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Abstract Radiotherapy and immunotherapy have already become the primary form of treatment for non-small-cell lung cancer (NSCLC), but are limited by high radiotherapy dose and low immune response rate. Herein, a multi-pronged strategy using a radio-immuno-enhancer (ZnO–Au@mSiO2) is developed by inducing tumor cells apoptosis and reprograming the immunosuppressive tumor microenvironment (TME). The radio-immuno-enhancer employed Au as a radiosensitizer, transition Zn ions as immune activators, which not only tremendously enhances the anti-proliferative activity of radiotherapy toward cancer cells, but also activates the immune response with multi-targets to let “exhausted” T cells “back to life” by triggering immunogenic cell death (ICD), immune checkpoint blockade (ICB) that target PD-1/PD-L1 and cGAS-STING under X-ray irradiation with a low dosage. The in vivo results demonstrate desirable antitumor and immunogenic effects of radio-immuno-enhancer-mediated immune activation by increasing the ratio of cytotoxic T cells (CTLs) and helper T cells. This work provides a feasible approach for future development of effective transition metal ion-activated radio-immunotherapeutic agents. Graphic Abstract

Radiotherapy is an important treatment for cancer, but it is associated with major side effects due to the high dose of radiation (generally more than 50 Gy). Because radiation’s low acute and late toxicity, many tumors are treated with fractionated radiation in small doses (

Abstract DNBSEQ employs a patterned array to facilitate massively parallel sequencing of DNA nanoballs (DNBs), leading to a considerable boost in throughput. By employing the ultra-high-density (UHD) array with an increased density of DNB binding sites, the throughput of DNBSEQ can be further expanded. However, the typical imaging system of the DNBSEQ sequencer is unable to resolve adjacent DNBs spaced smaller than the resolution limit, resulting in poor base-calling performance of the UHD array and hindering its practical application. In this study, we propose a deep-learning-based DNB image super-resolution network named DNBSRN to address this problem. DNBSRN has a specifically designed structure for DNB images and employs a histogram-matching-based preprocessing approach. For the eight DNB image datasets generated from the DNBSEQ sequencer using UHD arrays with 360 nm pitch, the base-calling performances are significantly improved after super-resolution reconstruction by DNBSRN and reached a comparable level to those of the regular density array. In terms of reconstruction speed, DNBSRN takes only 7.61 ms for an input image with 500 × 500 pixels, which minimizes its influence on throughput. Furthermore, compared with state-of-the-art super-resolution networks, DNBSRN demonstrates superior performance in terms of both the quality and speed of DNB image reconstruction. DNBSRN successfully addresses the DNB image super-resolution task. Integrating DNBSRN into the image analysis workflow of DNBSEQ will allow for the application of UHD array, hence enabling a considerable improvement in throughput as well as tremendous savings in unit reagent cost.

Abstract The high heterogeneity and severe side effects of chemotherapy are major factors contributing to the failure of osteosarcoma treatment. Herein, a comprehensive genomic analysis is conducted, and identified two prominent characteristics of osteosarcoma: significant cyclin‐dependent kinases 4 (CDK4) amplification and homologous recombination repair deficiency. Based on these findings, a co‐delivery system loaded with CDK4/6 inhibitors and poly ADP‐ribose polymerase (PARP) inhibitors is designed. By employing metal–organic frameworks (MOFs) as carriers, issue of drug insolubility is effectively addressed, while also enabling controlled release in response to the tumor microenvironment. To enhance targeting capability and biocompatibility, the MOFs are further coated with a bio‐membrane targeting B7H3. This targeted biomimetic co‐delivery system possesses several key features: 1) it can precisely target osteosarcoma with high B7H3 expression; 2) the combination of CDK4/6 inhibitors and PARP inhibitors exhibits synergistic effects, significantly impairing tumor's DNA repair capacity; and 3) the system has the potential for combination with photodynamic therapy, amplifying DNA repair defects to maximize tumor cell eradication. Furthermore, it is observed that this co‐delivery system can activate immune microenvironment, increasing CD8+ T cell infiltration and converting osteosarcoma from an immune‐cold to an immune‐hot tumor. In summary, the co‐delivery system is an effective therapeutic strategy and holds promise as a novel approach for osteosarcoma treatment.

Abstract Both copper (Cu2+/+) and iodine (I−) are essential elements in all living organisms. Increasing the intracellular concentrations of Cu or I ions may efficiently inhibit tumor growth. However, efficient delivery of Cu and I ions into tumor cells is still a challenge, as Cu chelation and iodide salts are highly water-soluble and can release in untargeted tissue. Here we report mitochondria-targeted Cu-I cluster nanoparticles using the reaction of Cu+ and I− to form stable bovine serum albumin (BSA) radiation-induced phosphors (Cu-I@BSA). These solve the stability issues of Cu+ and I− ions. Cu-I@BSA exhibit bright radioluminescence, and easily conjugate with the emission-matched photosensitizer and targeting molecule using functional groups on the surface of BSA. Investigations in vitro and in vivo demonstrate that radioluminescence under low-dose X-ray irradiation excites the conjugated photosensitizer to generate singlet oxygen, and combines with the radiosensitization mechanism of the heavy atom of iodine, resulting in efficient tumor inhibition in female mice. Furthermore, our study reveals that BSA protection causes the biodegradable Cu-I clusters to release free Cu and I ions and induce cell death by modulating mitochondrial function, damaging DNA, disrupting the tricarboxylic acid cycle, decreasing ATP generation, amplifying oxidative stress, and boosting the Bcl-2 pathway.

