The extension of the amyloid hypothesis to include non-protein metabolite assemblies invokes a paradigm for the pathology of inborn error of metabolism disorders. However, a direct demonstration of the assembly of metabolite amyloid-like structures has so far been provided only in vitro. Here, we established an in vivo model of adenine self-assembly in yeast, in which toxicity is associated with intracellular accumulation of the metabolite. Using a strain blocked in the enzymatic pathway downstream to adenine, we observed a non-linear dose-dependent growth inhibition. Both the staining with an indicative amyloid dye and anti-adenine assemblies antibodies demonstrated the accumulation of adenine amyloid-like structures, which were eliminated by lowering the supplied adenine levels. Treatment with a polyphenol inhibitor reduced the occurrence of amyloid-like structures while not affecting the dramatic increase in intracellular adenine concentration, resulting in inhibition of cytotoxicity, further supporting the notion that toxicity is triggered by adenine assemblies.
Adjuvant chemotherapy appears to be effective to control both local- and distant-recurrences in stage I UCS; adding radiotherapy to chemotherapy may be effective to control local-recurrence when the tumor exhibits multiple risk factors.
The aim of the present study was to determine whether the expression of hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase-IX (CA-IX), glucose transporter-1 (GLUT-1) or vascular endothelial growth factor (VEGF) was associated with the clinicopathological characteristics, lymph node metastasis or progression-free survival of patients with cervical cancer. Tumor tissue samples were obtained from 54 cervical cancer patients who had undergone radical hysterectomy. The expression of HIF-1α, CA-IX, GLUT-1 and VEGF was analyzed by immunohistochemical staining. Of the 54 cases, 28 were positive for HIF-1α, 35 for CA-IX, 40 for GLUT-1 and 23 for VEGF. It was revealed that HIF-1α expression was correlated with tumor stage and histology, CA-IX expression with tumor stage, tumor size, lymph node metastasis and lymph-vascular space involvement, GLUT-1 expression with tumor stage and lymph-vascular space involvement, and VEGF expression with microvessel density. The multivariate regression analysis indicated that CA-IX expression and lymph-vascular space involvement were independent variables associated with lymph node metastasis. Progression-free survival was shorter for patients who were positive for CA-IX or VEGF expression than for those who were negative for CA-IX or VEGF expression. The progression-free survival of patients treated with radiotherapy or chemo-radiotherapy following radical hysterectomy was also shorter for patients with positive CA-IX expression. These findings suggest that CA-IX expression is a possible risk factor for lymph node metastasis and disease recurrence in locally advanced cervical cancer patients.
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