Prostate cancer-related sexual dysfunction - the significance of social relations in men's reconstructions of masculinity.

Narrating illness experiences in a culturally acceptable manner is essential for retaining quality of life after the disruptive event of being diagnosed for prostate cancer. Psychological pressures caused by treatment side-effects such as erectile dysfunction require reinterpretation of the meanings and impacts of these side-effects on masculinity. This helps maintain coherence in men's lives. We studied how men employ culturally available discursive strategies (compensation, redefinition, recontextualisation, and normalisation) in reconstructing masculinity and sexuality. Our data consists of 22 interviews of heterosexual Finnish prostate cancer patients who had undergone surgery. The aim was to analyse the ways in which various life situations and social relations shaped and limited the use of these strategies. Discourse analysis revealed that older age, a supportive spouse, children, supportive male friends, and good health - were key elements men used in reconstructing a coherent new self-image and conception of life following cancer treatment. Men with sexually active male friends, men without families, younger men and men with new intimate relationships struggled to develop a new version of their masculinity. Being able to effectively utilise certain aspects of one's life situation in re-constructing masculinity is important in maintaining quality of life despite troublesome treatment side-effects.

Missingness in the expanded prostate cancer index short form (EPIC-26) - prevalence, patterns, and explanatory factors.

BACKGROUND: Researchers and clinicians using common clinical assessments need to attend to the prevalence of missing data to ensure the validity of the information gathered. The Expanded Prostate Cancer Index Short Form (EPIC-26) is a commonly used measurement scale used for assessing patients' quality of life, but the measure lacks comprehensive analysis on missing data. We aimed to explore the quantity of missing answers in EPIC-26 and to characterize patterns and possible explanations of missing data in the survey. METHODS: The survey sample consisted of 625 Finnish prostate cancer patients who participated in a study with a 1-year follow-up with three measurement points (0, 6, and 12 months). Descriptive statistics were used to describe the study population and missingness level. A logistic regression was performed for each EPIC domain to study factors related to missingness during the follow-up. RESULTS: Proportions of missing answers in EPIC-26 were low (3.1-3.9%) between survey rounds. As much as 37% of patients left at least one question unanswered during their follow-up. The hormonal domain produced the most missing answers. Questions about breast tenderness/enlargement (question 13.b.), hot flashes (question 13.a.), frequency of erections (question 10.), and ability to reach orgasm (question 8.b.) were most frequently left unanswered. Higher age, lower education level, no relationship, more severe cancer, lower function scores in some EPIC domains, lower treatment satisfaction or self-rated health were associated with missingness. CONCLUSIONS: Questions 13.b. and 13.a. might be considered female-specific symptoms, thus difficult to comprehend unless patients had already experienced side effects from androgen deprivation therapy. Questions 10. and 8.b. might be difficult to answer if the patient has been sexually inactive. To improve the measure's validity, the questionnaire's hormonal section requires additional explanation that the inquired symptoms are common treatment side effects of anti-androgen therapy; questions 8-10 require a not-applicable category for sexually inactive patients.

Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma.

Glioblastomas are aggressive brain tumors that are largely immunotherapy resistant. This is associated with immunosuppression and a dysfunctional tumor vasculature, which hinder T cell infiltration. LIGHT/TNFSF14 can induce high endothelial venules (HEVs) and tertiary lymphoid structures (TLS), suggesting that its therapeutic expression could promote T cell recruitment. Here, we use a brain endothelial cell-targeted adeno-associated viral (AAV) vector to express LIGHT in the glioma vasculature (AAV-LIGHT). We found that systemic AAV-LIGHT treatment induces tumor-associated HEVs and T cell-rich TLS, prolonging survival in αPD-1-resistant murine glioma. AAV-LIGHT treatment reduces T cell exhaustion and promotes TCF1+CD8+ stem-like T cells, which reside in TLS and intratumoral antigen-presenting niches. Tumor regression upon AAV-LIGHT therapy correlates with tumor-specific cytotoxic/memory T cell responses. Our work reveals that altering vascular phenotype through vessel-targeted expression of LIGHT promotes efficient anti-tumor T cell responses and prolongs survival in glioma. These findings have broader implications for treatment of other immunotherapy-resistant cancers.

Inactivation of mouse transmembrane prolyl 4-hydroxylase increases blood brain barrier permeability and ischemia-induced cerebral neuroinflammation.

Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs) regulate the hypoxic induction of >300 genes required for survival and adaptation under oxygen deprivation. Inhibition of HIF-P4H-2 has been shown to be protective in focal cerebral ischemia rodent models, while that of HIF-P4H-1 has no effects and inactivation of HIF-P4H-3 has adverse effects. A transmembrane prolyl 4-hydroxylase (P4H-TM) is highly expressed in the brain and contributes to the regulation of HIF, but the outcome of its inhibition on stroke is yet unknown. To study this, we subjected WT and P4htm-/- mice to permanent middle cerebral artery occlusion (pMCAO). Lack of P4H-TM had no effect on lesion size following pMCAO, but increased inflammatory microgliosis and neutrophil infiltration was observed in the P4htm-/- cortex. Furthermore, both the permeability of blood brain barrier and ultrastructure of cerebral tight junctions were compromised in P4htm-/- mice. At the molecular level, P4H-TM deficiency led to increased expression of proinflammatory genes and robust activation of protein kinases in the cortex, while expression of tight junction proteins and the neuroprotective growth factors erythropoietin and vascular endothelial growth factor was reduced. Our data provide the first evidence that P4H-TM inactivation has no protective effect on infarct size and increases inflammatory microgliosis and neutrophil infiltration in the cortex at early stage after pMCAO. When considering HIF-P4H inhibitors as potential therapeutics in stroke, the current data support that isoenzyme-selective inhibitors that do not target P4H-TM or HIF-P4H-3 would be preferred.

The expanded prostate cancer index composite short form (EPIC-26) for measuring health-related quality of life: content analysis of patients' spontaneous comments written in survey margins.

INTRODUCTION: This study investigates comments that prostate cancer patients spontaneously write in the margins of the Expanded Prostate Cancer Index Short Form (EPIC-26) questionnaire. We aim to show the possible barriers that patients face while answering the survey, and to consider how these barriers may affect the response data generated. We investigate the kind of information patients' comments on EPIC-26 contain, and patients' motivations to provide this information. We also study why some EPIC domains spark more comments than others. METHOD: We analyzed 28 pages of transcribed comments and four pages of supplementary letters from our survey participants (n = 496). Using inductive content analysis, we generated 10 categories describing the content of participants' comments, and four themes demonstrating their motives for commenting. The comments regarding each EPIC domain were quantified to discover any differences between domains. RESULTS: The sexual domain of EPIC-26 provoked over half of all comments. Patients without recent sexual activity or desire had difficulties answering sexual function questions 8-10. The lack of instructions on whether to take erectile aid use into account when answering erectile function questions led to a diversity of answering strategies. Patients with urinary catheters could not find suitable answer options for questions 1-4. All domains sparked comments containing additional information about experienced symptoms. CONCLUSION: Patients are mainly willing to report their symptoms, but a lack of suitable answer options causes missing data and differing answering strategies in the sexual and urinary domains of EPIC-26, weakening the quality of the response data received.

Tertiary Lymphoid Structures in the Central Nervous System: Implications for Glioblastoma.

Glioblastoma is the most common and aggressive brain tumor, which is uniformly lethal due to its extreme invasiveness and the absence of curative therapies. Immune checkpoint inhibitors have not yet proven efficacious for glioblastoma patients, due in part to the low prevalence of tumor-reactive T cells within the tumor microenvironment. The priming of tumor antigen-directed T cells in the cervical lymph nodes is complicated by the shortage of dendritic cells and lack of appropriate lymphatic vessels within the brain parenchyma. However, recent data suggest that naive T cells may also be primed within brain tumor-associated tertiary lymphoid structures. Here, we review the current understanding of the formation of these structures within the central nervous system, and hypothesize that promotion of tertiary lymphoid structures could enhance priming of tumor antigen-targeted T cells and sensitize glioblastomas to cancer immunotherapy.

Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma.

Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.

Perspectives of oncology nurses on peer support for patients with cancer.

PURPOSE: To understand the perspectives of oncology nurses on peer support for patients with cancer and the role of oncology nurses in its provision. METHOD: Thematic semi-structured interviews of 10 oncology nurses working in a single university hospital were conducted. The data were analysed using content analysis. RESULTS: Oncology nurses thought that peer support promotes the psychosocial wellbeing of patients with cancer by increasing their social contact and strengthening their emotional resources. In their daily work, oncology nurses engaged in several activities that promote the interactions between patients with cancer and informal forms of peer support. However, directing patients with cancer to formal peer support services outside specialised health care was not an established practice. Oncology nurses expressed several concerns about the availability of support and the coping ability of peer supporters and expressed scepticism about the reliability of information shared in peer support groups. CONCLUSIONS: The awareness of oncology nurses regarding formal peer support services appears rather limited. This knowledge gap should be reduced, such as through closer collaboration between hospitals and third sector cancer organisations, which does not appear effective at present based on the results. In addition, patients with cancer should be systematically informed about peer support.

