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Abstract Background Acapella plus active cycle of breathing technique (ACBT), external diaphragm pacemaker (EDP) plus ACBT have been shown to facilitate the recovery of functional capacity and lung function in patients suffering from airway obstruction but the efficacy in perioperative patients with lung cancer has not been proven. Methods We conducted a three-arm, prospective, randomized, assessor-blinded, controlled trial in patients with lung cancer who underwent thoracoscopic lobectomy or segmentectomy in the department of thoracic surgery, China. Patients were randomly assigned (1:1:1) to receive Acapella plus ACBT, EDP plus ACBT, or ACBT group (control group) using SAS software. The primary outcome was functional capacity, measured by the 6-minute walk test (6MWT). Results We recruited 363 participants over 17 months: 123 assigned to the Acapella plus ACBT group, 119 to the EDP plus ACBT group, and 121 to the ACBT group. Statistically significant differences were noted for functional capacity between the EDP plus ACBT and control groups at each follow-up time (1-week follow-up: difference = 47.25 m, 95% CI, 31.56–62.93; P

IntroductionThe limited response to immune checkpoint blockades (ICBs) in patients with hepatocellular carcinoma (HCC) highlights the urgent need for broadening the scope of current immunotherapy approaches. Lenvatinib has been shown a potential synergistic effect with ICBs. This study investigated the optimal method for combining these two therapeutic agents and the underlying mechanisms.MethodsThe effect of lenvatinib at three different doses on promoting tissue perfusion and vascular normalization was evaluated in both immunodeficient and immunocompetent mouse models. The underlying mechanisms were investigated by analyzing the vascular morphology of endothelial cells and pericytes. The enhanced immune infiltration of optimal-dose lenvatinib and its synergistic effect of lenvatinib and anti-PD-1 antibody was further evaluated by flow cytometry and immunofluorescence imaging.ResultsThere was an optimal dose that superiorly normalized tumor vasculature and increased immune cell infiltration in both immunodeficient and immunocompetent mouse models. An adequate concentration of lenvatinib strengthened the integrity of human umbilical vein endothelial cells by inducing the formation of the NRP-1-PDGFRβ complex and activating the Crkl-C3G-Rap1 signaling pathway in endothelial cells. Additionally, it promoted the interaction between endothelial cells and pericytes by inducing tyrosine-phosphorylation in pericytes. Furthermore, the combination of an optimal dose of lenvatinib and an anti-PD-1 antibody robustly suppressed tumor growth.ConclusionsOur study proposes a mechanism that explains how the optimal dose of lenvatinib induces vascular normalization and confirms its enhanced synergistic effect with ICBs.

Abstract Background Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849. Methods The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses. Results MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations. Conclusions In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR. Video Abstract

Abstract Background In the past decade, the field of tumour immunotherapy has made a great progress. However, the efficacy of immune checkpoint blocking (ICB) in the treatment of hepatocellular carcinoma (HCC) remains limited. Cytotoxic lymphocyte trafficking into tumours is critical for the success of ICB. Therefore, additional strategies that increase cytotoxic lymphocyte trafficking into tumours are urgently needed to improve patient immune responses. Methods Paired adjacent tissue and cancerous lesions with HBV‐associated HCC were subjected to RNA‐seq analysis. Bone morphogenetic protein (BMP9), which reflects vessel normalisation, was identified through Cytoscape software, clinical specimens and Gene Expression Omnibus (GEO) datasets for HCC. The functional effects and mechanism of BMP9 on the tumour vasculature were evaluated in cells and animals. An ultrasound‐targeted microbubble destruction (UTMD)‐mediated BMP9 delivery strategy was used to normalise the vasculature and evaluate therapeutic efficacy mediated by cytotoxic lymphocytes (NK cells) in combination with a PD‐L1 antibody in human cancer xenografts of immune‐deficient mice. Results We discovered that hepatitis B virus (HBV) infection‐induced downregulation of BMP9 expression correlated with a poor prognosis and pathological vascular abnormalities in patients with HCC. BMP9 overexpression in HBV‐infected HCC cells promoted intra‐tumoural cytotoxic lymphocyte infiltration via vascular normalisation by inhibiting the Rho‐ROCK‐myosin light chain (MLC) signalling cascade, resulting in enhanced efficacy of immunotherapy. Furthermore, UTMD‐mediated BMP9 delivery restored the anti‐tumour function of cytotoxic lymphocytes (NK cells) and showed therapeutic efficacy in combination with a PD‐L1 antibody in human cancer xenografts of immune‐deficient mice. Conclusions HBV‐induced BMP9 downregulation causes vascular abnormalities that inhibit intra‐tumoural cytotoxic lymphocyte infiltration, providing a rationale for developing and combining immunotherapy with BMP9‐based therapy to treat HBV‐associated HCC.

