Expressão imuno-histoquímica do ativador de plasminogênio do tipo uroquinase e seu receptor em carcinoma epidermoide de língua oral e sua relação com parâmetros clínico-patológicos

Squamous cell carcinoma (SCC ) is the most common malignancy of the oral cavity (OSCC), with a high mortality rate. Due to this, the discovery of biomarkers that facilitate the understanding of the biological behavior of the tumor and improve treatment is necessary. Urokinase type plasminogen activator (uPA) and its receptor, uPAR, are responsible for the proteolysis of structures of the basement membrana and extracellular matrix, facilitating tumor invasion. This study aims to assess the immuno expression of these proteins in 46 cases of squamous cell carcinoma of the oral tongue (OTSCC). These results were related to the presence of metastasis, clinical TNM staging, locoregional recurrence, outcome of the lesion and histological grading. Immunostaining of each case was evaluated semiquantitatively, in the front of invasion and center of the tumor, in which scores were assigned: 0 (0% of positive cells), 1 (1-10% of positive cells), 2 (11 -50% positive cells) and 3 (more than 50% positive cells). The expression of uPA was observed in 93.5% (n=43) of the cases in the front of invasion, with predominance of score 2 (n=16; 34.8%) and in 67.9% (n=31) of the cases in the center of the tumor, with predominance of score 1 (n=15; 32.6%). Overall, the immunoexpression of uPA was not associated with clinical parameters. Regarding the malignant histological grading, a higher expression of uPA was observed in cases of high-grade malignancy comp ared to low-grade malignancy (p=0.05). Regarding the morphological parameters, increased expression of uPA was observed in the worst mode of invasion (p=0.03 ). The expression of uPAR was observed in 73.9% of cases in the front of invasion, with a predominance of score 1 (n=21; 45.6 %), and in 47.5% (n=21) of the cases in the center of the tumor, with a predominance of score 0 (n=25; 54.4%). Although no statistical differences were observed in relation to lymph node metastasis, clinical TNM staging, outcome, and histological grading, there was a higher expression of uPAR in cases with locoregional recurrence (p=0.04). Regarding the tumor intra -localization, it was observed an increased expression of uPA and uPAR at the front of invasion in relation to the center of the tumor (p<0.001). Regarding the correlation between uPA and uPAR, there was no statistical sign ificance. Based on these results, it is suggested that uPA and uPAR are involved in the progression of CELO, mainly in the deeper region of the tumor.

Association of the XPD and XRCC3 gene polymorphisms with oral squamous cell carcinoma in a Northeastern Brazilian population: A pilot study

Objective to evaluate the association between XPD and XRCC3 polymorphisms and oral squamous cell carcinoma (OSCC). Design the sample consisted of 54 cases of OSCC and 40 cases of inflammatory fibrous hyperplasia (IFH). Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results XPD-Lys/Gln was more common in IFH (n = 28; 70%) than in OSCC (n = 24; 44.4%) (OR: 0.3; p < 0.05). XPD-Gln was more frequent in high-grade lesions (0.48) than in low-grade lesions (0.21) (OR: 3.4; p < 0.05). The Gln/Gln genotype was associated with III and IV clinical stages (OR: 0.07; p < 0.05). XRCC3-Met was more frequent in OSCC (0.49) than in IFH (0.35) (OR: 2.6; p < 0.05). The Met/Met genotype was associated with the presence of metastases (OR: 8.1; p < 0.05) and with III and IV clinical stages (OR: 0.07; p < 0.05). Conclusions in this sample, the frequency of XPD-Gln in IFH suggests that this variant may protect against OSCC. The presence of the XRCC3-Met allele seems to contribute to the development of OSCC, metastases and more advanced stages in these lesions.

Association of the XPD and XRCC3 gene polymorphisms with oral squamous cell carcinoma in a Northeastern Brazilian population: A pilot study

Objective to evaluate the association between XPD and XRCC3 polymorphisms and oral squamous cell carcinoma (OSCC). Design the sample consisted of 54 cases of OSCC and 40 cases of inflammatory fibrous hyperplasia (IFH). Genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results XPD-Lys/Gln was more common in IFH (n = 28; 70%) than in OSCC (n = 24; 44.4%) (OR: 0.3; p < 0.05). XPD-Gln was more frequent in high-grade lesions (0.48) than in low-grade lesions (0.21) (OR: 3.4; p < 0.05). The Gln/Gln genotype was associated with III and IV clinical stages (OR: 0.07; p < 0.05). XRCC3-Met was more frequent in OSCC (0.49) than in IFH (0.35) (OR: 2.6; p < 0.05). The Met/Met genotype was associated with the presence of metastases (OR: 8.1; p < 0.05) and with III and IV clinical stages (OR: 0.07; p < 0.05). Conclusions in this sample, the frequency of XPD-Gln in IFH suggests that this variant may protect against OSCC. The presence of the XRCC3-Met allele seems to contribute to the development of OSCC, metastases and more advanced stages in these lesions.