BackgroundSeveral clinical trials have shown that immunotherapy plays a pivotal role in the treatment of patients with metastatic synovial sarcoma. Immune-related genes (IRGs) have been demonstrated to predict the immunotherapy response in certain malignant tumours. However, the clinical significance of IRGs in patients with synovial sarcoma (SS) is still unclear.MethodsWe first combined the immune-related ImmPort gene set to search for SS related to metastatic and differentially expressed immune-related genes (DEIRGs) in the GSE40021 dataset from the GEO database. The soft tissue sarcoma database in TCGA was used for univariate Cox regression analyses to identify DEIRGs that were related to overall survival and to build an immune-related prognostic assessment model.ResultsThe study screened a total of six DEIRGs that were closely related to prognosis in metastatic SS. Further analysis showed that there was no significant difference in the expression of several immune checkpoints between the two groups in the GSE40021 data. Moreover, the GREM2 and CTSS genes were significantly expressed in metastatic patients. Further verification of clinical SS tissues from our centre by RT-qPCR analysis demonstrated reduced infiltration of activated NK cells and macrophages but increased M2-type macrophages in metastatic patients. Together, our study successfully constructed an immune-related prognostic assessment model and probably explains the poor efficacy of PD-1 inhibitors for SS patients.ConclusionThe research deepens our understanding of the tumor immune microenvironment and proposes a new immune mechanism for metastatic SS. Early intervention and reversal of immunosuppressive microenvironmental changes are expected to delay metastasis and improve survival.

Myeloid cells are known to play a crucial role in creating a tumor-promoting and immune suppressive microenvironment. Our previous study demonstrated that primary human monocytes can be polarized into immunosuppressive myeloid-derived suppressor cells (MDSCs) by cancer-associated fibroblasts (CAFs) in a 3D co-culture system. However, the molecular mechanisms underlying the immunosuppressive function of MDSCs, especially CAF-induced MDSCs, remain poorly understood. Using mass spectrometry-based proteomics, we compared cell surface protein changes among monocytes, in vitro differentiated CAF-induced MDSCs, M1/M2 macrophages, and dendritic cells, and identified an extracellular vesicle (EV)-mediated secretory phenotype of MDSCs. Functional assays using an MDSC/T-cell co-culture system revealed that blocking EV generation in CAF-induced MDSCs reversed their ability to suppress T-cell proliferation, while EVs isolated from CAF-induced MDSCs directly inhibited T-cell function. Furthermore, we identified fructose bisphosphatase 1 (FBP1) as a cargo protein that is highly enriched in EVs isolated from CAF-induced MDSCs, and pharmacological inhibition of FBP1 partially reversed the suppressive phenotype of MDSCs. Our findings provide valuable insights into the cell surface proteome of different monocyte-derived myeloid subsets and uncover a novel mechanism underlying the interplay between CAFs and myeloid cells in shaping a tumor-permissive microenvironment.

Bacterial wilt triggered by the soil-borne pathogenic bacterium Ralstonia solanacearum is one of the most serious diseases in tomato plants, leading to huge economic losses worldwide. Biological control is considered an environmentally friendly and sustainable way to manage soil-borne diseases. In this study, Streptomyces sp. STD57 isolated from the rhizosphere of Adenophora stricta showed strong antibacterial activity against R. solanacearum. Pot experiments showed that strain STD57 exhibited a significant biocontrol effect (81.7%) on tomato bacterial wilt in the greenhouse environment. Furthermore, strain STD57 could inhibit the growth of weeds (Amaranthus retroflexus, Portulaca oleracea, and Echinochloa crusgalli) but promote the growth of crops (wheat, rice, and tomato). The plant growth-promoting substance was identified as indoleacetic acid (IAA) by high-pressure liquid chromatography–mass spectrometry and genome analysis. Coarse separation of the fermented extracts revealed that the antibacterial and herbicidal substances were mainly in the fermentation supernatant and belonged to different products. These findings suggested that strain STD57 may be a potential biocontrol and bioherbicide agent useful in agriculture.

Abstract Background The outcomes of patients with tumors of the thoracolumbar spine treated with en bloc resection (EBR) using three-dimensional (3D)-printed endoprostheses are underreported. Methods We retrospectively evaluated patients with thoracolumbar tumors who underwent surgery at our institution. Logistic regression analysis was performed to identify the potential risk factors for surgical complications. Nomograms to predict complications were constructed and validated. Results A total of 53 patients with spinal tumors underwent EBR at our hospital; of these, 2 were lost to follow-up, 45 underwent total en bloc spondylectomy, and 6 were treated with sagittal en bloc spondylectomy. The anterior reconstruction materials included a customized 3D-printed artificial vertebral body (AVB) in 10 cases and an off-the-shelf 3D-printed AVB in 41 cases, and prosthesis mismatch occurred in 2 patients reconstructed with the off-the-shelf 3D-printed AVB. The median follow-up period was 21 months (range, 7–57 months). Three patients experienced local recurrence, and 5 patients died at the final follow-up. A total of 50 perioperative complications were encountered in 29 patients, including 25 major and 25 minor complications. Instrumentation failure occurred in 1 patient, and no prosthesis subsidence was observed. Using a combined surgical approach was a dependent predictor of overall complications, while Karnofsky performance status score, lumbar spine lesion, and intraoperative blood loss ≥ 2000 mL were predictors of major complications. Nomograms for the overall and major complications were constructed using these factors, with C-indices of 0.850 and 0.891, respectively. Conclusions EBR is essential for the management of thoracolumbar tumors; however, EBR has a steep learning curve and a high complication rate. A 3D-printed AVB is an effective and feasible reconstruction option for patients treated with EBR.

