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Multistage thermomechanical treatment experiments were conducted on Cu–Ni–Co–Si–Mg alloy strip prepared by the Heating Cooling Combined Mold (HCCM) horizontal continuous casting-cold rolling process. Effects of various heat treatments on the microstructure, mechanical properties, and electrical conductivity of the alloy were studied. The strengthening mechanisms and factors influencing the performance of each process has been analyzed. The tensile strength, yield strength, and electrical conductivity of Cu–Ni–Co–Si–Mg alloy can reach 894 MPa, 855 MPa, and 47.1 %IACS after a third-stage of thermomechanical treatment (TTMT). The cold rolling in first-stage of thermomechanical treatment (FTMT) not only caused work hardening of the alloy but also promoted the precipitation of solute atoms and the growth of second phase particles, limiting the increase in strength. Second-stage of thermomechanical treatment (STMT) effectively hindered the excessive growth of second phase particles in FTMT but shortened recrystallization process. The superior performance of Cu–Ni–Co–Si–Mg alloy after TTMT was attributed to dispersive precipitation of Ni, Co, and Si elements as (Ni, Co) 2Si phases in the copper matrix, strengthening the interaction between the precipitates and dislocations. A short process of HCCM horizontal continuous casting-cold rolling-thermomechanical treatment was developed to produce a high strength and highly electrically conductive Cu–Ni–Co–Si alloy strip used in lead frames.

Abstract Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum‐based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (TP53) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long‐term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying TP53 mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3‐kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3β) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c‐Myc) and Krueppel‐like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain‐containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c‐Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for TP53‐mutated CRC.

Abstract Triple-negative breast cancer (TNBC) is regarded as the deadliest subtype of breast cancer because of its high heterogeneity, aggressiveness, and limited treatment options. Toxoflavin has been reported to possess antitumor activity. In this study, a series of toxoflavin analogs were synthesized, among which D43 displayed a significant dose-dependent inhibitory effect on the proliferation of TNBC cells (MDA-MB-231 and HCC1806). Additionally, D43 inhibited DNA synthesis in TNBC cells, leading to cell cycle arrest at the G2/M phase. Furthermore, D43 consistently promoted intracellular ROS generation, induced DNA damage, and resulted in apoptosis in TNBC cells. These effects could be reversed by N-acetylcysteine. Moreover, D43 significantly inhibited the growth of breast cancer patient-derived organoids and xenografts with a favorable biosafety profile. In conclusion, D43 is a potent anticancer agent that elicits significant antiproliferation, oxidative stress, apoptosis, and DNA damage effects in TNBC cells, and D43 holds promise as a potential candidate for the treatment of TNBC.

Abstract The effect of MDANP effects on ER stress signalling not well known or elucidated. Endoplasmic reticulum (ER) stress plays a critical role in necrotizing enterocolitis (NEC) pathogenesis through the PERK-eIF2ɑ-QRICH1 axis. The present study aimed to explore the protective effects of MDANP in NEC development. Firstly, a function screening was designed to identify the candidate peptides in human milk, and then the identified peptides were validated in NEC patients. In vivo, NEC was induced in mice pups and divided into four groups: (1) control group, (2) NEC group, (3) MDANP + NEC group, and (4) NS + NEC group. In vitro, lentivirus-mediated QRICH1 silencing, was used to transfect NCM460 cell lines, then stimulated with LPS. After LPS stimulation, cells were treated with chemically synthesized MDANP, and the essential proteins in the QRICH1 signalling pathway in cells were tested and compared. After the small-scale screening, a peptide (SKSKKFRRPDIQYPDATDED) named MDANP was determined as the principal peptide. Its protective effect against NEC through inhibiting the expression of ERS key proteins and impeding the intestinal cells’ apoptosis was observed in the animal models. Furthermore, the inhibitive effect of MDANP on apoptosis of intestinal epithelial cells through modulating the PERK-eIF2ɑ-QRICH1 ERS pathway was also confirmed in vitro. Taken together, our data suggest that MDANP effectively ameliorates apoptosis in NEC through attenuating PERK-eIF2ɑ-QRICH1.

