Elina Mattila

CIP2A Is Associated with Human Breast Cancer Aggressivity

Purpose: To investigate the clinical relevance of the recently characterized human oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) in human breast cancer. Experimental Design: CIP2A expression (mRNA and protein) was measured in three different sets of human mammary tumors and compared with clinicopathologic variables. The functional role of CIP2A in breast cancer cells was evaluated by small interfering RNA–mediated depletion of the protein followed by an analysis of cell proliferation, migration, anchorage-independent growth, and xenograft growth. Results: CIP2A mRNA is overexpressed (n = 159) and correlates with higher Scarff-Bloom-Richardson grades (n = 251) in samples from two independent human breast cancer patients. CIP2A protein was found to be overexpressed in 39% of 33 human breast cancer samples. Furthermore, CIP2A mRNA expression positively correlated with lymph node positivity of the patients and with the expression of proliferation markers and p53 mutations in the tumor samples. Moreover, CIP2A protein expression was induced in breast cancer mouse models presenting mammary gland–specific depletion of p53 and either BRCA1 or BRCA2. Functionally, CIP2A depletion was shown to inhibit the expression of its target protein c-Myc. Loss of CIP2A also inhibited anchorage-independent growth in breast cancer cells. Finally, CIP2A was shown to support MDA-MB-231 xenograft growth in nude mice. Conclusions: Our data show that CIP2A is associated with clinical aggressivity in human breast cancer and promotes the malignant growth of breast cancer cells. Thus, these results validate the role of CIP2A as a clinically relevant human oncoprotein and warrant further investigation of CIP2A as a therapeutic target in breast cancer treatment. (Clin Cancer Res 2009;15(16):5092–100)

Negative regulation of EGFR signalling through integrin-|[alpha]|1|[beta]|1-mediated activation of protein tyrosine phosphatase TCPTP

Integrin-mediated cell adhesion regulates a multitude of cellular responses, including proliferation, survival and cross-talk between different cellular signalling pathways. So far, integrins have been mainly shown to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signalling. Here we show that a collagen-binding integrin α1β1 functions as a negative regulator of epidermal growth factor receptor (EGFR) signalling through the activation of a protein tyrosine phosphatase. The cytoplasmic tail of α1 integrin selectively interacts with a ubiquitously expressed protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) and activates it after cell adhesion to collagen. The activation results in reduced EGFR phosphorylation after EGF stimulation. Introduction of the α1 cytoplasmic domain peptide into cells induces phosphatase activation and inhibits EGF-induced cell proliferation and anchorage-independent growth of malignant cells. These data are the first demonstration of the regulation of TCPTP activity in vivo and represent a new molecular paradigm of integrin-mediated negative regulation of receptor tyrosine kinase signalling.

Mobile Diary for Wellness Management—Results on Usage and Usability in Two User Studies

The prevalence of lifestyle-related health problems is increasing rapidly. Many of the diseases and health risks could be prevented or alleviated by making changes toward healthier lifestyles. We have developed the Wellness Diary (WD), a concept for personal and mobile wellness management based on Cognitive-Behavioral Therapy (CBT). Two implementations of the concept were made for the Symbian Series 60 (S60) mobile phone platform, and their usability, usage, and acceptance were studied in two 3-month user studies. Study I was related to weight management and study II to general wellness management. In both the studies, the concept and its implementations were well accepted and considered as easy to use and useful in wellness management. The usage rate of the WD was high and sustained at a high level throughout the study. The average number of entries made per day was 5.32 (SD = 2.59, range = 0-14) in study I, and 5.48 (SD = 2.60, range = 0-17) in study II. The results indicate that the WD is well suited for supporting CBT-based wellness management.

