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Digital transformation has become an important channel for firms to build a competitive advantage in the digital economy. However, user participation, an important source of external knowledge for firms, has received limited attention in research related to digital transformation. Drawing on the knowledge-based view, the study uses a sample of 247 Chinese firms to investigate the impact of digital transformation on firm performance. The study examines the mediating role of user participation between digital transformation and firm performance and the moderating role of both environmental dynamics and absorptive capacity on the relationship between user participation and firm performance. Findings herein encourage digital transformation firms to pay attention to user participation, strengthen their ability to establish good relationships with users, improve their ability to absorb their knowledge, and make a strong effort to cultivate digital users.

BackgroundWe previously found that occupational exposure to diesel engine exhaust (DEE) was associated with alterations to 19 biomarkers that potentially reflect the mechanisms of carcinogenesis. Whether DEE is associated with biological alterations at concentrations under existing or recommended occupational exposure limits (OELs) is unclear.MethodsIn a cross-sectional study of 54 factory workers exposed long-term to DEE and 55 unexposed controls, we reanalysed the 19 previously identified biomarkers. Multivariable linear regression was used to compare biomarker levels between DEE-exposed versus unexposed subjects and to assess elemental carbon (EC) exposure-response relationships, adjusted for age and smoking status. We analysed each biomarker at EC concentrations below the US Mine Safety and Health Administration (MSHA) OEL (3), below the European Union (EU) OEL (3) and below the American Conference of Governmental Industrial Hygienists (ACGIH) recommendation (3).ResultsBelow the MSHA OEL, 17 biomarkers were altered between DEE-exposed workers and unexposed controls. Below the EU OEL, DEE-exposed workers had elevated lymphocytes (p=9E-03, false discovery rate (FDR)=0.04), CD4+ count (p=0.02, FDR=0.05), CD8+ count (p=5E-03, FDR=0.03) and miR-92a-3p (p=0.02, FDR=0.05), and nasal turbinate gene expression (first principal component: p=1E-06, FDR=2E-05), as well as decreased C-reactive protein (p=0.02, FDR=0.05), macrophage inflammatory protein-1β (p=0.04, FDR=0.09), miR-423-3p (p=0.04, FDR=0.09) and miR-122-5p (p=2E-03, FDR=0.02). Even at EC concentrations under the ACGIH recommendation, we found some evidence of exposure-response relationships for miR-423-3p (ptrend=0.01, FDR=0.19) and gene expression (ptrend=0.02, FDR=0.19).ConclusionsDEE exposure under existing or recommended OELs may be associated with biomarkers reflective of cancer-related processes, including inflammatory/immune response.

Interconnected carbon encapsulated silicon nanoparticles were fabricated via molecular self-assembly and in situ carbonization strategies, which can effectively dissipate expansion strain and enhance the lithium-ion reaction kinetics.

Reasonable size accuracy of the mechanical part may be a key for the design of the complex transmission mechanism; thus, it is very important to evaluate the size errors of each part. Taking the conjugate cam-spatial rank feeding transmission mechanism as an example, the functions, such as the near-dwelling, fast-forwarding, working feeding, slow-forwarding, far-dwelling, fast-returning, quick-feeding-back, and slow-returning, are realized with the appropriate conjugate cam governing equations. The analytical expressions of the conjugate cams and functions of the angular motion and angular velocity between the conjugate cam and crank are derived. Considering the real machining errors of part, a concept of parameter sensitivity is proposed, and the magnitude and direction of the influence of typical parameter errors on the mechanism motion transfer characteristics are evaluated by this concept. This method provides a reliable reference for the precision design of mechanical structure parameters.

