Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative demyelinating disease of the central nervous system. It is a complex and heterogeneous disease caused by a combination of ...genetic and environmental factors, and it can cluster in families.
to evaluate at gene-level the aggregate contribution of predicted damaging low-frequency and rare variants to MS risk in multiplex families.
We performed whole exome sequencing (WES) in 28 multiplex MS families with at least 3 MS cases (81 affected and 42 unaffected relatives) and 38 unrelated healthy controls. A gene-based burden test was then performed, focusing on two sets of candidate genes: i) literature-driven selection and ii) data-driven selection.
We identified 11 genes enriched with predicted damaging low-frequency and rare variants in MS compared to healthy individuals. Among them, UBR2 and DST were the two genes with the strongest enrichment (p = 5 × 10−4 and 3 × 10−4, respectively); interestingly enough the association signal in UBR2 is driven by rs62414610, which was present in 25% of analysed families.
Despite limitations, this is one of the first studies evaluating the aggregate contribution of predicted damaging low-frequency and rare variants in MS families using WES data. A replication effort in independent cohorts is warranted to validate our findings and to evaluate the role of identified genes in MS pathogenesis.
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•We evaluated at gene-level the aggregate contribution of damaging low-frequency and rare variants to multiple sclerosis risk in multiplex families adopting a literature-driven and data-driven candidate gene selection;•Twelve genes were identified to be enriched in damaging low-frequency and rare variants in multiple sclerosis affected subjects compared to unaffected individuals.•In UBR2 gene, one of the top associated genes, the signal was mostly driven by rs62414610-A, a missense damaging variant which was in 22% MS patients across 25% of families.
Multiple Sclerosis (MS) is caused by a still unknown interplay between genetic and environmental factors. Epigenetics, including DNA methylation, represents a model for environmental factors to ...influence MS risk.
Twenty-six affected and 26 unaffected relatives from 8 MS multiplex families were analysed in a multicentric Italian study using MeDIP-Seq, followed by technical validation and biological replication in two additional families of differentially methylated regions (DMRs) using SeqCap Epi Choice Enrichment kit (Roche®).
Associations from MeDIP-Seq across families were combined with aggregation statistics, yielding 162 DMRs at FDR ≤ 0.1. Technical validation and biological replication led to 2 hypo-methylated regions, which point to NTM and BAI3 genes, and to 2 hyper-methylated regions in PIK3R1 and CAPN13.
These 4 novel regions contain genes of potential interest that need to be tested in larger cohorts of patients.
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•The 233 genetic loci associated with MS explain less than 40% of disease heritability, leaving a role to epigenetics in disease risk•We compared whole-genome methylation profiles in whole blood of affected and unaffected relatives of 8 multiplex MS families•We used MeDIP-seq and technical and biological replication in 2 additional families using a custom panel•Due to the heterogeneity of results in families, we adopted a method which leveraged consistency of signal across families•Filtering criteria lead to 2 hypo- and 2 hyper-methylated DMRs which relate to NTM, BAI3, PIK3R1 and CAPN13 genes•Replication of these signals is needed in additional cohort of MS patients
•Multiple sclerosis can present with tumefactive relapsing lesions.•Brain biopsy could help in differential diagnosis.•Alemtuzumab led to a sustained remission after 4 years of follow-up.
Background:
The role of genetic factors in influencing the clinical expression of multiple sclerosis (MS) is unclear.
Objective:
The objective of this paper is to identify genes, pathways and ...networks implicated in age at onset (AAO) and severity, measured using the Multiple Sclerosis Severity Score (MSSS), of primary-progressive MS (PPMS).
Methods:
We conducted a genome-wide association study (GWAS) of 470 PPMS patients of Italian origin:. Allelic association of 296,589 SNPs with AAO and MSSS was calculated. Pathway and network analyses were also conducted using different tools.
