Journal articles on the topic 'Migrain candidate genes'
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de Vries, Boukje, Verneri Anttila, Tobias Freilinger, Maija Wessman, Mari A. Kaunisto, Mikko Kallela, Ville Artto, et al. "Systematic re-evaluation of genes from candidate gene association studies in migraine using a large genome-wide association data set." Cephalalgia 36, no. 7 (January 29, 2015): 604–14. http://dx.doi.org/10.1177/0333102414566820.
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Background Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set. Methods We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls. Results None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately. Conclusion The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.
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An, X. K., J. Fang, Z. Z. Yu, Q. Lin, C. X. Lu, H. L. Qu, and Q. L. Ma. "Multilocus analysis reveals three candidate genes for Chinese migraine susceptibility." Clinical Genetics 92, no. 2 (February 22, 2017): 143–49. http://dx.doi.org/10.1111/cge.12962.
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van der Vaart, Joy-Fleur, and Gabriele Susanne Merki-Feld. "Sex hormone-related polymorphisms in endometriosis and migraine: A narrative review." Women's Health 18 (January 2022): 174550572211113. http://dx.doi.org/10.1177/17455057221111315.
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Some evidence indicates endometriosis and migraine have a common genetic predisposition in sex-hormone genes, which could have important implications for the treatment of these two heterogenous conditions. To date, the genes responsibility remains unknown. Based on the biological hypothesis that polymorphisms of genes involved in sex-hormone pathways may influence estrogen levels and phenotypes of both disorders, we did a literature search for candidate sex-hormone genes and genes involved in the metabolism of estradiol. The aim was to review the evidence for shared sex-hormone-related polymorphisms between endometriosis and migraine and provide an exhaustive overview of the current literature. We included case-control studies investigating associations between candidate sex-hormone-related genes and the disorders endometriosis and migraine, respectively. Results showed three overlapping sex-hormone-associated polymorphisms in estrogen receptor genes that are associated with both conditions. To confirm possible associations with other sex-hormone genes, larger studies are needed.
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Buchwalder, Anne, Susan K. Welch, and Stephen J. Peroutka. "Exclusion of 5-HT2A and 5-HT2C Receptor Genes as Candidate Genes for Migraine." Headache: The Journal of Head and Face Pain 36, no. 4 (April 1996): 254–58. http://dx.doi.org/10.1046/j.1526-4610.1996.3604254.x.
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Gibson, Kate F., Anita Dos Santos, Nunu Lund, Rigmor Jensen, and Ioannis M. Stylianou. "Genetics of cluster headache." Cephalalgia 39, no. 10 (March 27, 2019): 1298–312. http://dx.doi.org/10.1177/0333102418815503.
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Background Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility. Methods We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection. Results The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME. Conclusions The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.
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Louter, MA, J. Fernandez-Morales, B. de Vries, B. Winsvold, V. Anttila, I. Fernandez-Cadenas, M. Vila-Pueyo, et al. "Candidate-gene association study searching for genetic factors involved in migraine chronification." Cephalalgia 35, no. 6 (August 28, 2014): 500–507. http://dx.doi.org/10.1177/0333102414547141.
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Introduction Chronic migraine (CM) is at the severe end of the clinical migraine spectrum, but its genetic background is unknown. Our study searched for evidence that genetic factors are involved in the chronification process. Methods We initially selected 144 single-nucleotide polymorphisms (SNPs) from 48 candidate genes, which we tested for association in two stages: The first stage encompassed 262 CM patients, the second investigated 226 patients with high-frequency migraine (HFM). Subsequently, SNPs with p values < 0.05 were forwarded to the replication stage containing 531 patients with CM or HFM. Results Eight SNPs were significantly associated with CM and HFM in the two-stage phase. None survived replication in the third stage. Discussion We present the first comprehensive genetic association study for migraine chronification. There were no significant findings. Future studies may benefit from larger, genome-wide data sets or should use other genetic approaches to identify genetic factors involved in migraine chronification.
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Азимова, Ю. Э., Н. С. Кондратьева, Е. А. Климов, and М. Л. Кукушкин. "Migraine genetics: Associative studies." Nauchno-prakticheskii zhurnal «Patogenez», no. 3() (September 29, 2018): 154–56. http://dx.doi.org/10.25557/2310-0435.2018.03.154-156.
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Статья посвящена анализу имеющихся на сегодняшний день данных генетических полиморфизмов, излучавшихся при мигрени. При мигрени гены-кандидаты мигрени сгруппированы в четыре функциональных семейства генов: гены нервной системы, гены сердечно-сосудистой системы, гормональные, воспалительные гены. Среди генов нервной системы значимость представляют гены, кодирующие структуру и функциональную активность калиевых каналов. Наибольший интерес представляют гены сердечно-сосудистой системы, которые как повышают риск мигрени, так и увеличивают риск коморбидных кардиоваскулярных заболеваний. Среди генов эндокринной системы роль в патогенезе мигрени играют полиморфизмы гена эстрогенового рецептора 1 типа. Для воспалительных генов циклооксегиназы 2, главного комплекса гистосовместимости HLA-DRB1, лимфотоксина альфа, фактора некроза опухоли альфа и бета найдены положительные ассоциации с мигренью. The article focused on analysis of currently available reports on genetic polymorphisms in migraine. The migraine candidate genes were grouped into four functional families: genes of the nervous system, genes of the cardiovascular system, hormonal genes, and inflammatory genes. Among the nervous system genes, the genes encoding the structure and functional activity of potassium channels are of a special significance. Of the greatest interest are the cardiovascular system genes, which increase the risk of both migraine and comorbid cardiovascular diseases. Among the endocrine system genes, polymorphisms of the type 1 estrogen receptor gene play a role in the pathogenesis of migraine. Positive associations with migraine were found for inflammatory genes of cyclooxygenase 2, the main histocompatibility complex HLA-DRB1, lymphotoxin alpha, and tumor necrosis factors alpha and beta.
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Rainero, Innocenzo, Alessandro Vacca, Flora Govone, Annalisa Gai, Lorenzo Pinessi, and Elisa Rubino. "Migraine: Genetic Variants and Clinical Phenotypes." Current Medicinal Chemistry 26, no. 34 (December 12, 2019): 6207–21. http://dx.doi.org/10.2174/0929867325666180719120215.
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Migraine is a common, chronic neurovascular disorder caused by a complex interaction between genetic and environmental risk factors. In the last two decades, molecular genetics of migraine have been intensively investigated. In a few cases, migraine is transmitted as a monogenic disorder, and the disease phenotype cosegregates with mutations in different genes like CACNA1A, ATP1A2, SCN1A, KCNK18, and NOTCH3. In the common forms of migraine, candidate genes as well as genome-wide association studies have shown that a large number of genetic variants may increase the risk of developing migraine. At present, few studies investigated the genotype-phenotype correlation in patients with migraine. The purpose of this review was to discuss recent studies investigating the relationship between different genetic variants and the clinical characteristics of migraine. Analysis of genotype-phenotype correlations in migraineurs is complicated by several confounding factors and, to date, only polymorphisms of the MTHFR gene have been shown to have an effect on migraine phenotype. Additional genomic studies and network analyses are needed to clarify the complex pathways underlying migraine and its clinical phenotypes.
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Haan, J., EE Kors, GM Terwindt, FLMG Vermeulen, MN Vergouwe, AMJM van den Maagdenberg, DS Gill, et al. "Alternating Hemiplegia of Childhood: No Mutations in the Familial Hemiplegic Migraine CACNA1A Gene." Cephalalgia 20, no. 8 (October 2000): 696–700. http://dx.doi.org/10.1046/j.0333-1024.2000.00095.x.
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Introduction Alternating hemiplegia of childhood (AHC) is a rare disorder mainly characterized by attacks of hemiplegia and mental retardation. It has been often associated with migraine. The CACNA1A gene on chromosome 19 is involved in familial hemiplegic migraine and other episodic cerebral disorders, but also with progressive neuronal damage. Methods We performed mutation analysis in this gene in four AHC patients, using single strand conformation polymorphism analysis. Results We found nine polymorphisms, but no mutations in any of the 47 exons. Conclusions Other cerebral ion channel genes remain candidate genes for AHC.
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KAYMAZ, Tugce, Ebru ÖNALAN, İlay BURAN KAVURAN, Ayşe BERİLGEN GÜRGÖZE, and Bülent MÜNGEN. "No Direct Association of Myelin Oligodendrocyte Glycoprotein (MOG) Gene Polymorphism (Val142leu) in Genetic Susceptibility to Migraine." Bolu Abant Izzet Baysal Universitesi Tip Fakultesi Abant Tip Dergisi 11, no. 3 (December 30, 2022): 295–303. http://dx.doi.org/10.47493/abantmedj.1080234.
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Objective: Genes which are involved in immune response portray possible candidate genes in migraine. One of those genes is that myelin oligodendrocyte glycoprotein (MOG) that plays an important role in mediating the complement cascade. The purpose of our study is to show the effect of MOG G511C (Val142Leu; rs2857766) polymorphism in migraine attack frequency.
Materials and Methods: In the cohort of 101 Turkish migraine patients and in a control group of 101 healthy subjects, MOG Val142Leu alleles’ distribution was examined. Restriction fragment length polymorphism (RFLP) was carried out to genotype this polymorphism.
Results: Although MOG Leu allele frequency was determined as under-represented in migraine patients, any significant difference between the patient and control groups’ genotype, and allele frequencies were not obtained [OR=0.47 (0.21-1.08), p=0.053 for genotypes; OR=0.50 (0.23-1.11), p=0.060 for alleles]. However, a statistically significant relationship between MOG G511C (Val142Leu) polymorphism and the decreased migraine attack frequency was determined [OR=11.71 (1.32-103.77), p=0.013]. Val/Leu genotype frequency increrased in migraine patients with two or fewer attacks per month.
Conclusion: Migraine attack frequency might be related with MOG Val142Leu heterozygote genotype. So we think that MOG gene might be related to genetic susceptibility to migraine in the human leukocyte antigen (HLA) region.
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Zhao, Huiying, Else Eising, Boukje de Vries, Lisanne S. Vijfhuizen, Verneri Anttila, Bendik S. Winsvold, Tobias Kurth, et al. "Gene-based pleiotropy across migraine with aura and migraine without aura patient groups." Cephalalgia 36, no. 7 (December 8, 2015): 648–57. http://dx.doi.org/10.1177/0333102415591497.
