68 research outputs found
Transcription factor 7-like 2 (TCF7L2) variant is associated with familial breast cancer risk: a case-control study
BACKGROUND: The transcription factor 7-like 2 (TCF7L2) is a critical component of the Wnt/β-catenin pathway. Aberrant TCF7L2 expression modifies Wnt signaling and mediates oncogenic effects through the upregulation of c-MYC and cyclin D. Genetic alterations in TCF7L2 may therefore affect cancer risk. Recently, TCF7L2 variants, including the microsatellite marker DG10S478 and the nearly perfectly linked SNP rs12233372, were identified to associate with type 2 diabetes. METHODS: We investigated the effect of the TCF7L2 rs12255372 variant on familial breast cancer (BC) risk by means of TaqMan allelic discrimination, analyzing BRCA1/2 mutation-negative index patients of 592 German BC families and 735 control individuals. RESULTS: The T allele of rs12255372 showed an association with borderline significance (OR = 1.19, 95% C.I. = 1.01-1.42, P = 0.04), and the Cochran-Armitage test for trend revealed an allele dose-dependent association of rs12255372 with BC risk (P(trend )= 0.04). CONCLUSION: Our results suggest a possible influence of TCF7L2 rs12255372 on the risk of familial BC
TP53-binding protein variants and breast cancer risk: a case-control study
INTRODUCTION: The TP53-binding protein (53BP1) has been shown to influence TP53-mediated transcriptional activation, thus playing a pivotal role in DNA damage signalling. Genetic aberrations in TP53 and in ATM and CHEK2 predispose to cancer. We have therefore examined the effects of 53BP1 single nucleotide polymorphisms (D353E, G412S, and K1136Q) and the novel 53BP1 6bp deletion (1347_1352delTATCCC) on breast cancer risk. METHODS: Allelic discrimination was performed to investigate the frequencies of 53BP1 D353E, G412S, and K1136Q and of 1347_1352delTATCCC in 353 patients with breast cancer and 960 control individuals. RESULTS: No significant association of 53BP1 D353E, G412S, or K1136Q with breast cancer risk was detected. 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34). CONCLUSION: The lack of association casts doubt on the putative effects of D353E, G412S, and K1136Q on breast cancer risk. Investigating a larger study cohort might elucidate the influence of the 6bp deletion 1347_1352delTATCCC. Studying the functional effect and the impact of this variant on the risk of other cancers may be revealing
Haplotype block structure study of the CFTR gene. Most variants are associated with the M470 allele in several European populations
An average of about 1700 CFTR (cystic fibrosis transmembrane conductance regulator) alleles from normal individuals from different European populations were extensively screened for DNA sequence variation. A total of 80 variants were observed: 61 coding SNSs (results already published), 13 noncoding SNSs, three STRs, two short deletions, and one nucleotide insertion. Eight DNA variants were classified as non-CF causing due to their high frequency of occurrence. Through this survey the CFTR has become the most exhaustively studied gene for its coding sequence variability and, though to a lesser extent, for its noncoding sequence variability as well. Interestingly, most variation was associated with the M470 allele, while the V470 allele showed an 'extended haplotype homozygosity' (EHH). These findings make us suggest a role for selection acting either on the M470V itself or through an hitchhiking mechanism involving a second site. The possible ancient origin of the V allele in an 'out of Africa' time frame is discussed
Full-Length L1CAM and Not Its Δ2Δ27 Splice Variant Promotes Metastasis through Induction of Gelatinase Expression
Tumour-specific splicing is known to contribute to cancer progression. In the case of the L1 cell adhesion molecule (L1CAM), which is expressed in many human tumours and often linked to bad prognosis, alternative splicing results in a full-length form (FL-L1CAM) and a splice variant lacking exons 2 and 27 (SV-L1CAM). It has not been elucidated so far whether SV-L1CAM, classically considered as tumour-associated, or whether FL-L1CAM is the metastasis-promoting isoform. Here, we show that both variants were expressed in human ovarian carcinoma and that exposure of tumour cells to pro-metastatic factors led to an exclusive increase of FL-L1CAM expression. Selective overexpression of one isoform in different tumour cells revealed that only FL-L1CAM promoted experimental lung and/or liver metastasis in mice. In addition, metastasis formation upon up-regulation of FL-L1CAM correlated with increased invasive potential and elevated Matrix metalloproteinase (MMP)-2 and -9 expression and activity in vitro as well as enhanced gelatinolytic activity in vivo. In conclusion, we identified FL-L1CAM as the metastasis-promoting isoform, thereby exemplifying that high expression of a so-called tumour-associated variant, here SV-L1CAM, is not per se equivalent to a decisive role of this isoform in tumour progression
A Model of Collective Interpretation
