Mechanical barriers and transforming growth factor beta inhibitor on epidural fibrosis in a rabbit laminectomy model

Background: TGF-β has been described as a mediator of fibrosis and scarring. Several studies achieved reduction in experimental scarring through the inhibition of TGF-β. Fibroblasts have been defined as the cell population originating fibrosis, blocking fibroblast invasion may impair epidural fibrosis appearance. For this purpose, biocompatible materials used as mechanical barriers and a TGF-β inhibitor peptide were evaluated in the reduction of epidural fibrosis. Methods: A L6 laminectomy was performed in 40 New Zealand white rabbits. Divided into four groups, each rabbit was assigned to receive either collagen sponge scaffold (CS group), gelatin-based gel (GCP group), P144® (iTGFβ group), or left untreated (control group). Four weeks after surgery, cell density, collagen content, and new bone formation of the scar area were determined by histomorphometry. Two experienced pathologists scored dura mater adhesion, scar density, and inflammatory infiltrate in a blinded manner. Results: In all groups, laminectomy site was filled with fibrous tissue and the dura mater presented adhesions. Only GCP group presented a significant reduction in collagen content and scar density. Conclusion: GCP treatment reduces epidural fibrosis although did not prevent dura mater adhesion completely

Early Proterozoic calc-alkaline and Middle Proterozoic tholeiitic dyke swarms from Central-Eastern Argentina: Petrology, geochemistry, Sr-Nd isotopes and tectonic implications

The Rio de La Plata craton in Argentina (Azul and Tandil regions) is characterized by Early Proterozoic (2·0 Ga) calc-alkaline and Middle Proterozoic (1·6 Ga) tholeiitic dyke swarms intruding the crystalline basement involved in the Transamazonian Orogeny (2·2-1·9 Ga). The calc-alkaline dykes have andesitic and rhyolitic compositions and trend east-west, whereas the tholeiitic dykes mainly trend N30°W and are represented by basalts with low (0·9-1·7 wt %) and high TiO2 (up to 3·7 wt %). The calc-alkaline dykes have primitive mantle (PM)-normalized trace element patterns enriched in Rb, Ba, K, La, Ce and Nd, and significant negative Nb and Ti anomalies. These dykes are characterized by εt(Nd) values of - 3 to - 4, similar to those of the EMI mantle component. Low-TiO2 tholeiitic dykes have low incompatible-element (IE) contents and PM-IE patterns with slightly positive or negative Nb spikes. They have variable εt(Nd) values (-0·5 to 12·1), which mainly reflect derivation from a depleted source mantle. High-TiO2 tholeiitic dykes have more enriched IE-PM patterns and are characterized by εt(Nd) values (-1·4 to -7·5) typical of an enriched source mantle. Chemical and isotopic data and melting modelling indicate that both calc-alkaline and tholeiitic dykes originated by different melting degrees of a heterogeneous source mantle, the variable IE enrichment of which may have occured in Late Archaean to Early Proterozoic times. The emplacement of the calc-alkaline dykes is associated with the transtensional stage of the Transamazonian Orogeny, whereas the tholeiitic dykes reflect extensional tectonics succeeding the Transamazonian event. The calc-alkaline and tholeiitic dykes are similar in emplacement age and characteristics to metamorphosed granites and volcanic rocks outcropping within the Namaqua fold belts of southwestern Africa (Richtersveld and Witberg-Aggeneys-Gamsberg provinces); this may indicate that the Rio de La Plata craton and southwestern Africa were contiguous in Early-Middle Proterozoic times.Facultad de Ciencias Naturales y MuseoLaboratorio de Entrenamiento Multidisciplinario para la Investigación Tecnológic

Early Proterozoic calc-alkaline and Middle Proterozoic tholeiitic dyke swarms from Central-Eastern Argentina: Petrology, geochemistry, Sr-Nd isotopes and tectonic implications

The Rio de La Plata craton in Argentina (Azul and Tandil regions) is characterized by Early Proterozoic (2·0 Ga) calc-alkaline and Middle Proterozoic (1·6 Ga) tholeiitic dyke swarms intruding the crystalline basement involved in the Transamazonian Orogeny (2·2-1·9 Ga). The calc-alkaline dykes have andesitic and rhyolitic compositions and trend east-west, whereas the tholeiitic dykes mainly trend N30°W and are represented by basalts with low (0·9-1·7 wt %) and high TiO2 (up to 3·7 wt %). The calc-alkaline dykes have primitive mantle (PM)-normalized trace element patterns enriched in Rb, Ba, K, La, Ce and Nd, and significant negative Nb and Ti anomalies. These dykes are characterized by εt(Nd) values of - 3 to - 4, similar to those of the EMI mantle component. Low-TiO2 tholeiitic dykes have low incompatible-element (IE) contents and PM-IE patterns with slightly positive or negative Nb spikes. They have variable εt(Nd) values (-0·5 to 12·1), which mainly reflect derivation from a depleted source mantle. High-TiO2 tholeiitic dykes have more enriched IE-PM patterns and are characterized by εt(Nd) values (-1·4 to -7·5) typical of an enriched source mantle. Chemical and isotopic data and melting modelling indicate that both calc-alkaline and tholeiitic dykes originated by different melting degrees of a heterogeneous source mantle, the variable IE enrichment of which may have occured in Late Archaean to Early Proterozoic times. The emplacement of the calc-alkaline dykes is associated with the transtensional stage of the Transamazonian Orogeny, whereas the tholeiitic dykes reflect extensional tectonics succeeding the Transamazonian event. The calc-alkaline and tholeiitic dykes are similar in emplacement age and characteristics to metamorphosed granites and volcanic rocks outcropping within the Namaqua fold belts of southwestern Africa (Richtersveld and Witberg-Aggeneys-Gamsberg provinces); this may indicate that the Rio de La Plata craton and southwestern Africa were contiguous in Early-Middle Proterozoic times.Facultad de Ciencias Naturales y MuseoLaboratorio de Entrenamiento Multidisciplinario para la Investigación Tecnológic

