolitinib abrogated NETs formation and reduced thrombosis in this murine model (Wolach, O,Sci. Transl. Med. 2018). Thus, a link between JAK2V617F expression, NETs formation and thrombosis has been suggested (Wolach, O, 2018). It remains unclear whether, in MPN patients, JAK/STAT independent pathways are implicated in the NETs formation. With this aim, we explored the effects of different cytoreductors in NETs formation. Patients and Methods: In a multicentric study conducted at Hospital General Universitario Morales Meseguer (Murcia, Spain) and Hospital del Mar (Barcelona, Spain), EDTA plasma samples were collected from MPN patients (n=104). Patients include polycythemia vera (PV, n=35, all of them JAK2V617F), essential thrombocythemia [ET, n=47; 38 JAK2V617F, 4 CALRmut, 5 triple negative (TN)], myelofibrosis (MF, n=9; 4 JAK2V617F, 2 CALRmut, 3 TN), and unclassifiable MPN by WHO-2016 (MPN-u, n=13; 12 JAK2V617F, 1 CALRmut). Samples were collected at different time points following up the disease: at diagnosis or before any cytoreductive treatment, time 0, (n=100), less than 6 months of treatment (time 6; n=60), from 6 to 12 months of treatment (time 12; n=60), and from 12 to 24 months of treatment (time 24; n=49). Among the 104 patients, we had clinical information about treatment on 99 cases, included hydroxyurea (HU, n=69), ruxolitinib (n=15), IFN-α (n=2), and non-treated (n=13, all basal samples). We measured citH3-DNA complexes, as specific marker of NETs, by ELISA using rabbit anti-citH3 (Abcam) and peroxidase-conjugated anti-DNA antibody (Cell Death Detection ELISA). The absorbance at 405 nm (A405) was measured in a plate reader (Biotek®). Thus, we followed up the NETosis marker evolution with treatment over time. One-tailed and paired Wilcoxon test was applied and p<0.05 was taken as statistical significance. Results: Overall, regardless of the treatment, we observed a reduction of citH3-DNA levels over time (Fig. 1A), being these significant between time 0 and times 6 and 12 (p=0.02 for both time-points), Importantly, patients treated with HU showed a substantial reduction of NETs in all time-points (Fig. 1B, left), which was statistically significant between times 0 and 6 (p=0.03) and between times 0 and 24 (p=0.02). Although in patients treated with ruxolitinib, the citH3-DNA levels seem to be reduced at time 12, the difference was not significant (Fig. 1B, right), probably because of the small sample size. Regarding the MPN phenotype, decrease of citH3-DNA levels over time was only observed in PV patients (Fig. 1C, left), specially at time 12 (p=0.03). In contrast, under cytoreductive treatment, ET patients did not show significant differences in NETs levels over time (Fig. 1C, middle). In MF, there were not enough samples to obtain a clear conclusion (Fig. 1C, right). Regarding the driver gene mutations, we detected a significant decrease in the citH3-DNA levels in JAK2V617F patients (Fig. 1D, left), specifically between basal time and times 6 and 12 (p<0.02 for both time-points). Unfortunately, there are not enough samples to obtain a clear conclusion in CALRmut (Fig. 1D, right) and TN patients. Conclusions: Our results showed that hydroxyurea reduces NETosis levels in plasma from MPN patients, suggesting that JAK-STAT independent pathways could be implicated in the NET formation. Hydroxyurea could decrease thrombosis in MPN patients, not just reducing the number of functionally abnormal cells in peripheral blood, but also by abrogating NET formation. Acknowledgements: This study was supported in part by ISCIII (PI18/00316 & PI16/0153) & Fundación Séneca (20644/JLI/18). Disclosures Bellosillo: Qiagen: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau.
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Castaño-Díez, Sandra, Monica Lopez-Guerra, Daniel Esteban, Francesca Guijarro, Alex Bataller Torralba, Paola Charry, Carlos Castillo, et al. "Myeloproliferative/Myelodysplastic Neoplasms Presenting All Diagnostic Criteria of Chronic Myelomonocytic Leukemia but with Absolute Peripheral Blood Monocytosis 0.5-1× 109/L Should be Classified As CMML." Blood 136, Supplement 1 (November 5, 2020): 10–11. http://dx.doi.org/10.1182/blood-2020-142819.
