Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype

Purpose: To investigate the proportion of breast cancers arising inpatients with germ line BRCA1 and BRCA2 mutations expressing basal markers and developing predictive tests for identification of high-risk patients. Experimental Design: Histopathologic material from 182 tumors in BRCA1 mutation carriers, 63 BRCA2 carriers, and 109 controls, collected as part of the international Breast Cancer Linkage Consortium were immunohistochemically stained for CK14, CK5/6, CK17, epidermal growth factor receptor (EGFR), and osteonectin. Results: All five basal markers were commoner in BRCA1 tumors than in control tumors (CK14: 61% versus 12%; CK5/6: 58% versus 7%; CK17: 53% versus 10%; osteonectin: 43% versus 19%; EGFR: 67% versus 21%; P < 0.0001 in each case). In a multivariate analysis, CK14, CK5/6, and estrogen receptor (ER) remained significant predictors of BRCA1 carrier status. In contrast, the frequency of basal markers in BRCA2 tumors did not differ significant from controls. Conclusion: The use of cytokeratin staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available, that may be useful in selecting patients for BRCA1 mutation testing. The high percentage of BRCA1 cases positive for EGFR suggests that specific anti-tyrosine kinase therapy may be of potential benefit in these patients.

Basal-like breast carcinomas: clinical outcome and response to chemotherapy

Background: Grade-III invasive ductal carcinomas of no special type (IDCs-NST) constitute a heterogeneous group of tumours with different clinical behaviour and response to chemotherapy. As many as 25% of all grade-III IDCs-NST are known to harbour a basal-like phenotype, as defined by gene expression profiling or immunohistochemistry for basal cytokeratins. Patients with basal-like breast carcinomas (BLBC) are reported to have a shorter disease-free and overall survival. Material and methods: A retrospective analysis of 49 patients with BLBC (as defined by basal cytokeratin expression) and 49 controls matched for age, nodal status and grade was carried out. Histological features, immunohistochemical findings for oestrogen receptor (ER), progesterone receptor (PgR) and HER2, and clinical outcome and survival after adjuvant chemotherapy were compared between the two groups. Results: It was more likely for patients with BLBCs to be found negative for ER (p < 0.0001), PgR (p < 0.0001) and HER2 (p < 0.01) than controls. Patients with BLBCs were found to have a significantly higher recurrence rate (p < 0.05) and were associated with significantly shorter disease-free and overall survival (both p, 0.05). In the group of patients who received anthracycline-based adjuvant chemotherapy (BLBC group, n = 47; controls, n = 49), both disease-free and overall survival were found to be significantly shorter in the BLBC group (p < 0.05). Conclusions: BLBCs are a distinct clinical and pathological entity, characterised by high nuclear grade, lack of hormone receptors and HER2 expression and a more aggressive clinical course. Standard adjuvant chemotherapy seems to be less effective in these tumours and new therapeutic approaches are indicated.

Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast

Aims: Cytokeratin (CK) 14, a myoepithelial marker, is also expressed in a proportion of breast carcinomas. There is evidence that these tumours show a differing metastatic pattern and clinical outcome from other invasive ductal carcinomas (IDCs) and may need different management. Currently, they are not identified in routine practice and no morphological guidelines exist to aid their identification. The aim of this study was to analyse the histological features of CK14+ IDC. Methods and results: A detailed histological review of 453 grade 3 IDCs revealed 88 (19.4%) that expressed CK14. Assessment was made independently by two pathologists using a standardized 'tick-box' proforma covering grade, architectural and cytological features. The results were analysed using logistic regression to identify features that predicted for basal phenotype. Concordance between the two pathologists was fair to good for most parameters (kappa 0.4-0.6). On multiple logistic regression, the basal phenotype was highly significantly associated with the presence of a central scar (P = 0.005), tumour necrosis (P < 0.0001), presence of spindle cells (P = 0.006) or squamous metaplasia (P < 0.0001), high total mitotic count (> 40 per 10 high-power field) (P = 0.0002) and high nuclear-cytoplasmic ratio (P = 0.0002). Conclusions: Specific morphological features are strongly associated with basal-like breast carcinoma. These could be used in routine diagnostic practice to identify this important subset of tumours.