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Introduction It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related. Aim Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO. Methods Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO. Results We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value ( pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) ( pbinomial-test = 1.5 × 10–4). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes ( TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue. Conclusions Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene ( NPFF) as a novel candidate risk gene for both types of migraine.
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Yang, Yuanhao, Lannie Ligthart, Gisela M. Terwindt, Dorret I. Boomsma, Astrid J. Rodriguez-Acevedo, and Dale R. Nyholt. "Genetic epidemiology of migraine and depression." Cephalalgia 36, no. 7 (March 9, 2016): 679–91. http://dx.doi.org/10.1177/0333102416638520.
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Background Migraine and major depressive disorder (commonly referred to as depression) are both common disorders with a significant impact on society. Studies in both clinical and community-based settings have demonstrated a strong relationship between migraine and depression. In addition to complicating the diagnosis, depression that is comorbid with migraine may lower treatment adherence, increase risk of medication overuse and is associated with migraine chronification, thus leading to higher direct and indirect costs and poorer health-related outcomes with increased disability. Aim The aim of this review is to summarise the current knowledge on the genetic epidemiology of migraine and depression and the possible biological mechanisms underlying their comorbidity. Methods We present a narrative review reporting on the current literature. Results and conclusions Epidemiological findings indicate that there is a bidirectional relationship between migraine and depression, with one disorder increasing the risk for the other and vice versa, suggesting shared biological mechanisms. Twin and family studies indicate that this bidirectional relationship can be explained, at least partly, by shared underlying genetically determined disease mechanisms. Although no genes have been robustly associated with the aetiology of both migraine and depression, genes from serotonergic, dopaminergic and GABAergic systems together with variants in the MTHFR and BDNF genes remain strong candidates.
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Smith, Robert A., Robert Curtain, Mick Ovcaric, Lotti Tajouri, John MacMillan, and Lyn Griffiths. "Investigation of the NOTCH3 and TNFSF7 Genes on C19p13 as Candidates for Migraine." Open Neurology Journal 2, no. 1 (May 19, 2008): 1–7. http://dx.doi.org/10.2174/1874205x00802010001.
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Sutherland, Heidi G., Neven Maksemous, Cassie L. Albury, Omar Ibrahim, Robert A. Smith, Rod A. Lea, Larisa M. Haupt, Bronwyn Jenkins, Benjamin Tsang, and Lyn R. Griffiths. "Comprehensive Exonic Sequencing of Hemiplegic Migraine-Related Genes in a Cohort of Suspected Probands Identifies Known and Potential Pathogenic Variants." Cells 9, no. 11 (October 28, 2020): 2368. http://dx.doi.org/10.3390/cells9112368.
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Hemiplegic migraine (HM) is a rare migraine disorder with aura subtype including temporary weakness and visual, sensory, and/or speech symptoms. To date, three main genes—CACNA1A, ATP1A2, and SCN1A—have been found to cause HM. These encode ion channels or transporters, important for regulating neuronal ion balance and synaptic transmission, leading to HM being described as a channelopathy. However, <20% of HM cases referred for genetic testing have mutations in these genes and other genes with roles in ion and solute transport, and neurotransmission has also been implicated in some HM cases. In this study, we performed whole exome sequencing for 187 suspected HM probands referred for genetic testing, but found to be negative for CACNA1A, ATP1A2, and SCN1A mutations, and applied targeted analysis of whole exome sequencing data for rare missense or potential protein-altering variants in the PRRT2, PNKD, SLC1A3, SLC2A1, SLC4A4, ATP1A3, and ATP1A4 genes. We identified known mutations and some potentially pathogenic variants in each of these genes in specific cases, suggesting that their screening improves molecular diagnosis for the disorder. However, the majority of HM patients were found not to have candidate mutations in any of the previously reported HM genes, suggesting that additional genetic factors contributing to the disorder are yet to be identified.
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Petschner, Peter, Daniel Baksa, Gabor Hullam, Dora Torok, Andras Millinghoffer, J. F. William Deakin, Gyorgy Bagdy, and Gabriella Juhasz. "A replication study separates polymorphisms behind migraine with and without depression." PLOS ONE 16, no. 12 (December 31, 2021): e0261477. http://dx.doi.org/10.1371/journal.pone.0261477.
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The largest migraine genome-wide association study identified 38 candidate loci. In this study we assessed whether these results replicate on a gene level in our European cohort and whether effects are altered by lifetime depression. We tested SNPs of the loci and their vicinity with or without interaction with depression in regression models. Advanced analysis methods such as Bayesian relevance analysis and a neural network based classifier were used to confirm findings. Main effects were found for rs2455107 of PRDM16 (OR = 1.304, p = 0.007) and five intergenic polymorphisms in 1p31.1 region: two of them showed risk effect (OR = 1.277, p = 0.003 for both rs11209657 and rs6686879), while the other three variants were protective factors (OR = 0.4956, p = 0.006 for both rs12090642 and rs72948266; OR = 0.4756, p = 0.005 for rs77864828). Additionally, 26 polymorphisms within ADGRL2, 2 in REST, 1 in HPSE2 and 33 mostly intergenic SNPs from 1p31.1 showed interaction effects. Among clumped results representing these significant regions, only rs11163394 of ADGRL2 showed a protective effect (OR = 0.607, p = 0.002), all other variants were risk factors (rs1043215 of REST with the strongest effect: OR = 6.596, p = 0.003). Bayesian relevance analysis confirmed the relevance of intergenic rs6660757 and rs12128399 (p31.1), rs1043215 (REST), rs1889974 (HPSE2) and rs11163394 (ADGRL2) from depression interaction results, and the moderate relevance of rs77864828 and rs2455107 of PRDM16 from main effect analysis. Both main and interaction effect SNPs could enhance predictive power with the neural network based classifier. In summary, we replicated p31.1, PRDM16, REST, HPSE2 and ADGRL2 genes with classic genetic and advanced analysis methods. While the p31.1 region and PRDM16 are worthy of further investigations in migraine in general, REST, HPSE2 and ADGRL2 may be prime candidates behind migraine pathophysiology in patients with comorbid depression.
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Gonçalves, Flavia Magazoni, Marcelo Rizzatti Luizon, and Jose G. Speciali. "Haplotypes in candidate genes related to nitric oxide pathway and vascular permeability associated with migraine and aura." Journal of Headache and Pain 13, no. 4 (March 25, 2012): 335–36. http://dx.doi.org/10.1007/s10194-012-0438-5.
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Gardner, Kathy. "The Genetic Basis of Migraine: How Much Do We Know?" Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 26, no. 3 (November 1999): 37–43. http://dx.doi.org/10.1017/s0317167100000184.
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Migraine with and without aura is thought to be genetically complex with aggregation in families due to a combination of environmental and genetic tendencies. Twin studies are most important in establishing the multifactorial nature of migraine with heritability approaching 50%. Familial hemiplegic migraine (FHM) on the other hand is an autosomal dominant, highly penetrant, though rare form of migraine with strong genetic tendency. Fifty percent of families with FHM are linked to chromosome 19p13 and mutations demonstrated for some in a brain expressed calcium channel alpha 1A subunit, CACNL1A4. Other FHM loci have been identified on chromosome 1q and further genetic heterogeneity is likely. The exact role of the mutated calcium channel in the pathway leading to hemiplegic migraine is yet to be established. Changes in the electrophysiologic properties of the mutated forms of the CACNL1A4 calcium channel expressed in heterologous systems help establish the functional significance of the mutations and suggest that chromosome 19p-linked FHM, an episodic disorder, represents a CNS channelopathy. Additional candidate genes causative for migraine might include other calcium channel subunits and related proteins important for neuronal membrane stability. Delineating the cascade of biochemical events leading to hemiplegic migraine will serve as a model for understanding the pathophysiology of more common forms of migraine. The evidence suggesting that some families of migraine with and without aura might also be related to the chromosome 19p locus, chromosome Xq28 locus, or DRD2 receptor polymorphisms is reviewed.
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Karwautz, AFK, S. Campos de Sousa, C. Wöber, G. Wagner, T. Li, A. Konrad, HE Zesch, et al. "Family-Based Analysis of Serotonin Transporter Gene Polymorphisms in Migraine With and Without Aura." Cephalalgia 27, no. 7 (July 2007): 773–80. http://dx.doi.org/10.1111/j.1468-2982.2007.01344.x.
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Genetic epidemiological twin studies have demonstrated a significant heritability for migraine, with >60% of liability to migraine either with or without aura coming from additive genetic factors. Because of the essential role of serotonin in the pathophysiology and treatment of migraine, genes of the serotonin system are candidates for involvement in migraine. Consequently, we examined two functional VNTR polymorphisms in the serotonin transporter gene, the 5-HTTLPR and the intron 2 VNTR, in a sample of 212 family trios each with a proband with childhood migraine, 153 with migraine without aura (MoA) and 59 with migraine with aura (MA). For the first time, we used transmission disequilibrium test analysis with the program TDTPHASE to examine the transmission of these two markers and their haplotypes to offspring affected by migraine. We found no significant transmission distortion of any marker, with the common L allele of the 5-HTTLPR transmitted 170 times and not transmitted 178 times, and the S allele 130 vs. 122 times. Likewise, the common 12 allele of the intron 2 VNTR was transmitted 201 times and not transmitted 188 times, and the 10 allele 107 vs. 120 times. The markers were not associated with MoA and MA and none of the haplotypes was associated with overall migraine, MoA or MA. The 5-HTTLPR and the intron 2 VNTRs do not play a major role in susceptibility to migraine.
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Hofele, K., R. Benecke, and G. Auburger. "Gene locus FPD1 of the dystonic Mount-Reback type of autosomal-dominant paroxysmal choreoathetosis." Neurology 49, no. 5 (November 1997): 1252–57. http://dx.doi.org/10.1212/wnl.49.5.1252.
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Genes for paroxysmal choreoathetosis have been localized to chromosomes 1p and 2q. We have reinvestigated one of the classic large autosomal-dominant pedigrees of the dystonic Mount-Reback type of paroxysmal choreoathetosis 20 years after its first assessment. These patients prefer diazepam for both prevention and treatment of attacks and did not develop addiction on an intermittent regime. Migraine occurred in a third of the patients. Genetic data localized the underlying mutation to the FPD1 locus (familial paroxysmal dyskinesia type 1) on chromosome 2q and support locus homogeneity for the Mount-Reback syndrome. The data also refine the FPD1 candidate region to 3.6 cM between the markers D2S164 and D2S2359, which may facilitate the investigation of the role of the candidate ion channel gene SLC2C.
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Udagawa, Tomokatsu, Patrick J. Atkinson, Beatrice Milon, Julia M. Abitbol, Yang Song, Michal Sperber, Elvis Huarcaya Najarro, et al. "Lineage-tracing and translatomic analysis of damage-inducible mitotic cochlear progenitors identifies candidate genes regulating regeneration." PLOS Biology 19, no. 11 (November 10, 2021): e3001445. http://dx.doi.org/10.1371/journal.pbio.3001445.
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Cochlear supporting cells (SCs) are glia-like cells critical for hearing function. In the neonatal cochlea, the greater epithelial ridge (GER) is a mitotically quiescent and transient organ, which has been shown to nonmitotically regenerate SCs. Here, we ablated Lgr5+ SCs using Lgr5-DTR mice and found mitotic regeneration of SCs by GER cells in vivo. With lineage tracing, we show that the GER houses progenitor cells that robustly divide and migrate into the organ of Corti to replenish ablated SCs. Regenerated SCs display coordinated calcium transients, markers of the SC subtype inner phalangeal cells, and survive in the mature cochlea. Via RiboTag, RNA-sequencing, and gene clustering algorithms, we reveal 11 distinct gene clusters comprising markers of the quiescent and damaged GER, and damage-responsive genes driving cell migration and mitotic regeneration. Together, our study characterizes GER cells as mitotic progenitors with regenerative potential and unveils their quiescent and damaged translatomes.
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de Vries, B., AH Stam, F. Beker, AMJM van den Maagdenberg, KRJ Vanmolkot, LAEM Laan, IB Ginjaar, et al. "CACNA1A Mutation Linking Hemiplegic Migraine and Alternating Hemiplegia of Childhood." Cephalalgia 28, no. 8 (August 2008): 887–91. http://dx.doi.org/10.1111/j.1468-2982.2008.01596.x.
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Familial hemiplegic migraine (FHM) and alternating hemiplegia of childhood (AHC) are severe neurological disorders that share clinical features. Therefore, FHM genes are candidates for AHC. We performed mutation analysis in the CACNA1A gene in a monozygotic twin pair with clinical features overlapping with both AHC and FHM and identified a novel de novo CACNA1A mutation. We provide the first evidence that a CACNA1A mutation can cause atypical AHC, indicating an overlap of molecular mechanisms causing AHC and FHM. These results also suggest that CACNA1A mutation scanning is indicated in patients with a severe neurological phenotype that includes paroxysmal (alternating) hemiplegia.
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Krist, Miloš, Pavel Munclinger, Martins Briedis, and Peter Adamík. "The genetic regulation of avian migration timing: combining candidate genes and quantitative genetic approaches in a long-distance migrant." Oecologia 196, no. 2 (May 7, 2021): 373–87. http://dx.doi.org/10.1007/s00442-021-04930-x.
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Fujita, Naoko, Yusuke Kazama, Noriko Yamagishi, Kyoko Watanabe, Saki Ando, Hiroyuki Tsuji, Shigeyuki Kawano, Nobuyuki Yoshikawa, and Ken Komatsu. "Development of the VIGS System in the Dioecious Plant Silene latifolia." International Journal of Molecular Sciences 20, no. 5 (February 27, 2019): 1031. http://dx.doi.org/10.3390/ijms20051031.
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(1) Background: Silene latifolia is a dioecious plant, whose sex is determined by XY-type sex chromosomes. Microbotryum lychnidis-dioicae is a smut fungus that infects S. latifolia plants and causes masculinization in female flowers, as if Microbotryum were acting as a sex-determining gene. Recent large-scale sequencing efforts have promised to provide candidate genes that are involved in the sex determination machinery in plants. These candidate genes are to be analyzed for functional characterization. A virus vector can be a tool for functional gene analyses; (2) Methods: To develop a viral vector system in S. latifolia plants, we selected Apple latent spherical virus (ALSV) as an appropriate virus vector that has a wide host range; (3) Results: Following the optimization of the ALSV inoculation method, S. latifolia plants were infected with ALSV at high rates in the upper leaves. In situ hybridization analysis revealed that ALSV can migrate into the flower meristems in S. latifolia plants. Successful VIGS (virus-induced gene silencing) in S. latifolia plants was demonstrated with knockdown of the phytoene desaturase gene. Finally, the developed method was applied to floral organ genes to evaluate its usability in flowers; (4) Conclusion: The developed system enables functional gene analyses in S. latifolia plants, which can unveil gene functions and networks of S. latifolia plants, such as the mechanisms of sex determination and fungal-induced masculinization.
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Frederiksen, Simona D., Kristian A. Haanes, Karin Warfvinge, and Lars Edvinsson. "Perivascular neurotransmitters: Regulation of cerebral blood flow and role in primary headaches." Journal of Cerebral Blood Flow & Metabolism 39, no. 4 (December 18, 2017): 610–32. http://dx.doi.org/10.1177/0271678x17747188.
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In order to understand the nature of the relationship between cerebral blood flow (CBF) and primary headaches, we have conducted a literature review with particular emphasis on the role of perivascular neurotransmitters. Primary headaches are in general considered complex polygenic disorders (genetic and environmental influence) with pathophysiological neurovascular alterations. Identified candidate headache genes are associated with neuro- and gliogenesis, vascular development and diseases, and regulation of vascular tone. These findings support a role for the vasculature in primary headache disorders. Moreover, neuronal hyperexcitability and other abnormalities have been observed in primary headaches and related to changes in hemodynamic factors. In particular, this relates to migraine aura and spreading depression. During headache attacks, ganglia such as trigeminal and sphenopalatine (located outside the blood-brain barrier) are variably activated and sensitized which gives rise to vasoactive neurotransmitter release. Sympathetic, parasympathetic and sensory nerves to the cerebral vasculature are activated. During migraine attacks, altered CBF has been observed in brain regions such as the somatosensory cortex, brainstem and thalamus. In regulation of CBF, the individual roles of neurotransmitters are partly known, but much needs to be unraveled with respect to headache disorders.
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Kaestner, Charlotte L., Amin Sobh, Jianping Li, Alberto Riva, Richard Lynn Bennett, and Jonathan D. Licht. "Functional CRISPR Screening Identifies Ptprg As a Driver of Migration and Adhesion in NSD2-E1099K ALL." Blood 138, Supplement 1 (November 5, 2021): 1149. http://dx.doi.org/10.1182/blood-2021-154009.
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Abstract Background: Acute Lymphoblastic Leukemia (ALL) is the most common childhood cancer and frequently infiltrates the central nervous system (CNS). CNS-directed therapy is currently limited to intrathecal and systemic high-dose methotrexate, or less commonly craniospinal irradiation, both of which are associated with substantial neurotoxicity. A lack of mechanistic understanding of the mechanisms of CNS infiltration presents an obstacle for the development of more specific and less toxic therapeutic approaches. We previously showed that ALL cells with a specific mutation (E1099K) in the histone methyltransferase NSD2 have aggressive CNS tropism by not only infiltrating the leptomeninges but also the brain parenchyma in murine xenografts models. Analysis of cBioPortal data shows that NSD2-E1099K is associated with a higher rate of testicular involvement in ALL also suggesting more aggressive infiltration behavior of the tumor. Accordingly, using gene editing to revert mutant NSD2 back to wild-type, we also showed that NSD2-E1099K cells have an enhanced ability to migrate and adhere in vitro. RNA-seq data on four NSD2-E1099K cell lines revealed genes that may play a role in ALL brain infiltration. However, it remains unknown which of those upregulated genes could be potential therapeutic targets against CNS leukemia. Aim: This study aims to Identify therapeutically targetable genes that are important for migration of NSD2-E1099K ALL cells Methods: Using a focused CRISPR-gene-knockout library of 5600 sgRNAs directed against 500 genes upregulated in NSD2-E1099K cells, we ascertained the necessity of the selected genes for migration in the RCH-ACV cell line. Candidate genes were evaluated for cellular dependency using a CRISPR-loss of function screen and the cancer dependency map portal. Overexpression of the candidate genes in NSD2-E1099K cell lines was confirmed with qPCR analysis. Candidate genes were validated by individual shRNA knockdown followed by migration and adhesion assays. Results: Our study identified genes whose knockout led to enhancement of migration and others whose knockout resulted in inhibition of migration. Protein Tyrosine Phosphatase Receptor Type G (PTPRG) was one of the top candidate genes whose knockout resulted in inhibition of migration. Dependency map analysis showed that PTPRG is not a commonly essential gene and a CRISPR-based-loss-of function screen performed in parallel to the migration screen confirmed that ALL cell survival is not dependent on PTPRG. We also found that PTPRG is overexpressed in multiple NSD2-E1099K ALL cell lines. Individual Knockdown of PTPRG in NSD2-E1099K ALL cell lines not only inhibited migration, but also led to a loss of adhesion ability to endothelial cells of the Blood Brain Barrier. Conclusions: Our findings implicate PTPRG as an important modulator of migration and adhesion in ALL cells and a potential therapeutic target for preventing ALL brain infiltration, especially in NSD2-E1099K ALL. Disclosures Licht: Epizyme: Research Funding.
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Peterson, Mark P., Mikus Abolins-Abols, Jonathan W. Atwell, Rebecca J. Rice, Borja Milá, and Ellen D. Ketterson. "Variation in candidate genes CLOCK and ADCYAP1 does not consistently predict differences in migratory behavior in the songbird genus Junco." F1000Research 2 (April 22, 2013): 115. http://dx.doi.org/10.12688/f1000research.2-115.v1.