BackgroundRight ventricular systolic dysfunction (RVSD) in patients with sepsis is an area of growing interest, but its prognostic significance remains unclear and additional tools are needed to improve our understanding. Right ventricular free wall strain (RV-FWS) is a relatively new parameter to assess RV function. This study aimed to investigate the potential correlation between impaired RV-FWS and prognostic outcomes in patients with sepsis.MethodsWe prospectively assessed right ventricular function in patients with sepsis within the initial 24 h of their hospital admission. RV-FWS, right ventricular global strain (RV-GS), fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE) were examined. RVSD was defined as impaired RV-FWS. Moreover, the association between RVSD and 30-day mortality rate was assessed.ResultsThis study included 89 patients. Among them, 27 (30.3%) succumbed to their illness within 30 days. The nonsurviving patients demonstrated significantly lower absolute RV-FWS (−19.7% ± 2.4% vs. −21.1% ± 2.1%, P = 0.008) and RV-GS (−17.7% ± 1.2% vs. −18.4% ± 1.4%, P = 0.032) values than the surviving patients. However, TAPSE and FAC values were not significantly different between the two groups. The optimal cutoff values for RV-FWS, RV-GS, FAC, and TAPSE were −19.0%, −17.9%, 36.5%, and 1.55 cm, respectively. Kaplan–Meier survival curves revealed that patients with impaired RV-FWS and RV-GS demonstrated lower 30-day survival rates, and the predictive performance of RV-FWS (hazard ratio [HR]: 3.97, 95% confidence interval [CI]: 1.85–8.51, P

Summary: The premetastatic niche (PMN) contributes to lung-specific metastatic tropism in osteosarcoma. However, the crosstalk between primary tumor cells and lung stromal cells is not clearly defined. Here, we dissect the composition of immune cells in the lung PMN and identify granulocytic myeloid-derived suppressor cell (gMDSC) infiltration as positively associated with immunosuppressive PMN formation and tumor cell colonization. Osteosarcoma-cell-derived extracellular vesicles (EVs) activate lung interstitial macrophages to initiate the influx of gMDSCs via secretion of the chemokine CXCL2. Proteomic profiling of EVs reveals that EV-packaged S100A11 stimulates the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway in macrophages by interacting with USP9X. High level of S100A11 expression or circulating gMDSCs correlates with the presentation of lung metastasis and poor prognosis in osteosarcoma patients. In summary, we identify a key role of tumor-derived EVs in lung PMN formation, providing potential strategies for monitoring or preventing lung metastasis in osteosarcoma.

This paper presents an improved beluga whale optimization (IBWO) algorithm, which is mainly used to solve global optimization problems and engineering problems. This improvement is proposed to solve the imbalance between exploration and exploitation and to solve the problem of insufficient convergence accuracy and speed of beluga whale optimization (BWO). In IBWO, we use a new group action strategy (GAS), which replaces the exploration phase in BWO. It was inspired by the group hunting behavior of beluga whales in nature. The GAS keeps individual belugas whales together, allowing them to hide together from the threat posed by their natural enemy, the tiger shark. It also enables the exchange of location information between individual belugas whales to enhance the balance between local and global lookups. On this basis, the dynamic pinhole imaging strategy (DPIS) and quadratic interpolation strategy (QIS) are added to improve the global optimization ability and search rate of IBWO and maintain diversity. In a comparison experiment, the performance of the optimization algorithm (IBWO) was tested by using CEC2017 and CEC2020 benchmark functions of different dimensions. Performance was analyzed by observing experimental data, convergence curves, and box graphs, and the results were tested using the Wilcoxon rank sum test. The results show that IBWO has good optimization performance and robustness. Finally, the applicability of IBWO to practical engineering problems is verified by five engineering problems.

Abstract Photothermal therapy has shown great promise for cancer treatment and second near-infrared (NIR-II) -absorbing particles could further improve its precision and applicability due to its superior penetration depth and new imaging ability. Herein, high NIR-II-absorbing polymer particles were prepared by using soluble isobutyl-substituted diammonium borates (P-IDI). The P-IDI showed stronger absorption at 1000–1100 nm, which exhibited excellent photostability, strong photoacoustic imaging ability and high photothermal conversion efficiency (34.7%). The investigations in vitro and in vivo demonstrated that the excellent photothermal effect facilitated complete tumor ablation and also triggered immunogenic cell death in activation of the immune response. The high solubility and excellent photothermal conversion ability demonstrated that polymer IDI particles were promising theranostic agents for treatment of tumors with minor side effects.

The digital trade ecosystem’s development relies on the growth of cross-border e-commerce platforms. To ensure the continued growth of China’s digital trade, it is crucial to consider the service capabilities of digital platforms and the digital transformation capabilities of cross-border e-commerce firms. This study explores the impact of these factors on the performance of cross-border e-commerce companies, with digital transformation capability acting as a mediator. Empirical research reveals that the service capability of digital platforms is composed of supply chain communication and cost control abilities, which partially mediate the relationship between digital platform serviceability and cross-border e-commerce enterprise performance. Moreover, both the service capabilities of digital platforms and the digital transformation capabilities of cross-border e-commerce companies have a positive and significant impact on enterprise performance.

Based on the development status of the domestic and foreign data trading market and platform thinking perspective, the economic overview and prospect of data trading in China were analyzed.Combined with the platform economy and the characteristics of data trading platform market development, the transaction mode, platform types, data source method, and characteristics of data trading platform were discussed in depth respectively.In addition, a analysis of typical domestic government-led data trading platforms was conducted.The study of data trading platform models and characteristics presented reference starting points for the government in the policy formulation of data trading platform cultivation and development.Also, it put forward positive suggestions for cultivating the data trading platform market.

The question concerning how digital consumption demand has been adapted and how matching business models have been built has become an important practical problem in the digital development of the retail industry. Considering the effects of COVID-19, whether new retail enterprises can maintain adequate competitiveness and risk resilience in the post-pandemic era deserves in-depth study. In comparing the development of traditional retail and new retail enterprises, we extracted and evaluated key factors of enterprise operating efficiency. Then, we measured the transformation efficiency of 65 enterprises in China listed in 2016 and 2020 by establishing a DEA model and the Malmquist index method. Finally, based on an empirical analysis demonstrating the necessity of traditional retail transformation, we analyzed retail enterprises’ efficiency and dynamic efficiency changes. The results show that the operating efficiency of enterprises using the new retail model was higher than those using the traditional retail model. The technical efficiency and total factor productivity were significantly improved after the new retail model was applied. Both technological progress and improved technological efficiency contributed to the improvement in total factor productivity during the COVID-19 pandemic.

