Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia ...are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional-cognitive factors, the mind-body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals.
The goal of this study was to determine whether an association exists between circulating microRNA (miRNA) levels and disease progression in chronic hepatitis C (CHC), whether plasma or extracellular ...vesicles (EVs) were optimal for miRNA measurement and their correlation with hepatic miRNA expression, and the mechanistic plausibility of this association. We studied 130 CHC patients prospectively followed over several decades. A comprehensive miRNA profile in plasma using microarray with 2578 probe sets showed 323 miRNAs differentially expressed between healthy individuals and CHC patients, but only six that distinguished patients with mild versus severe chronic hepatitis. Eventually, let‐7a/7c/7d‐5p and miR‐122‐5p were identified as candidate predictors of disease progression. Cross‐sectional analyses at the time of initial liver biopsy showed that reduced levels of let‐7a/7c/7d‐5p (let‐7s) in plasma were correlated with advanced histological hepatic fibrosis stage and other fibrotic markers, whereas miR‐122‐5p levels in plasma were positively correlated with inflammatory activity, but not fibrosis. Measuring let‐7s levels in EVs was not superior to intact plasma for discriminating significant hepatic fibrosis. Longitudinal analyses in 60 patients with paired liver biopsies showed that let‐7s levels in plasma markedly declined over time in parallel with fibrosis progression. However, circulating let‐7s levels did not parallel those in the liver. Conclusion: Of all miRNAs screened, the let‐7 family showed the best correlation with hepatic fibrosis in CHC. A single determination of let‐7s levels in plasma did not have superior predictive value for significant hepatic fibrosis compared with that of fibrosis‐4 index, but the rate of let‐7s decline in paired longitudinal samples correlated well with fibrosis progression. Pathway analysis suggested that low levels of let‐7 may influence hepatic fibrogenesis through activation of transforming growth factor β signaling in hepatic stellate cells. (Hepatology 2016;64:732‐745)
An immunologic portrait of cancer Ascierto, Maria Libera; De Giorgi, Valeria; Liu, Qiuzhen ...
Journal of translational medicine,
08/2011, Letnik:
9, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The advent of high-throughput technology challenges the traditional histopathological classification of cancer, and proposes new taxonomies derived from global transcriptional patterns. Although most ...of these molecular re-classifications did not endure the test of time, they provided bulk of new information that can reframe our understanding of human cancer biology. Here, we focus on an immunologic interpretation of cancer that segregates oncogenic processes independent from their tissue derivation into at least two categories of which one bears the footprints of immune activation. Several observations describe a cancer phenotype where the expression of interferon stimulated genes and immune effector mechanisms reflect patterns commonly observed during the inflammatory response against pathogens, which leads to elimination of infected cells. As these signatures are observed in growing cancers, they are not sufficient to entirely clear the organism of neoplastic cells but they sustain, as in chronic infections, a self-perpetuating inflammatory process. Yet, several studies determined an association between this inflammatory status and a favorable natural history of the disease or a better responsiveness to cancer immune therapy. Moreover, these signatures overlap with those observed during immune-mediated cancer rejection and, more broadly, immune-mediated tissue-specific destruction in other immune pathologies. Thus, a discussion concerning this cancer phenotype is warranted as it remains unknown why it occurs in immune competent hosts. It also remains uncertain whether a genetically determined response of the host to its own cancer, the genetic makeup of the neoplastic process or a combination of both drives the inflammatory process. Here we reflect on commonalities and discrepancies among studies and on the genetic or somatic conditions that may cause this schism in cancer behavior.
Abstract
Background
Adherence is a key factor for therapeutic success in patients with rheumatoid arthritis (RA). The aim of this study was to determine whether results from the 5-item Compliance ...Questionnaire for Rheumatology (CQR5) can predict future poor adherence to biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with RA, using medication possession ratio (MPR) as the gold standard comparator.
Methods
RA patients starting a bDMARD were prospectively followed for 12 months. At baseline, CQR5 was collected in relation to the prescribed bDMARD. Patients were dichotomised into good adherers and poor adherers, categories that were then used as the variable in a predictive function analysis of the CQR5 in order to determine the accuracy of the classification at the end of the study period in comparison with the MPR. The sensitivity, specificity, and likelihood ratio of detecting poor adherers were also determined because this is the clinically important purpose of the questionnaire. Satisfactory adherence was defined as > 80% compliance with the prescribed dose regimen.