Abstract Multiple tumors are synergistically promoted by c-Met and TRK, and blocking their cross-signalling pathway may give better effects. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited excellent anti-tumor activity by targeting c-Met and TRK. Models in vitro, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the positive drug Tepotinib. Models in vivo, 1D228 showed robust anti-tumor effect on gastric and liver tumor growth with 94.8% and 93.4% of the TGI, respectively, comparing 67.61% and 63.9% of Tepotinib. Importantly, compared with the combination of Larotrectinib and Tepotinib, 1D228 monotherapy in MKN45 xenograft tumor models showed stronger antitumor activity and lower toxicity. Mechanistic studies showed that 1D228 can largely inhibit the phosphorylation of TRKB and c-Met. Interestingly, both kinases, TRKs and c-Met, have been found to be co-expressed at high levels in patients with gastric cancer through IHC. Furthermore, bioinformatics analysis has revealed that both genes are abnormally co-expressed in multiple types of cancer. Cell cycle analysis found that 1D228 induced G0/G1 arrest by inhibiting cyclin D1. Additionally, vascular endothelial cells also showed a pronounced response to 1D228 due to its expression of TRKB and c-Met. 1D228 suppressed the migration and tube formation of endothelial cells, which are the key functions of tumor angiogenesis. Taken together, compound 1D228 may be a promising candidate for the next generation of c-Met and TRK inhibitors for cancer treatment, and offers a novel potential treatment strategy for cancer patients with abnormal expressions of c-Met or NTRK, or simultaneous of them.

Abstract The objective of this multicenter, single‐arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy‐THPy) in the treatment of patients with stage II–III HER2‐positive breast cancer. The present study enrolled patients with stage II–III HER2‐positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21‐day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention‐to‐treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7–75.8%), while the objective response rate was 89.1%. In the post‐hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy‐THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II–III HER2‐positive breast cancer.

Cu-1.3 wt%Ni-1.0 wt%Co-0.9 wt%Si-0.1 wt%Mg alloy strip with 10 mm in thickness produced by heating-cooling combined mold (HCCM) horizontal continuous casting was cold rolled. Microstructure evolution and mechanical properties of the cold-rolled alloy strips with different reduction were studied, and the deformation mechanism was clarified. The results showed that the continuous casting strips had axial columnar grain with main orientations and straight small angle grain boundaries, the elongation after fracture was up to 25.0%, which can be directly processed by large deformation cold rolling, and the maximum cumulative cold deformation was up to 99%.When the reduction was 40% and 60%, the dislocation bands crossed each other and shear bands formed, and the alternating distribution of soft/hard oriented grains were conducive to improve the deformation coordination ability of micro-region under high strain. When the deformation exceeded 80%, deformation twins formed and the twins had strong interaction with the shear band and grain boundaries, resulting in strong shear and rotation of the local grains. The tensile strength and hardness increased from 464 MPa to 137HV of the as-cast strip to 629 MPa and 208HV with reduction 90%, respectively, while the elongation decreased from 25.0% to 4.1%. These results can lay a foundation for the development of compact method for producing high performance Cu–Ni–Co–Si alloy strips.

BackgroundThis study aimed to objectively evaluate the severity of impulsivity [behavior inhibitory control (BIC) impairment] among adolescents with depression. In particular, those involved in non-suicidal self-injury (NSSI) behaviors, compared with those engaged in suicidal behaviors and adolescents without any self-injury behavior, using event-related potentials (ERPs) and event-related spectral perturbation (ERSP) within the two-choice oddball paradigm.MethodsParticipants with a current diagnosis of major depressive disorder (MDD) engaged in repetitive NSSI for five or more days in the past year (n = 53) or having a history of at least one prior complete suicidal behavior (n = 31) were recruited in the self-injury group. Those without self-injury behavior were recruited in the MDD group (n = 40). They completed self-report scales and a computer-based two-choice oddball paradigm during which a continuous electroencephalogram was recorded. The difference waves in P3d were derived from the deviant minus standard wave, and the target index was the difference between the two conditions. We focused on latency and amplitude, and time-frequency analyses were conducted in addition to the conventional index.ResultsParticipants with self-injury, compared to those with depression but without self-injury, exhibited specific deficits in BIC impairment, showing a significantly larger amplitude. Specifically, the NSSI group showed the highest value in amplitude and theta power, and suicidal behavior showed a high value in amplitude but the lowest value in theta power. These results may potentially predict the onset of suicide following repetitive NSSI.ConclusionThese findings contribute to substantial progress in exploring neuro-electrophysiological evidence of self-injury behaviors. Furthermore, the difference between the NSSI and suicide groups might be the direction of prediction of suicidality.