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Recent studies exploring the molecular genetic basis for migratory variation in animals have identified polymorphisms in two genes (CLOCK and ADCYAP1) that are linked to circadian rhythms and correlate with migratory propensity and phenology among individuals and populations. Results from these initial studies are mixed, however, and additional data are needed to assess the generality and diversity of the molecular mechanisms that regulate the biology of migration. We sequenced CLOCK and ADCYAP1 in 15 populations across the two species of the avian genus Junco, a North American lineage in which multiple recently diverged subspecies and populations range from sedentary to long-distance migrants. We found no consistent associations between allele length and migratory status across the genus for either CLOCK or ADCYAP1. However, within two subspecies groups, populations that migrate longer distances have longer CLOCK alleles on average. Additionally, there was a positive relationship between ADCYAP1 allele length and migratory restlessness (zugunruhe) among individuals within one of two captive populations studied—a result similar to those reported previously within captive blackcaps (Sylvia atricapilla). We conclude that, while both ADCYAP1 and CLOCK may correlate with migratory propensity within or among certain populations or species, previously identified relationships between migratory behavior and sequence variants cannot be easily generalized across taxa.
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Bahmad, Fayez, Steven R. DePalma, Saumil N. Merchant, Roberta L. Bezerra, Carlos A. Oliveira, Christine E. Seidman, and Jonathan G. Seidman. "Locus for Familial Migrainous Vertigo Disease Maps to Chromosome 5q35." Annals of Otology, Rhinology & Laryngology 118, no. 9 (September 2009): 670–76. http://dx.doi.org/10.1177/000348940911800912.
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Objectives: Migrainous vertigo (episodic vertigo associated with migraine) is sometimes inherited as an autosomal dominant trait. However, neither disease genes nor loci that might be responsible have been reported. We sought to map the genetic locus for familial migrainous vertigo in a 4-generation family and to define the progression of disease in this family. Methods: We studied 23 members in a family in whom migrainous vertigo was inherited as an autosomal dominant trait. Clinical information obtained included case histories and results of otolaryngological, neurologic, audiometric, and imaging evaluations. Genome-wide linkage analysis was performed with Affymetrix Genechip Human Mapping 10K microarrays. Genotyping of family members' DNA with microsatellite markers was used to further assess candidate loci identified from the whole-genome scan. Results: Of 23 family members, 10 suffered from migrainous vertigo beginning after 35 years of age. Migraine headaches usually preceded the onset of vertigo by 15 to 20 years. Longitudinal audiometric studies over 12 years showed stable, high-frequency sensorineural hearing loss consistent with presbycusis. Low-frequency or fluctuating hearing loss was not observed. The results of vestibular testing and imaging studies were unremarkable. Genetic analysis defined a 12.0 MB interval on chromosome 5q35 between loci rs244895 and D5S2073 that contained the disease gene (logarithm of odds score, 4.21). Conclusions: We report the first locus for familial migrainous vertigo, which mapped to 5q35.
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Urban, Martin, Alayne Cuzick, James Seager, Valerie Wood, Kim Rutherford, Shilpa Yagwakote Venkatesh, Jashobanta Sahu, et al. "PHI-base in 2022: a multi-species phenotype database for Pathogen–Host Interactions." Nucleic Acids Research 50, no. D1 (November 12, 2021): D837—D847. http://dx.doi.org/10.1093/nar/gkab1037.
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Abstract Since 2005, the Pathogen–Host Interactions Database (PHI-base) has manually curated experimentally verified pathogenicity, virulence and effector genes from fungal, bacterial and protist pathogens, which infect animal, plant, fish, insect and/or fungal hosts. PHI-base (www.phi-base.org) is devoted to the identification and presentation of phenotype information on pathogenicity and effector genes and their host interactions. Specific gene alterations that did not alter the in host interaction phenotype are also presented. PHI-base is invaluable for comparative analyses and for the discovery of candidate targets in medically and agronomically important species for intervention. Version 4.12 (September 2021) contains 4387 references, and provides information on 8411 genes from 279 pathogens, tested on 228 hosts in 18, 190 interactions. This provides a 24% increase in gene content since Version 4.8 (September 2019). Bacterial and fungal pathogens represent the majority of the interaction data, with a 54:46 split of entries, whilst protists, protozoa, nematodes and insects represent 3.6% of entries. Host species consist of approximately 54% plants and 46% others of medical, veterinary and/or environmental importance. PHI-base data is disseminated to UniProtKB, FungiDB and Ensembl Genomes. PHI-base will migrate to a new gene-centric version (version 5.0) in early 2022. This major development is briefly described.
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Костюк, С. А., О. С. Полуян, И. П. Марьенко, and М. В. Симирский. "Molecular-Genetic Markers of the Risk of Development of Chronization of Tension Headache and Migraine." Неврология и нейрохирургия. Восточная Европа, no. 3 (November 17, 2020): 381–91. http://dx.doi.org/10.34883/pi.2020.10.3.033.
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Введение. Хроническая головная боль напряженного типа и хроническая мигрень наиболее распространены среди населения работоспособного возраста и вызывают снижение продуктивности выполняемой работы, что приводит к дополнительным финансовым затратам. На сегодняшний день выделены гены-кандидаты, имеющие полиморфизмы и относящиеся к одной из физиологических или клеточных систем, нарушения работы которой могут потенцировать развитие данных заболеваний: гены, участвующие в синтезе, высвобождении и связывании нейромедиаторов (серотонин, дофамин) и нейропептидов (тахикинины).Цель. Установить молекулярно-генетические критерии риска хронизации головной боли напряженного типа и мигрени.Материалы и методы. Для выявления полиморфизмов указанных генов были разработаны специальные пары специфических олигонуклеотидных праймеров, оптимизированы состав амплификационной смеси и температурные профили реакции амплификации. Детекцию результатов по определению аллельных вариантов проводили методом горизонтального электрофореза с использованием маркера молекулярных масс. Определение генотипов полиморфных вариантов генов проводили с применением метода анализа кривых плавления продуктов ПЦР высокого разрешения.Результаты. На основании проведенных молекулярно-генетических исследований установлено, что статистически значимыми (p<0,05) достоверными факторами риска хронизации головной боли напряженного типа являются: выявление А-аллеля и AA-генотипа полиморфизма DBH3 гена дофамин-бета-гидроксилазы DBH; а также выявление G-аллеля и GG-генотипа полиморфизма Intron3SNP гена препротахикинина TAC1. Установлено, что статистически значимыми (p<0,05) достоверными факторами риска хронизации мигрени являются: выявление А-аллеля, GA- и АА-генотипов полиморфизма G29A гена транспортера серотонина SLC6A4; а также выявление G-аллеля и GG-генотипа полиморфизма rs7793277 гена препротахикинина TAC1.Выводы. Выявление в сыворотке крови указанных полиморфизмов генов дофамина и препротахикинина увеличивает риск хронизации головной боли напряженного типа в 1,395– 1,991 раза; риск хронизации мигрени – в 1,235–1,395 раза. Introduction. Chronic tension-type headache and chronic migraine are most common in the working-age population. They cause the decrease of the productivity, which leads to additional financial costs. Today, there were identified the “candidate genes” that have polymorphisms and belong to one of the physiological or cellular systems, the disorders of which can potentiate the development of these diseases: the genes involved in the synthesis, release, and binding of neurotransmitters (serotonin, dopamine) and neuropeptides (substance P, neurokinin A). To identify the polymorphisms of these genes, the special pairs of specific oligonucleotide primers were developed, the composition of the amplification mixture and the temperature profiles of the amplification reaction were optimized.Purpose. To establish the molecular genetic criteria of tension headache and migraine chronization risk.Materials and methods. The detection of the results for determination of allelic variants was carried out with horizontal electrophoresis using the molecular weight marker. Determination of the genotypes of polymorphic variants of genes was carried out using high resolution melting analysis. Results. On the base of the conducted molecular genetic studies, it was revealed that statistically significant (p<0.05) risk factors of tension headache chronization are the following: identification of the A-allele and AA-genotype of the DBH3 polymorphism of the dopamine-beta- hydroxylase gene DBH and identification of the G-allele and the GG-genotype of the Intron3SNP polymorphism of the preprotachykinin gene TAC1. It was revealed that statistically significant (p<0.05) risk factors of migraine chronization are the following: identification of the A-allele, GA- and AA-genotypes of the G29A polymorphism of the serotonin transporter gene SLC6A4, as well as identification of the G-allele and the GG-genotype of the rs7793277 polymorphism of the preprotachykinin gene TAC1Conclusions. The detection of these polymorphisms of the dopamine and preprotachykinin genesin the blood serum increases the risk of tension headache chronization by 1.395–1.991 times, the risk of migraine chronization – by 1.235-1.395 times.
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Tetteh, Kevin K. A., Alex Loukas, Cindy Tripp, and Rick M. Maizels. "Identification of Abundantly Expressed Novel and Conserved Genes from the Infective Larval Stage of Toxocara canis by an Expressed Sequence Tag Strategy." Infection and Immunity 67, no. 9 (September 1, 1999): 4771–79. http://dx.doi.org/10.1128/iai.67.9.4771-4779.1999.
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ABSTRACT Larvae of Toxocara canis, a nematode parasite of dogs, infect humans, causing visceral and ocular larva migrans. In noncanid hosts, larvae neither grow nor differentiate but endure in a state of arrested development. Reasoning that parasite protein production is orientated to immune evasion, we undertook a random sequencing project from a larval cDNA library to characterize the most highly expressed transcripts. In all, 266 clones were sequenced, most from both 3′ and 5′ ends, and similarity searches against GenBank protein and dbEST nucleotide databases were conducted. Cluster analyses showed that 128 distinct gene products had been found, all but 3 of which represented newly identified genes. Ninety-five genes were represented by a single clone, but seven transcripts were present at high frequencies, each composing >2% of all clones sequenced. These high-abundance transcripts include a mucin and a C-type lectin, which are both major excretory-secretory antigens released by parasites. Four highly expressed novel gene transcripts, termed ant (abundant novel transcript) genes, were found. Together, these four genes comprised 18% of all cDNA clones isolated, but no similar sequences occur in the Caenorhabditis elegans genome. While the coding regions of the four genes are dissimilar, their 3′ untranslated tracts have significant homology in nucleotide sequence. The discovery of these abundant, parasite-specific genes of newly identified lectins and mucins, as well as a range of conserved and novel proteins, provides defined candidates for future analysis of the molecular basis of immune evasion by T. canis.
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Schürks, Markus. "Response to: Flavia Magazoni Gonçalves, Marcello Rizzatti Luizon, Jose G. Speciali: “Haplotypes in candidate genes related to nitric oxide pathways and vascular permeability associated with migraine with aura”." Journal of Headache and Pain 13, no. 4 (April 12, 2012): 337–38. http://dx.doi.org/10.1007/s10194-012-0446-5.
