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Zhi-Hang Chen,1,&ast; Qian Zhou,2,&ast; Ze-Bin Chen,1,&ast; Wen-Xuan Xie,1 Zi-Min Song,1 Shui-Rong Lin,1 Wei Wang,3 Shun-Li Shen,1 Ming Kuang1 1Department of Liver Surgery, Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 2Department of Medical Statistics, Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China; 3Division of Interventional Ultrasound, Department of Medical Ultrasonics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Shun-Li Shen; Ming Kuang, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, People’s Republic of China, Tel +86 20-87755766, Email shenshli@mail.sysu.edu.cn; kuangm@mail.sysu.edu.cnPurpose: Liver resection and ablation remain the most common therapeutic options for Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC), but there is a lack of evidence to show which is the most suitable therapy. This study aimed to make concurrent multi-arm comparisons of the short-term and long-term outcomes of percutaneous ablation (PA), open (OLR) or laparoscopic liver resection (LLR) for these patients.Patients and Methods: This was a retrospective observational cohort study. A series of generalized propensity score methods for multiple treatment groups were performed to concurrently compare the clinical outcomes of these three treatment options to balance potential confounders. Regression standardization was used to account for hazard of all-cause mortality and recurrence of intergroup differences.Results: Of the 1778 patients included, 1237, 307 and 234 underwent OLR, LLR and PA, respectively. After overlap weighting, which was the optimal adjustment strategy, patients in the minimally invasive group (LLR and PA groups) had few postoperative complications and short postoperative hospital stays (both P < 0.001). The 5-year recurrence-free survival (RFS) rate and 5-year overall survival (OS) rate were significantly higher in the LLR group when compared with the OLR and PA groups (RFS: 55.6% vs 48.0% vs 30.2%, P < 0.001; OS: 89.1% vs 79.7% vs 84.0%, P = 0.020). Multivariable Cox analysis and regression standardization showed that LLR was an independent factor for better RFS when compared with OLR and PA. In subgroup analysis, the long-term outcomes of patients with BCLC stage A HCC were consistent with the whole population.Conclusion: In the observational study using various covariate adjustment analysis with excellent balance, LLR is not only minimally invasive, but also provides better RFS and equivalent OS for patients with BCLC stage 0-A HCC when compared with OLR and PA.Keywords: hepatocellular carcinoma, laparoscopic liver resection, generalized propensity score analysis, overlap weighting, clinical outcome

Fang-Yi Yu,&ast; Kua Zheng,&ast; Yin-Fang Wu,&ast; Shen-Wei Gao, Qing-Yu Weng, Chen Zhu, Yan-Ping Wu, Miao Li, Zhong-Nan Qin, Jia-Fei Lou, Zhi-Hua Chen, Song-Min Ying, Hua-Hao Shen, Wen Li Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wen Li, Tel +86-571-87783729, Fax +86-571-87068001, Email liwen@zju.edu.cnPurpose: This study aimed to explore the effect of Rapamycin (Rapa) in Staphylococcus aureus (S. aureus) pneumonia and clarify its possible mechanism.Methods: We investigated the effects of Rapa on S. aureus pneumonia in mouse models and in macrophages cultured in vitro. Two possible mechanisms were investigated: the mTOR-RPS6 pathway phosphorylation and phagocytosis. Furthermore, for the mechanism verification in vivo, mice with specific Mtor knockout in myeloid cells were constructed for pneumonia models.Results: Rapa exacerbated S. aureus pneumonia in mouse models, promoting chemokines secretion and inflammatory cells infiltration in lung. In vitro, Rapa upregulated the secretion of chemokines and cytokines in macrophages induced by S. aureus. Mechanistically, the mTOR-ribosomal protein S6 (RPS6) pathway in macrophages was phosphorylated in response to S. aureus infection, and the inhibition of RPS6 phosphorylation upregulated the inflammation level. However, Rapa did not increase the phagocytic activity. Accordingly, mice with specific Mtor knockout in myeloid cells experienced more severe S. aureus pneumonia.Conclusion: Rapa exacerbates S. aureus pneumonia by increasing the inflammatory levels of macrophages. Inhibition of mTOR-RPS6 pathway upregulates the expression of cytokines and chemokines in macrophages, thus increases inflammatory cells infiltration and exacerbates tissue damage.Keywords: Staphylococcus aureus, pneumonia, macrophage, rapamycin, mTOR- ribosomal protein S6 signaling pathway

Yu-Xiong Guo,1,2,* Hong-Xia Ma,1– 3,* Yu-Xin Zhang,2 Zhi-Hong Chen,2 Qiong-Xiang Zhai1,2 1The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510280, People’s Republic of China; 2Department of Pediatrics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 3Department of Pediatrics, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qiong-Xiang ZhaiDepartment of Pediatrics, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, People’s Republic of ChinaTel +86-2083827812-76222Fax +86-20-8328480Email zhaiqx_241@163.comBackground: Intellectual developmental disorders (IDD) generally refers to the persistent impairment of cognitive activities and mental retardation caused by physical damage to the brain or incomplete brain development. We aimed to explore its genetic causes.Methods: In this study, 21 IDD patients were recruited. The Gesell developmental scales (GDS) and Wechsler intelligence scale for children (WISC) were used to assess the impaired level of intellectual development for all probands. A superconducting MRI scanner (Philips AcsNT 3.0 T Philips, Best, The Netherlands) was used to perform a plain MRI scan of the skull on the probands. The whole-exome sequencing was carried out using next-generation sequencing in all probands and their families.Results: Eight had seizures and four had typical characteristics of autism. Pregnancy and delivery were uneventful except for three patients. Moderate IDD (52.4%) accounted for the majority. The abnormal MRI results included ventriculomegaly, pachygyria, broadening external cerebral space, abnormal signal change and agenesis of corpus callosum. Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASKgenes. The function areas result of gene-positive group were compared to that of gene-negative group. Not significant (p> 0.05) items were revealed after this analysis.Conclusion: Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASK genes. The function areas result of gene-positive group were not significantly different from the gene-negative group.Keywords: intellectual developmental disorders, gene variant, whole-exome sequencing

Jin-Kai Feng,1,* Ju-Xian Sun,1,* Zong-Han Liu,1,* Jing-Wen Gu,2,* Zhen-Hua Chen,3 Chang Liu,1 Wei-Xing Guo,1 Jie Shi,1 Shu-Qun Cheng1 1Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, People’s Republic of China; 2College of Basic Medical Sciences, Second Military Medical University, Shanghai, People’s Republic of China; 3Department of General Surgery, Zhejiang Provincial Armed Police Corps Hospital, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shu-Qun ChengDepartment of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai, 200433, People’s Republic of ChinaTel +86 21- 81875251Fax +86 21- 65562400Email chengshuqun@aliyun.comBackground: The occurrence of hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT) is rare. The aim of the study was to evaluate the effectiveness and safety of transarterial chemoembolization (TACE) for patients with unresectable HCC with BDTT.Methods: This retrospective study was conducted on newly diagnosed HCC and BDTT patients who were initially treated with TACE or conservative management (CM) from 2009 to 2018. Survival outcomes of patients treated with TACE were compared with those of patients given CM. Multivariate analyses were performed to identify independent prognostic factors related to survival.Results: Out of 100 patients included in this study, 40 patients underwent TACE, while the remaining 60 received CM. The median survival time of the TACE group was 8.0 months longer than that of the CM group (13.0 versus 5.0 months, P < 0.001). The 6-, 12-, 18-, 24-month overall survival (OS) rates were 90.0%, 52.5%, 22.5%, and 12.5%, respectively, for the TACE group compared with 26.7%, 8.3%, 5.0%, and 3.3%, respectively, for the CM group. Multivariate analyses showed that treatment allocation (hazard ratio [HR], 0.421; 95% confidence interval [CI], 0.243– 0.730; P = 0.002), Child–Pugh status (HR, 2.529; 95% CI, 1.300– 4.920; P = 0.006) and total bilirubin level (HR, 1.007; 95% CI, 1.004– 1.009; P < 0.001) on first admission were independent predictors of OS. There was no procedure-related mortality within one month after TACE treatment.Conclusion: TACE is a safe and effective treatment method that may improve the OS of patients with unresectable HCC with BDTT.Keywords: hepatocellular carcinoma, bile duct tumor thrombus, transarterial chemoembolization, conservative management, overall survival