Empowering Citizens for Well-being and Chronic Disease Management With Wellness Diary

Chronic conditions closely related to lifestyles are the major cause of disability and death in the developed world. Behavior change is the key to managing well-being and preventing and managing chronic diseases. Wellness diary (WD) is a mobile application designed to support citizens in learning about their behavior, and both making and maintaining behavior changes. WD has been found acceptable, useful, and suitable for long-term use as a part of an intervention. When used independently, however, it does not seem to have enough engaging and motivating features to support adoption and long-term commitment. The main improvement needs identified based on a review of WD-related studies were: personalization of the application to individual needs, increasing motivation during early use, maintaining motivation, and aiding in relapse recovery in long-term use. We present concepts to improve the personalization of WD as well as improvements to the feedback and interpretation of the self-observation data. We also present usage models on how this type of mobile application could be utilized.

The protein tyrosine phosphatase TCPTP controls VEGFR2 signalling

Vascular endothelial growth factor (VEGF) is a major angiogenic factor that triggers formation of new vessels under physiological and pathological conditions. However, the mechanisms that limit the VEGF responses in target cells and hence prevent excessive and harmful angiogenesis are not well understood. Here, our objective was to study whether T-cell protein tyrosine phosphatase (TCPTP, also known as PTN2), which we found to be expressed in human endothelial cells, could alter VEGF signalling by controlling phosphorylation of VEGFR2. We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. We found that TCPTP activity is induced upon integrin-mediated binding of endothelial cells to collagen matrix. TCPTP activation was also induced by using cell-permeable peptides from the cytoplasmic tail of the collagen-binding integrin α1. Controlled activation of TCPTP results in inhibition of VEGF-triggered endothelial cell proliferation, angiogenic sprouting, chemokinesis and chemotaxis. We conclude that matrix-controlled TCPTP phosphatase activity can inhibit VEGFR2 signalling, and the growth, migration and differentiation of human endothelial cells.

Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.

Mobile Mental Wellness Training for Stress Management: Feasibility and Design Implications Based on a One-Month Field Study

Background Prevention and management of work-related stress and related mental problems is a great challenge. Mobile applications are a promising way to integrate prevention strategies into the everyday lives of citizens. Objective The objectives of this study was to study the usage, acceptance, and usefulness of a mobile mental wellness training application among working-age individuals, and to derive preliminary design implications for mobile apps for stress management. Methods Oiva, a mobile app based on acceptance and commitment therapy (ACT), was designed to support active learning of skills related to mental wellness through brief ACT-based exercises in the daily life. A one-month field study with 15 working-age participants was organized to study the usage, acceptance, and usefulness of Oiva. The usage of Oiva was studied based on the usage log files of the application. Changes in wellness were measured by three validated questionnaires on stress, satisfaction with life (SWLS), and psychological flexibility (AAQ-II) at the beginning and at end of the study and by user experience questionnaires after one week’s and one month’s use. In-depth user experience interviews were conducted after one month’s use to study the acceptance and user experiences of Oiva. Results Oiva was used actively throughout the study. The average number of usage sessions was 16.8 (SD 2.4) and the total usage time per participant was 3 hours 12 minutes (SD 99 minutes). Significant pre-post improvements were obtained in stress ratings (mean 3.1 SD 0.2 vs mean 2.5 SD 0.1, P=.003) and satisfaction with life scores (mean 23.1 SD 1.3 vs mean 25.9 SD 0.8, P=.02), but not in psychological flexibility. Oiva was perceived easy to use, acceptable, and useful by the participants. A randomized controlled trial is ongoing to evaluate the effectiveness of Oiva on working-age individuals with stress problems. Conclusions A feasibility study of Oiva mobile mental wellness training app showed good acceptability, usefulness, and engagement among the working-age participants, and provided increased understanding on the essential features of mobile apps for stress management. Five design implications were derived based on the qualitative findings: (1) provide exercises for everyday life, (2) find proper place and time for challenging content, (3) focus on self-improvement and learning instead of external rewards, (4) guide gently but do not restrict choice, and (5) provide an easy and flexible tool for self-reflection.