Results:
No single association signal exceeded genome-wide significance in AAO and MSSS analyses. Nominally associated genes to AAO and MSSS were enriched in both traits for 10 pathways, including: “oxidative phosphorylation” (FDRAAO=9*10−4; FDRMSSS=3.0*10−2), “citrate (TCA) cycle” (FDRAAO=1.6*10−2; FDRMSSS=3.2*10−3), and “B cell receptor signaling” (FDRAAO=3.1*10−2; FDRMSSS=2.2*10−3). In addition, an enrichment of “chemokine signaling pathway” (FDR=9*10−4) for AAO and of “leukocyte transendothelial migration” (FDR=2.4*10−3) for MSSS trait was observed, among others. Network analysis revealed that p53 and CREB1 were central hubs for AAO and MSSS traits, respectively.
Conclusions:
Despite the fact that no major effect signals emerged in the present GWAS, our data suggest that genetic variants acting in the context of oxidative stress and immune dysfunction could modulate the onset and severity of PPMS.
Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity and mortality. In an uncontrolled study published in 2005, administration of CMV-specific hyperimmune globulin to ...pregnant women with primary CMV infection significantly reduced the rate of intrauterine transmission, from 40% to 16%.
We evaluated the efficacy of hyperimmune globulin in a phase 2, randomized, placebo-controlled, double-blind study. A total of 124 pregnant women with primary CMV infection at 5 to 26 weeks of gestation were randomly assigned within 6 weeks after the presumed onset of infection to receive hyperimmune globulin or placebo every 4 weeks until 36 weeks of gestation or until detection of CMV in amniotic fluid. The primary end point was congenital infection diagnosed at birth or by means of amniocentesis.
A total of 123 women could be evaluated in the efficacy analysis (1 woman in the placebo group withdrew). The rate of congenital infection was 30% (18 fetuses or infants of 61 women) in the hyperimmune globulin group and 44% (27 fetuses or infants of 62 women) in the placebo group (a difference of 14 percentage points; 95% confidence interval, -3 to 31; P=0.13). There was no significant difference between the two groups or, within each group, between the women who transmitted the virus and those who did not, with respect to levels of virus-specific antibodies, T-cell-mediated immune response, or viral DNA in the blood. The clinical outcome of congenital infection at birth was similar in the two groups. The number of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%).
In this study involving 123 women who could be evaluated, treatment with hyperimmune globulin did not significantly modify the course of primary CMV infection during pregnancy. (Funded by Agenzia Italiana del Farmaco; CHIP ClinicalTrials.gov number, NCT00881517; EudraCT no. 2008-006560-11.).
Currently, few evidences have shown the possible involvement of autoimmunity in patients affected by coronavirus disease 2019 (COVID‐19). In this study, we elucidate whether severe acute respiratory ...syndrome coronavirus disease 2 (SARS‐CoV‐2) stimulates autoantibody production and contributes to autoimmunity activation. We enrolled 40 adult patients (66.8 years mean age) admitted to Alessandria Hospital between March and April 2020. All the patients had a confirmed COVID‐19 diagnosis and no previously clinical record of autoimmune disease. Forty blood donors were analyzed for the same markers and considered as healthy controls. Our patients had high levels of common inflammatory markers, such as C reactive protein, lactate dehydrogenase, ferritin, and creatinine. Interleukin‐6 concentrations were also increased, supporting the major role of this interleukin during COVID‐19 infection. Lymphocyte numbers were generally lower compared with healthy individuals. All the patients were also screened for the most common autoantibodies. We found a significant prevalence of antinuclear antibodies, antineutrophil cytoplasmic antibodies, and ASCA immunoglobulin A antibodies. We observed that patients having a de novo autoimmune response had the worst acute viral disease prognosis and outcome. Our results sustain the hypothesis that COVID‐19 infection correlates with the autoimmunity markers. Our study might help clinicians to: (a) better understand the heterogeneity of this pathology and (b) correctly evaluate COVID‐19 clinical manifestations. Our data explained why drugs used to treat autoimmune diseases may also be useful for SARS‐CoV‐2 infection. In addition, we highly recommend checking patients with COVID‐19 for autoimmunity markers, mainly when deciding on whether to treat them with plasma transfer therapy.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
☑ Recent data sustain the idea that autoimmune phenomena exist in patients with coronavirus disease 2019 (COVID‐19), but other investigations are necessary to define the possible link between severe acute respiratory syndrome coronavirus disease 2 (SARS‐CoV‐2) infection and autoimmune disease onset.
