Intragroup contact with other mothers living in the same neighborhood benefits mothers' life satisfaction: The mediating role of group identification and social support.

Becoming a mother is often accompanied by a loss of social connections, which can reduce the availability of social support. This can increase maternal stress with negative health outcomes. Therefore, we examined how mothers' social contact with other mothers living in the same neighborhood can form a compensative source of social support and wellbeing. Data was collected from mothers (N = 443) of a child under school age while visiting the public maternity and child health clinics located in two neighborhoods in Helsinki, Finland. We found that mothers' frequent and positive contact with other local mothers was positively related with their life satisfaction through identification-based social support. Contact also had a specific indirect effect on life satisfaction through social support. Frequent positive contact with other local mothers can serve to scaffold the emergence of social identification, which in turn unlocks further social support with positive health effects.

Who is expected to make contact? Interpretative repertoires related to an intergroup encounter between Finnish majority mothers and immigrant mothers.

Although the benefits of contact for positive intergroup relations are widely acknowledged, less is known about how group members construct the agency and responsibility of contact participants in intergroup encounters. Using critical discursive psychology, we analysed the interpretative repertoires that Finnish majority mothers (N = 13) and mothers with an immigrant background (N = 10) used when talking about a hypothetical intergroup encounter among Finnish and immigrant mothers in a 'family café' (a group for mothers and children). Our analysis identified five interpretative repertoires that differed in terms of the levels of categorization used (individual, group, motherhood) and how agency and responsibility for initiating contact were discursively attributed to the parties in the intergroup encounter. Overall, constructing someone as agentic did not automatically result in their being portrayed as more responsible for making contact. Respondents described contact to occur with only two repertoires, in which both agency and responsibility for initiating contact were discursively attributed to the same party. This highlights the need to consider both agency and sense of responsibility as possible factors preceding intergroup contact.

First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis.

Binding of steroid hormones to their cognate receptors regulates the growth of most prostate and breast cancers. We hypothesized that CYP11A inhibition might halt the synthesis of all steroid hormones, because CYP11A is the only enzyme that catalyses the first step of steroid hormone biosynthesis. We speculated that a CYP11A inhibitor could be administered safely provided that the steroids essential for life are replaced. Virtual screening and systematic structure-activity relationship optimization were used to develop ODM-208, the first-in-class, selective, nonsteroidal, oral CYP11A1 inhibitor. Safety of ODM-208 was assessed in rats and Beagle dogs, and efficacy in a VCaP castration-resistant prostate cancer (CRPC) xenograft mouse model, in mice and dogs, and in six patients with metastatic CRPC. Blood steroid hormone concentrations were measured using liquid chromatography-mass spectrometry. ODM-208 binds to CYP11A1 and inhibited its enzymatic activity. ODM-208 administration led to rapid, complete, durable, and reversible inhibition of the steroid hormone biosynthesis in an adrenocortical carcinoma cell model in vitro, in adult noncastrated male mice and dogs, and in patients with CRPC. All measured serum steroid hormone concentrations reached undetectable levels within a few weeks from the start of ODM-208 administration. ODM-208 was well tolerated with steroid hormone replacement. The toxicity findings were considered related to CYP11A1 inhibition and were reversed after stopping of the compound administration. Steroid hormone biosynthesis can be effectively inhibited with a small-molecule inhibitor of CYP11A1. The findings suggest that administration of ODM-208 is feasible with concomitant corticosteroid replacement therapy.

Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1.

We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropin-treated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.

Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

RGD motifs on the surface of baculovirus enhance transduction of human lung carcinoma cells.

Baculovirus vectors have been shown to enter a variety of mammalian cell lines and gene transfer with wild-type baculovirus (WT) has been demonstrated both in vitro and in vivo. Different protein motifs have been displayed on the viral surface to serve as ligands for cell-specific receptor molecules. We have generated recombinant baculovirus vectors displaying an RGD-motif, recognized by alphaV integrin, on the viral surface. The RGD motifs within the C-terminus of coxsackie virus A9 and human parechovirus 1 VP1 proteins were fused to the N-terminus of the major envelope glycoprotein, gp64, of Autographa californica multiple nucleopolyhedrovirus. The recombinant RGD-presenting viruses bound more efficiently to the surface of human lung carcinoma cells (A549), known to contain alphaV integrins, as compared to WT baculovirus. In addition, the binding pattern of the RGD-displaying baculovirus showed extensive clustering. This most likely represents clustering of the integrin molecules on the cell surface, induced by binding of the RGD-displaying baculovirus. Finally, the transduction efficiency of an RGD-representing virus increased by almost three-fold as monitored by light emission measurements. In conclusion, these results suggest that the RGD-motif is functional on the surface of baculovirus and thereby these tropism-modified viruses bind more efficiently as well as enhance the transduction efficiency of human cancer cells expressing alphaV integrins.

Functional display of an alpha2 integrin-specific motif (RKK) on the surface of baculovirus particles.

The use of baculovirus vectors shows promise as a tool for gene delivery into mammalian cells. These insect viruses have been shown to transduce a variety of mammalian cell lines, and gene transfer has also been demonstrated in vivo. In this study, we generated two recombinant baculovirus vectors displaying an integrin-specific motif, RKK, as a part of two different loops of the green fluorescent protein (GFP) fused with the major envelope protein gp64 of Autographa californica M nucleopolyhedrovirus. By enzyme linked immunosorbent assays, these viruses were shown to bind a peptide representing the receptor binding site of an alpha2 integrin, the alpha2I-domain. However, the interaction was not strong enough to overcome binding of wild type gp64 to the unknown cellular receptor(s) on the surface of alpha2 integrin-expressing cells (CHO-alpha2beta1) or enhance the viral uptake. After treatment of these cells with phospholipase C, internalization of all viruses was blocked or decreased significantly. However, one of the RKK displaying viruses, AcGFP(K)gp64, was still able to internalize into CHO-alpha2beta1 cells, although at a lower level as compared to non-treated cells. This may indicate the possible utilization of a PLC independent alternative route via, in this case, the alpha2beta1 integrin.