User experiences of mobile wellness applications in health promotion: User study of Wellness Diary, Mobile Coach and SelfRelax

An ever-increasing number of people are affected by lifestyle-related health risks, such as overweight, physical inactivity and stress. An ongoing Nuadu trial studies the user acceptance and effectiveness of technologies in supporting the wellness management of working-age citizens. The technologies consist of different Web, mobile and wearable solutions. In this paper, we present the user experience results of three mobile wellness applications: the Wellness Diary, Mobile Coach and SelfRelax. We studied their usefulness, perceived usability, usage habits and motivational factors gathered during the first phase of the trial. The data were collected with user experience questionnaires and interviews, as well as actual usage logs from mobile applications. The findings indicate that the usage habits change during the usage period of more than two months towards more practical ways of use. The results also point out several aspects to be considered when developing future wellness applications for long-term use. These are, e.g. adaptability, versatility, guidance and usability.

Methods of Artificial Enlargement of the Training Set for Statistical Shape Models

Due to the small size of training sets, statistical shape models often over-constrain the deformation in medical image segmentation. Hence, artificial enlargement of the training set has been proposed as a solution for the problem to increase the flexibility of the models. In this paper, different methods were evaluated to artificially enlarge a training set. Furthermore, the objectives were to study the effects of the size of the training set, to estimate the optimal number of deformation modes, to study the effects of different error sources, and to compare different deformation methods. The study was performed for a cardiac shape model consisting of ventricles, atria, and epicardium, and built from magnetic resonance (MR) volume images of 25 subjects. Both shape modeling and image segmentation accuracies were studied. The objectives were reached by utilizing different training sets and datasets, and two deformation methods. The evaluation proved that artificial enlargement of the training set improves both the modeling and segmentation accuracy. All but one enlargement techniques gave statistically significantly (p < 0.05) better segmentation results than the standard method without enlargement. The two best enlargement techniques were the nonrigid movement technique and the technique that combines principal component analysis (PCA) and finite element model (FEM). The optimal number of deformation modes was found to be near 100 modes in our application. The active shape model segmentation gave better segmentation accuracy than the one based on the simulated annealing optimization of the model weights.

Feasibility of a Personal Health Technology-Based Psychological Intervention for Men with Stress and Mood Problems: Randomized Controlled Pilot Trial

Background Work-related stress is a significant problem for both people and organizations. It may lead to mental illnesses such as anxiety and depression, resulting in increased work absences and disabilities. Scalable interventions to prevent and manage harmful stress can be delivered with the help of technology tools to support self-observations and skills training. Objective The aim of this study was to assess the feasibility of the P4Well intervention in treatment of stress-related psychological problems. P4Well is a novel intervention which combines modern psychotherapy (the cognitive behavioral therapy and the acceptance and commitment therapy) with personal health technologies to deliver the intervention via multiple channels, includinggroup meetings, Internet/Web portal, mobile phone applications, and personal monitoring devices. Methods This pilot study design was a small-scale randomized controlled trial that compared the P4Well intervention with a waiting list control group. In addition to personal health technologies for self-assessment, the intervention consisted of 3 psychologist-assisted group meetings. Self-assessed psychological measures through questionnaires were collected offline pre- and post-intervention, and 6 months after the intervention for the intervention group. Acceptance and usage of technology tools were measured with user experience questionnaires and usage logs. Results A total of 24 subjects were randomized: 11 participants were followed up in the intervention group (1 was lost to follow-up) and 12 participants did not receive any intervention (control group). Depressive and psychological symptoms decreased and self-rated health and working ability increased. All participants reported they had benefited from the intervention. All technology tools had active users and 10/11 participants used at least 1 tool actively. Physiological measurements with personal feedback were considered the most useful intervention component. Conclusions Our results confirm the feasibility of the intervention and suggest that it had positive effects on psychological symptoms, self-rated health, and self-rated working ability. The intervention seemed to have a positive impact on certain aspects of burnout and job strain, such as cynicism and over-commitment. Future studies need to investigate the effectiveness, benefits, and possible problems of psychological interventions which incorporate new technologies. Trial Registration The Finnish Funding Agency for Technology and Innovation (TEKES), Project number 40011/08