Myosin Vb as a tumor suppressor gene in intestinal cancer.

Colorectal cancer causes >900,000 deaths every year and a deeper understanding of the molecular mechanisms underlying this disease will contribute to improve its clinical management and survival. Myosin Vb (MYO5B) regulates intracellular vesicle trafficking, and inactivation of this myosin disrupts the polarization and differentiation of intestinal epithelial cells causing microvillous inclusion disease (MVID), a rare congenital disorder characterized by intractable life-threatening diarrhea. Here, we show that the loss Myosin Vb interfered with the differentiation/polarization of colorectal cancer cells. Although modulation of Myosin Vb expression did not affect the proliferation of colon cancer cells, MYO5B inactivation increased their migration, invasion, and metastatic potential. Moreover, Myo5b inactivation in an intestine-specific knockout mouse model caused a >15-fold increase in the number of azoxymethane-initiated small intestinal tumors. Consistently, reduced expression of Myosin Vb in a cohort of 155 primary colorectal tumors was associated with shorter patient survival. In conclusion, we show here that loss of Myosin Vb reduces polarization/differentiation of colon cancer cells while enhancing their metastatic potential, demonstrating a tumor suppressor function for this myosin. Moreover, reduced expression of Myosin Vb in primary tumors identifies a subset of poor prognosis colorectal cancer patients that could benefit from more aggressive therapeutic regimens.

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.

Needs and Supports of People with Intellectual Disability and Their Families in Catalonia.

BACKGROUND: The study assesses the support needs of individuals with intellectual disability and their families in Catalonia. The present authors examine family quality of life (FQoL), identify the individual services required and assess families' perceptions of the extent to which their family member with intellectual disability and they themselves receive the services they need. MATERIALS AND METHODS: The N&S questionnaire (Needs and Supports for people with intellectual disability and their families) was administered to 2160 families with a family member with intellectual disability aged under 70 in Catalonia (Spain). RESULTS: Overall mean FQoL was quite high. FQoL was associated with family income, education, employment and percentage level of disability. Neither people with intellectual disability nor their families receive the specific support they need. CONCLUSIONS: Besides providing specific support for individuals with intellectual disability, local policymakers and practitioners should apply a family-centred approach to the provision of support for families in order to improve FQoL.

Spanish family quality of life scales: under and over 18 years old.

BACKGROUND: Researchers, professionals, and families have shown increasing concern with the family quality of life (FQoL) of people with intellectual disability (ID) and their families. The goals of this research were (a) to explore how Spanish families understand FQoL by developing 2 different measurement tools for families with a member with ID under and over 18 years old, and (b) to provide 2 diagnostic instruments that will be useful for designing action plans. METHOD: The study comprised 4 stages: (a) focus groups, (b) expert assessment, (c) pilot study, and (d) normalisation and standardisation. The data were collected in 5 regions in Spain, and 1,205 families with a member with ID took part in the normalisation and standardisation of the scales. RESULTS: Both FQoL scales were consistent and have valid psychometric characteristics. CONCLUSIONS: The scales have a diagnostic purpose for use in designing action plans aimed at producing significant changes in families' lives.