Jianyuan Song,* Xiaoxue Huang,* Zhuhong Chen, Mingqiu Chen, Qingliang Lin, Anchuan Li, Yuangui Chen, Benhua Xu Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, People’s Republic of China *These authors contributed equally to this work Objective: To explore the value of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in predicting downstaging to stage 0–I cancer after neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer.Materials and methods: We respectively investigated pretreatment CEA, pretreatment CA19-9, posttreatment CEA, posttreatment CA19-9, pre–post-CA19-9 ratio, and pre–post-CEA ratio in 674 patients with locally advanced rectal cancer receiving nCRT and determined the patients’ thresholds by using the receiver operating characteristic curve analysis. The association between downstaging (stage 0–I after nCRT), pathological complete response, and clinicopathological parameters was evaluated using the Pearson χ2 test. The clinicopathological parameters which were found to be significantly associated with downstaging were analyzed by logistic regression models and were incorporated into a scoring system.Results: Multivariate analysis showed that pretreatment CA19-9 level, posttreatment CEA level, pre–post-CEA ratio, and pre–post-CA19-9 ratio were significantly correlated with downstaging. Area under the curve of the scoring system was higher than that of parameters alone.Conclusion: The 4-factor scoring system with CA19-9 level, posttreatment CEA level, pre–post-CEA ratio, and pre–post-CA19-9 ratio is of more value in predicting downstaging to stage 0–I patients with locally advanced rectal cancer after nCRT than using the parameters alone. Keywords: CEA, CA19-9, neoadjuvant chemoradiotherapy, rectal cancer

Yong Wang,1 Jie-Sen Zhou,1 Xu-Chen Xu,1 Zhou-Yang Li,1 Hai-Pin Chen,1 Song-Min Ying,1 Wen Li,1 Hua-Hao Shen,1,2 Zhi-Hua Chen1 1Department of Respiratory and Critical Care Medicine, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 2State Key Laboratory of Respiratory Disease, Guangzhou, People’s Republic of China Introduction: Bronchial epithelial cell death and airway inflammation induced by cigarette smoke (CS) have been involved in the pathogenesis of COPD. GRP78, belonging to heat shock protein 70 family, has been implicated in cell death and inflammation, while little is known about its roles in COPD. Here, we demonstrate that GRP78 regulates CS-induced necroptosis and injury in bronchial epithelial cells.Materials and methods: GRP78 and necroptosis markers were examined in human bronchial epithelial (HBE) cell line, primary mouse tracheal epithelial cells, and mouse lungs. siRNA targeting GRP78 gene and necroptosis inhibitor were used. Expression of inflammatory cytokines, mucin MUC5AC, and related signaling pathways were detected.Results: Exposure to CS significantly increased the expression of GRP78 and necroptosis markers in HBE cell line, primary mouse tracheal epithelial cells, and mouse lungs. Inhibition of GRP78 significantly suppressed CS extract (CSE)-induced necroptosis. Furthermore, GRP78–necroptosis cooperatively regulated CSE-induced inflammatory cytokines such as interleukin 6 (IL6), IL8, and mucin MUC5AC in HBE cells, likely through the activation of nuclear factor (NF-κB) and activator protein 1 (AP-1) pathways, respectively.Conclusion: Taken together, our results demonstrate that GRP78 promotes CSE-induced inflammatory response and mucus hyperproduction in airway epithelial cells, likely through upregulation of necroptosis and subsequent activation of NF-κB and AP-1 pathways. Thus, inhibition of GRP78 and/or inhibition of necroptosis could be the effective therapeutic approaches for the treatment of COPD. Keywords: cigarette smoke, airway epithelium, glucose-regulated protein 78, necroptosis, airway injury

Ling Hou,1,* Zhi-hang Chen,2,* Dong Liu,3 Yuan-guo Cheng,2 Xiao-ping Luo1 1Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 2Department of Pharmacy, Beijing Institute of Microbiology and Epidemiology, Beijing, 3Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China *These authors contributed equally to this study Objective: Recombinant human growth hormone (rhGH) replacement therapy in children generally requires daily subcutaneous (sc) injections, which may be inconvenient for patients. Jintrolong® is a PEGylated rhGH with the purpose of weekly sc injections. The aim of the current study was to examine the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple sc doses of Jintrolong® vs daily doses of rhGH. Design and methods: Twelve children with growth hormone deficiency participated in this single-center, open-label, crossover Phase I trial. All subjects received daily sc injections of rhGH at 0.0286 mg/kg/d for 7 days, followed by a 4-week washout period and six weekly doses of Jintrolong® at 0.2 mg/kg/w. Results: In comparison with rhGH, sc injection of Jintrolong® produced a noticeably higher Cmax, significantly longer half-life (t1/2), and slower plasma clearance, signifying a profile suitable for long-term treatment. The ratio of the area under the concentration vs time curve (AUC) after the seventh and first injections (AUC(0–∞)7th/AUC(0–∞)1st) of rhGH was 1.02, while the AUC(0–∞)6th/AUC(0–∞)1st of Jintrolong® was 1.03, indicating no accumulation of circulating growth hormone. There was no significant difference in the change in insulin-like growth factor-1 expression produced by 7 days of sc rhGH and weekly Jintrolong® injections. There were no severe adverse events during the trial. Conclusion: The elimination rate of Jintrolong® was slower than that of sc rhGH. No progressive serum accumulation of Jintrolong® was found. The changes in insulin-like growth factor-1 expression produced by rhGH and Jintrolong® were comparable, indicating similar pharmacodynamics. Our results demonstrate that Jintrolong® is suitable for long-term growth hormone treatment in children with growth hormone deficiency. Keywords: long-acting growth hormone, phase I, multiple-dose

Deterministic creation of multiple ferroelectric states with intermediate values of polarization remains challenging due to the inherent bi-stability of ferroelectric switching. Here we show the ability to select any desired intermediate polarization value via control of the switching pathway in (111)-oriented PbZr0.2Ti0.8O3 films. Such switching phenomena are driven by kinetic control of the volume fraction of two geometrically different domain structures which are generated by two distinct switching pathways: one direct, bipolar-like switching and another multi-step switching process with the formation of a thermodynamically-stable intermediate twinning structure. Such control of switching pathways is enabled by the competition between elastic and electrostatic energies which favors different types of ferroelastic switching that can occur. Overall, our work demonstrates an alternative approach that transcends the inherent bi-stability of ferroelectrics to create non-volatile, deterministic, and repeatedly obtainable multi-state polarization without compromising other important properties, and holds promise for non-volatile multi-state functional applications.

Complex-oxide materials exhibit physical properties that involve the interplay of charge and spin degrees of freedom. However, an ambipolar oxide that is able to exhibit both electron-doped and hole-doped ferromagnetism in the same material has proved elusive. Here we report ambipolar ferromagnetism in LaMnO3, with electron-hole asymmetry of the ferromagnetic order. Starting from an undoped atomically thin LaMnO3 film, we electrostatically dope the material with electrons or holes according to the polarity of a voltage applied across an ionic liquid gate. Magnetotransport characterization reveals that an increase of either electron-doping or hole-doping induced ferromagnetic order in this antiferromagnetic compound, and leads to an insulator-to-metal transition with colossal magnetoresistance showing electron-hole asymmetry. These findings are supported by density functional theory calculations, showing that strengthening of the inter-plane ferromagnetic exchange interaction is the origin of the ambipolar ferromagnetism. The result raises the prospect of exploiting ambipolar magnetic functionality in strongly correlated electron systems.

Epitaxial strain is a powerful tool to manipulate the properties of ferroelectric materials. But despite extensive work in this regard, few studies have explored the effect of epitaxial strain on PbZr0.52Ti0.48O3. Here we explore how epitaxial strain impacts the structure and properties of 75 nm thick films of the morphotropic phase boundary composition. Single-phase, fully epitaxial films are found to possess "relaxed" or nearly "relaxed" structures despite growth on a range of substrates. Subsequent studies of the dielectric and ferroelectric properties reveal films with low leakage currents facilitating the measurement of low-loss hysteresis loops down to measurement frequencies of 30 mHz and dielectric response at background dc bias fields as large as 850 kV/cm. Despite a seeming insensitivity of the crystal structure to the epitaxial strain, the polarization and switching characteristics are found to vary with substrate. The elastic constraint from the substrate produces residual strains that dramatically alter the electric-field response including quenching domain wall contributions to the dielectric permittivity and suppressing field-induced structural reorientation. These results demonstrate that substrate mediated epitaxial strain of PbZr0.52Ti0.48O3 is more complex than in conventional ferroelectrics with discretely defined phases, yet can have a marked effect on the material and its responses. The role of epitaxial strain in affecting the properties of PbZr0.52Ti0.48O3 films is explored. Complex domain structures and property evolution are found despite films possessing nearly "relaxed" structures indicating that the elastic constraint from the substrate produces residual strains that dramatically alter the electric-field response including quenching domain wall contributions to the dielectric permittivity and suppressing field-induced structural reorientation.

A nonlinear thermodynamic formalism based on Ginzburg-Landau-Devonshire theory is developed to describe the total free energy density in (001)-oriented, compositionally graded, and monodomain ferroelectric films including the relative contributions and importance of flexoelectric, gradient, and depolarization energy terms. The effects of these energies on the evolution of the spontaneous polarization, dielectric permittivity, and the pyroelectric coefficient as a function of position throughout the film thickness, temperature, and epitaxial strain state are explored. In general, the presence of a compositional gradient and the three energy terms tend to stabilize a polar, ferroelectric state even in compositions that should be paraelectric in the bulk. Flexoelectric effects produce large built-in fields which diminish the temperature dependence of the polarization and susceptibilities. Gradient energy terms, here used to describe short-scale correlation between dipoles, have minimal impact on the polarization and susceptibilities. Finally, depolarization energy significantly impacts the temperature and strain dependence, as well as the magnitude, of the susceptibilities. This approach provides guidance on how to more accurately model compositionally graded films and presents experimental approaches that could enable differentiation and determination of the constitutive coefficients of interest. © 2014 American Physical Society.

Considerable work has focused on the use of epitaxial strain to engineer domain structures in ferroic materials. Here, we revisit the observed reduction of domain variants in rhombohedral BiFeO3 films on rare-earth scandate substrates. Prior work has attributed the reduction of domain variants to anisotropic in-plane strain, but our findings suggest that the monoclinic distortion of the substrate, resulting from oxygen octahedral rotation, is the driving force for variant selection. We study epitaxial BiFeO 3/DyScO3 (110)O heterostructures with and without ultrathin, cubic SrTiO3 buffer layers as a means to isolate the effect of "symmetry mismatch" on the domain formation. Two-variant stripe domains are observed in films grown directly on DyScO3, while four-variant domains are observed in films grown on SrTiO3-buffered DyScO3 when the buffer layer is >2nm thick. This work provides insights into the role of the substrate - beyond just lattice mismatch - in manipulating and controlling domain structure evolution in materials. © 2014 AIP Publishing LLC.

Abstract Conventional methods for identifying voltage sag sources are difficult to categorize accurately due to the complexity of transmission lines and the influence of noise. In order to solve the problem of difficulty in recognizing voltage sag sources of transmission lines under different locations, this paper proposes a new method for transmission line fault diagnosis based on modified wavelet denoising and multi‐location information convolution transformer. The improved wavelet denoising method proposed in this paper solves the problems of discontinuity and bias of the traditional wavelet denoising method, and is able to better reconstruct the original voltage signal in a strong noise environment. In addition, multi‐location information convolution transformer adopts a new model combining multi‐location information convolution and multi‐scale convolution transformer, which realizes the combination of global information and local context information capturing ability under multi‐location faults. This paper validates the method through simulation experiments and practical situations, and the results show that the method can well classify and identify the type and location of voltage sag sources in transmission lines.

Abstract Background Human immunodeficiency virus (HIV) infection screening and diagnosis are critical to control the HIV epidemic. Testing for anti-HIV antibodies (Ab) and antigens (Ag) in blood samples is the first step to screen people who have been potentially exposed to the virus. This study aimed to evaluate the performance of the MAGLUMI HIV Ab/Ag Combi for detection of HIV antibodies and antigens. Methods We used residual samples to assess the diagnostic specificity and sensitivity of the MAGLUMI HIV Ab/Ag Combi retrospectively. All samples that met the test criteria were tested with the MAGLUMI HIV Ab/Ag Combi according to manufacturer’s instruction. Results of the MAGLUMI HIV Ab/Ag Combi were compared with the Architect HIV Ag/Ab Combo test. Results The specificity of the MAGLUMI HIV Ab/Ag Combi was 99.85% in 5,057 unselected blood donors and 100.00% in 213 hospitalized patient samples, respectively. The sensitivity of the Test in 614 HIV-1 Ab, HIV-1 Ag or HIV-2 Ab positive samples was 100.00%. Seroconversion sensitivity from results of 30 panels was comparable between the MAGLUMI HIV Ab/Ag Combi and the Architect assay. Conclusions The reactivity of the MAGLUMI HIV Ab/Ag Combi test is comparable to the Architect HIV Ag/Ab Combo assay.

Abstract Background The mechanisms by which tumor-derived factors remodel the microenvironment of target organs to facilitate cancer metastasis, especially organ-specific metastasis, remains obscure. Our previous studies have demonstrated that SPP1 plays a key role in promoting metastasis of hepatocellular carcinoma (HCC). However, the functional roles and mechanisms of tumor-derived SPP1 in shaping the pre-metastatic niche (PMN) and promoting lung-specific metastasis are unclear. Methods Orthotopic metastasis models, experimental metastasis models, CyTOF and flow cytometry were conducted to explore the function of SPP1 in shaping neutrophil-dominant PMN and promoting HCC lung metastasis. The main source of CXCL1 in lung tissues was investigated via fluorescence activated cell sorting and immunofluorescence staining. The expression of neutrophils and neutrophil extracellular traps (NETs) markers was detected in the lung metastatic lesions of HCC patients and mouse lung specimens. The therapeutic significance was explored via in vivo DNase I and CXCR2 inhibitor assays. Results SPP1 promoted HCC lung colonization and metastasis by modifying pulmonary PMN in various murine models, and plasma SPP1 levels were closely associated with lung metastasis in HCC patients. Mechanistically, SPP1 binded to CD44 on lung alveolar epithelial cells to produce CXCL1, thereby attracting and forming neutrophil-abundant PMN in the lung. The recruited neutrophils were activated by SPP1 and then formed NETs-dominant PMN to trap the disseminated tumor cells and promote metastatic colonization. Moreover, early intervention of SPP1-orchestrated PMN by co-targeting the CXCL1-CXCR2 axis and NETs formation could efficiently inhibit the lung metastasis of HCC. Conclusions Our study illustrates that HCC-lung host cell-neutrophil interactions play important roles in PMN formation and SPP1-induced HCC lung metastasis. Early intervention in SPP1-orchestrated PMN via CXCR2 inhibitor and DNase I is a potential therapeutic strategy to combat HCC lung metastasis.

