Pharmacodynamics of the orexin type 1 (OX) receptor in colon cancer cell models: A two-sided nature of antagonistic ligands resulting from partial dissociation of Gq.

Background And Purpose: Orexins have important biological effects on the central and peripheral nervous systems. Their primary ability is to regulate the sleep-wake cycle. Orexins and their antagonists, via OX receptor have been shown to have proapoptotic and antitumor effects on various digestive cancers cell models.

Orexins mitigate obesity-associated dysfunctions in mice.

Objective: Obesity is a chronic disease that affects more than 400 million adults with severe comorbidities. The search for new treatments to reduce its negative consequences is necessary. Orexins are hypothalamic neuropeptides involved in various physiological processes related to obesity.

The Orexin receptors: Structural and anti-tumoral properties.

At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis.

The Orexin-A/OX1R System Induces Cell Death in Pancreatic Cancer Cells Resistant to Gemcitabine and Nab-Paclitaxel Treatment.

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth cause of cancer-associated death in the West. This type of cancer has a very poor prognosis notably due to the development of chemoresistance when treatments including gemcitabine and Abraxane (Nab-paclitaxel) were prescribed. The identification of new treatment circumventing this chemoresistance represents a key challenge.

Orexins: A promising target to digestive cancers, inflammation, obesity and metabolism dysfunctions.

Hypothalamic neuropeptides named hypocretin/orexins which were identified in 1998 regulate critical functions such as wakefulness in the central nervous system. These past 20 years had revealed that orexins/receptors system was also present in the peripheral nervous system where they participated to the regulation of multiple functions including blood pressure regulation, intestinal motility, hormone secretion, lipolyze and reproduction functions. Associated to these peripheral functions, it was found that orexins and their receptors were involved in various diseases such as acute/chronic inflammation, metabolic syndrome and cancers.

Orexins/Hypocretins and Cancer: A Neuropeptide as Emerging Target.

Over 20 years ago, orexin neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) produced from the same precursor in hypothalamus were identified. These two neurotransmitters and their receptors (OX1R and OX1R), present in the central and peripheral nervous system, play a major role in wakefulness but also in drug addiction, food consumption, homeostasis, hormone secretion, reproductive function, lipolysis and blood pressure regulation. With respect to these biological functions, orexins were involved in various pathologies encompassing narcolepsy, neurodegenerative diseases, chronic inflammations, metabolic syndrome and cancers.

Clustering 5-Year Multidimensional Health Care Trajectory Patterns in Alzheimer's Disease and Related Syndromes.

Objective: After diagnosis of Alzheimer's disease and related syndromes (ADRS), personalized care adapted to each patient's needs is recommended to provide a care plan and start symptomatic treatments according to guidelines. Over the past decade, dedicated structures and care have been implemented in various settings. Equal access to ADRS care, health care providers and services is crucial to ensure potential health benefits for everyone.

Impact of a Pharmacist-included Mobile Geriatrics team intervention on potentially inappropriate drug prescribing: protocol for a prospective feasibility study (PharMoG study).

Introduction: Research has shown that potentially inappropriate drug prescription (PIDP) is highly prevalent in older people. The presence of PIDPs is associated with adverse health outcomes. This study aims to evaluate the impact of a PHARmacist-included MObile Geriatrics (PharMoG) team intervention on PIDPs in older patients hospitalised in the medical, surgical and emergency departments of a university hospital.

The impact of a multi-domain intervention on cerebral glucose metabolism: analysis from the randomized ancillary FDG PET MAPT trial.

Background: The Multidomain Alzheimer Preventive Trial (MAPT) was designed to assess the efficacy of omega-3 fatty acid supplementation, multidomain intervention (MI), or a combination of both on cognition. Although the MAPT study was negative, an effect of MI in maintaining cognitive functions compared to placebo group was showed in positive amyloid subjects. A FDG PET study (MAPT-NI) was implemented to test the impact of MI on brain glucose metabolism.

Orexins as Novel Therapeutic Targets in Inflammatory and Neurodegenerative Diseases.

Orexins [orexin-A (OXA) and orexin-B (OXB)] are two isoforms of neuropeptides produced by the hypothalamus. The main biological actions of orexins, focused on the central nervous system, are to control the sleep/wake process, appetite and feeding, energy homeostasis, drug addiction, and cognitive processes. These effects are mediated by two G protein-coupled receptor (GPCR) subtypes named OX1R and OX2R.

Use of a robotic walking aid in rehabilitation to reduce fear of falling is feasible and acceptable from the end user's perspective: A randomised comparative study.

Objectives To determine the acceptability and feasibility of the use of a robotic walking aid to support the work of physiotherapists in reducing fear of falling in the rehabilitation of elderly patients with 'psychomotor disadaptation' (the most severe form of post-fall syndrome). Study design 20 participants with psychomotor disadaptation admitted to an academic rehabilitation ward were randomised to receive physiotherapist care supported by the SafeWalker® robotic walking aid or standard care only, for ten days. SafeWalker® supports the body weight whilst securing postural stability without relying on upper body strength or high cognitive demand.

The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role.

Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated.

, and demonstration of the antitumoral role of hypocretin-1/orexin-A and almorexant in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is still the poorest prognostic tumor of the digestive system. We investigated the antitumoral role of orexin-A and almorexant in PDAC. We analyzed the orexin receptor type 1 (OX1R) expression by immunohistochemistry in human normal pancreas, PDAC and its precursor dysplastic intraepithelial lesions.

Antisecretory Effects of Chimeric Somatostatin/Dopamine Receptor Ligands on Gastroenteropancreatic Neuroendocrine Tumors.

Objectives: The recent finding that gastroenteropancreatic neuroendocrine tumors expressed the dopaminergic D2 receptor in addition to somatostatin (sst) receptors suggested that multiple targeting approaches might decrease hormone hypersecretion more effectively than sst agonists alone.

Methods: To test this hypothesis, (i) we measured the expression of sst receptor type 2 (sst2 receptor) and D2 receptor in 11 gastroenteropancreatic neuroendocrine tumors and (ii) we compared the ability of lanreotide, cabergoline, their combination, and sst/D2 chimeric ligands to decrease chromogranin A (CgA), gastrin, or serotonin release in primary cultures derived from these tumors.

Results: Moderate to high positivity was observed for sst2 receptor and D2 receptor, the latter being more expressed in pancreatic tumors.

Impact of Orexin-A Treatment on Food Intake, Energy Metabolism and Body Weight in Mice.

Orexin-A and -B are hypothalamic neuropeptides of 33 and 28-amino acids, which regulate many homeostatic systems including sleep/wakefulness states, energy balance, energy homeostasis, reward seeking and drug addiction. Orexin-A treatment was also shown to reduce tumor development in xenografted nude mice and is thus a potential treatment for carcinogenesis. The aim of this work was to explore in healthy mice the consequences on energy expenditure components of an orexin-A treatment at a dose previously shown to be efficient to reduce tumor development.

Management of behavioural symptoms of dementia in a specialized unit care.

Background: In France, the Alzheimer Plan 2008-2012 has enabled the development of units specialized in managing the behavioural and psychological disorders found in cognitive pathologies, with an emphasis on both pharmacological and non-pharmacological treatments. The aim of this study was to analyze the evolution of behavioural symptoms, autonomy, and psychotropic drug prescriptions at a cognitive and behavioural unit in Toulouse, France.

Methods: Prospective study, with systematic analyze of data for patients hospitalized in a cognitive and behavioral unit.

Precuneus and Cingulate Cortex Atrophy and Hypometabolism in Patients with Alzheimer's Disease and Mild Cognitive Impairment: MRI and (18)F-FDG PET Quantitative Analysis Using FreeSurfer.

Objective: The objective of this study was to compare glucose metabolism and atrophy, in the precuneus and cingulate cortex, in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), using FreeSurfer.

Methods: 47 individuals (17 patients with AD, 17 patients with amnestic MCI, and 13 healthy controls (HC)) were included. MRI and PET images using (18)F-FDG (mean injected dose of 185 MBq) were acquired and analyzed using FreeSurfer to define regions of interest in the hippocampus, amygdala, precuneus, and anterior and posterior cingulate cortex.

Crucial role of the orexin-B C-terminus in the induction of OX1 receptor-mediated apoptosis: analysis by alanine scanning, molecular modelling and site-directed mutagenesis.

