Validation of PARADISE 24 and Development of PARADISE-EDEN 36 in Patients with Dementia.

Dementia was one of the conditions focused on in an EU (European Union) project called "PARADISE" (Psychosocial fActors Relevant to brAin DISorders in Europe) that later produced a measure called PARADISE 24, developed within the biopsychosocial model proposed in the International Classification of Functioning Disability and Health (ICF). The aims of this study are to validate PARADISE 24 on a wider sample of patients with mild to moderate dementia to expand PARADISE 24 by defining a more specific scale for dementia, by adding 18 questions specifically selected for dementia, which eventually should be reduced to 12. We enrolled 123 persons with dementia, recruited between July 2017 and July 2019 in home care and long-term care facilities, in Italy, and 80 participants were recruited in Warsaw between January and July 2012 as part of a previous cross-sectional study. The interviews with the patient and/or family were conducted by health professionals alone or as a team by using the Paradise data collection protocol. The psychometric analysis with the Rasch analysis has shown that PARADISE 24 and the selection of 18 additional condition-specific items can be expected to have good measurement properties to assess the functional state in persons with dementia.

A novel genome-wide in vivo screen for metastatic suppressors in human colon cancer identifies the positive WNT-TCF pathway modulators TMED3 and SOX12.

The progression of tumors to the metastatic state involves the loss of metastatic suppressor functions. Finding these, however, is difficult as in vitro assays do not fully predict metastatic behavior, and the majority of studies have used cloned cell lines, which do not reflect primary tumor heterogeneity. Here, we have designed a novel genome-wide screen to identify metastatic suppressors using primary human tumor cells in mice, which allows saturation screens. Using this unbiased approach, we have tested the hypothesis that endogenous colon cancer metastatic suppressors affect WNT-TCF signaling. Our screen has identified two novel metastatic suppressors: TMED3 and SOX12, the knockdown of which increases metastatic growth after direct seeding. Moreover, both modify the type of self-renewing spheroids, but only knockdown of TMED3 also induces spheroid cell spreading and lung metastases from a subcutaneous xenograft. Importantly, whereas TMED3 and SOX12 belong to different families involved in protein secretion and transcriptional regulation, both promote endogenous WNT-TCF activity. Treatments for advanced or metastatic colon cancer may thus not benefit from WNT blockers, and these may promote a worse outcome.

Oligodendrocytes as regulators of neuronal networks during early postnatal development.

Oligodendrocytes are the glial cells responsible for myelin formation. Myelination occurs during the first postnatal weeks and, in rodents, is completed during the third week after birth. Myelin ensures the fast conduction of the nerve impulse; in the adult, myelin proteins have an inhibitory role on axon growth and regeneration after injury. During brain development, oligodendrocytes precursors originating in multiple locations along the antero-posterior axis actively proliferate and migrate to colonize the whole brain. Whether the initial interactions between oligodendrocytes and neurons might play a functional role before the onset of myelination is still not completely elucidated. In this article, we addressed this question by transgenically targeted ablation of proliferating oligodendrocytes during cerebellum development. Interestingly, we show that depletion of oligodendrocytes at postnatal day 1 (P1) profoundly affects the establishment of cerebellar circuitries. We observed an impressive deregulation in the expression of molecules involved in axon growth, guidance and synaptic plasticity. These effects were accompanied by an outstanding increase of neurofilament staining observed 4 hours after the beginning of the ablation protocol, likely dependent from sprouting of cerebellar fibers. Oligodendrocyte ablation modifies localization and function of ionotropic glutamate receptors in Purkinje neurons. These results show a novel oligodendrocyte function expressed during early postnatal brain development, where these cells participate in the formation of cerebellar circuitries, and influence its development.

Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas.

Previous studies demonstrate the initiation of colon cancers through deregulation of WNT-TCF signalling. An accepted but untested extension of this finding is that incurable metastatic colon carcinomas (CCs) universally remain WNT-TCF-dependent, prompting the search for WNT-TCF inhibitors. CCs and their stem cells also require Hedgehog (HH)-GLI1 activity, but how these pathways interact is unclear. Here we define coincident high-to-low WNT-TCF and low-to-high HH-GLI transitions in patient CCs, most strikingly in their CD133(+) stem cells, that mark the development of metastases. We find that enhanced HH-GLI mimics this transition, driving also an embryonic stem (ES)-like stemness signature and that GLI1 can be regulated by multiple CC oncogenes. The data support a model in which the metastatic transition involves the acquisition or enhancement of a more primitive ES-like phenotype, and the downregulation of the early WNT-TCF programme, driven by oncogene-regulated high GLI1 activity. Consistently, TCF blockade does not generally inhibit tumour growth; instead, it, like enhanced HH-GLI, promotes metastatic growth in vivo. Treatments for metastatic disease should therefore block HH-GLI1 but not WNT-TCF activities.

Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion.

Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced beta CATENIN (beta CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases.

Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH.

Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH yield the rare genetic disorder trichothiodystrophy (TTD). Although this syndrome was initially associated with a DNA repair defect, individuals with TTD develop neurological features, such as microcephaly and hypomyelination that could be connected to transcriptional defects. Here we show that an XPD mutation in TTD mice results in a spatial and selective deregulation of thyroid hormone target genes in the brain. Molecular analyses performed on the mice brain tissue demonstrate that TFIIH is required for the stabilization of thyroid hormone receptors (TR) to their DNA-responsive elements. The limiting amounts of TFIIH found in individuals with TTD thus contribute to the deregulation of TR-responsive genes. The discovery of an unexpected stabilizing function for TFIIH deepens our understanding of the pathogenesis and neurological manifestations observed in TTD individuals.

Oligodendrocyte ablation affects the coordinated interaction between granule and Purkinje neurons during cerebellum development.

Oligodendrocytes (OLs) are the glial cells of the central nervous system (CNS) classically known to be devoted to the formation of myelin sheaths around most axons of the vertebrate brain. We have addressed the role of these cells during cerebellar development, by ablating OLs in vivo. Previous analyses had indicated that OL ablation during the first six postnatal days results into a striking cerebellar phenotype, whose major features are a strong reduction of granule neurons and aberrant Purkinje cells development. These two cell types are highly interconnected during cerebellar development through the production of molecules that help their proliferation, differentiation and maintenance. In this article, we present data showing that OL ablation has major effects on the physiology of Purkinje (PC) and granule cells (GC). In particular, OL ablation results into a reduction of sonic hedgehog (Shh), Brain Derived Neurotrophic Factor (BDNF), and Reelin (Rln) expression. These results indicate that absence of OLs profoundly alters the normal cerebellar developmental program.

Impaired light masking in dopamine D2 receptor-null mice.

Disruption of overt circadian rhythms can occur without influencing the endogenous pacemaker, the so-called 'masking' effect classically elicited by light. As the physiological pathways involved in light masking remain elusive, we analyzed mice lacking the dopamine D2 receptor. Although circadian rhythmicity was normal, D2R-null mice showed a markedly deficient light masking response, indicating that D2R-mediated signaling is an essential component of the neuronal pathways leading to light masking of circadian rhythms.