Abstract Background The anatomical location for lateral ligament reconstruction remains a significant challenge. With the development of arthroscopic technology, arthroscopic-assisted lateral ligament reconstruction can significantly facilitate the correct localization of anatomical points. However, there is limited evidence on the clinical efficacy of arthroscopic ligament reconstruction compared with percutaneous ligament reconstruction. Methods This study included 72 patients who underwent lateral ligament reconstruction for chronic lateral ankle instability from 2018 to 2022. The follow-up duration in the percutaneous(n = 35) and the arthroscopic(n = 37) groups was 6–30 months. The patients were evaluated before the operation, at 6 months after surgery, and at the final follow-up. The American Orthopaedic Foot and Ankle Society score (AOFAS), Karlsson-Peterson score, and Visual Analog Scale (VAS) were evaluated at each time point. The complications and the time required to return to sports were documented during the follow-up. Results All clinical evaluations significantly improved after surgery in both groups. There was no significant difference between the two groups in the AOFAS score, VAS score, and complications. The Karlsson-Peterson score (85.4 vs 83.6, p = 0.044), surgical duration (50.4 min vs 60.2 min, p

Abstract Background Near-infrared fluorescence (NIRF) imaging is an excellent choice for image-guided surgery due to its simple operation and non-invasiveness. Developing tumor-specific fluorescent molecular probes is key to fluorescence imaging-guided surgery. EGFR (epidermal growth factor receptor) is closely related to the proliferation and growth of tumor cells and is highly expressed in epithelial ovarian cancer (EOC). The study aims to construct a NIR fluorescent molecular probe using cetuximab (an EGFR monoclonal antibody) and investigate its feasibility for targeting EOC in vivo through fluorescence imaging. Methods We determined the expression of EGFR in EOC. NIR fluorescent molecular probe with cetuximab (cetuximab-Cy7) was chemically engineered and identified. The subcutaneous xenografted tumor model of EOC was induced using SKOV3-Luc cell line with positive expression of EGFR. Cetuximab-Cy7 was used for in vivo fluorescence imaging, and phosphate-buffered saline, free Cy7 dye and mouse isotype immunoglobulin G-Cy7 were used as controls. NIRF imaging system was performed to study the distribution and targeting of the probes. Tumors were imaged in situ and ex vivo, and fluorescent intensity was quantified. Resected specimens were analyzed to confirm diagnosis, and immunohistochemical (IHC) staining was used to identify EGFR expression. Results EGFR expression was increased in EOC tissues than fallopian tube tissues. The high expression of EGFR was significantly correlated with well-differentiation, residual lesions ≤ 1 cm, no recurrence and increased survival. NIRF imaging showed that the cetuximab-Cy7 enabled detection of tumor lesions in EOC-bearing mice with the optimal dose of 30 µg. The suitable imaging time window may be 24–96 h post-injection. Ex vivo fluorescence imaging indicated that fluorescent signal was mainly detected in the tumor and the lung. IHC results confirmed that xenografts were EGFR positive. Conclusion Cetuximab-Cy7 can specifically target the tumors of EOC xenografted nude mice. This research lays the foundation for future studies on EOC surgery navigation.

This study aimed to investigate the role of microtubule-affinity regulatory protein kinase 1 (MARK1) in hepatocellular carcinoma (HCC) progression, its association with sorafenib sensitivity, and the interplay between MARK1 and POTE Ankyrin domain family member E(POTEE) in HCC cells.

Ceramic products is one of the important carriers of various civilizations, reflecting the lifestyle, aesthetic concepts, and technological level of society at that time. In order to study the surface treatment design features of ceramic craft products, this article analyzed the ceramic features through computer vision technology and used residual neural networks to detect the surface treatment features of ceramic craft products. The extracted texture features were classified to study and analyze the coupling features of different glazes, colors, and shapes on the formation of different textures. This study used ResNeXt50-SSD, which combined ResNeXt50 and SSD (Single Shot MultiBox Detector) algorithms, to compare feature detection with LeNet-5, VGG-16, and MobileNetV2 network models. From the experimental findings, it can be concluded that ResNeXt50-SSD was the most effective for feature recognition of ceramic craft products, with precision, recall, and mAP of 94.3, 92.1, and 89.5%, respectively. Therefore, the combination of ResNeXt50 and SSD algorithms is an effective method for detecting surface treatment features of ceramic craft products.

Background: Fidgetin-like 1 (FIGNL1) is extensively overexpressed in a variety of cancers. It facilitates non‑small cell lung cancer tumor cell proliferation and hepatocellular carcinoma formation due to abnormal DNA repair. Clinically relevant data indicates that its high expression is linked with the poor prognosis of patients with renal clear-cell carcinoma, low-grade gliomas, and hepatocellular carcinoma. Nevertheless, the scope of FIGNL1’s involvement in cancer, particularly colorectal cancer (CRC), remains unclear. Aims: To investigate the function of FIGNL1 in CRC. Study Design: Cell culture study Methods: The TCGA database and immunohistochemistry analysis were employed to investigate FIGNL1 expression in CRC tissue. A cell viability assay was performed using the Cell Counting Kit-8. The cell migration and invasion were evaluated using the transwell assay. Small interfering RNA (siRNA) transfection was conducted to knockdown FIGNL1 expression. Infection with FIGNL1 overexpression lentivirus was performed to promote FIGNL1 overexpression. The STRING database was employed for predicting protein interaction. Results: FIGNL1 was substantially upregulated in human CRC tissues and was associated with TNM stages and lymph node metastasis in patients. The inhibition of CRC cell proliferation, migration, and invasion in Caco-2 cells was achieved by silencing FIGNL1 using siRNA. Additional investigations suggested that FIGNL1 overexpression could promote CRC cell proliferation, migration, and invasion via P38 signaling pathway activation in Colo-205 cells. Subsequent experiments demonstrated that FIGNL1-mediated P38 phosphorylation was contingent upon SPIDR interaction. Conclusion: These results implied that FIGNL1 was a potential anticancer drug target, which also offered a novel strategy for future CRC treatment.

Abstract The major histocompatibility complex class I antigen presentation pathways play pivotal roles in orchestrating immune responses. Recent studies have begun to explore the therapeutic potential of cysteines within the immunopeptidome, such as the use of covalent ligands to generate haptenated peptide neoepitopes for immunotherapy. In this work, we report a platform for mapping reactive cysteines on MHC-I-bound peptide antigens. We develop cell-impermeable sulfonated maleimide probes capable of capturing reactive cysteines on these antigens. Using these probes in chemoproteomic experiments, we discover that cysteines on MHC-I-bound antigens exhibit various degrees of reactivity. Moreover, interferon-gamma stimulation enhances the reactivity of cysteines at position 8 of 9-mer MHC-I-bound antigens. Finally, we demonstrate that targeting reactive cysteines on MHC-I-bound antigens with a maleimide-conjugated Fc-binding cyclic peptide contributes to the induction of antibody-dependent cellular phagocytosis.

Abstract Land hermit crabs are a group of shell-carrying crabs that have evolved remarkable terrestrial adaptations in behavior, morphology, physiology, and biochemistry. However, the genetic mechanisms underlying these adaptations remain unclear. In addition, usually it is very difficult to get good genome assemblies for crustaceans. In this study, we managed to assemble the first chromosome-level genome for a land hermit crab (Coenobita brevimanus) with careful manual curation. The final assembly spans 4.74 Gb, with the contig N50 of 1.75 Mb and scaffold N50 of 42.95 Mb, encompassing 117 chromosomes that account for 96.54% of the genome. The evaluations including genome BUSCO (95.26%), Merqury qv (35.88) and the mapping ratio of pair-end short reads (99.48%) showed the high-continuity of C. brevimanus genome assembly, making it the genome with the highest quality in crustaceans with genome size bigger than 3 Gb. The availability of this chromosome-scale genome of crustaceans represents a valuable resource for the land hermit crab, which represents an independent water-to-land transition evolutionary event in the animal kingdom.

