Immune checkpoint inhibitor therapy-induced autoimmune polyendocrine syndrome typeⅡand Crohn's disease:A case report

BACKGROUND The development of immune checkpoint inhibitors(ICIs)has heralded a new era in cancer treatment,enabling the possibility of long-term survival in patients with metastatic disease.Unfortunately,ICIs are increasingly implicated in the development of autoimmune diseases.CASE SUMMARY We present a man with squamous cell carcinoma of the oropharynx on a combination of teriprizumab,docetaxel,and cisplatin therapy who developed autoimmune polyendocrine syndrome typeⅡ(APS-2)including thyroiditis and type 1 diabetes mellitus and Crohn’s disease(CD).He developed thirst,abdominal pain,and fatigue after two-week treatment with the protein 1 ligand inhibitor teriprizumab.Biochemistry confirmed APS-2 and thyrotoxicosis.He was commenced on an insulin infusion.However,his abdominal pain persisted.Follow-up surgery confirmed CD and his abdominal pain was relieved by mesalazine.He was continued on insulin and mesalazine therapy.CONCLUSION Immunotherapy can affect all kinds of organs.When clinical symptoms cannot be explained by a single disease,clinicians should consider the possibility of multisystem damage.

蛇麻草精油香薰法对氯苯丙氨酸诱导失眠大鼠的助眠作用研究

目的探究蛇麻草精油香薰法对氯苯丙氨酸(PCPA)诱导失眠大鼠的行为学、部分神经递质含量及松果体的影响。方法腹腔注射PCPA复制失眠大鼠模型,随机分为模型组、薰衣草精油组(0.2%)、蛇麻草精油低浓度组(0.05%)、蛇麻草精油中浓度组(0.10%)及蛇麻草精油高浓度组(0.20%),每组12只,另设空白组12只。模型复制后,各治疗组分别以相应浓度精油香薰治疗,空白组和模型组熏蒸馏水。每天8 h,连续5 d。观察并记录各组大鼠一般状况;戊巴比妥钠协同睡眠实验观察大鼠睡眠潜伏期和睡眠持续期;旷场实验检测大鼠自发活动;酶联免疫吸附试验(ELISA)检测各组大鼠血清褪黑素(MT)、γ-氨基丁酸(GABA)、谷氨酸(Glu)含量;高效液相色谱仪测定各组大鼠下丘脑中去甲肾上腺素(NE)、多巴胺(DA)、五羟色胺(5-HT)含量;HE染色观察大鼠松果体病理学改变。结果与空白组比较,模型组睡眠潜伏期延长、睡眠持续期缩短(P<0.05);水平运动和垂直运动均减少(P<0.05)。与模型组比较,蛇麻草精油高浓度组睡眠潜伏期缩短、睡眠持续期延长(P<0.05);水平运动和垂直运动增加(P<0.05);血清MT、GABA含量上升,Glu含量下降,Glu/GABA下降(P<0.05);下丘脑中5-HT含量上升,NE和DA含量下降(P<0.05)。松果体细胞和神经胶质细胞形态结构正常、排列均匀、数目明显恢复。结论蛇麻草精油香薰法对失眠大鼠具有一定助眠作用,可能与改善松果体结构,促进MT、抑制性递质GABA及5-HT的分泌,以及抑制兴奋性递质Glu、NE、DA的分泌有关。

Effects of annealing on microstructure and mechanical properties of γ-TiAl alloy fabricated via laser melting deposition

The microstructure evolution and mechanical properties of the as-deposited γ-TiAl-based alloy specimen fabricated via laser melting deposition and as-annealed specimens at different temperatures were investigated.The results show that the microstructure of as-deposited specimen is composed of fineα2(Ti3Al)+γlamellae.With the increase of annealing temperature,the bulk γ m(TiAl)phase gradually changes from single γ phase toγphase+acicularα2 phase,finally small γ phase+lamellar α2+γ phase.Compared with the mechanical properties of as-depositedγ-TiAl alloy(tensile strength 469 MPa,elongation 1.1%),after annealing at 1260℃ for 30 min followed by furnace cooling(FC),the room-temperature tensile strength of the specimen is 543.4 MPa and the elongation is 3.7%,which are obviously improved.

