95 research outputs found
RAD51B in familial breast cancer
No full textCommon variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk
The second activating glucokinase mutation (A456V): Implications for glucose homeostasis and diabetes therapy
No full textIn this study, a second case of hyperinsulinemic hypoglycemia due to activation of glucokinase is reported. The 14-year-old proband had a history of neonatal hypoglycemia, treated with diazoxide. He was admitted with coma and convulsions due to nonketotic hypoglycemia. His BMI was 34 kg/m(2), and his fasting blood glucose ranged from 2.1 to 2.7 mmol/l, associated with inappropriately high serum levels of insulin, C-peptide, and proinsulin. An oral glucose tolerance test (OGTT) showed exaggerated responses of these peptides followed by profound hypoglycemia. Treatment with diazoxide and chlorothiazide was effective. His mother never had clinical hypoglycemic symptoms, even though her fasting blood glucose ranged from 2.9 to 3.5 mmol/l. Increases in serum insulin, C-peptide, and proinsulin in response to an OGTT suggested a lower threshold for glucose-stimulated insulin release (GSIR). Screening for mutations in candidate genes revealed a heterozygous glucokinase mutation in exon 10, substituting valine for alanine at codon 456 (A456V) in the proband and his mother. The purified recombinant glutathionyl S-transferase fusion protein of the A456V glucokinase revealed a decreased glucose S-0.5 (the concentration of glucose needed to achieve the half-maximal rate of phosphorylation) from 8.04 (wild-type) to 2.53 mmol/l. The mutant's Hill coefficient was decreased, and its maximal specific activity k(cat) was increased. Mathematical modeling predicted a markedly lowered GSIR threshold of 1.5 mmol/l. The theoretical and practical implications are manifold and significant
The Iron Age iron slags of Maastricht – Randwyck: processing or production?
No full textThe increasingly abundant presence of iron artefacts in Early Iron Age urnfield contexts, is not matched by a similarly exhaustive dataset on (local) iron production. Rather, I have argued elsewhere (Arnoldussen & Brusgaard 2015, 117), that evidence for Iron Age primary iron production (i.e. smelting) in the Netherlands is as yet absent (cf. Brusgaard et al. 2015, 359). Smithing, in contrast, appears to be well documented from the Middle Iron Age (c. 600-250 cal. BC) onwards: particularly associated finds of tuyere or crucible fragments with slag fragments hint at local ironworking (e.g. at Velsen-Santpoort, Oss-Ussen and Oss- Schalkskamp; Van Heeringen 1992, 73(157); 75 (159); Schinkel 1998, 91-93; fig. 126; Brusgaard et al. 2015, 357). Most of the local ironworking evidence, however, seems to pertain to the Middle and Late Iron Age periods (Arnoldussen & Brusgaard 2015, 117 table. 1, cf. Joosten 2004, 22-25) and it is generally assumed that prior to the Roman Period, no local smelting occurred (e.g. De Rijk 2003, 88; Joosten 2004, 30; Van den Broeke 2005, 688; Brusgaard et al. 2015, 359). If one wants to investigate the transition in ironworking technologies from (A) reworking imported iron billets or bars (e.g. Verhart 2006, 103, Van As 2013, 26, cf. De Rijk 2003; 82-83; 2007, 164, cf. Brusgaard et al. 2015, 359) to (B) local iron production (smelting), the ironworking evidence for the Early Iron Age (c. 800-600 cal BC) becomes of particular significance. For Oss-Ussen, six pits dated to the Early Iron Age have yielded slag fragments (Schinkel 1998, 55-56), that are unfortunately not yet studied in detail. For Maastricht – Randwijck, Dijkman (1989, 38) identified a series of slag fragments from an Early to Middle Iron Age ‘horseshoe-shaped feature’ as smelting debris. If this is correct, it would represent one of the earliest indications of local iron production (Brusgaard et al. 2015, 359, cf. Van den Broeke 1980, 108; 2012, 287). To investigate this claim, a set of slag fragments from the Maastricht – Randwijck feature has been restudied by the author in 2016
The Iron Age iron slags of Maastricht – Randwyck: processing or production?
No full textThe increasingly abundant presence of iron artefacts in Early Iron Age urnfield contexts, is not matched by a similarly exhaustive dataset on (local) iron production. Rather, I have argued elsewhere (Arnoldussen & Brusgaard 2015, 117), that evidence for Iron Age primary iron production (i.e. smelting) in the Netherlands is as yet absent (cf. Brusgaard et al. 2015, 359). Smithing, in contrast, appears to be well documented from the Middle Iron Age (c. 600-250 cal. BC) onwards: particularly associated finds of tuyere or crucible fragments with slag fragments hint at local ironworking (e.g. at Velsen-Santpoort, Oss-Ussen and Oss- Schalkskamp; Van Heeringen 1992, 73(157); 75 (159); Schinkel 1998, 91-93; fig. 126; Brusgaard et al. 2015, 357). Most of the local ironworking evidence, however, seems to pertain to the Middle and Late Iron Age periods (Arnoldussen & Brusgaard 2015, 117 table. 1, cf. Joosten 2004, 22-25) and it is generally assumed that prior to the Roman Period, no local smelting occurred (e.g. De Rijk 2003, 88; Joosten 2004, 30; Van den Broeke 2005, 688; Brusgaard et al. 2015, 359). If one wants to investigate the transition in ironworking technologies from (A) reworking imported iron billets or bars (e.g. Verhart 2006, 103, Van As 2013, 26, cf. De Rijk 2003; 82-83; 2007, 164, cf. Brusgaard et al. 2015, 359) to (B) local iron production (smelting), the ironworking evidence for the Early Iron Age (c. 800-600 cal BC) becomes of particular significance. For Oss-Ussen, six pits dated to the Early Iron Age have yielded slag fragments (Schinkel 1998, 55-56), that are unfortunately not yet studied in detail. For Maastricht – Randwijck, Dijkman (1989, 38) identified a series of slag fragments from an Early to Middle Iron Age ‘horseshoe-shaped feature’ as smelting debris. If this is correct, it would represent one of the earliest indications of local iron production (Brusgaard et al. 2015, 359, cf. Van den Broeke 1980, 108; 2012, 287). To investigate this claim, a set of slag fragments from the Maastricht – Randwijck feature has been restudied by the author in 2016
The Iron Age iron slags of Maastricht – Randwyck: processing or production?
No full textThe increasingly abundant presence of iron artefacts in Early Iron Age urnfield contexts, is not matched by a similarly exhaustive dataset on (local) iron production. Rather, I have argued elsewhere (Arnoldussen & Brusgaard 2015, 117), that evidence for Iron Age primary iron production (i.e. smelting) in the Netherlands is as yet absent (cf. Brusgaard et al. 2015, 359). Smithing, in contrast, appears to be well documented from the Middle Iron Age (c. 600-250 cal. BC) onwards: particularly associated finds of tuyere or crucible fragments with slag fragments hint at local ironworking (e.g. at Velsen-Santpoort, Oss-Ussen and Oss- Schalkskamp; Van Heeringen 1992, 73(157); 75 (159); Schinkel 1998, 91-93; fig. 126; Brusgaard et al. 2015, 357). Most of the local ironworking evidence, however, seems to pertain to the Middle and Late Iron Age periods (Arnoldussen & Brusgaard 2015, 117 table. 1, cf. Joosten 2004, 22-25) and it is generally assumed that prior to the Roman Period, no local smelting occurred (e.g. De Rijk 2003, 88; Joosten 2004, 30; Van den Broeke 2005, 688; Brusgaard et al. 2015, 359). If one wants to investigate the transition in ironworking technologies from (A) reworking imported iron billets or bars (e.g. Verhart 2006, 103, Van As 2013, 26, cf. De Rijk 2003; 82-83; 2007, 164, cf. Brusgaard et al. 2015, 359) to (B) local iron production (smelting), the ironworking evidence for the Early Iron Age (c. 800-600 cal BC) becomes of particular significance. For Oss-Ussen, six pits dated to the Early Iron Age have yielded slag fragments (Schinkel 1998, 55-56), that are unfortunately not yet studied in detail. For Maastricht – Randwijck, Dijkman (1989, 38) identified a series of slag fragments from an Early to Middle Iron Age ‘horseshoe-shaped feature’ as smelting debris. If this is correct, it would represent one of the earliest indications of local iron production (Brusgaard et al. 2015, 359, cf. Van den Broeke 1980, 108; 2012, 287). To investigate this claim, a set of slag fragments from the Maastricht – Randwijck feature has been restudied by the author in 2016
The Iron Age iron slags of Maastricht – Randwyck: processing or production?
