Reduced Androgen Receptor Expression Accelerates the Onset of ERBB2 Induced Breast Tumors in Female Mice

Androgen receptor (AR) is commonly expressed in both the epithelium of normal mammary glands and in breast cancers. AR expression in breast cancers is independent of estrogen receptor alpha (ERα) status and is frequently associated with overexpression of the ERBB2 oncogene. AR signaling effects on breast cancer progression may depend on ERα and ERBB2 status. Up to 30% of human breast cancers are driven by overactive ERBB2 signaling and it is not clear whether AR expression affects any steps of tumor progression in this cohort of patients. To test this, we generated mammary specific Ar depleted mice (MARKO) by combining the floxed allele of Ar with the MMTV-cre transgene on an MMTV-NeuNT background and compared them to littermate MMTV-NeuNT, Arfl/+ control females. Heterozygous MARKO females displayed reduced levels of AR in mammary glands with mosaic AR expression in ductal epithelium. The loss of AR dramatically accelerated the onset of MMTV-NeuNT tumors in female MARKO mice. In this report we show that accelerated MMTV-NeuNT-dependent tumorigenesis is due specifically to the loss of AR, as hormonal levels, estrogen and progesterone receptors expression, and MMTV-NeuNT expression were similar between MARKO and control groups. MMTV-NeuNT induced tumors in both cohorts displayed distinct loss of AR in addition to ERα, PR, and the pioneer factor FOXA1. Erbb3 mRNA levels were significantly elevated in tumors in comparison to normal mammary glands. Thus the loss of AR in mouse mammary epithelium accelerates malignant transformation rather than the rate of tumorigenesis.

Motion Correction Algorithm of Lung Tumors for Respiratory Gated PET Images

Respiratory gating in lung PET imaging to compensate for respiratory motion artifacts is a current research issue with broad potential impact on quantitation, diagnosis and clinical management of lung tumors. However, PET images collected at discrete bins can be significantly affected by noise as there are lower activity counts in each gated bin unless the total PET acquisition time is prolonged, so that gating methods should be combined with imaging-based motion correction and registration methods. The aim of this study was to develop and validate a fast and practical solution to the problem of respiratory motion for the detection and accurate quantitation of lung tumors in PET images. This included: (1) developing a computer-assisted algorithm for PET/CT images that automatically segments lung regions in CT images, identifies and localizes lung tumors of PET images; (2) developing and comparing different registration algorithms which processes all the information within the entire respiratory cycle and integrate all the tumor in different gated bins into a single reference bin. Four registration/integration algorithms: Centroid Based, Intensity Based, Rigid Body and Optical Flow registration were compared as well as two registration schemes: Direct Scheme and Successive Scheme. Validation was demonstrated by conducting experiments with the computerized 4D NCAT phantom and with a dynamic lung-chest phantom imaged using a GE PET/CT System. Iterations were conducted on different size simulated tumors and different noise levels. Static tumors without respiratory motion were used as gold standard; quantitative results were compared with respect to tumor activity concentration, cross-correlation coefficient, relative noise level and computation time. Comparing the results of the tumors before and after correction, the tumor activity values and tumor volumes were closer to the static tumors (gold standard). Higher correlation values and lower noise were also achieved after applying the correction algorithms. With this method the compromise between short PET scan time and reduced image noise can be achieved, while quantification and clinical analysis become fast and precise.

Avaliação da pressão inspiratória nasal sniff na população obesa

Introdução: a avaliação da pressão inspiratória nasal (SNIP) é considerada uma manobra complementar da Pressão Inspiratória Máxima estática (PImax) em várias condições clínicas, porém não há relatos na obesidade. Por outro lado, a obesidade tem um importante impacto nos músculos respiratórios especialmente com maiores gordura abdominal o que provavelmente pode ser detectado na avaliação da SNIP que mensura mais precisamente a pressão diafragmática. Objetivo: analisar em obesos a relação entre SNIP e variáveis respiratórias e marcadores de adiposidade. Material e Método: num estudo transversal um total de 92 obesos (38.3±10.2 anos) sem história de doença respiratória ou cardíaca diagnosticada. Foram avaliados na espirometria (capacidade vital forçada-CVF; volume expiratório forçado no primeiro segundo-VEF1; volume de reserva expiratório-VRE) e pressões respiratórias estática (PImax, PEmax e SNIP) e dinâmica (ventilação voluntária máxima-VVM). Sendo considerados os marcadores de adiposidade: índice de adiposidade corporal-IAC; índice de massa corporal-IMC e circunferências do quadril (CQ), cintura (CC) e pescoço (CP). Resultados: 65 obesos mórbidos (IMC=50.8±8.1Kg/m2) e 27 obesos não mórbidos (IMC=35.6±2.7Kg/m2) foram homogêneos (p>0.05) na SNIP (99.1±24.5cmH2O, 87% do predito) e PImax (107.3±26.4cmH2O, 109% do predito). Existe correlação (r=0.5) entre SNIP e PImax somente no grupo de obesos mórbidos. De acordo com as correlações houve associação entre variáveis respiratórias (CVF r=0.48; VEF1 r=0.54; e VVM r=0.54), valores antropométricos (idade r=-0.44) e SNIP somente para os obesos mórbidos. Esses achados foram certificados quando também comparados a quantidade de gordura ao redor do pescoço (CP≥43cm). O modelo de regressão linear stepwise mostrou que a VVM parece ser o melhor preditor para explicar a SNIP nos obesos mórbidos. Nestes obesos a SNIP foi levemente mais baixa (87%predito) que os valores esperados para indivíduos brasileiros saudáveis. Conclusão: em obesos mórbidos a SNIP é moderadamente relacionada a PImax. A SNIP parece ser mais relacionada a VVM que à marcadores de adiposidade.