Function of nonstructural 5A protein of genotype 2a in replication and infection of HCV with gene substitution

AIM:To explore the function of Nonstructural 5A(NS5A) protein of genotype 2a(JFH1)in the replication and infection of hepatitis C virus(HCV).METHODS:Intergenotypic chimera FL-J6JFH/J4NS5A was constructed by inserting NS5A gene from 1b stain HC-J4 by the overlapping polymerase chain reaction (PCR)method and the restriction enzyme reaction.In vitro RNA transcripts of chimera,prototype J6JFH and negative control J6JFH1(GND)were prepared and transfected into Huh-7.5 cells with liposomes.Immunofluorescence assay(IFA),fluorescence quantitative PCR and infection assay were performed to determine the protein expression and gene replication in Huh-7.5 cells.RESULTS:The HCV RNA levels in FL-J6JFH/J4NS5A chimera RNA transfected cells were significantly lower than the wild type at any indicated time point(2.58 ±5.97×106 vs 4.27±1.72×104,P=0.032).The maximal level of HCV RNA in chimera was 5.6±1.8× 104 GE/μg RNA at day 34 after transfection,while the wild type reached a peak level at day 13 which was 126 folds higher(70.65±14.11×105 vs 0.56±0.90 ×105,P=0.028).HCV proteins could also be detected by IFA in chimera-transfected cells with an obviously low level.Infection assay showed that FL-J6JFH/J4NS5A chimera could produce infectious virus particles,ranging from 10±5 ffu/mL to 78.3±23.6 ffu/mL,while that of FL-J6JFH1 ranged from 5.8±1.5×102 ffu/mL to 2.5±1.4×104 ffu/mL.CONCLUSION:JFH1 NS5A might play an important role in the robust replication of J6JFH1.The establishment of FL-J6JFH/J4NS5A provided a useful platform for studying the function of other proteins of HCV.

Genome-wide analysis of the B3 transcription factors reveals that RcABI3/VP1 subfamily plays important roles in seed development and oil storage in castor bean(Ricinus communis)

The B3 transcription factors(TFs)in plants play vital roles in numerous biological processes.Although B3 genes have been broadly identified in many plants,little is known about their potential functions in mediating seed development and material accumulation.Castor bean(Ricinus communis)is a non-edible oilseed crop considered an ideal model system for seed biology research.Here,we identified a total of 61 B3 genes in the castor bean genome,which can be classified into five subfamilies,including ABI3/VP1,HSI,ARF,RAV and REM.The expression profiles revealed that RcABI3/VP1 subfamily genes are significantly up-regulated in the middle and later stages of seed development,indicating that these genes may be associated with the accumulation of storage oils.Furthermore,through yeast one-hybrid and tobacco transient expression assays,we detected that ABI3/VP1 subfamily member RcLEC2 directly regulates the transcription of RcOleosin2,which encodes an oil-body structural protein.This finding suggests that RcLEC2,as a seed-specific TF,may be involved in the regulation of storage materials accumulation.This study provides novel insights into the potential roles and molecular basis of B3 family proteins in seed development and material accumulation.

Exploring the mechanism of Yuxuebi Pill in the treatment of osteoarthritis through network pharmacology and molecular docking

