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Abstract Background Relapsed head and neck squamous cell carcinoma (HNSCC) unrelated to HPV infection carries a poor prognosis. Novel approaches are needed to improve the clinical outcome and prolong survival in this patient population which has poor long-term responses to immune checkpoint blockade. This study evaluated the chemokine receptors CXCR1 and CXCR2 as potential novel targets for the treatment of HPV-negative HNSCC. Methods Expression of IL-8, CXCR1, and CXCR2 was investigated in HNSCC tissues and human cell line models. Inhibition of CXCR1/2 with the clinical stage, small molecule inhibitor, SX-682, was evaluated in vitro and in vivo using human xenografts and murine models of HNSCC, both as a monotherapy and in combination with the taxane chemotherapy, docetaxel. Results High levels of IL-8, CXCR1, and CXCR2 expression were observed in HPV-negative compared to HPV-positive HNSCC tumors or cell lines. Treatment of HPV-negative HNSCC cell lines in vitro with SX-682 sensitized the tumor cells to the cytotoxic activity of docetaxel. In vivo, treatment of HNSCC xenograft models with the combination of SX-682 plus docetaxel led to strong anti-tumor control resulting in tumor cures. This phenomenon was associated with an increase of microRNA-200c and a decreased expression of its target, tubulin beta-3, a protein involved in resistance to microtubule-targeting chemotherapies. In vivo treatment of a murine syngeneic model of HNSCC with SX-682 plus docetaxel led to potent anti-tumor efficacy through a simultaneous decrease in suppressive CXCR2+ polymorphonuclear, myeloid-derived suppressor cells and an increase in cytotoxic CD8+ T cells in the combination therapy treated tumors compared to controls. Conclusions This study reports, for the first time, mechanistic findings through which the combination of CXCR1/2 inhibition and docetaxel chemotherapy exhibits synergy in models of HPV-negative HNSCC. These findings provide rationale for the use of this novel combination approach to treat HPV-negative HNSCC patients and for future combination studies of CXCR1/2 inhibition, docetaxel, and immune-based therapies.

Objectives To evaluate the minimal clinically important difference (MCID) value for acupuncture treatment in chronic spontaneous urticaria (CSU), providing guidance for its application in CSU management.Design Secondary analysis of data from a multicentre randomised controlled trial.Setting Three tertiary hospitals across three cities in China.Participants 103 CSU patients (78.7% female) with an average age of 39.97 years.Interventions Participants received acupuncture treatment for 4 weeks in the original study.Outcome measures MCID and minimal detectable change (MDC) for the Urticaria Activity Score over 7 days (UAS7) in acupuncture treatment of CSU. Convergent validity assessed by intraclass correlation coefficient (ICC). Responsiveness evaluated through Spearman correlation between UAS7 improvements and anchor tools (physician’s and patient’s assessments). MDC calculated using SE of measurement of changes in UAS7 scores. MCID estimated using distribution-based and anchor-based methods.Results The ICC for UAS7 was 0.86. Improvements in UAS7 scores were significantly correlated with patient (r=0.44, p

Abstract Background Ethyl acetate extracts from Tetrastigma hemsleyanum (Sanyeqing) (EFT), a member of the Vitaceae plant family, have been shown to exhibit efficacy against a variety of cancers. In this light, our current study seeks to examine the mechanism of efficacy between EFT extracts and human pancreatic cancer PANC-1 cells. Methods The chemical components of EFT were analyzed by gas chromatography–mass spectrometry. The cytotoxicity of EFT on PANC-1 cells was measured using an MTT assay. In order to investigate EFT induction of cell cycle arrest, changes in cell-cycle distribution were monitored by flow cytometry. Wound healing and transwell assays were employed to investigate whether migration and invasion of PANC-1 cells were inhibited by EFT. Relative protein expression was detected using Western blot. Results GC-MS analysis of the chemical composition of EFT revealed that the majority of constituents were organic acids and their corresponding esters. EFT exhibits measurable cytotoxicity and inhibition of PANC-1 invasion. Growth inhibition was primarily attributed to downregulation of CDK2 which induces cell cycle arrest in the S-phase. Inhibition of metastasis is achieved through downregulation of mesenchymal-associated genes/activators, including ZEB1, N-cadherin, Vimentin, and Fibronectin. Meanwhile, the expression of E-cadherin was significantly increased by EFT treatment. Furthermore, downregulation of MMP-2 and MMP-9 were observed. Conclusion Treatment of PANC-1 with EFT demonstrated measurable cytotoxic effects. Furthermore, EFT evoked S phase arrest while inhibiting the migration and invasion of PANC-1 cells. Additionally, EFT inhibited the epithelial to mesenchymal transition and MMPs expression in PANC-1 cells. This study serves to confirm the strong therapeutic potential of EFT while identifying the mechanisms of action.