WHAT QUESTION DID THIS STUDY ADDRESS?
☑ In this monocentric study, we demonstrated how SARS‐CoV‐2 infection could be associated with an autoimmune response and development of autoantibodies.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
☑ Patients with COVID‐19 having an increased level of inflammatory markers and strong autoantibodies positivity (i.e., antinuclear antibodies and antineutrophil cytoplasmic antibodies) presented the worst clinical outcome.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
☑ These results suggest that the drugs normally used to treat autoimmune diseases should also be considered during SARS‐CoV‐2, improving public health. In addition, before starting a transfer plasma therapy, it is important to also evaluate the autoimmunity conditions of the patients with COVID‐19. Transferring antibodies or trying to neutralize them should be done with precaution. It is possible that the risk of developing or increasing the autoimmune response may enhance.
Summary
Background
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced ...HCC, clinical response is highly variable.
Aim
To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC.
Methods
In this prospective multicentre cohort study, patients with advanced‐stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively.
Results
A total of 634 patients with advanced‐stage HCC receiving sorafenib were recruited to the study, with a median follow‐up of 6692.3 person‐months at risk. The majority of patients were male (81%) with Child–Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8–18.6 months). 94% experienced at least one sorafenib‐related toxicity: 34% diarrhoea, 16% hypertension and 37% hand‐foot syndrome (HFS). Twenty‐one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib‐related diarrhoea (HR 0.76, 95% CI 0.61–0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37–0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51–0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose.
Conclusion
Development of sorafenib‐related toxicity including diarrhoea, hypertension and hand‐foot syndrome is associated with prolonged overall survival in patients with advanced‐stage HCC on sorafenib.
Linked ContentThis article is linked to Clare et al and Sharma papers. To view these articles visit https://doi.org/10.1111/apt.14033 and https://doi.org/10.1111/apt.14067.
GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is ...not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.
Background
Migraine attacks may present different features in different patients and also within the same patient. The percentage of patients reporting stereotyped attacks and those reporting attacks ...with different phenotypes has not been the object of specific investigations.
Objective
The objective of this article is to evaluate the percentage of migraine patients reporting the same characteristics, in terms of phenotype and response to symptomatic medications on three consecutive migraine attacks.
Methods
Thirty patients with migraine without aura prospectively recorded the features of three consecutive attacks in a headache diary. Characteristics recorded were: pain intensity, presence of nausea, vomiting, photophobia, phonophophia, osmophobia, allodynia, cranial autonomic symptoms (at least one), and premonitory symptoms. Patients were allowed to take frovatriptan as symptomatic medication, whose efficacy was evaluated as the two hours pain-free status.
Results
None of the patients presented identical characteristics on the three studied attacks. This was still the case if we reduced the number of variables evaluated from 11 to seven of the eight core features indicated by the ICHD. Considering just six variables: unilaterality and quality of pain, presence/absence of nausea, vomiting, photophobia and phonophobia, only two patients (6%) had identical features on three consecutive attacks.
With respect to the response to frovatriptan, 39% of patients had the same response, either positive (i.e. pain free after two hours) or negative (i.e. not pain free after two hours) on three consecutive attacks.
Conclusion
Migraine attacks show a high variability not just among patients, but also within the same patient. Our data indicate that stereotypy of attacks is uncommon, and reinforces the underlying logic of the current operational classification system.
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