Background:Osteoarthritis(OA)is one of the most common joint diseases which mainly involves damage to the articular cartilage andinvolves the entire joint tissue.Yuxuebi Pill(YXBP)is one of the traditional Chinese medicine compound drugs for the treatment of OA.In this study,we aimed to use network pharmacology and molecular docking technology to systematically explain the potential anti-OA mechanism of YXBP.Methods:We used the TCMSP database to query YXBP related natural compounds,and obtained potential targets of these natural compounds through PubChem and SwissTargetPrediction database.According to the OMIM database,GeneCard database,CTD database,and DrugBank database,the potential targets of OA were obtained.According to the location results of potential target genes of YXBP and OA,a PPI network was constructed and amplified to obtain the interaction between targets.We screened out the HUB target through topological analysis.In addition,we used David bioinformatics resources to enrich the GO biological processes and KEGG pathways.Molecular docking was used to verify the relationship between the core compounds and proteins.Results:This study identified five core components of YXBP for OA,including quercetin,beta-sitosterol,stigmasterol,kaempferol,and luteolin.At the same time,we obtained a total of 264 related targets for OA.Functional enrichment analysis suggested that YXBP exerted its pharmacological effects on OA by modulating multiple pathways,including the IL-17 signaling pathway,HIF-1 signaling pathway,JAK-STAT signaling pathway.The biological processes mainly involve inflammation,cell apoptosis,and cell cycle.Subsequently,based on molecular docking the key compounds could be found to spontaneously bind to the proteins.Conclusions:YXBP may exert an anti-OA effect through pathways,including the IL-17 signaling pathway,HIF-1 signaling pathway,JAK-STAT signaling pathway.The application of network pharmacology and molecular docking technology may provide a novel method for research of Chinese herbal medicine.YXBP may also provide a complementary treatment option for patients with OA.

Transcriptome profiling during double-flower development provides insight into stamen petaloid in cultivated Lilium

Asiatic hybrid lilies(Lilium spp.),as the biggest cultivar groups of the lily variety are an ornamental plant with elegant floral patterns and bright colors.We discovered a double-flower Asiatic hybrid cultivar‘Annemarie’s Dream’whose stamens convert into petaloid stamens in varying degrees.Double-flower is a significant ornamental trait of the flower organ.However,the molecular mechanism of stamen petaloid formation has not been widely studied in Asiatic hybrid lily.Therefore,we used RNA-seq to contrast transcriptomes of stamen,petaloid stamen and inner tepal at two developmental stages.In total,190,488 unigenes were obtained and 37,549 differentially expressed genes(DEGs)were identified.We focused on DEGs involved in phytohormone signaling and transcription factor regulation,especially the MADS-box genes(A-class gene LiAP1;B-class gene LiPI;C-class gene LiAG;E-class gene LiAGL6,LiSEP3).Furthermore,we performed weight gene co-expression network analysis(WGCNA)and identified two co-expressed MADS-box homeotic genes(LiAG,CL14315.Contig2_All;LiAP1,CL10060.Contig3_All)as hubs.We also found that CL3014.Contig2_All(PYL)and CL5627.Contig1_All(GID2)as phytohormone-related genes may participate in the regulation of the stamen petaloid during double-flower development.In summary,our findings provide an insight into the molecular regulatory network underlying stamen petaloid and thereby offering a theoretical basis for double-flower breeding in Lilium.

Visualization of ferromagnetic domains in vanadium-doped topological insulator thin films and heterostructures

Magnetically doped topological insulator(TI) thin films and related heterostructures have been extensively studied for years due to their exotic quantum transport properties and potential applications in low-dissipation electronic devices and quantum computation.The selection of magnetic dopants is crucial to realize a high-quality magnetic TI with a robust ferromagnetic ordering and a preserved topological band structure.In this paper,we briefly review the recent magnetic domain imaging works in vanadium-doped magnetic topological insulator thin films and heterostructures.Using cryogenic magnetic force microscopy and in situ transport measurements,a ferromagnetic domain behavior has been demonstrated in V-doped Sb2Te3(ST) and Cr,V co-doped(Bi,Sb)2Te3(BST) thin films.The direct visualization of long-range ferromagnetic ordering in a quantum anomalous Hall(QAH) system sheds light on enhancing the QAH temperature by improving the ferromagnetism.Taking advantage of the different coercivity of Cr-and V-doped BST films,an axion insulating state has been observed in Cr-doped BST/BST/V-doped BST sandwich heterostructures.The antiparallel magnetization alignment,which is the key ingredient for realization of axion insulating state,has been directly visualized via magnetic imaging at various magnetic fields.The V-doped ST/ST heterostructures also provide a platform for Berry phase engineering in momentum space.By suppressing the anomalous Hall effect in such heterostructures,an intrinsic topological Hall effect can be revealed,which resolved the long-term puzzle of the origin of THE in the ultrathin ferromagnetic thin films and two-dimensional ferromagnets.The review of magnetic domain imaging in vanadium-doped topological insulators and heterostructures inspires further exploration of quantum transport properties in magnetic topological insulators and deepens the understanding of the interplay between the magnetic ordering and topological electronic band structures in magnetic TIs and beyond.

