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1.
BMC Cancer ; 22(1): 1308, 2022 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-36513991

RESUMO

BACKGROUND: The discovery of the importance of the immune system and its role in oncogenesis led to the development of immunotherapy, a treatment that represents a major advance in oncology management. Due to the recent nature of immunotherapy, little is known about its side effects and their impact on quality of life. To date, there is no published study that accurately assesses the impact of immunotherapy on cognition, mood and/or fatigue in patients treated for cancer, despite potential neurological toxicities. The purpose of this study is to prospectively assess the incidence of cognitive impairment and cognitive complaints among cancer patients naïve for immunotherapy without concomitant anti-cancer treatment. METHODS: The Cog-Immuno trial is a multicentre longitudinal study addressing patients with cancer candidate to receive immunotherapy alone (n = 100). Immunotherapy treatment will include either anti-PD1/PDL1 or anti-CTLA4 monotherapy or combination therapy. Cognitive and quality of life assessment, electrocardiogram (ECG) and biological tests will be performed at baseline, thereafter 3, and 6 months after immunotherapy initiation. The primary endpoint is the proportion of patients treated by immunotherapy who will experience a decline in cognitive performances or in Montreal Cognitive Assessment (MoCA) score within 3 months after inclusion. Secondary endpoints concern: anxiety, depression, fatigue, clinical characteristics, biological data and neurophysiological measures (heart rate variability and hemispheric lateralization). A pre-clinical study will be conducted in cancer bearing mice receiving checkpoint inhibitors (ICI) with the evaluation of cognitive functions and emotional reactivity, collection of blood samples and investigation of neurobiological mechanisms from brain slices. DISCUSSION: Assessing and understanding the incidence and the severity of cognitive impairment and its impact on quality of life in cancer patients treated by immunotherapy is a major issue. The results of this study will provide information on the impact of these treatments on cognitive functions in order to help the physicians in the choice of the treatment. TRIAL REGISTRATION: NCT03599830, registered July 26, 2018. PROTOCOL VERSION: Version 5.1 dated from 2020/10/02.


Assuntos
Neoplasias , Qualidade de Vida , Animais , Camundongos , Estudos Prospectivos , Estudos Longitudinais , Imunoterapia/efeitos adversos , Cognição , Neoplasias/terapia , Fadiga/etiologia
2.
Cancers (Basel) ; 14(18)2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36139563

RESUMO

Chemotherapy-related cognitive impairment (CRCI) and fatigue constitute common complaints among cancer patient survivors. Panax quinquefolius has been shown to be effective against fatigue in treated cancer patients. We developed a behavioral C57Bl/6j mouse model to study the role of a Panax quinquefolius-based solution containing vitamin C (Qiseng®) or vitamin C alone in activity/fatigue, emotional reactivity and cognitive functions impacted by 5-Fluorouracil (5-FU) chemotherapy. 5-FU significantly reduces the locomotor/exploration activity potentially associated with fatigue, evokes spatial cognitive impairments and leads to a decreased neurogenesis within the hippocampus (Hp). Qiseng® fully prevents the impact of chemotherapy on activity/fatigue and on neurogenesis, specifically in the ventral Hp. We observed that the chemotherapy treatment induces intestinal damage and inflammation associated with increased levels of Lactobacilli in mouse gut microbiota and increased expression of plasma pro-inflammatory cytokines, notably IL-6 and MCP-1. We demonstrated that Qiseng® prevents the 5-FU-induced increase in Lactobacilli levels and further compensates the 5-FU-induced cytokine release. Concomitantly, in the brains of 5-FU-treated mice, Qiseng® partially attenuates the IL-6 receptor gp130 expression associated with a decreased proliferation of neural stem cells in the Hp. In conclusion, Qiseng® prevents the symptoms of fatigue, reduced chemotherapy-induced neuroinflammation and altered neurogenesis, while regulating the mouse gut microbiota composition, thus protecting against intestinal and systemic inflammation.

3.
Cancers (Basel) ; 13(14)2021 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-34298734

RESUMO

Cognitive side effects after cancer treatment threatening quality of life (QoL) constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are examples of next-generation therapy (NGT) administered to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment were reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ for 5 days per week for six consecutive weeks. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus highlighted ENZ-induced dopaminergic regulation within the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. The consequences of the mCRPC treatment ENZ on aged castrated mouse motivation to exploration and cognition should make reconsider management strategy of elderly prostate cancer patients.

