Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine.

Over the past decade, our understanding of the diversity of colorectal cancer has expanded significantly, raising hopes of tailoring treatments more precisely for individual patients. A key achievement in this direction was the establishment of the consensus molecular classification, particularly identifying the challenging consensus molecular subtype (CMS) CMS4 associated with poor prognosis. Because of its aggressive nature, extensive research is dedicated to the CMS4 subgroup. Recent years have unveiled molecular and microenvironmental features at the tissue level specific to CMS4 colorectal cancer. This has paved the way for mechanistic studies and the development of preclinical models. Simultaneously, efforts have been made to easily identify patients with CMS4 colorectal cancer. Reassessing clinical trial results through the CMS classification lens has improved our understanding of the therapeutic challenges linked to this subtype. Exploration of the biology of CMS4 colorectal cancer is yielding potential biomarkers and novel treatment approaches. This overview aims to provide insights into the clinico-biological characteristics of the CMS4 subgroup, the molecular pathways driving this subtype, and available diagnostic options. We also emphasize the therapeutic challenges associated with this subtype, offering potential explanations. Finally, we summarize the current tailored treatments for CMS4 colorectal cancer emerging from fundamental and preclinical studies.

Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer.

BACKGROUND: The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. METHODS: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. RESULTS: In silico analyses combined with cell-based assays identified the Wnt-ß-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, ß-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. CONCLUSIONS: An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

DLK1/DIO3 locus upregulation by a ß-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis.

The CTNNB1 gene, encoding ß-catenin, is frequently mutated in hepatocellular carcinoma (HCC, ∼30%) and in hepatoblastoma (HB, >80%), in which DLK1/DIO3 locus induction is correlated with CTNNB1 mutations. Here, we aim to decipher how sustained ß-catenin activation regulates DLK1/DIO3 locus expression and the role this locus plays in HB and HCC development in mouse models deleted for Apc (ApcΔhep) or Ctnnb1-exon 3 (ß-cateninΔExon3) and in human CTNNB1-mutated hepatic cancer cells. We identified an enhancer site bound by TCF-4/ß-catenin complexes in an open conformation upon sustained ß-catenin activation (DLK1-Wnt responsive element [WRE]) and increasing DLK1/DIO3 locus transcription in ß-catenin-mutated human HB and mouse models. DLK1-WRE editing by CRISPR-Cas9 approach impaired DLK1/DIO3 locus expression and slowed tumor growth in subcutaneous CTNNB1-mutated tumor cell grafts, ApcΔhep HB and ß-cateninΔExon3 HCC. Tumor growth inhibition resulted either from increased FADD expression and subsequent caspase-3 cleavage in the first case or from decreased expression of cell cycle actors regulated by FoxM1 in the others. Therefore, the DLK1/DIO3 locus is an essential determinant of FoxM1-dependent cell proliferation during ß-catenin-driven liver tumorigenesis. Targeting the DLK1-WRE enhancer to silence the DLK1/DIO3 locus might thus represent an interesting therapeutic strategy to restrict tumor growth in primary liver cancers with CTNNB1 mutations.

Informal coercion in inpatient mental healthcare: a scoping review protocol.

INTRODUCTION: Comprehending informal coercion, which encompasses a wide range of phenomena characterised by subtle and non-legalised pressures, can be complex. Its use is underestimated within the continuum of coercion in mental health, although its application may have a negative impact on the persons involved. A better understanding of informal coercion is crucial for improving mental healthcare and informing future research. This scoping review aims to explore the nature, extent and consequences of informal coercion in mental health hospitalisation to clarify this phenomenon, establish its boundaries more clearly and identify knowledge gaps. METHODS AND ANALYSIS: Following the methodological framework from the Joanna Briggs Institute, this scoping review will encompass 10 key steps. Literature searches will be conducted in electronic databases, including CINAHL, PubMed, MEDLINE, EMBASE, Web of Science, PsycINFO, and ProQuest Dissertation and Theses. Then, a search in grey literature sources (Open Grey, Grey Guide), psychiatric and mental health journals, government agencies and among the references of selected studies will be conducted. The research will include all literature focusing on informal coercion with inpatients aged 18 and above. Data will be extracted and analysed descriptively, mapping the available knowledge and identifying thematic patterns. The quality of included studies will be assessed using appropriate appraisal tools. An exploratory search was conducted in November 2023 and will be updated in December 2023 when the selection of relevant evidence will begin. ETHICS AND DISSEMINATION: Ethical approval is not required as this study involves the analysis of existing published literature. The findings will be disseminated through a peer-reviewed publication and presentations at relevant conferences. They will be shared with people living with mental disorders and professionals working in mental healthcare.