Improvement of microstructure and mechanical properties of Al−Cu−Li−Mg−Zn alloys through water-cooling centrifugal casting technique

The microstructure and mechanical properties of as-cast Al−Cu−Li−Mg−Zn alloys fabricated by conventional gravity casting and centrifugal casting techniques combined with rapid solidification were investigated.Experimental results demonstrated that compared with the gravity casting technique,the water-cooling centrifugal casting technique significantly reduces porosity,refinesα(Al)grains and secondary phases,modifies the morphology of secondary phases,and mitigates both macro-and micro-segregation.These improvements arise from the synergistic effects of the vigorous backflow,centrifugal field,vibration and rapid solidification.Porosity and coarse plate-like Al13Fe4/Al7Cu2Fe phase result in the fracture before the gravity-cast alloy reaches the yield point.The centrifugal-cast alloy,however,exhibits an ultra-high yield strength of 292.0 MPa and a moderate elongation of 6.1%.This high yield strength is attributed to solid solution strengthening(SSS)of 225.3 MPa,and grain boundary strengthening(GBS)of 35.7 MPa.Li contributes the most to SSS with a scaling factor of 7.9 MPa·wt.%^(-1).The elongation of the centrifugal-cast alloy can be effectively enhanced by reducing the porosity and segregation behavior,refining the microstructure and changing the morphology of secondary phases.

Gene Expression Profile of Persistent Postoperative Hypertension Patients with Aldosterone-producing Adenomas

Background：Hypertension often persists after adrenalectomy for primary aldosteronism （PA）.Many studies have analyzed the outcomes of adrenalectomy for aldosterone-producing adenomas （APA） to identify predictive factors for persistent hypertension.However,differentially expressed genes in persistent postoperative hypertension remain unknown.Our aim was to describe gene expression profile of persistent postoperative hypertension patients with APA.Methods：In this study,we described and compared gene expression profiles in persistent postoperative hypertension and postoperative normotension in Chinese patients with APA using microarray analysis.Confirmation was performed with quantitative real time-polymerase chain reaction analysis.Bioinformatic analysis （gene ontology analysis,pathway analysis and network analysis） was used for further research.Results：Microarray analysis identified a total of 99 differentially expressed genes,including 18 up-regulated and 81 down-regulated genes.Among the dysregulated genes were fat atypical cadherin 1 as well as fatty acid binding protein 4 and other genes that have not been previously studied in persistent postoperative hypertension with APA.Bioinformatics analysis indicated that differentially expressed genes were associated with lipid metabolic process,metal ion binding,and cell differentiation.Pathway analysis determined that five pathways corresponded to the dysregulated transcripts.The mRNAs-ncRNAs co-expression network was composed of 49 network nodes and 72 connections between 18 coding genes and 31 noncoding genes.Conclusions：This study revealed differentially expressed genes in persistent postoperative hypertension with APA and provided a resource of candidate genes for exploration of possible drug targets and prognostic markers.

Prediction model for mechanical properties of hot-rolled strips by deep learning

The prediction of the mechanical properties of hot-rolled strips is a very complex,highly dimensional and nonlinear problem,and the published models might lack reliability,practicability and generalization.Thus,a new model was proposed for predicting the mechanical properties of hot-rolled strips by deep learning.First,the one-dimensional numerical data were transformed into two-dimensional data for expressing the complex interaction between the influencing factors.Subsequently,a new convolutional network was proposed to establish the prediction model of tensile strength of hot-rolled strips,and an improved inception module was introduced into this network to abstract features from different scales.Many comparative experiments were carried out to find the optimal network structure and its hyperparameters.Finally,the prediction experiments were carried out on different models to evaluate the performance of the new convolutional network,which includes the stepwise regression,ridge regression,support vector machine,random forest,shallow neural network,Bayesian neural network,deep feed-forward network and improved LeNet-5 convolutional neural network.The results show that the proposed convolutional network has better prediction accuracy of the mechanical properties of hot-rolled strips compared with other models.

