Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of proton magnetic resonance spectroscopy (1H MRS) to diagnose brain tumors was investigated using in vitro high-resolution spectra. Fifty-eight surgically excised samples of brain tumors (12 glioblastomas, 4 anaplastic astrocytomas, 6 astrocytomas, 12 meningiomas, 6 neurinomas, 4 chordomas, 3 craniopharyngiomas, 2 pituitary adenomas, 2 malignant lymphomas, 1 ependymoma, 1 medulloblastoma, and metastatic brain tumors including 3 pulmonary adenocarcinomas, a hepatocellular carcinoma, and a renal cell carcinoma) and 4 nontumorous lobectomized brains were examined by in vitro 1H MRS. N-Acetyl-aspartate was demonstrated in normal tissues but could not be detected in nonneuroectodermal tumors. Total creatine was decreased in all brain tumors in comparison with normal brain tissues, but was relatively higher in neuroectodermal tumors than in other brain tumors. Choline-containing compounds were present in all tumors except craniopharyngioma, and their concentrations were particularly high in a metastatic brain tumor from hepatocellular carcinoma. The concentration of glycine was high in neuroectodermal tumors, whereas that of taurine was high in medulloblastoma, pituitary adenoma, and renal cell carcinoma. Alanine was increased in meningioma, glioma, and pituitary adenoma. Neurinoma had the largest inositol content among the tumors examined. Thus each type of brain tumor exhibited a characteristic MR spectrum. These data suggested that in vivo 1H MRS might provide clinically useful information about tumor metabolism and aid in the differential diagnosis of tumors. Although excellent anatomical localization of tumors can be readily obtained by MR imaging, MRS may provide additional information in cases in which the differential diagnosis of tumors by MR imaging is difficult.
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PMID:Proton magnetic resonance spectroscopy of brain tumors: an in vitro study. 780 3

Although T regulatory cells (Treg) are essential for the prevention of autoimmune diseases, their immunoregulatory function restrains the induction of immune responses against cancer. Thus, development of inhibitors of FOXP3, a key transcription factor for the immunosuppressive activity of Treg, might give new therapeutic opportunities. In a previous work we identified a peptide (named P60) able to enter into the cells, bind to FOXP3, and impair Treg activity in vitro and in vivo. Here we show that P60 binds to the intermediate region of FOXP3 and inhibits its homodimerization as well as its interaction with the transcription factor AML1. Alanine-scanning of P60 revealed the relevance of each position on FOXP3 binding, homodimerization, association with AML1 and inhibition of Treg activity. Introduction of alanine at positions 2, 5 and 11 improved the activity of the original P60, whereas alanine mutations at positions 1, 7, 8, 9, 10 and 12 were detrimental. Multiple mutation experiments allowed us to identify peptides with higher FOXP3 binding affinity and stronger biological activity than the original P60. Head to tail macrocyclization of peptide P60-D2A-S5A improved Treg inhibition and enhanced anti-tumor activity of anti-PD1 antibodies in a model of hepatocellular carcinoma. Introduction of a D-aminoacid at position 2 augmented significantly microsomal stability while maintained FOXP3 binding capacity and Treg inhibition in vitro. In vivo, when combined with the cytotoxic T-cell epitope AH1, it induced protection against CT26 tumor implantation. This study provides important structure-function relationships essential for further drug design to inhibit Treg cells in cancer.
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PMID:Blockage of FOXP3 transcription factor dimerization and FOXP3/AML1 interaction inhibits T regulatory cell activity: sequence optimization of a peptide inhibitor. 2906 40

KRAS mutations are detected in numerous human cancers, but there are few effective drugs for KRAS-mutated cancers. Transporters for amino acids and glucose are highly expressed on cancer cells, possibly to maintain rapid cell growth and metabolism. Alanine-serine-cysteine transporter 2 (ASCT2) is a primary transporter for glutamine in cancer cells. In this study, we developed a novel monoclonal antibody (mAb) recognizing the extracellular domain of human ASCT2, and investigated whether ASCT2 can be a therapeutic target for KRAS-mutated cancers. Rats were immunized with RH7777 rat hepatoma cells expressing human ASCT2 fused to green fluorescent protein (GFP). Splenocytes from the immunized rats were fused with P3X63Ag8.653 mouse myeloma cells, and selected and cloned hybridoma cells secreting Ab3-8 mAb were established. This mAb reacted with RH7777 transfectants expressing ASCT2-GFP proteins in a GFP intensity-dependent manner. Ab3-8 reacted with various human cancer cells, but not with non-cancer breast epithelial cells or ASCT2-knocked out HEK293 and SW1116 cells. In SW1116 and HCT116 human colon cancer cells with KRAS mutations, treatment with Ab3-8 reduced intracellular glutamine transport, phosphorylation of AKT and ERK, and inhibited in vivo tumor growth of these cells in athymic mice. Inhibition of in vivo tumor growth by Ab3-8 was not observed in HT29 colon and HeLa uterus cancer cells with wild-type KRAS. These results suggest that ASCT2 is an excellent therapeutic target for KRAS-mutated cancers.
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PMID:Anti-tumor effects of an antagonistic mAb against the ASCT2 amino acid transporter on KRAS-mutated human colorectal cancer cells. 3170 72