Abstract Background The current study set out to identify the miRNA-mRNA regulatory networks that influence the radiosensitivity in esophageal cancer based on the The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Methods Firstly, esophageal cancer-related miRNA-seq and mRNA-seq data were retrieved from the TCGA database, and the mRNA dataset of esophageal cancer radiotherapy was downloaded from the GEO database to analyze the differential expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) in radiosensitive and radioresistant samples, followed by the construction of the miRNA-mRNA regulatory network and Gene Ontology and KEGG enrichment analysis. Additionally, a prognostic risk model was constructed, and its accuracy was evaluated by means of receiver operating characteristic analysis. Results A total of 125 DEmiRNAs and 42 DEmRNAs were closely related to the radiosensitivity in patients with esophageal cancer. Based on 47 miRNA-mRNA interactions, including 21 miRNAs and 21 mRNAs, the miRNA-mRNA regulatory network was constructed. The prognostic risk model based on 2 miRNAs (miR-132-3p and miR-576-5p) and 4 mRNAs (CAND1, ZDHHC23, AHR, and MTMR4) could accurately predict the prognosis of esophageal cancer patients. Finally, it was verified that miR-132-3p/CAND1/ZDHHC23 and miR-576-5p/AHR could affect the radiosensitivity in esophageal cancer. Conclusion Our study demonstrated that miR-132-3p/CAND1/ZDHHC23 and miR-576-5p/AHR were critical molecular pathways related to the radiosensitivity of esophageal cancer.

Conventional X-ray-induced photodynamic therapy usually requires heavy-metal-containing inorganic scintillators and organic photosensitizers to generate singlet oxygen. Here, the authors develop an organic phosphorescent nanoscintillator for low-dose X-ray-induced photodynamic therapy of deep tumours.

Abstract Radiation therapy is one of the most commonly used methods in clinical cancer treatment, and radiosensitizers could achieve enhanced therapeutic efficacy by incorporating heavy elements into structures. However, the secondary excitation of these high-Z elements-doped nanosensitizers still imply intrinsic defects of low efficiency. Herein, we designed Bi-doped titanium dioxide nanosensitizers in which high-Z Bi ions with adjustable valence state (Bi3+ or Bi4+) replaced some positions of Ti4+ of anatase TiO2, increasing both X-rays absorption and oxygen vacancies. The as-prepared TiO2:Bi nanosensitizers indicated high ionizing radiation energy-transfer efficiency and photocatalytic activity, resulting in efficient electron–hole pair separation and reactive oxygen species production. After further modification with cancer cell targeting peptide, the obtained nanoplatform demonstrated good performance in U87MG cell uptakes and intracellular radicals-generation, severely damaging the vital subcellular organs of U87MG cells, such as mitochondrion, membrane lipid, and nuclei etc. These combined therapeutic actions mediated by the composition-tunable nanosensitizers significantly inhibited the U87MG tumor growth, providing a refreshing strategy for X-ray induced dynamic therapy of malignant tumors.

Abstract Background Different from Fe ions in Fenton reaction, Mn ions can function both as catalyst for chemodynamic therapy and immune adjuvant for antitumor immune responses. In Mn-mediated Fenton-like reaction, bicarbonate ( $${\text{HCO}}_{3}^{ - }$$ HCO 3 - ), as the most important component to amplify therapeutic effects, must be present, however, intracellular $${\text{HCO}}_{3}^{ - }$$ HCO 3 - is strictly limited because of the tight control by live cells. Results Herein, Stimuli-responsive manganese carbonate-indocyanine green complexes (MnCO3-ICG) were designed for intracellular marriage of bicarbonate and Mn ions as “immune ion reactors” to regulate intracellular redox homeostasis and antitumor immune responses. Under the tumor acidic environment, the biodegradable complex can release “ion reactors” of Mn2+ and $${\text{HCO}}_{3}^{ - }$$ HCO 3 - , and ICG in the cytoplasm. The suddenly increased $${\text{HCO}}_{3}^{ - }$$ HCO 3 - in situ inside the cells regulate intracellular pH, and accelerate the generation of hydroxyl radicals for the oxidative stress damage of tumors cells because $${\text{HCO}}_{3}^{ - }$$ HCO 3 - play a critical role to catalyze Mn-mediated Fenton-like reaction. Investigations in vitro and in vivo prove that the both CDT and phototherapy combined with Mn2+-enhanced immunotherapy effectively suppress tumor growth and realize complete tumor elimination. Conclusions The combination therapy strategy with the help of novel immune adjuvants would produce an enhanced immune response, and be used for the treatment of deep tumors in situ.

Improving the imaging of cancer may enhance the treatment of patients, Here, the authors develop a Mn(II) based nanoparticle contrast agent for MRI imaging and show that the nanoparticles can cross the brain barrier and image glioma cells.

Abstract Background Minimally invasive separation surgery (MISS) is a safe and effective surgical technique, the current optimal treatment for spinal metastases. However, the learning curve for this technique has not been analyzed. This study aimed to define and analyze the surgical learning curve of MISS for the treatment of spinal metastases with small incision and freehand pedicle screw fixation. Methods A continuous series of 62 patients with spinal metastases who underwent MISS were included. Each patient's operative data were accurately counted. The improvement of the patients' neurological function was followed up after surgery to evaluate the surgical treatment effect. Logarithmic curve-fit regression was used to analyze the surgical learning curve of MISS. The number of cases needed to achieve proficiency was analyzed. Based on this cut-off point, this series of cases was divided into the early phase and later phase groups. The influence of the time sequence of MISS on surgical data and surgical efficacy was analyzed. Results The operative time decreased gradually with the number of surgical cases increasing and stabilized after the 20th patient. There was no statistical difference in demographic characteristics and preoperative characteristics between the two groups. The mean operative time in the later phase group was about 39 min shorter than that in the early phase group (mean 227.95 vs. 189.02 min, P = 0.027). However, it did not affect other operative data or the surgical treatment effect. Conclusion The learning curve of MISS for spinal metastases is not steep. With the increase of surgeons' experience, the operative time drops rapidly and stabilizes within a certain range. MISS can be safely and effectively performed at the beginning of a surgeon's caree.