Representative analyses of garnet, plagioclase, orthopyroxene, ilmenite, hornblende and biotite for pre-tectonic mafic and metapelitic rocks in Gjelsvikfjella

A metamorphic petrological study, in conjunction with recent precise geochronometric data, revealed a complex P-T-t path for high-grade gneisses in a hitherto poorly understood sector of the Mesoproterozoic Maud Belt in East Antarctica. The Maud Belt is an extensive high-grade, polydeformed, metamorphic belt, which records two significant tectono-thermal episodes, once towards the end of the Mesoproterozoic and again towards the late Neoproterozoic/Cambrian. In contrast to previous models, most of the metamorphic mineral assemblages are related to a Pan-African tectono-thermal overprint, with only very few relics of late Mesoproterozoic granulite-facies mineral assemblages (M1) left in strain-protected domains. Petrological and mineral chemical evidence indicates a clockwise P-T-t path for the Pan-African orogeny. Peak metamorphic (M2b) conditions recorded by most rocks in the area (T = 709-785 °C and P = 7.0-9.5 kbar) during the Pan-African orogeny were attained subsequent to decompression from probably eclogite-facies metamorphic conditions (M2a). The new data acquired in this study, together with recent geochronological and geochemical data, permit the development of a geodynamic model for the Maud Belt that involves volcanic arc formation during the late Mesoproterozoic followed by extension at 1100 Ma and subsequent high-grade tectono-thermal reworking once during continent-continent collision at the end of the Mesoproterozoic (M1; 1090-1030 Ma) and again during the Pan-African orogeny (M2a, M2b) between 565 and 530 Ma. Post-peak metamorphic K-metasomatism under amphibolite-facies conditions (M2c) followed and is ascribed to post-orogenic bimodal magmatism between 500 and 480 Ma.

Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.

High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.

A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells.

Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3+/Nestin+/Sox2+ population lining the fourth ventricle and a Pax3+/NeuN+ parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53(fl/fl) mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67+, Nestin+, Olig2+, and largely GFAP- and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease.

Heavy mineral and bulk mineral compositions of cores from Kumano Basin

Coring during Integrated Ocean Drilling Program Expeditions 315, 316, and 333 recovered turbiditic sands from the forearc Kumano Basin (Site C0002), a Quaternary slope basin (Site C0018), and uplifted trench wedge (Site C0006) along the Kumano Transect of the Nankai Trough accretionary wedge offshore of southwest Japan. The compositions of the submarine turbiditic sands here are investigated in terms of bulk and heavy mineral modal compositions to identify their provenance and dispersal mechanisms, as they may reflect changes in regional tectonics during the past ca. 1.5 Myrs. The results show a marked change in the detrital signature and heavy mineral composition in the forearc and slope basin facies around 1 Ma. This sudden change is interpreted to reflect a major change in the sand provenance, rather than heavy mineral dissolution and/or diagenetic effects, in response to changing tectonics and sedimentation patterns. In the trench-slope basin, the sands older than 1 Ma were probably eroded from the exposed Cretaceous-Tertiary accretionary complex of the Shimanto Belt and transported via the former course of the Tenryu submarine canyon system, which today enters the Nankai Trough northeast of the study area. In contrast, the high abundance of volcanic lithics and volcanic heavy mineral suites of the sands younger than 1 Ma points to a strong volcanic component of sediment derived from the Izu-Honshu collision zones and probably funnelled to this site through the Suruga Canyon. However, sands in the forearc basin show persistent presence of blue sodic amphiboles across the 1 Ma boundary, indicating continuous flux of sediments from the Kumano/Kinokawa River. This implies that the sands in the older turbidites were transported by transverse flow down the slope. The slope basin facies then switched to reflect longitudinal flow around 1 Ma, when the turbiditic sand tapped a volcanic provenance in the Izu-Honshu collision zone, while the sediments transported transversely became confined in the Kumano Basin. Therefore, the change in the depositional systems around 1 Ma is a manifestation of the decoupling of the sediment routing pattern from transverse to long-distance axial flow in response to forearc high uplift along the megasplay fault.