4.
J Immunol ; 206(5): 1027-1038, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33483348

RESUMO

Alterations in the γδ T cell compartment have been reported in immunocompromised individuals infected with hepatitis E virus (HEV)-g3. We now report the analysis of blood γδ T cells from acutely HEV-infected individuals in the absence of immunosuppression. In these patients, non-Vδ2 (ND2) γδ T cells outnumbered otherwise predominant Vδ2 cells selectively in human CMV (HCMV)-seropositive patients and were higher than in HCMVpos controls, mimicking HCMV reactivation, whereas their serum was PCR-negative for HCMV. Stimulation of their lymphocytes with HEV-infected hepatocarcinoma cells led to an HEV-specific response in γδ subsets of HCMVpos individuals. HEV infection was associated with a lowered expression of TIGIT, LAG-3, and CD160 immune checkpoint markers on ND2 effector memory cells in HCMVneg but not in HCMVpos HEV patients. γδ cell lines, predominantly ND2, were generated from patients after coculture with hepatocarcinoma cells permissive to HEV and IL-2/12/18. Upon restimulation with HEV-infected or uninfected cells and selected cytokines, these cell lines produced IFN-γ and IL-10, the latter being induced by IL-12 in IFN-γ-producing cells and upregulated by HEV and IL-18. They were also capable of suppressing the proliferation of CD3/CD28-activated CD4 cells in transwell experiments. Importantly, IL-10 was detected in the plasma of 10 of 10 HCMVpos HEV patients but rarely in controls or HCMVneg HEV patients, implying that γδ cells are probably involved in IL-10 production at the acute phase of infection. Our data indicate that HEV mobilizes a pool of ND2 memory cells in HCMV carriers, promoting the development of an immunoregulatory environment.


Assuntos
Infecções por Citomegalovirus/imunologia , Hepatite E/imunologia , Interleucina-10/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Citomegalovirus/imunologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/virologia , Células Hep G2 , Hepatite E/sangue , Hepatite E/virologia , Vírus da Hepatite E/imunologia , Humanos , Memória Imunológica/imunologia
5.
Biomolecules ; 10(3)2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32204509

RESUMO

Overexpression of G protein-coupled receptors (GPCRs) in tumours is widely used to develop GPCR-targeting radioligands for solid tumour imaging in the context of diagnosis and even treatment. The human vasoactive neuropeptide urotensin II (hUII), which shares structural analogies with somatostatin, interacts with a single high affinity GPCR named UT. High expression of UT has been reported in several types of human solid tumours from lung, gut, prostate, or breast, suggesting that UT is a valuable novel target to design radiolabelled hUII analogues for cancer diagnosis. In this study, two original urotensinergic analogues were first conjugated to a DOTA chelator via an aminohexanoic acid (Ahx) hydrocarbon linker and then -hUII and DOTA-urantide, complexed to the radioactive metal indium isotope to successfully lead to radiolabelled DOTA-Ahx-hUII and DOTA-Ahx-urantide. The 111In-DOTA-hUII in human plasma revealed that only 30% of the radioligand was degraded after a 3-h period. DOTA-hUII and DOTA-urantide exhibited similar binding affinities as native peptides and relayed calcium mobilization in HEK293 cells expressing recombinant human UT. DOTA-hUII, not DOTA-urantide, was able to promote UT internalization in UT-expressing HEK293 cells, thus indicating that radiolabelled 111In-DOTA-hUII would allow sufficient retention of radioactivity within tumour cells or radiolabelled DOTA-urantide may lead to a persistent binding on UT at the plasma membrane. The potential of these radioligands as candidates to target UT was investigated in adenocarcinoma. We showed that hUII stimulated the migration and proliferation of both human lung A549 and colorectal DLD-1 adenocarcinoma cell lines endogenously expressing UT. In vivo intravenous injection of 111In-DOTA-hUII in C57BL/6 mice revealed modest organ signals, with important retention in kidney. 111In-DOTA-hUII or 111In-DOTA-urantide were also injected in nude mice bearing heterotopic xenografts of lung A549 cells or colorectal DLD-1 cells both expressing UT. The observed significant renal uptake and low tumour/muscle ratio (around 2.5) suggest fast tracer clearance from the organism. Together, DOTA-hUII and DOTA-urantide were successfully radiolabelled with 111Indium, the first one functioning as a UT agonist and the second one as a UT-biased ligand/antagonist. To allow tumour-specific targeting and prolong body distribution in preclinical models bearing some solid tumours, these radiolabelled urotensinergic analogues should be optimized for being used as potential molecular tools for diagnosis imaging or even treatment tools.


Assuntos
Proteínas de Neoplasias/metabolismo , Neoplasias , Compostos Radiofarmacêuticos , Receptores Acoplados a Proteínas G/metabolismo , Células A549 , Animais , Feminino , Células HEK293 , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Radioisótopos de Índio/química , Radioisótopos de Índio/farmacologia , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacologia , Urotensinas/química , Urotensinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Front Microbiol ; 11: 1, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082274

RESUMO

Recombinant strains of hepatitis E virus (HEV) with insertions of human genomic fragments or HEV sequence duplications in the sequence encoding the polyproline region (PPR) were previously described in chronically infected patients. Such genomic rearrangements confer a replicative advantage in vitro but little is known about their frequency, location, or origin. As the sequences of only a few virus genomes are available, we analyzed the complete genomes of 114 HEV genotype 3 strains from immunocompromised (n = 85) and immunocompetent (n = 29) patients using the single molecular real-time sequencing method to determine the frequency, location, and origin of inserted genomic fragments, plus the proportions of variants with genomic rearrangements in each virus quasispecies. We also examined the amino acid compositions and post-translational modifications conferred by these rearrangements by comparing them to sequences without human gene insertions or HEV gene duplications. We found genomic rearrangements in 7/114 (6.1%) complete genome sequences (4 HEV-3f, 1 HEV-3e, 1 HEV-3 h, and 1 HEV-3chi-new), all from immunocompromised patients, and 3/7 were found at the acute phase of infection. Six of the seven patients harbored virus-host recombinant variants, including one patient with two different recombinant variants. We also detected three recombinant variants with genome duplications of the PPR or PPR + X domains in a single patient. All the genomic rearrangements (seven human fragment insertions of varying origins and three HEV genome duplications) occurred in the PPR. The sequences with genomic rearrangements had specific characteristics: increased net load (p < 0.001) and more ubiquitination (p < 0.001), phosphorylation (p < 0.001), and acetylation (p < 0.001) sites. The human fragment insertions and HEV genome duplications had slightly different characteristics. We believe this is the first description of HEV strains with genomic rearrangements in patients at the acute phase of infection; perhaps these strains are directly transmitted. Clearly, genomic rearrangements produce a greater net load with duplications and insertions having different features. Further studies are needed to clarify the mechanisms by which such modifications influence HEV replication.

7.
Viruses ; 12(2)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991673

RESUMO

Hepatitis E virus (HEV) is a major concern in public health worldwide. Infections with HEV genotypes 3, 4, or 7 can lead to chronic hepatitis while genotype 1 infections can trigger severe hepatitis in pregnant women. Infections with all genotypes can worsen chronic liver diseases. As virions are lipid-associated in blood and naked in feces, efficient methods of propagating HEV clinical strains in vitro and evaluating the infectivity of both HEV forms are needed. We evaluated the spread of clinical strains of HEV genotypes 1 (HEV1) and 3 (HEV3) by quantifying viral RNA in culture supernatants and cell lysates. Infectivity was determined by endpoint dilution and calculation of the tissue culture infectious dose 50 (TCID50). An enhanced HEV production could be obtained varying the composition of the medium, including fetal bovine serum (FBS) and dimethylsulfoxide (DMSO) content. This increased TCID50 from 10 to 100-fold and allowed us to quantify HEV1 infectivity. These optimized methods for propagating and measuring HEV infectivity could be applied to health safety processes and will be useful for testing new antiviral drugs.


Assuntos
Vírus da Hepatite E/crescimento & desenvolvimento , Cultura de Vírus/métodos , Meios de Cultura , Genótipo , Células Hep G2 , Vírus da Hepatite E/genética , Humanos , RNA Viral/análise
8.
Gut ; 69(5): 901-910, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31727684

RESUMO

OBJECTIVE: Hepatitis E virus (HEV), one of the most common agent of acute hepatitis worldwide, is mainly transmitted enterically, via contaminated water for HEV genotypes 1 (HEV1) and HEV2, or by eating raw or undercooked infected meat for HEV genotype 3 (HEV3) and HEV4. However, little is known about how the ingested HEV reaches the liver or its ability to replicate in intestinal cells. DESIGN: We developed human primary cultures of small intestine epithelial cells and intestinal explants obtained from small bowel resections. The epithelial cells were also polarised on transwells. Cells were infected with Kernow-p6 strain or clinically derived virions. RESULTS: Primary intestinal cells supported the growth of Kernow-p6 strain and HEV1 and HEV3 clinically derived virions. Polarised enterocytes infected with HEV1 and HEV3 strains released HEV particles vectorially: mostly into the apical compartment with a little basally. Iodixanol density gradient centrifugation of enterocyte-derived HEV virions gave bands at a density of 1.06-1.08 g/cm3, corresponding to that of quasi-enveloped HEV particles. Ribavirin therapy inhibited HEV excretion from the basal surface but not from the apical side of infected human enterocytes. HEV virions also infected intestinal tissue explants. Lastly, HEV RNA and antigen were detected in the intestinal crypts of a chronically infected patient. CONCLUSION: HEV can replicate in intestinal cells and reaches the liver as quasi-enveloped virions.


Assuntos
Vírus da Hepatite E/genética , RNA Viral/genética , Ribavirina/farmacologia , Replicação Viral/genética , Células Cultivadas , Células Epiteliais , Genótipo , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Intestino Delgado/citologia , Sensibilidade e Especificidade
9.
Shock ; 54(4): 574-582, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31568223

RESUMO

INTRODUCTION: Urotensin II is a potent vasoactive peptide activating the the G protein-coupled urotensin II receptor UT, and is involved in systemic inflammation and cardiovascular functions. The aim of our work was to study the impact of the UT antagonist urantide on survival, systemic inflammation, and cardiac function during endotoxic shock. METHODS: C57Bl/6 mice were intraperitoneally injected with lipopolysaccharide (LPS) and then randomized to be injected either by urantide or NaCl 0.9% 3, 6, and 9 h (H3, H6, H9) after LPS. The effect of urantide on the survival rate, the levels of cytokines in plasma at H6, H9, H12, the expression level of nuclear factor-kappa B (NF-κB-p65) in liver and kidney (at H12), and the cardiac function by trans-thoracic echocardiography from H0 to H9 was evaluated. RESULTS: Urantide treatment improved survival (88.9% vs. 30% on day 6, P < 0.05). This was associated with changes in cytokine expression: a decrease in IL-6 (2,485 [2,280-2,751] pg/mL vs. 3,330 [3,119-3,680] pg/mL, P < 0.01) at H6, in IL-3 (1.0 [0.40-2.0] pg/mL vs. 5.8 [3.0-7.7] pg/mL, P < 0.01), and IL-1ß (651 [491-1,135] pg/mL vs. 1,601 [906-3,010] pg/mL, P < 0.05) at H12 after LPS administration. Urantide decreased the proportion of cytosolic NF-κB-p65 in liver (1.3 [0.9-1.9] vs. 3.2 [2.3-4], P < 0.01) and kidney (0.3 [0.3-0.4] vs. 0.6 [0.5-1.1], P < 0.01). Urantide improved cardiac function (left ventricular fractional shortening: 24.8 [21.5-38.9] vs. 12.0 [8.7-17.6] %, P < 0.01 and cardiac output: 30.3 [25.9-39.8] vs. 15.1 [13.0-16.9] mL/min, P < 0.0001). CONCLUSION: These results show a beneficial curative role of UT antagonism on cytokine response (especially IL-3), cardiac dysfunction, and survival during endotoxic shock in mice, highlighting a potential new therapeutic target for septic patients.


Assuntos
Citocinas/metabolismo , Fragmentos de Peptídeos/uso terapêutico , Urotensinas/uso terapêutico , Animais , Modelos Animais de Doenças , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Distribuição Aleatória , Receptores Acoplados a Proteínas G/metabolismo , Choque Séptico , Fator de Transcrição RelA/metabolismo
10.
Neurosci Biobehav Rev ; 107: 602-614, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31553925

RESUMO

A number of neurotoxicity associated with oncological treatments has been reported in non-central nervous system cancers. An expert group presents the state of the art and a guide to help the choice of appropriated tools to assess patient cognition in studies on oncology and neurobehavior in animal models. In addition, current cognitive rehabilitation programs currently under evaluation are also discussed. Cognitive assessments in oncology depend on the research question, study design, cognitive domains, patients' characteristics, psychometric properties of the tests, and whether the tests are supervised or not by a neuropsychologist. Batteries of electronic tests can be proposed, but several of them are characterized by weak psychometric developments. In order to improve the comprehension on the impact of cancer treatments on cognition, new animal models are in development, and would in the future include non-human primate models. By bringing together the skills and practices of oncologists, neurologists, neuropsychologists, neuroscientists, we propose a series of specific tools and tests that accompany the cognitive management of non-CNS cancer patients.


Assuntos
Disfunção Cognitiva/etiologia , Neoplasias/complicações , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/terapia , Humanos , Neoplasias/psicologia , Neoplasias/terapia
11.
J Virol ; 93(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30463960

RESUMO

Hepatitis E virus (HEV) is a common cause of acute viral hepatitis worldwide. Most HEV infections are asymptomatic, but immunocompromised patients infected with HEV genotype 3 (HEV3), HEV4, or HEV7 may develop chronic infections. The HEV particles in stools are naked (nHEV), while those in the serum and culture supernatants (eHEV) are associated with lipids. Hepatocytes are polarized epithelial cells that have basolateral (oriented toward the blood) and apical (oriented toward the bile) exosomal pathways. We isolated a subclone, F2, from the human hepatocarcinoma cell line HepG2/C3A that grew as a polarized monolayer culture and had better HEV production than HepG2/C3A cells. F2 cells cultured on semipermeable collagen inserts and infected basolaterally with nHEV3 released 94.6% of virus particles apically, those infected with eHEV3 released 96.8% apically, and eHEV1-infected cells released 99.3% apically. Transcytosis was not involved. Density gradient centrifugation and NP-40 treatment showed that HEV particles released both apically and basolaterally were lipid associated. The apically released HEV3 and HEV1 particles were six and nine times more infectious than those released basolaterally, respectively. Confocal microscopy indicated that the open reading frame 2 (ORF2) capsid protein colocalized apically with ORF3 virus protein, the apical marker DPP4, and the recycling endosome GTPase Rab27a. The amounts of soluble glycosylated ORF2 secreted apically and basolaterally were similar. These polarized-hepatocyte data suggest that infectious HEV particles are mainly released into bile, while the small fraction released into blood could spread HEV throughout the host.IMPORTANCE Hepatitis E virus (HEV) in stools is naked, while that in culture supernatants and patients' blood is lipid associated. Its life cycle in hepatocytes, polarized cells with a basolateral side communicating with blood and an apical side connected with bile, is incompletely understood. We have developed a polarized hepatocyte model and used the cells to analyze the supernatants bathing the apical and basolateral sides and HEV subcellular distribution. HEV particles from both sides were lipid associated, and most infectious HEV particles left the cell via its apical side. Similar amounts of the open reading frame 2 (ORF2) soluble capsid protein were secreted from both sides of the hepatocytes. This model mimicking physiological conditions should help clarify the HEV cell cycle in polarized hepatocytes.


Assuntos
Vírus da Hepatite E/metabolismo , Hepatócitos/virologia , Liberação de Vírus/fisiologia , Proteínas do Capsídeo/metabolismo , Carcinoma Hepatocelular/metabolismo , Técnicas de Cultura de Células , Linhagem Celular , Polaridade Celular , Células Epiteliais/virologia , Células Hep G2 , Hepatite E/virologia , Vírus da Hepatite E/patogenicidade , Vírus da Hepatite E/fisiologia , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Soro/virologia , Proteínas Virais
12.
Rev Med Virol ; 28(5): e1987, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29939461

RESUMO

Hepatitis E virus genotype 3 (HEV-3) can lead to chronic infection in immunocompromised patients, and ribavirin is the treatment of choice. Recently, mutations in the polymerase gene have been associated with ribavirin failure but their frequency before treatment according to HEV-3 subtypes has not been studied on a large data set. We used single-molecule real-time sequencing technology to sequence 115 new complete genomes of HEV-3 infecting French patients. We analyzed phylogenetic relationships, the length of the polyproline region, and mutations in the HEV polymerase gene. Eighty-five (74%) were in the clade HEV-3efg, 28 (24%) in HEV-3chi clade, and 2 (2%) in HEV-3ra clade. Using automated partitioning of maximum likelihood phylogenetic trees, complete genomes were classified into subtypes. Polyproline region length differs within HEV-3 clades (from 189 to 315 nt). Investigating mutations in the polymerase gene, distinct polymorphisms between HEV-3 subtypes were found (G1634R in 95% of HEV-3e, G1634K in 56% of HEV-3ra, and V1479I in all HEV-3efg, clade HEV-3ra, and HEV-3k strains). Subtype-specific polymorphisms in the HEV-3 polymerase have been identified. Our study provides new complete genome sequences of HEV-3 that could be useful for comparing strains circulating in humans and the animal reservoir.


Assuntos
Variação Genética , Genótipo , Vírus da Hepatite E/classificação , Vírus da Hepatite E/genética , Hepatite E/epidemiologia , Hepatite E/virologia , Animais , França/epidemiologia , Genoma Viral , Humanos , Mutação , Filogenia , Sequenciamento Completo do Genoma
13.
BMC Cancer ; 18(1): 110, 2018 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-29382311

RESUMO

CORRECTION: After publication of the original article [1] the authors found that Table 2 had been formatted incorrectly, meaning that some rows in the Table did not display the correct information. An updated version of Table 2 is included with this Correction. The original article has also been updated.