This study aims to find out the possible optimal therapy and assess the prognosis properly for patient with spontaneous rupture of hepatocellular carcinoma (HCC).Propensity score matching (PSM) analysis was used to study the data from 325 patients with ruptured HCC (RHCC) and 2,291 patients with non-RHCC.The incidence and hospital mortality of RHCC were 5.1% and 0.8% respectively, with a median overall survival (OS) time of 17 months. There was no difference between ruptured and non-RHCC patients undergoing conservation treatment in terms of OS. Trans-arterial embolization (TAE) was carried out in 69 (21.2%) cases with RHCC, with a median OS of 7 months, which was no difference from that of non-RHCC (pre- and post-PSM). One hundred and sixty-nine (52.0%) RHCC cases underwent one-stage hepatectomy, with a median OS and disease-free survival (DFS) of 30 and 6 months respectively, which were shorter than that of non-RHCC (post-PSM). TAE plus two-stage hepatectomy was performed in 30 RHCC cases, with a median OS and DFS of 28 and 10 months respectively; these outcomes were better than that from RHCC patients undergoing TAE alone or one-stage hepatectomy (post-PSM), which were no difference from that of non-RHCC patients undergoing hepatectomy. The risk of death for RHCC patient undergoing one-stage hepatectomy is 1.545 times higher than that of one undergoing TAE + two-stage hepatectomy.TAE plus two-stage hepatectomy might be the optimal treatment for RHCC patient. Under the premise of the same pathological properties, there is no difference in prognosis between ruptured and non-RHCC patients if the therapy is appropriate.

Several guidelines highlight the beneficial impact of exercise on the management of symptoms and health-related quality of life (HRQOL) in patients with fibromyalgia syndrome (FMS). However, few analyses have compared different types of exercise. We, therefore, intent to compare the effects of different exercise types on improving the overall HRQOL and typical symptoms in patients with FMS.Medline, Embase, the Cochrane Register of Clinical Trials, and NIH ClinicalTrials.gov were searched from inception to April 21, 2022. Randomized clinical trials (RCTs) were included to assess the impact of exercise intervention on health parameters in adult FMS patients. Data were extracted independently and a frequentist network meta-analyses (NMA) was performed to rank the effects of interventions according to P-scores. The NMA evidence certainty was assessed using the method recommended by Grading of Recommendations Assessment, Development, and Evaluation Working Group.A total of 57 RCTs were identified, including 3319 participants, involving 9 interventions (7 types of exercise, 2 controls). Of all treatments compared with usual care in efficacy outcomes, Mind-body exercise was associated with the best HRQOL (SMD, -12.12; 95% CI, -15.79 to -8.45). On the other characteristic symptom dimensions, based on moderate quality evidence, sensorimotor training was associated with minimal pain scores compared with usual care (SMD, -1.81; 95% CI, -2.81 to -0.82), whole body vibration therapy was most promising for improving sleep quality (SMD, -6.95; 95% CI, -10.03 to -3.87), pool-based aerobic exercise was most likely to ease anxiety (SMD, -4.83; 95% CI, -7.47 to -2.19), and whole body vibration was most likely to improve depression (SMD, -10.44; 95% CI, -22.00 to 1.12).Mind-body exercise seems to be the most effective exercise to improve the overall HRQOL of patients with FMS. But at the same time, clinicians still need to develop individualized exercise plans for patients according to their symptoms and accessibility.

Silicon (Si) is considered a promising anode material for rechargeable lithium-ion batteries (LIBs) due to its high theoretical capacity, low working potential, and safety features. However, the practical use of Si-based anodes is hampered by their huge volume expansion during the process of lithiation/delithiation, and they have relatively low intrinsic electronic conductivity, therefore seriously restricting their application in energy storage. Here, we propose a facile approach to directly transform siliceous biomass (bamboo leaves) into a porous carbon skeleton-wrapped Si nanodot architecture through a partial oxidization strategy and magnesium thermal reaction to obtain a high Si nanodot component composite (denoted as Si/C-O). With the synergistic effect of the porous carbon skeleton structure and uniformly dispersed Si nanodots, the Si/C-O composite anode with a stable structure that can avoid pulverization and accommodate volume expansion during cycling is fabricated. As expected, the biomass-converted Si/C-O anode not only presents a high Si component (59.7 wt %) by TGA but also exhibits an excellent capacity of 1013 mAh g

