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Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.

Objective: To explore the mechanism of circular RNA (circRNA)-AnnexinA7 (ANXA7) in non-small cell lung cancer (NSCLC) cisplatin (DDP) resistance through microRNA (miR)-545-3p to target Cyclin D1 (CCND1). Methods: DDP-resistant and non-resistant NSCLC tissues and normal tissues were collected. DDP-resistant cells (A549/DDP and H460/DDP) were constructed. circ-ANXA7, miR-545-3p, CCND1, P-Glycoprotein, and glutathione S-transferase-π in tissues and cells were measured. Analysis of circ-ANXA7 ring structure was performed, as well as detection of circ-ANXA7 distribution in cells. Cell proliferation was detected by MTT and colony formation assay, apoptosis rate was detected by flow cytometry, and cell migration and invasion were evaluated by Transwell assay. The targeting relationship between circ-ANXA7, miR-545-3p and CCND1 was verified. Measurement of tumor volume and quality in mice was performed. Results: Circ-ANXA7 and CCND1 were elevated, while miR-545-3p was suppressed in DDP-resistant NSCLC tissues and cells. Circ-ANXA7 combined with miR-545-3p, which targeted CCND1 to expedite A549/DDP cell proliferation, migration, invasion, DDP resistance, but inhibited cell apoptosis. Conclusion: Circ-ANXA7 enhances DDP resistance in NSCLC via absorbing miR-545-3p to target CCND1 and might be a latent therapeutic target for NSCLC.

BackgroundIncreasing evidence indicates the importance of CD8+ T cells in autoimmune attack against CNS myelin and axon in multiple sclerosis (MS). Previous research has also discovered that myelin-reactive T cells have memory phenotype functions in MS patients. However, limited evidence is available regarding the role of CD8+ memory T cell subsets in MS. This study aimed to explore potential antigen-specific memory T cell-related biomarkers and their association with disease activity.MethodsThe myelin oligodendrocyte glycoprotein (MOG)-specific CD8+ memory T cell subsets and their related cytokines (perforin, granzyme B, interferon (IFN)-γ) and negative co-stimulatory molecules (programmed cell death protein 1 (PD-1), T- cell Ig and mucin domain 3 (Tim-3)) were analyzed by flow cytometry and real-time PCR in peripheral blood of patients with relapsing-remitting MS.ResultsWe found that MS patients had elevated frequency of MOG-specific CD8+ T cells, MOG-specific central memory T cells (TCM), MOG-specific CD8+ effector memory T cells (TEM), and MOG-specific CD8+ terminally differentiated cells (TEMRA); elevated granzyme B expression on MOG-specific CD8+ TCM; and, on MOG-specific CD8+ TEM, elevated granzyme B and reduced PD-1 expression. The Expanded Disability Status Scale score (EDSS) in MS patients was correlated with the frequency of MOG-specific CD8+ TCM, granzyme B expression in CD8+ TCM, and granzyme B and perforin expression on CD8+ TEM, but with reduced PD-1 expression on CD8+ TEM.ConclusionThe dysregulation of antigen-specific CD8+ memory T cell subsets, along with the abnormal expression of their related cytokines and negative co-stimulatory molecules, may reflect an excessive or persistent inflammatory response induced during early stages of the illness. Our findings strongly suggest positive regulatory roles for memory T cell populations in MS pathogenesis, probably via molecular mimicry to trigger or promote abnormal peripheral immune responses. Furthermore, downregulated PD-1 expression may stimulate a positive feedback effect, promoting MS-related inflammatory responses via the interaction of PD-1 ligands. Therefore, these parameters are potential serological biomarkers for predicting disease development in MS.

Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare genetic leukoencephalopathy caused by duplication of the lamin B1 gene (LMNB1) or LMNB1 upstream deletions. Neuronal intranuclear inclusion disease (NIID) is another leukoencephalopathy due to GGC repeat expansion in the 5'-untranslated region of the NOTCH2NLC gene. Here, we report two Chinese ADLD families with neuroimaging and clinical features mimicking NIID.We conducted detailed medical history inquiry, neurological examinations, and magnetic resonance imaging in the two families. Candidate gene sequencing and whole exome sequencing (WES) with copy number variation analysis were used to screen the genetic variations. The special points on the clinical and neuroimaging findings in the current families and differential diagnosis of ADLD with NIID are discussed.The two families presented with slowly progressive, multiple central nervous system symptoms, including spastic paraplegia, autonomic dysfunction, ataxia, deep sensory loss, and tremor. Clinical phenotypes were consistent within the family. Transient hypoglycemia and transient dilated pupils indicating autonomic dysfunctions were recorded for the first time in ADLD. Brain MRI showed band-like hyperintensities at the cortico-medullary junction on DWI, typical for NIID. Skin biopsy and genetic sequencing of the NOTCH2NCL gene did not support the diagnosis of NIID. Further whole exome sequencing (WES) identified the duplication mutation spanning the entire LMNB1 gene.The novel feature of transient hypoglycemia and dilated pupils broadens the spectrum of autonomic dysfunction in ADLD. Clinical manifestations and neuroimaging of ADLD can mimic NIID. Although ADLD is even rarer than NIID, the differential diagnosis of these two diseases should not be confused.