This paper proposed a photodetector with a dual-injection structure. Input power is splitted into two beams by a 3 dB beam splitter at the incident end and then coupled into the photodetector, which can make the light field distribution in the germanium absorption layer more uniform. With the same active area structure, the responsivity of the dual-injection structure can be increased by 45.73% at 108.33 mW, the saturated optical power could be induced by 44.76%, and the bandwidth can be improved by 6.74 GHz at 20 mW comparing with the single-injection structure. The dual-injection structure improves the performance of the device without increasing the complexity.

The unnatural amino acid (UAA) incorporation technique through genetic code expansion has been extensively used in protein engineering for the last two decades. Mutations into UAAs offer more dimensions to tune protein structures and functions. However, the huge library of optional UAAs and various circumstances of mutation sites on different proteins urge rational UAA incorporations guided by artificial intelligence. Here we collected existing experimental proofs of UAA-incorporated proteins in literature and established a database of known UAA substitution sites. By program designing and machine learning on the database, we showed that UAA incorporations into proteins are predictable by the observed evolutional, steric and physiochemical factors. Based on the predicted probability of successful UAA substitutions, we tested the model performance using literature-reported and freshly-designed experimental proofs, and demonstrated its potential in screening UAA-incorporated proteins. This work expands structure-based computational biology and virtual screening to UAA-incorporated proteins, and offers a useful tool to automate the rational design of proteins with any UAA.

Background: Nasopharyngeal carcinoma (NPC) represents a highly aggressive malignant tumor. Competing endogenous RNAs (ceRNA) regulation is a common regulatory mechanism in tumors. The ceRNA network links the functions between mRNAs and ncRNAs, thus playing an important regulatory role in diseases. This study screened the potential key genes in NPC and predicted regulatory mechanisms using bioinformatics analysis.Methods: The merged microarray data of three NPC-related mRNA expression microarrays from the Gene Expression Omnibus (GEO) database and the expression data of tumor samples or normal samples from the nasopharynx and tonsil in The Cancer Genome Atlas (TCGA) database were both subjected to differential analysis and Weighted Gene Co-expression Network Analysis (WGCNA). The results from two different databases were intersected with WGCNA results to obtain potential regulatory genes in NPC, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. The hub-gene in candidate genes was discerned through Protein-Protein Interaction (PPI) analysis and its upstream regulatory mechanism was predicted by miRwalk and circbank databases.Results: Totally 68 upregulated genes and 96 downregulated genes in NPC were screened through GEO and TCGA. According to WGCNA, the NPC-related modules were screened from GEO and TCGA analysis results, and the genes in the modules were obtained. After the results of differential analysis and WGCNA were intersected, 74 differentially expressed candidate genes associated with NPC were discerned. Finally, fibronectin 1 (FN1) was identified as a hub-gene in NPC. Prediction of upstream regulatory mechanisms of FN1 suggested that FN1 may be regulated by ceRNA mechanisms involving multiple circRNAs, thereby influencing NPC progression through ceRNA regulation.Conclusion: FN1 is identified as a key regulator in NPC development and is likely to be regulated by numerous circRNA-mediated ceRNA mechanisms.

Ribonucleic acid (RNA) viruses pose heavy burdens on public-health systems. Synthetic biology holds great potential for artificially controlling their replication, a strategy that could be used to attenuate infectious viruses but is still in the exploratory stage. Herein, we used the genetic-code expansion technique to convert Enterovirus 71 (EV71), a prototypical RNA virus, into a controllable EV71 strain carrying the unnatural amino acid (UAA) Nε-2-azidoethyloxycarbonyl-L-lysine (NAEK), which we termed an EV71-NAEK virus. After NAEK supplementation, EV71-NAEK could recapitulate an authentic NAEK time- and dose-dependent infection in vitro, which could serve as a novel method to manipulate virulent viruses in conventional laboratories. We further validated the prophylactic effect of EV71-NAEK in two mouse models. In susceptible parent mice, vaccination with EV71-NAEK elicited a strong immune response and protected their neonatal offspring from lethal challenges similar to that of commercial vaccines. Meanwhile, in transgenic mice harboring a PylRS-tRNACUAPyl pair, substantial elements of genetic-code expansion technology, EV71-NAEK evoked an adjustable neutralizing-antibody response in a strictly external NAEK dose-dependent manner. These findings suggested that EV71-NAEK could be the basis of a feasible immunization program for populations with different levels of immunity. Moreover, we expanded the strategy to generate controllable coxsackieviruses for conceptual verification. In combination, these results could underlie a competent strategy for attenuating viruses and priming the immune system via artificial control, which might be a promising direction for the development of amenable vaccine candidates and be broadly applied to other RNA viruses.

Abstract Accurate diagnosis and effective treatment of primary liver tumors are of great significance, and optical imaging has been widely employed in clinical imaging-guided surgery for liver tumors. The second near-infrared window (NIR-II) emissive AIEgen photosensitizers have attracted a lot of attention with higher-resolution bioimaging and deeper penetration. NIR-II aggregation-induced emission-based luminogen (AIEgen) photosensitizers have better phototherapeutic effects and accuracy of the image-guided surgery/phototherapy. Herein, an NIR-II AIEgen phototheranostic dot was proposed for NIR-II imaging-guided resection surgery and phototherapy for orthotopic hepatic tumors. Compared with indocyanine green (ICG), the AIEgen dots showed bright and sharp NIR-II emission at 1250 nm, which extended to 1600 nm with high photostability. Moreover, the AIEgen dots efficiently generated reactive oxygen species (ROS) for photodynamic therapy. Investigations of orthotopic liver tumors in vitro and in vivo demonstrated that AIEgen dots could be employed both for imaging-guided tumor surgery of early-stage tumors and for ‘downstaging’ intention to reduce the size. Moreover, the therapeutic strategy induced complete inhibition of orthotopic tumors without recurrence and with few side effects. Graphical Abstract

