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Cancer genomic medicine using next‐generation sequencers has been developing. However, the number of patients who could receive genomically matched therapy is limited because off‐label use or patient‐oriented compassionate use was not permitted under National Health Insurance in Japan. To improve patient drug accessibility, we initiated a biomarker‐based basket‐type clinical trial (NCCH1901) in October 2019 under patient‐proposed healthcare services. We listed the drugs that had high medical needs but were not covered by National Healthcare Insurance. Then we included these drugs before patient proposal so that they could access off‐label drugs soon after they had the results of CGP tests. All drugs were provided free of charge by pharmaceutical companies. The objective was to administer off‐label drugs and to collect efficacy and safety data for these drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. As of January 31, 2022, we included 18 drug cohorts and 295 patients were treated in this study. The most common cancer was brain tumor, followed by carcinoma of endocrine organs and colorectal cancer. BRAF mutations and ERBB2 amplifications were the frequent genomic abnormalities to be enrolled. This study was one way to access off‐label drugs, and contributed significantly to providing treatment opportunities for patients in Japan. This is a progress report of a biomarker‐based basket‐type clinical trial (NCCH1901). About 300 patients were treated in this trial and patients with BRAF mutations and ERBB2 amplifications were the frequent genomic changes to be enrolled. This trial has contributed to increasing treatment opportunities for patients in Japan.

This case study describes the clinical course of a 39‐year‐old woman with metastatic breast cancer harboring a germline PALB2 mutation who was treated with a PARP inhibitor. She initially demonstrated a clinical benefit with reduced tumor markers and favorable imaging findings. However, disease progression occurred after eight months. Liquid biopsy‐based genomic profiling identified three PALB2 reversion mutations that restored homologous recombination, leading to treatment resistance. The case illustrates both the therapeutic potential of PARP inhibitors in PALB2‐mutated cancers and the emergence of resistance. It emphasizes the importance of liquid biopsy‐based genomic profiling for understanding tumor evolution and guiding treatment strategies. This case study describes the clinical course of a 39‐year‐old woman with metastatic breast cancer harboring a germline PALB2 mutation who was treated with a PARP inhibitor. Figure shows the PALB2 reverse mutation detected by liquid biopsy genomic profiling. The top panel shows a schematic diagram of the wild‐type PALB2 sequence. The second panel shows the germline PALB2 mutation. The third to fifth panels show the somatic PALB2 reversion mutations detected after the development of treatment resistance.

The KEAP1–NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C‐CAT database, which contains the gene‐panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in NRF2 and KEAP1 genes and their associations with clinical outcomes. Variants in the NRF2 gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The NRF2 variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the NRF2 variants in the ETGE motif were indicators of a worse prognosis. KEAP1 variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with KEAP1 and NRF2 variants. Our results indicate that genetic alteration of the KEAP1–NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences. This study examined variants in the KEAP1–NRF2 system for their correlation with cancer type specificity, prognosis, and biological characteristics from the pan‐cancer cohort. The results showed that the presence of variants in NRF2‐DLG, NRF2‐ETGE motifs, and KEAP1 gene play an important role in predicting patient prognosis and defining new therapeutic targets.

Background Germline mutations in BRCA1/2 are known to cause hereditary tumors in the breast, ovary, and other organs. With the widespread adoption of comprehensive diagnostics, including comprehensive genomic profiling (CGP) tests for solid tumors, many patients with BRCA1/2 variants have been identified. Methods In this study, we extracted and analyzed cases of BRCA1/2 variants that were presumed to be germline, which were repeatedly detected using the CGP test for solid tumors in northeastern Japan. The frequencies of BRCA1/2 variants in regional areas were compared with those of healthy individuals or nationwide cancer cohorts to investigate regional distribution. Results Our findings revealed regional disparities in BRCA1/2 pathogenic germline variants, while variants of unknown significance (VUS) showed no such differences. The regional distribution of BRCA1 and BRCA2 variants showed distinct patterns: pathogenic variants of BRCA1 exhibited regional differences and were less prevalent compared to VUS, whereas BRCA2 variants, including both pathogenic variants and VUS, did not exhibit such clear regional localization. This discrepancy in regional distribution between BRCA1 and BRCA2 variants could be attributed to factors such as the diversity of the genome, gender differences, and cancer types. Conclusions These results highlight the importance of considering regional differences in comparative cohort studies, particularly in assessing the differential extension of mutations in pathogenic changes and VUS. Moreover, a presumption of pathogenicity variants would need to be discussed at the regional level. Geographical distribution of the number of pathogenic variants of BRCA1/2 by prefecture. Plots with detections above the predicted values (95% Bayesian prediction interval) were marked with *.

Constrained groove pressing (CGP) as a severe plastic deformation (SPD) technique was applied on Al-Mn-Si sheets. In the following, direct- and cross-rolling were employed as supplementary processing in order to investigate the rolling-direction effect on CGPed sheets. The in-depth characterization of microstructural evolutions were employed using polarized light microscope and scanning electron microscope. Williamson-Hall analysis method was applied on X-ray diffraction (XRD) patterns of specimens. Analysis of XRD results revealed that post-rolling of CGPed sheets induced dynamic recrystallization (DRX) due to massive dislocations’ accumulation which follows by crystallite growth. The largest crystallite size which was 619 nm achieved after direct-rolling through the rolling strain of 1.27. Maximum acquired peak intensity ratio for rolled sheets was for (220) crystallographic plane similar to annealed one. Also, post-rolling had altered the distinguished plane from (111) for CGPed sheets into (220). Mechanical characteristics of specimens were examined using hardness and tension tests. Based on the obtained results, direct-rolling of CGPed samples was more susceptible for strength enhancement compared to cross-rolling. Optimum achieved values for yield and ultimate tensile strength were 155 and 197 MPa, respectively. Rolling in the both longitudinal and cross directions had almost similar effect on the final attained hardness.

