Purpose: This study was aimed at investigating whether the PPARg agonist pioglitazone-given in combination with trabectedin-is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin.Experimental Design: The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting.Results: We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARg agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation.Conclusions: The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.
Pleural mesothelioma (PM) is an aggressive tumor with few therapeutic options. Although patients with epithelioid PM (ePM) survive longer than non-epithelioid PM (non-ePM), heterogeneity of tumor response in ePM is observed. The role of the tumor immune microenvironment (TIME) in the development and progression of PM is currently considered a promising biomarker. A few studies have used high-throughput technologies correlated with TIME evaluation and morphologic and clinical data. This study aimed to identify different morphological, immunohistochemical, and transcriptional profiles that could potentially predict the outcome. A retrospective multicenter cohort of 129 chemonaive PM patients was recruited. Tissue slides were reviewed by dedicated pathologists for histotype classification and immunophenotype of tumor-infiltrating lymphocytes (TILs) and lymphoid aggregates or tertiary lymphoid structures (TLS). ePM (n = 99) survivors were further classified into long (>36 months) or short (<12 months) survivors. RNAseq was performed on a subset of 69 samples. Distinct transcriptional profiling in long and short ePM survivors was found. An inflammatory background with a higher number of B lymphocytes and a prevalence of TLS formations were detected in long compared to short ePM survivors. These results suggest that B cell infiltration could be important in modulating disease aggressiveness, opening a pathway for novel immunotherapeutic approaches.
The onset of chemo-resistant recurrence represents the principal cause of high-grade serous ovarian carcinoma (HGSOC) death. HGSOC masses are characterized by a hypoxic microenvironment, which contributes to the development of this chemo-resistant phenotype. Hypoxia regulated-miRNAs (HRMs) represent a molecular response of cancer cells to hypoxia and are involved in tumor progression. We investigated the expression of HRMs using miRNA expression data from a total of 273 advanced-stage HGSOC samples. The miRNAs associated with chemoresistance and survival were validated by RT-qPCR and target prediction, and comparative pathway analysis was conducted for target gene identification. Analysis of miRNA expression profiles indicated miR-23a-3p and miR-181c-5p over-expression as associated with chemoresistance and poor PFS. RT-qPCR data confirmed upregulation of miR-23a-3p in tumors from chemoresistant HGSOC patients and its significant association with shorter PFS. In silico miR-23a-3p target prediction and comparative pathway analysis identified platinum drug resistance as the pathway with the highest number of miR-23a-3p target genes. Among them, APAF-1 emerged as the most promising, being downregulated in platinum-resistant patients and in HGSOC chemo-resistant cells. These results highlight miR-23a-3p as a potential biomarker for HGSOC platinum response and prognosis and the miR23a-3p/APAF1 axis as a possible target to overcome platinum-resistance.
Plasma amino acid concentrations in 33 male alcoholic patients with pellagra (age 20-68 years) were compared with those in 17 healthy male subjects (age 20-45 years). Pellagra diagnosis was made on the basis of the typical clinical skin picture, and low urinary excretion of N'methylnicotinamide and N'methyl-2-pyridone-5-carboxamide (reduced by 70 and 80%, respectively, compared with controls). There were significant differences in body mass index, creatinine/high index and serum albumin between the two groups, indicating that besides pellagra the alcoholic patients had some degree of malnutrition. Of 17 plasma amino acids measured, the following had significantly lower concentrations in the pellagrins: tryptophan (3.65 vs 5.93 mumol/dl, pellagrin vs control), isoleucine (6.31 vs 11.13), leucine (11.54 vs 24.19), lysine (16.25 vs 34.47), methionine (2.61 vs 4.22), phenylalanine (5.71 vs 9.23), threonine (13.29 vs 26.81), valine (17.60 vs 41.06), alanine (42.54 vs 70.87), arginine (5.87 vs 10.09), tyrosine (5.57 vs 9.30). Glutamic acid was significantly higher in the pellagrins (18.45 vs 9.49). There was no difference between the groups of aspartic acid, glycine, histidine, proline and serine concentrations. It is concluded that pellagra is an important factor influencing the amino acid profiles in these patients. This finding should be taken into account when using plasma amino acid levels to assess the clinical status of the pellagrin.
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