Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings

High-level microsatellite instability (AISI-H) is demonstrated in 10 to 15% of sporadic colorectal cancers and in most cancers presenting In the inherited condition hereditary nonpolyposis colorectal cancer (HNPCC). Distinction between these categories of MSI-H cancer is of clinical importance and the aim of this study was to assess clinical, pathological, and molecular features that might he discriminatory. One hundred and twelve MSI-H colorectal cancers from families fulfilling the Bethesda criteria were compared with 57 sporadic MSI-H colorectal cancers. HNPCC cancers presented at a lower age (P < 0.001) with no sporadic MSI-H cancer being diagnosed before the age of 57 years. MSI was less extensive in HNPCC cancers with 72% microsatellite markers showing band shifts compared with 87% in sporadic tumors (P < 0.001). Absent immunostaining for hMSH2 was only found in HNPCC tumors. Methylation of bMLH1 was observed in 87% of sporadic cancers but also in 55% of HNPCC tumors that showed loss of expression of hMLH1 (P = 0.02). HNPCC cancers were more frequently characterized by aberrant beta -catenin immunostaining as evidenced by nuclear positivity (P < 0.001). Aberrant p53 immunostaining was infrequent in both groups. There were no differences with respect to 5q loss of heterozygosity or codon 12 K-ras mutation, which were infrequent in both groups. Sporadic MSI-H cancers were more frequently heterogeneous (P < 0.001), poorly differentiated (P = 0.02), mucinous (P = 0.02), and proximally located (P = 0.04) than RNPCC tumors. In sporadic MSI-H cancers, contiguous adenomas were likely to be serrated whereas traditional adenomas were dominant in HNPCC. Lymphocytic infiltration was more pronounced in HNPCC but the results did not reach statistical significance. Overall, HNPCC cancers were more like common colorectal cancer in terms of morphology and expression of beta -catenin whereas sporadic MSI-H cancers displayed features consistent with a different morphogenesis. No individual feature was discriminatory for all RN-PCC cancers. However, a model based on four features was able to classify 94.5% of tumors as sporadic or HNPCC. The finding of multiple differences between sporadic and familial MSI-H colorectal cancer with respect to both genotype and phenotype is consistent with tumorigenesis through parallel evolutionary pathways and emphasizes the importance of studying the two groups separately.

Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status

Background-The presence of high level DNA microsatellite instability (MSI-H) in colorectal cancer is associated with an improved prognosis, as is the presence of tumour infiltrating lymphocytes (TILs). It is not clear if TILs contribute directly to the survival advantage associated with MSI-H cancers through activation of an antitumour immune response. Aims-To correlate TIL and apoptosis rates in colorectal cancer stratified by MSI status. Methods-The distribution of TILs was characterised and quantified in a selected series of 102 sporadic colorectal cancers classified according to levels of MSI as 32 MSI-H, 30 MSI-low (MSI-L), and 40 microsatellite stable (MSS). Archival blocks were immunostained using the T cell markers CD3 and CD8, and the B cell marker CD20. Apoptosis of malignant epithelial cells was quantified by immunohistochemistry with the M30 CytoDEATH antibody. Results-Positive staining with anti-CD3 and negative staining with anti-CD20 identified virtually all TILs as T cells. The majority of CD3(+) TILs (>75%) also stained with anti-CDS. TILs were most abundant in MSI-H colorectal cancers in which 23/32 (72%) scored as TIL positive. Only 5/40 (12.5%) MSS tumours and 9/30 (30%) MSI-L cancers were TIL positive (p

Mice with genetic deletion of the heparin-binding growth factor midkine exhibit early preclinical features of Parkinson`s disease