Introduction: Treating orthopedic implant-associated infections, especially those caused by Staphylococcus aureus (S. aureus), remains a significant challenge. S. aureus has the ability to invade host cells, enabling it to evade both antibiotics and immune responses during infection, which may result in clinical treatment failures. Therefore, it is critical to identify the host cell type of implant-associated intracellular S. aureus infections and to develop a strategy for highly targeted delivery of antibiotics to the host cells. Objectives: Introduced an antibody-antibiotic conjugate (AAC) for the targeted elimination of intracellular S. aureus. Methods: The AAC comprises of a human monoclonal antibody (M0662) directly recognizes the surface antigen of S. aureus, Staphylococcus protein A, which is conjugated with vancomycin through cathepsin-sensitive linkers that are cleavable in the proteolytic environment of the intracellular phagolysosome. AAC, vancomycin and vancomycin combined with AAC were used in vitro intracellular infection and mice implant infection models. We then tested the effect of AAC in vivo and in vivo by fluorescence imaging, in vivo imaging, bacterial quantitative analysis and bacterial biofilm imaging. Results: In vitro, it was observed that AAC captured extracellular S. aureus and co-entered the cells, and subsequently released vancomycin to induce rapid elimination of intracellular S. aureus. In the implant infection model, AAC significantly improved the bactericidal effect of vancomycin. Scanning electron microscopy showed that the application of AAC effectively blocked the formation of bacterial biofilm. Further histochemical and micro-CT analysis showed AAC significantly reduced the level of bone marrow density (BMD) and bone volume fraction (BV/TV) reduction caused by bacterial infection in the distal femur of mice compared to vancomycin treatment alone. Conclusions: The application of AAC in an implant infection model showed that it significantly improved the bactericidal effects of vancomycin and effectively blocked the formation of bacterial biofilms, without apparent toxicity to the host.

Regulating macrophage phenotypes to reconcile the conflict between bacterial suppression and tissue regeneration is ideal for treating infectious skin wounds. Here, an injectable immunoregulatory hydrogel (SrmE20) that sequentially drives macrophage phenotypic polarization (M0 to M1, then to M2) was constructed by integrating anti-inflammatory components and proinflammatory solvents. In vitro experiments demonstrated that the proinflammatory solvent ethanol stabilized the hydrogel structure, maintained the phenolic hydroxyl group activity, and achieved macrophages' proinflammatory transition (M0 to M1) to enhance antibacterial effects. With ethanol depletion, the hydrogel's cations and phenolic hydroxyl groups synergistically regulated macrophages' anti-inflammatory transition (M1 to M2) to initiate regeneration. In the anti-contraction full-thickness wound model with infection, this hydrogel effectively eliminated bacteria and even achieved anti-inflammatory M2 macrophage accumulation at three days post-surgery, accelerated angiogenesis and collagen deposition. By sequentially driving macrophage phenotypic polarization, this injectable immunoregulatory hydrogel will bring new guidance for the care and treatment of infected wounds.

As the main technology of CBM development in the Qinshui CBM field, single-branch fractured horizontal wells have supported the breakthrough of 2 billion m3/year production of gas field. However, in the process of its large-scale application, there have been a series of problems, such as large difference in production among wells and poor adaptability in local areas, which seriously restrict the further improvement of CBM production in gas fields. On the one hand, although many key elements affecting the production of single-branch fractured horizontal wells have been identified, the core key elements are not clear. On the other hand, the understanding of the change rule of key elements on the plane is generally simple mathematical extrapolation or pure mathematical inversion, which lacks geological constraints and corrections, and has low reliability and resolution. Therefore, it is urgent to clear the core key elements that affect the production, and then establish targeted technical countermeasures on this basis. First of all, based on the objective geological conditions and the understanding of development and production practice in the Zhengzhuang block, the preliminary screening principle of the core key elements affecting the production of single−branch fractured horizontal wells was proposed, and nine elements were selected, including drilling length in pure coal seam, horizontal section inclination, total hydrocarbon, GR, number of fracturing stages, average sand gradient, average displacement gradient, average fluid volume gradient and desorption pressure gradient. Then, grey correlation analysis and single element analysis were used to determine the correlation degree between the nine elements of the preliminary screening and the production of single−branch fractured horizontal wells, and determine the internal mechanism of the elements' influence on the production. Secondly, from the three perspectives of resource base, reserve control and reconstruction, combined with the specific process of a single-branch fractured horizontal well deployment, reconstruction design and operation, nine elements were classified, and targeted technical countermeasures for production enhancement were established. In the stage of well location deployment, extrapolation data based on evaluation wells were used to initially identify the relatively enriched area, and the seismic data were processed by structure-oriented filtering + high−frequency coherence technology to delineate the local area for clearing hidden destructive structures in the area, and then straight/inclined wells were drilled to obtain GR and total hydrocarbons in the coal seam segment to determine the resource base of the well location deployment area. In the stage of well trajectory design and drilling, the waveform clustering technology was used to predict the distribution law of strongly deformed coal in the well location deployment area. The pre−stack depth migration of seismic data was processed to predict the thickness and fluctuation change law of coal seam in the well location deployment area, the well group mode was used to drill in batches, and the near−bit geological guidance technology was combined with the real drilling data to correct the local coal seam understanding in real time, to increase drilling length in pure coal seam, optimize well trajectory, ensure more high−quality fracturing stages, and improve reservoir control. In the reservoir reconstruction stage, GR (Gamma Ray), total hydrocarbon, well trajectory conditions and real drilling data were used to select fracturing stages, and the joint operation techniques of bridge plug setting, shooting and fracturing was used as a new fracturing technology to increase the displacement, sand and fluid volume, increase the reconstruction scale and strengthen the reconstruction, and improve resource utilization. Finally, relevant tests were carried out in the Zhengzhuang block by using the above countermeasures. A well group with 7 wells was deployed in the north of Zhengzhuang. Compared with the early single-branch fractured horizontal wells around the well group, the desorption pressure of the test wells is about 1-1.5 MPa higher than before, and the stable gas production is increased by nearly 5 000-10 000 m3/d. According to field practice tests, the core key elements affecting the production of single-branch fractured horizontal wells and the targeted production technical countermeasures established on this basis can greatly improve the stable gas production and desorption pressure of coalbed methane, which can help improve the production of the Qinshui coalbed methane field and provide important production practice experience and successful cases that can be learned from for peers who adopt the same main development technology.

The iron-based parts with different densities were prepared by powder metallurgy, and then were densified by ultrasonic shot peening. The diamond-like carbon (DLC) self-lubricating coatings were deposited on the sintered and shot peening samples with different densities by physical vapor deposition, and the binding force and tribological properties of DLC coatings were studied. The results show that the matrix with high density has the better binding force with coatings, and the matrix treated with shot peening shows much better binding force, which is about 28.0 N. However, in the process of ultrasonic shot peening, the surface layers of the matrix produce huge compressive stress, and the accumulation of residual stress in the matrix and the coatings may lead to the premature failure of coatings. To reduce the stress accumulation caused by ultrasonic shot peening process, the samples are annealed after shot peening, and show much higher binding force between the matrix and coatings, about 54.5 N. The frictional properties of samples with DLC coating are greatly improved, the friction coefficient of the samples without coatings is about 0.60, and that of the sintered samples with DLC coatings is about 0.15. Compared with the DLC coatings on the matrix after shot peening (friction coefficient 0.13 ~ 0.17), the lubricity of DLC coatings on the annealed matrix is more stable (friction coefficient 0.13).

Steam treatment (ST) is a widely used chemical strengthening method for the iron-based powder metallurgy (PM) products, which can form the dense protective films with strong adhesion force and high hardness on the product surface, showing the effects of corrosion resistance, wear resistance, and hardness enhancement. The reaction principle of steam treatment and the influence of reaction thermodynamics and dynamics on the quality of the steam treated protective films were described systematically in this paper. To promote the standardization of steam treatment process for the iron-based powder metallurgy parts, the detection methods of thickness, structure, composition, and binding force of the steam treatment protective films were summarized, based on the current production situation; and combined with the actual experimental results, the advantages and disadvantages for each detection method were explained.