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Oyama, Tomomi, Toshio Nagai, Hiroshi Wada, Atsuhiko Thomas Naito, Katsuhisa Matsuura, Koji Iwanaga, Toshinao Takahashi, et al. "Cardiac side population cells have a potential to migrate and differentiate into cardiomyocytes in vitro and in vivo." Journal of Cell Biology 176, no. 3 (January 29, 2007): 329–41. http://dx.doi.org/10.1083/jcb.200603014.
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Side population (SP) cells, which can be identified by their ability to exclude Hoechst 33342 dye, are one of the candidates for somatic stem cells. Although bone marrow SP cells are known to be long-term repopulating hematopoietic stem cells, there is little information about the characteristics of cardiac SP cells (CSPs). When cultured CSPs from neonatal rat hearts were treated with oxytocin or trichostatin A, some CSPs expressed cardiac-specific genes and proteins and showed spontaneous beating. When green fluorescent protein–positive CSPs were intravenously infused into adult rats, many more (∼12-fold) CSPs were migrated and homed in injured heart than in normal heart. CSPs in injured heart differentiated into cardiomyocytes, endothelial cells, or smooth muscle cells (4.4%, 6.7%, and 29% of total CSP-derived cells, respectively). These results suggest that CSPs are intrinsic cardiac stem cells and involved in the regeneration of diseased hearts.
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Parizadeh, Seyedamirabbas, Stephan Geley, Veronika Reiterer-Farhan, and Hesso Farhan. "Abstract 2404: Role of TPD52L2 in cell migration and triple negative breast cancer progression." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2404. http://dx.doi.org/10.1158/1538-7445.am2022-2404.
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Abstract The Golgi apparatus plays an important role in cell migration and the establishment of epithelial polarity. A dispersed (or fragmented) Golgi ribbon is often seen in stressed cells and in various pathologies, including neurodegeneration or cancer, but whether and how a fragmented Golgi apparatus affect cellular function is poorly defined. Previously our lab has performed and analyzed published RNAi screens to identify genes required to maintain the Golgi ribbon. These candidate genes were filtered for altered expression patterns in breast cancer patients and for their association with survival data. The selected genes reevaluated by RNAi in BT549 breast cancer cells to assess the effect on Golgi fragmentation. One of the most effective hits was TPD52L2, a poorly characterised gene that encodes a membrane-associated protein that is overexpressed in various types of cancer. The aim of this project is to investigate the role of TPD52L2 in cell migration and cell invasion in breast cancer in order to understand the role of Golgi fragmentation in tumorigenesis. In random cell migration assays in dense and sparse seeding conditions, TPD52L2 depleted cells showed an altered actin cytoskeleton and were found to migrate faster in dense seeding without any change in directional persistence. These findings suggest that TPD52L2 not only is required to maintain an intact Golgi structure but also plays an important role in cellular motility and potentially metastasis. Citation Format: Seyedamirabbas Parizadeh, Stephan Geley, Veronika Reiterer-Farhan, Hesso Farhan. Role of TPD52L2 in cell migration and triple negative breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2404.
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Ramos, Susana Isabel, Zarmeen Mussa, Bruno Giotti, Alexander Tsankov, and Nadejda Tsankova. "EPCO-25. MULTI-OMIC ANALYSIS OF THE GLIOBLASTOMA EPIGENOME AND TRANSCRIPTOME INFORMS OF MIGRATORY INTERNEURON-LIKE DEVELOPMENTAL REGULATORS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii121. http://dx.doi.org/10.1093/neuonc/noac209.460.
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Abstract Recent studies have demonstrated that, despite their nomenclature, gliomas recapitulate an interneuron progenitor-like state that drives tumor progression. During human neurodevelopment, interneurons arise from the subcortical ganglionic eminences and migrate tangentially into the neocortex, settling in the cortical plate where they integrate local neurocircuitry. Analogously, malignant glioblastoma (GBM) cells migrate from the tumor core into the surrounding healthy tissue. This innate infiltrative property renders these malignant cells elusive to surgical resection, leading to tumor recurrence. To understand the regulatory networks that drive tumor infiltration from a neurodevelopmental perspective, we generated a single-nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) dataset of 41,000 nuclei from the core and infiltrative edge of surgically resected GBM specimens (n = 4). Concurrently, we sequenced 46,000 nuclei from non-pathological, postmortem samples of second- and third-trimester neocortices (n = 17). We integrated these datasets with paired single-nucleus RNA sequencing (snRNA-seq) data and identified candidate regulatory TFs that exhibit high correlation between motif enrichment and TF expression. Using single-trajectory inference and pseudo-time analyses, we identified TCF12 as a potential driver of interneuron lineage fate in developing cortical progenitors. Given its implication in projection neuron migration, we were intrigued to find that TCF12 activity is highest in GBM cells with a migratory interneuron signature, hinting at its putative role in tumor infiltration. To understand the significance of these findings, we will interrogate other genes in the TCF12 regulatory network with the ultimate goal of identifying therapeutic targets that inhibit GBM infiltration.
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Cargnin, Sarah, Michele Viana, Grazia Sances, Cristina Tassorelli, and Salvatore Terrazzino. "A systematic review and critical appraisal of gene polymorphism association studies in medication-overuse headache." Cephalalgia 38, no. 7 (September 4, 2017): 1361–73. http://dx.doi.org/10.1177/0333102417728244.
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Purpose of review Medication-overuse headache is a secondary chronic headache disorder, evolving from an episodic primary headache type, caused by the frequent and excessive use of headache symptomatic drugs. While gene polymorphisms have been deeply investigated as susceptibility factors for migraine, little attention has been paid to medication-overuse headache genetics. In the present study we conducted a systematic review to identify, appraise and summarize the current findings of gene polymorphism association studies in medication-overuse headache. Methods A comprehensive literature search was conducted on PubMed and Web of Knowledge databases of primary studies that met the diagnostic criteria for medication-overuse headache according to the temporally-relevant Classification of Headache Disorder of the International Headache Society. Results A total of 17 candidate gene association studies focusing on medication-overuse headache were finally included in the qualitative review. Among these, 12 studies investigated the role of common gene polymorphisms as risk factors for medication-overuse headache susceptibility, six studies focused on the relationship with clinical features of medication-overuse headache patients, and four studies evaluated their role as determinants of clinical outcomes in medication-overuse headache patients. Conclusion Results of single studies show a potential role of polymorphic variants of the dopaminergic gene system or of other genes related to drug-dependence pathways as susceptibility factors for disease or as determinants of monthly drug consumption, respectively. In this systematic review, we summarize the findings of gene polymorphism association studies in medication-overuse headache and discuss the methodological issues that need to be addressed in the design of future studies.
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Voermans, Carlijn, William E. Lento, Mweia Uqoezwa, Leah N. DiMascio, Ali Chhotani, Frederique M. Rattis, and Tannishtha Reya. "Identification of Novel Regulators of Hematopoietic Stem Cell Mobilization." Blood 106, no. 11 (November 16, 2005): 1724. http://dx.doi.org/10.1182/blood.v106.11.1724.1724.
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Abstract In an effort to identify the molecular changes during hematopoietic stem cell (HSC) mobilization we have analyzed genome wide changes in gene expression in HSCs in response to the chemotherapeutic agent cyclophosphamide (Cy) and the growth factor granulocyte colony stimulating factor (G). Cy/G treatment leads to an initial loss of proliferating precursors, followed by a rapid expansion of stem and progenitor cells and their migration to the peripheral blood. While this approach has been capitalized on for harvesting hematopoietic stem cells in clinical therapy, the molecular regulation of this process remains less well understood. To analyze changes in gene expression that occur in vivo as HSCs proliferate and prepare to migrate out of the bone marrow, we enriched for HSC fractions by isolating cells that express c-kit (K), Sca-1(S) and low levels of Thy1.1(T) but do not express lineage (L) markers (KTLS) from untreated mice and mice treated with Cy, G or Cy/G. The gene expression profile of these cells was examined by microarray analysis, relative to HSCs isolated from untreated mice. Interestingly, among the genes upregulated by Cy/G, a large majority (>60%) were a consequence of synergistic activity between Cy and G, while the rest of the upregulated genes could be attributed to activation by Cy or G alone. To test whether this screen allowed identification of novel candidates that regulate HSC function we analyzed the role of transforming growth factor beta induced gene (Big-h3), a gene highly upregulated after Cy/G treatment. Big-h3 is an extracellular matrix protein that mediates the adhesion and migration of various cell types, however its role in HSCs is unknown. Our experiments indicate that overexpression of Big-h3 in HSCs leads to enhanced adhesion to fibronectin as well as upregulation of specific integrins. These experiments suggest that changes in adhesion are an integral component of HSC mobilization, and that Big-h3 is one regulator of such processes. Further functional analysis of other candidates will likely lead to identification of other novel regulators of HSC development and mobilization.
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Fischer, Matthew, Luo Jia, and Karen L. Edelblum. "Type I interferon enhances γδ intraepithelial lymphocyte migratory behavior via CD47 upregulation." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 17.17. http://dx.doi.org/10.4049/jimmunol.206.supp.17.17.
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Abstract γδ intraepithelial lymphocytes (IEL) migrate along the basement membrane and into the lateral intracellular space (LIS) between adjacent intestinal epithelial cells (IEC) and is critical to limit microbial translocation across the barrier. Although activated γδ IELs produce interferon (IFN)-α, whether IFNα directly influences γδ IEL migratory behavior remains unknown. To test this, intravital microscopy was performed on GFP γδ T cell reporter mice treated with PBS or IFNα (1 μg, i.v., 3h). We found that γδ IEL track speed was increased 30% and migration into the LIS was enhanced by 75% in IFNα-treated mice compared to controls. To identify candidate genes involved in regulating γδ IEL motility, we performed RNAseq on γδ IELs isolated from control and IFNα-treated mice. As expected, IFNα induced IFN-stimulated gene expression including CD47 (3.5-fold increase), a transmembrane protein involved in neutrophil transepithelial migration. Stimulation of ex vivo cultured γδ IELs with IFNα resulted in a 3-fold increase in CD47 expression compared to unstimulated controls. Next, to investigate whether IFNα enhances γδ IEL motility in vitro, GFP γδ IELs were co-cultured with enteroids expressing membrane tdTomato and treated with 10ng/ml IFNα for 3h. IFNα increased γδ IEL speed (4.5±0.2 vs 3.4±0.2 μm/min; p<0.05) and displacement (47±3.0 μm vs 34±3.1, p<0.05) relative to untreated controls. Addition of anti-CD47 blocking antibody (MIAP301) abrogated the IFNα-mediated increase in γδ IEL migratory behavior. Taken together, these data demonstrate that IFNα enhances γδ IEL motility via a CD47-mediated mechanism, and suggests that CD47 may represent a conserved mechanism of leukocyte migration within the epithelial barrier.
