Triple negative breast cancer: nanosolutions for a big challenge

Triple negative breast cancer (TNBC) is a particular immunopathological subtype of breast cancer that lacks expression of estrogen and progesterone receptors (ER/PR) and amplification of the human epidermal growth factor receptor 2 (HER2) gene. Characterized by aggressive and metastatic phenotypes and high rates of relapse, TNBC is the only breast cancer subgroup still lacking effective therapeutic options, thus presenting the worst prognosis. The development of targeted therapies, as well as early diagnosis methods, is vital to ensure an adequate and timely therapeutic intervention in patients with TNBC. This review intends to discuss potentially emerging approaches for the diagnosis and treatment of TNBC patients, with a special focus on nano-based solutions that actively target these particular tumors.

Logic programming and artificial neural networks in breast cancer detection

About 90% of breast cancers do not cause or are capable of producing death if detected at an early stage and treated properly. Indeed, it is still not known a specific cause for the illness. It may be not only a beginning, but also a set of associations that will determine the onset of the disease. Undeniably, there are some factors that seem to be associated with the boosted risk of the malady. Pondering the present study, different breast cancer risk assessment models where considered. It is our intention to develop a hybrid decision support system under a formal framework based on Logic Programming for knowledge representation and reasoning, complemented with an approach to computing centered on Artificial Neural Networks, to evaluate the risk of developing breast cancer and the respective Degree-of-Confidence that one has on such a happening.

Exploring female mice interstrain differences relevant for models of depression

Depression is an extremely heterogeneous disorder. Diverse molecular mechanisms have been suggested to underlie its etiology. To understand the molecular mechanisms responsible for this complex disorder, researchers have been using animal models extensively, namely mice from various genetic backgrounds and harboring distinct genetic modifications. The use of numerous mouse models has contributed to enrich our knowledge on depression. However, accumulating data also revealed that the intrinsic characteristics of each mouse strain might influence the experimental outcomes, which may justify some conflicting evidence reported in the literature. To further understand the impact of the genetic background, we performed a multimodal comparative study encompassing the most relevant parameters commonly addressed in depression, in three of the most widely used mouse strains: Balb/c, C57BL/6, and CD-1. Moreover, female mice were selected for this study taken into account the higher prevalence of depression in women and the fewer animal studies using this gender. Our results show that Balb/c mice have a more pronounced anxious-like behavior than CD-1 and C57BL/6 mice, whereas C57BL/6 animals present the strongest depressive-like trait. Furthermore, C57BL/6 mice display the highest rate of proliferating cells and brain-derived neurotrophic factor (Bdnf) expression levels in the hippocampus, while hippocampal dentate granular neurons of Balb/c mice show smaller dendritic lengths and fewer ramifications. Of notice, the expression levels of inducible nitric oxide synthase (iNos) predict 39.5% of the depressive-like behavior index, which suggests a key role of hippocampal iNOS in depression. Overall, this study reveals important interstrain differences in several behavioral dimensions and molecular and cellular parameters that should be considered when preparing and analyzing experiments addressing depression using mouse models. It further contributes to the literature by revealing the predictive value of hippocampal iNos expression levels in depressive-like behavior, irrespectively of the mouse strain.

An interactive web-based tool for breast reduction surgery simulation

In this work, we present a 3D web-based interactive tool for numerical modeling and simulation approach to breast reduction surgery simulation, to assist surgeons in planning all aspects related to breast reduction surgery before the actual procedure takes place, thereby avoiding unnecessary risks. In particular, it allows the modeling of the initial breast geometry, the definition of all aspects related to the surgery and the visualization of the post-surgery breast shape in a realistic environment.

Targeting lactate transport suppresses in vivo breast tumour growth.

BACKGROUND Most cancers, including breast cancer, have high rates of glucose consumption, associated with lactate production, a process referred as "Warburg effect". Acidification of the tumour microenvironment by lactate extrusion, performed by lactate transporters (MCTs), is associated with higher cell proliferation, migration, invasion, angiogenesis and increased cell survival. Previously, we have described MCT1 up-regulation in breast carcinoma samples and demonstrated the importance of in vitro MCT inhibition. In this study, we performed siRNA knockdown of MCT1 and MCT4 in basal-like breast cancer cells in both normoxia and hypoxia conditions to validate the potential of lactate transport inhibition in breast cancer treatment. RESULTS The effect of MCT knockdown was evaluated on lactate efflux, proliferation, cell biomass, migration and invasion and induction of tumour xenografts in nude mice. MCT knockdown led to a decrease in in vitro tumour cell aggressiveness, with decreased lactate transport, cell proliferation, migration and invasion and, importantly, to an inhibition of in vivo tumour formation and growth. CONCLUSIONS This work supports MCTs as promising targets in cancer therapy, demonstrates the contribution of MCTs to cancer cell aggressiveness and, more importantly, shows, for the first time, the disruption of in vivo breast tumour growth by targeting lactate transport.

