An update on breast cancer multigene prognostic tests-emergent clinical biomarkers

Multigene signatures generate crucial prognostic information particularly useful for cancer patients where clinical parameters and traditional immunohistochemical markers alone lead to equivocal prognosis. Clinicians are now provided with molecular tools that assist in the outline of adjuvant therapies, namely helping decide on the extension of adjuvant endocrine therapy or on suppressing adjuvant chemotherapy in patients were toxic effects are particularly deleterious or when this treatment is fundamentally not needed. The importance of cancer multigene prognostic signatures is well elucidated in the guidelines for adjuvant systemic therapy in early-stage breast cancer and the guidelines on disease staging that are progressively integrating gene expression assays as classification biomarkers. In addition to the predictive and prognostic value, some genetic tests provide intrinsic subtyping classification. Herewith, we compare the molecular tests OncotypeDX, MammaPrint, Prosigna, EndoPredict, Breast Cancer Index, Mammostrat, and IHC4 and report the eligibility of each one in the suitable setting. Through to now, there is not a commercially available multigene test that makes recommendations regarding adjuvant treatment for HER-2 and triple negative breast cancers. Thus, these patients still receive adjuvant chemotherapy. Importantly, triple negative carcinomas are very heterogeneous regarding prognosis and new molecular signatures that decipher this very heterogeneous subgroup of breast cancer may improve the clinical management of the disease.AV is a FCT fellow (SFRH/BPD/90303/2012

CDH3 (Cadherin 3, Type 1, P-Cadherin (Placental))

Review on CDH3 (Cadherin 3, Type 1, P-Cadherin (Placental)), with data on DNA, on the protein encoded, and where the gene is implicated

A new method to quantify and compare the multiple components of fitness-A study case with kelp niche partition by divergent microstage adaptations to Temperature

Point 1 Management of crops, commercialized or protected species, plagues or life-cycle evolution are subjects requiring comparisons among different demographic strategies. The simpler methods fail in relating changes in vital rates with changes in population viability whereas more complex methods lack accuracy by neglecting interactions among vital rates. Point 2 The difference between the fitness (evaluated by the population growth rate.) of two alternative demographies is decomposed into the contributions of the differences between the pair-wised vital rates and their interactions. This is achieved through a full Taylor expansion (i.e. remainder = 0) of the demographic model. The significance of each term is determined by permutation tests under the null hypothesis that all demographies come from the same pool. Point 3 An example is given with periodic demographic matrices of the microscopic haploid phase of two kelp cryptic species observed to partition their niche occupation along the Chilean coast. The method provided clear and synthetic results showing conditional differentiation of reproduction is an important driver for their differences in fitness along the latitudinal temperature gradient. But it also demonstrated that interactions among vital rates cannot be neglected as they compose a significant part of the differences between demographies. Point 4 This method allows researchers to access the effects of multiple effective changes in a life-cycle from only two experiments. Evolutionists can determine with confidence the effective causes for changes in fitness whereas population managers can determine best strategies from simpler experimental designs.CONICYT-FRENCH EMBASSADY Ph.D. gran

SRC inhibition prevents P-cadherin mediated signaling and function in basal-like breast cancer cells