Evaluation of a ToF Camera for Remote Surveying of Underground Cavities Excavated by Jet Boring

Cigar Lake is a high-grade uranium deposit, located in northern Saskatchewan, Canada. In order to extract the uranium ore remotely, thus ensuring minimal radiation dose to workers and also to access the ore from stable ground, the Jet Boring System (JBS) was developed by Cameco Corporation. This system uses a high-powered water jet to remotely excavate cavities. Survey data is required to determine the final shape, volume, and location of the cavity for mine planning purposes and construction. This paper provides an overview of the challenges involved in remotely surveying a JBS-mined cavity and studies the potential use of a time-of-flight (ToF) camera for remote cavity surveying. It reports on data collected and analyzed from inside an experimental environment as well as on real data acquired on site from the Cigar Lake and Rabbit Lake mines.

The Flotation of Niobium Oxide Minerals from Carbonatite Ores

Global niobium production is presently dominated by three operations, Araxá and Catalão (Brazil), and Niobec (Canada). Although Brazil accounts for over 90% of the world’s niobium production, a number of high grade niobium deposits exist worldwide. The advancement of these deposits depends largely on the development of operable beneficiation flowsheets. Pyrochlore, as the primary niobium mineral, is typically upgraded by flotation with amine collectors at acidic pH following a complicated flowsheet with significant losses of niobium. This research compares the typical two stage flotation flowsheet to a direct flotation process (i.e. elimination of gangue pre-flotation) with the objective of circuit simplification. In addition, the use of a chelating reagent (benzohydroxamic acid, BHA) was studied as an alternative collector for fine grained, highly disseminated pyrochlore. For the amine based reagent system, results showed that while comparable at the laboratory scale, when scaled up to the pilot level the direct flotation process suffered from circuit instability because of high quantities of dissolved calcium in the process water due to stream recirculation and fine calcite dissolution, which ultimately depressed pyrochlore. This scale up issue was not observed in pilot plant operation of the two stage flotation process as a portion of the highly reactive carbonate minerals was removed prior to acid addition. A statistical model was developed for batch flotation using BHA on carbonatite ore (0.25% Nb2O5) that could not be effectively upgraded using the conventional amine reagent scheme. Results showed that it was possible to produce a concentrate containing 1.54% Nb2O5 with 93% Nb recovery in ~15% of the original mass. Fundamental studies undertaken included FT-IR and XPS, which showed the adsorption of both the protonized amine and the neutral amine onto the surface of the pyrochlore (possibly at niobium sites as indicated by detected shifts in the Nb3d binding energy). The results suggest that the preferential flotation of pyrochlore over quartz with amines at low pH levels can be attributed to a difference in critical hemimicelle concentration (CHC) values for the two minerals. BHA was found to be absorbed on pyrochlore surfaces by a similar mechanism to alkyl hydroxamic acid. It is hoped that this work will assist in improving operability of existing pyrochlore flotation circuits and help promote the development of niobium deposits globally. Future studies should focus on investigation into specific gangue mineral depressants and inadvertent activation phenomenon related to BHA flotation of gangue minerals.

Heavy Minerals in Soils from the Athabasca Basin and the Implications for Exploration Geochemistry of Uranium Deposits at Depth

The Centennial deposit is a high grade (~8% U3O8), deeply buried (~950m), unconformity-related U deposit located in the south-central region of the Athabasca Basin in northern Saskatchewan, Canada. The mineral chemistry of fine fractions (<63 μm) of soils from grids above the Centennial deposit were examined to understand possible controls on the geochemistry and radiogenic 207Pb/206Pb ratios measured in the clay-size (<2 μm) fractions used for exploration. Soil samples distal and proximal to the deposit projection to the surface and geophysically defined structures were selected. Mineral abundances were determined using the scanning electron microscope and Mineral Liberation Analysis. Zircon was the only U-rich mineral identified with modal abundances >0.02% by weight. Monazite, which can be U-rich, was identified, but not in significant abundances. The source of the zircon and other heavy minerals is interpreted to be from sub-cropping sources that are >100 km up-ice from Centennial. Trace element analysis using laser ablation inductively coupled plasma mass spectrometry of hydroseparated zircon grains indicate that zircon abundances and zircon Pb concentrations in surficial samples have minimal effect on the radiogenic 207Pb/206Pb ratios in the clay-fraction of the samples, with the dominant source of radiogenic Pb being clay mineral surfaces that trapped Pb during secondary dispersion from the Centennial uranium deposit through faults and fractures to the surface. The REE patterns indicate HREE enrichment in the clay-fractions of samples that have higher abundances of zircon in the <20 μm fraction. Immobile elements such as HREE that are concentrated in zircon can be used as indicators of radiogenic Pb being sourced from minerals at the surface rather than being sourced from secondary dispersion from deeply buried U deposits.