Fungal antigenic variation using mosaicism and reassortment of subtelomeric genes' repertoires.

Surface antigenic variation is crucial for major pathogens that infect humans. To escape the immune system, they exploit various mechanisms. Understanding these mechanisms is important to better prevent and fight the deadly diseases caused. Those used by the fungus Pneumocystis jirovecii that causes life-threatening pneumonia in immunocompromised individuals remain poorly understood. Here, though this fungus is currently not cultivable, our detailed analysis of the subtelomeric sequence motifs and genes encoding surface proteins suggests that the system involves the reassortment of the repertoire of ca. 80 non-expressed genes present in each strain, from which single genes are retrieved for mutually exclusive expression. Dispersion of the new repertoires, supposedly by healthy carrier individuals, appears very efficient because identical alleles are observed in patients from different countries. Our observations reveal a unique strategy of antigenic variation. They also highlight the possible role in genome rearrangements of small imperfect mirror sequences forming DNA triplexes.

For a better understanding of the relationship between caregivers and young adults living with a concomitant substance-related mental health and substance use disorder: an integrative review / Mieux comprendre la relation entre les intervenants et les jeunes adultes vivant avec un trouble concomitant de santé mentale et lié à l'usage de substances : une revue intégrative des écrits

Introduction: The importance of a quality relationship between young adults living with dual diagnosis and their health care providers is well documented. Context: Although this complex phenomenon was mostly studied from an individual perspective, the results indicated the systemic nature of this relationship. Objective: This study aims to better understand the relationship between young adults living with dual diagnosis and their health care providers, with a systemic perspective. Method: Six data bases were consulted; manual research in gray literature and references screening enhanced the process. Results: Of a total of 532 studies and reports identified, 44 were included in the review. Thematic data analysis was carried out, and two themes were identified: the health care system as a constraining environment; and the relationship at the heart of care. Discussion: This study confirms the joint role played by the young adult in question and their health care provider in developing and maintaining the relationship, by acknowledging the importance of the care, of mutual confidence, and of a hierarchic relationship. Conclusion: This integrative review provides a basis for future nursing interventions that foreground the relationship and take a systemic approach.

Introduction: Plusieurs écrits soulignent l'importance de la qualité de la relation entre de jeunes adultes présentant un trouble concomitant de santé mentale et lié aux substances, et leurs intervenants. Contexte: Ce phénomène complexe a toutefois été étudié surtout dans une perspective individuelle, alors que plusieurs résultats soutiennent le caractère systémique de cette relation. Objectif: Mieux comprendre, selon une perspective systémique, le phénomène de la relation entre ces jeunes adultes et leurs intervenants. Méthode: Une revue intégrative, encadrée par une approche systémique, a été effectuée à partir de six bases de données, d'une recherche manuelle de la littérature grise et d'une vérification des références. Résultats: 532 écrits ont été recensés, et 44 d'entre eux ont servi pour l'analyse thématique qui a fait ressortir deux thèmes : l'environnement contraignant du système de santé et la relation au cœur des soins. Discussion: Cette étude corrobore le rôle conjoint joué par le jeune et l'intervenant dans le développement et le maintien de leur relation, en reconnaissant l'importance des soins, de la confiance réciproque et de la relation hiérarchique. Conclusion: Les résultats peuvent constituer l'assise pour le développement d'interventions infirmières mettant à l'avant-plan la relation selon une perspective systémique.