We propose a cognitively plausible formal model of collective interpretation. The model represents how members of a collective interact to interpret their environment. Current theories of collective interpretation focus on how heedful communication among members of a collective (i.e., how much individuals pay attention to others' interpretations) improves interpretive performance; their general assumption is that heed tends to be uniformly beneficial. By unpacking the micromechanisms that underlie such performance, our model reveals a more complex story. Heedfulness can benefit interpretive performance. It can help collectives properly interpret situations that are especially ambiguous, unknown, or novel. Conversely, heedfulness also generates conformity pressures that induce agents to give too much weight to others' interpretations, even if erroneous, thereby potentially degrading interpretive performance. These two effects join into a nonmonotonic trajectory that represents how heed relates to interpretive performance: due to its beneficial properties, performance increases with heed until it peaks before degrading due to conformity pressures. The form of this nonmonotonic relationship is contingent on the nature of the task: ambiguous situations make collectives vulnerable to too much heed: ambiguity ignites conformism; novel situations make collectives dependent on heed: novelty requires multiple eyes to be seen. In addition to these results, our model offers a flexible platform that future work can use to explore collective interpretation in a variety of organizational and supraorganizational contexts.We propose a cognitively plausible formal model of collective interpretation. The model represents how members of a collective interact to interpret their environment. Current theories of collective interpretation focus on how heedful communication among members of a collective (i.e., how much individuals pay attention to others' interpretations) improves interpretive performance; their general assumption is that heed tends to be uniformly beneficial. By unpacking the micromechanisms that underlie such performance, our model reveals a more complex story. Heedfulness can benefit interpretive performance. It can help collectives properly interpret situations that are especially ambiguous, unknown, or novel. Conversely, heedfulness also generates conformity pressures that induce agents to give too much weight to others' interpretations, even if erroneous, thereby potentially degrading interpretive performance. These two effects join into a nonmonotonic trajectory that represents how heed relates to interpretive performance: due to its beneficial properties, performance increases with heed until it peaks before degrading due to conformity pressures. The form of this nonmonotonic relationship is contingent on the nature of the task: ambiguous situations make collectives vulnerable to too much heed: ambiguity ignites conformism; novel situations make collectives dependent on heed: novelty requires multiple eyes to be seen. In addition to these results, our model offers a flexible platform that future work can use to explore collective interpretation in a variety of organizational and supraorganizational contexts
Dental metric standards for sex estimation in archaeological populations from Iran
Sex estimation of skeletal remains is one of the major components of forensic
identification of unknown individuals. Teeth are a potential source of information on
sex and are often recovered in archaeological or forensic contexts due to their post-mortem
longevity. Currently there is limited data on dental sexual dimorphism of
archaeological populations from Iran. This dissertation represents the first study to
provide a dental sex estimation method for Iron Age populations.
The current study was conducted on the skeletal remains of 143 adults from two Iron
Age populations in close temporal and geographic proximity in the Solduz Valley
(West Azerbaijan Province of Iran). 2D and 3D cervical mesiodistal and buccolingual
and root volume measurements of maxillary and mandibular teeth were used to
investigate the degree of sexual dimorphism in permanent dentition and to assess their
applicability in sex estimation. In total 1327, 457, and 480 anterior and posterior teeth
were used to collect 2D cervical, 3D cervical, and root volume measurements
respectively. 2D cervical measurements were taken using Hillson-Fitzgerald dental
calliper and 3D measurements were collected using CT images provided by Open
Research Scan Archive (ORSA) - Penn Museum. 3D models of the teeth were created
using manual segmentation in the Amira 6.01 software package. Since tooth density
largely differs from crown to apex, root segmentation required two threshold levels:
the segmentation of the root from the jaw and the segmentation of the crown from the
root. Thresholds used for root segmentation were calculated using the half maximum
height protocol of Spoor et al. (1993) for each skull, and thresholds used for crown
segmentation were set visually for each tooth separately. Data was analysed using
discriminant function analysis and posterior probabilities were calculated for all
produced formulae where sex was previously assessed from morphological features of
pelvis and skull. Bootstrapping was used to account for small sample sizes in the
analysis. Statistical analysis was carried out using SPSS 23. The percentage of sexual
dimorphism was also used to quantify the amount of sexual dimorphism in the sample.
The results showed that incisors and canines were the most sexually dimorphic teeth,
providing percentages of correct sex classification between 80% and 100% depending
on the measurement used. Root volume measurement was shown to be the most
sexually dimorphic variable providing an accuracy of over 90% in all functions.
The present study provided the first dental metric standards for sex estimation using
odontometric data in Iranian archaeological populations. Dental measurements,
particularly root volume measurements, were found to be of value for sex assessment
and the method presented here could be a useful tool for establishing accurate
demographic data from skeletal remains of the Iron Age from Iran
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