Results
Of the 210 RA patients enrolled (147 women and 63 men; mean age 58.6 ± 12.8 years; mean disease duration 7.4 ± 2.5 years), at the end of the 12-month follow-up, 152 patients (72.4%) were good adherers and 58 (27.6%) were poor adherers according to MPR. Predictive analyses showed that the sensitivity and specificity of the CQR5 in detecting poor adherence were respectively 89.9% (95% CI 84.07–94.10%) and 80.8% (95% CI 67.46–90.37%). The accuracy of the CQR5 was 83.04% (95% CI 77.27–87.85%), the positive likelihood ratio (i.e. detecting ≤ 80% adherence) 4.67 (95% CI 2.58–8.18), and the area under curve 0.85 (95% CI 0.79–0.89).
Conclusion
Higher baseline CQR5 scores significantly predict the treatment adherence of RA patients. This suggests that this instrument could be used for screening purposes in order to identify patients who are poorly adherent to bDMARDs.
Erythrocytes bind circulating immune complexes (ICs) and facilitate IC clearance from the circulation. Chronic hepatitis C virus (HCV) infection is associated with IC‐related disorders. In this ...study, we investigated the kinetics and mechanism of HCV and HCV‐IC binding to and dissociation from erythrocytes. Cell culture‐produced HCV was mixed with erythrocytes from healthy blood donors, and erythrocyte‐associated virus particles were quantified. Purified complement proteins, complement‐depleted serum, and complement receptor antibodies were used to investigate complement‐mediated HCV‐erythrocyte binding. Purified HCV‐specific immunoglobulin G (IgG) from a chronic HCV‐infected patient was used to study complement‐mediated HCV‐IC/erythrocyte binding. Binding of HCV to erythrocytes increased 200‐ to 1,000‐fold after adding complement active human serum in the absence of antibody. Opsonization of free HCV occurred within 10 minutes, and peak binding to erythrocytes was observed at 20‐30 minutes. Complement protein C1 was required for binding, whereas C2, C3, and C4 significantly enhanced binding. Complement receptor 1 (CR1, CD35) antibodies blocked the binding of HCV to erythrocytes isolated from chronically infected HCV patients and healthy blood donors. HCV‐ICs significantly enhanced complement‐mediated binding to erythrocytes compared to unbound HCV. Dissociation of complement‐opsonized HCV from erythrocytes depended on the presence of Factor I. HCV released by Factor I bound preferentially to CD19+ B cells compared to other leukocytes. Conclusion: These results demonstrate that complement mediates the binding of free and IC‐associated HCV to CR1 on erythrocytes and provide a mechanistic rationale for investigating the differential phenotypic expression of HCV‐IC–related disease.
We evaluated saliva (SAL) specimens for SARS-CoV-2 reverse transcriptase PCR (RT-PCR) testing by comparison of 459 prospectively paired nasopharyngeal (NP) or midturbinate (MT) swabs from 449 ...individuals with the aim of using saliva for asymptomatic screening. Samples were collected in a drive-through car line for symptomatic individuals (
= 380) and in the emergency department (ED) (
= 69). The percentages of positive and negative agreement of saliva compared to nasopharyngeal swab were 81.1% (95% confidence interval CI, 65.8% to 90.5%) and 99.8% (95% CI, 98.7% to 100%), respectively. The percent positive agreement increased to 90.0% (95% CI, 74.4% to 96.5%) when considering only samples with moderate to high viral load (cycle threshold
for the NP, ≤34). Pools of five saliva specimens were also evaluated on three platforms, bioMérieux NucliSENS easyMAG with ABI 7500Fast (CDC assay), Hologic Panther Fusion, and Roche Cobas 6800. The average loss of signal upon pooling was 2 to 3
values across the platforms. The sensitivities of detecting a positive specimen in a pool compared with testing individually were 94%, 90%, and 94% for the CDC 2019-nCoV real-time RT-PCR, Panther Fusion SARS-CoV-2 assay, and Cobas SARS-CoV-2 test, respectively, with decreased sample detection trending with lower viral load. We conclude that although pooled saliva testing, as collected in this study, is not quite as sensitive as NP/MT testing, saliva testing is adequate to detect individuals with higher viral loads in an asymptomatic screening program, does not require swabs or viral transport medium for collection, and may help to improve voluntary screening compliance for those individuals averse to various forms of nasal collections.
Several variants of SARS-CoV-2 have emerged. Those with mutations in the angiotensin-converting enzyme (ACE2) receptor binding domain (RBD) are associated with increased transmission and severity. In ...this study, we developed both antibody quantification and functional neutralization assays. Analyses of both COVID-19 convalescent and diagnostic cohorts strongly support the use of RBD antibody levels as an excellent surrogate to biochemical neutralization activities. Data further revealed that the samples from mRNA vaccinated individuals had a median of 17 times higher RBD antibody levels and a similar degree of increased neutralization activities against RBD-ACE2 binding than those from natural infections. Our data showed that N501Y RBD had fivefold higher ACE2 binding than the original variant. While some antisera from naturally infected subjects had substantially reduced neutralization ability against N501Y RBD, all blood samples from vaccinated individuals were highly effective in neutralizing it. Thus, our data indicates that mRNA vaccination may generate more neutralizing RBD antibodies than natural immunity. It further suggests a potential need to maintain high RBD antibody levels to control the more infectious SARS-CoV-2 variants.