Joint modelling of longitudinal and survival data on breast cancer

Tese de Doutoramento em Ciências (Especialidade em Matemática)

Female hippocampus vulnerability to environmental stress, a precipitating factor in tau aggregation pathology

Tau-mediated neurodegeneration is a central event in Alzheimer's disease (AD) and other tauopathies. Consistent with suggestions that lifetime stress may be a clinically-relevant precipitant of AD pathology, we previously showed that stress triggers tau hyperphosphorylation and accumulation; however, little is known about the etiopathogenic interaction of chronic stress with other AD risk factors, such as sex and aging. This study focused on how these various factors converge on the cellular mechanisms underlying tau aggregation in the hippocampus of chronically stressed male and female (middle-aged and old) mice expressing the most commonly found disease-associated Tau mutation in humans, P301L-Tau. We report that environmental stress triggers memory impairments in female, but not male, P301L-Tau transgenic mice. Furthermore, stress elevates levels of caspase-3-truncated tau and insoluble tau aggregates exclusively in the female hippocampus while it also alters the expression of the molecular chaperones Hsp90, Hsp70, and Hsp105, thus favoring accumulation of tau aggregates. Our findings provide new insights into the molecular mechanisms through which clinically-relevant precipitating factors contribute to the pathophysiology of AD. Our data point to the exquisite sensitivity of the female hippocampus to stress-triggered tau pathology.

Longitudinal analysis of tumor marker CEA of breast cancer patients from Braga's hospital

Allied to an epidemiological study of population of the Senology Unit of Braga’s Hospital that have been diagnosed with malignant breast cancer, we describe the progression in time of repeated measurements of tumor marker Carcinoembryonic antigen (CEA). Our main purpose is to describe the progression of this tumor marker as a function of possible risk factors and, hence, to understand how these risk factors influences that progression. The response variable, values of CEA, was analyzed making use of longitudinal models, testing for different correlation structures. The same covariates used in a previous survival analysis were considered in the longitudinal model. The reference time used was time from diagnose until death from breast cancer. For diagnostic of the models fitted we have used empirical and theoretical variograms. To evaluate the fixed term of the longitudinal model we have tested for a changing point on the effect of time on the tumor marker progression. A longitudinal model was also fitted only to the subset of patients that died from breast cancer, using the reference time as time from date of death until blood test.

Stage at presentation of breast cancer in Luanda, Angola - a retrospective study

Background: It is expected that, by 2020, 15 million new cases of cancer will occur every year in the world, one million of them in Africa. Knowledge of cancer trends in African countries is far from adequate, and improvements in cancer prevention efforts are urgently needed. The aim of this study was to characterize breast cancer clinically and pathologically at presentation in Luanda, Angola; we additionally provide quality information that will be useful for breast cancer care planning in the country. Methods: Data on breast cancer cases were retrieved from the Angolan Institute of Cancer Control, from 2006 to 2014. For women diagnosed in 2009 (5-years of follow-up), demographic, clinical and pathological information, at presentation, was collected, namely age at diagnosis, parity, methods used for pathological diagnoses, tumor pathological characteristics, stage of disease and treatment. Descriptive statistics were performed. Results: The median age of women diagnosed with breast cancer in 2009 was 47 years old (range 25–89). The most frequent clinical presentation was breast swelling with axillary lymph nodes metastasis (44.9 %), followed by a mass larger than 5 cm (14.2 %) and lump (12.9 %). Invasive ductal carcinoma was the main histologic type (81.8 %). Only 10.1 % of cancer cases had a well differentiated histological grade. Cancers were diagnosed mostly at advanced stages (66.7 % in stage III and 11.1 % in stage IV). Discussion: In this study, breast cancer was diagnosed at a very advanced stage. Although it reports data from a single cancer center in Luanda, Angola it reinforces the need for early diagnosis and increasing awareness. According to the main challenges related to breast cancer diagnosis and treatment herein presented, we propose a realistic framework that would allow for the implementation of a breast cancer care program, built under a strong network based on cooperation, teaching, audit, good practices and the organization of health services. Conclusion: Angola needs urgently a program for early diagnosis of breast cancer.