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Introduction Current diagnosis of chronic myelomonocytic leukemia (CMML) requires peripheral blood (pb) monocytosis ≥1×109/L. Accordingly, cases which fulfill other diagnostic criteria of CMML but not reaching the required pb monocytosis threshold would be classified as MDS or unclassifiable MPN/MDS according to WHO classification (Arber et al, Blood 2016) Recently, a group of authors (Geyer et al, Modern Pathology 2017) proposed the term oligomonocytic CMML (OM-CMML) for these patients with blood monocytes ≥10% of the WBCs, but only accounting for 0.5-1 × 109/L as an absolute value and fulfilling all other criteria of CMML and suggested that they should be managed as other patients with classical CMML despite lacking pb monocytosis ≥1×109/L. To address clinical value of this proposed newly entity, we analyzed the incidence, clinico-biological characteristics and outcome of a series of patients fulfilling the proposed criteria for OM-CMML from a single center with a long follow-up. Methods We included patients diagnosed between 1997 and 2019 who gathered the proposed criteria for OM-CMML (Geyer et al, Modern Pathology 2017). These patients were compared with a cohort of patients from the same study period diagnosed with classical CMML. Statistical analyses were performed using Rv3.1 and SPSS v20. Next generation targeted sequencing (NGS) was performed with Ion Ampliseq AML Research and Oncomine Myeloid Research Assay panel Results Overall, we included in the study 213 patients, including 35 (16%) who fulfilled the proposed criteria for OM-CMML. Median follow-up of alive patients was 42 months. In the OM-CMML group, 71% were males, median age was 74 years (51-92). OM-CMML patients presented at diagnosis with a lower leucocyte count (WBC) (median value, 4.6(2.2-7.5)x109/L vs 10(3-119)x109/L, p<0.001), neutrophil count (2(0.7-5.7)x109/Lvs5.1(0.5-57)x109/L; p<0.001), and monocyte count, both in terms of absolute figures (0.75(0.5-0.9)x109/Lvs1.9(0.6-33)x109/L;p<0.001) and relative percentage (15% (10-30) vs 20% (1.8-51);p<0.001). All OM-CMML patients corresponded to FAB non-leucocytosis, CMML-Myelodysplastic type (CMML-MD), whereas 62% of c-CMML patients were diagnosed as a CMML-MD subtype p<0.001). No other different clinical characteristic were observed (Table 1). Cytogenetic analysis showed an abnormal karyotype in 23% of OM-CMML patients. NGS at diagnosis was available in 26 pt, without observing significant differences regarding gene mutation frequency. At diagnosis 17% of OM-CMML patients were transfusion-dependent and the distribution according to CPSS categories was: low (48%), int-1 (23%), int-2 (26%) and high (3%) risk, without difference with c-CMML (Table 1). Progression to a c-CMML was observed in 67% (24) of OM-CMML pts with a median time to progression of 7 months (m) (1-149 m). We did not observe differences in transformation rate to AML (AML-t; 10 (28.5%) vs 44 (24.7%) among OM-CMML and c-CMML group, p=0.6) or cumulative incidence (CI) of AML-t between OM-CMML and c-CMML patients (50m-CI AML-t: 35%±7 vs 21±12, p=0.3) (Fig 1). Eight out of the 10 pt (80%) who developed an AML previously presented a c-CMML phase. Median time to AML-t was longer in OM-CMML pt: 60m (3-219) vs 13.7m (0.8-124), p=0.011. The percentage of patients who received treatment in OM-CMML cohort was similar to that of c-CMML pts: (28% vs 21%, p=0.37, respectively). Moreover, time to treatment requirement was similar in both patient cohorts (15m (0.9-211m) vs 10m (0.1-112), p=0.5, respectively). Finally, overall survival of OM-CMML did not differ from that of c-CMML (5-year Overall Survival: 45±16% vs 30±7%; p=0.31, Figure 2). Conclusion: Clinical features and evolution of patients with OM-CMML were comparable to that of patients with c-CMML, supporting similar classification and management criteria. Acknowledgement: PI16/01027 (JE; MDB), PI19/01476 (JE; MDB) Disclosures No relevant conflicts of interest to declare.
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MOUHAT, Stéphanie, Amor MOSBAH, Violeta VISAN, Heike WULFF, Muriel DELEPIERRE, Hervé DARBON, Stephan GRISSMER, Michel De WAARD, and Jean-Marc SABATIER. "The functional dyad of scorpion toxin Pi1 is not itself a prerequisite for toxin binding to the voltage-gated Kv1.2 potassium channels." Biochemical Journal 377, no. 1 (January 1, 2004): 25–36. http://dx.doi.org/10.1042/bj20030115.