Meng Tao,1,2 Jing Han,3 Juanyi Shi,1,2 Hao Liao,1,2 Kai Wen,1,2 Weidong Wang,1,2 Sintim Mui,1,2 Huoming Li,1,2 Yongcong Yan,1,2 Zhiyu Xiao1,2 1Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, People’s Republic of China; 3Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, People’s Republic of ChinaCorrespondence: Yongcong Yan; Zhiyu Xiao, Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Yanjiang West Road #107, Guangzhou, 510120, People’s Republic of China, Tel +86-15800039176 ; +86-13682283695, Fax +86 20 34071073, Email yanyc3@mail.sysu.edu.cn; xiaozhiy@mail.sysu.edu.cnAbstract: Lenvatinib, a multitargeted tyrosine kinase inhibitor (TKI), is one of the preferred targeted drugs for the treatment of advanced hepatocellular carcinoma (aHCC). Since the REFLECT study showed that lenvatinib was noninferior to sorafenib in overall survival (OS), lenvatinib monotherapy has been widely used for aHCC. Moreover, lenvatinib combination therapy, especially lenvatinib combined with immune checkpoint inhibitors (ICIs), has shown more encouraging clinical results. However, drug development and comprehensive treatment have not significantly improved the prognosis, and lenvatinib resistance is often encountered in treatment. The underlying molecular mechanism of lenvatinib resistance is still unclear, and studies to solve drug resistance are ongoing. The molecular mechanisms of lenvatinib resistance in patients with aHCC include the regulation of signaling pathways, the regulation of noncoding RNAs, the impact of the immune microenvironment, tumor stem cell activation and other mechanisms. This review aims to (1) summarize the progress of lenvatinib in treating aHCC, (2) delineate the known lenvatinib resistance mechanisms of current therapy, and (3) describe the development of therapeutic methods intended to overcome these resistance mechanisms.Keywords: lenvatinib, application, drug resistance, hepatocellular carcinoma

Knowing how to effectively predict the scale of future information cascades based on the historical trajectory of information dissemination has become an important topic. It is significant for public opinion guidance; advertising; and hotspot recommendation. Deep learning technology has become a research hotspot in popularity prediction, but for complex social platform data, existing methods are challenging to utilize cascade information effectively. This paper proposes a novel end-to-end deep learning network CAC-G with cascade attention convolution (CAC). This model can stress the global information when learning node information and reducing errors caused by information loss. Moreover, a novel Dynamic routing-AT aggregation method is investigated and applied to aggregate node information to generate a representation of cascade snapshots. Then, the gated recurrent unit (GRU) is employed to learn temporal information. This study’s validity and generalization ability are verified in the experiments by applying CAC-G on two public datasets where CAC-G is better than the existing baseline methods.

The object detection task in the medical field is challenging in terms of classification and regression. Due to its crucial applications in computer-aided diagnosis and computer-aided detection techniques, an increasing number of researchers are transferring the object detection techniques to the medical field. However, in existing work on object detection, researchers do not consider the low resolution of medical images, the high amount of noise, and the small size of the objects to be detected. Based on this, this paper proposes a new algorithmic model called the MS Transformer, where a self-supervised learning approach is used to perform a random mask on the input image to reconstruct the input features, learn a richer feature vector, and filter out excessive noise. To focus the model on the small objects that are being detected, the hierarchical transformer model is introduced in this paper, and a sliding window with a local self-attention mechanism is used to give a higher attention score to the small objects to be detected. Finally, a single-stage object detection framework is used to predict the sequence of sets at the location of the bounding box and the class of objects to be detected. On the DeepLesion and BCDD benchmark dataset, the model proposed in this paper achieves better performance improvement on multiple evaluation metric categories.

