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2D materials have attracted considerable attention in the past decades for their unique properties, making the understanding of their nucleation process key to effective synthesis. Traditional explanations of thin‐film growth, focusing on the competition between atom interactions at the interface and within layers, often fall short of explaining real experimental results. Herein, a penetrated nucleation mechanism is proposed for 2D materials growth on metal substrates, taking into account the role of metal substrate atoms. This approach leads to a better understanding of how the surface shape evolves in two specific ways during growth in real experimental findings. Supported by detailed first‐principles simulations of boron on metal substrates and thermodynamic analyses of other studies involving metals and nonmetals, the above‐proposed mechanism is validated. Moreover, a broad strategy for growing large‐scale 2D materials on metal surfaces without creating undesired alloy layers is also presented, by adjusting the interfacial interactions by surface passivation, validated by existing experiments. [ABSTRACT FROM AUTHOR]

Safe traffic is an important part of sustainable transportation. Road traffic accidents lead to a large number of casualties and property losses every year. Current research mainly studies some types of traffic accidents and ignores other types of traffic accidents; therefore, taking various types of road traffic accidents as a whole, an overall study of their influencing factors is urgently needed. To improve road traffic safety, taking various types of road traffic accidents as a whole, this paper analyzes the influencing factors and finds out the causative factors of road traffic accidents. A new index system of road traffic accident influencing factors is constructed based on the existing literature and real traffic data, and their subjective weights and objective weights are obtained by the analytic hierarchy process based on the subjective data and the normalization of the actual traffic data for Yizheng City, Yangzhou, China from January 2020 to December 2020, where the subjective weights are the main weights, and comprehensive weights are obtained by the minimum discrimination information principle correcting the subjective weights with the objective weights. Finally, the global weights, their ranks, and their weight differences are obtained. The main findings are as follows: (1) compared with the real traffic data, experts generally overestimate the impact of road factors on traffic accidents and underestimate the impact of human factors on traffic accidents; (2) in the first-level, human factors and road factors are the causative factors; (3) in the second-level, "motor vehicle drivers' misconduct", "road condition", and "road section" are the causative factors; and (4) in the third-level, "slippery road", "rain and snow weather", "intersection", and "untimely braking" are the causative factors. The research results can provide some scientific basis for improving road traffic safety. [ABSTRACT FROM AUTHOR]

Understanding the relationship between vehicle speed and the risk of sustaining a life-threatening injury has garnered continual attention. This study seeks to gain deep insight into the relationship between two-vehicle speeds and the risk of serious injury at intersections. The 2016–2018 crash data that occurred at intersections from the US Crash Report Sampling System (CRSS) were examined. We present a more general framework that allows the crash risk to be simultaneously linked to a universal two-dimensional variable of two-vehicle speeds, instead of the one-dimensional variable of impact speed calculated according to crash types in the existing literature. The results indicate that the risk of serious injury for head-on crashes in the medium-speed zone is mainly influenced by the faster vehicle although having little relation to the slower vehicle. More importantly, we find that the marginal relationship between the two-vehicle speeds and the crash risk is non-monotonic for angle and rear crashes. Finally, appropriate measures are suggested to reduce the crash risk at intersections, including alerting the driver not to cross intersections at exceedingly low speed, assisting the driver in making an emergency response at a medium speed, and warning the driver not to operate at a very high speed. [ABSTRACT FROM AUTHOR]

Simple Summary: The proximity to tumor cells is pivotal to the anti-tumor functions of CD8+ T cells, but the mechanism underlying the regulation of CD8+ T cell spatial distribution remains elusive. Here, we utilize the cellular neighborhood algorithm to identify the spatial architectures that regulate the localization and inter-cellular communication of CD8+ T cells in human pancreatic ductal adenocarcinoma. The presence of CD8+ T cells, CD4+ T cells, and other lymphocytes in the same cellular neighborhoods were identified as one type of spatial architecture that restricted the proximity of CD8+ T cells to tumor cells and heralded a poor prognosis. In such architecture, CD8+ T cells tended to aggregate around themselves and CD4+ T cells instead of approaching tumor cells. In this study, we identified a spatial architecture for the regulation of CD8+ T cells and deciphered a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner. The anti-tumor function of CD8+ T cells is dependent on their proximity to tumor cells. Current studies have focused on the infiltration level of CD8+ T cells in the tumor microenvironment, while further spatial information, such as spatial localization and inter-cellular communication, have not been defined. In this study, co-detection by indexing (CODEX) was designed to characterize PDAC tissue regions with seven protein markers in order to identify the spatial architecture that regulates CD8+ T cells in human pancreatic ductal adenocarcinoma (PDAC). The cellular neighborhood algorithm was used to identify a total of six conserved and distinct cellular neighborhoods. Among these, one unique spatial architecture of CD8+ T and CD4+ T cell-enriched neighborhoods enriched the majority of CD8+ T cells, but heralded a poor prognosis. The proximity analysis revealed that the CD8+ T cells in this spatial architecture were significantly closer to themselves and the CD4+ T cells than to the tumor cells. Collectively, we identified a unique spatial architecture that restricted the proximity of CD8+ T cells to tumor cells in the tumor microenvironment, indicating a novel immune evasion mechanism of pancreatic ductal adenocarcinoma in a topologically regulated manner and providing new insights into the biology of PDAC. [ABSTRACT FROM AUTHOR]