ObjectivesTo develop and validate various ultrasomics models based on endoscopic ultrasonography (EUS) for retrospective differentiating pancreatic neuroendocrine tumors (PNET) from pancreatic cancer.MethodsA total of 231 patients, comprising 127 with pancreatic cancer and 104 with PNET, were retrospectively enrolled. These patients were randomly divided into either a training or test cohort at a ratio of 7:3. Ultrasomics features were extracted from conventional EUS images, focusing on delineating the region of interest (ROI) for pancreatic lesions. Subsequently, dimensionality reduction of the ultrasomics features was performed by applying the Mann-Whitney test and least absolute shrinkage and selection operator (LASSO) algorithm. Eight machine learning algorithms, namely logistic regression (LR), light gradient boosting machine (LightGBM), multilayer perceptron (MLP), random forest (RF), extra trees, k nearest neighbors (KNN), support vector machine (SVM), and extreme gradient boosting (XGBoost), were employed to train prediction models using nonzero coefficient features. The optimal ultrasomics model was determined using a ROC curve and utilized for subsequent analysis. Clinical-ultrasonic features were assessed using both univariate and multivariate logistic regression. An ultrasomics nomogram model, integrating both ultrasomics and clinical-ultrasonic features, was developed.ResultsA total of 107 EUS-based ultrasomics features were extracted, and 6 features with nonzero coefficients were ultimately retained. Among the eight ultrasomics models based on machine learning algorithms, the RF model exhibited superior performance with an AUC= 0.999 (95% CI 0.9977 - 1.0000) in the training cohort and an AUC= 0.649 (95% CI 0.5215 - 0.7760) in the test cohort. A clinical-ultrasonic model was established and evaluated, yielding an AUC of 0.999 (95% CI 0.9961 - 1.0000) in the training cohort and 0.847 (95% CI 0.7543 - 0.9391) in the test cohort. Subsequently, the ultrasomics nomogram demonstrated a significant improvement in prediction accuracy in the test cohort, as evidenced by an AUC of 0.884 (95% CI 0.8047 - 0.9635) and confirmed by the Delong test. The calibration curve and decision curve analysis (DCA) depicted this ultrasomics nomogram demonstrated superior accuracy. They also yielded the highest net benefit for clinical decision-making compared to alternative models.ConclusionsA novel ultrasomics nomogram was proposed and validated, that integrated clinical-ultrasonic and ultrasomics features obtained through EUS, aiming to accurately and efficiently identify pancreatic cancer and PNET.

Oilseed rape (Brassica napus) is a crucial global oil crop. It is generally cultivated in rotation with rice in southern China’s Yangtze River Basin, where the wet soil and residue retention after rice harvest significantly hinder its seedling establishment. Hence, this study developed a strip-tillage seeder for oilseed rape seeding following rice harvest. Additionally, seedling establishment, soil infiltration and evaporation post-seeding, soil moisture change, oilseed yield, and weed occurrence under strip tillage (ST) were compared with conventional shallow rotary-tillage (SR) and deep rotary-tillage (DR) seeding practices. Compared to SR and DR, the results demonstrated that ST had a higher seeding efficiency and 53.8% and 80.2% lower energy consumption, respectively. ST also enhanced seedling growth and oilseed yield formation more effectively than the competitor tillage treatments, with an oilseed yield increase exceeding 6%. Additionally, ST improved water infiltration and reduced soil water evaporation, resulting in higher topsoil (0–20 cm) moisture during the critical growth stages. Furthermore, ST reduced soil disturbance, significantly decreasing the density of the dominant weed, Polypogon fugax. Overall, ST seeding technology has the potential to improve the productivity of oilseed rape in rice–oilseed rape rotation systems, and its yield superiority is mainly due to seedling establishment improvement and soil moisture adjustment.

Background: The stability, efficacy, and safety of omalizumab at different doses and regimens for chronic spontaneous urticaria (CSU) are yet to be studied. Objective: A systematic review (SR) with meta-analysis (MA) and trial sequential analysis (TSA) was performed to assess the efficacy and safety of omalizumab in CSU. Methods: Randomised controlled trials (RCTs) of administering omalizumab versus placebo for CSU were searched. Random-effects MAs were performed using planned subgroup analyses. TSA was performed to control for the risk of random errors and assess the stability of our MA results. Publication bias was visually assessed using a contour-enhanced funnel plot and the trim-and-fill method. The quality of RCTs was assessed using the Cochrane Risk of Bias Tool 2. Results: Twelve studies met the inclusion criteria. Omalizumab had remarkable effects on the patient percentage of the weekly urticaria activity score is zero (UAS = 0) [RR 4.64, 95% CI (3.38, 6.37)], percentage of no angioedema-burdened days [MD 3.15, 95% CI (0.10, 6.19], patient percentage of UAS ≤6 [RR 3.05, 95% CI (2.46, 3.78)], and patient percentage of the weekly itch severity score minimally important difference (ISS7 MID) [RR 1.50, 95% CI (1.36, 1.66)]. Omalizumab was well tolerated across studies [RR 0.98, 95% CI (0.90, 1.08)]. TSA confirmed the above results, except for “the percentage of no angioedema-burdened day”. Conclusion: Among the different doses and courses assessed, omalizumab (300 mg, 12 weeks) can be recommended as an effective treatment for patients with CSU. However, whether omalizumab improves angioedema requires further investigation. The clinical management of angioedema accompanying CSU requires further attention.

Abstract Background Atopic dermatitis (AD) is a common skin disease that is hard to completely cure in a short time. Guidelines recommend the use of topical corticosteroids (TCS) as first‐line anti‐inflammatory therapy for AD, but long‐term use has significant side effects. Microecological agents (MA), including probiotics, prebiotics and synbiotics, have been widely reported as a potential adjunctive therapy of AD, but whether MA can contribute to AD treatment is currently controversial. Therefore, we conducted a systematic review and meta‐analysis to investigate whether MA as an add‐on therapy for AD has synergistic and attenuated effects and to further understand the role of MA in clinical interventions for AD. Methods We systematically searched Medline, Embase, Web of Science, Cochrane Library and PsycINFO databases up to Apr 11, 2023, and bibliographies were also manually searched, for potentially relevant studies regarding MA as additional therapy of AD. The Cochrane Risk of Bias Tool for assessing risk of bias was used to assess the quality of randomized controlled trials (RCTs). Two reviewers screened studies, extracted data, and evaluated the risk of bias independently. The primary outcomes (SCORAD scores and the number of adverse events) and the secondary outcomes (pruritus scores, the quality of life and the frequency of TCS) were extracted from each article. The data were combined and analyzed to quantify the safety and efficacy of the treatment. R (V4.4.3) software was used for data synthesis. The certainty of the evidence was evaluated with the Grade of Recommendation, Assessment, Development and Evaluation (GRADE) system. We also performed a trial sequential analysis to assess the reliability of the evidence. Results A total of 21 studies, including 1230 individuals, were identified, 20 of which met the eligibility criteria for the meta‐analysis. Our pooled meta‐analyses showed that compared with controls, oral MA as an add‐on therapy was associated with significantly lower SCORAD scores (MD = −5.30, 95% CI −8.50, −1.55, p 0.05). Conclusions This meta‐analysis showed that MA plus TCS could be an effective and safe treatment for patients with AD to relieve relevant symptoms, which might be used as an add‐on therapy in the treatment of AD. However, due to the limited number of studies, results should be interpreted with caution. Further studies with a larger sample size are needed to explore the optimal protocol of MA plus TCS.

Abstract Background Polycystic ovary syndrome (PCOS) is a complex reproductive disorder, that affects approximately 5–10% of women of reproductive age. The disease is complex because its evolution may be impacted by genetic, lifestyle and environmental factors. Previous studies have emphasized the important roles of estrogen receptors in the pathogenesis of PCOS. Objective To use whole exome sequencing (WES) to assess possible pathogenic factors in a PCOS patient who exhibited estrogen insensitivity during hormone replacement therapy (HRT) treatment. Methods Genome sequencing and variant filtering via WES were performed in a patient with PCOS. DNA extraction from 364 unrelated female controls without PCOS was followed by PCR amplification, Sanger sequencing and sequence alignment. Evolutionary conservation analysis, protein structural modelling and in silico prediction were applied to analyse the potential pathogenicity of the novel ESR1 mutation. Result(s) During the controlled ovarian hyperstimulation (COH) period of an IVF cycle, the patient experienced markedly prolonged ovarian stimulation due to a poor response to gonadotropins (Gn) and elevated serum FSH. A novel heterozygous ESR1 mutation, c.619G > A/p.A207T, leading to the replacement of a highly conserved alanine with a threonine, was identified in this patient, via WES analysis. This novel variant was not identified in 364 unrelated female controls without PCOS, or in the Exome Aggregation Consortium (ExAC) or 1000 Genome Project. Conclusion(s) We identified a novel heterozygous ESR1 mutation in a Han Chinese PCOS woman exhibiting clinical signs of estrogen insensitivity. This study may provide new strategies for IVF therapy, especially for patients who exhibit estrogen insensitivity during IVF cycle.

Background Enzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer.Methods Models of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity.Results Resistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells.Conclusion NK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.

BackgroundAtherosclerosis (AS) is one of the leading causes of the cardio-cerebral vascular incident. The constantly emerging evidence indicates a close association between nonalcoholic fatty liver disease (NAFLD) and AS. However, the exact molecular mechanisms underlying the correlation between these two diseases remain unclear. This study proposed exploring the common signature genes, pathways, and immune cells among AS and NAFLD.MethodsThe common differentially expressed genes (co-DEGs) with a consistent trend were identified via bioinformatic analyses of the Gene Expression Omnibus (GEO) datasets GSE28829 and GSE49541, respectively. Further, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. We utilized machine learning algorithms of lasso and random forest (RF) to identify the common signature genes. Then the diagnostic nomogram models and receiver operator characteristic curve (ROC) analyses were constructed and validated with external verification datasets. The gene interaction network was established via the GeneMANIA database. Additionally, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis were performed to explore the co-regulated pathways and immune cells.ResultsA total of 11 co-DEGs were identified. GO and KEGG analyses revealed that co-DEGs were mainly enriched in lipid catabolic process, calcium ion transport, and regulation of cytokine. Moreover, three common signature genes (PLCXD3, CCL19, and PKD2) were defined. Based on these genes, we constructed the efficiently predictable diagnostic models for advanced AS and NAFLD with the nomograms, evaluated with the ROC curves (AUC = 0.995 for advanced AS, 95% CI 0.971–1.0; AUC = 0.973 for advanced NAFLD, 95% CI 0.938–0.998). In addition, the AUC of the verification datasets had a similar trend. The NOD-like receptors (NLRs) signaling pathway might be the most crucial co-regulated pathway, and activated CD4 T cells and central memory CD4 T cells were significantly excessive infiltration in advanced NAFLD and AS.ConclusionWe identified three common signature genes (PLCXD3, CCL19, and PKD2), co-regulated pathways, and shared immune features of NAFLD and AS, which might provide novel insights into the molecular mechanism of NAFLD complicated with AS.

Short-chain fatty acids (SCFAs) are metabolites of gut microbes that can modulate the host inflammatory response, and contribute to health and homeostasis. Since the introduction of the gut-skin axis concept, the link between SCFAs and inflammatory skin diseases has attracted considerable attention. In this review, we have summarized the literature on the role of SCFAs in skin inflammation, and the correlation between SCFAs and inflammatory skin diseases, especially atopic dermatitis, urticaria, and psoriasis. Studies show that SCFAs are signaling factors in the gut-skin axis and can alleviate skin inflammation. The information presented in this review provides new insights into the molecular mechanisms driving gut-skin axis regulation, along with possible pathways that can be targeted for the treatment and prevention of inflammatory skin diseases.

Abstract Objectives Our study aimed to explore the clinical therapeutic effects of ultrasound-guided five-point injection of botulinum toxin type A for patients with trapezius hypertrophy. Methods Twenty female patients diagnosed with trapezius hypertrophy were enrolled in this study. The thicknesses of the trapezius muscle were measured by using the ultrasound scanner to locate the thickest point of trapezius, followed by labelling the other four points around the first point. Botulinum toxin type A was injected bilaterally (50 IU/side, 5 points/side) in the trapezius muscle of these patients. The surgery effects were evaluated by thicknesses of the trapezius muscle, intramuscular needle electromyographic and electroneurographic examinations, appearance changes and patients’ satisfactions. Results Statistically significant differences in thicknesses of the trapezius muscle were observed at 4 weeks (p

The prognostic value of the sequential organ failure assessment (SOFA) score for critically ill elderly patients with acute infective endocarditis (IE) remains unknown. From January 2015 to December 2019, 111 elderly (≥65 years) patients with acute IE were consecutively included and divided into a low SOFA (

Many landslides are triggered by excess precipitation. In the eastern part of China, landslides caused by extreme rainfall from typhoons in the monsoon season are the main geomorphological process with catastrophic impacts on society and the environment. In this study, Wenzhou City in eastern China was taken as the study area, and we compiled a detailed inventory of rainfall-triggered landslides between 1999 and 2016. The developmental characteristics of these landslides were determined with an emphasis on temporo-spatial distribution. The results showed that most of the landslides were located in the mountainous area of the western part of Wenzhou City. Landslides triggered by typhoon rainfall were commonly concentrated in a short period from July to September, when more than 70% of the landslides occurred. The landslides in this region were mainly of the debris-flow type, most of which were on a small scale, but had severe effects because of large elevation differences and long runout distances. Because the precipitation in typhoon events was commonly extreme, the initiation area of most landslides coincided with the region of highest hourly precipitation. Our results can provide reference data and guidelines for developing an early warning system for landslides and risk reduction in the study area.

ObjectivesTo provide us with some evidence to develop more targeted stroke intervention strategies, improve the health awareness of stroke among children, and advocate the health promotion campaign of “small hands holding big hands” among parents and children, we have conducted a health education program on stroke among primary school students in Dali.MethodsThis study has applied stratified random cluster sampling in Dali of Yunnan, China. We compared the improvement of students' knowledge of stroke before and after our health education program in primary school students of Dali in October 2020. Data were collected through 3 rounds of survey by using the same questionnaire.ResultsThere were 215 participants aged 7–8 years old sampled in the first phase of the study and 145 participants in the follow-up study. The knowledge of stroke among the participants was relatively low in the pre-intervention survey. After the health education, all the indicators on stroke knowledge were improved. The correct rates in stroke definition, sequelae, and “1-2-0” identification were increased from 0 to 66.05%, to 53.95% and 64.19%, respectively, in both pre-intervention and post-intervention surveys. The correct rate of stroke knowledge was about 4.83–92.41% 3 months after the intervention. The mean score of the questionnaire was 4.25 ± 0.19 in the pre-intervention survey, and that was 15.85 ±0.27 in the post-intervention one. The mean score was 14.02 ± 0.28 post-3-month test. The score in the 3-month survey after the intervention was 11.55% lower than that in the post-intervention score.ConclusionsThe effect of stroke-related knowledge in the health education program for children is improved significantly and this can last for 3 months but it also had attenuation. We should repeat pertinent health education among students.

Up-conversion photoluminescence in colloidal quantum dots is generally believed to be mediated by thermal activation from defect states. Here, the authors reveal that highly-efficient up-conversion photoluminescence instead is related to electron-phonon coupling.

In order to reduce the great harm of infectious diarrhoeal disease caused by Norovirus infection to human health,based on the transmission characteristics of Norovirus,the transmission dynamics behavior of Norovirus was studied.Taking into account the characteristics that the latent infected with Norovirus can also transmit the disease,a dynamic model of Norovirus transmission with nonlinear incidence was established.The basic reproduction number R0of the model was calculated and then the stability of the disease-free equilibrium point and the endemic equilibrium point were proved by using the Lyapunov function and the geometric method.The results show that when R0≤1,the disease-free equilibrium point is globally asymptotically stable and the disease disappears; when R0>1,under certain conditions,the endemic equilibrium point is global asymptotically stable.The theoretical results are verified by numerical simulation.The research results have enriched the theory of infectious virus transmission and provide a reference for the study of virus transmission mechanism.

Abstract Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer’s disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, Aβ-associated astrosomes from 5xFAD mice and AD patient serum were specifically transported to mitochondria, induced mitochondrial clustering, and upregulated the fission protein Drp-1 at a concentration corresponding to 5 femtomoles Aβ/L of medium. Aβ-associated astrosomes, but not wild type or control human serum exosomes, mediated binding of Aβ to voltage-dependent anion channel 1 (VDAC1) and subsequently, activated caspases. Aβ-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances Aβ neurotoxicity in AD and may comprise a novel target for therapy.

Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β activation signatures and collagen-rich environments have both been associated with T cell exclusion and lack of responses to immunotherapy. Here, we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8+ T cells, and repolarized suppressive macrophage populations, resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.

Abstract Background Surgical stress induces the release of neuroendocrine mediators and cytokines during perioperative period, which may have adverse effects on cancer patients. While the surgical stress responsse can be affected by anesthetic technique. Therefore, we designed this study to assess whether subcostal transversus abdominis plane (TAP) block can affect perioperative neuroendocrine stress response, postoperative analgesia and postoperative recovery in patients undergoing radical gastrectomy under general anesthesia. Methods Sixty-five patients were recruited. Patients randomly received general anesthesia (control group), or general anesthesia combined with TAP block (40 mL of 0.375% ropivacaine) (TAP group). The primary outcome was neuroendocrine levels including norepinephrine (NE), epinephrine (E), cortisol (Cor), glucose (Glu), interleukin (IL)-6 and IL-10 during 48 h after surgery. Secondary outcomes included pain score, hemodynamic variables and recovery characteristics. Results Data from 61 of 65 patients were analyzed. The levels of NE, E, Cor, and Glu were blunt by TAP block during perioperative period. The levels of IL-6 and IL-10 were significantly lower in TAP group than in control group. TAP block efficiently relieved postoperative acute pain up to 12 h postoperatively with more stable perioperative hemodynamics compared with control group. Conclusions Subcostal TAP block blunts perioperative stress response and provides efficient analgesia, with good hemodynamic stability and minimal adverse effects.

Abstract Background Clinically, for stem cell-based therapy (SCBT), autologous stem cells are considered better than allogenic stem cells because of little immune rejection and no risk of communicable disease infection. However, severe maxillofacial bone defects restoration needs sufficient autologous stem cells, and this remains a challenge worldwide. Human gingival mesenchymal stem cells (hGMSCs) derived from clinically discarded, easily obtainable, and self-healing autologous gingival tissues, have higher proliferation rate compared with autologous bone marrow mesenchymal stem cells (hBMSCs). But for clinical bone regeneration purpose, GMSCs have inferior osteogenic differentiation capability. In this study, a TGF-β signaling inhibitor SB431542 was used to enhance GMSCs osteogenesis in vitro and to repair minipig severe maxillofacial bone defects. Methods hGMSCs were isolated and cultured from clinically discarded gingival tissues. The effects of SB431542 on proliferation, apoptosis, and osteogenic differentiation of hGMSCs were analyzed in vitro, and then, SB431542-treated hGMSCs composited with Bio-Oss® were transplanted into immunocompromised mice subcutaneously to explore osteogenic differentiation in vivo. After that, SB431542-treated autologous pig GMSCs (pGMSCs) composited with Bio-Oss® were transplanted into circular confined defects (5 mm × 12 mm) in minipigs maxillary to investigate severe bone defect regeneration. Minipigs were sacrificed at 2 months and nude mice at 8 weeks to retrieve specimens for histological or micro-CT or CBCT analysis. Effects of SB431542 on TGF-β and BMP signaling in hGMSCs were investigated by Western Blot or qRT-PCR. Results One micromolar of SB431542 treatment induced a robust osteogenesis of hGMSCs in vitro, without adverse effect on apoptosis and growth. In vivo, 1 μM SB431542 treatment also enabled striking osteogenesis of hGMSCs subcutaneously in nude mice and advanced new bone formation of pGMSCs in minipig maxillary bone defect model. In addition, SB431542-treated hGMSCs markedly increased bone-related proteins expression, and BMP2 and BMP4 gene expression. Conversely, SMAD3 protein-dependent TGF-β signal pathway phosphorylation was decreased. Conclusions Our study show that osteogenic differentiation of GMSCs treated with TGF-β signaling inhibitor SB431542 was increased, and SB431542-treated autologous pig GMSCs could successfully repair minipig severe maxillofacial bone defects. This preclinical study brings about a promising large bone regeneration therapeutic potential of autologous GMSCs induced by SB431542 in clinic settings.

Abstract Genetic testing for germline mutations in BRCA1/2 of patients with breast cancer (BC) is part of routine patient care. However, BRCA1/2 mutations account only for a fraction of familial BC. A custom panel of 22 gene sequencing was performed on each patient. Among the 481 female patients, 135 patients were detected to carry pathogenic (P)/likely pathogenic (LP) mutations (28.1%), which corresponded to 12 different cancer predisposition genes [14.6% (70/481) on BRCA1 gene, 5.0% (24/481) on BRCA2 gene, 8.5% (41/481) on non‐BRCA1/2 genes]. Moreover, 24.7% (119/481) of patients had mutation of unknown significance (VUS) in these genes. The most common (8/481) pathogenic mutation is BRCA1 c.5470_5477del, while BRIP1 2392 C > T of patients was detected. All the mutations detected were mainly seen in the homologous recombinant repair pathway. Compared to BRCA2 mutation, BRCA1 mutation is higher in younger female patients (P

Designing core/shell quantum dots with desired optoelectronic properties remains a challenge. Here, the authors investigate the negative and positive trions dynamics within a quantum dot, proposing an Auger engineering strategy based on geometry-dependent dielectrics for tuning optical properties.

The mechanisms of brucellosis transmission are diverse and complex, especially the role of young animals in the spread of brucellosis has not been well studied. In this article, a new deterministic system that incorporates various stages of susceptible individuals and time delay of infection is proposed. Under general biological assumptions, the qualitative properties and stability of the system are studied, the results illustrate that the global dynamics of equilibrium points depend on the basic reproduction number $R_0$: If $R_0\leq 1$, animal brucellosis will eventually die out; and if $R_0> 1$, animal brucellosis is persistent and eventually tends to the endemic steady state. These results suggest that distributed time delay is harmless for the dynamics of the spread of brucellosis when $R_0$ is greater than one or less than or equal to one. Finally, periodic phenomena are found by numerical analysis if the assumptions are not true.

Background: Currently, there is no validated multivariate model to predict probability of coronary artery spasm (CAS) in patients with acute chest pain. Methods: A total of 976 consecutive patients with acute chest pain were enrolled. Patients were divided into two groups based on the presence of significant CAS. To adjust potential confounders, a multivariable analysis was performed and a clinical diagnostic score system for CAS was utilized for score derivation. Results: Multivariable analysis model selected 6 predictors for CAS. The integer score was assigned to each predictors: angina at rest alone (10 points), positive of hyperventilation test (8 points), allergies (3 points), asthma, ST-segment elevation and myocardial bridge (2 points each). We showed that the clinical diagnostic score system had accuracy in predicting CAS, as measured by the area under the curve (AUC), which was 0.952–0.966. The cut-off baseline value for the clinical diagnostic score system was set to 11–12 points with specificity of 91.0–93.3% and sensitivity of 90.7–92.9%, respectively. Conclusion: A clinical diagnostic score system was derived and validated as an accurate tool for estimating the pretest probability of CAS in patients with acute chest pain. Keywords: Acute chest pain, Coronary artery spasm, Clinical diagnostic score system

A large number of bubbles generated by the air agitation device in an external melting ice storage system can cause the disturbance of the ice–water mixture, which can enhance the heat transfer and contribute to the reduction in energy consumption. The structural design and optimization of the air agitation device in an external melting ice storage system is the key issue for energy savings. In this study, the influence of different orifice spacings and diameters on the distribution of the gas–liquid flow field, gas holdup, heat-transfer coefficient, and power consumption in the ice storage tank was investigated by numerical simulation. The simulated results showed that the heat-transfer coefficient of the ice–water mixture with air bubbles should be 3–5 times higher than the natural convection when the air superficial velocity is 0.03 m/s. The gas holdup was mainly affected by the orifice spacing, and the maximum varied from 5.0% to 8.2%. When the orifice spacing was less than 150 mm, the gas holdup changed a little in the horizontal direction, and the uniformity became worse when the orifice spacing was larger than 180 mm. An orifice diameter larger than 3 mm can improve the heat transfer and cause less air-compressing energy consumption, which decreased by approximately 1.62%.

Purpose: Considerable evidence suggests that inflammation and malnutrition are common in patients with acute kidney injury (AKI) and correlated with mortality of various diseases. Despite this, few studies have reported the underlying predictive effects of inflammatory and nutritional markers in combination on the mortality of AKI patients. Herein, we aimed to explore the values of PCT and CRP as well as the ratios of PCT/Alb and CRP/Alb in the poor prognosis of patients with sepsis-induced AKI.Patients and Methods: A total of 171 patients with AKI, caused by abdominal infection-evoked sepsis, were retrospectively studied and divided into a survival group (107 cases) and a non-survival group (64 cases). Univariate analysis was used to compare the clinical data of the two groups. Multivariate logistic regression analysis was used to analyze the independent risk factors of poor prognosis in patients with sepsis-induced AKI. The ROC curve was used to evaluate the diagnostic value of PCT, CRP, PCT/Alb, and CRP/Alb in the poor prognosis of patients with sepsis-induced AKI.Results: Univariate analysis revealed that the values of PCT, CRP, CRP/Alb, and PCT/Alb were significantly different between AKI survival and non-survival groups, and further analysis found that PCT and PCT/Alb were independent risk factors for poor prognosis in patients with sepsis-induced AKI after adjusting with age and gender. Of note, the predictive accuracy (0.864 vs. 0.807), specificity (83.2 vs. 69.2), and sensitivity (79.7 vs. 76.6) of PCT/Alb were all higher than that of the simple PCT.Conclusions: The ratio of PCT to Alb is an independent risk factor possessing a robust and accurate risk assessment for the poor prognosis of patients with sepsis-induced AKI, and it offers the potential to improve the management of this type of disease and a lower resultant mortality.

This study aimed to evaluate the accuracy and prognostic value of the sequential organ failure assessment (SOFA) score combined with C-reactive protein (CRP) in patients with complicated infective endocarditis (IE). A total of 246 consecutive patients with complicated IE were included in the multicentric prospective observational study. These patients were divided into four groups depending on the SOFA score and CRP optimal cutoff values (≥5 points and ≥17.6 mg/L, respectively), which were determined using the receiver operating characteristic analysis: low SOFA and low CRP (n = 83), low SOFA and high CRP (n = 87), high SOFA and low CRP (n = 25), and high SOFA and high CRP (n = 51). The primary endpoint was in-hospital death, and the secondary endpoint was long-time mortality, defined as subsequent readmission and 3-years mortality in the follow-up period. High SOFA score and high CRP were associated with approximately 29.410% (15/51) of higher incidence of in-hospital death with an area under the curve of 0.872. Multivariate analyses showed that age [odds ratio (OR) = 2.242, 1.142–4.401], neurological failure (Glasgow Coma Scale ≤ 12) (OR = 2.513, 1.041–4.224), Staphylococcus aureus (OR = 2.151, 1.252–4.513), SOFA ≥ 5 (OR = 9.320, 3.621–16.847), and surgical treatment (OR = 0.121, 0.031–0.342) were clinical predictors for in-hospital death. On following up for 12–36 months, SOFA ≥ 5 (p = 0.000) showed higher mortality. A high SOFA score combined with increased CRP levels is associated with in-hospital mortality. Also, SOFA score, but not CRP, predicts long-term mortality in complicated IE.

Abstract: Microtubules are polymers composed of αβ-tubulin subunits that provide structure to cells and play a crucial role in in the development and function of neuronal processes and cilia, microtubule-driven extensions of the plasma membrane that have sensory (primary cilia) or motor (motile cilia) functions. To stabilize microtubules in neuronal processes and cilia, α tubulin is modified by the posttranslational addition of an acetyl group, or acetylation. We discovered that acetylated tubulin in microtubules interacts with the membrane sphingolipid, ceramide. However, the molecular mechanism and function of this interaction are not understood. Here, we show that in human induced pluripotent stem cell–derived neurons, ceramide stabilizes microtubules, which indicates a similar function in cilia. Using proximity ligation assays, we detected complex formation of ceramide with acetylated tubulin in Chlamydomonas reinhardtii flagella and cilia of human embryonic kidney (HEK293T) cells, primary cultured mouse astrocytes, and ependymal cells. Using incorporation of palmitic azide and click chemistry–mediated addition of fluorophores, we show that a portion of acetylated tubulin is S-palmitoylated. S-palmitoylated acetylated tubulin is colocalized with ceramide-rich platforms in the ciliary membrane, and it is coimmunoprecipitated with Arl13b, a GTPase that mediates transport of proteins into cilia. Inhibition of S-palmitoylation with 2-bromo palmitic acid or inhibition of ceramide biosynthesis with fumonisin B1 reduces formation of the Arl13b-acetylated tubulin complex and its transport into cilia, concurrent with impairment of ciliogenesis. Together, these data show, for the first time, that ceramide-rich platforms mediate membrane anchoring and interaction of S-palmitoylated proteins that are critical for cilium formation, stabilization, and function.

Stomatal closure is one of the earliest responses to water stress but residual water losses may continue through the cuticle and incomplete stomatal closure. Residual conductance (gres) plays a large role in determining time to mortality but we currently do not understand how do drought and shade interact to alter gres because the underlying drivers are largely unknown. Furthermore, gres may play an important role in models of water use, but the exact form in which gres should be incorporated into modeling schemes is currently being discussed. Here we report the results of a study where two different oak species were experimentally subjected to highly contrasting levels of drought (resulting in 0, 50 and 80% losses of hydraulic conductivity) and radiation (photosynthetic photon flux density at 1,500 μmol m–2 s–1 or 35–45 μmol m–2 s–1). We observed that the effects of radiation and drought were interactive and species-specific and gres correlated positively with concentrations of leaf non-structural carbohydrates and negatively with leaf nitrogen. We observed that different forms of measuring gres, based on either nocturnal conductance under high atmospheric water demand or on the water mass loss of detached leaves, exerted only a small influence on a model of stomatal conductance and also on a coupled leaf gas exchange model. Our results indicate that, while understanding the drivers of gres and the effects of different stressors may be important to better understand mortality, small differences in gres across treatments and measurements exert only a minor impact on stomatal models in two closely related species.

We reported that amyloid β peptide (Aβ42) activated neutral SMase 2 (nSMase2), thereby increasing the concentration of the sphingolipid ceramide in astrocytes. Here, we show that Aβ42 induced mitochondrial fragmentation in wild-type astrocytes, but not in nSMase2-deficient cells or astrocytes treated with fumonisin B1 (FB1), an inhibitor of ceramide synthases. Unexpectedly, ceramide depletion was concurrent with rapid movements of mitochondria, indicating an unknown function of ceramide for mitochondria. Using immunocytochemistry and super-resolution microscopy, we detected ceramide-enriched and mitochondria-associated membranes (CEMAMs) that were codistributed with microtubules. Interaction of ceramide with tubulin was confirmed by cross-linking to N-[9-(3-pent-4-ynyl-3-H-diazirine-3-yl)-nonanoyl]-D-erythro-sphingosine (pacFACer), a bifunctional ceramide analog, and binding of tubulin to ceramide-linked agarose beads. Ceramide-associated tubulin (CAT) translocated from the perinuclear region to peripheral CEMAMs and mitochondria, which was prevented in nSMase2-deficient or FB1-treated astrocytes. Proximity ligation and coimmunoprecipitation assays showed that ceramide depletion reduced association of tubulin with voltage-dependent anion channel 1 (VDAC1), an interaction known to block mitochondrial ADP/ATP transport. Ceramide-depleted astrocytes contained higher levels of ATP, suggesting that ceramide-induced CAT formation leads to VDAC1 closure, thereby reducing mitochondrial ATP release, and potentially motility and resistance to Aβ42. Our data also indicate that inhibiting ceramide generation may protect mitochondria in Alzheimer's disease.

Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral SMase-2 (nSMase2), an enzyme generating ceramide from SM, as a potential repressor for hepatocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed a marked increase of SM in the tumor. Unexpectedly, tumor tissues presented with more than a 7-fold increase of C16-ceramide, concurrent with upregulation of ceramide synthase 5. The fro/fro liver tumor, but not adjacent tissue, exhibited substantial accumulation of lipid droplets, suggesting that nSMase2 deficiency is associated with tumor growth and increased neutral lipid generation in the tumor. Tumor tissue expressed significantly increased levels of CD133 and EpCAM mRNA, two markers of liver cancer stem-like cells (CSCs) and higher levels of phosphorylated signal transducer and activator of transcription 3, an essential regulator of stemness. CD133(+) cells showed strong labeling for SM and ceramide. In conclusion, these results suggest that SMase-2 deficiency plays a role in the survival or proliferation of CSCs, leading to spontaneous tumors, which is associated with tumor-specific effects on lipid homeostasis.

Abstract The further practical applications of halide perovskite quantum dots (QDs) are blocked by problems of instability and nonradiative Auger recombination manifested as photoluminescence blinking. Here, single core/shell structured perovskite semiconductor QDs are successfully fabricated by capping CsPbBr3 QD core with CdS shell. It is demonstrated that CsPbBr3/CdS core/shell QDs exhibit ultrahigh chemical stability and nonblinking photoluminescence with high quantum yield due to the reduced electronic traps within the core/shell structure. Efficiency of amplified spontaneous emission exhibits obvious enhancement compared to that of pure CsPbBr3 QDs, originating from the mitigated competition between stimulated emission and suppressed nonradiative biexciton Auger recombination. Furthermore, low‐threshold whispering‐gallery‐mode lasing with a high‐quality factor is achieved by incorporating CsPbBr3/CdS QDs into microtubule resonators. Density functional theory (DFT)‐based first‐principles calculations are also performed to reveal the atomic interface structure, which supports the existence of CsPbBr3/CdS structure. An interesting feature of spatially separated charge density at CsPbBr3/CdS interface is found, which may greatly contribute to the suppressed Auger recombination. The results provide a practical approach to improve the stability and suppress the blinking of halide perovskite QDs, which may pave the way for future applications for various optoelectronic devices.

Ceramide-rich platforms (CRPs) mediate association of proteins with the sphingolipid ceramide and may regulate protein interaction in membrane contact sites to the cytoskeleton, organelles, and infectious pathogens. However, visualization of ceramide association to proteins is one of the greatest challenges in understanding the cell biology of ceramide. Here we introduce a novel labeling technique for ceramide-associated proteins (CAPs) by combining photoactivated cross-linking of a bioorthogonal and bifunctional ceramide analog, pacFACer with proximity ligation assays (PLAs). pacFACer cross-linked to CAPs is covalently attached to a fluorophore using click chemistry. PLAs use antibodies to: (1) the candidate CAP and the fluorophore (PLA1); and (2) the CAP and ceramide (PLA2). PLA1 shows the subcellular localization of a particular CAP that is cross-linked to pacFACer, while PLA2 tests if the cross-linked CAP forms a complex with endogenous ceramide. Two proteins, tubulin and voltage-dependent anion channel 1 (VDAC1), were cross-linked to pacFACer and showed PLA signals for a complex with ceramide and pacFACer, which were predominantly colocalized with microtubules and mitochondria, respectively. Binding of tubulin and VDAC1 to ceramide was confirmed by coimmunoprecipitation assays using anti ceramide antibody. Cross-linking to pacFACer was confirmed using click chemistry-mediated attachment of biotin and streptavidin pull-down assays. Inhibition of ceramide synthases with fumonisin B1 (FB1) reduced the degree of pacFACer cross-linking and complex formation with ceramide, while it was enhanced by amyloid beta peptide (Aβ). Our results show that endogenous ceramide is critical for mediating cross-linking of CAPs to pacFACer and that a combination of cross-linking with PLAs (cross-link/PLA) is a novel tool to visualize CAPs and to understand the regulation of protein interaction with ceramide in CRPs.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.