Participative Facility Planning for Obstetrical and Neonatal Care Processes: Beginning of Life Process

Peer reviewe

Children show right-lateralized effects of spoken word-form learning

Peer reviewe

Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements

Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors

Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements

New insights into the molecular mechanisms of ROR1, ROR2, and PTK7 signaling from the proteomics and pharmacological modulation of ROR1 interactome

ROR1, ROR2, and PTK7 are Wnt ligand-binding members of the receptor tyrosine kinase family. Despite their lack of catalytic activity, these receptors regulate skeletal, cardiorespiratory, and neurological development during embryonic and fetal stages. However, their overexpression in adult tissue is strongly connected to tumor development and metastasis, suggesting a strong pharmacological potential for these molecules. Wnt5a ligand can activate these receptors, but lead to divergent signaling and functional outcomes through mechanisms that remain largely unknown. Here, we developed a cellular model by stably expressing ROR1, ROR2, and PTK7 in BaF3 cells that allowed us to readily investigate side-by-side their signaling capability and functional outcome. We applied proteomic profiling to BaF3 clones and identified distinctive roles for ROR1, ROR2, and PTK7 pseudokinases in modulating the expression of proteins involved in cytoskeleton dynamics, apoptotic, and metabolic signaling. Functionally, we show that ROR1 expression enhances cell survival and Wnt-mediated cell proliferation, while ROR2 and PTK7 expression is linked to cell migration. We also demonstrate that the distal C-terminal regions of ROR1 and ROR2 are required for receptors stability and downstream signaling. To probe the pharmacological modulation of ROR1 oncogenic signaling, we used affinity purification coupled to mass spectrometry (AP-MS) and proximity-dependent biotin identification (BioID) to map its interactome before and after binding of GZD824, a small molecule inhibitor previously shown to bind to the ROR1 pseudokinase domain. Our findings bring new insight into the molecular mechanisms of ROR1, ROR2, and PTK7, and highlight the therapeutic potential of targeting ROR1 with small molecule inhibitors binding to its vestigial ATP-binding site.Peer reviewe

Glucocorticoids induce differentiation and chemoresistance in ovarian cancer by promoting ROR1-mediated stemness

Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC.Peer reviewe

Nuorten aikuisten toimintakyvyn väestöryhmittäiset erot

Toimintakyvyn tutkimuksessa tarkastellaan usein ikääntyneiden toimintakykyä, mutta jo nuorilla aikuisilla on havaittavissa toimintakyvyn rajoitteita ja väestöryhmien välisiä eroja toimintakyvyssä. Tutkimuksessa selvitettiin nuorten aikuisten toimintakykyä eri ulottuvuuksilla, toimintakyvyn rajoitteiden kasautumista sekä näiden väestöryhmittäisiä eroja. Aineistona oli Alueellisen terveys- ja hyvinvointitutkimuksen (ATH) 20–34-vuotiaat vastaajat vuosilta 2012 ja 2013 (8070 vastaajaa, vastausprosentti 37). Menetelminä käytettiin ristiintaulukointia, logistista regressioanalyysia, luottamusvälejä ja ikävakiointia. Nuorilla miehillä oli naisia parempi liikkumiskyky. Psyykkisen toimintakyvyn rajoitteet olivat molemmilla sukupuolilla toimintakyvyn ulottuvuuksien rajoitteista yleisimpiä. Sosiaalisen toimintakyvyn rajoitteet olivat miehillä naisia yleisempiä. Työkyvyssä ja päivittäisistä toimista suoriutumisessa ei ollut tilastollisesti merkitseviä eroja miesten ja naisten välillä. Seitsemällä prosentilla vastaajista oli rajoitteita vähintään kolmella viidestä toimintakyvyn ulottuvuudesta. Sekä yksittäisten toimintakyvyn ulottuvuuksien rajoitteet että rajoitteiden kasautuminen olivat yhteydessä vähäiseen koulutukseen ja toimeentulovaikeuksiin. Avioliitossa olevilla rajoitteiden kasautuminen oli muita vähäisempää. Naisilla työllisillä, kotiäideillä ja opiskelijoilla oli toimintakyvyn rajoitteiden kasautumista harvemmin kuin työttömillä ja työvoiman ulkopuolisilla. Vaikka nuorten aikuisten toimintakykyongelmat ovat vielä suhteellisen harvinaisia, on väestöryhmien välillä havaittavissa merkittäviä eroja toimintakyvyssä ja toimintakykyrajoitteiden kasautumista tietyille väestöryhmille. Tulevien vuosien terveys- ja hyvinvointierojen vähentämiseksi nuorten aikuisten toimintakykyerojen kaventamiseen tulisi kiinnittää huomiota. Abstract Socio-demographic differences in functional ability among young adults in Finland Studies concerning functional ability often focus on ageing employees and senior citizens. Nevertheless, limitations in functional ability exist also among young adults and studies has shown that occurrence of limitations might be associated with socio-demographic characteristics. The aim of this study is to examine 1) whether there are limitations in different dimensions of functional ability among young adults in Finland; 2) whether the limitations on several dimensions cumulate on same persons; and 3) whether there are differences between socio-demographic groups regarding functional ability. Data of Regional Health and Wellbeing Study (ATH) 2012-2013 include 8,070 young adults aged 20-34. The response rate was 37%. Analysis methods included cross tabulation, logistic regression analysis and confidence intervals. Age standardization and sample weights were applied. Physical functional ability was better among men than among women. Among both men and women, limitations in psychological functional ability were most common out of all functional dimensions. Limitations in social functional ability were more common among men than women. There were no differences between men and women in ability to work or capacity to perform daily chores. Seven percent of all respondents had limitations on at least three out of five dimensions of functional ability. Both the occurrence and the accumulation of limitations in functional abilities were associated with lower level of education and financial problems. Married respondents were less likely to have accumulations of limitations. Among women, employees, students and housewives had less accumulation of limitations than unemployed women or women outside the labour force. Although limitations of functional ability are relatively rare among young adults, the results show that there are significant differences in both occurrence and accumulation of limitations between socio-demographic groups. It is essential to identify the most vulnerable socio-demographic groups among young adults in order to prevent widening gaps in health and wellbeing in future

Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention

Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-gamma (SNCG), SALL2, and PP1 gamma, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Our phosphoproteomics analyses demonstrated that PTK7 modulates cell adhesion and Rho-GTPase signaling to sustain epithelial-mesenchymal transition (EMT) and cell plasticity, which was confirmed by high-content image analysis of 3D models. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.Peer reviewe