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Pi1 is a 35-residue scorpion toxin cross-linked by four disulphide bridges that acts potently on both small-conductance Ca2+-activated (SK) and voltage-gated (Kv) K+ channel subtypes. Two approaches were used to investigate the relative contribution of the Pi1 functional dyad (Tyr-33 and Lys-24) to the toxin action: (i) the chemical synthesis of a [A24,A33]-Pi1 analogue, lacking the functional dyad, and (ii) the production of a Pi1 analogue that is phosphorylated on Tyr-33 (P-Pi1). According to molecular modelling, this phosphorylation is expected to selectively impact the two amino acid residues belonging to the functional dyad without altering the nature and three-dimensional positioning of other residues. P-Pi1 was directly produced by peptide synthesis to rule out any possibility of trace contamination by the unphosphorylated product. Both Pi1 analogues were compared with synthetic Pi1 for bioactivity. In vivo, [A24,A33]-Pi1 and P-Pi1 are lethal by intracerebroventricular injection in mice (LD50 values of 100 and 40 µg/mouse, respectively). In vitro, [A24,A33]-Pi1 and P-Pi1 compete with 125I-apamin for binding to SK channels of rat brain synaptosomes (IC50 values of 30 and 10 nM, respectively) and block rat voltage-gated Kv1.2 channels expressed in Xenopus laevis oocytes (IC50 values of 22 µM and 75 nM, respectively), whereas they are inactive on Kv1.1 or Kv1.3 channels at micromolar concentrations. Therefore, although both analogues are less active than Pi1 both in vivo and in vitro, the integrity of the Pi1 functional dyad does not appear to be a prerequisite for the recognition and binding of the toxin to the Kv1.2 channels, thereby highlighting the crucial role of other toxin residues with regard to Pi1 action on these channels. The computed simulations detailing the docking of Pi1 peptides on to the Kv1.2 channels support an unexpected key role of specific basic amino acid residues, which form a basic ring (Arg-5, Arg-12, Arg-28 and Lys-31 residues), in toxin binding.
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Misman, Siti Norsuha, Mohd Shahril Firdaus Ab Razak, Nur Syahirah Ahmad Sobri, and Latiffah Zakaria. "Virulence Pattern of Pyricularia oryzae Pathotypes Towards Blast Monogenic Lines." Tropical Life Sciences Research 32, no. 3 (September 30, 2021): 147–60. http://dx.doi.org/10.21315/tlsr2021.32.3.8.
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Rice blast caused by Pyricularia oryzae (P. oryzae) is one of the most serious diseases infecting rice worldwide. In the present study, virulence pattern of six P. oryzae pathotypes (P0.0, P0.2, P1.0, P3.0, P7.0 and P9.0) identified from the blast pathogen collected in Peninsular Malaysia, were evaluated using a set of 22 IRRI-bred blast resistance lines (IRBL) as well as to determine the resistance genes involved. The information on the virulence of the blast pathotypes and the resistance genes involved is important for breeding of new rice variety for durable resistance against blast disease. The IRBL was established from 22 monogenic lines, harbouring 22 resistance genes [Pia, Pib, Pii, Pit, Pi3, Pi5(t), Pish, Pi1, Pik, Pik-s, Pik-m, Pik-h, Pik-p, Pi7(t), Pi9, Piz, Piz-5, Piz-t, Pi19, Pi20(t), Pita-2, and Pita=Pi4(t)]. Based on the disease severity patterns, the tested pathotypes were avirulence towards seven IRBLs [IRBLi-F5, IRBLk-Ka, IRBLkh-K3, IRBLz-Fu, IRBLsh-S, IRBLPi7 (t) and IRBL9-W] of which these IRBLs harbouring Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9 resistance genes, respectively. Therefore, the results suggested that the seven IRBLs carrying seven resistance genes [Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9] would be suitable candidates of resistance genes to be incorporated in new breeding lines to combat the current blast pathotypes in the field.
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Misman, Siti Norsuha, Mohd Shahril Firdaus Ab Razak, Nur Syahirah Ahmad Sobri, and Latiffah Zakaria. "Virulence Pattern of Pyricularia oryzae Pathotypes Towards Blast Monogenic Lines." Tropical Life Sciences Research 32, no. 3 (September 30, 2021): 147–60. http://dx.doi.org/10.21315/tlsr2021.32.3.8.