Fe–Fe3P adhesive premixed powders were prepared by using hyperbranched polyester as the binders. The microstructure of the powders was observed by scanning electron microscope. The effect of hyperbranched polyester binder content (mass fraction) on the properties of the Fe−Fe3P powder mixture and the sintered products was studied. The results show that the proportion of small particle size powders with particle size ≤10 μm (mostly Fe3P powders) in the bonded mixed powders accounts for 0.65% of the total number of powder particles, which is significantly lower than that of the un-bonded mixed powders (5.93%). Hyperbranched polyester can successfully bond the Fe3P powders to the iron powder surface, which is beneficial to improve the uniformity of phosphorus in the mixed powders and prevent segregation. The Fe–Fe3P bonded mixed powders with 0.10% terminal hydroxyl hyperbranched polyester show the best powder fluidity and loose packing density. The pressing pressure of the Fe–Fe3P green billets with the same density increases with the increase of the mass fraction of hyperbranched polyester. The addition of hyperbranched polyester binder can reduce the size change rate of the sintered body before and after sintering, improve the transverse fracture strength of the sintered body, and maintain good bonding property in the actual production process.

In this paper, we analyze the outage performance of Unmanned Aerial Vehicles (UAVs)-enabled downlink Non-Orthogonal Multiple Access (NOMA) communication systems with the Semi-Grant-Free (SGF) transmission scheme. A UAV provides coverage services for a Grant-Based (GB) user and one Grant-Free (GF) user is allowed to utilize the same channel resource opportunistically. The analytical expressions for the exact and asymptotic Outage Probability (OP) of the GF user are derived. The results demonstrate that no-zero diversity order can be achieved only under stringent conditions on users' quality of service requirements. Subsequently, an efficient Dynamic Power Allocation (DPA) scheme is proposed to relax such data rate constraints. The analytical expressions for the exact and asymptotic OP of the GF user with the DPA scheme are derived. Finally, Monte Carlo simulation results are presented to validate the correctness of the derived analytical expressions and demonstrate the effects of the UAV's location and altitude on the OP of the GF user.

There are many ships and ports in Shanghai coastal zones, where disastrous weather occurs frequently. Meteorological disasters often threaten the safety of people’s lives and properties along the coast and in the ports. In the past, the meteorological warnings for Shanghai coastal zones are mainly based on those issued for Yangshan Port by Shanghai Marine Meteorological Centre (SMMC), which are called “unified warnings”. However, there are obvious differences in the time and intensity of meteorological disasters in each region, and the unified warnings cannot meet the needs of the production and operation of the shipping and ports. In 2020, Shanghai coastal zones were divided into five sub-zones, where the meteorological forecast and warnings were carried out separately from July 2020. Based on hourly observational data of the representative stations in Shanghai coastal zones and warning signal data from 2016 to 2022, the gale events are selected to analyse the statistical characteristics of temporal and spatial distribution and evaluate the forecast quality and the economic benefits of the zonal warnings. The results show that: (1) The farther away from the coastline, the more gale days, the higher the wind speed and the longer the duration; the higher the wind speed during the process, the more obvious the difference of wind scale. In particular, the wind scale caused by typhoons can range up to 5 levels. (2) Compared with the “unified warning”, the missing alarm rate (MAR) of gale warnings in each sea area has been reduced significantly, by up to 5%, the false alarm rate (FAR) for the western part of Yangtze River estuary is reduced by more than 8% and the TS score is significantly improved by more than 10%. (3) The advance time of gale warnings has been reduced by more than 3 hours, the maintaining duration has been shortened by more than 16 hours at most, which can reduce the loss of nearly 18 million RMB and improve the production efficiency of the coastal zones of Shanghai greatly. The results of this paper show that refined marine meteorological forecasts and early warnings provide a safety guarantee for marine transportation and port production operations, resulting in significant social and economic benefits and the enhancement of the comprehensive guarantee level of marine meteorological services in Shanghai. In the next step, we will continue to research and develop more refined objective forecast methods adapted to this business, then build a regional shared operational system platform and extend it to the Yangtze River Delta region, so as to promote the high-quality development of shipping meteorological integration in the Yangtze River Delta region.

Abstract Pile foundation structures are widely used in the construction of high-piled wharves in coastal soft soil areas due to their excellent adaptability to such environments. However, the extensive, deep backfilling involved in constructing these wharves can easily induce negative skin friction (NSF) on the piles, resulting in safety issues such as excessive settlement during the service life of the structures. This paper presents an indoor model experiment to examine the distribution of the THE NSF under varying pile-top loads and surcharge effects on single pile and double-sleeve pile foundations. The potential of double-sleeve pile foundations to mitigate the NSF was also explored. The results show that the axial force within the double-sleeve pile’s protected section remains essentially stable, though it is affected by the surface surcharge in the unprotected section. Time effect is exhibited both for the axial force and the NSF, gradually increasing over time. Compared to single piles, double-casing pile foundations can effectively isolate the down drag load caused by surrounding soil settlement, thereby reducing or eliminating the NSF on the pile sides.

Abstract Background Solute Carrier Family 4 Member 4 (SLC4A4) is a membrane protein‐coding gene for a Na+/HCO3 − cotransporter and plays a crucial role in regulating pH, bicarbonate secretion and homeostasis. However, the prognostic and immunological role of SLC4A4 in colon cancer remains unknown. Method In this study, expression profiles of SLC4A4 were retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, to which a variety of bioinformatic analyses were performed. Sangerbox, Xiantao, ESTIMATE and TIMER online tools were used to delve into the relationship between SLC4A4 expression and immune cell infiltration. The role of SLC4A4 in the proliferation and migration of colon cancer cells was verified by CCK8, EdU and wound healing assays. The related molecules and pathways that SLC4A4 may affect were validated by bioinformatic prediction and western blotting analysis. Results The expression levels of SLC4A4 were significantly lower in colon cancer tissues than in normal tissues and its low expression was positively correlated with poor prognosis. TIMER and ESTIMATE showed that SLC4A4 broadly influenced immune cell infiltration. Experiments in vitro demonstrated that SLC4A4 inhibited partial epithelial-mesenchymal transition (EMT) phenotypes. Conclusions To conclude, our study revealed that SLC4A4 is lowly expressed in colon cancer tissues, and SLC4A4 may inhibit the progression of colon cancer via regulating partial EMT phenotypes and immune cell infiltration, which may provide new perspectives for the development of more precise and personalized immune anti-tumor therapies.

Abstract Background Episodic memory naturally deteriorates with age, and its deficits are widely recognized as the most significant feature and the most sensitive indicator of cognitive decline. It has been suggested that adopting a healthy lifestyle can play a protective role in preserving episodic memory. This study aimed to systematically examine the relationship between lifestyle factors (social activities, leisure activities, physical activities, internet use, smoking, alcohol drinking, and sleep quality) and episodic memory in middle-aged and older adults. Methods The current study included 10,392 participants from the Chinese Health and Retirement Longitudinal Survey. A linear mixed model was used to explore the associations between lifestyle factors and episodic memory performance and the age- and sex-specific effects of the association. Results Low-frequency alcohol drinking, higher engagement in social, leisure, and physical activities, increased internet use, and improved sleep quality were associated with better episodic memory performance in middle-aged and older adults. Stratified analyses demonstrated that internet use significantly correlated with episodic memory performance in middle-aged adults but not in older adults. On the other hand, sleep quality showed a significant association with episodic memory performance in women but not in men. Conclusions This study highlights the association between various lifestyle factors and episodic memory performance, with variations observed based on age and sex. Adopting healthy lifestyle factors can have positive effects on episodic memory in middle-aged adults, emphasizing the importance of adhering to healthy lifestyles from middle age onwards to counteract episodic memory decline.