Insect wings are subject to strong selective pressure, resulting in the evolution of remarkably diverse wing morphologies that largely determine flight capacity. However, the genetic basis and regulatory mechanisms underlying wing size and shape development are not well understood. The silkworm Bombyx mori micropterous (mp) mutant exhibits shortened wing length and enlarged vein spacings, albeit without changes in total wing area. Thus, the mp mutant comprises a valuable genetic resource for studying wing development. In this study, we used molecular mapping to identify the gene responsible for the mp phenotype and designated it Bmmp. Phenotype-causing mutations were identified as indels and single nucleotide polymorphisms in noncoding regions. These mutations resulted in decreased Bmmp messenger RNA levels and changes in transcript isoform composition. Bmmp null mutants were generated by clustered regularly interspaced short palindromic repeats (CRISPR) / CRISPR-associated protein 9 and exhibited changed wing shape, similar to mp mutants, and significantly smaller total wing area. By examining the expression of genes critical to wing development in wildtype and Bmmp null mutants, we found that Bmmp exerts its function by coordinately modulating anterior-posterior and proximal-distal axes development. We also studied a Drosophila mp mutant and found that Bmmp is functionally conserved in Drosophila. The Drosophila mp mutant strain exhibits curly wings of reduced size and a complete loss of flight capacity. Our results increase our understanding of the mechanisms underpinning insect wing development and reveal potential targets for pest control.

Selecting and controlling the number of highest ranked features involved in the model training process, in such a way as to avoid underfitting and overfitting and allow an RMSE of 0.11 wt% in the model testing with a set of independent test samples.

Introduction Previous articles reported on the tip–apex distance, lag screw placement, fracture pattern, reduction quality, osteoporosis and other factors associated with second surgery. The current study focused on investigating the association of the matching degree between proximal femoral intramedullary nail and femoral medullary cavity on reoperation rate. Patients and methods A retrospective cohort study was conducted. It included patients with intertrochanteric fracture who were treated with proximal femoral anti-rotatory intramedullary nail (PFNA) between January 2016 and April 2021. The gap between the intramedullary nail and the femoral medullary cavity was equal to the difference in diameter between the two. According to the gap size, all patients were divided into three groups, as follows: high-matching group: gap ≤ 2 mm; middle-matching group: 2 Results A total of 203 eligible patients were recorded, including 78 males (38.4%) and 125 females (61.6%). They had a mean age of 77.8 ± 9.9 years old and an average follow-up time of 58.1 ± 24.0 weeks. Twenty-seven patients (13.3%) needed a second operation. Coxa varus combined with screw cutting was the most common reason for reoperation (11 cases). Unstable fracture pattern with poor reduction grade tended to contribute to reoperation, whose odds ratio (OR) was 6.61 (95% confidence interval [CI], 1.98–22.09; P = 0.002). The three groups had 11 cases (13.7%), 12 cases (13.8%) and 4 cases (11.1%) of reoperation, respectively, and logistic regression showed no significant association was noted between matching degree of intramedullary nail and reoperation rate. Conclusions The matching degree between proximal femoral intramedullary nail and femoral medullary cavity did not seem to be an important factor for reoperation, which offered more options of intramedullary nail size intraoperatively and reduced implants stock from inventory.

Due to the intrinsic inertness of alkanes, strong oxidative conditions are typically required to enable their C(sp3)−H functionalization. Herein, a paired electrocatalysis strategy was developed by integrating oxidative catalysis with reductive catalysis in one cell without interference, in which earth-abundant iron and nickel are employed as the anodic and cathodic catalysts, respectively. This approach lowers the previously high oxidation potential required for alkane activation, enabling electrochemical alkane functionalization at the ultra-low oxidation potential of ~0.25 V under mild conditions. Structurally diverse alkenes, including challenging all-carbon tetrasubstituted olefins, can be accessed via this electrochemical C(sp3)−H alkenylation using readily available alkenyl electrophiles.