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Rice blast caused by Pyricularia oryzae (P. oryzae) is one of the most serious diseases infecting rice worldwide. In the present study, virulence pattern of six P. oryzae pathotypes (P0.0, P0.2, P1.0, P3.0, P7.0 and P9.0) identified from the blast pathogen collected in Peninsular Malaysia, were evaluated using a set of 22 IRRI-bred blast resistance lines (IRBL) as well as to determine the resistance genes involved. The information on the virulence of the blast pathotypes and the resistance genes involved is important for breeding of new rice variety for durable resistance against blast disease. The IRBL was established from 22 monogenic lines, harbouring 22 resistance genes [Pia, Pib, Pii, Pit, Pi3, Pi5(t), Pish, Pi1, Pik, Pik-s, Pik-m, Pik-h, Pik-p, Pi7(t), Pi9, Piz, Piz-5, Piz-t, Pi19, Pi20(t), Pita-2, and Pita=Pi4(t)]. Based on the disease severity patterns, the tested pathotypes were avirulence towards seven IRBLs [IRBLi-F5, IRBLk-Ka, IRBLkh-K3, IRBLz-Fu, IRBLsh-S, IRBLPi7 (t) and IRBL9-W] of which these IRBLs harbouring Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9 resistance genes, respectively. Therefore, the results suggested that the seven IRBLs carrying seven resistance genes [Pii, Pik, Pik-h, Piz, Pish, Pi7(t) and Pi9] would be suitable candidates of resistance genes to be incorporated in new breeding lines to combat the current blast pathotypes in the field.
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Ma, Jianbing, M. H. Jia, and Y. Jia. "Characterization of Rice Blast Resistance Gene Pi61(t) in Rice Germplasm." Plant Disease 98, no. 9 (September 2014): 1200–1204. http://dx.doi.org/10.1094/pdis-09-13-1014-re.
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Identification of resistance (R) genes to races of Magnaporthe oryzae in rice (Oryza sativa) germplasm is essential for the development of rice cultivars with long-lasting blast resistance. In the present study, one major quantitative trait locus, qPi93-3, was fine mapped using a recombinant inbred line (RIL), F8 RIL171, derived from the cross between ‘Nipponbare’ and ‘93-11’. RIL171 contained a heterozygous qPi93-3 allele which was found to be resistant against nine U.S. common races—ID1, IA1, IB49, IE1, IA45, IB1, IC17, IB45, and IH1—of M. oryzae. An F2 mapping population consisting of 2,381 individuals derived from RIL171 was evaluated with a field isolate (race) ARB82 (IA1) of M. oryzae under greenhouse conditions. Disease reaction of a resistant/susceptible ratio of 3:1 was identified with F2:F3 families. In total, 12 simple sequence repeat markers spanning qPi93-3 were used for fine mapping. Consequently, qPi93-3 was delimited to 4.2 Mb between RM3246 and RM7102. Three insertion-deletion (InDel) markers located between RM3246 and RM7102, that had previously used to map Pi61(t), showed that qPi93-3 was Pi61(t). The existence of Pi61(t) in 136 rice germplasm lines from the United States Department of Agriculture rice core collection was evaluated using Pi61(t)-specific InDel markers. Pi61(t) was identified as a source of resistance in 5 of the 136 lines. The characterized germplasm will be useful for rice breeders to use for improving blast resistance.
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Mohamed Hoesein, Firdaus A. A., Pim A. de Jong, Jan-Willem J. Lammers, Willem P. T. M. Mali, Michael Schmidt, Harry J. de Koning, Carlijn van der Aalst, et al. "Airway wall thickness associated with forced expiratory volume in 1 second decline and development of airflow limitation." European Respiratory Journal 45, no. 3 (January 22, 2015): 644–51. http://dx.doi.org/10.1183/09031936.00020714.
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Airway wall thickness and emphysema contribute to airflow limitation.We examined their association with lung function decline and development of airflow limitation in 2021 male smokers with and without airflow limitation. Airway wall thickness and emphysema were quantified on chest computed tomography and expressed as the square root of wall area of a 10-mm lumen perimeter (Pi10) and the 15th percentile method (Perc15), respectively. Baseline and follow-up (median (interquartile range) 3 (2.9–3.1) years) spirometry was available.Pi10 and Perc15 correlated with baseline forced expiratory volume in 1 s (FEV1) (r= −0.49 and 0.11, respectively (p<0.001)). Multiple linear regression showed that Pi10 and Perc15 at baseline were associated with a lower FEV1 after follow-up (p<0.05). For eachsdincrease in Pi10 and decrease in Perc15 the FEV1 decreased by 20 mL and 30.2 mL, respectively. The odds ratio for developing airflow limitation after 3 years was 2.45 for a 1-mm higher Pi10 and 1.46 for a 10-HU lower Perc15 (p<0.001).A greater degree of airway wall thickness and emphysema was associated with a higher FEV1 decline and development of airflow limitation after 3 years of follow-up.