Alignments and differentiations: People with illness experiences seeking legitimate positions as health service developers and producers.

Health policies and strategies promote the involvement of people with illness experiences in service development and production, integrating them into settings that have traditionally been domains of health professionals. In this study, we focus on the perspectives of people with personal illness experiences and explore how they justify involvement, position themselves as legitimate actors and forge collaborative relationships with health professionals. We have used discourse analysis in analysing individual interviews conducted with peer support workers and experts by experience (n = 17) who currently work in Finnish health services. The interviewees utilised discourses of empowerment, efficiency and patient-centeredness, aligning themselves with the justifications constructed by patient movements additionally to those found in current health policies. Both groups wanted to retain critical distance from professionals in order to voice criticisms of current care practices, yet they also frequently aligned themselves with professionals in order to gain legitimacy for their involvement. They adopted professional traits that moved them further from being lay participants sharing personal experiences and adopted an expert position. Although national-level policies provided backing and legitimacy for involvement, the lack of local-level guidance could hinder the practical implementation and make involvement largely dependent of professionals' discretion.

Expertise, advocacy and activism: A qualitative study on the activities of prostate cancer peer support workers.

Peer support workers are now working with patients in a variety of settings, coming into close contact and even work alongside health professionals. Despite the potentially influential position peer support workers hold in relation to those engaged in support activities, their role, duties and their relationship to peers and health professionals lack clarity and is often defined by other actors. This study explores how peer support workers interpret and define the activities, responsibilities and knowledge associated with their work. Using methods of membership categorisation analysis, we analysed interview materials generated by conducting individual semi-structured interviews during the autumn of 2016 with prostate cancer peer support workers (n = 11) who currently volunteer as support workers in Finland. Although the peer support workers acknowledged the psychosocial aspects of the work, we argue that their interpretations extend far beyond this and encompass expertise, advocacy and activism as central features of their work. These can be used to strengthen their position as credible commentators and educators on issues relating to cancer and men's health; raise awareness and represent the 'patient's voice' and attempt to influence both policy and clinical practice. These findings suggest that by categorising their work activities in different ways, voluntary sector actors such as peer support workers can attempt to portray themselves as legitimate authorities on a range of issues and influence decision-making ranging from individual level treatment decisions all the way to health policy.

Temporal Dynamics of VEGFA-Induced VEGFR2/FAK Co-Localization Depend on SHB.

Focal adhesion kinase (FAK) is essential for vascular endothelial growth factor-A (VEGFA)/VEGF receptor-2 (VEGFR2)-stimulated angiogenesis and vascular permeability. We have previously noted that presence of the Src homology-2 domain adapter protein B (SHB) is of relevance for VEGFA-stimulated angiogenesis in a FAK-dependent manner. The current study was conducted in order address the temporal dynamics of co-localization between these components in HEK293 and primary lung endothelial cells (EC) by total internal reflection fluorescence microscopy (TIRF). An early (<2.5 min) VEGFA-induced increase in VEGFR2 co-localization with SHB was dependent on tyrosine 1175 in VEGFR2. VEGFA also enhanced SHB co-localization with FAK. FAK co-localization with VEGFR2 was dependent on SHB since it was significantly lower in SHB deficient EC after VEGFA addition. Absence of SHB also resulted in a gradual decline of VEGFR2 co-localization with FAK under basal (prior to VEGFA addition) conditions. A similar basal response was observed with expression of the Y1175F-VEGFR2 mutant in wild type EC. The distribution of focal adhesions in SHB-deficient EC was altered with a primarily perinuclear location. These live cell data implicate SHB as a key component regulating FAK activity in response to VEGFA/VEGFR2.

Practical nursing students' discursive practices on smoking in Finland.

PURPOSE: Based on focus groups, we analyse how practical nursing students deal with being as smokers and future healthcare workers. The way they justify their smoking is discussed within a group of peers. METHODS: The study has a qualitative design with an inductive approach using focus group interviews (FGIs) for data collection. A total of 29 students were interviewed in five groups of five and one group of four participants. RESULTS: In the analysis, we found four different discursive practices the students utilized for rationalizing their own smoking and coping with the moral dilemma of smoking in a context of health care where smoking is forbidden: (1) students normalized smoking with references to its prevalence within their social circles, (2) the students asserted that their smoking was under control, (3) students considered themselves responsible smokers, and (4) students identified smoking as a part of their identity. CONCLUSION: Training should support the growth of professional identity and address the smoker's identity right from the start of education. Smokers need special attention in the formulation of professional identity, however, without being stigmatized any further.