Multidrug resistance (MDR) is the major cause of chemotherapy failure, which is usually caused by the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2. To date, no MDR modulator has been clinically approved. Here, we found that lazertinib (YH25448; a novel third-generation tyrosine kinase inhibitor [TKI]) could enhance the anticancer efficacy of MDR transporter substrate anticancer drugs in vitro，in vivo, and ex vivo. Mechanistically, lazertinib was shown to inhibit the drug efflux activities of ABCB1 and ABCG2 and thus increase the intracellular accumulation of the transporter substrate anticancer drug. Moreover, lazertinib was found to stimulate the ATPase activity of ABCB1/ABCG2 and inhibit the photolabeling of the transporters by 125I-iodoarylazidoprazosin (IAAP). However, lazertinib neither changed the expression or locolization of ABCB1 and ABCG2 nor blocked the signal pathway of Akt or Erk1/2 at a drug concentration effective for MDR reversal. Overall, our results demonstrate that lazertinib effectively reverses ABCB1- or ABCG2-mediated MDR by competitively binding to the ATP-binding site and inhibiting drug efflux function. This is the first report demonstrating the novel combined use of lazertinib and conventional chemotherapeutical drugs to overcome MDR in ABCB1/ABCG2-overexpressing cancer cells.

Ti(C,N)-xCrMnFeCoNi-(15wt.%-x)Ni cermets (x = 0wt.%, 5wt.%, 10wt.%, 15wt.%) were fabricated by low-pressure sintering. Because of the sluggish diffusion effect of high-entropy alloy (HEA), the grain growth of cermets containing HEA binder is inhibited. The FCC binder phases of cermets with CrMnFeCoNi/Ni binders generate a uniform dispersion, motivating to form many complete and moderate rim phases and wet the ceramic particles. Furthermore, the hardness of cermets roughly increases, while the strength and fracture toughness maintain the change tendency of rising the peak and then falling with CrMnFeCoNi additions. Ti(C,N)-5wt.% CrMnFeCoNi-10wt.% Ni cermets obtains a prominent mechanical property combination with hardness of 1646 ± 13.5 HV30, strength of 2181 ± 167.2 MPa and fracture toughness of 9.1 ± 0.11 MPa m1/2. Besides, the cermets containing CrMnFeCoNi/Ni binders obtain reduced friction coefficients and low wear rates at 750 °C compared with Ti(C,N)–Ni cermets and Ti(C,N)-HEA cermets. The superior high-temperature wear resistance is ascribed to the thermal softening resistance of CrMnFeCoNi, strengthening and toughening effect of CrMnFeCoNi/Ni on matrix and the transition of wear mechanism from abrasive wear and the removal of tribochemical layers to the removal of tribochemical layers. The cutting lifetime of cermets containing CrMnFeCoNi/Ni binders is increased by 40%–70% in comparison with Ti(C,N)–Ni cermets during machining 17-4 PH stainless steel. Concisely, Ti(C,N)-based cermets with outstanding mechanical, wear resistance and cutting properties can be obtained by partially replacing Ni with 5–10 wt.% CrMnFeCoNi.

Tumor immunotherapy, particularly the use of immune checkpoint inhibitors, has yielded impressive clinical benefits. Therefore, it is critical to accurately screen individuals for immunotherapy sensitivity and forecast its efficacy. With the application of artificial intelligence (AI) in the medical field in recent years, an increasing number of studies have indicated that the efficacy of immunotherapy can be better anticipated with the help of AI technology to reach precision medicine. This article focuses on the current prediction models based on information from histopathological slides, imaging-omics, genomics, and proteomics, and reviews their research progress and applications. Furthermore, we also discuss the existing challenges encountered by AI in the field of immunotherapy, as well as the future directions that need to be improved, to provide a point of reference for the early implementation of AI-assisted diagnosis and treatment systems in the future.