With the ChemCam instrument, laser-induced breakdown spectroscopy (LIBS) has successively contributed to Mars exploration by determining the elemental compositions of soils, crusts, and rocks. The American Perseverance rover and the Chinese Zhurong rover respectively landed on Mars on February 18 and May 15, 2021, further increase the number of LIBS instruments on Mars. Such an unprecedented situation requires a reinforced research effort on the methods of LIBS spectral data analysis. Although the matrix effects correspond to a general issue in LIBS, they become accentuated in the case of rock analysis for Mars exploration, because of the large variation of rock compositions leading to the chemical matrix effect, and the difference in surface physical properties between laboratory standards (in pressed powder pellet, glass or ceramic) used to establish calibration models and natural rocks encountered on Mars, leading to the physical matrix effect. The chemical matrix effect has been tackled in the ChemCam project with large sets of laboratory standards offering a good representation of various compositions of Mars rocks. The present work more specifically deals with the physical matrix effect which is still lacking a satisfactory solution. The approach consists in introducing transfer learning in LIBS data treatment. For the specific application of total alkali-silica (TAS) classification of rocks (either with a polished surface or in the raw state), the results show a significant improvement in the ability to predict of pellet-based models when trained together with suitable information from rocks in a procedure of transfer learning. The correct TAS classification rate increases from 25% for polished rocks and 33.3% for raw rocks with a machine learning model, to 83.3% with a transfer learning model for both types of rock samples.

Since the outbreak of SARS-CoV-2/COVID-19 in Wuhan, China in 2019, it has rapidly spread to the world, and the number of infections has gradually increased. The hospitalization rate of patients has also gradually increased, which poses a huge challenge to hospitals and medical staff for patients with SARS-CoV-2 requiring surgical treatment. Therefore, avoiding cross-infection in the operating room is an important protective work. The operating room is an important department of the hospital, scientific and reasonable management is particularly important. Therefore, we have put forward corresponding suggestions and strategies for preoperative preparation and evaluation of patients, intraoperative management, postoperative terminal management, and protection of medical staff, and hope that these measures can better prevent and control the infection of SARS-CoV-2 in the operating room.

Background: Chemotherapy drugs commonly used for cancer therapy, but chemotherapy has limitation due to side effects. Current studies suggest natural products are reducing the side effects of chemotherapy medicines. In this study, we examined the side effects of doxorubicin (Dox) in esophageal cancer cells (CSCs) derived tumors in vivo. Methods: Esophageal cancer cells (YMI) were treated in vitro with daphnetin (DAP) along with DOX. The MTT assay was used for estimating the cell viability and Annexin/7-AAD was used for the determination of apoptosis. Cell cycle arrest was conducted using the PI-staining method. The potential effect of DAP was evaluated by the estimation of oxidative stress such as total antioxidant capacity (TAC), malondialdehyde (MDA) and superoxide dismutase (SOD) and body weight in the xenograft mice. Results: DAP can protect Dox cell toxicity by suppressing cell apoptosis of ESCC. DAP arrest the cells as S-phase. In vivo experimental study showed that Dox simultaneously with DAP decreases the tumor size along with increased body weight in the nude mice compared to Dox alone treated group mice. Dox along with the DAP exhibited less systemic toxicity and reduced oxidative stress fraction circulation. Conclusion: The result suggests that daphnetin may be used as an adjuvant therapy to reduce the systemic toxicity of chemotherapeutic agents, such as DOX, in stem cell treatment with ESCC cancer.

Our study elucidates the prognostic role of cluster of differentiation (CD) 24 expression in oral squamous cell carcinoma (OSCC) and determines whether targeting CD24 enhances the anti-tumor immune response by inhibiting tumor-associated macrophages (TAMs).The expression of CD24 and CD68 was analyzed immunohistochemically via tissue microarrays constructed using 56 cohorts of patients with OSCC and 20 control specimens. Further, CD24 was inhibited in an allograft squamous cell carcinoma (SCC) related mouse model with CD24mAb to determine the tumor volume and weight. Changes in immune cells such as TAMs and T cells in the tumor microenvironment (TME) were analyzed by Flow cytometry. The expression of CD4, CD8, and Ki67 was analyzed via immunohistochemistry. The inhibition of CD24 was confirmed by Western blot and immunohistochemistry.CD24 was overexpressed in OSCC. High expression of CD24 indicated poor survival in patients with OSCC (p = 0.0334). CD24 expression was significantly correlated with CD68 (p = 0.0424). The inhibition of CD24 delayed tumor growth in vivo. A decrease in TAMs number and an increase in T cell number were confirmed, while the ability of tumor proliferation was impaired.Targeting CD24 could enhance anti-tumor immune response by inhibiting TAMs.