As a fundamental task in computer vision, object detection has long been a challenging visual task. However, current object detection models lack attention to salient features when fusing the lateral connections and top-down information flows in feature pyramid networks (FPNs). To address this, we propose a method for object detection based on an enhanced bi-directional attention feature pyramid network, which aims to enhance the feature representation capability of lateral connections and top-down links in FPN. This method adopts the triplet module to give attention to salient features in the original multi-scale information in spatial and channel dimensions, establishing an enhanced triplet attention. In addition, it introduces improved top and down attention to fuse contextual information using the correlation of features between adjacent scales. Furthermore, adaptively spatial feature fusion and self-attention are introduced to expand the receptive field and improve the detection performance of deep levels. Extensive experiments conducted on the PASCAL VOC, MS COCO, KITTI, and CrowdHuman datasets demonstrate that our method achieves performance gains of 1.8%, 0.8%, 0.5%, and 0.2%, respectively. These results indicate that our method has significant effects and is competitive compared with advanced detectors. [ABSTRACT FROM AUTHOR]

SOS1 is an essential guanine nucleotide exchange factor for RAS that also plays a critical role in the activation of the small GTPase RAC mediated by BCR-ABL in leukemogenesis. Despite this, small molecule inhibitors targeting SOS1 have shown limited efficacy in clinical trials for KRAS mutant cancers, and their potential as a therapeutic approach for chronic myeloid leukemia (CML) remains largely unexplored. In this study, we developed a potent SOS1 PROTAC SIAIS562055, which was designed by connecting a CRBN ligand to an analogue of the SOS1 inhibitor BI-3406. SIAIS562055 exhibited sustained degradation of SOS1 and inhibition of downstream ERK pathways, resulting in superior anti-proliferative activity compared to small molecule inhibitors. SIAIS562055 also potentiated the activity of both KRAS inhibitors in KRAS-mutant cancers and ABL inhibitors in BCR-ABL+ CML. In KRAS-mutant xenografts, SIAIS562055 displayed promising antitumor potency as a monotherapy and enhanced ERK inhibition and tumor regression when combined with KRAS inhibitors, overcoming acquired resistance. In CML cells, SIAIS562055 promoted the active uptake of BCR-ABL inhibitors by upregulating the carnitine/organic cation transporter SLC22A4. SIAIS562055 and BCR-ABL inhibitors synergistically enhanced inhibition of ABL phosphorylation and downstream signaling, demonstrating robust antitumor activities in both mouse xenografts and primary CML patient samples. In summary, this study suggests that PROTAC-mediated SOS1 degradation represents an effective therapeutic strategy for treating not only KRAS-mutant cancers but also BCR-ABL-harboring leukemia.

The overexpression of BCL-x L is closely associated with poor prognosis in hepatocellular carcinoma (HCC). While the strategy of combination of BCL-x L and MCL-1 for treating solid tumors has been reported, it presents significant hepatotoxicity. SIAIS361034, a novel proteolysis targeting chimera (PROTAC) agent, selectively induces the ubiquitination and subsequent proteasomal degradation of BCL-x L through the CRBN-E3 ubiquitin ligase. When combined with sorafenib, SIAIS361034 showed a potent synergistic effect in inhibiting hepatocellular carcinoma development both in vitro and in vivo. Since SIAIS361034 exhibits a high degree of selectivity for degrading BCL-x L in hepatocellular carcinoma, the hepatotoxicity typically associated with the combined inhibition of BCL-x L and MCL-1 is significantly reduced, thereby greatly enhancing safety. Mechanistically, BCL-x L and MCL-1 sequester the BH3-only protein BIM on mitochondria at baseline. Treatment with SIAIS361034 and sorafenib destabilizes BIM/BCL-x L and BIM/MCL1 association, resulting in the liberation of more BIM proteins to trigger apoptosis. Additionally, we discovered a novel compensatory regulation mechanism in hepatocellular carcinoma cells. BIM can rapidly respond to changes in the balance between BCL-x L and MCL-1 through their co-transcription factor MEF2C to maintain apoptosis resistance. In summary, the combination therapy of SIAIS361034 and sorafenib represents an effective and safe approach for inhibiting hepatocellular carcinoma progression. The novel balancing mechanism may also provide insights for combination and precision therapies in the treatment of hepatocellular carcinoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC., Methods: In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety., Results: From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred., Conclusions: In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting., Clinical Trial Registration: NCT04720131., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Stage II colon cancer has varying risks for metastasis, and treatment strategies depend on molecular and clinicopathological features. While tumor-sidedness is a well-accepted prognostic factor for stage III/IV colon cancer, its role in stage II is controversial. Understanding its effect in stage II is crucial for improving treatment strategies., Methods: We analyzed clinical and follow-up data of colon cancer from the Surveillance, Epidemiology, and End Results database (2004-2017). Patients were divided into a primary study cohort (2010-2017) and a validation cohort (2004-2009). The baseline characteristics between right-sided colon cancer (RCC) and left-sided colon cancer (LCC) groups were compared. Moreover, the effect of tumor size on cancer-specific survival (CSS) was evaluated using Kaplan-Meier analysis., Results: The study involved 87,355 patients in the study cohort and 65,858 in the validation cohort. Of the study cohort, 52.3% were diagnosed with RCC. The median age was 64 years old, with 48.5% females and 76.8% of white people. In addition, stage II RCC showed better CSS compared with LCC (5-year CSS 88.0% vs 85.5%, P  <   0.001), while stage III/IV RCC demonstrated poorer outcomes. Multivariate Cox regression analysis identified that the right-sidedness was a positive prognostic factor in stages I/II but negative in stages III (HR 1.10, P  <   0.001) and IV (HR 1.26, P  <   0.001). Chemotherapy rates decreased in RCC, particularly in stage II (RCC vs LCC: 16.2% vs 28.5%, P  <   0.001). Subgroup analysis, stratified by T3/T4 stages and chemotherapy status, further highlighted better survival outcomes in RCC., Conclusions: RCC is associated with a significantly better prognosis in stage II. The importance of considering tumor-sidedness in clinical decision-making and the design of future clinical trials should be emphasized., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)