Abstract Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even “undruggable”, after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.

Background Although endoscopic submucosal dissection (ESD) is considered to be a curative treatment for early colorectal cancer, additional surgery with lymph node dissection is routinely recommended for patients treated in non-curative ESD, owing to the risk of residual cancer and lymph node metastasis (LNM). However, in clinical practice, few patients are found to have either residual cancer or LNM after additional surgery. Therefore, we conducted this study to determine the risk factors associated with residual cancer and LNM. Methods Patients with early colorectal cancer after non-curative ESD and additional surgery from January 2015 to May 2019 were retrospectively identified. Clinicopathological characteristics were collected to determine the predictors of residual cancer and LNM. Results A total of 62 patients were enrolled for analysis in this study. After additional surgery, residual cancer and LNM was detected in 12 patients (19.35%). Clinicopathological comparison of patients with the presence or absence of residual cancer and LNM demonstrated that piecemeal resection (80% vs. 14.04%, P

Objectives To evaluate the incidence, risk factors and clinical significance of four types of tumor progression (TP) after microwave ablation (MWA) of single hepatocellular carcinoma (HCC) of

A risk assessment for storm surge disasters can provide scientific support for coastal management as well as marine disaster prevention and mitigation. By taking the Wenchang City of Hainan Province as a pilot area, a risk assessment approach for typhoon-induced storm surge disasters is introduced in detail in this article. First, a numerical simulation system for storm surge inundation is developed, which is applied for the simulation and calculation of the probable maximum storm surge in Wenchang, and the obtained inundation areas and depths are used to assess the storm surge hazard. Then, the data of land use and disaster-bearing bodies are used to classify and assess the vulnerability of Wenchang. Finally, by taking the community as unit, the risk assessment for typhoon-induced storm surge affecting Wenchang is performed by combining the assessment results of both hazard and vulnerability, thereby obtaining a level map of risk distribution. The results show that there are risks of typhoon-induced storm surge in most of the coastal areas of Wenchang, especially for its northeast and east coastal areas, where the risks reach Levels I–II. This approach can be conveniently applied to risk assessments of storm surge in other coastal areas. Note that this approach focuses on the current risk of typhoon-induced storm surge in coastal areas, and further studies will be conducted on the assessment methods for the potential risk.

Wear and corrosion resistant austenitic cast irons were prepared by powder metallurgy (P/M). In this system, equivalent Mn were doped to replace nickel with a constant Nieq (the Ni equivalent number) to reduce the cost. Conventional high nickel cast iron was employed as a reference in this study. The hardness, dry sliding wear behavior and corrosion behavior of conventional and P/M cast iron were investigated under the same conditions. The result demonstrates that a little difference in hardness is found between Mn0-C (Mn-0wt% prepared by cast) and Mn0-PM (Mn-0wt% prepared by P/M). However, the wear resistance of Mn0-PM is better than Mn0-C due to the evenly distributed lubricating graphite. The wear resistance of P/M cast iron increases with the increase of Mn content which is attributed to the increased hardness. The corrosion behaviors for all the materials tested by using potentiodynamic polarization curves and electrochemical impedance spectroscopy (EIS) are almost the same, largely due to the formation of austenite matrix. Thereinto, Mn5-PM holds the best corrosion behavior with the lowest corrosion current density and highest polarization resistance. Because the potential difference between matrix and carbide is lower than that between matrix and graphite. The decreased graphite with the increased carbide induces a strong corrosion resistance in Mn5-PM.