BACKGROUND: Basal-like breast cancer (BLBC) is a poor prognosis subgroup of triple-negative carcinomas that still lack specific target therapies and accurate biomarkers for treatment selection. P-cadherin is frequently overexpressed in these tumors, promoting cell invasion, stem cell activity and tumorigenesis by the activation of Src-Family kinase (SRC) signaling. Therefore, our aim was to evaluate if the treatment of BLBC cells with dasatinib, the FDA approved SRC inhibitor, would impact on P-cadherin induced tumor aggressive behavior. METHODS: P-cadherin and SRC expression was evaluated in a series of invasive Breast Cancer and contingency tables and chi-square tests were performed. Cell-cell adhesion measurements were performed by Atomic Force Microscopy, where frequency histograms and Gaussian curves were applied. 2D and 3D cell migration and invasion, proteases secretion and self-renew potential were evaluated in vitro. Student's t-tests were used to determine statistically significant differences. The cadherin/catenin complex interactions were evaluated by in situ proximity-ligation assay, and statistically significant results were determined by using Mann-Whitney test with a Bonferroni correction. In vivo xenograft mouse models were used to evaluate the impact of dasatinib on tumor growth and survival. ANOVA test was used to evaluate the differences in tumor size, considering a confidence interval of 95%. Survival curves were estimated by the Kaplan-Meier's method, using the log-rank test to assess significant differences for mice overall survival. RESULTS: Our data demonstrated that P-cadherin overexpression is significantly associated with SRC activation in breast cancer cells, which was also validated in a large series of primary tumor samples. SRC activity suppression with dasatinib significantly prevented the in vitro functional effects of P-cadherin overexpressing cells, as well as their in vivo tumorigenic and metastatic ability, by increasing mice overall survival. Mechanistically, SRC inhibition affects P-cadherin downstream signaling, rescues the E-cadherin/p120-catenin complex to the cell membrane, recovering cell-cell adhesion function. CONCLUSIONS: In conclusion our findings show that targeting P-cadherin/SRC signaling and functional activity may open novel therapeutic opportunities for highly aggressive and poor prognostic basal-like breast cancer.This work was funded by Laço Grant 2014, by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by FCT - Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Ensino Superior under the projects PTDC/SAU-GMG/120049/ 2010-FCOMP-01-0124-FEDER-021209, PEst-C/SAU/LA0003/2013, NORTE-01- 0145-FEDER-000029 and POCI-01-0145-FEDER-016390. FCT funded the research grants of ASR (SFRH/BPD/75705/2011), ARN (SFRH/BD/100380/2014), BS (SFRH/ BPD/104208/2014), AFV (SFRH/BPD/90303/2012), as well as JP with Programa IFCT 2013 (FCT Investigator). IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274)

3D Activity Recognition using Motion History and Binary Shape Templates

This paper presents our work on activity recognition in 3D depth images. We propose a global descriptor that is accurate, compact and easy to compute as compared to the state-of-the-art for characterizing depth sequences. Activity enactment video is divided into temporally overlapping blocks. Each block (set of image frames) is used to generate Motion History Templates (MHTs) and Binary Shape Templates (BSTs) over three different views - front, side and top. The three views are obtained by projecting each video frame onto three mutually orthogonal Cartesian planes. MHTs are assembled by stacking the difference of consecutive frame projections in a weighted manner separately for each view. Histograms of oriented gradients are computed and concatenated to represent the motion content. Shape information is obtained through a similar gradient analysis over BSTs. These templates are built by overlaying all the body silhouettes in a block, separately for each view. To effectively trace shape-growth, BSTs are built additively along the blocks. Consequently, the complete ensemble of gradient features carries both 3D shape and motion information to effectively model the dynamics of an articulated body movement. Experimental results on 4 standard depth databases (MSR 3D Hand Gesture, MSR Action, Action-Pairs, and UT-Kinect) prove the efficacy as well as the generality of our compact descriptor. Further, we successfully demonstrate the robustness of our approach to (impulsive) noise and occlusion errors that commonly affect depth data

Spectrum of ankylosing spondylitis in Portugal. Development of BASDAI, BASFI, BASMI and mSASSS reference centile charts

The availability of population-specific normative data regarding disease severity measures is essential for patient assessment. The goals of the current study were to characterize the pattern of ankylosing spondylitis (AS) in Portuguese patients and to develop reference centile charts for BASDAI, BASFI, BASMI and mSASSS, the most widely used assessment tools in AS. AS cases were recruited from hospital outpatient clinics, with AS defined according to the modified New York criteria. Demographic and clinical data were recorded. All radiographs were evaluated by two independent experienced readers. Centile charts for BASDAI, BASFI, BASMI and mSASSS were constructed for both genders, using generalized linear models and regression models with duration of disease as independent variable. A total of 369 patients (62.3% male, mean ± (SD) age 45.4 ± 13.2 years, mean ± (SD) disease duration 11.4 ± 10.5 years, 70.7% B27-positive) were included. Family history of AS in a first-degree relative was reported in 17.6% of the cases. Regarding clinical disease pattern, at the time of assessment 42.3% had axial disease, 2.4% peripheral disease, 40.9% mixed disease and 7.1% isolated enthesopatic disease. Anterior uveitis (33.6%) was the most common extra-articular manifestation. The centile charts suggest that females reported greater disease activity and more functional impairment than males but had lower BASMI and mSASSS scores. Data collected through this study provided a demographic and clinical profile of patients with AS in Portugal. The development of centile charts constitutes a useful tool to assess the change of disease pattern over time and in response to therapeutic interventions