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Fu, Lingchen, Yen-Chiu Lin-Lee, Lan Pham, Archie Tamayo, and Richard J. Ford. "BAFF-R Receptor Functions in Transcription Regulation in Genes Critical to Survival and Proliferation in Normal and Neoplastic Human B Lymphocytes." Blood 112, no. 11 (November 16, 2008): 4478. http://dx.doi.org/10.1182/blood.v112.11.4478.4478.
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Abstract B-lymphocyte stimulator (BLyS also called BAFF), is a potent cell survival factor expressed in many hematopoietic cells. However, many aspects of BLyS signaling pathway remain unclear. In order to investigate BLyS signaling pathway, we studied the function of BAFF-R (also called BR3), a major BLyS receptor, in normal and neoplastic B cell survival and proliferation. In our initial study, we found that BAFF-R was also present in nucleus, in addition to its presence in the plasma membrane of B cells. A candidate nuclear localization sequence was identified in the BAFF-R protein sequence. We also found BAFF-R mediated transcriptional activity, that could be increased through over expression of a NF-κB family member c-rel. Further study showed that BAFF-R co-localized with, c-rel in the nucleus and bound to the NF-κB binding site on the promoters of NF-κB target genes such as BLyS, CD154, Bcl-xL, Bfl-1/A1 and IL-8. The IκB kinase (IKK) protein complex is critical for regulating NF-κB pathway activation. The IKK complex includes three important subunits: the catalytic subunits IKKα and IKKβ (also known as IKK1 and IKK2) and the regulatory subunit IKKγ (also known as NEMO). In the cytoplasm, activation of the IKK complex induces processing of precursors p105 and p100 into p50 and p52 respectively, resulting in NF-κB subunit dimeric partners that migrate from the cytoplasm into the nucleus. In recent studies, IKKα has also been identified in the cell nucleus, functioning in histone H3 phosphorylation. Although IKKβ was also previously observed in the cell nucleus, its nuclear function has been obscure. Besides functioning as a transcriptional co-factor with c-rel, we also found BAFF-R interacted with IKKβ in the nucleus of normal and neoplastic (lymphoma) B cells, enhancing histone H3 phosphorylation through IKKβ by immuno precipitation experiments and in vitro kinase assays. Inhibition of BAFF-R entry into the nucleus by BAFF-R NLS mutant transfection, decreased the level of phosphorylated histone H3 compared to the controls in NHL-B cells. These findings not only demonstrate a novel nuclear function of IKKβ, but also determine a new mechanism of how BAFF-R promotes survival and proliferation of normal B cells and NHL-B cells. In addition to activating NF-κB pathways in the plasma membrane, BAFF-R also functions as a transcriptional regulator binding to NF-κB targeted gene promoters possibly through a chromatin remodeling mechanism(s).
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Hwang, William L., Jennifer Su, Jimmy A. Guo, Carina Shiau, Jaimie L. Barth, Hannah I. Hoffman, Prajan Divakar, et al. "Abstract C052: Identifying mediators of perineural invasion in pancreatic cancer using spatial transcriptomics." Cancer Research 82, no. 22_Supplement (November 15, 2022): C052. http://dx.doi.org/10.1158/1538-7445.panca22-c052.
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Abstract Intratumoral nerves play important and versatile roles in cancer initiation, progression, recurrence, treatment-resistance, metastasis, morbidity, and mortality for many malignancies but the diverse molecular mechanisms underlying tumor-nerve crosstalk remain largely unknown. One of the differentiating hallmarks of pancreatic ductal adenocarcinoma (PDAC) is an exceptionally high frequency of perineural invasion (PNI), a histopathologic manifestation of tumor-nerve crosstalk whereby cancer cells recruit, migrate towards, and envelop or invade peripheral nerves. Evidence for some neurochemicals/neurotrophins involved in PNI have been uncovered, but most of the underlying work was limited by a lack of cell-type specificity, spatial context, and fragmented focus on individual pathways. To address these shortcomings, we set out to comprehensively identify cell-type specific genes spatially linked to PNI in patient tumors and then dissect the functional roles of these genes through live imaging of dorsal root ganglia (DRG) sensory neurons incubated in conditioned media from cancer cell organoids overexpressing candidate genes via CRISPR activation (CRISPRa). First, we performed whole transcriptome digital spatial profiling (NanoString GeoMx) on twelve custom tissue microarrays (n=288 cores) derived from intratumorally-matched malignant regions with and without PNI in primary resected PDAC specimens (n=31 patients). Differential gene expression (DE) analysis (FDR < 0.001) for PNI demonstrated that for malignant cells there were 271 enriched and 65 depleted genes, and for fibroblasts there were 16 enriched and 27 depleted genes. We further evaluated associations between PNI and expression of malignant subtypes previously identified from single-nucleus RNA-seq applied to 43 primary resected PDAC specimens. We found that malignant cells engaged in PNI were enriched in the mesenchymal, basaloid and neural-like progenitor (NRP) subtypes and depleted in the classical subtype. To test these associations functionally, we generated isogenic murine organoid lines (KrasG12D/+;Trp53FL/FL;R26-dCas9-VPR) overexpressing subtype-driving transcription factors and collected conditioned media. DRG sensory neurons demonstrate enhanced and suppressed growth kinetics when grown in NRP and classical conditioned media, respectively; mesenchymal and basal-like conditioned media do not appear to influence growth kinetics. These results suggest that while mesenchymal, basaloid, and NRP cells likely all play a role in cancer cell invasion of nerves, NRP cells may have an additional role in tumor-nerve tropism. Additional experiments exploring the functional effects of the top enriched and depleted genes from the DE analysis are ongoing. We anticipate that this study will provide a high-resolution understanding of critical intercellular interactions in the PDAC tumor microenvironment that facilitate PNI and tumor-nerve crosstalk more broadly to guide novel therapeutic strategies. Citation Format: William L. Hwang, Jennifer Su, Jimmy A. Guo, Carina Shiau, Jaimie L. Barth, Hannah I. Hoffman, Prajan Divakar, Jason W. Reeves, Eric Miller, Grissel Cervantes-Jaramillo, William Freed-Pastor, Vanessa Funes, Jennifer Y. Wo, Theodore S. Hong, Carlos Fernandez-del Castillo, Lei Zheng, Andrew J. Aguirre, David T. Ting, Mari Mino-Kenudson, Tyler Jacks. Identifying mediators of perineural invasion in pancreatic cancer using spatial transcriptomics [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 C052.
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Senior, Jessica, Amanda Dalby, Joao Correia, Jeremy Pike, Kayley Jaworska, Steve Thomas, Alan Smith, and Anke Brüning-Richardson. "MODL-26. EVOLUTION OF MULTI-FACETED GLIOBLASTOMA MICROENVIRONMENTS IN 3D." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii296. http://dx.doi.org/10.1093/neuonc/noac209.1153.
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Abstract Glioblastomas (GBM) account for poor prognosis and dismal survival rates in patients due to their highly aggressive infiltrative nature to rapidly migrate within the brain. Experimental treatments for GBMs using animal models often elicit severe side effects and there are major doubts regarding the usefulness of such in vivo models when undergoing animal to human clinical translation. Here, we describe the development of a series of 3D bioengineered GBM models towards the generation of a more physiologically representative system in which candidate drugs can be tested. Glioma cell lines U87 and U251 derived from human GBM were used along with associated knockdowns of previously described anti-migratory and pro-migratory genes or anti-migratory inhibitors to examine their roles in the actin polymerization pathway in cancer cell migration. GBM models were fabricated by implantation of spheroids within hydrogel microenvironments that were fashioned to exhibit migratory collagen tracts within a non-cell adhesive outer shell. The distribution of collagen was organised to have low, intermediate, and high-density regions within the construct, replicating the complexity of native GBM. 3D models were then cultured under control conditions (media only) or treated with anti-migratory drugs (CCG-1423, rhosin or combination). Using light-sheet and confocal microscopy, migration velocity, cell phenotype and migratory behaviours were analysed in live and fixed tumour mimics. In models where migration is promoted, actin was vastly upregulated and cells assumed a migratory mesenchymal phenotype, whereas under anti-migratory drug treatment, cells were amoeboid in shape with a dramatic reduction in actin expression and consequently limited migration velocity. Here, we have demonstrated that it is possible to develop biologically-relevant GBM models that capture the anisotropic nature of the tumour microenvironment using multi-layer biopolymer engineering. The ultimate goal of this research is to develop technology that can help provide personalised treatments for GBM and subsequently improve patient outcomes.
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Ferguson, Mark W. J. "Palate development." Development 103, Supplement (September 1, 1988): 41–60. http://dx.doi.org/10.1242/dev.103.supplement.41.
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In all vertebrates, the secondary palate arises as bilateral outgrowths from the maxillary processes. In birds and most reptiles, these palatal shelves grow initially horizontally, but do not fuse with each other resulting in physiological cleft palate. In crocodilians, shelf fusion occurs resulting in an intact secondary palate. Mammalian palatal shelves initially grow vertically down the side of the tongue, but elevate at a precise time to a horizontal position above the dorsum of the tongue and fuse with each other to form an intact palate. Palatal shelf-elevation is the result of an intrinsic shelf elevating force, chiefly generated by the progressive accumulation and hydration of hyaluronic acid. In all vertebrates the nasal epithelium differentiates into pseudostratified ciliated columnar cells and the oral epithelia differentiates into stratified squamous cells, but the medial edge epithelial (MEE) phenotype differs in different groups. In mammals, the MEE of opposing shelves adhere to each other to form an epithelial seam which then disrupts by cell death and cell migration into the mesenchyme accompanied by an epitheliomesenchymal transformation. In birds, the MEE keratinize resulting in cleft palate whereas, in alligators, the MEE migrate onto the nasal aspect of the palate. In all vertebrates, this regional, temporal and species-specific epithelial differentiation is specified by the underlying mesenchyme. Signalling of this interaction is complex but involves both extracellular matrix and soluble factors e.g. minor collagen types, tenascin, EGF, TGFα, TGFβ, PDGF, FGF. These soluble growth factors have a biphasic effect: directly on the epithelia and on the mesenchyme where they stimulate or inhibit cell division and synthesis of specific extracellular matrix molecules. The extracellular matrix molecules (and bound growth factors) synthesized by the mesenchymal cells may then directly affect the epithelium. These signals cause differential gene expression via second messenger systems e.g. cAMP, cGMP, Ca2+, pH, pI etc. Molecular markers for nasal, medial and oral epithelial cell differentiation include the types of cytokeratin intermediate filaments and specific cell surface molecules recognized by monoclonal antibodies: the genes for such molecules are probably expressed in response to mesenchymal signals. Using such an approach, it is possible to go from a morphological description of palate development to a cellular analysis of the mechanisms involved and then to identification of candidate genes that may be important for screening and diagnosis of cleft palate.
