Although promising, the clinical benefit provided by dendritic cell (DC)-based vaccines is still limited and the choice of the optimal antigen formulation is still an unresolved issue. We have ...developed a new DC-based vaccination protocol for aggressive and/or refractory lymphomas which combines the unique features of interferon-conditioned DC (IFN-DC) with highly immunogenic tumor cell lysates (TCL) obtained from lymphoma cells undergoing immunogenic cell death. We show that treatment of mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines with 9-cis-retinoic acid and IFNα (RA/IFNα) induces early membrane exposure of Calreticulin, HSP70 and 90 together with CD47 down-regulation and enhanced HMGB1 secretion. Consistently, RA/IFNα-treated apoptotic cells and -TCLs were more efficiently phagocytosed by DCs compared to controls. Notably, cytotoxic T cells (CTLs) generated with autologous DCs pulsed with RA/IFNα-TCLs more efficiently recognized and specifically lysed MCL or DLBCL cells or targets loaded with several HLA-A*0201 cyclin D1 or HLA-B*0801 survivin epitopes. These cultures also showed an expansion of Th1 and Th17 cells and an increased Th17/Treg ratio. Moreover, DCs loaded with RA/IFNα-TCLs showed enhanced functional maturation and activation. NOD/SCID mice reconstituted with human peripheral blood lymphocytes and vaccinated with autologous RA/IFNα-TCL loaded-IFN-DCs showed lymphoma-specific T-cell responses and a significant decrease in tumor growth with respect to mice treated with IFN-DC unpulsed or loaded with untreated TCLs. This study demonstrates the feasibility and efficacy of the use of RA/IFNα to generate a highly immunogenic TCL as a suitable tumor antigen formulation for the development of effective anticancer DC-based vaccines.
Inflammatory gene expression is modulated by posttranscriptional regulation via RNA-binding proteins (RBPs), which regulate mRNA turnover and translation by binding to conserved mRNA sequences. Their ...role in COPD is only partially defined. This study evaluated RBPs tristetraprolin (TTP), human antigen R (HuR), and AU-rich element-binding factor 1 (AUF-1) expression using lung tissue from COPD patients and control subjects and probed their function in epithelial responses in vitro.
RBPs were detected by immunohistochemistry in bronchial and peripheral lung samples from mild-to-moderate stable COPD patients and age/smoking history-matched controls; RBPs and RBP-regulated genes were evaluated by Western blot, ELISA, protein array, and real-time PCR in human airway epithelial BEAS-2B cell line stimulated with hydrogen peroxide, cytokine combination (cytomix), cigarette smoke extract (CSE), and following siRNA-mediated silencing. Results were verified in a microarray database from bronchial brushings of COPD patients and controls. RBP transcripts were measured in peripheral blood mononuclear cell samples from additional stable COPD patients and controls.
Specific, primarily nuclear immunostaining for the RBPs was detected in structural and inflammatory cells in bronchial and lung tissues. Immunostaining for AUF-1, but not TTP or HuR, was significantly decreased in bronchial epithelium of COPD samples vs controls. In BEAS-2B cells, cytomix and CSE stimulation reproduced the RBP pattern while increasing expression of AUF-1-regulated genes, interleukin-6, CCL2, CXCL1, and CXCL8. Silencing expression of AUF-1 reproduced, but not enhanced, target upregulation induced by cytomix compared to controls. Analysis of bronchial brushing-derived transcriptomic confirmed the selective decrease of AUF-1 in COPD vs controls and revealed significant changes in AUF-1-regulated genes by genome ontology.
Downregulated AUF-1 may be pathogenic in stable COPD by altering posttranscriptional control of epithelial gene expression.
An abstract of the study of Montico et al about the role of non-coding RNAs in resistance to targeted therapies in cutaneous melanoma is presented. Among other things activating BRAF mutations are ...effectively targeted by specific inhibitors, such as vemurafenib, which have shown important clinical responses in advanced cutaneous melanoma (CM). However, their clinical effectiveness is impaired by the emergence of an early drug resistance. Non coding RNAs (ncRNAs) are of increasing biologic and therapeutic relevance considering their role in modulating gene expression. RNA sequencing identified about 230 mapped InoRNAs significantly differentially expressed between VR-resistant and -sensitive CM cell lines, thus indicating a difference in the IncRNA expression profiles. Gene ontology analysis revealed that the top of the neighbor coding gene function of differentially expressed lncRNAs involved apoptosis and cellular component movement, including the TGF-β pathway genes. Though additional studies are required, our findings suggest that IncRNAs may be involved in BRAFi resistance by regulating the anti-apoptotic and tumor-progressive aspects of TGF-β signaling in CM.
Abstract Epstein–Barr virus (EBV) is a ubiquitous human γ-herpes virus that has established an elegant strategy to persist as a life-long asymptomatic infection in memory B lymphocytes. EBV has ...potent transforming properties for B lymphocytes and it is pathogenically associated with a variety of lymphomas of B or NK/T cell origin. The viral latency programs expressed can hijack or deregulate cellular pathways critical for cell proliferation and survival, while impairing anti-viral immune responses. Similar effects may also be induced by EBV-encoded micro-RNAs, which may have a pathogenic role particularly in lymphomas showing a restricted expression of viral proteins. Of note, recent data have challenged the view that only the EBV latency is relevant for lymphomagenesis, suggesting that lytic EBV replication may also contribute to the development of EBV-associated lymphoproliferations. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion are providing the rationale for innovative and tailored treatment approaches for EBV-driven lymphomas.
Purposes
Brachytherapy has been indicated as an alternative option for treating cystic craniopharyngiomas. Despite the difficulties regarding the complex nuclear infrastructure and consequent small ...number of brachytherapy studies, recent discoveries relating tumour characteristics to sensitivity to brachytherapy have stimulated this extensive systematic review and meta-analysis of the recent results aiming to summarise its efficacy and complications.
Methods
The systematic review was structured using PRISMA statements. The MEDLINE database was systematically reviewed from March 2010 to February 2021 to identify qualified trials dealing with radioisotope brachytherapy in cystic craniopharyngiomas in the paediatric population, emphasising tumour control rates and complications.
Results
A total of 228 individuals were analysed, of which 66 were children. The minimum average follow-up was 5 years. Considering the paediatric trials, partial and complete responses were achieved in 89% of patients with exclusively cystic lesions, compared to 58% in non-exclusively cystic lesions. The former observed progression in 3% of patients, while in the latter, 35% was reported. Visual and endocrine improvement reached 64% and 20%, respectively, in the first group, in contrast to 48% and 7% in the second group, respectively. There were similar results considering the non-exclusive paediatric series, but with less expressive numbers.
Conclusion
These results reinforce the positive impact of radioisotope brachytherapy in the treatment of predominant monocystic or multicystic craniopharyngiomas, especially in the paediatric population, grounded by impressive tumour control rates, lower morbidities and single application in the majority of the cases. In the future, specific morphological tumour characteristics might be considered for a more assertive patient selection.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit ...the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by (3)Hthymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.
PDF