For a better understanding of the relationship between caregivers and young adults living with a concomitant substance-related mental health and substance use disorder: An integrative review / Mieux comprendre la relation entre les intervenants et les jeunes adultes vivant avec un trouble concomitant de santé mentale et lié à l'usage de substances : une revue intégrative des écrits

INTRODUCTION: The importance of a quality relationship between young adults living with dual diagnosis and their health care providers is well documented. CONTEXT: Although this complex phenomenon was mostly studied from an individual perspective, the results indicated the systemic nature of this relationship. OBJECTIVE: This study aims to better understand the relationship between young adults living with dual diagnosis and their health care providers, with a systemic perspective. METHOD: Six data bases were consulted; manual research in gray literature and references screening enhanced the process. RESULTS: Of a total of 532 studies and reports identified, 44 were included in the review. Thematic data analysis was carried out, and two themes were identified: the health care system as a constraining environment; and the relationship at the heart of care. DISCUSSION: This study confirms the joint role played by the young adult in question and their health care provider in developing and maintaining the relationship, by acknowledging the importance of the care, of mutual confidence, and of a hierarchic relationship. CONCLUSION: This integrative review provides a basis for future nursing interventions that foreground the relationship and take a systemic approach.

Introduction: Plusieurs écrits soulignent l'importance de la qualité de la relation entre de jeunes adultes présentant un trouble concomitant de santé mentale et lié aux substances, et leurs intervenants. Contexte : ce phénomène complexe a toutefois été étudié surtout dans une perspective individuelle, alors que plusieurs résultats soutiennent le caractère systémique de cette relation. Objectif: Mieux comprendre, selon une perspective systémique, le phénomène de la relation entre ces jeunes adultes et leurs intervenants. Méthode: Une revue intégrative, encadrée par une approche systémique, a été effectuée à partir de six bases de données, d'une recherche manuelle de la littérature grise et d'une vérification des références. Résultats: 532 écrits ont été recensés, et 44 d'entre eux ont servi pour l'analyse thématique qui a fait ressortir deux thèmes : l'environnement contraignant du système de santé et la relation au cœur des soins. Discussion: Cette étude corrobore le rôle conjoint joué par le jeune et l'intervenant dans le développement et le maintien de leur relation, en reconnaissant l'importance des soins, de la confiance réciproque et de la relation hiérarchique. Conclusion: Les résultats peuvent constituer l'assise pour le développement d'interventions infirmières mettant à l'avant-plan la relation selon une perspective systémique.

Downregulation of mitochondrial complex I induces ROS production in colorectal cancer subtypes that differently controls migration.

BACKGROUND: Colorectal cancer (CRC) can be classified into four molecular subtypes (CMS) among which CMS1 is associated with the best prognosis, while CMS4, the mesenchymal subtype, has the worst outcome. Although mitochondria are considered to be hubs of numerous signaling pathways, the study of mitochondrial metabolism has been neglected for many years. Mitochondrial Complex I (CI) plays a dual role, both in energy and reactive oxygen species (ROS) production. However, the possible contribution of CI to tumorigenesis in cancer remains unclear. The purpose of this study was to investigate the CI under the prism of the CMS classification of CRC in ex vivo models. METHODS: Biochemical dosages, bioenergetics analysis and western-blot were used to characterize CI expression, function and redox balance in LoVo and MDST8 cell lines, belonging to CMS1 and CMS4 subgroups, respectively. Cell proliferation and migration were assessed by xCELLigence technology. Overproduction or scavenging of mitochondrial ROS (mtROS) were performed to analyze the effect of mtROS on proliferation, migration, and mesenchymal markers. Focal adhesion kinase (FAK) and its activation were analyzed by immunofluorescence. We assessed the distribution of two CI scores in CRC cohorts according to CMS classification and their relevance for patient survival. RESULTS: We found that CI is downregulated in CMS4 cells and is associated with elevated mtROS. We establish for the first time that in these migrating cells, mtROS production is maintained at optimal levels not only through changes in CI activity but also by inactivation/acetylation of superoxide dismutase 2 (SOD2), a major mitochondrial antioxidant enzyme. We show that promoting or scavenging mtROS both mitigate CMS4 cells' migration. Our results also point to a mtROS-mediated focal adhesion kinase (FAK) activation, which likely sustains their migratory phenotype. Using cohorts of CRC patients, we document that the expression of CI is downregulated in the CMS4 subgroup, and that low CI expression is associated with poor prognosis. Patients' datasets reveal an inverse correlation between CI and the epithelial-mesenchymal transition (EMT) pathway. CONCLUSION: We showed that inhibition of CI contributes to heighten mtROS, which likely foster MDST8 migration and might account for the specific EMT signature of CMS4 tumors. These data reveal a novel role of mitochondrial CI in CRC, with biological consequences that may be targeted with anti- or pro-oxidant drugs in clinical practice.

