Pervasive melt percolation reactions in ultra-depleted refractory harzburgites at the Mid-Atlantic Ridge, 15° 20′N : ODP Hole 1274A

Author Posting. © The Authors, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 153 (2007): 303-319, doi:10.1007/s00410-006-0148-6.ODP Leg 209 Site 1274 mantle peridotites are highly refractory in terms of lack of residual clinopyroxene, olivine Mg# (up to 0.92) and spinel Cr# (~0.5), suggesting high degree of partial melting (>20%). Detailed studies of their microstructures show that they have extensively reacted with a pervading intergranular melt prior to cooling in the lithosphere, leading to crystallization of olivine, clinopyroxene and spinel at the expense of orthopyroxene. The least reacted harzburgites are too rich in orthopyroxene to be simple residues of low-pressure (spinel field) partial melting. Cu-rich sulfides that precipitated with the clinopyroxenes indicate that the intergranular melt was generated by no more than 12% melting of a MORB mantle or by more extensive melting of a clinopyroxene-rich lithology. Rare olivine-rich lherzolitic domains, characterized by relics of coarse clinopyroxenes intergrown with magmatic sulfides, support the second interpretation. Further, coarse and intergranular clinopyroxenes are highly depleted in REE, Zr and Ti. A two-stage partial melting/melt-rock reaction history is proposed, in which initial mantle underwent depletion and refertilization after an earlier high pressure (garnet field) melting event before upwelling and remelting beneath the present-day ridge. The ultra-depleted compositions were acquired through melt re-equilibration with residual harzburgites.Funding for this research was provided by Centre National de la Recherche Scientifique-Institut National des Sciences de l’Univers (Programme Dynamique et Evolution de la Terre Interne)

CpG island methylation is a common finding in colorectal cancer cell lines

Tumour cell lines are commonly used in colorectal cancer (CRC) research, including studies designed to assess methylation defects. Although many of the known genetic aberrations in CRC cell lines have been comprehensively described, no studies have been performed on their methylation status. In this study, 30 commonly used CRC cell lines as well as seven primary tumours from individuals with hereditary nonpolyposis colorectal cancer (HNPCC) were assessed for methylation at six CpG islands known to be hypermethylated in colorectal cancer: hMLH1, p16, methylated in tumour (MINT-)-1, -2, -12 and -31. The cell lines were also assessed for microsatellite instability (MSI), ploidy status, hMLH1 expression, and mutations in APC and Ki-ras. Methylation was frequently observed at all examined loci in most cell lines, and no differences were observed between germline-derived and sporadic cell lines. Methylation was found at MINT 1 in 63%, MINT 2 in 57%, MINT 12 in 71%, MINT 31 in 53%, p16 in 71%, and hMLH1 in 30% of cell lines. Overall only one cell line, SW1417, did not show methylation at any locus. Methylation was found with equal frequency in MSI and chromosomally unstable lines. MSI was over-represented in the cell lines relative to sporadic CRC, being detected in 47% of cell lines. The rate of codon 13 Ki-ras mutations was also over three times that expected from in vivo studies. We conclude that CpG island hypermethylation, whether acquired in vivo or in culture, is a ubiquitous phenomenon in CRC cell lines. We suggest that CRC cell lines may be only representative of a small subset of real tumours, and this should be taken into account in the use of CRC cell lines for epigenetic studies

Identification of microbial DNA in human cancer

<p>Abstract</p> <p>Background</p> <p>Microorganisms have been associated with many types of human diseases; however, a significant number of clinically important microbial pathogens remain to be discovered.</p> <p>Methods</p> <p>We have developed a genome-wide approach, called Digital Karyotyping Microbe Identification (DK-MICROBE), to identify genomic DNA of bacteria and viruses in human disease tissues. This method involves the generation of an experimental DNA tag library through Digital Karyotyping (DK) followed by analysis of the tag sequences for the presence of microbial DNA content using a compiled microbial DNA virtual tag library.</p> <p>Results</p> <p>To validate this technology and to identify pathogens that may be associated with human cancer pathogenesis, we used DK-MICROBE to determine the presence of microbial DNA in 58 human tumor samples, including brain, ovarian, and colorectal cancers. We detected DNA from Human herpesvirus 6 (HHV-6) in a DK library of a colorectal cancer liver metastasis and in normal tissue from the same patient.</p> <p>Conclusion</p> <p>DK-MICROBE can identify previously unknown infectious agents in human tumors, and is now available for further applications for the identification of pathogen DNA in human cancer and other diseases.</p