14.
BMC Cancer ; 17(1): 549, 2017 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-28814281

RESUMO

BACKGROUND: New generation hormone-therapies (NGHT) targeting the androgen signalling pathway are nowadays proposed to elderly patients with metastatic castration-resistant prostate cancer (CRPCa). The impact of these treatments on cognitive function has never been evaluated whereas cognitive impairment may have an impact on the autonomy and the treatment adherence. The aim of this study is to prospectively assess the incidence of cognitive impairment in elderly men after treatment by NGHT for a metastatic CRPCa. METHODS/DESIGN: The Cog-Pro study is a multicentre longitudinal study including CRPCa patients ≥70 years old treated with NGHT (n = 134), control metastatic prostate cancer patients without castration resistance treated with first generation androgen deprivation therapy (n = 55), and healthy participants (n = 33), matched on age and education. Cognitive, geriatric and quality of life assessment and biological tests will be performed at baseline, 3, 6 and 12 months after start of the treatment (inclusion time). The primary endpoint is the proportion of elderly patients receiving a NGHT who will experience a decline in cognitive performances within 3 months after study enrollment. Secondary endpoints concern: autonomy, quality of life, anxiety, depression, cognitive reserve, adherence to hormone-therapy, comparison of the cognitive impact of 2 different NGHT (abiraterone acetate and enzalutamide), impact of co-morbidities and biological assessments. DISCUSSION: Evaluating, understanding and analyzing the incidence, severity of cognitive impairments and their impact on quality of life, autonomy and adherence in this group of patients with advanced disease is a challenge. This study should help to improve cancer care of elderly patients and secure the use of oral treatments as the risk of non-observance does exist. Our results will provide up-to date information for patients and caregivers on impact of these treatments on cognitive function in order to help the physicians in the choice of the treatment. TRIAL REGISTRATION: NCT02907372 , registered: July 26, 2016.

15.
Biochimie ; 141: 70-79, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28483690

RESUMO

The hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide. Although HEV is a small, naked RNA virus, HEV particles become associated with lipids in the blood of infected patients and in the supernatant of culture systems. The egress of these particles from cells implies the exocytosis pathway but the question of the role of the resulting HEV RNA containing exosomes and the nature of the lipids they contain has not been fully addressed. We determined the lipid proportions of exosomes from uninfected and HEV-infected cells and their role in HEV spreading. We cultured a suitable HEV strain on HepG2/C3A cells and analyzed the population of exosomes containing HEV RNA using lipidomics methods and electron microscopy. We also quantified HEV infectivity using an infectivity endpoint method based on HEV RNA quantification to calculate the tissue culture infectious dose 50. Exosomes produced by HEV-infected HepG2/C3A cells contained encapsidated HEV RNA. These HEV RNA-containing exosomes were infectious but ten times less than stools. HEV from stools, but not exosome-associated HEV from culture supernatant, was neutralized by anti-HEV antibodies in a dose-dependent manner. HEV infection did not influence the morphology or lipid proportions of the bulk of exosomes. These exosomes contained significantly more cholesterol, phosphatidylserine, sphingomyelin and ceramides than the parent cells, but less phosphoinositides and polyunsaturated fatty acids. Exosomes play a major role in HEV egress but HEV infection does not modify the characteristics of the bulk of exosomes produced by infected cells. PS and cholesterol enriched in these vesicles could then be critical for HEV entry. HEV particles in exosomes are protected from the immune response which could lead to the wide circulation of HEV in its host.


Assuntos
Micropartículas Derivadas de Células/imunologia , Exossomos/imunologia , Vírus da Hepatite E/imunologia , Hepatite E/imunologia , Lipídeos de Membrana/imunologia , Células Hep G2 , Hepatite E/patologia , Humanos
16.
Front Pharmacol ; 8: 138, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28377717