BackgroundNonsuicidal self-injury (NSSI) is a common mental health threat in adolescents, peaking in adolescence with a lifetime prevalence of ~17%–60%, making it a high-risk risk factor for suicide. In this study, we compared changes in microstate parameters in depressed adolescents with NSSI, depressed adolescents, and healthy adolescents during exposure to negative emotional stimuli, and further explored the improvement of clinical symptoms and the effect of microstate parameters of repetitive transcranial magnetic stimulation (rTMS) in depressed adolescents with NSSI, and more evidence was provided for potential mechanisms and treatment optimization for the occurrence of NSSI behaviors in adolescents.MethodsSixty-six patients with major depressive disorder (MDD) exhibiting NSSI behavior (MDD + NSSI group), 52 patients with MDD (MDD group), and 20 healthy subjects (HC group) were recruited to perform neutral and negative emotional stimulation task. The age range of all subjects was 12–17 years. All participants completed the Hamilton Depression Scale, the Patient Health Questionnaire-9, the Ottawa Self-Injury Scale and a self-administered questionnaire to collect demographic information. We provided two different treatments to 66 MDD adolescents with NSSI; 31 patients received medication and completed post-treatment scale assessments and EEG acquisitions, and 21 patients received medication combined with rTMS and completed post-treatment scale assessments and EEG acquisitions. Multichannel EEG was recorded continuously from 64 scalp electrodes using the Curry 8 system. EEG signal preprocessing and analysis was performed offline, using the EEGLAB toolbox in MATLAB. Use the Microstate Analysis Toolbox in EEGLAB for segmentation and computation of microstates, and calculate a topographic map of the microstate segmentation of the EEG signal for a single subject in each dataset, and four parameters were obtained for each microstate classification: global explained variance (GEV), mean duration (Duration), average number of occurrences per second (Occurrence), and average percentage of total analysis time occupied (Coverage), which were then statistically analyzed.ResultsOur results indicate that MDD adolescents with NSSI exhibit abnormalities in MS 3, MS 4, and MS 6 parameters when exposed to negative emotional stimuli compared to MDD adolescents and healthy adolescents. The results also showed that medication combined with rTMS treatment improved depressive symptoms and NSSI performance more significantly in MDD adolescents with NSSI compared to medication treatment, and affected MS 1, MS 2, and MS 4 parameters in MDD adolescents with NSSI, providing microstate evidence for the moderating effect of rTMS.ConclusionMDD adolescents with NSSI showed abnormal changes in several microstate parameters when receiving negative emotional stimuli, and compared to those not receiving rTMS treatment, MDD adolescents with NSSI treated with rTMS showed more significant improvements in depressive symptoms and NSSI performance, as well as improvements in EEG microstate abnormalities.

Federated learning (FL) and blockchains exhibit significant commonality, complementarity, and alignment in various aspects, such as application domains, architectural features, and privacy protection mechanisms. In recent years, there have been notable advancements in combining these two technologies, particularly in data privacy protection, data sharing incentives, and computational performance. Although there are some surveys on blockchain-based federated learning (BFL), these surveys predominantly focus on the BFL framework and its classifications, yet lack in-depth analyses of the pivotal issues addressed by BFL. This work aims to assist researchers in understanding the latest research achievements and development directions in the integration of FL with blockchains. Firstly, we introduced the relevant research in FL and blockchain technology and highlighted the existing shortcomings of FL. Next, we conducted a comparative analysis of existing BFL frameworks, delving into the significant problems in the realm of FL that the combination of blockchain and FL addresses. Finally, we summarized the application prospects of BFL technology in various domains such as the Internet of Things, Industrial Internet of Things, Internet of Vehicles, and healthcare services, as well as the challenges that need to be addressed and future research directions.