CVD coatings were deposited on the cermets and cemented carbides tools. Uncoated cermets, coated cermets and cemented carbides tools were used for hardened AISI H13 steel machining. Face-centered cubic structure of the cermets attribute to the direct growth of the TiN coatings. TiN and TiCN shows (2 0 0) preferred orientation on the cermets. The hexagonal closepacked structure of the cemented carbides make the TiN coatings nucleate first and then grow. TiN and TiCN shows (1 1 1) preferred orientation on the cemented carbides. When the cutting speed reaches and exceeds 700 r/min, the coated cermets have the longest life. The excellent diffusion and adhension wear resistance at elevated temperature of the coated cermets result a better surface quality of workpiece. Keywords: Cermets, Structure, Coatings, Cutting performance

Background: After general anesthesia, many pediatric patients present with emergence delirium (ED). The aim of this study was to determine whether dexmedetomidine intranasal premedication accompanied by a cartoon video 30 min before general anesthesia would have an effect on reducing emergence delirium in preschool children.Methods: One hundred and forty children aged 3–6 year undergoing elective strabismus surgery were randomly to be premedicated with 2 μg kg−1 intranasal dexmedetomidine accompanied by the viewing of a cartoon video (Group DV) or without any premedication as usual (Group C). The primary outcome was the incidence of emergence delirium at the postanesthesia care unit (PACU), evaluated by the Pediatric Anesthesia Emergence Delirium (PAED) scale. The secondary outcomes included: the Modified Yale Preoperative Anxiety Scale (mYPAS) upon separation from parents; the Induction Compliance Checklist score (ICC); the PACU discharge time; the parental satisfaction score; the incidences of the side effects and the Post-Hospital Behavior Questionnaire (PHBQ) score during the first day after surgery.Results: The incidence of emergence agitation (PAED score ≥ 10) was reduced in Group DV compared with Group C [8 (11.4%) vs. 24 (34.3%); P = 0.001]. None of the patients in the DV group experienced severe emergence agitation (PAED score ≥ 15), as compared with the C group (P = 0.006). The mYPAS score upon separation from parents (P < 0.001) and the incidence of poor coordination (ICC ≥ 4) during induction (P < 0.001) were significantly lower in Group DV than in Group C. In Group DV, the PACU discharge time was longer (P < 0.001), and the parental satisfaction score was higher (P < 0.001). However, during the first day after surgery, the PHBQ score was lower in Group DV compared with Group C (P = 0.001).Conclusions: Premedication with 2 μg kg−1 intranasal dexmedetomidine accompanied by cartoon video viewing can dramatically reduce emergence delirium in preschool children undergoing strabismus surgery, relieve preoperative anxiety and improve the parental satisfaction and the postoperative behavior changes during the first day after surgery.Clinical Trial Registration: ChiCTR2000030678.

The contribution of factors including fuel type, fire-weather conditions, topography and human activity to fire regime attributes (e.g. fire occurrence, size distribution and severity) has been intensively discussed. The relative importance of those factors in explaining the burn probability (BP), which is critical in terms of fire risk management, has been insufficiently addressed. Focusing on a subtropical coniferous forest with strong human disturbance in East China, our main objective was to evaluate and compare the relative importance of fuel composition, topography, and human activity for fire occurrence, size and BP. Local BP distribution was derived with stochastic fire simulation approach using detailed historical fire data (1990-2010) and forest-resource survey results, based on which our factor contribution analysis was carried out. Our results indicated that fuel composition had the greatest relative importance in explaining fire occurrence and size, but human activity explained most of the variance in BP. This implies that the influence of human activity is amplified through the process of overlapping repeated ignition and spreading events. This result emphasizes the status of strong human disturbance in local fire processes. It further confirms the need for a holistic perspective on factor contribution to fire likelihood, rather than focusing on individual fire regime attributes, for the purpose of fire risk management.

To solve the problem of long response time when users obtain suitable cutting parameters through the Internet based platform, a case-based reasoning framework is proposed. Specifically, a Hamming distance and Euclidean distance combined method is designed to measure the similarity of case features which have both numeric and category properties. In addition, AHP (Analytic Hierarchy Process) and entropy weight method are integrated to provide features weight, where both user preferences and comprehensive impact of the index have been concerned. Grey relation analysis is used to obtain the similarity of a new problem and alternative cases. Finally, a platform is also developed on Visual Studio 2015, and a case study is demonstrated to verify the practicality and efficiency of the proposed method. This method can obtain cutting parameters which is suitable without iterative calculation. Compared with the traditional PSO (Particle swarm optimization algorithm) and GA (Genetic algorithm), it can obtain faster response speed. This method can provide ideas for selecting processing parameters in industrial production. While guaranteeing the characteristic information is similar, this approach can select processing parameters which is the most appropriate for the production process and a lot of time can be saved. [ABSTRACT FROM AUTHOR]