No full textThe increasingly abundant presence of iron artefacts in Early Iron Age urnfield contexts, is not matched by a similarly exhaustive dataset on (local) iron production. Rather, I have argued elsewhere (Arnoldussen & Brusgaard 2015, 117), that evidence for Iron Age primary iron production (i.e. smelting) in the Netherlands is as yet absent (cf. Brusgaard et al. 2015, 359). Smithing, in contrast, appears to be well documented from the Middle Iron Age (c. 600-250 cal. BC) onwards: particularly associated finds of tuyere or crucible fragments with slag fragments hint at local ironworking (e.g. at Velsen-Santpoort, Oss-Ussen and Oss- Schalkskamp; Van Heeringen 1992, 73(157); 75 (159); Schinkel 1998, 91-93; fig. 126; Brusgaard et al. 2015, 357). Most of the local ironworking evidence, however, seems to pertain to the Middle and Late Iron Age periods (Arnoldussen & Brusgaard 2015, 117 table. 1, cf. Joosten 2004, 22-25) and it is generally assumed that prior to the Roman Period, no local smelting occurred (e.g. De Rijk 2003, 88; Joosten 2004, 30; Van den Broeke 2005, 688; Brusgaard et al. 2015, 359). If one wants to investigate the transition in ironworking technologies from (A) reworking imported iron billets or bars (e.g. Verhart 2006, 103, Van As 2013, 26, cf. De Rijk 2003; 82-83; 2007, 164, cf. Brusgaard et al. 2015, 359) to (B) local iron production (smelting), the ironworking evidence for the Early Iron Age (c. 800-600 cal BC) becomes of particular significance. For Oss-Ussen, six pits dated to the Early Iron Age have yielded slag fragments (Schinkel 1998, 55-56), that are unfortunately not yet studied in detail. For Maastricht – Randwijck, Dijkman (1989, 38) identified a series of slag fragments from an Early to Middle Iron Age ‘horseshoe-shaped feature’ as smelting debris. If this is correct, it would represent one of the earliest indications of local iron production (Brusgaard et al. 2015, 359, cf. Van den Broeke 1980, 108; 2012, 287). To investigate this claim, a set of slag fragments from the Maastricht – Randwijck feature has been restudied by the author in 2016
Two novel mutations in RNU4ATAC in two siblings with an atypical mild phenotype of microcephalic osteodysplastic primordial dwarfism type 1
No full textDiscovery of molecular pathways mediating 1,25-dihydroxyvitamin D3 protection against cytokine-induced inflammation and damage of human and male mouse islets of Langerhans.
No full textProtection against insulitis and diabetes by active vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), in nonobese diabetic mice has until now mainly been attributed to its immunomodulatory effects, but also protective effects of this hormone on inflammation-induced β-cell death have been reported. The aim of this study was to clarify the molecular mechanisms by which 1,25(OH)2D3 contributes to β-cell protection against cytokine-induced β-cell dysfunction and death. Human and mouse islets were exposed to IL-1β and interferon-γ in the presence or absence of 1,25(OH)2D3. Effects on insulin secretion and β-cell survival were analyzed by glucose-stimulated insulin release and electron microscopy or Hoechst/propidium iodide staining, respectively. Gene expression profiles were assessed by Affymetrix microarrays. Nuclear factor-κB activity was tested, whereas effects on secreted chemokines/cytokines were confirmed by ELISA and migration studies. Cytokine exposure caused a significant increase in β-cell apoptosis, which was almost completely prevented by 1,25(OH)2D3. In addition, 1,25(OH)2D3 restored insulin secretion from cytokine-exposed islets. Microarray analysis of murine islets revealed that the expression of approximately 4000 genes was affected by cytokines after 6 and 24 hours (n = 4; >1.3-fold; P < .02), of which nearly 250 genes were modified by 1,25(OH)2D3. These genes belong to functional groups involved in immune response, chemotaxis, cell death, and pancreatic β-cell function/phenotype. In conclusion, these findings demonstrate a direct protective effect of 1,25(OH)2D3 against inflammation-induced β-cell dysfunction and death in human and murine islets, with, in particular, alterations in chemokine production by the islets. These effects may contribute to the beneficial effects of 1,25(OH)2D3 against the induction of autoimmune diabetes.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe
RAD51B in Familial Breast Cancer
No full textCommon variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737
and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast
cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer
predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the
coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for
identification of possible recurrent founder mutations. In addition, we studied the known rs999737,
rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583
controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that
were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense
mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in
additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and
Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the
Finnish datasets or in the large BCAC dataset. The association with previously identified risk
variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also
among familial cases in the BCAC dataset. The most significant association was observed for the
haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15,
95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24,
95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective
alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common
variation at the RAD51B region is significantly associated with familial breast cancer risk
Estandarización del cariotipo del visón americano ("Mustella Viso")
No full textEl cariotipo del visón consta de 14 autosomas y un par de cromosomas sexuales. Se propone un sistema en el cual la fila 1 consta de cinco grandes cromosomas metacéntricos ordenados por tamaño, la fila 2 consta de cinco cromosomas submetacéntricos ordenados por tamaño y la fila 3 consta de tres acrocéntricos ordenados por tamaño. La identificación de los cromosomas individuales está basada en bandeos R-, Q- y N. Se propone un sistema de numeración para las bandas individuales que cubre un total aproximado de 100 bandas. Se presentan resultados de hibridación in situ para más de 50 cósmidos seleccionados por contener repetición de dinucleótidos. Mediante esas hibridaciones se localiza un marcador sobre todos los cromosomas. Cinco cósmidos muestran resultados de fuerte hibridación en centrómeros, incluyendo la región del organizador nuclear y el cromosoma Y. Resultados mas detallados pueden apreciarse en el servidor http//www.husdir.kvl.dkfmink.htm
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