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Yoshihara, Hiroki, Michelle L. Churchman, Jennifer L. Peters, David B. Finkelstein, Elisabeth M. Paietta, Mark R. Litzow, and Charles G. Mullighan. "Functional and Genomic Characterization of the Interaction between Acute Lymphoblastic Leukemia Cells and the Microenvironment Identifies Pathways for Therapeutic Intervention." Blood 132, Supplement 1 (November 29, 2018): 1550. http://dx.doi.org/10.1182/blood-2018-99-117894.
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Abstract Introduction Residence and interaction with a specialized bone marrow microenvironment is important for normal hematopoietic stem cells and for initiation and progression of myeloid malignancies, but the role of the microenvironment in propagation and therapeutic response of acute lymphoblastic leukemia (ALL) is not well known. Prior work has identified the efficacy of inhibiting FAK signaling, which is deregulated by IKZF1 alterations resulting in induction of THY1-Integrin alpha 5 adhesion in Ph-positive (Ph+) ALL. Here, we hypothesized that this mechanism may be more broadly important in ALL. We applied a systematic integrated genomic/imaging/functional approach to define the nature of interaction and identify changes in leukemic cells upon interaction that may be targetable. Materials and methods Time-lapse confocal imaging was performed to examine how leukemia cells migrate and adhere to mesenchymal stem cells (MSCs). NALM6 (DUX4/ERG), MHH-CALL2 (hypodiploid), 697 (TCF3-PBX1), Reh (ETV6-RUNX1) and SUP-B15 (Ph+) cell lines were cultured with immortalized human bone marrow MSCs transduced with telomerase reverse transcriptase (hTERT) (Mihara, Br J Haematol. 2003;120:846). For RNA-sequencing, non-adherent cell line cells were collected after two days of coculture with hTERT while adherent cells were trypsinized and collected. Both samples were sorted for CD19 positive population. Fresh primary ALL samples were cultured on bone marrow MSCs derived from patients with no hematological disease and collected with the same procedure for RT-PCR. Multicolor immunofluorescence imaging was utilized to observe expression of multiple molecules involved in adherence. Results Time-lapse imaging showed that leukemia cells have a dynamic interaction with MSC monolayers, with temporary adherence, accompanied by dynamic change in their shape. NALM6 cells adherent to MSCs reduced cell cycling, with an increase in the ratio of G0/G1 cells (26.7% to 48.0%) and decrease in S phase (60.7 to 41.8%). Analysis of gene expression showed 138 upregulated genes (log2FC >2 and FDR <0.05) in adherent cells which were common in all five cell lines, with striking upregulation leading to gene expression associated with gene ontology of extracellular matrix organization and collagen fibril organization. Representative genes were validated in adherent NALM6 cells by immunoblotting (FN1, TIMP1, and LGALS1). Pathway analysis showed that transforming growth factor beta 1 (TGFB1) was the top ranked upstream regulator (p-value of overlap 5.26E-35) in that 44 of 65 genes had measurement direction consistent with activation of TGFB1 signaling. In addition, other upstream regulators that may be involved were beta-estradiol, fibroblast growth factor 2, and tumor necrosis factor. Adhesion of leukemia cells to stroma may induce integrin expression and downstream signaling. Our transcriptomic analysis showed that integrins (A5, B1, A3 and B5) and caveolin 1 (CAV1), a main component of the caveolae plasma membranes, are highly transcribed in adherent leukemia cells. As hTERT cells showed unexpectedly low expression of THY1, a common MSC marker, we utilized primary bone marrow MSC for subsequent analysis. Immunoblotting assay showed enhanced expression of CAV1 in all cell lines adhered to MSCs. Multicolor immunofluorescence imaging demonstrated CAV1 and ITGB1 expression on leukemia cells that localized adjacent to stromal cells, which confirms that these molecules were upregulated upon adhesion to MSCs. Moreover, primary ALL cells showed remarkable upregulation of CAV1, ITGB1, ITGA3, and ITGB5 when the cells were adherent to MSCs. Conclusions Our results demonstrate that ALL cells dynamically interact with microenvironment cells, inducing changes in cell morphology, cell cycling, and adhesion, which may facilitate altered responsiveness to therapy. Transcriptional results suggest that TGFβ signaling is an upstream regulator after cell adhesion to MSCs. While integrins and CAV1 mediate the signaling, these pathway and molecules will be candidates for exploring inhibitors of signaling, which may affect their interaction and make them novel therapeutic targets. Figure. Figure. Disclosures Mullighan: Loxo Oncology: Research Funding; Cancer Prevention and Research Institute of Texas: Consultancy; Amgen: Honoraria, Speakers Bureau; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau.
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Geng, Huimin, Huaxin Gao, Cigall Kadoch, Ming Lu, Lingjing Chen, Rana Anjum, Lisa Drew, et al. "Targeting NF-KB Activation in Novel Intracranial Models of CNS Lymphoma." Blood 128, no. 22 (December 2, 2016): 777. http://dx.doi.org/10.1182/blood.v128.22.777.777.
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Abstract Among the clinical subtypes of diffuse large B-cell lymphoma, central nervous system (CNS) lymphomas, both primary (PCNSL) and secondary (SCNSL), are generally associated with the worst prognosis. Moreover, PCNSL typically exhibits multifocal dissemination, prompting its description as a whole brain disease. An accumulation of genomic data suggests that aberrant NF-kB pro-survival signaling may be a critical factor in the pathogenesis of CNS lymphoma. To date, however, there has been an absence of mechanistic studies to interrogate the mediators and significance of NF-kB activation in CNS lymphoma invasion. Recently our lab derived the first panel of xenografts yet established from PCNSL patients (n=7), and defined their invasive properties in murine models. These novel model systems provide a unique opportunity to study key regulatory mechanisms as well as novel targeted therapies of CNS lymphoma invasion and growth within the brain. We determined that the intracranial growth patterns of the xenografts can be classified based upon reproducible patterns of invasiveness. Two xenografts derived from SCNSL failed to infiltrate brain parenchyma or to migrate to the contralateral hemisphere; instead these tumors exhibited solely a meningeal dissemination pattern, largely growing in the ventricles. By contrast, five of the xenografts exhibited diffuse brain invasion into bilateral hemispheres. In addition, we noted that CNS lymphoma xenografts with an invasive phenotype can be sub-divided phenotypically into moderately vs. highly invasive tumors. After standard injection of 200,000 tumor cells/brain, the highly invasive lymphomas were reproducibly lethal to mice within 3 weeks post-implantation and yielded ~ 1X106 lymphoma cells/brain at necropsy. Under identical conditions, the moderately-invasive lymphoma xenografts were lethal to mice within 1-3 months and yielded between 3-5 X106lymphoma cells/brain. Notably each of the highly invasive CNS lymphoma xenografts were derived from CNS lymphomas that contained the activating L265P mutation of MYD88 (activator of NF-kB via IRAK1/4) and/or Y196H mutation of CD79B (activator of NF-kB), whereas the non-invasive xenografts contained wild type MYD88 and CD79B. We analyzed RNA-seq expression data of these xenograft samples to evaluate relationship of individual genes and signaling pathways with the distinct subclasses of CNS lymphomas in terms of invasiveness. Upregulated signatures in the pro-invasive phenotype are significantly enriched with NF-kB target genes (http://lymphochip.nih.gov/signaturedb/) (FDR<3e-4). For example, as expected, the most invasive xenografts derived from CNS lymphoma specimens expressed high RelA (p65) and NFKB1, core components of the NF-kB multimeric complex. The invasive CNS lymphoma xenografts also exhibited upregulation of MYD88, SYK and PIM1/2, inducers of NF-kB activation. Conversely, the non-invasive xenografts expressed a signature of predominantly non-NF-kB-induced genes including SPRY1/2 (negative regulators of receptor tyrosine kinases) and TIMP2 (negative regulator of invasion). Gene set enrichment analysis confirmed a similar pattern of transcripts expressed in highly invasive PCNSL isolated from diagnostic specimens in patients (N=23; FDR <0.017). Given that the L265P mutation of MYD88 represents a candidate key driver of NF-kB activation in CNS lymphoma, we evaluated the preclinical efficacy of AZ1495, a novel and potent inhibitor of IRAKs. We demonstrated CNS penetration of AZ1495 after PO administration to mice with intracranial lymphoma xenografts, yielding a mean brain/plasma partition coefficient of 0.8. AZ1495 potently antagonized NF-kB activation as demonstrated by p-p65 immunoblot analysis of tumor lysates isolated from murine CNS lymphoma xenografts, within 3 hrs of administration. AZ1495 monotherapy resulted in > 2-fold delay in both intracranial plus spinal progression in a dissemination model of CNS lymphoma using L265P mutant OCI-LY10 cells engineered for bioluminescence (p<0.01). Finally, AZ1495 treatment resulted in a >2-fold increase in median OS in a patient-derived model of L265P mutant PCNSL. These results support the preclinical utility of these models to dissect impact of NF-kB inhibition on CNS lymphoma progression as well as the clinical potential of IRAK antagonism as a means to target NF-kB activation in L265P mutant CNS lymphomas. Disclosures Anjum: Astra Zeneca: Employment. Drew:Astra Zeneca: Employment. Degorce:Astra Zeneca: Employment. Dillman:Astra Zeneca: Employment. Mayo:Astra Zeneca: Employment. Rubenstein:Celgene: Research Funding; Genentech: Research Funding.