Artificial intelligence (AI) based on the perspective of data elements is widely used in the healthcare informatics domain. Large amounts of clinical data from electronic medical records (EMRs), electronic health records (EHRs), and electroencephalography records (EEGs) have been generated and collected at an unprecedented speed and scale. For instance, the new generation of wearable technologies enables easy-collecting peoples’ daily health data such as blood pressure, blood glucose, and physiological data, as well as the application of EHRs documenting large amounts of patient data. The cost of acquiring and processing health big data is expected to reduce dramatically with the help of AI technologies and open-source big data platforms such as Hadoop and Spark. The application of AI technologies in health big data presents new opportunities to discover the relationship among living habits, sports, inheritances, diseases, symptoms, and drugs. Meanwhile, with the development of fast-growing AI technologies, many promising methodologies are proposed in the healthcare field recently. In this paper, we review and discuss the application of machine learning (ML) methods in health big data in two major aspects: (1) Special features of health big data including multimodal, incompletion, time validation, redundancy, and privacy. (2) ML methodologies in the healthcare field including classification, regression, clustering, and association. Furthermore, we review the recent progress and breakthroughs of automatic diagnosis in health big data and summarize the challenges, gaps, and opportunities to improve and advance automatic diagnosis in the health big data field.

The slime mold algorithm (SMA) and the arithmetic optimization algorithm (AOA) are two novel meta-heuristic optimization algorithms. Among them, the slime mold algorithm has a strong global search ability. Still, the oscillation effect in the later iteration stage is weak, making it difficult to find the optimal position in complex functions. The arithmetic optimization algorithm utilizes multiplication and division operators for position updates, which have strong randomness and good convergence ability. For the above, this paper integrates the two algorithms and adds a random central solution strategy, a mutation strategy, and a restart strategy. A hybrid slime mold and arithmetic optimization algorithm with random center learning and restart mutation (RCLSMAOA) is proposed. The improved algorithm retains the position update formula of the slime mold algorithm in the global exploration section. It replaces the convergence stage of the slime mold algorithm with the multiplication and division algorithm in the local exploitation stage. At the same time, the stochastic center learning strategy is adopted to improve the global search efficiency and the diversity of the algorithm population. In addition, the restart strategy and mutation strategy are also used to improve the convergence accuracy of the algorithm and enhance the later optimization ability. In comparison experiments, different kinds of test functions are used to test the specific performance of the improvement algorithm. We determine the final performance of the algorithm by analyzing experimental data and convergence images, using the Wilcoxon rank sum test and Friedman test. The experimental results show that the improvement algorithm, which combines the slime mold algorithm and arithmetic optimization algorithm, is effective. Finally, the specific performance of the improvement algorithm on practical engineering problems was evaluated.

Core-shelled nanoparticles NaYF4:Ln3+@NaYF4 with multicolor narrow-band persistent luminescence enable a new multidimensional optical information-storage technology.

Cervical cancer is the most important female genital cancer that develops from the cervix, a lower part of uterus. Houttuynia cordata is ubiquitously present in Asian countries, and traditionally prescribed to treat infections and oedema. Our study emphasizes on biological synthesis route for developing copper nanocomplex using Houttuynia cordata (Hc-CuONPs) plant extract. The UV–visible spectroscopy study of Hc-CuONPs revealed the maximum peak at 350 nm, which proved the formation of Hc-CuONPs and FT-IR absorption peaks revealed the existence of different functional groups. The results of high-resolution TEM and X-ray diffraction studies revealed that the Hc-CuONPs have face centred cubic structure along with 40–45 nm in size. The temperature conditions of the synthesized Hc-CuONPs were spherical and circular morphologies. Furthermore, the Hc-CuONPs (IC50=5 µg/ml) exhibited toxicity on cervical cancer cells (HeLa). The intracellular reactive oxygen species (ROS) level in the control and Hc-CuONPs-treated HeLa cells was monitored by DCFH-DA staining and the apoptotic cell death was detected by using the dual (AO/EtBr) staining, propidium iodide and DAPI staining assays. Our results from the fluorescent staining analysis evidenced that the Hc-CuONPs have inhibited the cell proliferation and promoted the apoptotic cell death in HeLa cells. The Hc-CuONPs promoted the apoptosis by targeting the PI3K/Akt signalling pathways in HeLa cells. Our results explored that the Hc-CuONPs are effective against in vitro HeLa cancer cells.

The application of STING agonists and the blockade of the SIRPα–CD47 signaling axis are emerging immunotherapeutic strategies. Here the authors show that hybrid cellular membrane nanovesicles loaded with a STING agonist or overexpressing high-affinity SIRPα variants can be exploited to promote anti-tumor immune responses.

Growing evidence indicates a link between retinoic acid (RA) metabolism and sarcoma progression or immunity in laboratory studies. However, a comprehensive analysis of RA abnormality in the sarcoma population is still lacking. Herein, we systematically analyzed the molecular features of 19 retinoic acid metabolism-related enzymes and sarcoma patients’ clinical information based on TCGA/TARGET/GSE datasets. We identified two RA expression subtypes, which were related to distinct clinical survival outcomes and exhibited different biological features. Gene set enrichment analysis indicated a set of immune pathways were enriched in G1 while oncogenic pathways were enriched in G2. Immune cell infiltration analysis using the TIMER algorithm revealed more CD4+ and CD8+ T cell infiltration in G1 subgroups than in G2. Moreover, we generated a seven genes signature to predict the RA metabolism index based on the LASSO-penalized Cox regression model. Survival analysis demonstrated the significant prognostic differences between high- and low-risk groups among different bone and soft tissue datasets. A higher risk index was associated with less T cell CD8+ infiltration. The predictive ability of the RA risk score was validated in 71 bone or soft tissue sarcoma clinical samples. These results indicated that RA-based classification could distinguish sarcoma patients with different clinical outcomes and immune statuses, which may help to explore better treatment decision-making for sarcoma patients.