Background And Purpose: Orexins (A and B) are hypothalamic peptides that interact with OX1 and OX2 receptors and are involved in the sleep/wake cycle. We previously demonstrated that OX1 receptors are highly expressed in colon cancer tumours and colonic cancer cell lines where orexins induce apoptosis and inhibit tumour growth in preclinical animal models. The present study explored the structure-function relationships of orexin-B and OX1 receptors.

[Management of behavioral symptoms in dementia in a specialized unit care].

Unlabelled: The project "Plan Alzheimer 2008-2012" allowed the development of units specialized in management of behavioral disorders in dementia, by favoring pharmacological and non-pharmacological approaches.

Objectives: Our article analyses the evolution of behavioral symptoms, autonomy and prescription of psychotropic drugs, in "Cognitive and Behavioral Unit" of Toulouse (France). Second outcome is the analysis of early unplanned readmission for behavioral reasons.

Effects of lactoferrin on intestinal epithelial cell growth and differentiation: an in vivo and in vitro study.

This study was designed to analyse the effects of human (h) and bovine lactoferrin (bLF) on the growth and differentiation of intestinal cells using the mice model supplemented with Lactoferrin (LF) and the enterocyte-like model of Caco-2 cells which spontaneously differentiate after confluency. In mice, bLF supplementation increased jejunal villus height and the expression of several intestinal brush border membrane enzymes activities. Addition of bLF or hLF to undifferentiated Caco-2 cells was able to increase cell proliferation with confluency being reached more rapidly.

The orexin type 1 receptor is overexpressed in advanced prostate cancer with a neuroendocrine differentiation, and mediates apoptosis.

Aim: In the present study, we have examined the presence of orexins and their receptors in prostate cancer (CaP) and investigated their effects on the apoptosis of prostate cancer cells.

Methods: We have localised the orexin type 1 and 2 receptors (OX1R and OX2R) and orexin A (OxA) in CaP sections of various grades and we have quantified tumour cells containing OX1R. Expression of OX1R was evaluated in the androgeno-dependent (AD) LNCaP and the androgeno-independent (AI) DU145 prostate cancer cells submitted or not to a neuroendocrine differentiation.

[Description of cognitive-behavioral specialized units in France: results of a national investigation].

Through a national survey, the SFGG's UCC Task Force worked and liaised with the DGOS as to establish a national inventory of the UCCs in France. 43 of the 55 newly opened UCCs in 2011 filled up the survey. These UCCs largely supported patients meeting the admission criteria's from the book of specifications edited by the public department.

Behavioral and psychological subsyndromes in Alzheimer's disease using the Neuropsychiatric Inventory.

Objective: Behavioral and psychological symptoms of dementia represent common clinical features of dementias, contributing to the heterogeneous phenotypic expression of Alzheimer's disease (AD). During the last two decades, several studies explored the possible presence of neuropsychiatric subsyndromes in dementia by examining the internal structure of the Neuropsychiatric Inventory (NPI). The aim of the present review is to present available evidence coming from studies adopting factor analysis to explore the NPI and describe neuropsychiatric clusters of symptoms in AD.

[Frailty: learnings from the SAFEs cohort study and future perspectives for the research].

Even though the efforts in research have detailed further the physiopathology and the dynamics of the frailty process an operational definition of frailty is still far from being unequivocal. Studies carried out from the SAFEs cohort study allowed a pragmatic approach in the identification of the at-risk groups for the lost of independency during the hospital stay and factors influencing their future at short-, mid- and long-term. Based upon these results, we propose to discuss the relevance of the current operational indicators of frailty in order to show that clinical markers or indicators are insufficient to differentiate the frailty process from normal ageing.

The orexin receptor OX(1)R in colon cancer: a promising therapeutic target and a new paradigm in G protein-coupled receptor signalling through ITIMs.

An exciting aspect of the heptahelical orexin receptor 1 (OX(1)R) has emerged recently, when it was shown that it drives apoptosis in human colon cancer cell lines. Here we review recent findings related to the role of OX(1)R in colorectal cancers and the unexpected mechanism whereby this G protein-coupled receptor works. The OX(1)R is aberrantly expressed at all steps of primary colorectal tumour progression and after local (lymph node) or distant (liver, lung) metastasis.