There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson`s disease (PD) begin many years before the appearance of the characteristic motor symptoms and that impairments in olfactory, cognitive and motor functions are associated with time-dependent disruption of dopaminergic neurotransmission in different brain areas. Midkine is a 13-kDa retinoic acid-induced heparin-binding growth factor involved in many biological processes in the central nervous system such as cell migration, neurogenesis and tissue repair. The abnormal midkine expression may be associated with neurochemical dysfunction in the dopaminergic system and cognitive impairments in rodents. Here, we employed adult midkine knockout mice (Mdk(-/-)) to further investigate the relevance of midkine in dopaminergic neurotransmission and in olfactory, cognitive and motor functions. Mdk(/-) mice displayed pronounced impairments in their olfactory discrimination ability and short-term social recognition memory with no gross motor alterations. Moreover, the genetic deletion of midkine decreased the expression of the enzyme tyrosine hydroxylase in the substantia nigra reducing partially the levels of dopamine and its metabolites in the olfactory bulb and striatum of mice. These findings indicate that the genetic deletion of midkine causes a partial loss of dopaminergic neurons and depletion of dopamine, resulting in olfactory and memory deficits with no major motor impairments. Therefore, Mdk(-/-) mice may represent a promising animal model for the study of the early stages of PD and for testing new therapeutic strategies to restore sensorial and cognitive processes in PD.

Pathologic features of breast cancers in women with previous benign breast disease

To compare pathologic features of the cancers arising after different types of benign breast disease (BBD), we reviewed the invasive breast cancer slides of 169 women with a previous benign biopsy result. Lesions were categorized previously as nonproliferative, proliferative without atypia, or atypical hyperplasia. Pathologic features of the cancers were evaluated without knowledge of the previous BBD category. Estrogen and progesterone receptor immunohistochemistry was performed on available tissue blocks. The median times between a benign result and cancer were 100, 124, and 92 months for women with nonproliferative lesions, proliferative lesions without atypia, and atypical hyperplasia, respectively. Cancers in the 3 groups did not differ significantly in tumor size, axillary lymph node status, or histologic grade, and there was no significant difference in the distribution of histologic types of breast cancer. Lymphatic vessel invasion, extensive intraductal component, and hormone receptor status did not differ among BBD categories. The pathologic features of breast cancers that develop in women with a previous benign biopsy result do not vary according to the histologic category of the previous BBD.

Precipitation hardening of Cu-Fe-Cr alloys - Part II - Microstructural characterisation

This research is part of a project whose scope was to investigate the engineering properties of new non-commercial alloy formulations based on the Cu rich corner of the Cu-Fe-Cr ternary system with the primary aim of exploring the development of a new cost-effective high-strength, high-conductivity copper alloy. Promising properties have been measured for the following alloys: Cu-0.7wt%Cr-0.3wt%Fe and Cu-0.7wt%Cr-2.0wt%Fe. This paper reports on the microstructural characterisation of these alloys and discusses the mechanical and electrical properties of these alloys in terms of their microstructure, particularly the formation of precipitates. These alloys have evinced properties that warrant further investigation. Cost modelling has shown that Cu-0.7wt%Cr-0.3wt%Fe is approximately 25% cheaper to produce than commercial Cu-1%Cr. It has also been shown to be more cost efficient on a yield stress and % IACS per dollar basis. The reason for the cost saving is that the Cu-0.7%Cr-0.3%Fe alloy can be made with low carbon ferro-chrome additions as the source of chromium rather than the more expensive Cu-Cr master-alloy. For applications in which cost is one of the primary materials selection criteria, it is envisaged that there would be numerous applications in both cast and wrought form, where the Cu-0.7%Cr-0.3%Fe alloy would be more suitable than Cu-1%Cr. (C) 2001 Kluwer Academic Publishers.

Nuclear PTEN expression and clinicopathologic features in a population-based series of primary cutaneous melanoma

Germline mutations of the PTEN tumor-suppressor gene, on 10q23, cause Cowden syndrome, an inherited hamartoma syndrome with a high risk of breast, thyroid and endometrial carcinomas and, some suggest, melanoma. To date, most studies which strongly implicate PTEN in the etiology of sporadic melanomas have depended on cell lines, short-term tumor cultures and noncultured metastatic melanomas. The only study which reports PTEN protein expression in melanoma focuses on cytoplasmic expression, mainly in metastatic samples. To determine how PTEN contributes to the etiology or the progression of primary cutaneous melanoma, we examined cytoplasmic and nuclear PTEN expression against clinical and pathologic features in a population-based sample of 150 individuals with incident primary cutaneous melanoma. Among 92 evaluable samples, 30 had no or decreased cytoplasmic PTEN protein expression and the remaining 62 had normal PTEN expression. In contrast, 84 tumors had no or decreased nuclear expression and 8 had normal nuclear PTEN expression. None of the clinical features studied, such as Clark's level and Breslow thickness or sun exposure, were associated with cytoplasmic PTEN expressional levels. An association with loss of nuclear PTEN expression was indicated for anatomical site (p = 0.06) and mitotic index (p = 0.02). There was also an association for melanomas to either not express nuclear PTEN or to express p53 alone, rather than both simultaneously (p = 0.02). In contrast with metastatic melanoma, where we have shown previously that almost two-thirds of tumors have some PTEN inactivation, only one-third of primary melanomas had PTEN silencing. This suggests that PTEN inactivation is a late event likely related to melanoma progression rather than initiation. Taken together with our previous observations in thyroid and islet cell tumors, our data suggest that nuclear-cytoplasmic partitioning of PTEN might also play a role in melanoma progression. (C) 2002 Wiley-Liss, Inc.