Abstract Purpose This study aims to investigate the risk factors for lymph node metastasis (LNM) in synchronous multiple primary lung cancer (sMPLC) using clinical and CT features, and to offer guidance for preoperative LNM prediction and lymph node (LN) resection strategy. Materials and methods A retrospective analysis was conducted on the clinical data and CT features of patients diagnosed with sMPLC at the Third Affiliated Hospital of Kunming Medical University from January 1, 2018 to December 31, 2022. Patients were classified into two groups: the LNM group and the non-LNM (n-LNM) group. The study utilized univariate analysis to examine the disparities in clinical data and CT features between the two groups. Additionally, multivariate analysis was employed to discover the independent risk variables for LNM. The diagnostic efficacy of various parameters was evaluated using the receiver operating characteristic (ROC) curve. Results Among the 688 patients included in this study, 59 exhibited LNM. Univariate analysis revealed significant differences between the LNM and n-LNM groups in terms of gender, smoking history, CYFRA21-1 level, CEA level, NSE level, lesion type, total lesion diameter, main lesion diameter, spiculation sign, lobulation sign, cavity sign, and pleural traction sign. Logistic regression identified CEA level (OR = 1.042, 95%CI: 1.009-1.075), lesion type (OR = 9.683, 95%CI: 3.485-26.902), and main lesion diameter (OR = 1.677, 95%CI: 1.347-2.089) as independent predictors of LNM. The regression equation for the joint prediction was as follows: logit(p)= -7.569+0.041*CEA level +2.270* lesion type +0.517* main lesion diameter.ROC curve analysis showed that the AUC for CEA level was 0.765 (95% CI, 0.694–0.836), for lesion type was 0.794 (95% CI, 0.751–0.838), for main lesion diameter was 0.830 (95% CI, 0.784–0.875), and for the combine predict model was 0.895 (95% CI, 0.863–0.928). Conclusion The combination of clinical and imaging features can better predict the status of LNM of sMPLC, and the prediction efficiency is significantly higher than that of each factor alone, and can provide a basis for lymph node management decision.

Abstract Oxidative stress (OS) is believed to be a significant factor in the decline of semen quality, with mitochondrial DNA copy number (mtDNAcn) serving as a sensitive biomarker for both semen quality and mitochondrial dysfunction resulting from oxidative stress. While glutathione S-transferases (GSTs) are commonly known as ‘antioxidant’ enzymes, there is ongoing debate regarding the relationship between GST genotypes and semen quality. In a study involving 568 male volunteers from the outpatient department of Puyang Reproductive Medicine Center, sperm mtDNAcn, semen quality, and GSTM1/GSTT1 genotypes were analyzed to investigate the potential link between GSTM1/GSTT1 gene variations and semen quality, as well as the impact of GSTs gene variations on the connection between sperm mtDNAcn and semen quality. Adjusting for variables such as age, BMI, smoking, and alcohol consumption, it was found that mtDNAcn was significantly correlated with decreased sperm concentration and total sperm count (b = − 0.109, − 0.128, respectively; P = 0.002, 0.001, respectively). GSTM1 was associated with progressive motility (OR 0.390, 95% CI 0.218, 0.697), Straight line velocity (VSL) (OR = 0.606, 95% CI 0.385, 0.953), and Straightness (STR) (OR 0.604, 95% CI 0.367, 0.994), while GSTT1 was linked to progressive motility (OR 0.554, 95% CI 0.324, 0.944) and Beat crossover frequency (OR 0.624, 95% CI 0.397, 0.982). The GSTT1 was found to moderate the relationship between mtDNAcn and sperm motility parameters linearity (LIN), STR, and Wobble (WOB), with additive interaction effects observed between GSTT1 and mtDNAcn on LIN, STR, and WOB (P for interaction = 0.008, 0.034, 0.010, respectively). Overall, this study suggests that GSTT1 and GSTM1 gene variations may play a role in sperm motility, with GSTT1 potentially influencing the impact of oxidative stress on sperm motility.

Abstract Triptolide (TP), a major active component of the herb Tripterygium wilfordii Hook F, has been shown excellent pharmacological effects on rheumatoid arthritis. However, TP is prone to causing severe organ toxicity, which limits its clinical application. In recent years, microneedle technology has provided a new option for the treatment of arthritis due to its advantages of efficient local transdermal drug delivery. In this study, we constructed a microneedle platform to deliver TP locally to the joints, thereby enhancing TP penetration and reducing systemic toxicity. Additionally, we investigated whether acupoint drug delivery can produce a synergistic effect of needles and drugs. First, TP was loaded into microneedles using polyvinylpyrrolidone and hyaluronic acid as matrix materials. Next, we established a rat adjuvant-induced arthritis (AIA) model to evaluate the therapeutic effect of TP-loaded microneedles. The experiments showed that TP-loaded microneedles alleviated the AIA rats’ inflammatory response, joint swelling, and bone erosion. However, there was no significant difference in the therapeutic effect observed in the acupoint and non-acupoint administration groups. In conclusion, TP-loaded microneedles have the advantages of safety, convenience, and high efficacy over conventional administration routes, laying a foundation for the transdermal drug delivery system-based treatment of rheumatoid arthritis.

Abstract Background Overconsumption of retinoic acid (RA) or its analogues/derivatives has been linked to severe craniomaxillofacial malformations, such as cleft palate and midface hypoplasia. It has been noted that RA disturbed the proliferation and migration of embryonic palatal mesenchymal (EPM) cells in these malformations, yet the exact mechanisms underlying these disruptions remained unclear. Methods A model of retinoic acid (RA)-induced cleft palate in fetal mice was successfully established. Histological alterations in the palate were evaluated using Hematoxylin and Eosin (H&E) staining and RNA in situ hybridization (RNAscope). Cellular proliferation levels were quantified via the Cell Counting Kit-8 (CCK-8) assay and EdU incorporation assay, while cell migration capabilities were investigated using wound healing and Transwell assays. Mitochondrial functions were assessed through Mito-Tracker fluorescence, mitochondrial reactive oxygen species (ROS) measurement, ATP level quantification, and mitochondrial DNA (mtDNA) copy number analysis. Differential gene expression and associated signaling pathways were identified through bioinformatics analysis. Alterations in the transcriptional and translational levels of Lhx6 and genes associated with mitophagy were quantified using quantitative PCR (qPCR) and Western blot analysis, respectively. Mitochondrial morphology and the mitochondrial autophagosomes within cells were examined through transmission electron microscopy (TEM). Results Abnormal palatal development in mice, along with impaired proliferation and migration of human embryonic palatal mesenchymal (HEPM) cells, was associated with RA affecting mitochondrial function and concomitant downregulation of Lhx6. Knockdown of Lhx6 in HEPM cells resulted in altered cell proliferation, migration, and mitochondrial function. Conversely, the aberrant mitochondrial function, proliferation, and migration observed in RA-induced HEPM cells were ameliorated by overexpression of Lhx6. Subsequent research demonstrated that Lhx6 ameliorated RA-induced dysfunction in HEPM cells by modulating PINK1/Parkin-mediated mitophagy, thereby activating the MAPK signaling pathways. Conclusion Lhx6 is essential for mitochondrial homeostasis via tuning PINK1/Parkin-mediated mitophagy and MAPK signaling pathways. Downregulation of Lhx6 by RA transcriptionally disturbs the mitochondrial homeostasis, which in turn leads to the proliferation and migration defect in HEPM cells, ultimately causing the cleft palate. Graphical abstract

Abstract Background Cerebral venous thrombosis (CVT) is a rare but serious condition that can lead to significant morbidity and mortality. Virchow’s triad elucidates the role of blood hypercoagulability, blood flow dynamics, and endothelial damage in the pathogenesis of CVT. Cerebral venous congestion (CVC) increases the risk of cerebral venous sinus thrombosis and can lead to recurrent episodes and residual symptoms. However, the precise mechanism by which blood congestion leads to thrombosis remains unclear. Our objective was to investigate the cellular and molecular alterations linked to CVC through analysis of the pathological morphology of venous sinus endothelial cells and transcriptomic profiling. Results This study demonstrated a remarkable correlation between CVC and the phenotypic transformation of endothelial cells from an anticoagulant to a procoagulant state. The findings revealed that cerebral venous stasis results in tortuous dilatation of the venous sinuses, with slow blood flow and elevated pressure in the sinuses and damaged endothelial cells of the retroglenoid and internal jugular vein ligation (JVL) rat model. Mechanistically, analysis of transcriptomic results of cerebral venous sinus endothelial cells showed significant activation of platelet activation, complement and coagulation cascades pathway in the JVL rats. Furthermore, the expression of von Willebrand factor (vWF) and coagulation factor VIII (F8) in the complement and coagulation cascades and Fgg and F2 in the platelet activation was increased in the cerebral venous sinuses of JVL rats than in sham rats, suggesting that endothelial cell injury in the venous sinus induced by CVC has a prothrombotic effect. In addition, endothelial cell damage accelerates coagulation and promotes platelet activation. Significantly, the concentrations of vWF, F2 and F8 in venous sinus blood of patients with internal jugular vein stenosis were higher than in their peripheral blood. Conclusion Collectively, our data suggest that CVC can induce endothelial cell damage, which then exhibits a procoagulant phenotype and ultimately increases the risk of CVT. This research contributes to our understanding of the pathophysiology of CVC associated with procoagulant factors and reexamines the components of Virchow’s triad in the context of CVC.