To find potential α-glucosidase inhibitors, indolo[1,2-b]isoquinoline derivatives (1–20) were screened for their α-glucosidase inhibitory effects. All derivatives presented potential α-glucosidase inhibitory effects with IC50 values of 3.44 ± 0.36~41.24 ± 0.26 μM compared to the positive control acarbose (IC50 value: 640.57 ± 5.13 μM). In particular, compound 11 displayed the strongest anti-α-glucosidase activity, being ~186 times stronger than acarbose. Kinetic studies found that compounds 9, 11, 13, 18, and 19 were all reversible mix-type inhibitors. The 3D fluorescence spectra and CD spectra results revealed that the interaction between compounds 9, 11, 13, 18, and 19 and α-glucosidase changed the conformational changes of α-glucosidase. Molecular docking and molecular dynamics simulation results indicated the interaction between compounds and α-glucosidase. In addition, cell cytotoxicity and drug-like properties of compound 11 were also investigated.

Abstract As the predominant modification in RNA, N6-methyladenosine (m6A) has attracted increasing attention in the past few years since it plays vital roles in many biological processes. This chemical modification is dynamic, reversible and regulated by several methyltransferases, demethylases and proteins that recognize m6A modification. M6A modification exists in messenger RNA and affects their splicing, nuclear export, stability, decay, and translation, thereby modulating gene expression. Besides, the existence of m6A in noncoding RNAs (ncRNAs) could also directly or indirectly regulated gene expression. Colorectal cancer (CRC) is a common cancer around the world and of high mortality. Increasing evidence have shown that the changes of m6A level and the dysregulation of m6A regulatory proteins have been implicated in CRC carcinogenesis and progression. However, the underlying regulation laws of m6A modification to CRC remain elusive and better understanding of these mechanisms will benefit the diagnosis and therapy. In the present review, the latest studies about the dysregulation of m6A and its regulators in CRC have been summarized. We will focus on the crucial roles of m6A modification in the carcinogenesis and development of CRC. Moreover, we will also discuss the potential applications of m6A modification in CRC diagnosis and therapeutics.

Abstract In this article, studying distributed optimisation over time‐varying directed networks where a group of agents aims at cooperatively minimising a sum of local objective functions is focused on. Each agent uses only local computation and communication in the overall process without leaking their private information. Via incorporating both a distributed heavy‐ball method and a distributed Nesterov method, a double accelerated distributed algorithm leveraging a gradient‐tracking technique and using uncoordinated step‐sizes, is developed. By employing both row‐ and column‐stochastic weight matrices, the proposed algorithm can bypass the implementation of doubly stochastic weight matrices and avoid eigenvector estimation existing in some algorithms using only row‐ or column‐stochastic weight matrices. Under the assumptions that the agents' local objective functions are smooth and strongly convex, and the aggregated directed networks of every finite consecutive directed network are strongly connected, the proposed algorithm is proved to converge linearly to the global optimal solution when the largest step‐size is positive and sufficiently small, and the largest momentum parameter is non‐negative. The proposed algorithm is also applied to fixed directed networks which are considered as a special case of time‐varying directed networks. Simulation results further verify the effectiveness of the proposed algorithm and correctness of the theoretical findings.

Cellular mesenchymal–epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands (MTDLs) strategy provides a logical approach to drug combinations and would adequately address the pathological complexity of cancer. In this work, we designed and synthesized a series of selenium-containing tepotinib derivatives by means of selenium-based bioisosteric modifications and evaluated their antiproliferative activity. Most of these selenium-containing hybrids exhibited potent dual inhibitory activity toward c-Met and TrxR. Among them, compound 8b was the most active, with an IC50 value of 10 nM against MHCC97H cells. Studies on the mechanism of action revealed that compound 8b triggered cell cycle arrest at the G1 phase and caused ROS accumulations by targeting TrxR, and these effects eventually led to cell apoptosis. These findings strongly suggest that compound 8b serves as a dual inhibitor of c-Met and TrxR, warranting further exploitation for cancer therapy.

