Long non-coding RNAs play a role in the pathogenesis of psoriatic arthritis by regulating microRNAs and genes involved in inflammation and metabolic syndrome

Psoriatic arthritis (PsA) is an inflammatory arthritis, characterized by inflammation of entheses and synovium, leading to joint erosions and new bone formation. It affects 10-30% of patients with psoriasis, and has an estimated prevalence of approximately 1%. PsA is considered to be primarily an autoimmune disease, driven by autoreactive T cells directed against autoantigens present in the skin and in the joints. However, an autoinflammatory origin has recently been proposed. Long noncoding RNAs (lncRNAs) are RNAs more than 200 nucleotides in length that do not encode proteins. LncRNAs play important roles in several biological processes, including chromatin remodeling, transcription control, and post-transcriptional processing. Several studies have shown that lncRNAs are expressed in a stage-specific or lineage-specific manner in immune cells that have a role in the development, activation, and effector functions of immune cells. LncRNAs are thought to play a role in several diseases, including autoimmune disorders. Indeed, a few lncRNAs have been identified in systemic lupus erythematosus, rheumatoid arthritis, and psoriasis. Although several high-throughput studies have been performed to identify lncRNAs, their biological and pathological relevance are still unknown, and most transcriptome studies in autoimmune diseases have only assessed protein-coding transcripts. No data are currently available on lncRNAs in PsA. Therefore, by microarray analysis, we have investigated the expression profiles of more than 50,000 human lncRNAs in blood samples from PsA patients and healthy controls using Human Clariom D Affymetrix chips, suitable to detect rare and low-expressing transcripts otherwise unnoticed by common sequencing methodologies. Network analysis identified lncRNAs targeting highly connected genes in the PsA transcriptome. Such genes are involved in molecular pathways crucial for PsA pathogenesis, including immune response, glycolipid metabolism, bone remodeling, type 1 interferon, wingless related integration site, and tumor necrosis factor signaling. Selected lncRNAs were validated by RT-PCR in an expanded cohort of patients. Moreover, modulated genes belonging to meaningful pathways were validated by RT-PCR in PsA PBMCs and/or by ELISA in PsA sera. The findings indicate that lncRNAs are involved in PsA pathogenesis by regulating both microRNAs and genes and open new avenues for the identification of new biomarkers and therapeutical targets

Upregulated Expression of Toll-like Receptor 4 in Peripheral Blood of Ischaemic Stroke Patients Correlates with Cyclooxygenase 2 Expression

AbstractObjectivesAn inflammatory process following stroke in human brains and systemic inflammatory responses after stroke in humans have been reported by numerous investigators. The aim of the study was to investigate if genes involved in the cyclooxygenase 2 (COX-2) pathway are upregulated at peripheral level in patients after transient ischaemic attack (TIA) and stroke.Design of StudyBlood samples were obtained from two groups of patients undergoing carotid endarterectomy. The first group included 25 patients who presented TIA or ischaemic stroke. The second group included 35 patients who had an asymptomatic internal carotid artery stenosis. Total RNA was isolated and the expression of Toll-like Receptor 4 (TLR4), COX-2, membrane-associated Prostaglandin E synthase (mPGES-1), Prostaglandin E2 receptors (EP3 and EP4) was analysed by real time RT-PCR.ResultsExpression of COX-2 and TLR4 were significantly increased in symptomatic patients (p<0.001). Correlation analysis showed that TLR4 expression significantly correlated with COX-2 expression (R=0.65; p<0.01) in ischaemic stroke patients. This correlation was not observed in TIA and asymptomatic patients.ConclusionsOur results suggest that the peripheral mechanism of inflammatory injury after stroke may be mediated by TLR4 through a COX-2-dependent pathway

Secondary hypogammaglobulinemia in Waldmann's disease treated with subcutaneous immunoglobulins

Primary intestinal lymphangiectasia (PIL) is rare disorder characterized by congenital malformation or obstruction of intestinal lymphatic drainage; it is responsible for protein losing enteropathy leading to lymphopenia, hypoalbuminemia and hypogammaglobulinemia. A low-fat diet associated with medium-chain triglyceride supplementation is the cornerstone of PIL management. The administration of intravenous immunoglobulins does not always lead to satisfactory plasma levels and therefore the replacement therapy with immunoglobulins is controversial. We describe here the case of a patient with PIL and severe hypogammaglobulinemia treated with immunoglobulins. The striking aspect of this case is the clinical and serological benefit obtained with the subcutaneous compared to the intravenous immunoglobulins administration

Guidelines for the diagnosis and treatment of basal cell carcinoma: a GRADE approach for evidence evaluation and recommendations by the Italian Association of Medical Oncology

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care

Timing of sentinel node biopsy independently predicts disease-free and overall survival in clinical stage I-II melanoma patients: A multicentre study of the Italian Melanoma Intergroup (IMI)

Background: Sentinel lymph node biopsy (SNB) still remains a key procedure to appropriately stage melanoma patients and to select those who are candidate to novel treatments with immunotherapy and targeted therapy in the adjuvant setting. The impact of timing of SNB on disease-free survival (DFS) and overall survival (OS) is still unclear. Material and methods: The study was conducted at 6 Italian Melanoma Intergroup (IMI) centres and included 8953 consecutive clinical stage I-II melanoma patients who were diagnosed, treated, and followed up between November 1997 and March 2018. All patients were prospectively included in dedicated IMI database. Multivariable Cox regression analyses were performed to investigate how baseline characteristics and time interval until SNB are related to DFS and OS. Results: Considering the whole population, at multivariable analysis, after adjusting for age, gender, Breslow thickness, site, ulceration, and the SNB status, a delay in the timing of SNB was associated with a better DFS (adjusted hazard ratio [aHR, delayed versus early SNB] 0.98, 95% confidence interval [CI] 0.97\u20130.99, p < 0.001) and OS (aHR 0.98, 95% CI 0.97\u20130.99, p = 0.001). Specifically, in patients with a negative SNB status, a beneficial impact of delayed SNB (i.e. at least 32 days after primary excision) was confirmed for DFS (aHR 0.70, 95%CI 0.63\u20130.79, p < 0.001) and OS (aHR 0.69, 95%CI 0.61\u20130.78, p < 0.001), whereas in those with a positive SNB status, DFS (aHR 0.96, 95%CI 0.84\u20131.09, p = 0.534) and OS (aHR 0.94 95%CI 0.81\u20131.08, p = 0.374) were not significantly different in patients with early or delayed SNB. Conclusions: Our study does not support a strict time interval for SNB. These results may be useful for national guidelines, for counselling patients and reducing the number of high urgency referrals

Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors.

BACKGROUND: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. PATIENTS AND METHODS: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. RESULTS: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. CONCLUSIONS: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor

The role of sentinel node tumor burden in modeling the prognosis of melanoma patients with positive sentinel node biopsy: an Italian melanoma intergroup study (N = 2,086)

Background The management of melanoma patients with metastatic melanoma in the sentinel nodes (SN) is evolving based on the results of trials questioning the impact of completion lymph node dissection (CLND) and demonstrating the efficacy of new adjuvant treatments. In this landscape, new prognostic tools for fine risk stratification are eagerly sought to optimize the therapeutic path of these patients. Methods A retrospective cohort of 2,086 patients treated with CLND after a positive SN biopsy in thirteen Italian Melanoma Centers was reviewed. Overall survival (OS) was the outcome of interest; included independent variables were the following: age, gender, primary melanoma site, Breslow thickness, ulceration, sentinel node tumor burden (SNTB), number of positive SN, non-sentinel lymph nodes (NSN) status. Univariate and multivariate survival analyses were performed using the Cox proportional hazard regression model. Results The 3-year, 5-year and 10-year OS rates were 79%, 70% and 54%, respectively. At univariate analysis, all variables, except for primary melanoma body site, were found to be statistically significant prognostic factors. Multivariate Cox regression analysis indicated that older age (P &lt; 0.0001), male gender (P = 0.04), increasing Breslow thickness (P &lt; 0.0001), presence of ulceration (P = 0.004), SNTB size (P &lt; 0.0001) and metastatic NSN (P &lt; 0.0001) were independent negative predictors of OS. Conclusion The above results were utilized to build a nomogram in order to ease the practical implementation of our prognostic model, which might improve treatment personalization

Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α is considered to play a role. In the present study the putative involvement of TNF-α gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-α gene polymorphisms in a Caucasian COPD population. METHODS: TNF-α gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 ± 13%, and compared with a Dutch population control group of 358 subjects. RESULTS: The data showed that the TNF-α +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-α gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-α polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-α +489G/A genotype in patients without radiological emphysema (χ(2)-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed. CONCLUSION: Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-α +489G/A gene polymorphism

Nationwide multidisciplinary consensus on the clinical management of Merkel cell carcinoma: a Delphi panel

Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma. The MCC incidence rate has rapidly grown over the last years, with Italy showing the highest increase among European countries. This malignancy has been the focus of active scientific research over the last years, focusing mainly on pathogenesis, new therapeutic trials and diagnosis. A national expert board developed 28 consensus statements that delineated the evolution of disease management and highlighted the paradigm shift towards the use of immunological strategies, which were then presented to a national MCC specialists panel for review. Sixty-five panelists answered both rounds of the questionnaire. The statements were divided into five areas: a high level of agreement was reached in the area of guidelines and multidisciplinary management, even if in real life the multidisciplinary team was not always represented by all the specialists. In the diagnostic pathway area, imaging played a crucial role in diagnosis and initial staging, planning for surgery or radiation therapy, assessment of treatment response and surveillance of recurrence and metastases. Concerning diagnosis, the usefulness of Merkel cell polyomavirus is recognized, but the agreement and consensus regarding the need for cytokeratin evaluation appears greater. Regarding the areas of clinical management and follow-up, patients with MCC require customized treatment. There was a wide dispersion of results and the suggestion to increase awareness about the adjuvant radiation therapy. The panelists unanimously agreed that the information concerning avelumab provided by the JAVELIN Merkel 200 study is adequate and reliable and that the expanded access program data could have concrete clinical implications. An immunocompromised patient with advanced MCC can be treated with immunotherapy after multidisciplinary risk/benefit assessment, as evidenced by real-world analysis and highlighted in the guidelines. A very high consensus regarding the addition of radiotherapy to treat the ongoing focal progression of immunotherapy was observed. This paper emphasizes the importance of collaboration and communication among the interprofessional team members and encourages managing patients with MCC within dedicated multidisciplinary teams. New insights in the treatment of this challenging cancer needs the contribution of many and different experts

Modulation of Brain Activity during Action Observation: Influence of Perspective, Transitivity and Meaningfulness

The coupling process between observed and performed actions is thought to be performed by a fronto-parietal perception-action system including regions of the inferior frontal gyrus and the inferior parietal lobule. When investigating the influence of the movements' characteristics on this process, most research on action observation has focused on only one particular variable even though the type of movements we observe can vary on several levels. By manipulating the visual perspective, transitivity and meaningfulness of observed movements in a functional magnetic resonance imaging study we aimed at investigating how the type of movements and the visual perspective can modulate brain activity during action observation in healthy individuals. Importantly, we used an active observation task where participants had to subsequently execute or imagine the observed movements. Our results show that the fronto-parietal regions of the perception action system were mostly recruited during the observation of meaningless actions while visual perspective had little influence on the activity within the perception-action system. Simultaneous investigation of several sources of modulation during active action observation is probably an approach that could lead to a greater ecological comprehension of this important sensorimotor process