Evaluation of Basal Serum Adrenocorticotropic Hormone and Cortisol Levels and Their Relationship with Nonalcoholic Fatty Liver Disease in Male Patients with Idiopathic Hypogonadotropic Hypogonadism

Background： Prolonged gonadal hormone deficiency in patients with idiopathic hypogonadotropic hypogonadism （IHH） may produce adverse effects on the endocrine homeostasis and metabolism. This study aimed to compare basal serum adrenocorticotropic hormone （ACTH） and cortisol levels between male IHH patients and healthy controls. Moreover, this study compared the basal hypothalamic-pituitary-adrenal （HPA） axis in patients with and without nonalcoholic fatty liver disease （NAFLD）, and also evaluated the relationship between basal HPA axis and NAFLD in male IHH patients. Methods： This was a retrospective case-control study involving 75 Chinese male IHH patients （mean age 21.4 ± 3.8 years, range 17 30 years） and 135 healthy controls after matching tbr gender and age. All subjects underwent physical examination and blood testing for serum testosterone, luteinizing hormone, follicle-stimulating hormone. ACTH, and cortisol and biochemical tests. Results： Higher basal serum ACTH levels （8.25 ±3.78 pmol/L vs. 6.97 ±2.81 pmol/L） and lower cortisol levels （366.70 ±142.48 nmol/L vs. 452.82 ± 141.53 nmol/L） were observed ill male IHH patients than healthy subjects （all P 〈 0.05）. IHH patients also showed higher metabolism parameters and higher prevalence rate of NAFLD （34.9% vs. 4.4%） than the controls （all P 〈 0.05）. Basal serum ACTH （9.91 ±4.98 pmol/L vs. 7.60 ±2.96 pmol/L） and dehydroepiandrosterone sulfate （2123.7 ±925.8 μg/L vs. 1417.1 ±498.4 μg/L） levels were significantly higher in IHH patients with NAFLD than those without NAFLD （all P 〈 0.05）. We also found that basal serum ACTH levels were positively correlated with NAFLD （r = 0.289, P 〈 0.05） and triglyceride levels （r - 0.268, P 〈 0.05） in male IHH patients. Furthermore, NAFLD was independently associated with ACTH levels in male IHH patients by multiple linear regression analysis. Conclusions： The male IHH patients showed higher basal serum ACTH levels and lower cortisol levels than matched healthy controls. NAFLD was an independent associated factor for ACTH levels in male IHH patients. These preliminary findings provided evidence of the relationship between basal serum ACTH and NAFLD in male IHH patients.

Light-activated nitric-oxide overproduction theranostic nanoplatform based on long-circulating biomimetic nanoerythrocyte for enhanced cancer gas therapy

The limited intratumoral perfusion of nitric oxide(NO)-carrying nanoparticles into solid tumors caused by the inherent biological barriers in vivo greatly attenuates their generated efficacy. Herein, through entrapping heat-sensitive NO donors(BNN6)on mesoporous polydopamine nanoparticles(M-PDA) and subsequently enveloping with red blood cells membranes, a heatresponsive biomimetic theranostic nanoerythrocyte(M/B@R) is developed to boost NO-based cancer therapy. The reserved intact structure of red blood cells membranes(RBCm) endows M/B@R with superior biosafety and stealth properties for prolonged circulation time and subsequent enhanced tumor accumulation. Once internalized in tumors and excited by nearinfrared light(NIR, 808 nm) irradiation, M/B@R can not only yield plenty of heat for photothermal therapy(PTT) but also achieve the overproduction of NO for highly-efficient NO gas therapy due to its high loading capacity and NIR-absorbing property of M-PDA. The generated NO further ensures the formation of ONOO^(-) which possesses remarkable toxicity to tumor as well as alleviating tumor hypoxia. It is found that M/B@R with NIR as the excitation source can significantly induce synthetic lethality to tumors via the hyperthermia, DNA damage and the ease of tumor hypoxia. Simultaneously, M/B@R also exhibits the potential for bimodal fluorescence and photothermal imaging. The RBCm-camouflaged NO delivery nanoplatform with bimodal imaging capability in this work may provide a new combinatorial paradigm to induce PTT/NO for cancer theranostic applications.