Metabolic Characterization of Antifolate Responsiveness and Non-responsiveness in Malignant Pleural Mesothelioma Cells

Antifolates are a class of drugs effective for treating malignant pleural mesothelioma (MPM). The majority of antifolates inhibit enzymes involved in purine and pyrimidine synthesis such as dihydrofolate reductase (DHFR), thymidylate synthase (TYMS), and glycinamide ribonucleotide formyltransferase (GART). In order to select the most suitable patients for effective therapy with drugs targeting specific metabolic pathways, there is a need for better predictive metabolic biomarkers. Antifolates can alter global metabolic pathways in MPM cells, yet the metabolic profile of treated cells has not yet been clearly elucidated. Here we found that MPM cell lines could be categorized into two groups according to their sensitivity or resistance to pemetrexed treatment. We show that pemetrexed susceptibility could be reversed and DNA synthesis rescued in drug-treated cells by the exogenous addition of the nucleotide precursors hypoxanthine and thymidine (HT). We observed that the expression of pemetrexed-targeted enzymes in resistant MPM cells was quantitatively lower than that seen in pemetrexed-sensitive cells. Metabolomic analysis revealed that glycine and choline, which are involved in one-carbon metabolism, were altered after drug treatment in pemetrexed-sensitive but not resistant MPM cells. The addition of HT upregulated the concentration of inosine monophosphate (IMP) in pemetrexed-sensitive MPM cells, indicating that the nucleic acid biosynthesis pathway is important for predicting the efficacy of pemetrexed in MPM cells. Our data provide evidence that may link therapeutic response to the regulation of metabolism, and points to potential biomarkers for informing clinical decisions regarding the most effective therapies for patients with MPM

Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome-wide association study.

Background and Aim: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). Methods: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results: In this GWAS, we found that two SNPs were associated with HCC at Conclusions: SNPs i

media1.mp4

Fig. 11. Time-lapse measurement results of the scattered images obtained in the blue box in Fig. 10(a). (a), (b), (c), (d), (e), and (f) are the fluorescent images (a) at the initial time as 0 min, and after (b) 10 min, (c) 20 min, (d) 30 min, 40 min, and 50 min, respectively. See the movie file as media1.mp4

media2.mp4

Fig. 12. Time-lapse measurement results of numerically reconstruct images in the blue box by the proposed method. (a), (b), (c), (d), (e), and (f) are the images after 0 min, 10 min, 20 min, 30 min, 40 min, and 50 min, respectively. See the movie file as media2.mp4

media4.mp4

Fig. 14. Time-lapse measurement results of the reconstructed image in the red box of Fig. 10 by proposed method. (a), (b), (c), (d), (e), and (f) are the images after 0 min, 10 min, 20 min, 30 min, 40 min, and 50 min, respectively. See the movie file as media4.mp4

media3.mp4

Fig. 13. Time-lapse measurement results of the scattered images obtained in the red box in Fig. 10 (a). (a), (b), (c), (d), (e), and (f) are the fluorescent images (a) at the initial time as 0 min, and after (b) 10 min, (c) 20 min, (d) 30 min, 40 min, and 50 min, respectively. See the movie file as media3.mp4

Corrosion Damage Detection in Headrace Tunnel Using YOLOv7 with Continuous Wall Images

Infrastructure that was constructed during the high economic growth period of Japan is starting to deteriorate; thus, there is a need for the maintenance and management of these structures. The basis of maintenance and management is the inspection process, which involves finding and recording damage. However, in headrace tunnels, the water supply is interrupted during inspection; thus, it is desirable to comprehensively photograph and record the tunnel wall and detect damage using the captured images to significantly reduce the water supply interruption time. Given this background, the aim of this study is to establish an investigation and assessment system for deformation points in the inner walls of headrace tunnels and to perform efficient maintenance and management of the tunnels. First, we develop a mobile headrace photography device that photographs the walls of the headrace tunnel with a charge-coupled device line camera. Next, we develop a method using YOLOv7 for detecting chalk marks at the damage locations made during cleaning of the tunnel walls that were photographed by the imaging system, and these results are used as a basis to develop a system that automatically accumulates and plots damage locations and distributions. For chalking detection using continuous wall surface images, a high accuracy of 99.02% is achieved. Furthermore, the system can evaluate the total number and distribution of deteriorated areas, which can be used to identify the causes of change over time and the occurrence of deterioration phenomena. The developed system can significantly reduce the duration and cost of inspections and surveys, and the results can be used to select priority repair areas and to predict deterioration through data accumulation, contributing to appropriate management of headrace tunnels

TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria

PINK1 is activated by autophosphorylation and forms a high-molecular-weight complex, thereby initiating the selective removal of damaged mitochondria by autophagy. Other than translocase of the outer mitochondrial membrane complexes, members of PINK1-containing protein complexes remain obscure. By mass spectrometric analysis of PINK1 co-immunoprecipitates, we identify the inner membrane protein TIM23 as a component of the PINK1 complex. TIM23 downregulation decreases PINK1 levels and significantly delays autophosphorylation, indicating that TIM23 promotes PINK1 accumulation in response to depolarization. Moreover, inactivation of the mitochondrial protease OMA1 not only enhances PINK1 accumulation but also represses the reduction in PINK1 levels induced by TIM23 downregulation, suggesting that TIM23 facilitates PINK1 activation by safeguarding against degradation by OMA1. Indeed, deficiencies of pathogenic PINK1 mutants that fail to interact with TIM23 are partially restored by OMA1 inactivation. These findings indicate that TIM23 plays a distinct role in activating mitochondrial autophagy by protecting PINK1