Family Resilience as an Emerging Concept in Neonatology: Evidence From a Metasummary Review.

BACKGROUND: Family resilience can be observed through specific resilience-promoting processes, namely, shared belief systems, communication, and organizational processes, but the concept remains mostly unstudied in neonatology. This metasummary aims to evaluate the frequency of family resilience processes in qualitative scientific literature to illustrate how family resilience is exhibited in the neonatal intensive care unit (NICU) setting. METHODS: A search among 4 databases yielded 7029 results, which were reviewed for inclusion. Following Sandelowski and Barroso's qualitative metasummary method, findings from each study were independently coded and frequency effect size was calculated. RESULTS: Forty-six primary qualitative studies published between 2016 and 2022 conducted with parents of preterm infants who discussed their NICU hospitalization experience were included in this metasummary. All 9 of Walsh's family resilience processes were identified in the literature, and their frequency effect size ranged from 4% to 91%. Four additional themes emerged pertaining to specific family resilience behaviors exhibited by NICU families. CONCLUSION: This analysis sheds new light on the most recent qualitative evidence of parents' experiences in the NICU by analyzing it through the lens of family resilience and posits family resilience as a promising concept in relation to the predominance of the family-centered care philosophy in neonatal units.

Transcriptomic Signatures of MSI-High Metastatic Colorectal Cancer Predict Efficacy of Immune Checkpoint Inhibitors.

PURPOSE: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10% to 40% of patients with MSI mCRC will experience a primary resistance to ICI. EXPERIMENTAL DESIGN: In two cohorts of patients with MSI mCRC treated with ICI (exploratory, N = 103; validation, N = 35), 3' RNA sequencing was performed from primary tumors. Previously described single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. RESULTS: In the exploratory cohort, the unsupervised clustering allowed the identification of three clusters of tumors with distinct transcriptional profiles: cluster A ("stromalHIGH-proliferationLOW"), cluster B ("stromalHIGH-proliferationMED"), and cluster C ("stromalLOW-proliferationHIGH"), with an enrichment of patients progressing at first disease assessment under ICI in cluster A (30% vs. 12% in cluster B and 8.1% in cluster C; P = 0.074). Progression-free survival (PFS) was also significantly shorter in patients belonging to cluster A, compared with clusters B or C (P < 0.001) with 2-year PFS rates of 33.5%, 80.5%, and 78.3%, respectively. In multivariate analysis, PFS was still significantly longer in patients belonging to cluster B [HR, 0.19; 95% confidence interval (CI), 0.08-0.45; P < 0.001] and cluster C (HR, 0.25; 95% CI, 0.10-0.59; P = 0.02), compared with patients belonging to cluster A. The association of this clustering with PFS under ICI was confirmed in the validation cohort. PFS related to non-ICI-based regimens was not significantly different according to cluster. CONCLUSIONS: This unsupervised transcriptomic classification identified three groups of MSI mCRCs with different compositions of TME cells and proliferative capacities of TME/tumor cells. The "stromalHIGH-proliferationLOW" cluster is associated with a poorer prognosis with ICI treatment.

New hormone receptor-positive breast cancer mouse cell line mimicking the immune microenvironment of anti-PD-1 resistant mammary carcinoma.

BACKGROUND: Progress in breast cancer (BC) research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best studied mouse strain, C57BL/6, is also the only one for which multiple genetic variants are available to facilitate the exploration of the cancer-immunity dialog. Driven by the fact that no hormone receptor-positive (HR+) C57BL/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. METHODS: BC was induced in female C57BL/6 mice using a synthetic progesterone analog (medroxyprogesterone acetate, MPA) combined with a DNA damaging agent (7,12-dimethylbenz[a]anthracene, DMBA). Cell lines were established from these tumors and selected for dual (estrogen+progesterone) receptor positivity, as well as transplantability into C57BL/6 immunocompetent females. RESULTS: One cell line, which we called B6BC, fulfilled these criteria and allowed for the establishment of invasive estrogen receptor-positive (ER+) tumors with features of epithelial to mesenchymal transition that were abundantly infiltrated by myeloid immune populations but scarcely by T lymphocytes, as determined by single-nucleus RNA sequencing and high-dimensional leukocyte profiling. Such tumors failed to respond to programmed cell death-1 (PD-1) blockade, but reduced their growth on treatment with ER antagonists, as well as with anthracycline-based chemotherapy, which was not influenced by T-cell depletion. Moreover, B6BC-derived tumors reduced their growth on CD11b blockade, indicating tumor sustainment by myeloid cells. The immune environment and treatment responses recapitulated by B6BC-derived tumors diverged from those of ER+ TS/A cell-derived tumors in BALB/C mice, and of ER- E0771 cell-derived and MPA/DMBA-induced tumors in C57BL/6 mice. CONCLUSIONS: B6BC is the first transplantable HR+ BC cell line derived from C57BL/6 mice and B6BC-derived tumors recapitulate the complex tumor microenvironment of locally advanced HR+ BC naturally resistant to PD-1 immunotherapy.