Molecular Genetic Analysis of 103 Sporadic Colorectal Tumours in Czech Patients

The Czech Republic has one of the highest incidences of colorectal cancer (CRC) in Europe. To evaluate whether sporadic CRCs in Czech patients have specific mutational profiles we analysed somatic genetic changes in known CRC genes (APC, KRAS, TP53, CTNNB1, MUTYH and BRAF, loss of heterozygosity (LOH) at the APC locus, microsatellite instability (MSI), and methylation of the MLH1 promoter) in 103 tumours from 102 individuals. The most frequently mutated gene was APC (68.9% of tumours), followed by KRAS (31.1%), TP53 (27.2%), BRAF (8.7%) and CTNNB1 (1.9%). Heterozygous germline MUTYH mutations in 2 patients were unlikely to contribute to the development of their CRCs. LOH at the APC locus was found in 34.3% of tumours, MSI in 24.3% and MLH1 methylation in 12.7%. Seven tumours (6.9%) were without any changes in the genes tested. The analysis yielded several findings possibly specific for the Czech cohort. Somatic APC mutations did not cluster in the mutation cluster region (MCR). Tumours with MSI but no MLH1 methylation showed earlier onset and more severe mutational profiles compared to MSI tumours with MLH1 methylation. TP53 mutations were predominantly located outside the hot spots, and transitions were underrepresented. Our analysis supports the observation that germline MUTYH mutations are rare in Czech individuals with sporadic CRCs. Our findings suggest the influence of specific ethnic genetic factors and/or lifestyle and dietary habits typical for the Czech population on the development of these cancers

Primitive layered gabbros from fast-spreading lower oceanic crust

Three-quarters of the oceanic crust formed at fast-spreading ridges is composed of plutonic rocks whose mineral assemblages, textures and compositions record the history of melt transport and crystallization between the mantle and the sea floor. Despite the importance of these rocks, sampling them in situ is extremely challenging owing to the overlying dykes and lavas. This means that models for understanding the formation of the lower crust are based largely on geophysical studies and ancient analogues (ophiolites) that did not form at typical mid-ocean ridges. Here we describe cored intervals of primitive, modally layered gabbroic rocks from the lower plutonic crust formed at a fast-spreading ridge, sampled by the Integrated Ocean Drilling Program at the Hess Deep rift. Centimetre-scale, modally layered rocks, some of which have a strong layering-parallel foliation, confirm a long-held belief that such rocks are a key constituent of the lower oceanic crust formed at fast-spreading ridges. Geochemical analysis of these primitive lower plutonic rocks-in combination with previous geochemical data for shallow-level plutonic rocks, sheeted dykes and lavas-provides the most completely constrained estimate of the bulk composition of fast-spreading oceanic crust so far. Simple crystallization models using this bulk crustal composition as the parental melt accurately predict the bulk composition of both the lavas and the plutonic rocks. However, the recovered plutonic rocks show early crystallization of orthopyroxene, which is not predicted by current models of melt extraction from the mantle and mid-ocean-ridge basalt differentiation. The simplest explanation of this observation is that compositionally diverse melts are extracted from the mantle and partly crystallize before mixing to produce the more homogeneous magmas that erupt

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

It is well acknowledged from observations in humans that iron deficiency during pregnancy can be associated with a number of developmental problems in the newborn and developing child. Due to the obvious limitations of human studies, the stage during gestation at which maternal iron deficiency causes an apparent impairment in the offspring remains elusive. In order to begin to understand the time window(s) during pregnancy that is/are especially susceptible to suboptimal iron levels, which may result in negative effects on the development of the fetus, we developed a rat model in which we were able to manipulate and monitor the dietary iron intake during specific stages of pregnancy and analyzed the developing fetuses. We established four different dietary-feeding protocols that were designed to render the fetuses iron deficient at different gestational stages. Based on a functional analysis that employed Auditory Brainstem Response measurements, we found that maternal iron restriction initiated prior to conception and during the first trimester were associated with profound changes in the developing fetus compared to iron restriction initiated later in pregnancy. We also showed that the presence of iron deficiency anemia, low body weight, and changes in core body temperature were not defining factors in the establishment of neural impairment in the rodent offspring

Evaluating the Number of Stages in Development of Squamous Cell and Adenocarcinomas across Cancer Sites Using Human Population-Based Cancer Modeling