Lactate accumulation in the tumor microenvironment was shown to be closely related to tumor growth and immune escape, and suppression of lactate production by inhibiting lactate dehydrogenase A (LDHA) has been pursued as a potential novel antitumor strategy. However, only a few potent LDHA inhibitors have been developed and most of them did not show potent antitumor effects in vivo. To this end, we designed new LDHA inhibitors and obtained a novel potent LDHA inhibitor, ML-05. ML-05 inhibited cellular lactate production and tumor cell proliferation, which was associated with inhibition of ATP production and induction of reactive oxygen species and G

Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by Amyloid-β accumulation-induced neuronal injury. Emerging evidence shows that circular RNA (circRNA) is involved in AD development. The aim of this study was to illustrate the role of circ-HUWE1 in Amyloid-β accumulation-induced neuronal injury. Quantitative real-time PCR (qPCR) or western blot was conducted for the expression analysis of circ-HUWE1, miR-433-3p, and fibroblast growth factor 7 (FGF7). In functional assays, cell viability was determined by CCK-8 assay, and cell apoptosis was examined by flow cytometry assay, the protein levels of apoptosis-related markers, and caspase1 or caspase3 activity. The release of pro-inflammatory factors was monitored by ELISA. The predicted binding relationship between miR-433-3p and circ-HUWE1 or FGF7 was validated by dual-luciferase reporter assay. We discovered that circ-HUWE1 absence alleviated Amyloid-β-induced cell viability degradation, cell apoptosis, and inflammatory responses in SK-N-SH cells. MiR-433-3p was a target of circ-HUWE1, and miR-433-3p inhibition reversed the effects of circ-HUWE1 knockdown. In addition, FGF7 was a downstream target of miR-433-3p whose function could be abolished by FGF7 reintroduction. Circ-HUWE1 positively regulated FGF7 expression via competitively targeting miR-433-3p. Moreover, circ-HUWE1 knockdown activated the WNT signaling pathway in Amyloid-β-treated SK-N-SH cells by targeting the miR-433-3p/FGF7 axis. In conclusion, circ-HUWE1 knockdown alleviates Amyloid-β-induced neuronal injury in SK-N-SH cells via miR-433-3p release-mediated FGF7 depletion.

Overexpression of nectin cell adhesion protein 4 correlates with cancer progression and poor prognosis in many human malignancies. Enfortumab vedotin (EV) is the first nectin-4-targeting antibody drug conjugate approved by the US Food and Drug Administration for treatment of urothelial cancer. However, inadequate efficacy has limited progress in the treatment of other solid tumors with EV. Furthermore, ocular, pulmonary, and hematological toxic side effects are common in nectin-4-targeted therapy, which frequently results in dose reduction and/or treatment termination. Thus, we designed a second generation nectin-4-specific drug, 9MW2821, based on interchain-disulfide drug conjugate technology. This novel drug contained a site-specifically conjugated humanized antibody and the cytotoxic moiety monomethyl auristatin E. The homogenous drug-antibody ratio and novel linker chemistry of 9MW2821 increased the stability of conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. In preclinical evaluation, 9MW2821 exhibited nectin-4 specific cell binding, efficient internalization, bystander killing, and equivalent or superior antitumor activity compared with EV in both cell-line-derived xenograft and patient-derived xenograft models. In addition, 9MW2821 demonstrated a favorable safety profile; the highest non-severely toxic dose in monkey toxicological studies was 6 mg/kg, with milder adverse events compare to EV. Overall, 9MW2821 is a nectin-4-directed, investigational antibody-drug conjugate based on innovative technology that endowed the drug with compelling preclinical antitumor activity and a favorable therapeutic index. The 9MW2821 antibody-drug conjugate is being investigated in a Phase I/II clinical trial (NCT05216965) in patients with advanced solid tumors.

We developed a coupled hydro-mechanical (HM) model based on a semi-logarithmic swelling law to reproduce the outcomes of swelling tests of a clay-sulfate rock specimen collected from the Freudenstein tunnel, which was constructed in Triassic Grabfeld Formation (formerly Gipskeuper = “Gypsum Keuper”) in Southwest Germany in the period of 1987–1991. The swelling tests were conducted using an oedometer apparatus under constrained (no strain) or constant load conditions. We used the strain–time data obtained from the laboratory testing to calibrate the HM model. We then ran a sensitivity analysis to reveal the importance of influential parameters, namely the maximum swelling pressure $${\sigma }_{max}^{sw}$$ σ max sw , swelling parameter $$k$$ k , and diffusion coefficient $$D$$ D on the long-term swelling behaviour of clay-sulfate rocks under the oedometer conditions. The HM model is capable of predicting long-term swelling deformations, i.e., model results were found to agree reasonably well with the experimental data. The results also show that using only 12 months experimental strain–time data to calibrate the HM model leads to an underestimation of swelling strains at the equilibrium condition. The findings show that at least 24 months experimental data is required for the model calibration.

Oxygen reduction reaction (ORR), an essential reaction in metal–air batteries and fuel cells, still faces many challenges, such as exploiting cost-effective nonprecious metal electrocatalysts and identifying their surface catalytic sites. Here we introduce bulk defects, Frank partial dislocations (FPDs), into metallic cobalt to construct a highly active and stable catalyst and demonstrate an atomic-level insight into its surface terminal catalysis. Through thermally dealloying bimetallic carbide (Co 3 ZnC), FPDs were in situ generated in the final dealloyed metallic cobalt. Both theoretical calculations and atomic characterizations uncovered that FPD-driven surface terminations create a distinctive type of surface catalytic site that combines concave geometry and compressive strain, and this two-in-one site intensively weakens oxygen binding. When being evaluated for the ORR, the catalyst exhibits onset and half-wave potentials of 1.02 and 0.90 V (versus the reversible hydrogen electrode), respectively, and negligible activity decay after 30,000 cycles. Furthermore, zinc–air batteries and H 2 –O 2 /air fuel cells built with this catalyst also achieve remarkable performance, making it a promising alternative to state-of-the-art Pt-based catalysts. Our findings pave the way for the use of bulk defects to upgrade the catalytic properties of nonprecious electrocatalysts.

Supplementary Figure S1 shows Exatecan cytotoxicity and sensitivity to multidrug resistant genes. Supplementary Figure S2 shows Exatecan and DXd/SN-38 sensitivity to multidrug resistant genes. Supplementary Figure S3 shows Exatecan toxicity in rat. Supplementary Figure S4 shows the design and optimization of T moiety. Supplementary Figure S5 shows physicochemical and functional equivalence of Tras-GGFG-DXd and DS-8201a. Supplementary Figure S6 show physicochemical profile of antibody-exatecan conjugates enabled by T moiety. Supplementary Figure S7 shows additional T moiety-exatecan and belotecan conjugates. Supplementary Figure S8 shows in vitro and in vivo stability of MTX-1000. Supplementary Figure S9 shows cellular dynamics and mechanism of MTX-1000. Supplementary Figure S10 shows colon cancer organoid response to ADCs. Supplementary Figure S11 shows bystander killing effect of MTX-1000, T-DM1 and Tras-GGFG-DXd in coculture conditions in vitro. Supplementary Figure S12 shows hematology and serum chemistry of MTX-1000 in monkey. Supplementary Figure S13 shows T moiety-exatecan ADCs show potent antitumor efficacy and improved therapeutic index. Supplementary Figure S14 shows T moiety-exatecan ADCs show higher antitumor potency in PDX models and better intratumor pharmacodynamic response. Supplementary Figure S15 shows T moiety-exatecan ADCs overcome treatment-resistance due to improved therapeutic index and intratumor pharmacodynamic response. Supplementary Figure S16 shows overcoming MDR resistance by T moiety exatecan ADCs or a combination of MDR inhibitor with DXd/SN-38 ADCs. Supplementary Figure S17 shows Exatecan/MTX-1000 and PARP/ATR inhibitor synergize in colon cancer cells. Supplementary Figure S18 shows a patient-derived xenograft (PDX) model with EGFR triple mutation. Supplementary Figure S19 shows MTX-1000 induces immunological cell death and enhances antitumor immunity of anti-PD-1.

