Mesenchymal stem/stromal cells (MSCs) comprise a heterogeneous population of cells with multilineage differentiation potential, the ability to modulate oxidative stress, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects. Recent data indicate that these paracrine factors may play a key role in MSC-mediated effects in modulating various acute and chronic pathological conditions. MSCs are found in virtually all organs of the body. Bone marrow-derived MSCs (BM-MSCs) were discovered first, and the bone marrow was considered the main source of MSCs for clinical application. Subsequently, MSCs have been isolated from various other sources with the adipose tissue, serving as one of the alternatives to bone marrow. Adipose tissue-derived MSCs (ASCs) can be more easily isolated; this approach is safer, and also, considerably larger amounts of ASCs can be obtained compared with the bone marrow. ASCs and BM-MSCs share many biological characteristics; however, there are some differences in their immunophenotype, differentiation potential, transcriptome, proteome, and immunomodulatory activity. Some of these differences may represent specific features of BM-MSCs and ASCs, while others are suggestive of the inherent heterogeneity of both BM-MSC and ASC populations. Still other differences may simply be related to different isolation and culture protocols. Most importantly, despite the minor differences between these MSC populations, ASCs seem to be as effective as BM-MSCs in clinical application, and, in some cases, may be better suited than BM-MSCs. In this review, we will examine in detail the ontology, biology, preclinical, and clinical application of BM-MSCs versus ASCs.

MicroRNAs (miRNAs) are small non-coding RNAs 18-25 nucleotides in length that downregulate gene expression during various crucial cell processes such as apoptosis, differentiation and development. Changes in the expression profiles of miRNAs have been observed in a variety of human tumors, including colorectal cancer (CRC). Functional studies indicate that miRNAs act as tumor suppressors and oncogenes. These findings significantly extend Vogelstein's model of CRC pathogenesis and have shown great potential for miRNAs as a novel class of therapeutic targets. Several investigations have also described the ability of miRNA expression profiles to predict prognosis and response to selected treatments in CRC patients, and support diagnosis of CRC among cancer of unknown primary site. miRNAs' occurrence has been repeatedly observed also in serum and plasma, and miRNAs as novel minimally invasive biomarkers have indicated reasonable sensitivity for CRC detection and compare favorably with the fecal occult blood test. In this review, we summarize the knowledge regarding miRNAs' functioning in CRC while emphasizing their significance in pathogenetic signaling pathways and their potential to serve as disease biomarkers and novel therapeutic targets.

Poor immune reconstitution after haploidentical stem cell transplantation results in a high mortality from viral infections and relapse. One approach to overcome this problem is to selectively deplete the graft of alloreactive cells using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient peripheral blood mononuclear cells (PBMCs), and this can result in graft versus host disease (GVHD). We have refined this approach using recipient Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) as stimulators to activate donor alloreactive T cells. Our studies demonstrate that allodepletion with an anti-CD25 immunotoxin following stimulation with HLA-mismatched host LCLs more consistently depleted in vitro alloreactivity than stimulation with host PBMCs, as assessed in primary mixed lymphocyte reactions (MLRs). Allodepletion using this approach specifically abrogates cytotoxic T-cell responses against host LCLs. In interferon-␥ (IFN-␥) enzymelinked immunospot (ELISPOT) assays, antiviral responses to adenovirus and cytomegalovirus (CMV) were preserved following allodepletion. Likewise, using HLA-A2-pp65 tetramers, we have shown that the frequency of CMV-specific T cells is unaffected by allodepletion. Moreover, the donor anti-EBV response is partially retained by recognition of EBV antigens through the nonshared haplotype. Finally, we studied whether allodepletion affects the response to candidate tumor antigens in myeloid malignancies. Using HLA-A2-PR1 tetramer analysis, we found that the frequency of T cells recognizing the PR1 epitope of proteinase 3 was not significantly different in allodepleted and unmanipulated PBMCs from patients with chronic myeloid leukemia (CML) undergoing transplantation. Based on these data, we have embarked on a phase 1 clinical trial of addback of allo-LCL-depleted donor T cells in the haplo-identical setting.

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MicroRNAs are endogenously expressed regulatory noncoding RNAs. Previous studies showed altered expression levels of several microRNAs in glioblastomas. In this study, we examined the expression levels of selected microRNAs in 22 primary glioblastomas and six specimens of adult brain tissue by real-time PCR method. In addition, we examined methylation status of MGMT promoter by methylation-specific real-time PCR, as this has been shown to be a predictive marker in glioblastomas. MGMT methylation status was not correlated with response to concomitant chemoradiotherapy with temozolomide (RT/TMZ). MiR-221 (p=0,016), miR-222 (p=0,038), miR-181b (p=0,036), miR-181c (p=0,043) and miR-128a (p=0,001) were significantly down-regulated in glioblastomas. The most significant change was observed for up-regulation in miR-21 expression in glioblastomas (p<0,001). MiR-181b and miR-181c were significantly down-regulated in patients who responded to RT/TMZ (p=0,016; p=0,047, respectively) in comparison to patients with progredient disease. Our data indicate for the first time that expression levels of miR-181b and miR-181c could serve as a predictive marker of response to RT/TMZ therapy in glioblastoma patients.