Air passenger traffic prediction is crucial for the effective operation of civil aviation airports. Despite some progress in this field, the prediction accuracy and methods need further improvement. This paper proposes an integrated approach to the prediction of air passenger index as follows. Firstly, the air passenger index is defined and classified by the K-means clustering method. And then, based on mutual information (MI) principle, the information entropy is used to analyze and select the key influencing factors of air passenger travel. By incorporating the MI principle into the support vector regression (SVR) framework, this paper presents an innovative MI-SVR machine learning model used to predict the air passenger index. Finally, the proposed model is validated by air passenger throughput data of the Shanghai Pudong International Airport (PVG), China. The experimental results prove MI-SVR model feasibility and effectiveness by comparing them with conventional methods, such as ARIMA, LSTM, and other machine learning models. Besides, it is shown that the prediction effect of each model could be improved by introducing influencing factors based on MI. The main findings are considered instrumental to the airport operation and air traffic optimization.

We studied the relationship between the absorption layer length and the performance of Ge-on-Si microring resonator photodetectors. The principle of optimizing the absorption layer length based on the light field distribution was proposed. In the Ge-on-Si photodetectors, the transmission light field is alternately distributed among the germanium absorption layer and the silicon waveguide layer, and gradually absorbed by the germanium layer. For the Ge-on-Si microring resonator photodetectors, the length of the germanium absorption layer should be set to achieve the maximum light field distribution in the silicon layer at the end of the photodetector, then the remaining optical power can be coupled back to the silicon waveguide and transmit in the microring for absorption again. We demonstrated by simulation that, the device with optimized length of 11 μm has larger bandwidth, smaller dark current, and higher responsivity than the device with 14 μm absorption layer by simulation @1550nm.

Osteosarcoma (OSA) is the most common bone malignancy and displays high heterogeneity of molecular phenotypes. This study aimed to characterize the molecular features of OSA by developing a classification system based on the gene expression profile of the tumor microenvironment. Integrative analysis was performed using specimens and clinical information for OSA patients from the TARGET program. Using a matrix factorization method, we identified two molecular subtypes significantly associated with prognosis, S1 (infiltration type) and S2 (escape type). Both subtypes displayed unique features of functional significance features and cellular infiltration characteristics. We determined that immune and stromal infiltrates were abundant in subtype S1 compare to that in subtype S2. Furthermore, higher expression of immune checkpoint PDCD1LG2 and HAVCR2 was associated with improved prognosis, while a preferable chemotherapeutic response was associated with FAP-positive fibroblasts in subtype S1. Alternatively, subtype S2 is characterized by a lack of effective cytotoxic responses and loss of major histocompatibility complex class I molecule expression. A gene classifier was ultimately generated to enable OSA classification and the results were confirmed using the GSE21257 validation set. Correlations between the percentage of fibroblasts and/or fibrosis and CD8+ cells, and their clinical responses to chemotherapy were assessed and verified based on 47 OSA primary tumors. This study established a new OSA classification system for stratifying OSA patient risk, thereby further defining the genetic diversity of OSA and allowing for improved efficiency of personalized therapy.

BackgroundFew studies investigated the effectiveness of adjuvant chemotherapy (ACT) in patients with optimal response to neoadjuvant chemotherapy (NACT), and an optimal number of treatment cycles for these patients remains unknown.MethodsA total of 261 Chinese patients with FIGO stage IB2-IIB cervical cancer who obtained an optimal response to NACT were included after radical surgery, and the disease-free survival (DFS) and overall survival (OS) of these patients treated with different cycles of postoperative ACT were compared using the Log-rank test and multivariate analysis.ResultsWe found that the prognosis of optimal responders treated with postoperative ACT was significantly better than those without further adjuvant therapy. The multivariate analysis showed that postoperative ACT was an independent prognostic factor for DFS. However, there was no significant difference in the DFS and OS between patients who had three cycles of ACT and those with six cycles. Further analysis revealed a significant association of six cycles of ACT with the risk of leukopenia, nausea/vomiting, and rash.ConclusionOur data suggest that additional three cycles of ACT after surgery may improve the clinical outcome of optimal responders in terms of DFS, OS, and drug toxicity.

Background: Osteosarcoma (OSA), the most common primary bone malignancy in children and adolescents, is prone to metastases and unfavorable prognosis. Owing to its strong genomic heterogeneity, traditional chemotherapy, or targeted immunotherapy has not effectively improved the related overall survival for decades. Since the landscape of the OSA tumor immune microenvironment is scarcely known, despite it playing a crucial role in predicting clinical outcomes and therapeutic efficacies, we aimed to elucidate its molecular characteristics.Methods: The immune signature of 101 OSA samples was explored using transcriptome profiling and clinical characteristics retrieved from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program. Correlations between the prognostic immune markers and their clinical chemotherapy responses were assessed and verified based on 45 OSA primary tumors.Findings: We identified the heterogeneity underlying tumor immune signature in OSA, and found CD4+ T cells and macrophage markers CD4/IFNGR2/CD68 to be feasible prognostic factors, exerting significantly positive correlation with each other. Specifically, CSF1R, which plays an essential role in the regulation of proliferation and differentiation of macrophages, was found to be a specific signature associated with CD4/CD68, with improved OSA clinical outcomes.Interpretation: The immune landscape based on CD4/CD68/CSF1R gene signatures showed considerable promise for prognostic and therapeutic stratification in OSA patients. A specific immune signature for OSA, abundantly consisting of Th1-polarized CD4+ T cells and CSF1R-related CD68+ macrophages, may improve the predictive efficacy of chemotherapy and improve prognosis in patients with OSA.

