Guillaume Grolez

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug’s clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers.MethodsThe PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking.ResultsA total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected.ConclusionDespite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.

TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment

Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C>T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C>T/p.P170L, c.239C>T/p.T80M, c.346C>T/p.R116C, c.445G>A/p.E149K, c.511C>T/p.R171W), and a stop mutation (c.489C>G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.

TRPM8 inhibits endothelial cell migration via a non-channel function by trapping the small GTPase Rap1

Endothelial cell adhesion and migration are critical steps of the angiogenic process, whose dysfunction is associated with tumor growth and metastasis. The TRPM8 channel has recently been proposed to play a protective role in prostate cancer by impairing cell motility. However, the mechanisms by which it could influence vascular behavior are unknown. Here, we reveal a novel non-channel function for TRPM8 that unexpectedly acts as a Rap1 GTPase inhibitor, thereby inhibiting endothelial cell motility, independently of pore function. TRPM8 retains Rap1 intracellularly through direct protein–protein interaction, thus preventing its cytoplasm–plasma membrane trafficking. In turn, this mechanism impairs the activation of a major inside-out signaling pathway that triggers the conformational activation of integrin and, consequently, cell adhesion, migration, in vitro endothelial tube formation, and spheroid sprouting. Our results bring to light a novel, pore-independent molecular mechanism by which endogenous TRPM8 expression inhibits Rap1 GTPase and thus plays a critical role in the behavior of vascular endothelial cells by inhibiting migration.

Magnetic Resonance Imaging Features of the Nigrostriatal System: Biomarkers of Parkinson’s Disease Stages?

Introduction Magnetic resonance imaging (MRI) can be used to identify biomarkers in Parkinson’s disease (PD); R2* values reflect iron content related to high levels of oxidative stress, whereas volume and/or shape changes reflect neuronal death. We sought to assess iron overload in the nigrostriatal system and characterize its relationship with focal and overall atrophy of the striatum in the pivotal stages of PD. Methods Twenty controls and 70 PD patients at different disease stages (untreated de novo patients, treated early-stage patients and advanced-stage patients with L-dopa-related motor complications) were included in the study. We determined the R2* values in the substantia nigra, putamen and caudate nucleus, together with striatal volume and shape analysis. We also measured R2* in an acute MPTP mouse model and in a longitudinal follow-up two years later in the early-stage PD patients. Results The R2* values in the substantia nigra, putamen and caudate nucleus were significantly higher in de novo PD patients than in controls. Early-stage patients displayed significantly higher R2* values in the substantia nigra (with changes in striatal shape), relative to de novo patients. Measurements after a two-year follow-up in early-stage patients and characterization of the acute MPTP mouse model confirmed that R2* changed rapidly with disease progression. Advanced-stage patients displayed significant atrophy of striatum, relative to earlier disease stages. Conclusion Each pivotal stage in PD appears to be characterized by putative nigrostriatal MRI biomarkers: iron overload at the de novo stage, striatal shape changes at early-stage disease and generalized striatal atrophy at advanced disease.

Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib

BackgroundProstate cancer is the second leading cause of male cancer death in developed countries. Although the role of angiogenesis in its progression is well established, the efficacy of anti-angiogenic therapy is not clearly proved. Whether this could depend on differential responses between tumor and normal endothelial cells has not been tested.MethodsWe isolated and characterized three lines of endothelial cells from prostate cancer and we tested the effect of Sunitinib and Sorafenib, and the combined treatment with the anti-androgen Casodex, on their angiogenic functions.ResultsEndothelial cells isolated from prostate tumors showed angiogenic properties and expression of androgen and vascular endothelial cell growth factor receptors. Sunitinib affected their proliferation, survival and motility while Sorafenib only showed a minor effect. At variance, Sunitinib and Sorafenib showed similar cytotoxic and anti-angiogenic effects on normal endothelial cells. Sorafenib and Sunitinib inhibited vascular endothelial cell growth factor receptor2 phosphorylation of prostate cancer endothelial cells, while they differentially modulated Akt phosphorylation as no inhibitory effect of Sorafenib was observed on Akt activation. The combined treatment of Casodex reverted the observed resistance to Sorafenib both on cell viability and on Akt activation, whereas it did not modify the response to Sunitinib.ConclusionsOur study demonstrates a resistant behavior of endothelial cells isolated from prostate cancer to Sorafenib, but not Sunitinib. Moreover, it shows the benefit of a multi-target therapy combining anti-angiogenic and anti-hormonal drugs to overcome resistance.

TRPM8 and prostate: a cold case?

While originally cloned from the prostate in 2001, transient receptor potential, melastatin member 8 (TRPM8) has since been identified as the cold/menthol receptor in the peripheral nervous system. This discovery has led to hundreds of studies regarding the role of this channel in pain and thermosensation phenomena, while relegating TRPM8 involvement in cancer to a secondary role. Despite these findings, there is growing evidence that TRPM8 should be carefully studied within the frame of carcinogenesis, especially in the prostate, where it is highly expressed and where many teams have confirmed variations in its expression during cancer progression. Its regulation by physiological factors, such as PSA and androgens, has proved that TRPM8 can exhibit an activity beyond that of a cold receptor, thus explaining how the channel can be activated in organs not exposed to temperature variations. With this review, we aim to provide a brief overview of the current knowledge regarding the complex roles of TRPM8 in prostate carcinogenesis and to show that this research path still represents a “hot” topic with potential clinical applications in the short term.