Glioblastoma multiforme (GBM) is the most frequently occurring primary malignant brain tumor; patients with GBM often have a very poor prognosis and differing responses to treatment. Therefore, it is very important to find new biomarkers that can predict clinical outcomes and help in treatment decisions. MicroRNAs are small, non-coding RNAs that function as post-transcriptional regulators of gene expression and play a key role in the pathogenesis of GBM. In a group of 38 patients with primary GBM, we analyzed the expression of eight microRNAs (miR-21, miR-128a, miR-181c, miR-195, miR-196a, miR-196b, miR-221, and miR-222). In addition, we examined the methylation status of O-6-methylguanine-DNA methyltransferase (MGMT) promoter by high-resolution melting analysis, as this has been shown to be a predictive marker in GBM. MGMT methylation status correlated with progression-free survival (P = 0.0201; log-rank test) as well as with overall survival (P = 0.0054; log-rank test). MiR-195 (P = 0.0124; log-rank test) and miR-196b (P = 0.0492; log-rank test) positively correlated with overall survival. Evaluation of miR-181c in combination with miR-21 predicted time to progression within 6 months of diagnosis with 92% sensitivity and 81% specificity (P < 0.0001). Our data confirmed that the methylation status of MGMT but also miR-21, miR-181c, miR-195, and miR-196b to be associated with survival of GBM patients. Above all, we suggest that the combination of miR181c and miR-21 could be a very sensitive and specific test to identify patients at high risk of early progression after surgery. (Cancer Sci 2011; 102: 2186-2190 G lioblastoma multiforme (GBM) is the most frequently occurring primary malignant brain tumor of astrocytic origin.(1)Despite the introduction of modern therapeutic approaches, this cancer remains generally associated with very poor prognosis.(2) A significant benefit of overall survival (OS) has been achieved in patients treated with concomitant chemoradiotherapy with temozolomide (RT ⁄ TMZ), an alkylating agent. However, not all patients are sensitive to this therapy. (3,4) Because of an extremely short median survival time of glioblastoma patients and diversity in therapy response, it is very important to identify new biomarkers that can be used in prognosis and prediction of therapeutic response and ⁄ or clinical outcome in GBM patients in order to rationalize treatment decisions.MicroRNAs (miRNAs) are highly conserved, small, non-coding RNAs, 18-25 nucleotides in length, that function as posttranscriptional regulators of gene expression by silencing their mRNA targets. Bioinformatics tools estimate that miRNAs regulate up to one-third of human genes including a significant number of oncogenes, tumor suppressor genes, and genes associated with the invasion, dissemination, and chemoresistance of tumors.(5) Therefore, these molecules play significant roles in the pathogenesis of many cancers, including GBM. (6,7) In the context of this tumor, recent published reports have proposed that some miRNAs tha...

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BackgroundMicroRNAs are endogenously expressed regulatory noncoding RNAs. Previous studies have shown altered expression levels of several microRNAs in renal cell carcinoma.MethodsWe examined the expression levels of selected microRNAs in 38 samples of conventional renal cell carcinoma (RCC) and 10 samples of non-tumoral renal parenchyma using TaqMan real-time PCR method.ResultsThe expression levels of miRNA-155 (p < 0.0001), miRNA-210 (p < 0.0001), miRNA-106a (p < 0.0001) and miRNA-106b (p < 0.0001) were significantly over-expressed in tumor tissue, whereas the expression of miRNA-141 (p < 0.0001) and miRNA-200c (p < 0.0001) were significantly decreased in RCC samples. There were no significant differences between expression levels of miRNA-182 and miRNA-200b in tumor samples and renal parenchyma. Our data suggest that expression levels of miRNA-106b are significantly lower in tumors of patients who developed metastasis (p = 0.030) and miR-106b is a potential predictive marker of early metastasis after nephrectomy in RCC patients (long-rank p = 0.032).ConclusionsWe have confirmed previous observations obtained by miRNA microarray analysis using standardized real-time PCR method. For the first time, we have identified a prognostic significance of miRNA-106b, which, after validation on a larger group of patients, maybe useful as a promising biomarker in patients with RCC.