MiR-29b antagonizes the pro-inflammatory tumor-promoting activity of multiple myeloma-educated dendritic cells.

Dendritic cells (DCs) have a key role in regulating tumor immunity, tumor cell growth and drug resistance. We hypothesized that multiple myeloma (MM) cells might recruit and reprogram DCs to a tumor-permissive phenotype by changes within their microRNA (miRNA) network. By analyzing six different miRNA-profiling data sets, miR-29b was identified as the only miRNA upregulated in normal mature DCs and significantly downregulated in tumor-associated DCs. This finding was validated in primary DCs co-cultured in vitro with MM cell lines and in primary bone marrow DCs from MM patients. In DCs co-cultured with MM cells, enforced expression of miR-29b counteracted pro-inflammatory pathways, including signal transducer and activator of transcription 3 and nuclear factor-κB, and cytokine/chemokine signaling networks, which correlated with patients' adverse prognosis and development of bone disease. Moreover, miR-29b downregulated interleukin-23 in vitro and in the SCID-synth-hu in vivo model, and antagonized a Th17 inflammatory response. All together, these effects translated into strong anti-proliferative activity and reduction of genomic instability of MM cells. Our study demonstrates that MM reprograms the DCs functional phenotype by downregulating miR-29b whose reconstitution impairs DCs ability to sustain MM cell growth and survival. These results underscore miR-29b as an innovative and attractive candidate for miRNA-based immune therapy of MM.

A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival.

Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.

Magnetic resonance imaging based classification of anatomic relationship between the cochleovestibular nerve and anterior inferior cerebellar artery in patients with non-specific neuro-otologic symptoms.

In this study, we aimed to assess anatomical relationship between the anterior inferior cerebellar artery (AICA) and cochleovestibular nerve (CNV) in patients with non-specific cochleovestibular symptoms using magnetic resonance imaging (MRI). One-hundred and forty patients with non-specific neuro-otologic symptoms were assessed using cranial and temporal MRI. Classification was performed according to four different types of anatomical relationship observed between the AICA and CVN. In type 1 (point compression), the AICA compresses only a limited portion of the CVN. In type 2 (longitudinal compression), the AICA approaches the CVN as both traverse parallel to each other. In type 3 (loop compression), the vascular loop of the AICA encircles the CVN. In type 4 (indentation), the AICA compresses the CVN so as to make an indentation in the nerve. The anatomical relationship between the CVN and AICA was encountered in 19 out of 140 (13.6%) patients (20 ears). The VCC was unilateral in 18 patients (94.7%) and bilateral in one patient (5.3%). There was no other vascular structure causing VCC to the CVN except for vertebral artery that was seen in 2 out of 140 patients (1.4%). These were unilateral cases. There were tinnitus, vertigo or dizziness, hearing loss, and both hearing loss and vertigo in 5 (25%), 13 (65%), 1 (5%) and 1 (5%) ears of 20 patients, respectively. There was no relationship between the cochleovestibular symptoms and type of compression (p>0.05). Neurovascular relationship between the CVN and AICA can be imaged properly using MR and MR based classification may help reporting this relationship in a standard way. Although, MR images can show the anatomical relationship accurately, diagnosis of vascular conflict should not be based on imaging findings alone.