Poloxamers Have Vaccine-Adjuvant Properties by Increasing Dissemination of Particulate Antigen at Distant Lymph Nodes.

Vaccine technology is still facing challenges regarding some infectious diseases, which can be addressed by innovative drug delivery systems. In particular, nanoparticle-based vaccines combined with new types of adjuvants are actively explored as a platform for improving the efficacy and durability of immune protection. Here, biodegradable nanoparticles carrying an antigenic model of HIV were formulated with two combinations of poloxamers, 188/407, presenting or not presenting gelling properties, respectively. The study aimed to determine the influence of poloxamers (as a thermosensitive hydrogel or a liquid solution) on the adaptive immune response in mice. The results showed that poloxamer-based formulations were physically stable and did not induce any toxicity using a mouse dendritic cell line. Then, whole-body biodistribution studies using a fluorescent formulation highlighted that the presence of poloxamers influenced positively the dissemination profile by dragging nanoparticles through the lymphatic system until the draining and distant lymph nodes. The strong induction of specific IgG and germinal centers in distant lymph nodes in presence of poloxamers suggested that such adjuvants are promising components in vaccine development.

A novel Chr1-miR-200 driven whole transcriptome signature shapes tumor immune microenvironment and predicts relapse in early-stage lung adenocarcinoma.

BACKGROUND: In Lung adenocarcinoma (LUAD), targeted therapies and immunotherapies have moved from metastatic to early stage and stratification of the relapse risk becomes mandatory. Here we identified a miR-200 based RNA signature that delineates Epithelial-to-mesenchymal transition (EMT) heterogeneity and predicts survival beyond current classification systems. METHODS: A miR-200 signature was identified using RNA sequencing. We scored the miR-200 signature by WISP (Weighted In Silico Pathology), used GSEA to identify pathway enrichments and MCP-counter to characterize immune cell infiltrates. We evaluate the clinical value of this signature in our series of LUAD and using TCGA and 7 published datasets. RESULTS: We identified 3 clusters based on supervised classification: I is miR-200-sign-down and enriched in TP53 mutations IIA and IIB are miR-200-sign-up: IIA is enriched in EGFR (p < 0.001), IIB is enriched in KRAS mutation (p < 0.001). WISP stratified patients into miR-200-sign-down (n = 65) and miR-200-sign-up (n = 42). Several biological processes were enriched in MiR-200-sign-down tumors, focal adhesion, actin cytoskeleton, cytokine/receptor interaction, TP53 signaling and cell cycle pathways. Fibroblast, immune cell infiltration and PDL1 expression were also significantly higher suggesting immune exhaustion. This signature stratified patients into high-vs low-risk groups, miR-200-sign-up had higher DFS, median not reached at 60 vs 41 months and within subpopulations with stage I, IA, IB, or II. Results were validated on TCGA data on 7 public datasets. CONCLUSION: This EMT and miR-200-related prognostic signature refines prognosis evaluation independently of tumor stage and paves the way towards assessing the predictive value of this LUAD clustering to optimize perioperative treatment.

Intratumor heterogeneity and cell secretome promote chemotherapy resistance and progression of colorectal cancer.