Phenotypic and genomic analysis of multiple myeloma minimal residual disease tumor cells: a new model to understand chemoresistance

Persistence of chemoresistant minimal residual disease (MRD) plasma cells (PCs) is associated with inferior survival in multiple myeloma (MM). Thus, characterization of the minor MRD subclone may represent a unique model to understand chemoresistance, but to our knowledge, the phenotypic and genetic features of the MRD subclone have never been investigated. Here, we compared the antigenic profile of MRD vs diagnostic clonal PCs in 40 elderly MM patients enrolled in the GEM2010MAS65 study and showed that the MRD subclone is enriched in cells overexpressing integrins (CD11a/CD11c/CD29/CD49d/CD49e), chemokine receptors (CXCR4), and adhesion molecules (CD44/CD54). Genetic profiling of MRD vs diagnostic PCs was performed in 12 patients; 3 of them showed identical copy number alterations (CNAs), in another 3 cases, MRD clonal PCs displayed all genetic alterations detected at diagnosis plus additional CNAs that emerged at the MRD stage, whereas in the remaining 6 patients, there were CNAs present at diagnosis that were undetectable in MRD clonal PCs, but also a selected number of genetic alterations that became apparent only at the MRD stage. The MRD subclone showed significant downregulation of genes related to protein processing in endoplasmic reticulum, as well as novel deregulated genes such as ALCAM that is prognostically relevant in MM and may identify chemoresistant PCs in vitro. Altogether, our results suggest that therapy-induced clonal selection could be already present at the MRD stage, where chemoresistant PCs show a singular phenotypic signature that may result from the persistence of clones with different genetic and gene expression profiles. This trial was registered at www.clinicaltrials.gov as #NCT01237249

Prognostic value of antigen expression in multiple myeloma: a PETHEMA/GEM study on 1,265 patients enrolled in four consecutive clinical trials

Persistence of minimal residual disease (MRD) after treatment for myeloma predicts inferior outcomes, but within MRD-positive patients there is great heterogeneity with both early and very late relapses. Among different MRD techniques, flow cytometry provides additional information about antigen expression on tumor cells, which could potentially contribute to stratify MRD-positive patients. We investigated the prognostic value of those antigens required to monitor MRD in 1265 newly diagnosed patients enrolled in the GEM2000, GEM2005MENOS65, GEM2005MAS65 and GEM2010MAS65 protocols. Overall, CD19pos, CD27neg, CD38lo, CD45pos, CD81pos, CD117neg and CD138lo expression predicted inferior outcomes. Through principal component analysis, we found that simultaneous CD38lowCD81posCD117neg expression emerged as the most powerful combination with independent prognostic value for progression-free survival (HR:1.69; P=0.002). This unique phenotypic profile retained prognostic value among MRD-positive patients. We then used next-generation flow to determine antigen stability throughout the course of the disease, and found that the expression of antigens required to monitor MRD is mostly stable from diagnosis to MRD stages, except for CD81 whose expression progressively increased from baseline to chemoresistant tumor cells (14 vs 28%). Altogether, we showed that the phenotypic profile of tumor cells provides additional prognostic information, and could be used to further predict risk of relapse among MRD-positive patients

Minimal residual disease monitoring and immune profiling using second generation flow cytometry in elderly multiple myeloma

The value of minimal residual disease (MRD) in multiple myeloma (MM) has been more frequently investigated in transplant-eligible than elderly patients. Since an optimal balance between treatment efficacy and toxicity is of utmost importance in elderly MM, sensitive MRD monitoring might be particularly valuable in this patient population. Here, we used 2nd generation 8-color multiparameter-flow-cytometry (MFC) to monitor MRD in 162 transplant-ineligible MM patients enrolled in the PETHEMA/GEM2010MAS65 study, The transition from 1st to 2nd generation MFC resulted in increased sensitivity, and allowed to identify three patient groups according to MRD levels: MRD-negative (75-years (HR:4.8; P<.001), and those with high-risk cytogenetics (HR:12.6; P=.01). Using 2nd generation MFC, immune profiling concomitant to MRD monitoring also contributed to identify patients with poor, intermediate and favorable outcome (25%, 61% and 100% OS at 3-years; P=.01); the later patients being characterized by an increased compartment of mature B-cells. Our results show that similarly to transplant-candidates, MRD monitoring is one of the most relevant prognostic factors in elderly MM, irrespectively of patients’ age and cytogenetic risk