Severe plastic deformation (SPD) is routinely employed to modify microstructure to obtain improved mechanical properties, particularly strength. Constrained groove pressing (CGP) is one of the SPD techniques that has gained prominence recently. However, the efficacy of the method in terms of homogeneity of microstructure and properties has not been well explored. In this work, we examine the microstructure and mechanical properties of CGP processed Cu-Zn alloy sheet and also explore homogeneity in their characteristics. We found that CGP is very effective in improving the mechanical properties of the alloy. Although the reduction in grain size with the number of passes in CGP is not as huge (~38 µm in annealed sample to ~10.2 µm in 1 pass sample) as is expected from a SPD technique, but there is a drastic improvement in ultimate tensile strength (~230 to ~380 MPa) which shows the effectiveness of this process. However, when mechanical properties were examined at smaller length scale using micro-indentation technique, it was found that hardness values of CGP processed samples were non-uniform along transverse direction with a distinct sinusoidal variation. Uniaxial tensile test data also showed strong anisotropy along principal directions. The cause of this anisotropy and non-uniformity in mechanical properties was found to lie in microstructural inhomogeneity which was found to exist at the length scale of the grooves of the die.

To achieve an ultra-fine grained structure, 2 passes of constrained groove pressing (CGP) were performed on AZ31 Mg alloy sheets at a temperature of 250 °C. To examine the deformation and fracture behavior of the produced alloy sheets, tensile tests conducted at different temperatures ranging from 25 to 200 °C and strain rates varying from 0.001 to 0.1 s −1 . The Box-Behnken design was utilized to conduct experiments, and the response surface methodology was employed to represent the output responses in terms of the key parameters. At a strain rate of 0.0505 s −1 and a temperature of 200 °C, the maximum elongation of 23% was observed, whereas, the material exhibited the yield strength of 128 MPa and the ultimate strength of 163 MPa. Ductile fracture morphology was noticed with increasing temperature. The %elongation slightly decreased as a result of the coarsening of grains at 250 °C. A specialized experimental setup incorporating heating systems was utilized to facilitate high-temperature constrained groove pressing (CGP) on materials that are difficult to deform. A systematic investigation was carried out to analyze the microstructure and mechanical properties of AZ31 Mg alloy sheets subjected to CGP. The study aimed to highlight the influence of the number of passes and thermal deformation on these properties.

Purpose Enterococcus faecalis ( E. faecalis ) is an important commensal microbiota member of the human gastrointestinal tract. It has been shown in many studies that infection rates with E. faecalis in gastric cancer significantly increase. It has been scientifically proven that some infections develop during the progression of cancer, but it is still unclear whether this infection factor is beneficial (reduction in metastasis) or harmful (increase in proliferation, invasion, stem cell-like phenotype) of the host. These opposed data can significantly contribute to the understanding of cancer progress when analyzed in detail. Methods The gene expression data were retrieved from Array Express (E-MEXP-3496). Variance, t test and linear regression analysis, hierarchical clustering, network, and pathway analysis were performed. Results In this study, we identified altered genes involved in E. faecalis infection in the gastric cell line MKN74 and the relevant pathways to understand whether the infection slows down cancer progression. Twelve genes corresponding 15 probe sets were downregulated following the live infection of gastric cancer cells with E. faecalis . We identified a network between these genes and pathways they belong to. Pathway analysis showed that these genes are mostly associated with cancer cell proliferation. Conclusion NDC80, NCAPG, CENPA, KIF23, BUB1B, BUB1, CASC5, KIF2C, CENPF, SPC25, SMC4, and KIF20A genes were found to be associated with gastric cancer pathogenesis. Almost all of these genes are effective in the proliferation of cancer cells, especially during the infection process. Therefore, it is hypothesized that downregulation of these genes may affect gastric cancer pathogenesis by reducing cell proliferation. And, it is predicted that E. faecalis infection may be an important factor for gastric cancer.

Background and purpose: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant‐like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. Experimental approach: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. Key results: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant‐like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant‐like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. Conclusions and Implications: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA‐ergic transmission in this disorder. British Journal of Pharmacology (2006) 149, 581–590. doi:10.1038/sj.bjp.0706845

It has been reported that selective GABA(B) receptor antagonists can enhance cognitive performance in a variety of learning paradigms. This prompted us to examine the effects of some more potent and newly synthesised GABAB antagonists CGP 71982, CGP 62349 and CGP 55845A in an active avoidance test in rats. A two-way active avoidance test with negative reinforcement was performed for the first 5 of 12 days of antagonist administration. CGP 71982 and CGP 55845A at all doses applied (0.01-1.0 mg/kg) had an improving effect on learning, and memory retention on day 12; the rats made more avoidances in both sessions compared to controls. CGP 62349 was only active at the lowest dose tested (0.01 mg/kg). The present study confirms that GABA(B) receptor antagonists can enhance cognitive performance but provides no insight into the mechanism of action of these novel antagonists.