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Merrien, Magali, Agata Magdalena Wasik, Christopher Melén, Kristina Sonnevi, Birger Christensson, Björn E. Wahlin, and Birgitta Sander. "Cannabinoid Receptors and CXCR4 Cross-Talk in Lymphoma Cells." Blood 132, Supplement 1 (November 29, 2018): 4121. http://dx.doi.org/10.1182/blood-2018-99-112096.
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Abstract Background: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with a high rate of relapses after therapy. Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with varied outcome. For both diseases there is a need for new therapies. Cannabinoid receptors (CBs), which are overexpressed in most cases of MCL and CLL compared to normal B cells (Islam et al., 2003; Gustafsson et al., 2008; Freund et al., 2016) are promising novel therapeutic targets. CBs are membrane-bound receptors that convey signals from the microenvironment to the cells. There are two types of CBs: CB1 and CB2. CB1 is suggested to be involved in retention and/or egress of MCL cells from the tissue to the blood circulation (Wasik et al., 2014). CB2 is expressed by normal B-cells where it regulates positioning and retention of cells in tissue (Pereira et al., 2009; Basu et al., 2011; Muppidi et al., 2011) and in pre-B-cell acute lymphoblastic leukemia, involved in the energy metabolism (Chan et al., 2017). The retention/egress of the B-cell lymphoma cells is mainly regulated by chemokine receptors and adhesion molecules. The chemokine receptor CXCR4 is one of the most highly expressed chemokine receptors in MCL and CLL. 2-arachidonoylglycerol (2-AG, CB1/CB2 endogenous ligand) and CXCL12 (CXCR4 ligand) are synthetized and secreted by stromal cells in the bone marrow (Kose et al., 2018; Burger and Gribben, 2014). The endocannabinoids levels in cancer are suggested to have a role in cancer progression (Sailler et al., 2014) while CXCL12 is already a candidate target for therapy using a CXCR4 inhibitor AMD3100. Aim: To investigate a possible crosstalk between CBs and CXCR4 in MCL and CLL cells. Methods: Patients with newly diagnosed MCL (n=8) or CLL (n=25) gave informed consent to participate in the study. Lymphoma cells were enriched by negative selection. Fifteen primary lymphoma samples and the JeKo MCL cell line were subjected to chemotaxis towards CXCL12 and/or 2-AG. CXCR4 membrane expression was assessed by flow cytometry. Selective CB1 and CB2 antagonists were used to investigate the underlying mechanisms. CB1, CB2 and CXCR4 encoding genes levels were measured by qPCR and normalized to B cells from tonsil. Results and Conclusion: 2-AG induced chemotaxis in 11/15 MCL and CLL samples. In JeKo, 2-AG-induced migration was blocked by a CB2 antagonist, suggesting that signaling via CB2 is involved. When the primary cells were subjected to migration towards CXCL12, two patterns of chemotaxis were observed. The first pattern was seen in 7/15 samples that migrated towards CXCL12. In these samples, the migration was inhibited when 2-AG was combined with CXCL12. The second type of response was observed in 8/15 samples, those samples did not migrate towards CXCL12 but chemotaxis was enhanced by combining 2-AG and CXCL12. MCL and CLL samples expressed variable mRNA levels of CB1 (RFI range: 0.0-204) and CB2 (RFI range: 0.8-14.3) and all expressed CXCR4 at mRNA (RFI range: 0.1-215.8) and protein (MFI range: 1278-19301) levels that did not differ neither between the two diseases nor between the two migratory groups. When all 15 samples were combined, CB1 mRNA levels, but not CB2 mRNA, correlated to the chemotaxis towards CXCL12 (Spearman correlation coefficient = 0.626; p=0.01). In contrast, CB2 mRNA levels, but not CB1, correlated to chemotaxis towards 2-AG (Spearman correlation coefficient = 0.532; p=0.04), which is in agreement with the effects observed in JeKo. Furthermore, CB1 and CB2 mRNA levels correlated to chemotaxis towards the combination of CXCL12 and 2-AG both (for CB1 mRNA: Spearman correlation coefficient= 0.588; p=0.02 and for CB2 mRNA: 0.589; p=0.02). Neither CXCL12-induced CXCR4 receptor internalization, nor recycling was influenced by 2-AG incubation. Our findings indicate a novel pathway regulating chemotaxis of MCL and CLL implicating a cross-talk between CBs and CXCR4. The fact that the capacity to internalize CXCR4 remained intact after incubation with 2-AG suggests that the reduced CXCL12-mediated migration when 2-AG was combined could be due to an impaired downstream signaling in lymphoma cells. Importance: Lymphoma cells residing in the tissue receive pro-survival stimuli and are protected from chemotherapy by signals from the microenvironment. A better understanding of how lymphoma cell migration and tissue retention are regulated can be a step towards more efficient therapies. Disclosures Wahlin: Gilead: Consultancy, Honoraria, Research Funding; Roche: Research Funding.
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Frederiksen, Simona Denise. "Prioritizing Suggestive Candidate Genes in Migraine: An Opinion." Frontiers in Neurology 13 (June 15, 2022). http://dx.doi.org/10.3389/fneur.2022.910366.
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Fernandez, Francesca, Robert P. Curtain, Natalie J. Colson, Micky Ovcaric, John MacMillan, and Lyn R. Griffiths. "Association analysis of chromosome 1 migraine candidate genes." BMC Medical Genetics 8, no. 1 (August 29, 2007). http://dx.doi.org/10.1186/1471-2350-8-57.
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Bainomugisa, Charlotte K., Heidi G. Sutherland, Richard Parker, Allan F. Mcrae, Larisa M. Haupt, Lyn R. Griffiths, Andrew Heath, et al. "Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine." Frontiers in Neuroscience 15 (June 22, 2021). http://dx.doi.org/10.3389/fnins.2021.678350.
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Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC arrays and analyzed. Multiple testing correction was performed using the Bonferroni method and 10% false discovery rate (FDR). We validated 11 candidate genes previously associated with PTSD including DOCK2, DICER1, and ADCYAP1. In the epigenome-wide scan, seven novel CpGs were significantly associated with PTSD within/near IL37, WNT3, ADNP2, HTT, SLFN11, and NQO2, with all CpGs except the IL37 CpG hypermethylated in PTSD. These results were significantly enriched for genes whose DNA methylation was previously associated with migraine (p-value = 0.036). At 10% FDR, 132 CpGs in 99 genes associated with PTSD were also associated with migraine in the migraine twin samples. Genes associated with PTSD were overrepresented in vascular smooth muscle, axon guidance and oxytocin signaling pathways, while genes associated with both PTSD and migraine were enriched for AMPK signaling and longevity regulating pathways. In conclusion, these results suggest that common genes and pathways are likely involved in PTSD and migraine, explaining at least in part the co-morbidity between the two disorders.
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MacClellan, Leah R., Timothy D. Howard, John W. Cole, O. Colin Stine, Wayne H. Giles, Jeffery R. O'Connell, Marcella A. Wozniak, Barney J. Stern, Braxton D. Mitchell, and Steven J. Kittner. "Relation of Candidate Genes that Encode for Endothelial Function to Migraine and Stroke." Stroke 40, no. 10 (October 2009). http://dx.doi.org/10.1161/strokeaha.109.557462.
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Krivosheeva, Irina A., Alexandra Yu Filatova, Sergei A. Moshkovskii, Ancha V. Baranova, and Mikhail Yu Skoblov. "Analysis of candidate genes expected to be essential for melanoma surviving." Cancer Cell International 20, no. 1 (October 7, 2020). http://dx.doi.org/10.1186/s12935-020-01584-2.
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Abstract Introduction Cancers may be treated by selective targeting of the genes vital for their survival. A number of attempts have led to discovery of several genes essential for surviving of tumor cells of different types. In this work, we tried to analyze genes that were previously predicted to be essential for melanoma surviving. Here we present the results of transient siRNA-mediated knockdown of the four of such genes, namely, UNC45A, STK11IP, RHPN2 and ZNFX1, in melanoma cell line A375, then assayed the cells for their viability, proliferation and ability to migrate in vitro. In our study, the knockdown of the genes predicted as essential for melanoma survival does not lead to statistically significant changes in cell viability. On the other hand, for each of the studied genes, mobility assays showed that the knockdown of each of the target genes accelerates the speed of cells migrating. Possible explanation for such counterintuitive results may include insufficiency of the predicting computational models or the necessity of a multiplex knockdown of the genes. Aims To examine the hypothesis of essentiality of hypomutated genes for melanoma surviving we have performed knockdown of several genes in melanoma cell line and analyzed cell viability and their ability to migrate. Methods Knockdown was performed by siRNAs transfected by Metafectene PRO. The levels of mRNAs before and after knockdown were evaluated by RT-qPCR analysis. Cell viability and proliferation were assessed by MTT assay. Cell migration was assessed by wound healing assay. Results The knockdown of the genes predicted as essential for melanoma survival does not lead to statistically significant changes in cell viability. On the other hand, for each of the studied genes, mobility assays showed that the knockdown of each of the target genes accelerates the speed of cells migrating. Conclusion Our results do not confirm initial hypothesis that the genes predicted essential for melanoma survival as a matter of fact support the survival of melanoma cells.
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Delmore, Kira, Juan Carlos Illera, Javier Pérez-Tris, Gernot Segelbacher, Juan S. Lugo Ramos, Gillian Durieux, Jun Ishigohoka, and Miriam Liedvogel. "The evolutionary history and genomics of European blackcap migration." eLife 9 (April 21, 2020). http://dx.doi.org/10.7554/elife.54462.
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Seasonal migration is a taxonomically widespread behaviour that integrates across many traits. The European blackcap exhibits enormous variation in migration and is renowned for research on its evolution and genetic basis. We assembled a reference genome for blackcaps and obtained whole genome resequencing data from individuals across its breeding range. Analyses of population structure and demography suggested divergence began ~30,000 ya, with evidence for one admixture event between migrant and resident continent birds ~5000 ya. The propensity to migrate, orientation and distance of migration all map to a small number of genomic regions that do not overlap with results from other species, suggesting that there are multiple ways to generate variation in migration. Strongly associated single nucleotide polymorphisms (SNPs) were located in regulatory regions of candidate genes that may serve as major regulators of the migratory syndrome. Evidence for selection on shared variation was documented, providing a mechanism by which rapid changes may evolve.