Supplementary note shows the analytical characterization of the ADCs, and synthesis of drug-linkers

Supplementary Table S1 shows cytotoxicity of exatecan compared to DXd. Supplementary Table S2 shows selected hematologic parameters and biochemical parameters from the repeat-dose administration of exatecan mesylate studies in rats. Supplementary Table S3 shows in vitro ADC stability study of total antibody, ADC and free payload. Supplementary Table S4 shows pharmacokinetic parameters of total antibody, ADC and free payload. Supplementary Table S5 shows ADC (T: T-1000-e; D: DS-8201a) internalization rate on cell lines with different HER2 expression level. Supplementary Table S6 shows correlation of exatecan release and target expression. Supplementary Table S7 shows In vitro cytotoxicicity of HER-targeting MTX-1000, TROP2 targeting MTX-132 and HER3-targeting Patritumab-T1000-exatecan and their counterpart DXd-ADC.

PDF - 84K, Legends for Supplementary Figures.

Antibody–drug conjugates (ADC) using DNA topoisomerase I inhibitor DXd/SN-38 have transformed cancer treatment, yet more effective ADCs are needed for overcoming resistance. We have designed an ADC class using a novel self-immolative T moiety for traceless conjugation and release of exatecan, a more potent topoisomerase I inhibitor with less sensitivity to multidrug resistance (MDR). Characterized by enhanced therapeutic indices, higher stability, and improved intratumoral pharmacodynamic response, antibody–T moiety–exatecan conjugates targeting HER2, HER3, and TROP2 overcome the intrinsic or treatment resistance of equivalent DXd/SN-38 ADCs in low-target-expression, large, and MDR+ tumors. T moiety–exatecan ADCs display durable antitumor activity in patient-derived xenograft and organoid models representative of unmet clinical needs, including EGFR ex19del/T790M/C797S triple-mutation lung cancer and BRAF/KRAS–TP53 double-mutant colon cancer, and show synergy with PARP/ATR inhibitor and anti–PD-1 treatment. High tolerability of the T moiety–exatecan ADC class in nonhuman primates supports its potential to expand the responding patient population and tumor types beyond current ADCs.Significance:ADCs combining a novel self-immolative moiety and topoisomerase I inhibitor exatecan as payload show deep and durable response in low-target-expressing and MDR+ tumors resistant to DXd/SN-38 ADCs without increasing toxicity. This new class of ADCs has the potential to benefit an additional patient population beyond current options.See related commentary by Gupta et al., p. 817.This article is highlighted in the In This Issue feature, p. 799

PDF - 194K, MT189 causes cellular microtubulin depolymerization in a time-dependent manner and induces reversible M arrest.

PDF - 37K, MT189 inhibits the proliferation of HeLa and SMMC-7721 cells in a time- and concentration-dependent manner.

Colchicine site–targeted tubulin inhibitors are a promising type of anticancer drugs. MT189 is a new derivative of MT119, a previously reported colchicine site–binding antitubulin agent. In this study, MT189 was demonstrated to retain the property of MT119 in disrupting microtubulin via binding to the colchicine site, causing mitotic arrest and inducing apoptosis, and to display 8.7-fold enhanced proliferative inhibition in a panel of cancer cells. MT189 was shown to elicit in vivo anticancer effects on MDA-MB-231 xenografts in nude mice, and the tumor growth was suppressed by 35.9% over 14 days. MT189 led to degradation of MCL-1, a member of the antiapoptotic BCL-2 protein family. Its overexpression reduced but its silenced expression increased the apoptotic induction followed by the treatment with MT189. Moreover, the treatment with MT189 caused activation of the MEKK1/TAK1–MKK4–JNK signaling pathway. The activated JNK resulted in phosphorylation of MCL-1, which facilitated its ubiquitination-mediated degradation. Our results show that MT189 inhibits microtubulin polymerization by binding to the colchicine site. Relief of apoptotic suppression by MCL-1 degradation together with mitotic arrest contributes to the anticancer activity of MT189. Mol Cancer Ther; 13(6); 1480–91. ©2014 AACR.

Supplementary Figures and Tables

PDF - 636K, Whether MT189 induces the colocalization of JNK or p-JNK with α-tubulin was examined by confocal microscopy.

PDF - 18K, The chemical structure of MT189 and its synthesis approach.

PDF - 21K, MT189 displays an enhanced in vitro proliferation-inhibitory activity when compared with its parental compound MT119.

PDF - 44K, MT189 changes the levels of MCL-1 protein and induces apoptosis.