Background: Nano drug delivery system (NDDS) can significantly improve the delivery and efficacy of drugs against pancreatic cancer (PC) in many ways. The purpose of this study is to explore the related research fields of NDDS for PC from the perspective of bibliometrics.Methods: Articles and reviews on NDDS for PC published between 2003 and 2022 were obtained from the Web of Science Core Collection. CiteSpace, VOSviewer, R-bibliometrix, and Microsoft Excel were comprehensively used for bibliometric and visual analysis.Results: A total of 1329 papers on NDDS for PC were included. The number of papers showed an upward trend over the past 20 years. The United States contributed the most papers, followed by China, and India. Also, the United States had the highest number of total citations and H-index. The institution with the most papers was Chinese Acad Sci, which was also the most important in international institutional cooperation. Professors Couvreur P and Kazuoka K made great achievements in this field. JOURNAL OF CONTROLLED RELEASE published the most papers and was cited the most. The topics related to the tumor microenvironment such as “tumor microenvironment”, “tumor penetration”, “hypoxia”, “exosome”, and “autophagy”, PC treatment-related topics such as “immunotherapy”, “combination therapy”, “alternating magnetic field/magnetic hyperthermia”, and “ultrasound”, and gene therapy dominated by “siRNA” and “miRNA” were the research hotspots in the field of NDDS for PC.Conclusion: This study systematically uncovered a holistic picture of the performance of NDDS for PC-related literature over the past 20 years. We provided scholars to understand key information in this field with the perspective of bibliometrics, which we believe may greatly facilitate future research in this field.

OBJECTIVE Neuropathic pain caused by traumatic neuromas is an extremely intractable clinical problem. Disorderly scar tissue accumulation and irregular and immature axon regeneration around the injury site mainly contribute to traumatic painful neuroma formation. Therefore, successfully preventing traumatic painful neuroma formation requires the effective inhibition of irregular axon regeneration and disorderly accumulation of scar tissue. Considering that chondroitin sulfate proteoglycans (CSPGs) can act on the growth cone and effectively inhibit axon regeneration, the authors designed and manufactured a CSPG-gelatin blocker to regulate the CSPGs’ spatial distribution artificially and applied it in a rat model after sciatic nerve neurectomy to evaluate its effects in preventing traumatic painful neuroma formation. METHODS Sixty female Sprague Dawley rats were randomly divided into three groups (positive group: no covering; blank group: covering with gelatin blocker; and CSPG group: covering with the CSPG-gelatin blocker). Pain-related factors were evaluated 2 and 8 weeks postoperatively (n = 30). Neuroma growth, autotomy behavior, and histological features of the neuromas were assessed 8 weeks postoperatively (n = 30). RESULTS Eight weeks postoperatively, typical bulb-shaped neuromas did not form in the CSPG group, and autotomy behavior was obviously better in the CSPG group (p < 0.01) than in the other two groups. Also, in the CSPG group the regenerated axons showed a lower density and more regular and improved myelination (p < 0.01). Additionally, the distribution and density of collagenous fibers and the expression of α–smooth muscle actin were significantly lower in the CSPG group than in the positive group (p < 0.01). Regarding pain-related factors, c-fos, substance P, interleukin (IL)–17, and IL-1β levels were significantly lower in the CSPG group than those in the positive and blank groups 2 weeks postoperatively (p < 0.05), while substance P and IL-17 remained lower in the CSPG group 8 weeks postoperatively (p < 0.05). CONCLUSIONS The authors found that CSPGs loaded in a gelatin blocker can prevent traumatic neuroma formation and effectively relieve pain symptoms after sciatic nerve neurotomy by blocking irregular axon regeneration and disorderly collagenous fiber accumulation in the proximal nerve stump. These results indicate that covering the proximal nerve stump with CSPGs may be a new and promising strategy to prevent traumatic painful neuroma formation in the clinical setting.

A simple and efficient visible-light-induced photoredox-catalyzed diarylation of N-methacryloyl-2-arylbenzoimidazoles with aryl diazonium salts was developed. The reaction provides a convenient access to a variety of benzimidazoisoquinolinones through the construction of two C C bonds in one step under mild reaction conditions.