Geochronological and structural evolution of the western and central Kaoko Belt in NW Namibia

This thesis focusses on the tectonic evolution and geochronology of part of the Kaoko orogen, which is part of a network of Pan-African orogenic belts in NW Namibia. By combining geochemical, isotopic and structural analysis, the aim was to gain more information about how and when the Kaoko Belt formed. The first chapter gives a general overview of the studied area and the second one describes the basis of the Electron Probe Microanalysis dating method. The reworking of Palaeo- to Mesoproterozoic basement during the Pan-African orogeny as part of the assembly of West Gondwana is discussed in Chapter 3. In the study area, high-grade rocks occupy a large area, and the belt is marked by several large-scale structural discontinuities. The two major discontinuities, the Sesfontein Thrust (ST) and the Puros Shear Zone (PSZ), subdivide the orogen into three tectonic units: the Eastern Kaoko Zone (EKZ), the Central Kaoko Zone (CKZ) and the Western Kaoko Zone (WKZ). An important lineament, the Village Mylonite Zone (VMZ), has been identified in the WKZ. Since plutonic rocks play an important role in understanding the evolution of a mountain belt, zircons from granitoid gneisses were dated by conventional U-Pb, SHRIMP and Pb-Pb techniques to identify different age provinces. Four different age provinces were recognized within the Central and Western part of the belt, which occur in different structural positions. The VMZ seems to mark the limit between Pan-African granitic rocks east of the lineament and Palaeo- to Mesoproterozoic basement to the west. In Chapter 4 the tectonic processes are discussed that led to the Neoproterozoic architecture of the orogen. The data suggest that the Kaoko Belt experienced three main phases of deformation, D1-D3, during the Pan-African orogeny. Early structures in the central part of the study area indicate that the initial stage of collision was governed by underthrusting of the medium-grade Central Kaoko zone below the high-grade Western Kaoko zone, resulting in the development of an inverted metamorphic gradient. The early structures were overprinted by a second phase D2, which was associated with the development of the PSZ and extensive partial melting and intrusion of ~550 Ma granitic bodies in the high-grade WKZ. Transcurrent deformation continued during cooling of the entire belt, giving rise to the localized low-temperature VMZ that separates a segment of elevated Mesoproterozoic basement from the rest of the Western zone in which only Pan-African ages have so far been observed. The data suggest that the boundary between the Western and Central Kaoko zones represents a modified thrust zone, controlling the tectonic evolution of the Kaoko belt. The geodynamic evolution and the processes that generated this belt system are discussed in Chapter 5. Nd mean crustal residence ages of granitoid rocks permit subdivision of the belt into four provinces. Province I is characterised by mean crustal residence ages <1.7 Ga and is restricted to the Neoproterozoic granitoids. A wide range of initial Sr isotopic values (87Sr/86Sri = 0.7075 to 0.7225) suggests heterogeneous sources for these granitoids. The second province consists of Mesoproterozoic (1516-1448 Ma) and late Palaeo-proterozoic (1776-1701 Ma) rocks and is probably related to the Eburnian cycle with Nd model ages of 1.8-2.2 Ga. The eNd i values of these granitoids are around zero and suggest a predominantly juvenile source. Late Archaean and middle Palaeoproterozoic rocks with model ages of 2.5 to 2.8 Ga make up Province III in the central part of the belt and are distinct from two early Proterozoic samples taken near the PSZ which show even older TDM ages of ~3.3 Ga (Province IV). There is no clear geological evidence for the involvement of oceanic lithosphere in the formation of the Kaoko-Dom Feliciano orogen. Chapter 6 presents the results of isotopic analyses of garnet porphyroblasts from high-grade meta-igneous and metasedimentary rocks of the sillimanite-K-feldspar zone. Minimum P-T conditions for peak metamorphism were calculated at 731±10 °C at 6.7±1.2 kbar, substantially lower than those previously reported. A Sm-Nd garnet-whole rock errorchron obtained on a single meta-igneous rock yielded an unexpectedly old age of 692±13 Ma, which is interpreted as an inherited metamorphic age reflecting an early Pan-African granulite-facies event. The dated garnets survived a younger high-grade metamorphism that occurred between ca. 570 and 520 Ma and apparently maintained their old Sm-Nd isotopic systematics, implying that the closure temperature for garnet in this sample was higher than 730 °C. The metamorphic peak of the younger event was dated by electronmicroprobe on monazite at 567±5 Ma. From a regional viewpoint, it is possible that these granulites of igneous origin may be unrelated to the early Pan-African metamorphic evolution of the Kaoko Belt and may represent a previously unrecognised exotic terrane.

