Novel Approaches to Improve Myeloma Cell Killing by Monoclonal Antibodies

The monoclonal antibodies (mAbs) have significantly changed the treatment of multiple myeloma (MM) patients. However, despite their introduction, MM remains an incurable disease. The mAbs currently used for MM treatment were developed with different mechanisms of action able to target antigens, such as cluster of differentiation 38 (CD38) and SLAM family member 7 (SLAMF7) expressed by both, MM cells and the immune microenvironment cells. In this review, we focused on the mechanisms of action of the main mAbs approved for the therapy of MM, and on the possible novel approaches to improve MM cell killing by mAbs. Actually, the combination of anti-CD38 or anti-SLAMF7 mAbs with the immunomodulatory drugs significantly improved the clinical effect in MM patients. On the other hand, pre-clinical evidence indicates that different approaches may increase the efficacy of mAbs. The use of trans-retinoic acid, the cyclophosphamide or the combination of anti-CD47 and anti-CD137 mAbs have given the rationale to design these types of combinations therapies in MM patients in the future. In conclusion, a better understanding of the mechanism of action of the mAbs will allow us to develop novel therapeutic approaches to improve their response rate and to overcome their resistance in MM patients

Bovine pestivirus is a new alternative virus for multiple myeloma oncolytic virotherapy

The oncolytic viruses have shown promising results for the treatment of multiple myeloma. However, the use of human viruses is limited by the patients' antiviral immune response. In this study, we investigated an alternative oncolytic strategy using non-human pathogen viruses as the bovine viral diarrhea virus (BVDV) that were able to interact with CD46

A spatial multi-scale fluorescence microscopy toolbox discloses entry checkpoints of SARS-CoV-2 variants in Vero E6 cells

: We exploited a multi-scale microscopy imaging toolbox to address some major issues related to SARS-CoV-2 interactions with host cells. Our approach harnesses both conventional and super-resolution fluorescence microscopy and easily matches the spatial scale of single-virus/cell checkpoints. After its validation through the characterization of infected cells and virus morphology, we leveraged this toolbox to reveal subtle issues related to the entry phase of SARS-CoV-2 variants in Vero E6 cells. Our results show that in Vero E6 cells the B.1.1.7 strain (aka Alpha Variant of Concern) is associated with much faster kinetics of endocytic uptake compared to its ancestor B.1.177. Given the cell-entry scenario dominated by the endosomal "late pathway", the faster internalization of B.1.1.7 could be directly related to the N501Y mutation in the S protein, which is known to strengthen the binding of Spike receptor binding domain with ACE2. Remarkably, we also directly observed the central role of clathrin as a mediator of endocytosis in the late pathway of entry. In keeping with the clathrin-mediated endocytosis, we highlighted the non-raft membrane localization of ACE2. Overall, we believe that our fluorescence microscopy-based approach represents a fertile strategy to investigate the molecular features of SARS-CoV-2 interactions with cells

Targeting DNA2 Overcomes Metabolic Reprogramming in 1q21 Multiple Myeloma

View full abstracthttps://openworks.mdanderson.org/leading-edge/1018/thumbnail.jp

Чувствительность детекторов ионизирующего излучения на основе наноструктурной керамики Al2O3

Работа выполнена при финансовой поддержке Минобрнауки РФ (договор №14.125.13.4696-МК – грант Президента РФ)

Hypoxia-inducible factor (HIF)-1 alpha come target terapeutico nella angiogenesi e nella distruzione ossea indotta da mieloma multiplo in vitro ed in vivo

Hypoxia-inducible transcription factor-1 (HIF-1α) is overexpressed in multiple myeloma (MM) cells within the hypoxic microenvironment. Herein we explored the effect of persistent HIF-1α inhibition by a lentivirus shRNA pool on proliferation, survival and transcriptional and pro-angiogenic profiles of MM cells either in vitro or in vivo in mouse models. Among the significantly modulated genes (326 and 361 genes in hypoxic and normoxic condition, respectively), we found that HIF-1α inhibition in MM cells down-regulates the pro-angiogenic molecules VEGF, IL8, IL10, CCL2, CCL5 and MMP9. Interestingly, pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1α. The effect of HIF-1α inhibition on a human myeloma cell line was assessed in vivo in NOD/SCID mice both in a subcutaneous and an intratibial model. HIF-1α inhibition caused a dramatic reduction in the weight and volume of the tumor burden in both mouse models. Moreover, a significant reduction of the number of vessels and VEGF immunostaining was observed. Finally, in the intra-tibial experiments HIF-1α inhibition significantly blocked JJN3-induced bone destruction. Overall our data indicate that HIF-1α suppression in MM cells significantly blocks MM-induced angiogenesis and reduces MM tumor burden and bone destruction in vivo, supporting HIF-1α as a potential therapeutic target in MM

Stress genitoriale, benessere psicologico e stili parentali in genitori di bambini con Disturbi Specifici di Apprendimento

In un\u2019ottica sistemica che prevede il passaggio, nella pratica clinica cosi\u300 come nella metodologia della ricerca, dall\u2019analisi del singolo all\u2019analisi del sistema, nel presente studio sono state approfondite le possibili implicazioni della presenza di una diagnosi di DSA sul sistema familiare e, in particolare, sulle figure genitoriali. Lo studio e\u300 stato condotto su 40 coppie di genitori: 20 coppie di genitori di bambini con diagnosi di DSA e 20 coppie di genitori di bambini con sviluppo tipico. L\u2019eta\u300 dei figli era compresa tra 8 e 14 anni e ciascuno aveva ricevuto una diagnosi di DSA nell\u2019arco temporale massimo di 2 anni. La batteria sperimentale prevedeva la somministra- zione delle scale: PSI-SF (Abidin, 1983), SCL-90 (Derogatis, 1977), Parenting Scale (Arnold et al., 1993), per la valutazione rispettivamente dello stress genitoriale, dell\u2019ansia e degli stili genitoriali. I risultati hanno evidenziato la presenza di un mag- gior livello di stress genitoriale nei genitori del gruppo sperimentale e stili genitoriali maggiormente caratterizzati da una polarizzazione sugli estremi lassismo-rigidita\u300. Non sono emerse differenze significative in relazione alla dimensione psicopatologica. Verranno discusse le implicazioni di tali osservazioni per la pratica clinica

Role of Galectins in Multiple Myeloma

Galectins are a family of lectins that bind β-galactose-containing glycoconjugates and are characterized by carbohydrate-recognition domains (CRDs). Galectins exploit several biological functions, including angiogenesis, regulation of immune cell activities and cell adhesion, in both physiological and pathological processes, as tumor progression. Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by the tight adhesion between tumoral PCs and bone marrow (BM) microenvironment, leading to the increase of PC survival and drug resistance, MM-induced neo-angiogenesis, immunosuppression and osteolytic bone lesions. In this review, we explore the expression profiles and the roles of galectin-1, galectin-3, galectin-8 and galectin-9 in the pathophysiology of MM. We focus on the role of these lectins in the interplay between MM and BM microenvironment cells showing their involvement in MM progression mainly through the regulation of PC survival and MM-induced angiogenesis and osteoclastogenesis. The translational impact of these pre-clinical pieces of evidence is supported by recent data that indicate galectins could be new attractive targets to block MM cell growth in vivo and by the evidence that the expression levels of LGALS1 and LGALS8, genes encoding for galectin-1 and galectin-8 respectively, correlate to MM patients’ survival