We demonstrate in this work online in situ characterization of potash fertilizer, a powder material, at its final production stage in factory on the production conveyer belt for quality assessment, with a specifically developed laser-induced breakdown spectroscopy (LIBS) instrument and dedicated data treatment software based on machine learning. Besides the usual difficulties encountered in online LIBS analysis, the specific challenge resides in moisture variation in the product, which results in a complex sample of powder of particle size ∼100 μm mixed with water (H2O). The influence on the LIBS spectrum was clearly observed, while no detailed physical model is available to describe such an influence. In addition, the emission line intensity from hydrogen (Hα line) observed in the spectrum did not show a clear relationship to the H2O concentration. The approach of analysis by correlation of the whole spectrum to the concentration was used to first determine the H2O concentration, which was further used as an additional parameter to concatenate with a LIBS spectrum in the formation of a generalized spectrum. The last was used as the input vector to train a potassium chloride (KCl) concentration calibration model. More specifically, LIBS spectra were first transformed into 2-D images with continuous wavelet transform (CWT). A convolutional neural network (CNN) then allowed mapping of the spectrum-images to the H2O concentrations of the corresponding samples, while a back-propagation neural network (BPNN) mapped generalized spectra to the KCl concentrations of the samples. The tests with online LIBS spectra and the corresponding offline analysis data of 119 samples taken during the period of LIBS measurements demonstrate advanced analytical performances of the trained models for H2O and KCl. Comparison between the model-predicted concentrations and the data from the offline analysis shows determination biases which fulfil the requirements of the concerned national standards (bias ≦0.20% for H2O and ≦0.598% for KCl) for the quasi totality of the tested samples.

This work was designed to observe and further correct the physical matrix effect in the analysis of solid materials with laser-induced breakdown spectroscopy (LIBS), an effect that arises when a calibration model established with a set of certified reference materials (CRMs) with a smooth surface is used for prediction with LIBS spectra acquired from materials with an irregular surface, such as scraps produced by an automobile shredder for example. CRMs of an aluminum alloy were prepared in such way that one half of the surface of each sample was mechanically destroyed to present an asperity similar to a scrap. LIBS measurements were then performed in the two halves of the sample surface in the same conditions. The spectra acquired from the smooth part of the sample surface served as a training data set to train calibration models, while those taken from the irregular part of the surface were used as a validation data set to assess the prediction performance of the calibration models. Four elements (magnesium, silicon, iron, and zinc), which are important for the recycling of aluminum alloy scraps, were analyzed. The study started with univariate models, where the influence of the surface asperity was clearly observed. A first correction with internal standard normalization showed limited effectiveness. Further improvements were attempted using a machine learning-based multivariate regression, where the calibration performance of the models was significantly improved thanks to an optimized correction of the chemical matrix effect, whereas the prediction performance was still unsatisfactory due to the surface asperity alternation of the validation samples. A transfer learning-based regression model, where a part of the irregular samples joined the training data set, was thus developed to effectively correct both chemical and physical matrix effects and allowed significantly improved the performances of both calibrations, with a relative error of calibration (REC) at 2.3%, and prediction for irregular samples, with a relative error of prediction (REP) at 16.3% on average for the 4 tested elements.

To explore a new approach for fabricating the load bearing implants with the combination of bioactivity, biocompatibility, and mechanical properties, mechanically mixed hydroxyapatite (HA) and titanium (Ti) powders containing 30, 50, and 70 wt% Ti were sprayed onto a 316L stainless steel substrate using a warm spray (WS) process. The microstructures, phase compositions, chemical structures, and mechanical properties of WS HATi composite coatings were comprehensively investigated and compared to those of WS HA coating. Experimental results indicate that the cross-sectional microstructures of WS HATi composite coatings present typical lamellar structures composed of curved stripes formed by well-deformed and oxidized Ti splats and limited deformed HA splats, and are significantly influenced by the Ti content in the original powders. Phase constitutions of the composite coatings mainly consist of HA, Ti, TiO2, and TiO. Chemical structures of HA in the composite coatings deposited using powders with Ti content less than 30% are similar to the structures in the original powder. The microhardness, elastic modulus, and bond strength of the coatings increased from 0.32 ± 0.15 GPa to 1.41 ± 0.31 GPa, from 1.37 ± 0.28 GPa to 23.28 ± 3.45 GPa, and from 17.3 ± 2.2 MPa to 34.8 ± 3.2 MPa, respectively. The abrasive wear weight loss of the coatings on Al2O3 abrasive paper decreased from 2.9 mg to 1 mg, as the addition of Ti particles in original powders increased from 0 to 70%.