Loss of p16 expression is associated with histological features of melanoma invasion

While mutations of CDKN2A are associated with melanoma predisposition, the precise role of its gene product p16 in the development of sporadic melanoma is less clearly understood. We sought to determine the prevalence of p16 expression using immunohistochemical analysis in a population-based sample of melanoma tumours, and also to identify histological, phenotypic and environmental factors associated with the presence or absence of p16 expression. We conducted face-to-face interviews with 108 patients newly diagnosed with melanoma to ascertain their history of sun exposure, and recorded various phenotypic parameters. Paraffin sections of tumours from these patients were stained with an anti-p16 monoclonal antibody following antigen retrieval. Overall, 52 (48%) tumours expressed p16; nodular melanomas had significantly lower levels of p16 immunoreactivity than superficial spreading melanomas (P = 0.015). While no association was found between p16 expression and host phenotype, loss of p16 staining was associated with thicker lesions (p = 0.084) and a high mitotic index (P = 0.013). Taken together, these findings are consistent with loss of p16 being a late event in the progression of sporadic primary melanomas, being associated with tumours of a more aggressive nature. (C) 2002 Lippincott Williams Wilkins.

Investigations of growth processes in Y-Ba-Cu-O materials by microstructural examination of quenched samples

Y-Ba-Cu-O samples with additions of Y2O3 and CeO2 were quenched during seeded isothermal melt processing and examined by optical microscopy and scanning electron microscopy. Large YBa2Cu3O7-y (Y123) particles in the starting powder were found to form a distinct type of melt during heating, which was unaffected by the Y2O3 or CeO2 additives. This type of melt later formed regions with a low concentration of Y2BaCuO5 (Y211) particles in the Y123 matrix. The maximum growth rate of Y123 that could be sustained in the sample was found to be lower in the melt formed from large Y123 particles, and this may lead to growth accidents and subgrains in some samples.

The martensitic transformation in ceramics - its role in transformation toughening

This paper reviews the current knowledge and understanding of martensitic transformations in ceramics - the tetragonal to monoclinic transformation in zirconia in particular. This martensitic transformation is the key to transformation toughening in zirconia ceramics. A very considerable body of experimental data on the characteristics of this transformation is now available. In addition, theoretical predictions can be made using the phenomenological theory of martensitic transformations. As the paper will illustrate, the phenomenological theory is capable of explaining all the reported microstructural and crystallographic features of the transformation in zirconia and in some other ceramic systems. Hence the theory, supported by experiment, can be used with considerable confidence to provide the quantitative data that is essential for developing a credible, comprehensive understanding of the transformation toughening process. A critical feature in transformation toughening is the shape strain that accompanies the transformation. This shape strain, or nucleation strain, determines whether or not the stress-induced martensitic transformation can occur at the tip of a potentially dangerous crack. If transformation does take place, then it is the net transformation strain left behind in the transformed region that provides toughening by hindering crack growth. The fracture mechanics based models for transformation toughening, therefore, depend on having a full understanding of the characteristics of the martensitic transformation and, in particular, on being able to specify both these strains. A review of the development of the models for transformation toughening shows that their refinement and improvement over the last couple of decades has been largely a result of the inclusion of more of the characteristics of the stress-induced martensitic transformation. The paper advances an improved model for the stress-induced martensitic transformation and the strains resulting from the transformation. This model, which separates the nucleation strain from the subsequent net transformation strain, is shown to be superior to any of the constitutive models currently available. (C) 2002 Elsevier Science Ltd. All rights reserved.