GIS analysis of the accuracy of Tomas Lopez's historical cartography in the Canary Islands (1742 - 1746)

The accuracy of Tomás López´s historical cartography of the Canary Islands included in the “Atlas Particular” of the Kingdoms of Spain, Portugal and Adjacent Islands” is analyzed. For this purpose, we propose a methodology based on Geographic Information Systems (GIS), a comparison of digitized historical cartography population centres with current ones. This study shows that the lineal error value is small for the smaller islands: Lanzarote, El Hierro, La Palma and La Gomera. In the large islands of Tenerife, Fuerteventura and Gran Canaria, the error is smaller in central zones but increases towards the coast. This indicates that Tomás López began his cartography starting from central island zones, accumulating errors due to lack of geodetic references as he moved toward the coast.

Evidence formulti-cycle sedimentation and provenance constraints from

Laser ablation ICP-MS U–Pb analyses were conducted on detrital zircons of Triassic sandstone and conglomerate from the Lusitanian basin in order to: i) document the age spectra of detrital zircon; ii) compare U–Pb detrital zircon ages with previous published data obtained from Upper Carboniferous, Ordovician, Cambrian and Ediacaran sedimentary rocks of the pre-Mesozoic basement of western Iberia; iii) discuss potential sources; and iv) test the hypothesis of sedimentary recycling. U–Pb dating of zircons established a maximum depositional age for this deposit as Permian (ca. 296Ma),which is about sixty million years older compared to the fossil content recognized in previous studies (Upper Triassic). The distribution of detrital zircon ages obtained points to common source areas: the Ossa–Morena and Central Iberian zones that outcrop in and close to the Porto–Tomar fault zone. The high degree of immaturity and evidence of little transport of the Triassic sediment suggests that granite may constitute primary crystalline sources. The Carboniferous age of ca. 330 Ma for the best estimate of crystallization for a granite pebble in a Triassic conglomerate and the Permian–Carboniferous ages (ca. 315Ma) found in detrital zircons provide evidence of the denudation of Variscan and Cimmerian granites during the infilling of continental rift basins in western Iberia. The zircon age spectra found in Triassic strata are also the result of recycling from the Upper Carboniferous Buçaco basin,which probably acted as an intermediate sediment repository.U–Pb data in this study suggest that the detritus from the Triassic sandstone and conglomerate of the Lusitanian basin is derived fromlocal source areas with features typical of Gondwana,with no sediment from external sources from Laurussia or southwestern Iberia.

Efecte de la recurrència dels incendis sobre la vegetació i el sòl a les zones de matollar del Macizo Central Ourensano

El matollar sec europeu format per Erica australis, Erica arborea, Pterosparum tridentatum, Halimium lasianthum i Calluna vulgaris com a espècies predominants és cremat en les serralades del Massís Central de forma repetida durant el pas dels anys. Això ha sigut, tradicionalment, a causa de la necessitat de mantenir-lo transitable per al bestiar, encara que altres circumstàncies s’han afegit actualment a aquesta necessitat, que incrementen el risc d’incendi d’aquesta comunitat, disparant-se el número d’incendis en els últims 30 anys. Sabent això, vam decidir realitzar un estudi a les zones de matollar que trobem al Massís Central situat a la zona del Concello de Villariño de Conso, a Ourense, per conèixer com es comporten les espècies característiques d’aquest tipus d’ecosistema després dels incendis, mitjançant la realització de mostrejos i perfils del sòl. D’aquesta manera hem volgut veure com es desenvolupen les espècies vegetals de matollar al llarg del temps, després de ser cremats. Gràcies a l’estudi hem pogut veure com el matollar observat te unes característiques que li permet sobreviure als incendis i tindre una capacitat de regeneració elevada després de patir aquesta pertorbació. Això es degut a la capacitat per rebrotar d’aquestes espècies arbustives i a la seva competitivitat. També hem vist com a necessari, donar un valor econòmic a la bona conservació de l’hàbitat, per tal de que la població local abandoni pràctiques de gestió forestal nocives, com el foc.