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Driessen, Nicole N., Roy Ummels, Janneke J. Maaskant, Sudagar S. Gurcha, Gurdyal S. Besra, Gary D. Ainge, David S. Larsen, et al. "Role of Phosphatidylinositol Mannosides in the Interaction between Mycobacteria and DC-SIGN." Infection and Immunity 77, no. 10 (August 3, 2009): 4538–47. http://dx.doi.org/10.1128/iai.01256-08.
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ABSTRACT The C-type lectin dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is the major receptor on DCs for mycobacteria of the Mycobacterium tuberculosis complex. Recently, we have shown that although the mannose caps of the mycobacterial surface glycolipid lipoarabinomannan (ManLAM) are essential for the binding to DC-SIGN, genetic removal of these caps did not diminish the interaction of whole mycobacteria with DC-SIGN and DCs. Here we investigated the role of the structurally related glycolipids phosphatidylinositol mannosides (PIMs) as possible ligands for DC-SIGN. In a binding assay with both synthetic and natural PIMs, DC-SIGN exhibited a high affinity for hexamannosylated PIM6, which contains terminal α(1→2)-linked mannosyl residues identical to the mannose cap on ManLAM, but not for di- and tetramannosylated PIM2 and PIM4, respectively. To determine the role of PIM6 in the binding of whole mycobacteria to DC-SIGN, a mutant strain of M. bovis bacillus Calmette-Guérin deficient in the production of PIM6 (ΔpimE) was created, as well as a double knockout deficient in the production of both PIM6 and the mannose caps on LAM (ΔpimE ΔcapA). Compared to the wild-type strain, both mutant strains bound similarly well to DC-SIGN and DCs. Furthermore, the wild-type and mutant strains induced comparable levels of interleukin-10 and interleukin-12p40 when used to stimulate DCs. Hence, we conclude that, like ManLAM, PIM6 represents a bona fide DC-SIGN ligand but that other, as-yet-unknown, ligands dominate in the interaction between mycobacteria and DCs.
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Ayala, Rosa, Pau Montesinos, Eva Barragán, Joaquin Martinez-Lopez, Miguel A. Sanz, Yanira Ruiz-Heredia, Santiago Barrio, et al. "Validation of the High-Risk Prognostic Score Defined By the Presence of Mutations in NRAS or TP53 in a Cohort of 497 Patients with Acute Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 4–5. http://dx.doi.org/10.1182/blood-2020-137467.
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INTRODUCTION Older AML patients have a different mutational landscape compared to younger patients. The prognostic classification of AML proposed by the European Leukemia Net (2017) is based on the presence of mutations in FLT3 (ITD), NPM1, CEBPA, RUNX1, ASXL1 and TP53. However, our group has identified a high-risk prognostic score in older patients with AML, who are undergoing treatment with azacitidine or low-dose cytarabine plus fludarabine, which predict a shorter survival. OBJECTIVE Validation of the previously identified high-risk prognostic score, defined by the presence of mutations in NRAS or TP53, in 3 cohorts of patients with AML who have been studied by NGS with a custom panel in the healthcare practice (Cohort 1: Intensive treatment; cohort 2: Hypomethylating agents and cohort 3: low-dose cytarabine) METHODS The study was conducted on a series of 535 patients diagnosed with AML (mean age 67). Patients evaluated for OS and RFS were 497 cases: intensive treatment (schemes 3+7 or similar; n=238), hypomethylating agents (azacitidine, decitabine; n=113) and treated with low-dose cytarabine (n=146). 