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Thymus Cancer [keywords]
- Transcriptome sequencing of neonatal thymic epithelial cells. [Journal Article]
- Sci Rep 2013 May 17.:1860.
In order to gain novel insights into thymus biology, we analysed the whole transcriptome of cortical and medullary thymic epithelial cells (cTECs and mTECs) and of skin epithelial cells (ECs). Consistent with their ability to express ectopic genes, mTECs expressed more genes than other cell populations. Out of a total of 15,069 genes expressed in TECs, 25% were differentially expressed by at least 5-fold in cTECs vs. mTECs. Genes expressed at higher levels in cTECs than mTECs regulate numerous cell functions including cell differentiation, cell movement and microtubule dynamics. Many positive regulators of the cell cycle were overexpressed in skin ECs relative to TECs. Our RNA-seq data provide novel systems-level insights into the transcriptional landscape of TECs, highlight substantial divergences in the transcriptome of TEC subsets and suggest that cell cycle progression is differentially regulated in TECs and skin ECs.
- Enhanced-affinity murine TCRs for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection. [JOURNAL ARTICLE]
- Blood 2013 May 14.
Many of the most promising tumor antigens for T cell-based cancer immunotherapies are unmodified self-antigens. Unfortunately, the avidity of T cells specific for these antigens is limited by central tolerance during T cell development in the thymus, resulting in decreased anti-tumor efficacy of these T cells. One approach to overcome this obstacle is to mutate TCR genes from naturally occurring T cells in order to enhance the affinity for the target antigen. These enhanced affinity TCRs can then be developed for use in TCR gene therapy. Although significantly enhanced affinity TCRs have been generated using this approach, it is not clear if these TCRs, which bypass the affinity limits imposed by negative selection, remain unresponsive to the low levels of self-antigen generally expressed by some normal tissues. Here we show that two variants of a high affinity WT1-specific TCR with enhanced affinity for WT1 are safe, and do not mediate autoimmune tissue infiltration or damage when transduced into peripheral CD8 T cells and transferred in vivo. However, if expressed in developing T cells and subjected to thymic selection, the same enhanced-affinity TCRs signal tolerance mechanisms in the thymus resulting in T cells with attenuated antigen sensitivity in the periphery.
- Thymomas and thymic carcinomas. [Journal Article]
- J Natl Compr Canc Netw 2013 May 1; 11(5):562-76.
Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors.
- Antitumor activity of a polysaccharide from Pleurotus eryngii on mice bearing renal cancer. [Journal Article]
- Carbohydr Polym 2013 Jun 20; 95(2):615-20.
One water-soluble polysaccharide (PEPw), with an average molecular weight of 2.5×10(4)Da, was isolated from the fruiting bodies of Pleurotus eryngii and subjected to composition analysis and evaluated for the antitumor and immunomodulatory activity. PEPw was composed of arabinose, mannose and galactose in a molar ratio of 1.2:2.3:6.2 and had a backbone mainly consisting of 1,6-linked-Galp, 1,2,6-linked-Galp and 1,4-linked-Manp residues, which was occasionally terminated with terminal-Araf attached to O-2 of 1,2,6-linked-Galp residue. The animal experiment results showed that PEPw significantly increased relative thymus and spleen indices, promoted the spleen lymphocytes proliferation induced by ConA or LPS, elevated the activities of NK cell and CTL in spleen, and increased the serum concentration of TNF-α and IL-2 in Renca tumor-bearing mice. As a result, the tumor growth was significantly inhibited by PEPw treatment at the doses of 50, 100 and 200mg/kg in a dose-dependent manner. These data indicated that the anti-tumor activity of PEPw may be related to the activation of the immune response in tumor-bearing mice.
- Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. [JOURNAL ARTICLE]
- Nat Immunol 2013 May 5.
Natural T helper 17 (nTH17) cells are a population of interleukin 17 (IL-17)-producing cells that acquire effector function in the thymus during development. Here we demonstrate that the serine/threonine kinase Akt has a critical role in regulating nTH17 cell development. Although Akt and the downstream mTORC1-ARNT-HIFα axis were required for generation of inducible TH17 (iTH17) cells, nTH17 cells developed independently of mTORC1. In contrast, mTORC2 and inhibition of Foxo proteins were critical for development of nTH17 cells. Moreover, distinct isoforms of Akt controlled the generation of TH17 cell subsets, as deletion of Akt2, but not of Akt1, led to defective generation of iTH17 cells. These findings define mechanisms regulating nTH17 cell development and reveal previously unknown roles of Akt and mTOR in shaping subsets of T cells.
- Synthesis, cytotoxic activity and DNA-interaction studies of novel anthraquinone-thiosemicarbazones with tautomerizable methylene group. [JOURNAL ARTICLE]
- Eur J Med Chem 2013 Apr 9.:228-238.
A series of novel anthraquinone-thiosemicarbazone derivatives in a tautomerizable keto-imine form was synthesized and tested for their in vitro cytotoxic activity against human cancer cells (HeLa, MDA-MB-361, MDA-MB-453, K562, A549) and human normal MRC-5 cells. Several compounds efficiently inhibited cancer cell growth at micromolar concentrations, especially against K562 and HeLa cells. As determined by flow cytometric analysis, anthraquinone-thiosemicarbazone caused significant increase in the number of sub-G1 phase of HeLa cells and apoptosis in a concentration-dependent manner. Also, inhibition of caspase-3, -8, and -9 with specific caspase inhibitors reduced the apoptosis mediated by the tested compounds in HeLa cells. All anthraquinone-thiosemicarbazones exhibit calf thymus DNA-binding activity, but no cleavage of plasmid DNA was observed.