RESUMO

Purpose: Cognitive impairment in cancer patients induced, at least in part, by treatment are frequently observed and likely have negative impacts on patient quality of life. Such cognitive dysfunctions can affect attention, executive functions, and memory and processing speed, can persist after treatment, and their exact causes remain unclear. The aim of this review was to create an inventory and analysis of clinical studies evaluating biological markers and risk factors for cognitive decline in cancer patients before, during, or after therapy. The ultimate objectives were to identify robust markers and to determine what further research is required to develop original biological markers to enable prevention or adapted treatment management of patients at risk. Method: This review was guided by the PRISMA statement and included a search strategy focused on three components: "cognition disorders," "predictive factors"/"biological markers," and "neoplasms," searched in PubMed since 2005, with exclusion criteria concerning brain tumors, brain therapy, and imaging or animal studies. Results: Twenty-three studies meeting the criteria were analyzed. Potential associations/correlations were identified between cognitive impairments and specific circulating factors, cerebral spinal fluid constituents, and genetic polymorphisms at baseline, during, and at the end of treatment in cancer populations. The most significant results were associations between cognitive dysfunctions and genetic polymorphisms, including APOE-4 and COMT-Val; increased plasma levels of the pro-inflammatory cytokine, IL-6; anemia; and hemoglobin levels during chemotherapy. Plasma levels of specific hormones of the hypothalamo-pituitary-adrenal axis are also modified by treatment. Discussion: It is recognized in the field of cancer cognition that cancer and comorbidities, as well as chemotherapy and hormone therapy, can cause persistent cognitive dysfunction. A number of biological circulating factors and genetic polymorphisms, can predispose to the development of cognitive disorders. However, many predictive factors remain unproven and discordant findings are frequently reported, warranting additional clinical and preclinical longitudinal cohort studies, with goals of better characterization of potential biomarkers and identification of patient populations at risk and/or particularly deleterious treatments. Research should focus on prevention and personalized cancer management, to improve the daily lives, autonomy, and return to work of patients.

17.
J Pain Symptom Manage ; 50(6): 830-41, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26344551

RESUMO

CONTEXT: Although cognitive impairments have been identified in patients with non-central nervous system cancer, especially breast cancer, the respective roles of cancer and therapies, and the mechanisms involved in cognitive dysfunction remain unclear. OBJECTIVES: To report a state-of-the-art update from the International Cognitive and Cancer Task Force conference held in 2012. METHODS: A report of the meeting and recent new perspectives are presented. RESULTS: Recent clinical data support that non-central nervous system cancer per se may be involved in cognitive dysfunctions associated with inflammation parameters. The role of chemotherapy on cognitive decline was confirmed in colorectal and testicular cancers. Whereas the impact of hormone therapy remains debatable, some studies support a negative impact of targeted therapies on cognition. Regarding interventions, preliminary results of cognitive rehabilitation showed encouraging results. The methodology of future longitudinal studies has to be optimized by a priori end points, the use of validated test batteries, and the inclusion of control groups. Comorbidities and aging are important factors to be taken into account in future studies. Preclinical studies in animal models highlighted the role of cancer itself on cognition and support the possible benefits of prevention/care during chemotherapy. Progress in neuroimaging will help specify neural processes affected by treatments. CONCLUSION: Clinical data and animal models confirmed that chemotherapy induces direct cognitive deficit. The benefits of cognitive rehabilitation are still to be confirmed. Studies evaluating the mechanisms underlying cognitive impairments using advanced neuroimaging techniques integrating the evaluation of genetic factors are ongoing.


Assuntos
Cognição , Neoplasias/psicologia , Neoplasias/terapia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/prevenção & controle , Humanos , Neoplasias/diagnóstico por imagem
18.
Infect Genet Evol ; 35: 50-5, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26218544

RESUMO

Southwest France is a highly endemic region for hepatitis E virus (HEV). This study examined the circulation of HEV strains between 2003 and 2014 in the Midi-Pyrénées, and compared these data with those from the rest of France. The polyproline region (PPR) of the ORF1 region of the HEV genome was also analyzed. HEV genotype was determined by sequencing a 348-nt fragment within the ORF2 gene for 333 strains in the Midi-Pyrénées and for 571 strains from the rest of France. PPR region was characterized for 56 strains. The frequency of subgenotype 3f decreased over time, whereas subgenotype 3c increased in the Midi-Pyrénées. Repartition of strains did not differ in the Midi-Pyrénées compared to the rest of France. HEV3i and HEV4 have been recently detected throughout France. PPR lengths showed that two major groups of HEV3f exist. Our study shows that HEV3 distribution in the Midi-Pyrénées was similar to the whole of France. Local dietary habits could explain the higher seroprevalence in the Midi-Pyrénées rather the circulation of a particular variant in this region.


Assuntos
Vírus da Hepatite E/classificação , Vírus da Hepatite E/isolamento & purificação , Hepatite E/virologia , Evolução Molecular , França , Genoma Viral , Genótipo , Vírus da Hepatite E/genética , Humanos , Dados de Sequência Molecular , Peptídeos/genética , Filogenia , Filogeografia , Análise de Sequência de RNA/métodos
19.
PLoS One ; 9(12): e113533, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25436776

RESUMO

Cancer and treatments may induce cognitive impairments in cancer patients, and the causal link between chemotherapy and cognitive dysfunctions was recently validated in animal models. New cancer targeted therapies have become widely used, and their impact on brain functions and quality of life needs to be explored. We evaluated the impact of everolimus, an anticancer agent targeting the mTOR pathway, on cognitive functions, cerebral metabolism, and hippocampal cell proliferation/vascular density in mice. Adult mice received everolimus daily for 2 weeks, and behavioral tests were performed from 1 week after the last treatment. Everolimus-treated mice displayed a marked reduction in weight gain from the last day of the treatment period. Ex vivo analysis showed altered cytochrome oxidase activity in selective cerebral regions involved in energy balance, food intake, reward, learning and memory modulation, sleep/wake cycle regulation, and arousal. Like chemotherapy, everolimus did not alter emotional reactivity, learning and memory performances, but in contrast to chemotherapy, did not affect behavioral flexibility or reactivity to novelty. In vivo hippocampal neural cell proliferation and vascular density were also unchanged after everolimus treatments. In conclusion, two weeks daily everolimus treatment at the clinical dose did not evoke alteration of cognitive performances evaluated in hippocampal- and prefrontal cortex-dependent tasks that would persist at one to four weeks after the end of the treatment completion. However, acute everolimus treatment caused selective CO modifications without altering the mTOR effector P70S6 kinase in cerebral regions involved in feeding behavior and/or the sleep/wake cycle, at least in part under control of the solitary nucleus and the parasubthalamic region of the hypothalamus. Thus, this area may represent a key target for everolimus-mediating peripheral modifications, which has been previously associated with symptoms such as weight loss and fatigue.


Assuntos
Antineoplásicos/administração & dosagem , Sistema Nervoso Central/fisiologia , Cognição/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Sirolimo/análogos & derivados , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sistema Nervoso Central/citologia , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Everolimo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Sirolimo/administração & dosagem
20.
J Virol ; 88(20): 12017-25, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25100839

RESUMO

Little is known about virus adaptation in immunocompromised patients with chronic genotype 3 hepatitis E virus (HEV3) infections. Virus-host recombinant strains have been isolated recently from chronically infected patients. The nature and incidence of such recombinant events occurring during infections of solid-organ transplant (SOT) recipients are essentially unknown. The polyproline region (PPR) of strains isolated from SOT patients was sequenced during the acute-infection phase (n = 59) and during follow-up of patients whose infections became chronic (n = 27). These 27 HEV strains included 3 (11%) that showed recombinant events 12, 34, 48, or 88 months after infection. In one strain, parts of the PPR and the RNA-dependent RNA polymerase were concomitantly inserted. In the second, a fragment of a human tyrosine aminotransferase (TAT) gene was inserted first, followed by a fragment of PPR. A fragment of the human inter-α-trypsin inhibitor (ITI) gene was inserted in the third. All the inserted sequences were rich in aliphatic and basic amino acids. In vitro growth experiments suggest that the ITI insertion promoted more vigorous virus growth. In silico studies showed that the inserted sequences could provide potential acetylation, ubiquitination, and phosphorylation sites. We found that recombinant events had occurred in the HEV PPR in approximately 11% of the strains isolated from chronically infected transplant patients followed up in Toulouse University Hospital. These inserted fragments came from the HEV genome or a human gene and could enhance virus replication. Importance: Hepatitis E virus (HEV) can cause chronic infections in immunocompromised patients, including solid-organ transplant (SOT) recipients. Two strains that had undergone recombination with human ribosomal genes were described recently. The strains with inserted sequences replicated better in vitro. Little is known about the frequency of such recombinant events or how such an insertion enhances replication. We therefore investigated 59 SOT patients infected with HEV and found 3 strains with 4 recombinant events in 27 of these patients whose infection became chronic. The 4 inserted sequences were of different origins (human gene or HEV genome), but all were enriched in aliphatic and basic amino acids and provided potential regulation sites. Our data indicate that recombinant events occur in approximately 11% of strains isolated from chronically infected patients. The structures of the inserted sequences provide new clues as to how the inserted sequences could foster virus replication.


Assuntos
Vírus da Hepatite E/química , Hospedeiro Imunocomprometido , Transplante de Órgãos , Peptídeos/química , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA , Genoma Viral , Vírus da Hepatite E/genética , Vírus da Hepatite E/patogenicidade , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Homologia de Sequência de Aminoácidos
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