38 patients on supportive therapy were excluded. Mutational profile was identified at diagnosis by NGS technique (Ion Torrent System), using a custom panel of 41 genes involved in myeloid pathologies: ASXL1, BCOR, BCORL1, CALR, CBL, CEBPA, DNMT3A, EPAS1, EPOR, ETV6, EZH2, FLT3, IDH1, IDH2, JAK2, KDM6A, KIT, KMT2A, KRAS, MPL, NF1, NPM1, NRAS, PHF6, PRPF40B, RAD21, RUNX1, SETBP1, SF3A1, SF3B1, SH2B3, SMC1A, SRSF2, STAG2, TET2, THPO, TP53, U2AF1, VHL, WT1 y ZRSR2. The mean OS and RFS were compared by means of Kaplan-Meier curves using the log-rank test. The bioinformatics analysis was performed with the SPSS software. RESULTS The median SG and RFS of this series was 10.8 months and 6.9 months respectively. The mutational profile in older patients was different from that analyzed in younger patients. We observed greater presence of mutations in NPM1 in younger patients (34.4 vs 18.6%, p=0.04), while in older than 65 years were identified more mutations in ASXL1 (3.9 vs 16.6%, p<0.01) or RUNX1 (8.6 vs 18.4%, p=0.005). No differences were observed in TP53, NRAS, TET2, DNMT3A and FLT3-ITD. However, we detected differences in VAF distribution of variants with lower VAF in younger patients in NPM1 (0.9 vs 5%, p=0.001), RUNX1 (4.1 vs 9.1%, p=0.003), ASXL1 (1.5 vs 8.2%, p<0.001) and TP53 (5.9 vs 14%, p<0.001) The median OS for intensively treated patients with a low-risk prognostic score was 49.1 months (17.56, 80.60) vs. 18.9 (14.98, 22.79) for high-risk patients (p=0.015). The median RFS was 45.2 months (5.2; 85.14) for low-risk patients vs. 42.1 (18.35; 65.92) for high-risk patients (p=0.167). The median OS for low-risk patients treated with hypomethylating agents was 13.2 months (9.02, 17.47) vs. 4.8 (1.6, 7.9) for patients with a high-risk score (p=0.002). The median RFS was 9.9 months (7.4, 12.3) for low-risk patients vs. 14.9 (10.1, 19.8) for high-risk patients (p=0.682). The median OS for patients treated with low-dose cytarabine was 8.4 months (4.9, 12.1) for low risk vs. 3.1 (1.22, 4.94) for high risk (p<0.001). The median RFS was 6.8 months (5.28, 8.42) for low-risk patients vs. 3.7 (2.75, 4.66) for those with a high-risk score (p=0.008). CONCLUSIONS We have confirm that exist differences in the mutational profile between older and younger AML patients and these differences have implications in the definition of risk of these patients. The prognostic score defined by the presence of mutations in the TP53 and NRAS genes, has been validated as an adverse prognostic factor across the three treatment groups studied (intensive treatment, hypomethylating agents and low-dose cytarabine) for OS, and this score no predict risk of relapse in the cohorts with intensive and hypomethylating treatments at difference to the low-dose cytarabine cohort. ML.M. enjoys a research grant from the Spanish Society of Hematology and Hemotherapy. This work has been financed thanks to the aid PI16/01225 and PI19/01518, from the Instituto de Salud Carlos III (Ministerio de Economía, Industria y Competitividad) and co-financed by the European Development Fund. Disclosures Montesinos: Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding. Martinez-Lopez:Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; BMS: Consultancy, Research Funding. Sanz:Teva, Daiichi-Sankyo, Orsenix, AbbVie, Novartis, and Pfizer: Other: Consulting or Advisory Role.
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Kanyange, Lydia, Ye-Yang Fan, Zhen-Hua Zhang, De-Run Huang, Ting-Xu Huang, Jie-Yun Zhuang, and Yu-Jun Zhu. "Genetic Association between Blast Resistance and Yield Traits in Rice Detected Using a High-Density Bin Map." Agronomy 12, no. 5 (May 12, 2022): 1173. http://dx.doi.org/10.3390/agronomy12051173.