Integrated Management for Sustainable Development of Coastal Zones – A Gis Based Study on the Central Kerala Coast

The present study focuses on the stability of the coast, exploitation of the coastal resources, human activities within the study are that extends from Fort Cochin at north to Thottappally at south, central Kerala State and hinterlands, socio-economic problems of the coastal community and the environmental issues arising in the recent past due to human activities. The objective of the study is critically analyse the coastal zone region and prevailing situation and to propose a comprehensive management plan for the sustainable development of the region under study. The thesis covers varied aspects of coastal uses like fisheries, tourism, land use, water resources etc. To critically examine the above scenarios, the ILWIS (Integrated Land and Water Information Systems) – GIS software has been used. A satellite image of the area has been used for the coastline change detection and land use patterns. The outcome of the present study will be beneficial to the various stakeholders within the coastal region and its hinterlands. To further add, this study should find better applications to similar or near-similar situations of Southeast Asia where identical scenarios are noticeable.

Chemical composition and fermentation characteristics of grain and different parts of the stover from maize land races harvested at different growing periods in two zones of central Mexico

The objective of this work was to determine the rumen fermentation characteristics of maize land races used as forage in central Mexico. In vitro gas production (ml per 200 mg dry matter (DM)) incubations were carried out, and cumulative gas volumes were fitted to the Krishnamoorthy et al. (1991) model. The trial used a split-plot design with cultivation practices associated with maize colour (COL) as the main plot with three levels: white, yellow and black maize; growing periods (PER) were the split plots where PER1, PER2 and PER3 represented the first, second and third periods, respectively and two contrasting zones (Z1 = valley and Z2 = mountain) were used as blocking factors. The principal effects observed were associated with the maturity of the plants and potential gas production increased (P < 0.05) in stems (PER 1 = 51.8, PER2 = 56.3, PER3 = 58.4 ml per 200 mg DM) and in whole plant (PER 1 = 60.9, PER2 = 60.8, PER3= 70.9 ml per 200 mg DM). An inverse effect was observed with fermentation rates in leaves (P < 0.01) with 0.061, 0.053 and 0.0509 (per h) and in whole plant (P < 0.05) with 0.068, 0.057, 0.050 (per h) in PER1, PER2 and PER3 respectively. The digestibility of the neutral-detergent fibre (NDF) decreased with maturity especially in leaves (P < 0.05) with values of 0.71, 0.67 and 0.66 g/kg; in rachis (P < 0.01) 0.75, 0.72, and 0.65 in PER1, PER2 and PER3 respectively. The NDF content in leaves in leaves (668, 705 and 713 g/kg DM for PER1, PER2 and PER3, respectively), stems (580, 594 and 644 g/kg DM) and, husk (663, 774 and, 808 g/kg DM) increased (P < 0.05) with increasing plant maturity, rachis were significantly different between periods (P < 0.01). The structure with-the best nutritive characteristics was the husk, because it had the lowest fibre contents, especially in acid-detergent lignin, with values of 22.6, 28.6 and 37.6 g/kg DM in PER1, PER2 and PER3, respectively.

High resolution simulation of the variability of surface energy balance fluxes across central London with urban zones for energy partitioning

The parameterization of surface heat-flux variability in urban areas relies on adequate representation of surface characteristics. Given the horizontal resolutions (e.g. ≈0.1–1km) currently used in numerical weather prediction (NWP) models, properties of the urban surface (e.g. vegetated/built surfaces, street-canyon geometries) often have large spatial variability. Here, a new approach based on Urban Zones to characterize Energy partitioning (UZE) is tested within a NWP model (Weather Research and Forecasting model;WRF v3.2.1) for Greater London. The urban land-surface scheme is the Noah/Single-Layer Urban Canopy Model (SLUCM). Detailed surface information (horizontal resolution 1 km)in central London shows that the UZE offers better characterization of surface properties and their variability compared to default WRF-SLUCM input parameters. In situ observations of the surface energy fluxes and near-surface meteorological variables are used to select the radiation and turbulence parameterization schemes and to evaluate the land-surface scheme

Chemical composition of rocks and minerals from the Central Atlantic fracture zones

The monograph summarizes materials on geology and deep structure of the Central Atlantic fracture zones. These materials have been obtained during eight expeditions of R/V ''Akademik Nikolaj Strakhov''. The studies have been based on the integrated geological approach. As a result, many new tectonic, magmatic, metallogenic and historical-geological features of these phenomenal structures of the deep ocean have been revealed.