- Synthesis, characterization and in vitro pharmacological evaluation of new water soluble Ni(II) complexes of 4N-substituted thiosemicarbazones of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde. [JOURNAL ARTICLE]
- Eur J Med Chem 2013 Apr 6.:179-189.
Four new Ni(II) complexes of general formula [Ni(H2-Qtsc-R)2](NO3)2 (H2-Qtsc-R = 4N-substituted thiosemicarbazones of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde, where R = H (1), Me (2), Et (3), or Ph (4)) have been synthesized and characterized. The geometry of the complexes was confirmed by single crystal X-ray crystallography for one of the complexes (3). The binding affinity of the complexes with DNA and protein have been studied which indicate that they could interact with calf thymus DNA and bovine serum albumin protein. Investigations of antioxidative properties showed that all the complexes have strong radical scavenging properties. Cytotoxic studies showed that the complexes exhibited effective cytotoxic activity against a panel of human cancer cells without affecting the normal cells much.
- Novel naphthalimide polyamine derivatives as potential antitumor agents. [Journal Article]
- Mol Biol Rep 2013 Jun; 40(6):4129-37.
A novel series of naphthalimide polyamine conjugates were designed, synthesized and evaluated for in vitro antiproliferative activity against human leukemia (Jurkat), human cervical adenocarcinoma (HeLa), human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549) cell lines. From the six derivatives, the new I1 and A3 exhibited highest antiproliferative activity with the IC50 values of 5.67-11.02 μmol·L(-1). Cell cycle analysis of Jurkat cells exposed to I1 at a concentration of 30 μmol × L(-1) for 24 h exhibited a mild increase in S and G2/M fraction caused by accumulation of cells. This arrest was followed by an increase in sub-G0/G1 after 48 h of incubation. Jurkat cells exposed to A3 at a concentration of 30 μmol × L(-1) for 24 h showed an increase in G0/G1 fraction and after 48 h an increase in G2/M fraction followed by an increase in sub-G0/G1 after 72 h of incubation. Moreover, the A3 compound was observed to displace the intercalating agent ethidium bromide from calf thymus DNA using fluorescence spectroscopy. The apparent binding constant was estimated to be 3.1 × 10(6) M(-1) what indicates non-intercalating mode of DNA binding. On the other hand, we found no inhibitory effect of studied compounds on topoisomerase I and topoisomerase II activity. Finally, the localization of these compounds in the cells due to their inherent fluorescence was investigated with the fluorescence microscopy. Our results suggest that the naphthalimide polyamine conjugates rapidly penetrate to the cancer cells. Further studies are necessary to investigate the precise mechanism of action and to find out the relationship between the structure, character and position of substituents of naphthalimide polyamine conjugates and their biological activities.
- Identification of novel mutations of TP53, ALK and RET gene in metastatic thymic squamous cell carcinoma and its therapeutic implication. [JOURNAL ARTICLE]
- Lung Cancer 2013 Apr 29.
Thymic tumors are epithelial tumors of the thymus for which multimodal therapies are often ineffective because of a lack of standardized regimens. Due to the low incidence, the molecular pathology and genomic abnormalities of thymic epithelial tumors are largely unknown. In this study, we report our comprehensively genomic study on a case of metastatic thymic tumor. Using next generation deep DNA sequencing technology, we sequenced 190 segments of 46 cancer genes of the cancer genome to cover 739 COSMIC mutations in 604 loci. Among these sequenced cancer genes, we identified that three low frequency (~10% of cells) mutations in the TP53 gene (c.782+1G>T), ALK gene (c.3551C>T), and RET gene (c.2651A>T). To the best of our knowledge, this is the first study to show those mutations in thymic tumor. Of note, our study further indicates comprehensive molecular analysis may facilitate development of novel diagnostic and therapeutic strategies for thymic tumors.
- Synthesis, properties, and antitumor effects of a new mixed phosphine gold(I) compound in human colon cancer cells. [JOURNAL ARTICLE]
- J Inorg Biochem 2013 Mar 29.:78-87.
The antineoplastic potential of a new stable mixed phosphine gold(I) complex containing tris(tert-butyl)phosphine (tBu3P) and bis(diphenylphosphino)ethene (dppet), namely [Au(tBu3P)(dppet)Cl], has been investigated in the human colon cancer HCT-116 cell line. The (31)P NMR solution study, confirms the structural features observed in the solid state and, in addition, indicates partial formation of dinuclear cationic [Au(tBu3P)2](+) and [Au(dppet)2](+) species. The ionic character and strong Au-P bonds of this gold(I) species are similar to those of the most active antitumor gold compounds so far studied. The title compound was found to exhibit strong cytotoxicity, showing 85 fold greater toxicity than cisplatin (IC50=0.45μM vs IC50=39.16 for cisplatin at 24h) on the HCT-116 line. The cytotoxic effects were, at least partly, mediated by the induction of apoptotic cell death as evidenced by the sub-G1 cell accumulation, oligonucleosomal DNA fragmentation, caspase-3 activation and the release of cytochrome c from the mitochondria. The gold(I) compound showed little interaction with DNA measured through fluorescence quenching studies with calf thymus DNA. The inhibitory effect of the gold(I) compound on intracellular redox proteins has been also observed in pretreated HCT-116 cells. The compound was particularly effective in inhibiting thioredoxin reductase, that is likely responsible for the increased ROS production, and subsequent apoptosis induction via the mitochondrial pathway.