Since March 2020, the outbreak of Sars-CoV-2 pandemic has changed medical practice and daily routine around the world. Huge efforts from pharmacological industries have led to the development of ...COVID-19 vaccines. In particular two mRNA vaccines, namely the BNT162b2 (Pfizer-BioNTech) and the mRNA-1273 (Moderna), and a viral-vectored vaccine, i.e. ChAdOx1 nCoV-19 (AstraZeneca), have recently been approved in Europe. Clinical trials on these vaccines have been published on the general population showing a high efficacy with minor adverse events. However, specific data about the efficacy and safety of these vaccines in patients with immune-mediated inflammatory diseases (IMIDs) are still lacking. Moreover, the limited availability of these vaccines requires prioritizing some vulnerable categories of patients compared to others. In this position paper, we propose the point of view about the management of COVID-19 vaccination from Italian experts on IMIDs and the identification of high-risk groups according to the different diseases and their chronic therapy.
BackgroundCoronavirus disease 2019 (COVID-19) results in robust but dysregulated acute immune response characterized by pro-inflammatory cytokine production and T-cell exhaustion, but little is known ...concerning immune response following recovery. We assessed immune function in convalescent plasma donors (CCD) who had recovered from COVID-19.MethodsThe cellular immune response and T-cell receptor (TCR) diversity in CCD was investigated using the nCounter host response and TCR diversity panels. 270 CCD and 40 healthy donor (HD) blood samples collected 11 to 193 days after diagnosis were analyzed. The CCD samples were from 162 donors, 69 donated more than once. All HD donated only once.ResultsMany genes were differentially expressed for months following infection. Analysis of samples collected 0 to 90 days post-diagnosis found that 19 of 773 genes were differentially expressed among CCD and HD (FDR < 0.05) (figure 1a). At 90 to 120 days, 120 to 150 and >150 post-diagnosis, 13, 58 and 4 genes were differentially expressed respectively (FDR < 0.05) (figures 1b-d). At 120 to 150 days the differentially expressed genes included those in Treg differentiation, type III interferon signaling and chemokine signaling pathways. 76 genes were differently expressed at least once during the time windows described above. (Figure 1e). Among CCD, the expression of CTLA-4, ICOS, ICOSLG, OSM and CXCR4 were initially elevated but fell to HD levels at the end of the study period. The expression of LILRA6, CCR2 and CX3CR1 increased or remained elevated throughout (figure 1f).A subset of samples departed notably from the average trend. The transcriptome of each CCD sample was scored by its similarity to the mean transcriptome of HD samples. This analysis revealed 21 CCD samples from 19 unique donors were highly perturbed from HD samples (figure 2a). Among these highly perturbed samples 80% were collected > 90 days post-diagnosis. The perturbed samples clustered into two groups, labelled P1 and P2 (figure 2b) and displayed dysregulation of distinct gene sets (figures 2c, 2d). The P1 were characterized by increased expression of genes in myeloid inflammation, type 1 interferon and innate immune signaling pathways, lower COVID antibody levels and increased T-cell receptor diversity. P2 were characterized by highly up-regulated CD44, BCL2, TGFB1, IL18BP, IL27RA, and IL11RA.Abstract 953 Figure 1Longitudinal trends in CCD gene expression. a-d: Differential expression results in HD vs. 4 time windows of CCD. Genes with FDR <0.1 are labeled; e: average CCD log2 fold-changes from HD over time. Color is only given for times where the Loess regression is different from the mean HD with p < 0.05; f: longitudinal results for selected genes. Orange lines connect CCD samples over time. Blue lines show inner 95% quantiles of HD samplesAbstract 953 Figure 2CCD with more severe departure from HD gene expression. a: CCD samples (in orange) were scored for perturbation from the mean HD (in blue), and 21 highly perturbed sample subsets emerged; b: clustering of the 21 highly perturbed patients. The dendrogram was cut to define two groups. c: volcano plots comparing expression in P1 (left) and P2 (right) vs. CCD; d: longitudinal trends of selected genes perturbed in P1 and P2ConclusionsImmune dysregulation in CCD continues at least 6 months post-infection. Some CCDs experienced marked transcriptional changes which may be the result of COVID-19 reactivation and could be responsible for long-haul syndrome.AcknowledgementsN/ATrial RegistrationNCT04360278ReferencesN/A Ethics ApprovalN/AConsentN/A
Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic ...liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.
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