Effects of photodynamic therapy with topical and systemic aminolevulinic acid on ultraviolet induced tumors in hairless mice

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development and characterization of long-circulating emulsions to target solid tumors

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development of a novel approach for brain delivery : dendritic nanocarriers for the enhanced delivery of methotrexate to the brain tumors

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Source localization of reaction-diffusion models for brain tumors

We propose a mathematically well-founded approach for locating the source (initial state) of density functions evolved within a nonlinear reaction-diffusion model. The reconstruction of the initial source is an ill-posed inverse problem since the solution is highly unstable with respect to measurement noise. To address this instability problem, we introduce a regularization procedure based on the nonlinear Landweber method for the stable determination of the source location. This amounts to solving a sequence of well-posed forward reaction-diffusion problems. The developed framework is general, and as a special instance we consider the problem of source localization of brain tumors. We show numerically that the source of the initial densities of tumor cells are reconstructed well on both imaging data consisting of simple and complex geometric structures.

Effects of photodynamic therapy with topical and systemic aminolevulinic acid on ultraviolet induced tumors in hairless mice

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development and characterization of long-circulating emulsions to target solid tumors

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Development of a novel approach for brain delivery : dendritic nanocarriers for the enhanced delivery of methotrexate to the brain tumors

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Discerning the sub-phonemic identity of pre-nasal /æ/ in British Columbia English

There are two features of /æ/ in British Columbia (BC) English that are widely attested in the literature: it is undergoing retraction and lowering and it is sensitive to the influence of certain following consonants. The present study aims to utilize both features to evaluate the phonological status of /æ/ before nasal consonants in BC English by examining the progression of sound change and the phonemic organization of /æ/ in different environments. Specifically, production and perception results are taken together to evaluate the phonetic position of pre-nasal /æ/ relative to other environments. These results are interpreted within a modular feedforward architecture of phonology to establish the phonological (allophonic) and phonetic (shallowphonic) rules that govern the internal relationships between the subphonemic elements of /æ/ in BC English. Further, the findings of this study provide evidence for the allophone being the target of sound change, rather than the phoneme.

Synthetic Lethal Targeting of ARID1A-Mutant Ovarian Clear Cell Tumors with Dasatinib

New targeted approaches to ovarian clear cell carcinomas (OCCC) are needed, given the limited treatment options in this disease and the poor response to standard chemotherapy. Using a series of high-throughput cell-based drug screens in OCCC tumor cell models, we have identified a synthetic lethal (SL) interaction between the kinase inhibitor dasatinib and a key driver in OCCC, ARID1A mutation. Imposing ARID1A deficiency upon a variety of human or mouse cells induced dasatinib sensitivity, both in vitro and in vivo, suggesting that this is a robust synthetic lethal interaction. The sensitivity of ARID1A-deficient cells to dasatinib was associated with G₁ -S cell-cycle arrest and was dependent upon both p21 and Rb. Using focused siRNA screens and kinase profiling, we showed that ARID1A-mutant OCCC tumor cells are addicted to the dasatinib target YES1. This suggests that dasatinib merits investigation for the treatment of patients with ARID1Amutant OCCC. Mol Cancer Ther; 15(7); 1472-84. Ó2016 AACR.

Frequency of mutations and polymorphisms in borderline ovarian tumors of known cancer genes.

Borderline ovarian tumors represent an understudied subset of ovarian tumors. Most studies investigating aberrations in borderline tumors have focused on KRAS/BRAF mutations. In this study, we conducted an extensive analysis of mutations and single-nucleotide polymorphisms (SNPs) in borderline ovarian tumors. Using the Sequenom MassArray platform, we investigated 160 mutations/polymorphisms in 33 genes involved in cell signaling, apoptosis, angiogenesis, cell cycle regulation and cellular senescence. Of 52 tumors analyzed, 33 were serous, 18 mucinous and 1 endometrioid. KRAS c.35G>A p.Gly12Asp mutations were detected in eight tumors (six serous and two mucinous), BRAF V600E mutations in two serous tumors, and PIK3CA H1047Y and PIK3CA E542K mutations in a serous and an endometrioid BOT, respectively. CTNNB1 mutation was detected in a serous tumor. Potentially functional polymorphisms were found in vascular endothelial growth factor (VEGF), ABCB1, FGFR2 and PHLPP2. VEGF polymorphisms were the most common and detected at four loci. PHLPP2 polymorphisms were more frequent in mucinous as compared with serous tumors (P=0.04), with allelic imbalance in one case. This study represents the largest and most comprehensive analysis of mutations and functional SNPs in borderline ovarian tumors to date. At least 25% of borderline ovarian tumors harbor somatic mutations associated with potential response to targeted therapeutics.