Event-based prospective memory (ProM) refers to remembering to execute planned actions in response to a target ProM cues. Encoding modality influences ProM performance; visual encoding has been studied more than auditory encoding. Further, it has not yet been examined whether different encoding may influence ProM performance in different encoding modalities. This study examines the effects of encoding modality (visual vs. auditory), cue-encoding specificity (specific cue vs. non-specific cue), and encoding modes (standard vs. implementation intention) on event-based ProM tasks. In Experiment 1, cue specificity and encoding modality were manipulated as a within-groups encoding of visual cues is more commonly and between-groups variable. Results revealed the facilitative effect of cue specificity on ProM performance. Also, with respect to encoding modality, participants showed better performance when receiving auditory instructions compared with the visual encoding condition. In Experiment 2, as in Experiment 1, cue specificity and encoding modality were manipulated. Encoding mode was added as a new between-group variable. Result revealed that there was a significant interaction between encoding modality and encoding modes. Visual implementation intention encoding was a more effective method for improving ProM performance compared with visual standard encoding. Furthermore, there was a significant interaction between cue-encoding specificity and encoding modes. Implementation intention encoding enhances ProM performance in non-specific cue-encoding conditions. Overall, the present study found that (1) auditory encoding modality showed superior ProM performance compared with visual encoding, although implementation intention had facilitative on ProM performance regardless of the encoding modalities, and (2) there was better ProM performance under specific encoding compared with non-specific encoding, and implementation intention had a facilitative effect on ProM performance in the non-specific condition.

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound (R, S)-12a strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC50 value of 0.002 μM, compared to tepotinib (IC50 = 0.013 μM). Mechanistic studies revealed that compound (R, S)-12a significantly inhibited c-Met activation, as well as the downstream AKT signaling pathway, and suppressed wound closure. Moreover, compound (R, S)-12a induced cellular apoptosis and cell cycle arrest at the G1 phase in a dose-dependent fashion.

The inability of T cells to properly mount anti-tumour immunity underlies failed cancer immune surveillance or therapy. Here the authors show that a microRNA, miR-155, suppresses Ship1 phosphatase expression to modulate epigenetic reprogramming of CD8 T cell differentiation via the Phf19/PRC2 axis, thereby implicating a novel aspect of cancer immunity regulation.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity.Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed.Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3–4 AEs.Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.

Background/Aims: Endothelial progenitor cells (EPCs), which can be isolated from the bone marrow or the peripheral blood, have generated interest because of their capacity to migrate to sites of vascularization and endothelialization and differentiate into endothelial cells in a process termed neovasculogenesis. EPCs are therefore possible regenerative tools for the treatment of vascular diseases and potential targets for the inhibition of angiogenesis during tumor development. Here, we investigated the mechanisms underlying the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the acceleration of EPC proliferation and colony formation. Methods: EPCs were isolated, identified and cultured in the presence of GM-CSF. The effect of GM-CSF on endothelial cell colony formation and proliferation was examine by colony formation assay and MTT assay, separately. Cell cycle was analyzed by flow cytometry. The expression of cyclin D1 and cyclin E were detected by western bloting. JAK/Stat, PI3K/Akt and MAPK signaling were analyzed. Results: GM-CSF accelerated the G1/S phase transition in EPCs by upregulating the expression of cyclins D1 and E. The GM-CSF induced increase in the levels of cyclin D1 and the subsequent phosphorylation of the retinoblastoma (Rb) protein activated E2F-1, resulting in the upregulation of the transcription of cyclin E. Furthermore, the induction of cyclin D1 expression and cell cycle progression by GM-CSF was mediated by the PI3K/Akt, JNK and ERK signaling pathways through the phosphorylation of GSK3β or the activation of AP-1 transcription factors. Conclusion: Our findings shed light on the mechanisms underlying the effect of GM-CSF on the modulation of cell cycle progression in EPCs, which is important considering their role in vascular repair and their therapeutic potential in several diseases.

A fast pedestrian recognition algorithm based on multisensor fusion is presented in this paper. Firstly, potential pedestrian locations are estimated by laser radar scanning in the world coordinates, and then their corresponding candidate regions in the image are located by camera calibration and the perspective mapping model. For avoiding time consuming in the training and recognition process caused by large numbers of feature vector dimensions, region of interest-based integral histograms of oriented gradients (ROI-IHOG) feature extraction method is proposed later. A support vector machine (SVM) classifier is trained by a novel pedestrian sample dataset which adapt to the urban road environment for online recognition. Finally, we test the validity of the proposed approach with several video sequences from realistic urban road scenarios. Reliable and timewise performances are shown based on our multisensor fusing method.