Factors related to self-rated health and life satisfaction one year after radical prostatectomy for localised prostate cancer: a cross-sectional survey.

BACKGROUND: Localised prostate cancer affects patient's quality of life in many ways. The aim of this study was to explore factors related to self-rated health and life satisfaction for patients treated for prostate cancer, and to compare the results of these generic quality-of-life measures to the prostate cancer-specific quality-of-life measure (UCLA Prostate Cancer Index), which focuses on physical functioning. MATERIAL AND METHODS: This cross-sectional survey was carried out among 183 men who underwent radical prostatectomy in 2012-2015 at a university hospital in Finland and were seen 1 year postsurgery. Approval from an ethics committee and written consents from participants were received. A questionnaire was used to evaluate patients' perceived quality of life. Logistic regression model, Spearman's correlation, Kruskal-Wallis test and Mann-Whitney U-test were used to analyse factors related to quality of life. RESULTS: Of the 183 men in the study, 63% rated their health status as good, and 70% were satisfied with their lives after prostatectomy. Older age and better urinary function were the only factors that explained both better self-rated health and better satisfaction with life. The patients seemed not to interpret problems with sexual function as health-related problems. In our sample, sexual dysfunction was relatively severe, but patients considered them to be less harmful than urinary or bowel symptoms. Interestingly, 24% of the men with low sexual function did not find that dysfunction bothersome. CONCLUSIONS: Objectively measured physical functioning is not necessarily in line with patients' experienced satisfaction with life and their self-ratings of health. More longitudinal and qualitative research is needed about the meanings that patients attach to physical treatment side effects and the extent to which they can adapt to them over time. With a bigger sample and longer follow-up time, it would be possible to identify men who particularly benefited from pretreatment counselling.

Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity.

The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and antitumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T-cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and colocalization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG-treated gliomas displayed decreased numbers of IL35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control antitumor immunity. Mol Cancer Ther; 17(9); 1961-72. ©2018 AACR.

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.

Seeking certainty through narrative closure: men's stories of prostate cancer treatments in a state of liminality.

Radical treatments of prostate cancer often lead to a pervasive liminal state that is characterised by multiple uncertainties that relate both to a possible recurrence of cancer and recovery from side effects, such as erectile and urinary dysfunctions. Liminality can make it difficult for cancer patients to narrate their experiences, as their stories lack a definite ending. After interviews with 22 Finnish men who had undergone radical prostatectomy, we analysed how men produce closure in their illness narratives. Focusing on the timelines of control visits or their anticipated recovery from side effects, these interviewees sought provisional certainty within a seemingly chaotic future. By locating erectile dysfunction in the wider context of a life-course and interpreting their fading sexuality as a 'natural' consequence of ageing, these men were adjusting to their post-operative lives. Our study further shows that the inability to adjust personal experiences to positive culturally available storylines that provide a chance for the narrative reconstruction of life, can cause materialised negative consequences, such as relationship breakdowns.

Wnt5a Deficiency Leads to Anomalies in Ureteric Tree Development, Tubular Epithelial Cell Organization and Basement Membrane Integrity Pointing to a Role in Kidney Collecting Duct Patterning.

The Wnts can be considered as candidates for the Congenital Anomaly of Kidney and Urinary Tract, CAKUT diseases since they take part in the control of kidney organogenesis. Of them Wnt5a is expressed in ureteric bud (UB) and its deficiency leads to duplex collecting system (13/90) uni- or bilateral kidney agenesis (10/90), hypoplasia with altered pattern of ureteric tree organization (42/90) and lobularization defects with partly fused ureter trunks (25/90) unlike in controls. The UB had also notably less tips due to Wnt5a deficiency being at E15.5 306 and at E16.5 765 corresponding to 428 and 1022 in control (p<0.02; p<0.03) respectively. These changes due to Wnt5a knock out associated with anomalies in the ultrastructure of the UB daughter epithelial cells. The basement membrane (BM) was malformed so that the BM thickness increased from 46.3 nm to 71.2 nm (p<0.01) at E16.5 in the Wnt5a knock out when compared to control. Expression of a panel of BM components such as laminin and of type IV collagen was also reduced due to the Wnt5a knock out. The P4ha1 gene that encodes a catalytic subunit of collagen prolyl 4-hydroxylase I (C-P4H-I) in collagen synthesis expression and the overall C-P4H enzyme activity were elevated by around 26% due to impairment in Wnt5a function from control. The compound Wnt5a+/-;P4ha1+/- embryos demonstrated Wnt5a-/- related defects, for example local hyperplasia in the UB tree. A R260H WNT5A variant was identified from renal human disease cohort. Functional studies of the consequence of the corresponding mouse variant in comparison to normal ligand reduced Wnt5a-signalling in vitro. Together Wnt5a has a novel function in kidney organogenesis by contributing to patterning of UB derived collecting duct development contributing putatively to congenital disease.

