Abstract In order to study the feasibility of electromagnetic ultrasonic method on the welding residual stress detection in Q345R plate, experiments and numerical simulations were carried out. The welding residual stress in the plate was firstly measured by electromagnetic acoustic transducer (EMAT). Then, finite element model of welding process was established to predict the residual stress in plate, who’s rationality was verified by blind hole experiment. At last, the average of numerical simulation results at five points along the plate’s thickness direction was compared with the electromagnetic ultrasonic measurement results. The results show that the residual stress measured by EMAT is consistent with those from numerical simulation in direction of the weld. However, in the vertical direction of the weld, the deviation between EMAT results and numerical simulation is relatively large near the weld fusion line. This phenomenon is also found in the junction between the heat affected zone and the base metal.
Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.
ABSTRACT Metastasis remains a leading cause of cancer‐related deaths, defined by a complex, multi‐step process in which tumor cells spread and form secondary growths in distant tissues. Despite substantial progress in understanding metastasis, the molecular mechanisms driving this process and the development of effective therapies remain incompletely understood. Elucidating the molecular pathways governing metastasis is essential for the discovery of innovative therapeutic targets. The rapid advancements in sequencing technologies and the expansion of biological databases have significantly deepened our understanding of the molecular drivers of metastasis and associated drug resistance. This review focuses on the molecular drivers of metastasis, particularly the roles of genetic mutations, epigenetic changes, and post‐translational modifications in metastasis progression. We also examine how the tumor microenvironment influences metastatic behavior and explore emerging therapeutic strategies, including targeted therapies and immunotherapies. Finally, we discuss future research directions, stressing the importance of novel treatment approaches and personalized strategies to overcome metastasis and improve patient outcomes. By integrating contemporary insights into the molecular basis of metastasis and therapeutic innovation, this review provides a comprehensive framework to guide future research and clinical advancements in metastatic cancer.
The present study aimed to examine whether the enzyme activity of aldehyde dehydrogenase (ALDH) was regulated by Nodal and histamine in the human alveolar adenocarcinoma A549 cell line. The regulated enzyme activity of ALDH was analyzed by flow cytometry in the A549 cell line. ALDH1 and Nodal expression was investigated by immunohistochemistry in28 cases of lung mixed adenocarcinoma. The enzyme activity of ALDH was upregulated by histamine and agonists of histamine H1 receptor (H1R) and histamine H2 receptor (H2R). ALDH activity was also downregulated by recombinant human Nodal and antagonists of H1R and H2R in the A549 cell line. In addition, expression of Nodal and ALDH1 were inversely correlated in lung mixed adenocarcinoma. ALDH enzyme activity was regulated by Nodal and histamine in lung adenocarcinoma.
Biomarkers, including DNA methylation, have shown a great potential for use in personalized medicine for BC and especially for the diagnosis of BC in developing countries. According to the bisulfite sequencing PCR in twelve specimens (BC and matched normal tissues), nine genetic probes were designed to detect the frequency of methylation of the promoters in a total of 302 paired cases of BC and matched normal breast tissues. Finally, a total of 900 serum samples were used to validate the use of these methylation biomarkers for clinical diagnosis of BC. A high frequency of promoter methylation of SFN , HOXA11 , P16 , RARβ , PCDHGB7 , hMLH1 , WNT5a , HOXD13 , and RASSF1a was observed in BC tissues. The methylation frequencies of HOXD13 and hMLH1 increased with the progression of BC. The methylation frequencies of HOXD13 and WNT5a were significantly higher in BC. We found that methylation modification-positive samples were most consistently associated with luminal BC. Finally, we confirmed that RASSF1a , P16 , and PCDHGB7 displayed a significant sensitivity and specificity as diagnostic biomarkers for BC (P<0.001), and a panel that combined these three genes displayed increased significance (AUC, 0.781; P<0.001). These data suggest that epigenetic markers in serum can potentially be used to diagnose BC. The identification of additional BC-specific methylated genes would improve the sensitivity and specificity of this approach. This study could also indicate that different molecular subtypes of BC are caused by distinct genetic and epigenetic mechanisms.
Colorectal cancer (CRC) is one of the most common malignant tumors in the world, with high prevalence and low 5-year survival. Most of the CRC patients show excessive activation of the Wnt/β-catenin pathway which is a vital target for CRC treatment. Based on multiple CRC cell lines with different nuclear expression of β-catenin, NU2058 is identified from a small molecule library consisting of 280 bioactive compounds and found to selectively inhibit the proliferation of CRC cells with nuclear β-catenin activation in vitro and in vivo. The translational significance of NU2058 alone or in combination with chemotherapeutic drugs oxaliplatin and irinotecan (SN38) in CRC is demonstrated in orthotopic tumor model and patient-derived xenograft models. By integrating limited proteolysis-small molecule mapping (LiP-SMap) and mass spectrometry (MS), Ran-binding protein 3 (RanBP3) is identified as the direct target of NU2058. The results show that RanBP3 is a tumor suppressor in CRC and is associated with patient survival. Mechanistically, NU2058 increases the interaction of RanBP3 and β-catenin to promote nuclear export of β-catenin, which further inhibits transcription of c-Myc and cyclin D1 to induce cell senescence. Collectively, NU2058 may serve as a promising therapeutic agent for CRC patients with selective disruption of pathologic Wnt/β-catenin signaling.
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