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Avoiding linkage drag of the resistance genes will facilitate the use of gene resources for rice breeding. This study was conducted to confirm the avoidance of linkage drag due to Pi26 and Pi25 blast resistance genes, and to analyze the association of Pi26, Pi25, Pib and Pita with quantitative trait loci (QTL) for yield traits. A recombinant inbred line population was derived from an indica rice cross Dan 71/Zhonghui 161. A linkage map consisting of 1219 bin markers, 22 simple sequence repeats and five gene markers was constructed. A total of 75 QTL were identified, including 2 for leaf blast resistance and 73 for eight yield traits. The two QTL for blast resistance were closely linked and located in the Pi26 and Pi25 regions, explaining 69.06 and 12.73% of the phenotypic variance, respectively. In a region covering Pi26 and Pi25, QTL were detected for grain yield and its key components. The alleles for enhancing blast resistance and grain yield were all from Dan 71. Not only was the linkage drag due to Pi26 and Pi25 avoided, but the results also indicate that these resistance genes may be used for simultaneously enhancing blast resistance and grain yield in rice. In the Pib and Pita regions, QTL was not detected for blast resistance, but was for yield traits. In each region, the allele for improving trait performance was derived from the parent carrying the resistance allele. In addition, four QTL clusters for grain weight and size, qGL4/qGW4.1, qGL11.2/qRLW11, qTGW11/qGW11 and qGL12/qGW12/qRLW12, were shown to be promising candidates for map-based cloning.
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Li, Yuan Zhe, Gong Yong Jin, Kum Ju Chae, and Young Min Han. "Quantitative Assessment of Airway Changes in Fibrotic Interstitial Lung Abnormality Patients by Chest CT According to Cumulative Cigarette Smoking." Tomography 8, no. 2 (April 3, 2022): 1024–32. http://dx.doi.org/10.3390/tomography8020082.
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Purpose: The aim of this study was to evaluate the role of Pi10 in patients with fibrotic interstitial lung abnormality (fibrotic ILA) in a chest CT, according to cumulative cigarette smoking. Methods: We retrospectively assessed 54 fibrotic ILA patients and 18 healthy non-smokers (control) who underwent non-enhanced CT and pulmonary function tests. We quantitatively analyzed airway changes (the inner luminal area, airway inner parameter, airway wall thickness, Pi10, skewness, and kurtosis) in the chest CT of fibrotic ILA patients, and the fibrotic ILA patients were categorized into groups based on pack-years: light, moderate, heavy. Airway change data and pulmonary function tests among the three groups of fibrotic ILA patients were compared with those of the control group by one-way ANOVA. Results: Mean skewness (2.58 ± 0.36) and kurtosis (7.64 ± 2.36) in the control group were significantly different from those of the fibrotic ILA patients (1.89 ± 0.37 and 3.62 ± 1.70, respectively, p < 0.001). In fibrotic ILA group, only heavy smokers had significantly increased Pi10 (mean increase 0.04, p = 0.013), increased airway wall thickness of the segmental bronchi (mean increase 0.06 mm, p = 0.005), and decreased lung diffusing capacity for carbon monoxide (p = 0.023). Conclusion: Pi10, as a biomaker of quantitative CT in fibrotic ILA patients, can reveal that smoking affects airway remodeling.
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Nimmagadda, Suresh, Poongodi Geetha-Loganathan, and Joy M. Richman. "PI15 modulates patterning of avian face." Developmental Biology 331, no. 2 (July 2009): 430. http://dx.doi.org/10.1016/j.ydbio.2009.05.158.
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Cameron, G. G. "Book review: Polymer electrolytes. F. M. Gray. Royal Society of Chemistry, Cambridge, 1997. pp. 175, price £39.50. ISBN 0-85404-557-0." Polymer International 46, no. 1 (May 1998): 78. http://dx.doi.org/10.1002/(sici)1097-0126(199805)46:1<78::aid-pi16>3.0.co;2-i.
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Ditengou, Franck Anicet, Dulceneia Gomes, Hugues Nziengui, Philip Kochersperger, Hanna Lasok, Violante Medeiros, Ivan A. Paponov, et al. "Characterization of auxin transporter PIN6 plasma membrane targeting reveals a function for PIN6 in plant bolting." New Phytologist 217, no. 4 (December 8, 2017): 1610–24. http://dx.doi.org/10.1111/nph.14923.
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Galindo, L., P. Robledo, D. Guinart, E. J. Pérez, A. Cuenca-Royo, E. Menoyo, C. Fernandez, et al. "CB1-5-HT2A heteromers in schizophrenia patients: Human studies in pro-neurons of the olfactory epithelium." European Psychiatry 41, S1 (April 2017): s811. http://dx.doi.org/10.1016/j.eurpsy.2017.01.1572.