Den lilla kemifabriken : En studie för att undersöka om nyttan av skogsrester kan ökas i norra Sveriges inland

The background of this work is to suggest ways to take care of branches and tops of trees that today are left out in the north of Sweden after logging because it has to low value to be worth transporting. A solution to this is to place small chemical factories in the sparsely populated areas in the inland of Norrland that can take care of the forest residues and break it into valuable chemicals directly in the forest an then transport it to a market. The aim of this work was to find out if it´s a good idea to invest in these small chemical factories in the north of Sweden. This study has been carried out using literature study and interviews of key people. The largest part of the result comes from the interviews. The results of this study show that the small chemical factory is a good idea. Forest residues contains many valuable substances that should be greater used today. The results section of the report describes various factor that are crucial for the small chemical factory and these are: the products that can be produced, what technology that is suitable, if there is an market, who should be taking care of the factory and how the inland endurance will be affected. The conclusions that can be drawn from the study is that the small chemical factory should produce high-grade-sary chemicals directed at the chemical market. It may also be noted that there is existing technology that can be used in the factories, what has been done in the laboratories today can be implemented in the factory. The market will obviously depend on which product that will be produces, but finding a suitable market should not be impossible. The inland endurance will be positively impacted, among other things, the social endurance is enhances when these small chemical factories creates job opportunities in the inland and it can lead to decreasing the emigration.

Virtual Clinical Trials in PET Imaging for Improved Diagnosis of and Evaluation of Therapies for Cancer

Thesis (Ph.D.)--University of Washington, 2016-08

CYR61 and TAZ Upregulation and Focal Epithelial to Mesenchymal Transition May Be Early Predictors of Barrett’s Esophagus Malignant Progression

Barrett's esophagus is the major risk factor for esophageal adenocarcinoma. It has a low but non-neglectable risk, high surveillance costs and no reliable risk stratification markers. We sought to identify early biomarkers, predictive of Barrett's malignant progression, using a meta-analysis approach on gene expression data. This in silico strategy was followed by experimental validation in a cohort of patients with extended follow up from the Instituto Português de Oncologia de Lisboa de Francisco Gentil EPE (Portugal). Bioinformatics and systems biology approaches singled out two candidate predictive markers for Barrett's progression, CYR61 and TAZ. Although previously implicated in other malignancies and in epithelial-to-mesenchymal transition phenotypes, our experimental validation shows for the first time that CYR61 and TAZ have the potential to be predictive biomarkers for cancer progression. Experimental validation by reverse transcriptase quantitative PCR and immunohistochemistry confirmed the up-regulation of both genes in Barrett's samples associated with high-grade dysplasia/adenocarcinoma. In our cohort CYR61 and TAZ up-regulation ranged from one to ten years prior to progression to adenocarcinoma in Barrett's esophagus index samples. Finally, we found that CYR61 and TAZ over-expression is correlated with early focal signs of epithelial to mesenchymal transition. Our results highlight both CYR61 and TAZ genes as potential predictive biomarkers for stratification of the risk for development of adenocarcinoma and suggest a potential mechanistic route for Barrett's esophagus neoplastic progression.

Breast Carcinoma with Choriocarcinomatous Differentiation; a Rare Case

Objectives: Breast carcinoma with choriocarcinomatous differentiation is a rare entity, generally presenting with high-grade disease and an aggressive clinical course with overall survival of less than a year Case: A 69-year-old woman with a diagnosis of pT1N0M0 invasive ductal carcinoma with choriocarcinomatous differentiation received six cycles of adjuvant chemotherapy and is still disease free on the 23rd month after diagnosis, showing a better prognosis than most other cases reported in the literature. Conclusion: The reason for the poor prognosis for this type of breast carcinoma remains unclear. Standard chemotherapeutic agents administered for breast carcinoma may be used for choriocarcinomatous differentiation.

16α-[18F]-fluoro-17ß-oestradiol ([18F]FES): A biomarker for imaging oestrogen receptor expression with positron emission tomography (PET)

International audience