BACKGROUND:In China, the disease burden of cervical cancer remains substantial. Human papillomavirus (HPV) vaccines are expensive and not yet centrally funded. To inform immunization policy, understanding the economic burden of the disease is necessary. This study adopted a societal perspective and investigated costs and quality of life changes associated with cervical cancer from diagnosis to one year after final discharge in Henan province, China. METHODS:Inpatient records of cervical cancer patients admitted to the largest cancer hospital in Henan province between Jan. 2017 and Dec. 2018 were extracted. A telephone interview with four modules was conducted in Jun.-Jul. 2019 with a 40% random draw of patients to obtain direct non-medical costs and indirect costs associated with inpatients, costs associated with outpatient visits, and changes in quality of life status using the EQ-5D-5L instrument. Direct medical expenditures were converted to opportunity costs of care using cost-to-charge ratios obtained from hospital financial reports. For each clinical stage (IA-IV), total costs per case from diagnosis to one year after final discharge were extrapolated based on inpatient records, responses to the telephone interview, and recommendation on outpatient follow-ups by Chinese cervical cancer treatment guidelines. Loss in quality-adjusted life years was obtained using the 'under the curve' method and regression predictions. RESULTS:A total of 3,506 inpatient records from 1,323 patients were obtained. Among 541 randomly selected patients, 309 completed at least one module of the telephone interview. The average total costs per case associated with cervical cancer from diagnosis to one year after final discharge ranged from $8,066-$22,888 (in 2018 US Dollar) and the quality-adjusted life years loss varied from 0.05-0.26 for IA-IV patients. CONCLUSIONS:The economic burden associated with cervical cancer is substantial in Henan province. Our study provided important baseline information for cost-effectiveness analysis of HPV immunization program in China.

In the ultimatum game (UG), mid-value offers are unfair but not so unreasonable as to be rejected immediately. As a consequence, they are difficult for responders to evaluate because of the conflict that arises between two key processes, namely inequity aversion and self-interests. Since there is no clear consensus in the literature on event-related potential (ERP) as to how mid-value offers are processed, we designed an experiment to explore how the ability to reject offers influences key ERP signatures. By manipulating the right to reject offers based on game type (ultimatum game, UG or dictator game, DG), our study explored how ERPs were influenced by three types of offers available to participants (fair, unfair and mid-value). We recorded the electroencephalogram results of 28 participants while they responded to the three kinds of offers in the UG and the DG. We observed that mid-value offers in the UG elicited more negative feedback-related negativity and N400 than did the unfair offers. However, these ERP patterns were specific to the UG. Furthermore, we interpreted these results as further electrophysiological evidence of the interaction between the two processing systems during the UG.

Context. Human papillomavirus (HPV) testing is widely used in cervical cancer screening in women; however, its efficiency in triaging women with atypical squamous cells of undetermined significance (ASC-US) needs to be validated. Objective. To evaluate the performance of HPV16/18 in the triage of women with ASC-US. Methods. Women presenting for routine cervical cancer screening had cervical specimens collected, with which both liquid-based cytology (LBC) and hrHPVs were examined; those with ASC-US cytology underwent colposcopy. HPV16/18 and 12 other types were tested with domestic hybridization capture and chemiluminescence signal amplification (DH3). Performance characteristics of HPV test (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for identification of cervical intraepithelium neoplasma (CIN) grade 2 or worse (CIN2+), and CIN grade 3 or worse (CIN3+)) were determined using standard statistical tests. Results. 317 women with ASC-US were eligible for the study. HrHPV prevalence was 15.77% (50/317); HPV16/18 prevalence was 3.61% (20/317). Sensitivity and specificity of HPV16/18 for detection of CIN 2+ were 64.71% and 97% and 64.29% and 96.37% for detection of CIN 3+, respectively. The positive predictive values (PPVs) and negative predictive values (NPVs) of HPV16/18 were 55.00% and 97.98% for CIN2+ and 45.00% and 98.32% for CIN3+, respectively. Conclusion. HPV16/18 can be considered as an effective method to triage women with ASC-US as its good clinical performance. Trial Registration. This trial is registered with Henan Cancer Hospital Medical Ethics Committee on July 5, 2016 (http://www.anti-cancer.com.cn), with registry no.: 2016037.

Introduction: Researchers have made efforts to distinguish the behavioral differences and underlying mechanisms that explain the various possible outcomes of dieting (success, failure and relapse). Although extensive research has demonstrated that eating behavior and individual impulsiveness are closely related to subjective appetite and decision making, very few studies have investigated how subjective and appetite impulsiveness is affected by reactive dieting.Methods: In the present study, we utilized the power of food scale (PFS) and the intertemporal choice task and to examine subjective appetite and impulsivity of decision making in orthodontic patients. As a result of their orthodontic devices and the subsequent pain and discomfort caused by eating, these patients become reactive dieters. In order to explore the dynamic influence of orthodontic treatment on appetite and impulsiveness, we collected data for both patients and control participants across three testing sections. We also computed a regression model for further exploration in explaining how potential factors contributed to different choices.Results: We found that the orthodontic group scored significantly lower in PFS than the control group, which indicated a suppression in appetite. Besides, reward and waiting time were significant factors in computational perspective. Moreover, although patients showed a bias in choosing smaller, immediate reward options, they exhibited a decrease in the delay discounting rate as treatment progressed. These findings confirm that subjective appetite and impulsiveness were inhibited due to reactive dieting.

MUC1 is associated with cellular transformation and tumorigenicity and is considered as an important tumor-associated antigen (TAA) for cancer therapy. We previously reported that anti-MUC1 monoclonal antibody C595 (MAb C595) plus docetaxel (DTX) increased efficacy of DTX alone and caused cultured human epithelial ovarian cancer (EOC) cells to undergo apoptosis. To further study the mechanisms of this combination-mediated apoptosis, we investigated the effectiveness of this combination therapy in vivo in an intraperitoneal (i.p.) EOC mouse model. OVCAR-3 cells were implanted intraperitoneally in female athymic nude mice and allowed to grow tumor and ascites. Mice were then treated with single MAb C595, DTX, combination test (MAb C595 and DTX), combination control (negative MAb IgG(3) and DTX) or vehicle control i.p. for 3 weeks. Treated mice were killed 4 weeks post-treatment. Ascites volume, tumor weight, CA125 levels from ascites and survival of animals were assessed. The expression of MUC1, CD31, Ki-67, TUNEL and apoptotic proteins in tumor xenografts was evaluated by immunohistochemistry. MAb C595 alone inhibited i.p. tumor growth and ascites production in a dose-dependent manner but did not obviously prevent tumor development. However, combination test significantly reduced ascites volume, tumor growth and metastases, CA125 levels in ascites and improved survival of treated mice compared with single agent-treated mice, combination control or vehicle control-treated mice (P