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IntroductionDespite multiple clinical and preclinical studies investigating schizophrenia, the neurobiological basis of this disease is still unknown. The dysregulation of the serotonergic system, in particular the 5-HT2A receptor and the endocannabinoid system have been postulated as possible causes of schizophrenia.ObjectivesThe aim of this study is to evaluate the expression of CB1-5-HT2A receptor heteromers in primary cultures of pro-neurons from the olfactory epithelium in schizophrenia patients and control subjects.MethodsWe recruited a group of 10 healthy volunteers and 10 patients diagnosed with schizophrenia, who were treated with atypical antipsychotics, were clinically stable and had an illness duration range from 1 up to 15 years. The patients were diagnosed with schizophrenia from the medical record and confirmed by the structured clinical interview for DSM disorders. The expression of CB1-5-HT2A receptor heteromers in primary cultures of pro-neurons from the olfactory epithelium was quantified using proximity ligation assays and confocal microscopy.ResultsOlfactory epithelium pro-neurons were viable and expressed the neuronal marker, III-β tubulin. We also established the presence and the functionality of CB1-5-HT2A receptor heteromers in these cells using the proximity ligation and cAMP activity assays, respectively. Heteromer expression was significantly increased in schizophrenia patients with respect to controls.ConclusionsThis highly innovative methodology will allow the noninvasive, low-cost study of new biomarkers for schizophrenia in a model closely related to the central nervous system.Disclosure of interestThe authors have not supplied their declaration of competing interest.AcknowledgmentsThis work was supported by grants from DIUE-Generalitat-de Catalunya (2014SGR 680), Instituto de Salud Carlos III (PI14/00210) and (PI10/01708) FIS-FEDER-Funds. LG is supported by the Instituto-de Salud Carlos III through a “Río Hortega” (CM14/00111).
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Foong, Pik Mun, Roghayeh Abedi Karjiban, Yahaya M. Normi, Abu Bakar Salleh, and Mohd Basyaruddin Abdul Rahman. "Bioinformatics survey of the metal usage by psychrophilic yeast Glaciozyma antarctica PI12." Metallomics 7, no. 1 (2015): 156–64. http://dx.doi.org/10.1039/c4mt00163j.
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Derkach, K. V., I. O. Zakharova, A. A. Bakhtyukov, V. N. Sorokoumov, V. S. Kuznetsova, and A. O. Shpakov. "Characterization and biological activity of new 4-oxo-1,4-dihydrocinnoline-based inhibitors of the tyrosine phosphatase PTP1B and TCPTP." Biomeditsinskaya Khimiya 68, no. 6 (2022): 427–36. http://dx.doi.org/10.18097/pbmc20226806427.
Full textAbstract:
Functional disorders in obesity are largely due to a decrease in tissue sensitivity to insulin and leptin. One of the ways to restore it is inhibition of protein phosphotyrosine phosphatase 1B (PTP1B) and T-cell protein phosphotyrosine phosphatase (TCPTP), negative regulators of the insulin and leptin signaling. Despite progress in the development of inhibitors of these phosphatases, commercial preparations based on them have not been developed yet, and the mechanisms of action are poorly understood. The aim of the work was to study the effect of new derivatives of 4-oxo-1,4-dihydrocinnoline (PI04, PI06, PI07) on the activity of PTP1B and TCPTP, as well as to study the effect of their five-day administration (i.p., 10 mg/kg/day) to Wistar rats with diet-induced obesity on body weight and fat, metabolic and hormonal parameters, and gene expression of phosphatase and insulin and leptin receptors in the liver. It has been shown that PI04 is a mild, low selective inhibitor of both phosphatases (PTP1B, IC50=3.42(2.60–4.51) μM; TCPTP, IC50=4.16(3.49–4.95) μM), while PI06 and PI07 preferentially inhibit PTP1B (IC50=3.55 (2.63–4.78) μM) and TCPTP (IC50=1.45(1.18–1.78) μM), respectively. PI04 significantly reduced food intake, body weight and fat, attenuated hyperglycemia, normalized glucose tolerance, basal and glucose-stimulated levels of insulin and leptin, and insulin resistance index. Despite the anorexigenic effect, PI06 and PI07 were less effective, having little effect on glucose homeostasis and insulin sensitivity. PI04 significantly increased the expression of the PTP1B and TCPTP genes and decreased the expression of the insulin and leptin receptor genes. PI06 and PI07 had little effect on these indicators. Thus, PI04, the inhibitor of PTP1B and TCPTP phosphatases, restored metabolic and hormonal parameters in obese rats with greater efficiency than inhibitors of PTP1B (PI06) and TCPTP (PI07). This indicates the prospect of creating mixed PTP1B/TCPTP inhibitors for correction of metabolic disorders.