The major underlying cause for the high mortality rate in colorectal cancer (CRC) relies on its drug resistance, to which intratumor heterogeneity (ITH) contributes substantially. CRC tumors have been reported to comprise heterogeneous populations of cancer cells that can be grouped into 4 consensus molecular subtypes (CMS). However, the impact of inter-cellular interaction between these cellular states on the emergence of drug resistance and CRC progression remains elusive. Here, we explored the interaction between cell lines belonging to the CMS1 (HCT116 and LoVo) and the CMS4 (SW620 and MDST8) in a 3D coculture model, mimicking the ITH of CRC. The spatial distribution of each cell population showed that CMS1 cells had a preference to grow in the center of cocultured spheroids, while CMS4 cells localized at the periphery, in line with observations in tumors from CRC patients. Cocultures of CMS1 and CMS4 cells did not alter cell growth, but significantly sustained the survival of both CMS1 and CMS4 cells in response to the front-line chemotherapeutic agent 5-fluorouracil (5-FU). Mechanistically, the secretome of CMS1 cells exhibited a remarkable protective effect for CMS4 cells against 5-FU treatment, while promoting cellular invasion. Secreted metabolites may be responsible for these effects, as demonstrated by the existence of 5-FU induced metabolomic shifts, as well as by the experimental transfer of the metabolome between CMS1 and CMS4 cells. Overall, our results suggest that the interplay between CMS1 and CMS4 cells stimulates CRC progression and reduces the efficacy of chemotherapy.

Crisis plans in mental health: A scoping review.

Crisis situations are frequent among people with mental health disorders. Several interventions have been developed to act in prevention, including crisis plans recognized as particularly effective in reducing coercive measures. In the literature, several models of crisis plans are proposed with similar aims and contents. Based on the methodology proposed by the Joanna Briggs Institute, a scoping review was conducted to map the state of knowledge on crisis plans in adult mental health settings. The literature search conducted on six databases (CINAHL, PubMed, Medline, EMBASE, PsychINFO and Cochrane) yielded 2435 articles. Of these, 122 full-text articles were assessed for eligibility, and 78 met the inclusion criteria. Studies were critically appraised using the Joanna Briggs Institute appraisal tools, and data were extracted by two independent reviewers. Content analysis identified a typology of crisis plans: (1) the legal crisis plan and (2) the formal crisis plan. Five modalities were identified for its completion: the sections, the moment, the completion steps, the people involved and the training of key actors. Most identified outcomes are consistent with the main purpose of the intervention, which is crisis prevention. However, the most identified outcomes focused on the service user's recovery and indicated that crisis plans could provide an opportunity to operationalize recovery in mental healthcare, thus suggesting an evolution in the aim of the intervention. Future research should further focus on the modalities of crisis plans to guide the implementation in clinical practice.

A proof of concept for targeting the PrPC - Amyloid ß peptide interaction in basal prostate cancer and mesenchymal colon cancer.

The cellular prion protein PrPC partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrPC and CAV1 across cancer. Using cell-based assays, we show that PrPC regulates the expression of and interacts with CAV1. PrPC additionally controls the expression of the amyloid precursor protein APP and of the Aß generating enzyme BACE1, and regulates the levels of Aß, whose accumulation is a central event in Alzheimer's disease. We further identify DKK1 and DKK3, involved in both Alzheimer's disease and cancer progression, as targets of the PrPC-dependent axis. Finally, we establish that antibody-mediated blocking of the Aß-PrPC interaction delays the growth of prostate cancer cell line-derived xenografts and prevents the development of metastases. Our data additionally support an enrichment of the Aß-PrPC-dependent pathway in the basal subtype of prostate cancer, associated with anti-hormonal therapy resistance, and in mesenchymal colon cancer, associated with poor prognosis. Thus, based on a parallel with neurodegenerative diseases, our results bring to light an Aß-PrPC axis and support the potential of targeting this pathway in patients with selected subtypes of prostate and colon cancer.

Cell Fusion May Be Involved in the Homothallic Mating of Pneumocystis Species.

Pneumocystis species are obligate fungal biotrophs that colonize the lungs of mammals. They cause deadly pneumonia in immunocompromised hosts. The sexual phase seems obligate during their life cycle and essential for survival because it is believed to ensure proliferation and transmission between hosts. Here, we consider if the sexual phase is initiated by the fusion of two cells or by nucleus duplication in order to generate diploid cells that can undergo meiosis. The juxtaposition of the nucleus-associated organelles of pairs of cells with fused cytoplasmic membranes demonstrated that cell fusion can occur. Nevertheless, the frequency of cell fusion remains to be determined, and it cannot be excluded that both cell fusion and nucleus duplication are used to ensure the occurrence of the essential sexual phase. In vitro culturing of these fungi is a major milestone that could clarify the issue.