Yukioka Hospital

Simple SummaryThree different murine glioma cell lines were modified to downregulate expression of the murine LDH-A gene using shRNA knockdown (KD) and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar in each of the cell lines. However, an unexpected increase in the aggressiveness was observed in LDH-A KD and GNE-R-140 treated GL261 intracranial gliomas, but not in CT2A and ALTS1C1 i.c. gliomas. Our results show that LDH-A KD and GNE-R-140 treated GL261 cells are better able to metabolize lactate as a primary carbon source through the TCA cycle, and are a net consumer of lactate. These results suggest that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, and that metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis may lead to the unexpected development and activation of alternative metabolic pathways resulting in enhanced tumor-cell survival in a nutrient-limited environment, leading to increased tumor aggressiveness.The effects of the LDH-A depletion via shRNA knockdown on three murine glioma cell lines and corresponding intracranial (i.c.) tumors were studied and compared to pharmacologic (GNE-R-140) inhibition of the LDH enzyme complex, and to shRNA scrambled control (NC) cell lines. The effects of genetic-shRNA LDH-A knockdown and LDH drug-targeted inhibition (GNE-R-140) on tumor-cell metabolism, tumor growth, and animal survival were similar. LDH-A KD and GNE-R-140 unexpectedly increased the aggressiveness of GL261 intracranial gliomas, but not CT2A and ALTS1C1 i.c. gliomas. Furthermore, the bioenergetic profiles (ECAR and OCR) of GL261 NC and LDH-A KD cells under different nutrient limitations showed that (a) exogenous pyruvate is not a major carbon source for metabolism through the TCA cycle of native GL261 cells; and (b) the unique upregulation of LDH-B that occurs in GL261 LDH-A KD cells results in these cells being better able to: (i) metabolize lactate as a primary carbon source through the TCA cycle, (ii) be a net consumer of lactate, and (iii) showed a significant increase in the proliferation rate following the addition of 10 mM lactate to the glucose-free media (only seen in GL261 KD cells). Our study suggests that inhibition of LDH-A/glycolysis may not be a general strategy to inhibit the i.c. growth of all gliomas, since the level of LDH-A expression and its interplay with LDH-B can lead to complex metabolic interactions between tumor cells and their environment. Metabolic-inhibition treatment strategies need to be carefully assessed, since the inhibition of glycolysis (e.g., inhibition of LDH-A) may lead to the unexpected development and activation of alternative metabolic pathways (e.g., upregulation of lipid metabolism and fatty-acid oxidation pathways), resulting in enhanced tumor-cell survival in a nutrient-limited environment and leading to increased tumor aggressiveness.

Background Proximal horizontal tears of the triangular fibrocartilage complex (TFCC) represent the tears at the proximal surface of the articular disk with a normal appearance of the distal surface. Preoperative diagnosis of TFCC flap tears is challenging. Objectives This report aims to present a diagnostic method using computed tomography (CT) arthrography for the proximal horizontal flap tears of the TFCC and to report our clinical outcomes. Patients and Methods Six patients were included who were preoperatively suspected to have proximal horizontal flap tears of the TFCC via CT arthrography. Arthrography was conducted by injecting dye into the distal radioulnar joint (DRUJ), and CT images were obtained immediately following arthrography. We performed arthroscopic or direct flap debridement with concomitant surgeries: ulnar shortening with positive ulnar variance and corrective osteotomy with the malunion following distal radius fracture. Results Preoperative CT arthrography clearly revealed the flaps to be flipped over toward the radiopalmar side of the DRUJ in four cases and a teardrop-shaped dye defect in two. We were able to identify the dislocated flap by arthroscopy avulsed from the proximal aspect of the articular disk within the DRUJ in all six cases. The mean pain level decreased from 10 preoperatively to 0.3 postoperatively on the visual analog scale. The mean patient-rated wrist evaluation score decreased from 43.5 preoperatively to 11.2 postoperatively. Conclusions Our study shows that CT arthrography can be a promising method for diagnosing proximal horizontal flap tears of the TFCC. Debridement of the flaps and concomitant surgeries showed satisfactory clinical results. Level of Evidence This is a Level 4, diagnostic study.