Schliemann's excavations at Troy, 1870-1873

This study is based on Schliemann's unpublished Troy excavation note books from 1870-73. It attempts to reconstruct his activities, to locate and identify the features he found, and to stratify and date the several thousand objects he recorded. There is some degree of synthesis with the later findings of Dörpfeld and Blegen, and a review, in the light of all these findings, of the chronology of the Bronze Age strata. The study covers all periods from Early Bronze Age to Byzantine, and all classes of material. A reconstructed contour-plan permits a new and closer understanding of Schliemann's progress. Fifty-two areas of work are distinguished in each of which an outline stratigraphy can be reconstructed. Objects are assigned to specific strata, although Schliemann's frequent failure to specify from which trench which objects came can inject varying degrees of uncertainty into the operation. The sequence of fortifications on the North side of the site is greatly clarified, especially for Troy II and VI. Buildings in the citadel interior are more closely dated, and the sequence in Troy II is substantially re-organised to allow for at least twelve building-phases. The earth-movements supposed to have demolished Troy VI are unlikely to have antedated late VIIa. Troy I-II.4 belong to EBII (c.3000-2465); wheelmade plates and one-handled tankards first appear in II.1. Troy II.5-III belong to EBIII (c.2465-2005); two-handled cups and tankards appear in II.5 after an increase of wheelmade plain ware in II.4. Troy III is contemporary with early Middle Helladic. Troy IV-V belong to the Anatolian Middle Bronze Age (c.2005-1712), and VI-VII are purely Late Bronze Age (c.1712-1070). VIh was destroyed c.1270(?), probably around the end of LHIIIBl, and VIIa was destroyed c.1190(?) during LHIIIC

ATM Mutations and Phenotypes in Ataxia-Telangiectasia Families in the British Isles: Expression of Mutant ATM and the Risk of Leukemia, Lymphoma, and Breast Cancer

SummaryWe report the spectrum of 59 ATM mutations observed in ataxia-telangiectasia (A-T) patients in the British Isles. Of 51 ATM mutations identified in families native to the British Isles, 11 were founder mutations, and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features. We report, in two A-T families, an ATM mutation (7271T→G) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes (relative risk 12.7; P=.0025), although there is a less severe A-T phenotype in terms of the degree of cerebellar degeneration. This mutation (7271T→G) also allows expression of full-length ATM protein at a level comparable with that in unaffected individuals. In addition, we have studied 18 A-T patients, in 15 families, who developed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin lymphoma, mostly in childhood. A wide variety of ATM mutation types, including missense mutations and in-frame deletions, were seen in these patients. We also show that 25% of all A-T patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein

Comparison of the Effects of Two Topical Fluoride Regimens on Demineralized Enamel in vivo

The purpose of this investigation was to study the intra-oral remineralization of acid-softened enamel by a NaF dentifrice compared with that from a combination of topical F agents. Bovine enamel slabs were demineralized with 0.1 mol/L lactic acid at pH 4.0 for 14 hr and then mounted in a removable mandibular appliance. Control slabs were worn for 96 hr by seven adult males who brushed daily with a F-free dentifrice. Test slabs were brushed with a NaF dentifrice 4 x / day or with the same dentifrice 4 x /day and a 0.02% APF mouthrinse and a 0.4% SnF2 gel which were applied oncelday for three days. The natural dentition was also brushed with the NaF dentifrice during both test periods. Microhardness testing was performed on sound enamel, and after acid-softening, intra-oral exposure (IOE), and acid resistance testing (ART) in 0.01 mol/L lactic acid at pH 4.0 for 24 hr. Control and test slabs were etched with 0.5 mol/L HClO4 for from 15 to 60 sec. The F content was measured with a F electrode and PO4 by spectrophotometry. Contact microradiography and image analyses were performed on control and test slabs so that changes in mineral content resulting from treatment could be assessed. Both test groups were significantly harder after both IOE and ART than were controls, but no differences appeared between the effects of the two test groups. The F content of control slabs was significantly less than that of both test groups, and the combination-treated slabs showed greater F than did the dentifrice-treated slabs. Microradiographs revealed a higher mineral content in the basal 2/3 of combination-treated lesions, while diffuse mineral deposition occurred, especially subjacent to the surface in the dentifrice-treated lesions. Control lesions showed little added mineral.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66793/2/10.1177_00220345880670061301.pd

The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2

Purpose : The morphologic and molecular phenotype of breast cancers may help identify patients who are likely to carry germline mutations in BRCA1 and BRCA2. This study evaluates the immunohistochemical profiles of tumors arising in patients with mutations in these genes. Materials and Methods: Samples of breast cancers obtained from the International Breast Cancer Linkage Consortium were characterized morphologically and immunohistochemically using antibodies to estrogen receptor, progesterone receptor, HER-2 (c-erbB-2 oncogene), and p53 protein. Results: Breast cancers in patients with BRCA1 germline mutations are more often negative for estrogen receptor, progesterone receptor, and HER-2, and are more likely to be positive for p53 protein compared with controls. In contrast, BRCA2 tumors do not show a significant difference in the expression of any of these proteins compared with controls. Conclusion: BRCA1 has a distinctive morphology and immunohistochemical phenotype. The combined morphologic and immunohistochemical data can be used to predict the risk of a young patient harboring a germline mutation in BRCA1. The BRCA2 phenotype is currently not well defined. (C) 2002 by American Society of Clinical Oncology

Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility

We recently reported that a sequence variant in the cell-cycle-checkpoint kinase CHEK2 (CHEK2 1100delC) is a low-penetrance breast cancer-susceptibility allele in noncarriers of BRCA1 or BRCA2 mutations. To investigate whether other CHEK2 variants confer susceptibility to breast cancer, we screened the full CHEK2 coding sequence in BRCA1/2-negative breast cancer cases from 89 pedigrees with three or more cases of breast cancer. We identified one novel germline variant, R117G, in two separate families. To evaluate the possible association of R117G and two germline variants repo

A role for XRCC2 gene polymorphisms in breast cancer risk and survival

Background The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer. Methods The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC). Results The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10−4, minor allele frequency (MAF)=0.23). This SNP yielded an ORrec of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-ORrec of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01). Conclusions These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK

Personalizing Breast Cancer Screening Based on Polygenic Risk and Family History

_Background:_ We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. _Methods:_ Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age and interval. The benefits and harms were compared with those seen with 3 established screening guidelines. _Results:_ Women with a breast cancer family history who initiated biennial screening at age 40 years had a 36% increase in life-years gained and 20% more breast cancer deaths averted, but 21% more overdiagnoses and 63% more false positives. Screening tailored to PRS vs biennial screening from50 to 74 years had smaller positive effects on life-years gained and breast cancer deaths averted but also smaller increases in overdiagnoses and false positives. Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained and breast cancer deaths averted. _Conclusions:_ Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected

A genome-wide association scan on estrogen receptor-negative breast cancer

Introduction: Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk.Methods: We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases.Results: Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer share