Search

Abstract Background Trauma represents a significant global health challenge.The development of an effective scoring tool capable of predicting mortality risk in trauma cases is essential. This study aimed to investigate the combined effects of quick sequential organ failure assessment (qSOFA) and hypothermia (H) along with prothrombin time (PT) in predicting the prognosis of patients with severe trauma. Methods A retrospective cohort study was conducted to analyze data from severe trauma patients in the Trauma Database of the Trauma Center at the Second Affiliated Hospital of Soochow University between January 2017 and December 2021. Patients were categorized into survival and non-survival groups based on clinical outcomes. Baseline and clinical data were compared between the groups, and prognostic factors were explored using logistic regression analysis. Receiver operating characteristic (ROC) curves generated by 10-fold cross-validation using the caret in R programming language were used to assess the predictive efficacy of Injury Severity Score (ISS) and qSOFA + H + PT score for trauma patient mortality. Results A total of 509 severe trauma patients (377 males and 132 females) were included, with a median age of 53 years (range: 42–65 years). The mortality rate was found to be 23.4%. Logistic regression analysis revealed that age, ISS, and qSOFA + H + PT were significant predictors of death in severe trauma patients, with odds ratios of 1.035 (95%CI:1.014–1.057), 1.052 (95%CI:1.017–1.090), and 6.124 (95%CI:3.107–12.072), respectively (P

Abstract Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based “2 × 2” symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10–9 M for human PD1 and 2.557 × 10–8 M for human CD47, respectively, where the CD47 binding is significantly weaker as compared to the binding affinity of HX008 to PD1 as well as the binding affinity of SIRPα-Fc to CD47, leading to little binding to RBCs and platelets and is contrasting to many CD47-agents in development. However, HX009 effectively and simultaneously binds to the PD1 and CD47 on PD1+CD47+ T-cells via cis-binding and elicits enhanced T cell activation compared to the parental HX008. HX009 caused little cytokine-release in human peripheral blood mononuclear cells. HX009 cross-species binds to cynomolgus monkey PD1/CD47 but not to rodents, making cynomolgus monkeys the choice of species to investigate the pharmacokinetics (PK) and toxicology of HX009. HX009’s anti-tumor activities were confirmed in several humanized preclinical mouse models by determining either its anti-PD1 (humanized hu-CD47-MC38 models) or anti-CD47 (HuT-102 lymphoma CDX and three PDX-AML models) functions, although limited available humanized models have hindered broadly demonstration of enhanced anti-tumor activities contributed from the dual targeting of the BsAb. The expanded DLBCL-PDX trial data suggested that both EBV-status and OX40 expression could potentially be two positive predictors for response to HX009. An intravenous (IV) infusion PK study in cynomolgus monkey revealed its largely vasculature distribution, terminal half-life (T1/2) of ~ 50 h, and dose-proportional exposure without accumulation. The anti-drug antibody (ADA) was observed in all monkeys as expected, affecting the PK parameters of repeated administration. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150 mg/kg, while the repeated-dose (once weekly for 4 weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15 mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009’s candidacy for its clinical development.

Background and objective Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC), which is featured by low incidence, high malignancy rate, robust aggressive behavior and inferior prognosis. To date, there is no standardized treatment. The aim of this study is to better understand and accumulate more clinical experience of the disease by summarizing the clinicopathological features, diagnosis methods, therapeutic regimen and prognostic factors of PSC. Methods A total of 39 patients with PSC who diagnosed and received treatment in Beijing Chest Hospital from December 2013 to December 2023 were retrospectively recruited, and information including demographic characteristics, clinicopathological features, tumor-node-metastasis (TNM) stage, diagnosis method and therapeutic regimen were carefully collected. Meanwhile, follow-up was conducted. Kaplan-Meier method was used to analyze the prognostic factors of the disease. Results The PSC patients in this study ranged in age from 45 to 76 years old, including 35 males and 4 females. There were no specific clinical manifestations of PSC at initial diagnosis. Among the 39 patients, 20 underwent surgical resection and 19 received palliative chemoradiation or symptomatic supportive treatment. The 1-year and 5-year survival rates were 61.90% and 35.20% respectively. Univariate analysis indicated that family history of carcinoma, primary tumor site, TNM stage, lymph node metastasis, distant metastasis, whether or not received surgical resection, surgical method, treatment regimens, tumor tissue programmed cell death ligand 1 (PD-L1) expression ≥1% and mesenchymal-epithelial transition factor (MET) pathway abnormalities were correlated with the overall survival (OS) of patients (P

To further improve the accuracy of sensorless control at medium and high speeds for permanent magnet synchronous motor (PMSM) and expand its applicability, this paper proposes a new scheme that uses a sliding mode observer and a frequency-locked loop (FLL) for control. The combination of the super-twisting algorithm (STA) and fractional calculus algorithm (FCA) is applied to the observer, which improves the convergence speed and accuracy. In response to the limitations of phase-locked loops (PLLs), a second-order generalized integral frequency-locked loop (SOGI-FLL) is introduced into the control system to be compounded to form a novel control system with compensation, which filters the signal while achieving accurate tracking of rotor position information. Finally, a series of experiments were conducted to compare the performance of the proposed control scheme with conventional control schemes. The superiority and feasibility of the sensorless control scheme were verified through experimental results on a permanent magnet synchronous motor platform.

Abstract Background To determine the predictive value of interstitial lung abnormalities (ILA) for epidermal growth factor receptor (EGFR) mutation status and assess the prognostic significance of EGFR and ILA in patients with non-small cell lung cancer (NSCLC). Methods We reviewed 797 consecutive patients with a histologically proven diagnosis of primary NSCLC from January 2013 to October 2018. Of these, 109 patients with NSCLC were found to have concomitant ILA. Multivariate logistic regression analysis was used to identify the significant clinical and computed tomography (CT) findings in predicting EGFR mutations. Cox proportional hazard models were used to identify significant prognostic factors. Results EGFR mutations were identified in 22 of 109 tumors (20.2%). Multivariate analysis showed that the models incorporating clinical, tumor CT and ILA CT features yielded areas under the receiver operating characteristic curve (AUC) values of 0.749, 0.838, and 0.849, respectively. When combining the three models, the independent predictive factors for EGFR mutations were non-fibrotic ILA, female sex, and small tumor size, with an AUC value of 0.920 (95% confidence interval[CI]: 0.861–0.978, p

Abstract With just four building blocks, low sequence information density, few functional groups, poor control over folding, and difficulties in forming compact folds, natural DNA and RNA have been disappointing platforms from which to evolve receptors, ligands, and catalysts. Accordingly, synthetic biology has created “artificially expanded genetic information systems” (AEGIS) to add nucleotides, functionality, and information density. With the expected improvements seen in AegisBodies and AegisZymes, the task for synthetic biologists shifts to developing for expanded DNA the same analytical tools available to natural DNA. Here we report one of these, an enzyme-assisted sequencing of expanded genetic alphabet (ESEGA) method to sequence six-letter AEGIS DNA. We show how ESEGA analyses this DNA at single base resolution, and applies it to optimized conditions for six-nucleotide PCR, assessing the fidelity of various DNA polymerases, and extending this to AEGIS components with functional groups. This supports the renewed exploitation of expanded DNA alphabets in biotechnology.

Abstract Background The vestibular aqueduct (VA) serves an essential role in homeostasis of the inner ear and pathogenesis of Ménière’s disease (MD). The bony VA can be clearly depicted by high-resolution computed tomography (HRCT), whereas the optimal sequences and parameters for magnetic resonance imaging (MRI) are not yet established. We investigated VA characteristics and potential factors influencing MRI-VA visibility in unilateral MD patients. Methods One hundred patients with unilateral MD underwent MRI with three-dimensional sampling perfection with application optimized contrasts using different flip angle evolutions (3D-SPACE) sequence and HRCT evaluation. The imaging variables included MRI-VA and CT-VA visibility, CT-VA morphology and CT-peri-VA pneumatization. Results The most frequent type of MRI-VA and CT-VA visualization was invisible VA and continuous VA, respectively. The MRI-VA visibility was significantly lower than CT-VA visibility. MRI-VA visibility had a weak positive correlation with ipsilateral CT-VA visualization. For the affected side, the MRI-VA visualization was negatively correlated with the incidence of obliterated-shaped CT-VA and positively with that of tubular-shaped CT-VA. MRI-VA visualization was not affected by CT-peri-VA pneumatization. Conclusion In patients with MD, the VA visualization on 3D-SPACE MRI is poorer than that observed on CT and may be affected by its osseous configuration. These findings may provide a basis for further characterization of VA demonstrated by MRI and its clinical significance.

Abstract CSF1R is a receptor tyrosine kinase responsible for the growth/survival/polarization of macrophages and overexpressed in some AML patients. We hypothesized that a novel multi-kinase inhibitor (TKi), narazaciclib (HX301/ON123300), with high potency against CSF1R (IC50 ~ 0.285 nM), would have anti-AML effects. We tested this by confirming HX301’s high potency against CSF1R (IC50 ~ 0.285 nM), as well as other kinases, e.g. FLT3 (IC50 of ~ 19.77 nM) and CDK6 (0.53 nM). An in vitro proliferation assay showed that narazaciclib has a high growth inhibitory effect in cell cultures where CSF1R or mutant FLT3-ITD variants that may be proliferation drivers, including primary macrophages (IC50 of 72.5 nM) and a subset of AML lines (IC50

Objective: In this work, the optimal preparation process parameters of selenium-curcumin nanoparticles (SeNPs@Cur) were explored and its protective effect on alcoholic liver injury was evaluated. Methods: On the basis of single factor experiment, with particle size as the index, curcumin dosage, molar ratio of VC to Na2SeO3, reaction time and reaction temperature were selected as influence factors. The process parameters of SeNPs@Cur were optimized by response surface methodology, and its structure was characterized by scanning electron microscope (SEM), fourier transform infrared spectrometer (FT-IR) and energy dispersive spectrometer (EDS). The protective effect of SeNPs@Cur on ethanol-induced LO2 cell injury was investigated by MTT method. Results: The optimal conditions of SeNPs@Cur were list as follows: Curcumin dosage of 5.92 mg/mL, molar ratio of VC to Na2SeO3 of 10.39:1, the reaction time of 1.98 h, and the reaction temperature of 34.00 ℃. Under these conditions, the SeNPs@Cur with a minimum size of (100.79±3.46) nm was obtained. The loading rate of curcumin and the selenium content in the sample were 12.80%±0.80% and 23.32%±0.07%, respectively. Further structural identification showed that the prepared SeNPs@Cur was dispersed spherical nanoparticles. Moreover, compared with the model group, after treatments with different dosages of SeNPs@Cur, the cell viabilities increased from 58.06%±0.43% to 71.43%±1.39%, 77.33%±3.54%, and 85.41%±4.61%, respectively, indicating that SeNPs@Cur had a protective effect on LO2 cells damaged by ethanol in a concentration-dependent manner. Conclusion: The SeNPs@Cur with anti-alcoholic liver injury effect was successfully obtained, which provided new technical means and theoretical reference data for formulation improvement and application of curcumin.

Objective: We aimed to investigate the association between the angular trajectory of the vestibular aqueduct (ATVA) with other radiological parameters of temporal bone and clinical characteristics in patients with Ménière’s disease (MD). Methods: A total of 125 unilateral MD patients and 118 controls were enrolled. Computer tomography (CT)-based radiological parameters included ATVA, vestibular aqueduct (VA) visibility, VA morphology, the vertical part of the posterior semicircular canal—the posterior fossa distance (PPD), and peri-VA pneumatization. The clinical characteristics of MD patients included gender, age of diagnosis/onset, disease duration, migraine history, clinical staging, and the results of audio-vestibular tests. The radiological parameters and clinical characteristics in MD patients were compared. Results: Compared with control ears, ATVA ≥ 140° was more prevalent and ATVA ≤ 120° was less frequent in the MD-affected side. For the MD-affected side, MD patients with ATVA ≥ 140° exhibited more severe VA invisibility and obliteration and higher male preponderance than those with ATVA ≤ 120°. Other radio-clinical features did not differ between these two subgroups. Conclusion: In the current study, ATVA ≥ 140°, an indicator of a hypoplastic endolymphatic sac, was found in approximately one-third of the affected and unaffected ears of patients with MD, as well as in a minority of controls. This suggests that the indices may be a predisposing factor rather than a specific marker for the MD ear. The male preponderance in MD patients with hypoplastic ES suggests a gender difference in the anatomical factors for MD pathogenesis.

AimCoronary artery lesion (CAL) is a common yet serious complication in children with Kawasaki disease. The aim of the present study was to evaluate the influencing factors of CAL in children with Kawasaki disease, to provide reference for the clinical treatment and care of children with Kawasaki disease.DesignA retrospective cohort study.MethodsChildren with Kawasaki disease treated in a tertiary hospital in China between 1 January 2021 and 31 December 2022 were selected. The characteristics and clinical data of children with Kawasaki disease were analyzed. Spearman’s correlation analysis was conducted to evaluate the relationship between CAL and the characteristics of children with Kawasaki disease. A logistic regression analysis was used to analyze the influencing factors of CAL in children with Kawasaki disease.ResultsIn total, 185 children with Kawasaki disease were included; the incidence of CAL in children with Kawasaki disease was 18.38%. Pearson’s correlation analysis showed that gender (r = 0.504), age (r = 0.611), duration of fever ≥10 days (r = 0.579), hemoglobin (Hb) (r = 0.623), and C-reactive protein (CRP) (r = 0.558) were all correlated with the CAL in children with Kawasaki disease (all p

Abstract Both PD1/PD-L1 and CD47 blockades have demonstrated limited activity in most subtypes of NHL save NK/T-cell lymphoma. The hemotoxicity with anti-CD47 agents in the clinic has been speculated to account for their limitations. Herein we describe a first-in-class and rationally designed bispecific antibody (BsAb), HX009, targeting PD1 and CD47 but with weakened CD47 binding, which selectively hones the BsAb for tumor microenvironment through PD1 interaction, potentially reducing toxicity. In vitro characterization confirmed: (1) Both receptor binding/ligand blockade, with lowered CD47 affinity; (2) functional PD1/CD47 blockades by reporter assays; (3) T-cell activation in Staphylococcal-enterotoxin-B-pretreated PBMC and mixed-lymphocyte-reaction. In vivo modeling demonstrated antitumor activity in Raji-B and Karpass-229-T xenograft lymphomas. In the humanized mouse syngeneic A20 B-lymphoma (huCD47-A20) HuGEMM model, which has quadruple knocked-in hPD1xhPD-L1xhCD47xhSIRPα genes and an intact autologous immune-system, a contribution of effect is demonstrated for each targeted biologic (HX008 targeting PD1 and SIRPα-Fc targeting CD47), which is clearly augmented by the dual targeting with HX009. Lastly, the expression of the immune-checkpoints PD-L1/L2 and CD47 seemed co-regulated among a panel of lymphoma-derived-xenografts, where HX009 maybe more effective in those with upregulated CD47. Our data warrants HX009’s further clinical development for treating NHLs.

BackgroundEmerging infectious diseases pose a significant threat to both human and animal populations. Rapid de novo identification of protective antigens from a clinical isolate and development of an antigen-matched vaccine is a golden strategy to prevent the spread of emerging novel pathogens.MethodsHere, we focused on Actinobacillus pleuropneumoniae, which poses a serious threat to the pig industry, and developed a general workflow by integrating proteosurfaceomics, secretomics, and BacScan technologies for the rapid de novo identification of bacterial protective proteins from a clinical isolate.ResultsAs a proof of concept, we identified 3 novel protective proteins of A. pleuropneumoniae. Using the protective protein HBS1_14 and toxin proteins, we have developed a promising multivalent subunit vaccine against A. pleuropneumoniae.DiscussionWe believe that our strategy can be applied to any bacterial pathogen and has the potential to significantly accelerate the development of antigen-matched vaccines to prevent the spread of an emerging novel bacterial pathogen.

Introduction Depressive symptoms have surfaced as the principal mental health concern among patients with breast cancer, with surgical interventions potentially exacerbating these symptoms and adversely influencing clinical outcomes. This study protocol is designed to investigate the efficacy of low-dose esketamine administered perioperatively on depressive symptoms in patients with breast cancer. It also aims to illuminate the potential neurobiological underpinnings of this effect.Methods and analysis This research represents a single-centre, prospective, randomised, double-blind, placebo-controlled study. The trial anticipates enrolling 108 female patients exhibiting mild-to-severe depressive symptoms who are slated for radical mastectomy. Through stratified randomisation, eligible patients will be systematically assigned to either the esketamine group (0.25 mg/kg) or placebo group (0.9% saline) in a 1:1 ratio. The primary outcome is the response rate at the third postoperative day. Secondary outcomes encompass the remission rate, depression-related scores, depression severity and safety-related endpoints. Tertiary (exploratory) outcomes involve alterations in brain-derived neurotrophic factor and resting-state functional brain connectivity.Ethics and dissemination The Clinical Trial Ethics Committee at The First Affiliated Hospital of Anhui Medical University has conferred ethical approvals for this trial (approval number: PJ2023-05-25). Results from this trial will be disseminated in peer-reviewed journals and presented at professional symposiums.Trial registration number Chinese Clinical Trials Registry (ChiCTR2300071062).

Abstract Objective We aimed to investigate the impact of the position, configuration and neurovascular contact of the anterior inferior cerebellar artery (AICA) in cerebellopontine angle (CPA) and internal auditory canal (IAC) on the clinical features of patients with unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). Methods One hundred and thirty‐six patients with unilateral ISSNHL were enrolled. All patients received detailed history inquiry and standard treatments. Pure tone audiometry and magnetic resonance imaging (MRI) of CPA‐IAC were performed. The MRI findings of both ears were evaluated by the Chavda, Gorrie and Kazawa systems. The association between radiological findings and clinical data were analyzed. Results (1) No significant interaural difference in the position, configuration and neurovascular contact of AICA was observed. (2) There was no significant association between the AICA loop and concomitant vertigo or pre‐treatment audiometric configuration in the affected ear. (3) Concomitant tinnitus seemed to be affected by the configuration of AICA categorized by Kazawa system, while the Chavda and Gorrie classification of AICA loop was unassociated with tinnitus. (4) Hearing outcomes were not compromised by the position or configuration of AICA based on the Chavda and Kazawa systems. Patients with Gorrie type B tended to have better hearing recovery than those with type C. Conclusions In patients with ISSNHL, the position, configuration and neurovascular contact of AICA in the CPA‐IAC were unassociated with the side of hearing loss, audiometric configurations, or concomitant vertigo. The neurovascular contact graded by Gorrie system might be associated with hearing outcomes.

Abstract Background Anlotinib as a third‐line or beyond therapy for extensive‐stage small‐cell lung cancer (ES‐SCLC) was studied. This single‐arm phase II trial was to investigate the value of anlotinib plus platinum‐etoposide as first‐line treatment in ES SCLC. Methods The primary endpoint was progression‐free survival (PFS) and objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), time to progression (TTP), duration of remission (DoR), and safety. The subgroups of preset liver metastasis and brain metastasis were analyzed. Results In 35 ES‐SCLC patients, the median PFS, ORR, DCR, and OS were 8.02 months [95% confidence interval (CI): 6.90–9.66], 85.71% (95% CI: 69.74–95.19), 94.29% (95% CI: 80.84–99.30), and 15.87 months (95% CI: 10.38–18.89), respectively. The median PFS in the liver metastasis and brain metastasis subgroups was 7.33 months (95% CI: 4.76–9.69) and 7.34 months (95% CI: 5.68–9.20), respectively. The most common AEs with grade 3–4 were hand–foot syndrome (17%), granulocytosis (17%), stomatitis (14%), hypertriglyceridemia (11%), hypercholesterolemia (11%), as well as nausea and vomiting (11%), and no grade 5 AEs were recorded. Conclusions Anlotinib combined with platinum‐etoposide provided an effective and safe therapy for patients with ES‐SCLC.

Abstract The numerous hierarchical architectures of 2D assemblies endow them with a new dimension to realize novel properties. From theoretical perspective, freedoms stem from in‐plane and out‐plane mechanical properties of 2D materials separately, which makes 2D materials embrace more than one “persistence length” giving rise to the diverse morphologies. However, the understanding of 3D architecture formation in 2D assemblies is still in its infancy. In fact, there is even no theoretical classification or reference to help clarify structural difference among numerous experimental obtained 2D assemblies. Based on the theoretical model composed by 2D sheets and Lennard‐Jones liquids, solution concentration dependence of 2D materials conformation is systematically studied, and a ln K behavior is uncovered that can realize the theoretical conformation prediction of 2D materials. More importantly, the digital production line (solution processing procedure) is set up toward establishing the 2D assemblies’ digital factory. The obtained structures may provide a reference to 2D assemblies, which benefits the understanding of the structural difference among different experiments and even help to guide the experimental design of 2D assemblies with targeted architectures and properties.

Abstract Deep neural networks have achieved great success in both computer vision and natural language processing tasks. How to improve the gradient flows is crucial in training very deep neural networks. To address this challenge, a gradient enhancement approach is proposed through constructing the short circuit neural connections. The proposed short circuit is a unidirectional neural connection that back propagates the sensitivities rather than gradients in neural networks from the deep layers to the shallow layers. Moreover, the short circuit is further formulated as a gradient truncation operation in its connecting layers, which can be plugged into the backbone models without introducing extra training parameters. Extensive experiments demonstrate that the deep neural networks, with the help of short circuit connection, gain a large margin of improvement over the baselines on both computer vision and natural language processing tasks. The work provides the promising solution to the low‐resource scenarios, such as, intelligence transport systems of computer vision, question answering of natural language processing.

Tree mortality plays a fundamental role in the dynamics of forest ecosystems, yet it is one of the most difficult phenomena to accurately predict. Various modeling strategies have been developed to improve individual tree mortality predictions. One less explored strategy is the use of a multistage modeling approach. Potential improvements from this approach have remained largely unknown. In this study, we developed a novel multistage approach and compared its performance in individual tree mortality predictions with a more conventional approach using an identical individual tree mortality model formulation. Extensive permanent plot data (n ​= ​9442) covering the Acadian Region of North America and over multiple decades (1965–2014) were used in this study. Our results indicated that the model behavior with the multistage approach better depicted the observed mortality and showed a notable improvement over the conventional approach. The difference between the observed and predicted numbers of dead trees using the multistage approach was much smaller when compared with the conventional approach. In addition, tree survival probabilities predicted by the multistage approach generally were not significantly different from the observations, whereas the conventional approach consistently underestimated mortality across species and overestimated tree survival probabilities over the large range of DBH in the data. The new multistage approach also predictions of zero mortality in individual plots, a result not possible in conventional models. Finally, the new approach was more tolerant of modeling errors because it based estimates on ranked tree mortality rather than error-prone predicted values. Overall, this new multistage approach deserves to be considered and tested in future studies.

As patients are dissatisfied with the excessive weight of Co-based knee femoral components, it is an urgent need to reduce their weight without compromising the excellent mechanical properties. In the present study, femoral components of knee with Ti6Al4V alloy (86 g) or Co–Cr alloy (192 g) were printed by selective laser melting (SLM). In order to improve the mechanical properties and biocompatibility of 3D-printed Ti6Al4V, TiN and TiCrN coating layers were deposited on the surface of SLM Ti6Al4V using arc ion plating (AIP) system. The surface characterizations were analyzed by scanning electron microscopy (SEM) equipped with energy dispersive spectrometer (EDS), X-ray diffraction (XRD), contact angle tensiometer, and contact profilometer. The wear property, hardness value and corrosion resistance in phosphate buffered saline (PBS) were also investigated through vickers hardness, sliding wear test, electrochemical impedance spectroscopy and potentiodynamic polarization. The antibacterial capability and biocompatibility were assessed with Staphylococcus aureus and mesenchymal stem cells (MSCs) in vitro. Results illustrated that, after coating SLM Ti6Al4V with thin TiN and TiCrN layers, the hardness, anti-wear performance and corrosion resistance of SLM Ti6Al4V were significantly improved and became comparable to SLM CoCr. The TiN and TiCrN coated SLM Ti6Al4V also showed moderate antibacterial ability, and excellent biocompatibility in comparation with SLM Ti6Al4V and SLM CoCr.

Abstract Background Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. Recently, the drug resistance information transmitted by exosomal miRNAs has attracted much attention. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored. Methods We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients. Results Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 and miR-3913-5p expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-3913-5p was associated with TNM stage, platelet count, tumor marker carcinoembryonic antigen, and distant metastases. In patients with EGFR exon 21 L858R mutation, the increased expression levels of miR-184 and miR-3913-5p derived from serum exosomes indicated osimertinib resistance. Similarly, for T790M-positive patients, the level of exosome-derived miR-3913-5p can be used as a predictive marker for osimertinib resistance. Conclusions The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance. Graphic Abstract

Objective To explore the reasons for wrong connection between anticoagulant and normal saline solution during apheresis platelet donation, as well as the preventive measures, so as to ensure the safety of apheresis platelet donors. Methods Manual checking in the first phase (December 2008 to September 2016) was compared with double checking (manual checking plus information system) in the second phase (October 2016 to October 2020) via bilateral testing using Fisher's Exact Test to study pre-post-improvement differences. Results The incidence of solution connection errors during apheresis platelet donation in the first phase was 1.02/10 000, and the error incidence between Amicus and Trima + Mcs®+ blood cell separator was statistically significant (P0.05). After the performance of double checking in the second phase, no wrong connection of anticoagulant and saline solution occurred. Conclusion The double checking method assisted by manual and information system can effectively prevent the wrong connection between anticoagulant and normal saline solution.

Abstract To identify the risk factors of mortality for the coronavirus disease 19 (COVID-19) patients admitted to intensive care units (ICUs) through a retrospective analysis. The demographic, clinical, laboratory, and chest imaging data of patients admitted to the ICU of Huoshenshan Hospital from February 10 to April 10, 2020 were retrospectively analyzed. Student's t-test and Chi-square test were used to compare the continuous and categorical variables, respectively. The logistic regression model was employed to ascertain the risk factors of mortality. This retrospective study involved 123 patients, including 64 dead and 59 survivors. Among them, 57 people were tested for interleukin-6 (IL-6) (20 died and 37 survived). In all included patients, the oxygenation index (PaO2/FiO2) was identified as an independent risk factor (odd ratio [OR] = 0.96, 95% confidence interval [CI]: 0.928–0.994, p = 0.021). The area under the curve (AUC) was 0.895 (95% CI: 0.826–0.943, p

Abstract The strain rate and temperature effects on the deformation behavior of crystalline metal materials have always been a research hotspot. In this paper, a strain rate dependent thermo-elasto-plastic constitutive model was established to investigate the deformation behavior of crystalline metal materials. Firstly, the deformation gradient was re-decomposed into three parts: thermal part, elastic part and plastic part. Then, the thermal strain was introduced into the total strain and the thermo-elastic constitutive equation was established. For the plastic behavior, a new relation between stress and plastic strain was proposed to describe the strain rate and temperature effects on the flow stress and work-hardening. The stress–strain curves were calculated over wide ranges of strain rates (10–6–6000 s−1) and temperatures (233–730 K) for three kinds of crystalline metal materials with different crystal structure: oxygen free high conductivity copper for face centered cubic metals, Tantalum for body centered cubic metals and Ti–6Al–4V alloy for two phase crystal metals. The comparisons between the calculation and experimental results reveal that the present model describes the deformation behavior of crystalline metal materials well. Also, it is concise and efficient for the practical application.

Dictionary-based fault diagnosis methods, focusing on storing feature patterns of known faults, have been widely used for electromechanical systems. The state of component degradation caused soft faults, however, are continuously changeable. Thus, conventional dictionaries cannot be applied for diagnosis of soft faults with multi-degradation levels. To address this issue, this article develops a new type of dictionary by combining the unit residual signal vector (URV) and the linear discriminant analysis (LDA) for feature transformation, which is referred to as URV-LDA dictionary. The unit residual signal vector keeps the fault feature growth trends but eliminates the degradation severity influence. The linear discriminant analysis is then implemented to find the best projection directions for classification. Specifically, two dictionaries named as the URV-MLDA binary-value dictionary and the URV-SLDA unique-value dictionary are proposed. To validate the efficiency of two developed dictionaries, an electromagnetic relay is carried out and two conventional methods are compared. The comparison results show the developed dictionaries can better solve the soft faults issues with significant increases on diagnostic accuracy.

This study was conducted to investigate the effects of incorporating varying proportions of nutraceutical-rich mushroom (Cordycepes militaris) flour (1%, 3% and 5%) on the physicochemical, antioxidant and sensory properties of cookies. Results showed that the contents of crude protein, ash and fiber of supplemented coo kies were higher than that of control cookies. Spread ratio and hardness decreased as the C.militaris flour incorporation level increased. The color values of cookies also varied with the increasing levels of C. militaris flour. Furthermore, fortification of C. militaris flour improved the functional quality of cookies by significantly enhancing the phenolic contents and antioxidant activities (P < 0.05). Sensory evaluation of cookies indicated that the addition of 3% C. militaris flour was more acceptable. Overall, enriched cookies have more functional components and effective antioxidant capacity than plain wheat cookies. Their supplementation could provide the consumers a novel cereal-based product with health-promoting benefits.

ObjectiveWe aimed to evaluate the diagnostic performance of some anatomical variables with regard to endolymphatic sac (ES) and duct (ED), measured by non-contrast three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions (3D-SPACE) magnetic resonance imaging (MRI), in differentiating vestibular migraine (VM) from unilateral Ménière's disease (MD).MethodsIn this study, 81 patients with VM, 97 patients with unilateral MD, and 50 control subjects were enrolled. The MRI-visualized parameters, such as the distance between the vertical part of the posterior semicircular canal and the posterior fossa (MRI-PP distance) and visibility of vestibular aqueduct (MRI-VA), were measured bilaterally. The diagnostic value of the MRI-PP distance and MRI-VA visibility for differentiating VM from unilateral MD was examined.Results(1) Compared with the VM patients, patients with unilateral MD exhibited shorter MRI-PP distance and poorer MRI-VA visibility. No differences in the MRI-PP distance and MRI-VA visibility were detected between patients with VM and control subjects. (2) No significant interaural difference in the MRI-PP distance and MRI-VA visibility was observed in patients with VM and those with unilateral MD, respectively. (3) Area under the curve (AUC) showed a low diagnostic value for the MRI-PP distance and MRI-VA visibility, respectively, in differentiating between the VM and unilateral MD.ConclusionsBased on non-enhanced MRI-visualized measurement, anatomical variables with regard to the endolymphatic drainage system differed significantly between the patients with VM and those with unilateral MD. Further investigations are needed to improve the diagnostic value of these indices in differentiating VM from unilateral MD.

The development of bioactive carrier with controlled delivery of Bone morphogenetic protein (BMP-2) is an important part in bone regeneration. Our study fabricated novel modified nanomaterials based on poly-l-lysine functionalized graphene oxide (GO-PLL) and explore its potential applications for BMP-2 delivery. GO-PLL was used to modify BMP-2 encapsulated bovine serum albumin (BSA) nanoparticles (GO-PLL/BMP-2) by self-assembling technology. The physiochemical and biological properties of GO-PLL modified BSA nanoparticles were investigated in vitro. Additionally, rabbit calvarial bone defects were created to investigate bone formation ability in the presence of GO-PLL/BMP-2 loaded alginate/gelatin scaffolds. The results suggested BSA particles were spatially interacted with GO-PLL complexes by strong electrostatic attraction. When compared with BMP-2 encapsulated BSA nanoparticles, a pronounced decrease in BMP-2 gentle release was observed in the presence of GO-PLL/BMP-2 nanoparticles, and extended to over 14-day release periods. More importantly, GO-PLL/BMP-2 nanoparticles significantly enhanced alkaline phosphatase activity (ALP) and matrix mineralization, and exhibited favorable bone formation ability when loaded into alginate/gelatin scaffolds. These results demonstrated that PLL functionalized GO complexes are considered as appropriate delivery system for BSA modification, and have great potential for BMP-2 delivery in bone regeneration.

Abstract Background Glycogen is a multibranched polysaccharide of glucose produced by cells to store energy and plays a key role in cancer. A previously reported fluorescent probe (CDg4) was shown to selectively bind glycogen in mouse embryonic stem cells, however the molecule was not evaluated in cancer cells. We report the synthesis and biological evaluation of a dual-modality imaging probe based on CDg4, for positron emission tomography (PET) and fluorescence microscopy. Results A fluorine-18 radiolabelled derivative of CDg4, ([ 18 F]5) for in vivo quantification of total glycogen levels in cancer cells was developed and synthesised in 170 min with a non-decay corrected radiochemical yield (RCY n.d.c) of 5.1 ± 0.9% (n = 4) in > 98% radiochemical purity. Compound 5 and [ 18 F]5 were evaluated in vitro for their potential to bind glycogen, but only 5 showed accumulation by fluorescence microscopy. The accumulation of 5 was determined to be specific as fluorescent signal diminished upon the digestion of carbohydrate polymers with α-amylase. PET imaging in non-tumour bearing mice highlighted rapid hepato-biliary-intestinal elimination of [ 18 F]5 and almost complete metabolic degradation after 60 min in the liver, plasma and urine, confirmed by radioactive metabolite analysis. Conclusions Fluorescent compound 5 selectively accumulated in glycogen containing cancer cells, identified by fluorescence microscopy; however, rapid in vivo metabolic degradation precludes further investigation of [ 18 F]5 as a PET radiopharmaceutical.

We propose an ID Preserving Face Super-Resolution Generative Adversarial Networks (IP-FSRGAN) to reconstruct realistic super-resolution face images from low-resolution ones. Inspired by the success of generative adversarial networks (GAN), we introduce a novel ID preserving module to help the generator learn to infer the facial details and synthesize more realistic super-resolution faces. Our method produces satisfactory visual results and also quantitatively outperforms state-of-the-art super-resolution methods on the face datasets including CASIA-Webface, CelebA, and LFW datasets under the metrics of PSNR, SSIM, and cosine similarity. In addition, we propose a framework to apply IP-FSRGAN model to address the face verification task on low-resolution face images. The synthesized 4× super-resolution faces achieve a verification accuracy of 97.6%, improved from 92.8% of low resolution faces. We also prove by experiments that the proposed IP-FSRGAN model demonstrates excellent robustness under different downsample scaling factors and extensibility to various face verification models.

Abstract The old well sidetracking technology is an effective means to stabilize production and increase recovery in later stage of gas field development. Based on economical and reservoir geologic parameters of Sulige low-permeability gas field in China, method and procedure of old well sidetracking selection standards are established, which can effectively improve the sidetracking effect and adequately develop remaining gas. Comprehensively considering corresponding economic parameters including sidetracking drilling cost, operating cost, management cost, gas production rate and gas price, recoverable reserve standard of sidetracking well is determined first. According to gas recovery, gas-bearing area, porosity and gas saturation, standards of remaining geological reserve, reserve abundance and gas pay thickness of sidetracking well are obtained. According to extension direction and distribution characteristics of the sand body in research area, numerical simulation conceptual model of typical sidetracking horizontal well is established, and then standards of old gas well production rate and gas cumulative production rate for sidetracking are obtained. According to the standards, well Su 36-6-9CH is selected to be sidetracked as a horizontal well and its development effect is good. The method has important value of popularization and application in similar low-permeability gas reservoir.

Fluid charging and formation pressure evolution are of great significance for shale gas exploration and development. Taking the Longmaxi formation shale in southeast Chongqing as the research object, the fluid activity and pressure evolution process were studied by means of thin section observation, fluid inclusion analysis and testing, and basin numerical simulation. The results show that the area of the southeast of Chongqing, the Longmaxi formation of dike filling minerals, is mainly quartz vein and calcite part of the veins and arteries, and vein body captures the rich organic inclusions in minerals, sees fgas-liquid two-phase brine inclusions and methane inclusions, combining with the temperature and salinity of brine inclusions, and shows that the area has experienced two phases of oil and gas filling, the first period of gas-liquid fluid. The second stage is gas fluid. Combined with burial history and thermal maturation history, it is found that the filling time of oil and gas is late Cretaceous and Paleocene, respectively. In the Cretaceous, the pressure coefficient of Longmaxi formation reached the maximum value of 2.2 and remained above 1.5 overpressure after pressure unloading in the later period. In terms of the frequency of inclusions, the charging amount of the first stage is relatively large, and the charging time corresponds to the peak period of the palaeo-formation pressure. At the same time, fluid charging can timely supplement the pressure after unloading, which is conducive to high and stable production of shale gas.

Abstract Recently, electrical stimulation as a physical stimulus draws lots of attention. It shows great potential in disease treatment, wound healing, and mechanism study because of significant experimental performance. Electrical stimulation can activate many intracellular signaling pathways, and influence intracellular microenvironment, as a result, affect cell migration, cell proliferation, and cell differentiation. Electrical stimulation is using in tissue engineering as a novel type of tool in regeneration medicine. Besides, with the advantages of biocompatible conductive materials coming into view, the combination of electrical stimulation with suitable tissue engineered scaffolds can well combine the benefits of both and is ideal for the field of regenerative medicine. In this review, we summarize the various materials and latest technologies to deliver electrical stimulation. The influences of electrical stimulation on cell alignment, migration and its underlying mechanisms are discussed. Then the effect of electrical stimulation on cell proliferation and differentiation are also discussed.

Objective: The goal of this study is to explore the effect of wrist-ankle acupuncture combined with 5-Hz repetitive transcranial magnetic stimulation (rTMS) on improving spastic state and motor function of children with spastic cerebral palsy by measuring electrophysiological parameters and behaviors.Methods: Twenty-five children with spastic cerebral palsy were enrolled in a single-blind and randomized controlled trial. The control group received 20 sessions of 5-Hz rTMS over the affected hemisphere with 1,000 pulses. The experimental group was given wrist-ankle acupuncture on the basis of the control group. Gross motor function measure (GMFM-66), muscle tension, and electrophysiological parameters of the two groups were assessed at baseline and after intervention.Results: After treatment, the GMFM-66 scores in the same groups were significantly improved (p < 0.001). Besides, the R-value of soleus, gastrocnemius, and hamstring muscle decreased (p < 0.05), and the results showed a trend of shortening MEP latency, increasing amplitude and duration (p < 0.05). Compared to the controlled group, the experimental group displayed more excellent changes in the GMFM-66 scores and motor evoked potential (MEP) latency. The statistical results showed that the increase of GMFM-66 score and the shortening of MEP latency in the experimental group were greater than that in the control group (p < 0.05). However, no significant differences were found in the assessment of muscle tension, amplitude, and duration of MEPs between two groups (p > 0.05).Conclusion: Wrist-ankle acupuncture combined with 5-Hz rTMS is optimal to improve gross motor function and enhance the conductivity of corticospinal tract in children with cerebral palsy but cannot highlight its clinical superiority in improving spasticity.Clinical Trial Registration: [http://www.chictr.org.cn/index.aspx], identifier [chictr2000039495].

Abstract Heart diseases caused by structure and function degradation is troubling millions of people all over the world. With the extension of human lifespan, the demand for heart valve replacement is rapidly increasing. However, the currently used prostheses of heart valve in clinic such as mechanical and tissue valves all have serious limitations over long‐term stability after implanting. Therefore, novel artificial heart valves with outstanding durability and low degradation risk are still in great demands, despite of numerous studies in the literature. The sophisticated, multiscale structure of native heart valve is believed to be the key to its mechanical and biological durability during long‐term cyclic motion. In this review, we discussed the complex structure of the native heart valve as well as their contributions to the valve's cyclic work. In addition, representative and state of the art studies of biomimetic heart valves inspired by the natural valve are also introduced. Based on these, the structural and functional design of future novel biomimetic heart valves are proposed.

BackgroundMalignant tumors accompanied with malignant pleural effusion (MPE) often indicate poor prognosis. The therapeutic effect and mechanism of intrapleural injection of anti-programmed cell death protein 1 (PD1) on MPE need to be explored.MethodsA preclinical MPE mouse model and a small clinical study were used to evaluate the effect of intrapleural injection of anti-PD1 antibody. The role of immune cells was observed via flow cytometry, RNA-sequencing, quantitative PCR, western blot, immunohistochemistry, and other experimental methods.ResultsIntrathoracic injection of anti-PD1 monoclonal antibody (mAb) has significantly prolonged the survival time of mice (P = 0.0098) and reduced the amount of effusion (P = 0.003) and the number of cancer nodules (P = 0.0043). Local CD8+ T cells participated in intrapleural administration of anti-PD1 mAb. The proportion of CD69+, IFN-γ+, and granzyme B+ CD8+ T cells in the pleural cavity was increased, and the expression of TNF-α and IL-1β in MPE also developed significantly after injection. Local injection promoted activation of the CCL20/CCR6 pathway in the tumor microenvironment and further elevated the expression of several molecules related to lymphocyte activation. Clinically, the control rate of intrathoracic injection of sintilimab (a human anti-PD1 mAb) for 10 weeks in NSCLC patients with MPE was 66.7%. Local injection improved the activity and function of patients’ local cytotoxic T cells (CTLs).ConclusionsIntrapleural injection of anti-PD1 mAb could control malignant pleural effusion and the growth of cancer, which may be achieved by enhancing local CTL activity and cytotoxicity.

Tellurium was successfully incorporated into proteins and applied to protein structure determination through X-ray crystallography. However, studies on tellurium modification of DNA and RNA are limited. This review highlights the recent development of Te-modified nucleosides, nucleotides, and nucleic acids, and summarizes the main synthetic approaches for the preparation of 5-PhTe, 2′-MeTe, and 2′-PhTe modifications. Those modifications are compatible with solid-phase synthesis and stable during Te-oligonucleotide purification. Moreover, the ideal electronic and atomic properties of tellurium for generating clear isomorphous signals give Te-modified DNA and RNA great potential applications in 3D crystal structure determination through X-ray diffraction. STM study also shows that Te-modified DNA has strong topographic and current peaks, which immediately suggests potential applications in nucleic acid direct imaging, nanomaterials, molecular electronics, and diagnostics. Theoretical studies indicate the potential application of Te-modified nucleosides in cancer therapy.

Developing influenza vaccines that protect against a broad range of viruses is a global health priority. Several conserved viral proteins or domains have been identified as promising targets for such vaccine development. However, none of the targets is sufficiently immunogenic to elicit complete protection, and vaccine platforms that can enhance immunogenicity and deliver multiple antigens are desperately needed. Here, we report proof-of-concept studies for the development of next-generation influenza vaccines using the bacteriophage T4 virus-like particle (VLP) platform. Using the extracellular domain of influenza matrix protein 2 (M2e) as a readout, we demonstrate that up to ~1,281 M2e molecules can be assembled on a 120 x 86 nanometer phage capsid to generate M2e-T4 VLPs. These M2e-decorated nanoparticles, without any adjuvant, are highly immunogenic, stimulate robust humoral as well as cellular immune responses, and conferred complete protection against lethal influenza virus challenge. Potentially, additional conserved antigens could be incorporated into the M2e-T4 VLPs and mass-produced in E. coli in a short amount of time to deal with an emerging influenza pandemic.

Merging Sanger sequences is frequently needed during the gene cloning process. In this study, we provide a Python script that is able to assemble multiple overlapping Sanger sequences. The script utilizes the overlapping regions within the tandem Sanger sequences to merge the Sanger sequences. The results demonstrate that the script can produce the merged sequence from the input Sanger sequences in a single run. The script offers a simple and free method for merging Sanger sequences and is useful for gene cloning.

BackgroundImmune-related adverse events (irAEs) have been reported to be associated with the efficacy of immunotherapy. Herein, we conducted a meta-analysis to demonstrate that irAEs could predict the efficacy of immune checkpoint inhibitors (ICIs) in lung cancer patients.MethodsLiterature on the correlation between irAEs and the efficacy of immunotherapy in lung cancer patients were searched to collect the data on objective response rate (ORR), overall survival (OS), or progression-free survival (PFS) of the patients. These data were incorporated into the meta-analysis.ResultsA total of 34 records encompassing 8,115 patients were examined in this study. The irAEs occurrence was significantly associated with higher ORR {risk ratio (RR): 2.43, 95% confidence interval (CI) [2.06–2.88], p < 0.00001} and improved OS {hazard ratio (HR): 0.51, 95% CI [0.43–0.61], p < 0.00001}, and PFS (HR: 0.50, 95% CI [0.44–0.57], p < 0.00001) in lung cancer patients undergoing ICIs. Subgroup analysis revealed that OS was significantly longer in patients who developed dermatological (OS: HR: 0.53, 95%CI [0.42–0.65], p < 0.00001), endocrine (OS: HR: 0.55, 95%CI [0.45–0.67], p < 0.00001), and gastrointestinal irAEs (OS: HR: 0.58, 95%CI [0.42–0.80], p = 0.0009) than in those who did not. However, hepatobiliary, pulmonary, and high-grade (≥3) irAEs were not correlated with increased OS and PFS.ConclusionThe occurrence of irAEs in lung cancer patients, particularly dermatological, endocrine, and gastrointestinal irAEs, is a predictor of enhanced ICIs efficacy.

Acute respiratory distress syndrome (ARDS) is characterized by an uncontrollable cytokine storm, which is associated with high mortality due to lack of effective treatment. Regulatory T cells (Tregs) play an indispensable role in maintaining immune homeostasis and CD39 is considered as a functional cell marker of Tregs. In this study, we aimed to evaluate the effect of CD39+ Tregs on acute lung injury (ALI) and investigate the frequency of CD39+ Tregs in ARDS patients. We found that after lipopolysaccharide (LPS) treatment, CD39−/− mice exhibited more severe inflammation and wild type (WT) mice exhibited a decreased frequency of CD39+ Tregs in the peripheral blood. Furthermore, CD39+ Tregs had a protective effect on LPS-induced inflammation in vitro and the adoptive transfer of CD39+ Tregs had a therapeutic effect on ALI in vivo. We further sought to explore the mechanisms that affect CD39 expression on Tregs. LPS-induced inflammation in the lung impaired the immunosuppressive effect of Tregs via the autophagy-mediated downregulation of CD39. In addition, CD39 induced the expression of itself in Tregs via activating the ERK1/2-FOS pathway. Consistent with this finding, the frequency of CD39+ Tregs was also decreased in the peripheral blood of ARDS patients and was positively correlated with disease severity. Our results suggested that the adoptive transfer of CD39+ Tregs may provide a novel method for the clinical prevention and treatment of ARDS.

The selection of tests required to make complex systems testable is a fundamental of system-level fault diagnosis. To evaluate the test selection, testability metric estimation (TME) is required. The influence of unreliable (imperfect) tests, whose outcomes are non-deterministic due to unstable environmental conditions, test equipment errors, and component tolerances, should be considered for accurate TME. Previously, researchers considered a TME model using a Bernoulli distribution with the assumption that the variations of different test outcomes are independent. However, this assumption is not always true. To address the issue, a joint distribution-based TME model was developed derived from the copula function to quantify the influence of dependent outcomes of unreliable tests. The efficacy of the developed TME model was verified with a linear voltage divider and a negative feedback circuit.

Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [18F]fluoromethyl-[1,2-2H4]-choline ([18F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [18F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [18F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. The effects of hypoxia on [18F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [18F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [18F]-D4-FCH and [18F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k5) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics.

Context: Corydalis yanhusuo W.T. Wang (Papaveraceae) (Rhizoma Corydalis) showed inhibitory effects on rabbit platelet aggregation induced by ADP, thrombin (THR) or arachidonic acid (AA). Objective: This study separates and identifies the possible target-related platelet proteins and suggests possible signal cascades of RC antiplatelet aggregation. Materials and methods: Based on comparative proteomics, the differentially expressed platelet proteins treated before and after with 50 mg/mL RC 90% ethanol extract (for 15 min at 37 °C) were analyzed and identified by two dimensional gel electrophoresis (2-DE) and MALDI-TOF-MS/MS. To further verify the possible signalling pathways of RC antiplatelet aggregation function, the concentration of calcium (Ca2+) was measured by Fura-2/AM fluorescence (Ex 340/380 nm, Em 500 nm) (RC final concentrations of 0.0156–0.1563 mg/mL), the levels of P-selectin and cyclic guanosine monophosphate (cGMP) were quantified by ELISA (OD. 450 nm) (RC final concentrations of 0.0156–1.5625 mg/mL), and the 5-hydroxytryptamine (5-HT) level was measured using ortho-phthalaldehyde (OPT) fluorescence (Ex 340 nm, Em 470 nm) (RC final concentrations of 0.3125–1.5625 mg/mL). Results: The expression of 52 proteins were altered in rabbit platelets after the treatment and the MALDI-TOF-MS analysis indicated that those proteins include 12 cytoskeleton proteins, 7 cell signalling proteins, 3 molecular chaperone proteins, 6 proteins related to platelet function, 16 enzymes and 7 other related proteins. Furthermore, RC extract could decrease the levels of 5-HT [inhibition rate of 96.80% (p

Similar mechanical properties to native bone, excellent biocompatibility and osseointegration are key factors for interbody fusion cage. In the present study, porous Ti6Al4V cage with computer designed macro- and micro-architecture was reproduced by selective laser melting (SLM). Dense Ti6Al4V discs with six different angles were fabricated to investigate the effects of additive angle (inevitable in SLM manufacturing) on surface properties and biocompatibility. As angle increased, both surface roughness and hydrophobicity increased due to increases in the number of unmelted metallic particles. In the early stage of cell culture, more elongated MC3T3E1 cells were observed at higher additive angle, but cell adhesion and proliferation with different angle did not show statistically differences. Bullet-shaped Ti6Al4V cage with opened window, porosity of 70% and pore size of 600 μm revealed elastic modulus of 0.51 ± 0.04 GPa and ultimate compressive strength of 94.7 MPa at 0.29% strain, which is comparable with the commercialized polyetheretherketone cage. In vivo evaluation of Beagle tibia model through histological analysis showed that the cylindrical porous body with same porosity and pore size achieved similar bone ingrowth as commercialized porous tantalum implant at 4 and 12 weeks, indicating SLM fabricated porous Ti6Al4V cage holds great potential for spinal fusion. Keywords: Selective laser melting, Additive angle, Interbody fusion cage, Mechanical properties, Biocompatibility, Bone ingrowth

Bacteriophages (phages) are the most abundant and widely distributed organisms on Earth, constituting a virtually unlimited resource to explore the development of biomedical therapies. The therapeutic use of phages to treat bacterial infections (“phage therapy”) was conceived by Felix d’Herelle nearly a century ago. However, its power has been realized only recently, largely due to the emergence of multi-antibiotic resistant bacterial pathogens. Progress in technologies, such as high-throughput sequencing, genome editing, and synthetic biology, further opened doors to explore this vast treasure trove. Here, we review some of the emerging themes on the use of phages against infectious diseases. In addition to phage therapy, phages have also been developed as vaccine platforms to deliver antigens as part of virus-like nanoparticles that can stimulate immune responses and prevent pathogen infections. Phage engineering promises to generate phage variants with unique properties for prophylactic and therapeutic applications. These approaches have created momentum to accelerate basic as well as translational phage research and potential development of therapeutics in the near future.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.