In ophthalmology, the quality of fundus images is critical for accurate diagnosis, both in clinical practice and in artificial intelligence (AI)-assisted diagnostics. Despite the broad view provided by ultrawide-field (UWF) imaging, pseudocolor images may conceal critical lesions necessary for precise diagnosis. To address this, we introduce UWF-Net, a sophisticated image enhancement algorithm that takes disease characteristics into consideration. Using the Fudan University ultra-wide-field image (FDUWI) dataset, which includes 11 294 Optos pseudocolor and 2415 Zeiss true-color UWF images, each of which is rigorously annotated, UWF-Net combines global style modeling with feature-level lesion enhancement. Pathological consistency loss is also applied to maintain fundus feature integrity, significantly improving image quality. Quantitative and qualitative evaluations demonstrated that UWF-Net outperforms existing methods such as contrast limited adaptive histogram equalization (CLAHE) and structure and illumination constrained generative adversarial network (StillGAN), delivering superior retinal image quality, higher quality scores, and preserved feature details after enhancement. In disease classification tasks, images enhanced by UWF-Net showed notable improvements when processed with existing classification systems over those enhanced by StillGAN, demonstrating a 4.62% increase in sensitivity (SEN) and a 3.97% increase in accuracy (ACC). In a multicenter clinical setting, UWF-Net-enhanced images were preferred by ophthalmologic technicians and doctors, and yielded a significant reduction in diagnostic time ((13.17 ± 8.40) s for UWF-Net enhanced images vs (19.54 ± 12.40) s for original images) and an increase in diagnostic accuracy (87.71% for UWF-Net enhanced images vs 80.40% for original images). Our research verifies that UWF-Net markedly improves the quality of UWF imaging, facilitating better clinical outcomes and more reliable AI-assisted disease classification. The clinical integration of UWF-Net holds great promise for enhancing diagnostic processes and patient care in ophthalmology.

Abstract The National Health Service (NHS) in England has set hospitals a target of achieving > 85% in a metric called ‘capped theatre utilisation’ (CTU), as central to its post-pandemic surgical waiting list recovery planning. This could serve as a model internationally, as other countries seek to improve operating theatre efficiency. Our review presents an analysis of what CTU means in the context of other measures of theatre ‘utilisation’, serving as a tutorial for clinical leaders, managers and all staff involved in theatres better to understand the metrics sometimes being used to assess their performance. We present results of a theoretical sensitivity analysis to assess how CTU values vary for hypothetical operating lists of three different structures (number of cases, their duration, and intercase gap times), as the stated start and finish times are shifted backwards and forwards in time. We then present results of our interrogation of the NHS Model Health Operating Theatres database to assess hospitals' CTU performance over three years. We discovered that in theory, CTU was especially sensitive to both stated list start times and list structure. The relationship to start time was asymmetric: early starts in one list did not compensate for loss of CTU value with late start in another list, when values were averaged across lists. This sensitivity analysis also predicted wide weekly CTU fluctuations, with values 85%, especially for tertiary referral centres predominantly undertaking long, complex procedures. Our interrogation of the database confirmed these predictions. Moreover, we discovered many instances of implausible CTU values and underlying patterns indicating fundamental flaws in the CTU algorithm, rather than data entry errors. We conclude that CTU, and the NHS target of 85%, is not a suitable metric for operating theatre performance. It has proved unachievable in any sustainable way, and its underlying algorithm produces aberrant values. We discuss the serious consequences of basing other national policies or funding models on a fundamentally flawed metric. These results have lessons for international healthcare systems.

Abstract Objective This meta-analysis aims to compare the clinical efficacy of mesh non-fixation and fixation in laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair, systematically evaluating the application value of the mesh non-fixation technique in clinical settings. Methods A computerized search of PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov databases was conducted to identify randomized controlled trials (RCTs) comparing mesh non-fixation and fixation in TAPP inguinal hernia repair. Meta-analysis was performed using RevMan 5.3 software, and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence grading system was employed for outcome quality assessment. Publication bias analysis was performed using Begg’s test. A trial sequential analysis (TSA) was performed using TSA 0.9.5.10 Beta software. Results A total of nine RCTs involving 1,879 inguinal hernia patients were included. Meta-analysis results demonstrated that, compared to the fixation group, the non-fixation group exhibited significantly lower seroma occurrence rate [RR = 0.43, 95% CI (0.20, 0.89), P = 0.02, heterogeneity P = 0.28, I²=22%], Visual Analog Scale (VAS) pain score at 6 months postoperatively [MD=-0.21, 95% CI (-0.29, -0.12), P

Abstract Background Trabectedin (Tbt) is an alkylating agent prescribed for soft tissue sarcomas after treatment failure of first line agents. While cardiomyopathy can occur with Tbt treatment after anthracycline exposure, Tbt-induced fulminant myocardial cytotoxic injury in the setting of other systemic cytotoxicity associated with Tbt has not been reported. Case presentation 51-year-old female with hypertension, hyperlipidemia, metastatic leiomyosarcoma with progression of disease despite several lines of chemotherapy including doxorubicin-based therapy was started on Trabectedin (Tbt) 5 days prior to presentation with symptoms of fever, myalgias, arthralgias, and palpitations. She was admitted for management of rhabdomyolysis, acute kidney and liver injuries which were reportedly known to be associated with Tbt treatment. A baseline electrocardiogram (ECG) revealed sinus tachycardia with non-specific T-wave changes, and a transthoracic echocardiogram (TTE) was unremarkable. However, on day 3 of hospitalization, an episode of asymptomatic sustained monomorphic ventricular tachycardia with a heart rate of 150 beats per minute was captured on telemetry. A 12-lead ECG revealed new septal T-wave inversions. Labs revealed rising hs-TnI levels (peak at 37,933ng/L) and serum markers suggested multi-organ failure. Steroids were initiated given its role in treating multi-organ Tbt-induced toxicity. A cardiac MRI to rule out myocarditis and left heart catheterization to rule out obstructive coronary artery disease were forgone due to acute renal failure. A right heart catheterization with an endomyocardial biopsy was performed revealing normal cardiac filling pressures and indices. Pathology showed cytoplasmic vacuoles indicating drug-induced myocardial cytotoxicity. Serial echocardiograms revealed preserved biventricular function. The patient’s clinical condition deteriorated with multi-organ failure despite maximal supportive care in the intensive care unit. She ultimately passed away, and an autopsy was declined. Conclusion This is the first reported case of fulminant myocardial injury after initiation of Tbt with histologic evidence of drug-induced myocardial cytotoxicity. While it is unclear if anthracyclines potentiate Tbt cytotoxic injury as in this case, it is plausible; and that Tbt-induced cardiotoxicity ranges from subclinical to fulminant. Given increasing use of Tbt in refractory high-grade sarcomas, raising awareness of its toxicity profile will improve early detection and outcomes.