BACKGROUND: Adenocarcinomas (ACs) and squamous cell carcinomas (SCCs) differ by clinical and molecular characteristics. We evaluated the characteristics of carcinogenesis by modeling the age patterns of incidence rates of ACs and SCCs of various organs to test whether these characteristics differed between cancer subtypes. METHODOLOGY/PRINCIPAL FINDINGS: Histotype-specific incidence rates of 14 ACs and 12 SCCs from the SEER Registry (1973-2003) were analyzed by fitting several biologically motivated models to observed age patterns. A frailty model with the Weibull baseline was applied to each age pattern to provide the best fit for the majority of cancers. For each cancer, model parameters describing the underlying mechanisms of carcinogenesis including the number of stages occurring during an individual's life and leading to cancer (m-stages) were estimated. For sensitivity analysis, the age-period-cohort model was incorporated into the carcinogenesis model to test the stability of the estimates. For the majority of studied cancers, the numbers of m-stages were similar within each group (i.e., AC and SCC). When cancers of the same organs were compared (i.e., lung, esophagus, and cervix uteri), the number of m-stages were more strongly associated with the AC/SCC subtype than with the organ: 9.79±0.09, 9.93±0.19 and 8.80±0.10 for lung, esophagus, and cervical ACs, compared to 11.41±0.10, 12.86±0.34 and 12.01±0.51 for SCCs of the respective organs (p<0.05 between subtypes). Most SCCs had more than ten m-stages while ACs had fewer than ten m-stages. The sensitivity analyses of the model parameters demonstrated the stability of the obtained estimates. CONCLUSIONS/SIGNIFICANCE: A model containing parameters capable of representing the number of stages of cancer development occurring during individual's life was applied to the large population data on incidence of ACs and SCCs. The model revealed that the number of m-stages differed by cancer subtype being more strongly associated with ACs/SCCs histotype than with organ/site

Versican but not decorin accumulation is related to malignancy in mammographically detected high density and malignant-appearing microcalcifications in non-palpable breast carcinomas

<p>Abstract</p> <p>Background</p> <p>Mammographic density (MD) and malignant-appearing microcalcifications (MAMCs) represent the earliest mammographic findings of non-palpable breast carcinomas. Matrix proteoglycans versican and decorin are frequently over-expressed in various malignancies and are differently involved in the progression of cancer. In the present study, we have evaluated the expression of versican and decorin in non-palpable breast carcinomas and their association with high risk mammographic findings and tumor characteristics.</p> <p>Methods</p> <p>Three hundred and ten patients with non-palpable suspicious breast lesions, detected during screening mammography, were studied. Histological examination was carried out and the expression of decorin, versican, estrogen receptor α (ERα), progesterone receptor (PR) and c-erbB2 (HER-2/neu) was assessed by immunohistochemistry.</p> <p>Results</p> <p>Histological examination showed 83 out of 310 (26.8%) carcinomas of various subtypes. Immunohistochemistry was carried out in 62/83 carcinomas. Decorin was accumulated in breast tissues with MD and MAMCs independently of the presence of malignancy. In contrast, versican was significantly increased only in carcinomas with MAMCs (median ± SE: 42.0 ± 9.1) and MD (22.5 ± 10.1) as compared to normal breast tissue with MAMCs (14.0 ± 5.8), MD (11.0 ± 4.4) and normal breast tissue without mammographic findings (10.0 ± 2.0). Elevated levels of versican were correlated with higher tumor grade and invasiveness in carcinomas with MD and MAMCs, whereas increased amounts of decorin were associated with <it>in situ </it>carcinomas in MAMCs. Stromal deposition of both proteoglycans was related to higher expression of ERα and PR in tumor cells only in MAMCs.</p> <p>Conclusions</p> <p>The specific accumulation of versican in breast tissue with high MD and MAMCs only in the presence of malignant transformation and its association with the aggressiveness of the tumor suggests its possible use as molecular marker in non-palpable breast carcinomas.</p

The Insulin Receptor Substrate 1 (Irs1) in Intestinal Epithelial Differentiation and in Colorectal Cancer

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R. Analysis of IRS1 immunostaining in 24 cases of primary CRC with paired colonic epithelium and hepatic metastasis showed that staining intensity was significantly higher in metastases relative to both primary CRC (P<0.01) and colonic epithelium (P<0.01). Primary and metastatic CRCs, compared to colonic epithelium, contained significantly higher numbers of IRS1-positive cells (P = 0.013 and P = 0.014, respectively). Pathologic correlations in 163 primary CRCs revealed that diffuse IRS1 staining was associated with tumors combining differentiated phenotype and aggressive markers (high Ki67, p53, and ß-catenin). In Caco 2 IRS1 and InsR were maximally expressed after polarization, while IGF1R was highest in pre-polarized cells. No nuclear IRS1 was detected, while, with polarization, phosphorylated IRS1 (pIRS1) shifted from the lateral to the apical plasma membrane and was expressed in surface cells only. In HT29, that carry mutations constitutively activating survival signaling, IRS1 and IGF1R decreased with polarization, while pIRS1 localized in nuclear spots throughout the course. Overall, these data provide evidence that IRS1 is modulated according to CRC differentiation, and support a role of IRS1 in CRC progression and liver metastatization