RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits

Mutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD

HIV/STI co-infection among men who have sex with men in Spain

In Spain, neither the HIV nor the STI national surveillance systems collect information on HIV/STI co-infection. However, there are two networks based on HIV/STI clinics which gather this data. We describe HIV prevalence in men who have sex with men (MSM) diagnosed with infectious syphilis and/or gonorrhoea in 15 STI clinics; and concurrent diagnoses of STI in MSM newly diagnosed with HIV in 19 HIV/STI clinics. In total, 572 MSM were diagnosed with infectious syphilis and 580 with gonorrhoea during 2005-2007. HIV prevalence among syphilis and gonorrhoea cases was 29.8% and 15.2% respectively. In the multivariate analysis, HIV/syphilis co-infection was associated with being Latin American; having a history of STI; reporting exclusively anal intercourse; and having sex with casual or several types of partners. HIV and gonorrhoea co-infection was associated with age older than 45 years; having no education or only primary education completed; and having a history of STI. In total, 1,462 HIV infections were newly diagnosed among MSM during 2003-2007. Of these, 31.0% were diagnosed with other STI at the same time. Factors associated with STI co-infection among new HIV cases in MSM were being Latin American; and having sex with casual partners or with both steady and casual partners. In Spain, a considerable proportion of MSM are co-infected with HIV and STI.This work was funded by two grants (36646/07; 36794/08) from the Foundation for Research and Prevention of AIDS in Spain (Fundación para la Investigación y la Prevención del SIDA en España–FIPSE).S

FAHN/SPG35 : a narrow phenotypic spectrum across disease classifications

The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers

Treatment challenges in and outside a network setting: Head and neck cancers

Head and neck cancer (HNC) is a rare disease that can affect different sites and is characterized by variable incidence and 5-year survival rates across Europe. Multiple factors need to be considered when choosing the most appropriate treatment for HNC patients, such as age, comorbidities, social issues, and especially whether to prefer surgery or radiation-based protocols. Given the complexity of this scenario, the creation of a highly specialized multidisciplinary team is recommended to guarantee the best oncological outcome and prevent or adequately treat any adverse effect. Data from literature suggest that the multidisciplinary team-based approach is beneficial for HNC patients and lead to improved survival rates. This result is likely due to improved diagnostic and staging accuracy, a more efficacious therapeutic approach and enhanced communication across disciplines. Despite the benefit of MTD, it must be noted that this approach requires considerable time, effort and financial resources and is usually more frequent in highly organized and high-volume centers. Literature data on clinical research suggest that patients treated in high-accrual centers report better treatment outcomes compared to patients treated in low-volume centers, where a lower radiotherapy-compliance and worst overall survival have been reported. There is general agreement that treatment of rare cancers such as HNC should be concentrated in high volume, specialized and multidisciplinary centers. In order to achieve this goal, the creation of international collaboration network is fundamental. The European Reference Networks for example aim to create an international virtual advisory board, whose objectives are the exchange of expertise, training, clinical collaboration and the reduction of disparities and enhancement of rationalize migration across Europe. The purpose of our work is to review all aspects and challenges in and outside this network setting planned for the management of HNC patients

Treatment challenges in and outside a specialist network setting: Pancreatic neuroendocrine tumours

Pancreatic Neuroendocrine Neoplasms comprise a group of rare tumours with special biology, an often indolent behaviour and particular diagnostic and therapeutic requirements. The specialized biochemical tests and radiological investigations, the complexity of surgical options and the variety of medical treatments that require individual tailoring, mandate a multidisciplinary approach that can be optimally achieved through an organized network. The present study describes currents concepts in the management of these tumours as well as an insight into the challenges of delivering the pathway in and outside a Network

Testicular germ-cell tumours and penile squamous cell carcinoma: Appropriate management makes the difference

Germ-cell tumours (GCT) of the testis and penile squamous cell carcinoma (PeSCC) are a rare and a very rare uro-genital cancers, respectively. Both tumours are well defined entities in terms of management, where specific recommendations - in the form of continuously up-to-dated guide lines-are provided. Impact of these tumour is relevant. Testicular GCT affects young, healthy men at the beginning of their adult life. PeSCC affects older men, but a proportion of these patients are young and the personal consequences of the disease may be devastating. Deviation from recommended management may be a reason of a significant prognostic worsening, as proper treatment favourably impacts on these tumours, dramatically on GCT and significantly on PeSCC. RARECAREnet data may permit to analyse how survivals may vary according to geographical areas, histology and age, leading to assume that non-homogeneous health-care resources may impact the cure and definitive outcomes. In support of this hypothesis, some epidemiologic datasets and clinical findings would indicate that survival may improve when appropriate treatments are delivered, linked to a different accessibility to the best health institutions, as a consequence of geographical, cultural and economic barriers. Finally, strong clues based on epidemiological and clinical data support the hypothesis that treatment delivered at reference centres or under the aegis of a qualified multi-institutional network is associated with a better prognosis of patients with these malignancies. The ERN EURACAN represents the best current European effort to answer this clinical need

iPS cell cultures from a Gerstmann-Sträussler-Scheinker patient with the Y218N PRNP mutation recapitulate tau pathology

Gerstmann-Sträussler-Scheinker (GSS) syndrome is a fatal autosomal dominant neurodegenerative prionopathy clinically characterized by ataxia, spastic paraparesis, extrapyramidal signs and dementia. In some GSS familiar cases carrying point mutations in the PRNP gene, patients also showed comorbid tauopathy leading to mixed pathologies. In this study we developed an induced pluripotent stem (iPS) cell model derived from fibroblasts of a GSS patient harboring the Y218N PRNP mutation, as well as an age-matched healthy control. This particular PRNP mutation is unique with very few described cases. One of the cases presented neurofibrillary degeneration with relevant Tau hyperphosphorylation. Y218N iPS-derived cultures showed relevant astrogliosis, increased phospho-Tau, altered microtubule-associated transport and cell death. However, they failed to generate proteinase K-resistant prion. In this study we set out to test, for the first time, whether iPS cell-derived neurons could be used to investigate the appearance of disease-related phenotypes (i.e, tauopathy) identified in the GSS patien

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe