Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population

Background: Albeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis. Methodology/Principal Findings: Immunoproteasomes and PA28-ab regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendrocytes, macrophages/macroglia and lymphocytes. Furthermore, in a genetic study on 1262 Italian MS cases and 845 controls we observed that HLA-A*02+ female subjects carrying the immunoproteasome LMP2 codon 60HH variant have a reduced risk to develop MS. Accordingly, immunoproteasomes carrying the LMP2 60H allele produce in vitro a lower amount of the HLA-A*0201 restricted immunodominant epitope MBP111\u2013119. Conclusion/Significance: The immunoproteasome LMP2 60HH variant reduces the risk to develop MS amongst Italian HLAA* 02+ females. We propose that such an effect is mediated by the altered proteasome-dependent production of a specific MBP epitope presented on the MHC class I. Our observations thereby support the hypothesis of an involvement of immunoproteasome in the MS pathogenesis

Conservative methotrexate treatment of a scar pregnancy case: adding evidence to the evidence

A single case of ultrasonographic-guided local injection of methotrexate for managing scar pregnancy is reported. The outcome was successful and had no side effects. The case was reported to increase the evidence supporting this type of management

Role of loss of pten in phospho-akt (p-akt) positive patients with advanced non-small cell lung cancer (nsclc) treated with gefitinib

Background: In a previous trial, evaluating the correlation between P-AKT status and gefitinib activity, compared to the P-AKT negative group, P-AKT positive patients had a better RR (P=0.003), disease control rate (P<0.001), and significantly longer TTP (P=0.004) (PASCO 2004). In that study however, almost 40% of P-AKT positive patients did not benefit from gefitinib therapy. The hypothesis from preclinical data indicated that loss of PTEN can lead to aberrant AKT activation, and finally to gefitinib resistance. Based on the above data we decided to investigate if the loss of PTEN could be responsible for the lack of gefitinib activity in P-AKT positive patients. Patients and methods: Specimens from patients enrolled in our previous trial were evaluated for PTEN expression by immunohistochemistry. Paraffin-embedded tissue sections were stained with mouse monoclonal anti-PTEN antibodies. Results: Among the 106 NSCLC patients enrolled onto the AKT trial, 99 were evaluable for PTEN status. In the whole population, loss of PTEN was observed in 40.4% of patients. No difference in RR, disease control rate, TTP, and OS was observed between patients with and without loss of PTEN (CR+PR: 7.5% versus 15.2%; CR+PR+SD: 40% versus 37.3%; median TTP: 3.4 versus 2.98 months, P= 0.7; median OS: 8.4 versus 11.4 months, P= 0.41). In the univariate analysis, loss of PTEN was not related to P-AKT status, gender, histology, PS, skin toxicity, and smoking history. Among the 51 P-AKT positive patients, 48 were evaluated for PTEN expression, and 19 had loss of PTEN (39.5%). RR and disease control rate were not different in the group with and without loss of PTEN (CR+PR: 15.7% versus 24.1%; CR+PR+SD: 57.8% versus 51.7%, respectively). No difference between the two groups was observed in TTP (median 5.1 versus 4.2 months) and OS (median 8.9 versus 11.4 months). Conclusions: These results suggest that detection of loss of PTEN is not useful in selecting patients potentially resistant to gefitinib therapy

Immunoproteasome and LMP2 polymorphism in aged and Alzheimer's disease brains

In this study, we investigated the presence and role of immunoproteasome and its LMP2 subunit polymorphism at codon 60 in Alzheimer's disease (AD). Immunoproteasome was present in brain areas such as hippocampus and cerebellum and localized in neurons, astrocytes and endothelial cells. A higher expression of immunoproteasome was found in brain of AD patients than in brain of non-demented elderly, being its expression in young brain negligible or absent. Furthermore, AD affected regions showed a partial decrease in proteasome trypsin-like activity. The study of LMP2 polymorphism (R/H) showed that it does not influence LMP2 expression (neither the mRNA nor mature protein) in brain tissue. However, control brain areas of AD patients carrying the RR genotype showed an increased proteasome activity in comparison with RH carriers. To test whether this effect of the genotype might be related to AD onset we performed a genetic study, which allowed us to exclude an association of LMP2 codon 60 polymorphism with AD onset, despite its influence on the proteasome activity in human brain. © 2005 Elsevier Inc. All rights reserved

Is There an Interplay between Immune Checkpoint Inhibitors, Thromboprophylactic Treatments and Thromboembolic Events? Mechanisms and Impact in Non-Small Cell Lung Cancer Patients

PD-1 pathway blockade has been shown to promote proatherogenic T-cell responses and destabilization of atherosclerotic plaques. Moreover, preclinical evidence suggests a potential synergy of antiplatelet drugs with immune checkpoint inhibitors (ICIs). We conducted an analysis within a prospective observational protocol (APOLLO study) to investigate the rates, predictors, and prognostic significance of thromboembolic events (TE) and thromboprophylaxis in patients with advanced NSCLC treated with ICIs. Among 217 patients treated between April 2014 and September 2018, 13.8% developed TE events. Current smoking status (HR 3.61 (95% CI 1.52–8.60), p = 0.004) and high (>50%) PD-L1 (HR 2.55 (95% CI 1.05–6.19), p = 0.038) resulted in being independent TE predictors. An increased risk of death following a diagnosis of TE (HR 2.93; 95% CI 1.59–5.42; p = 0.0006) was observed. Patients receiving antiplatelet treatment experienced longer progression-free survival (PFS) (6.4 vs. 3.4 months, HR 0.67 (95% CI 0.48–0.92), p = 0.015) and a trend toward better OS (11.2 vs. 9.6 months, HR 0.78 (95% CI 0.55–1.09), p = 0.14), which were not confirmed in a multivariate model. No impact of anticoagulant treatment on patients’ outcomes was observed. NSCLC patients treated with ICIs bear a consistent risk for thrombotic complications, with a detrimental effect on survival. The impact of antiplatelet drugs on ICIs efficacy deserves further investigation in prospective trials