Secreted Wnt antagonist Dickkopf-1 controls kidney papilla development coordinated by Wnt-7b signalling.

Wnt signalling regulates several aspects of kidney development such as nephrogenesis, ureteric bud branching and organisation of the collecting duct cells. We addressed the potential involvement of Dickkopf-1 (Dkk1), a secreted Wnt pathway antagonist. Dkk1 is expressed in the developing mouse kidney by pretubular cell aggregates and the nephrons derived from them. Besides the mesenchyme cells, the epithelial ureteric bud and more mature ureteric bud derivatives in the medulla and the papilla tip express the Dkk1 gene. To reveal the potential roles of Dkk1, we generated a floxed allele and used three Cre lines to inactivate Dkk1 function in the developing kidney. Interestingly, Dkk1 deficiency induced by Pax8Cre in the kidneys led in newborn mice to an overgrown papilla that was generated by stimulated proliferation of the collecting duct and loop of Henle cells, implying a role for Dkk1 in the collecting duct and/or loop of Henle development. Since Pax8Cre-induced Dkk1 deficiency reduced marker gene expression, Scnn1b in the collecting duct and Slc12a1 in the loop of Henle, these results together with the extended papilla phenotype are likely reasons for the decreased amount of ions and urine produced by Dkk1-deficient kidneys in the adult. Recombinant Dkk1 protein in cultured cells inhibited Wnt-7b-induced canonical Wnt signalling, which is critical for collecting duct and loop of Henle development. Moreover, Dkk1 deficiency led to an increase in the expression of canonical Wnt signalling of target Lef-1 gene expression in the stromal cells of the developing papilla. Based on the results, we propose that Dkk1 controls the degree of Wnt-7b signalling in the papilla to coordinate kidney organogenesis.

Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development.

Germ cells are the foundation of an individual, since they generate the gametes and provide the unique genome established through meiosis. The sex-specific fate of the germline in mammals is thought to be controlled by somatic signals, which are still poorly characterized. We demonstrate here that somatic Wnt signalling is crucial for the control of female germline development. Wnt-4 maintains germ cell cysts and early follicular gene expression and provides a female pattern of E-cadherin and beta-catenin expression within the germ cells. In addition, we find that Stra8 expression is downregulated and the Cyp26b1 gene is expressed ectopically in the partially masculinized Wnt-4-deficient ovary. Wnt-4 may control meiosis via these proteins since the Cyp26b1 enzyme is known to degrade retinoic acid (RA) and inhibit meiosis in the male embryo, and Stra8 induces meiosis in the female through RA. Reintroduction of a Wnt-4 signal to the partially masculinized embryonic ovary, in fact, rescues the female property to a certain degree, as seen by inhibition of Cyp26b1 and induction of Irx3 gene expression. Wnt-4 deficiency allows only 20% of the germ cells to initiate meiosis in the ovary, whereas meiosis is inhibited completely in the Wnt-4/Wnt-5a double mutant. These findings indicate a critical role for Wnt signalling in meiosis. Thus, the Wnt signals are important somatic cell signals that coordinate presumptive female follicle development.

The embryonic aorta-gonad-mesonephros region as a generator of haematopoietic stem cells.

During mammalian embryonic development the definitive haematopoietic stem cells (HSCs) may arise either in the extra-embryonic mesoderm or in the aorta-gonad-mesonephros (AGM) region that forms in close proximity to the assembling urogenital system, generating the gonad, cortex of the adrenal gland and metanephros. Researchers have been attempting for a long time to define the region of importance for generating the definitive HSCs that colonize the fetal liver and bone marrow, the two major sites where haematopoiesis takes place in the adult. The fetal liver might gain HSCs from both of the primary haematopoietic sources, but the extra-embryonic HSCs seem not to be able to colonize adult bone marrow directly. It is known that the microenvironment around the HSCs is important for directing cell fates, but we do not yet have much idea about the cell-cell interactions, tissue interactions and molecules that regulate cell behaviour in the AGM. We will here discuss the contribution of the AGM to definitive haematopoiesis in mammals and review some of the cell-cell interactions and associated signalling systems involved in the development of AGM stem cells.