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Nanofluids heat transfer in a helical coil under pulsation condition was numerically simulated. The dynamic single phase model which considered Brownian motion effect was utilized to study the Al2O3 nanofluids heat transfer in helical coils. The reliability test results were consistent with experimental results. Then, pulsation was further imposed. The influence of the pulsation frequency on the heat transfer performance was explored. And the changes of instantaneous h with frequency were further studied to interpret the results. The axial velocity contours, axial velocity distributions, and cross-section velocity vectors at various planes along the coil were examined. The results revealed that there was an optimum pulsation frequency for heat transfer augmentation within the scope of Re. The secondary flow generated in cross region and the counter-rotating vortex formed in the axial direction all devoted to the helical coil heat transfer augmentation under pulsation.

The microstructure and mechanical properties of the Mg–3Sn–2Al–1Zn (TAZ321) alloy extruded at 180–250°C and at a ram speed of 0.08 mm/s were investigated by optical microscope, X-ray diffraction, s...

This study focuses on the inbound container unloading and stacking problem at container terminals and achieves both a reasonable unloading sequence and the optimal yard stacking distribution. A formulation is proposed as the relational expression between the expected number of rehandles and the stacking height. Based on the formulation, an integer programming model is established to both find the optimal stacking distribution and unloading sequence and attempt to minimize the expected number of rehandles. The model can be solved by the commercial solver for small-scale instances. To solve for large-scale instances in the real world, a two-stage search algorithm is designed, therein incorporating an initial stage for generating the feasible solution and a neighborhood search stage for finding the optimal solution. The algorithm can find an optimal solution in polynomial time, which is proved by theoretical methods and evidenced by numerical experiments.

This paper is concerned with a conditional test for regression coefficients in ultrahigh dimensional linear models. Conditioning on a subset of important predictors in the model, we test the overall significance of regression coefficients of the remaining ultrahigh dimensional predictors. We first propose a conditional U-statistic test (CUT) based on an estimated U-statistic for a high dimensional linear regression model and prove that its null asymptotic distribution is normal under some mild assumptions. However, the empirical power of the proposed test is inversely affected by the dimensionality of predictors. To this end, we further propose a two-stage CUT with screening (CUTS) procedure to reduce the dimensionality under the sparsity assumption and enhance the empirical power based on random data splitting strategy. In the first stage, we divide data randomly into two equal halves and apply the conditional sure independence screening to the first half to reduce the dimensionality; In the second stage, we apply the proposed CUT test to the second half. To eliminate the effect of random data splitting and further enhance the empirical power, we also develop a powerful ensemble algorithm based on multiple splitting strategy and prove that the family-wise error rate is asymptotically controlled at a given significance level. We demonstrate the excellent finite-sample performances of the proposed conditional test via Monte Carlo simulations and a real data analysis.

Superconducting joints are one of the key technologies to make Ba1-xKxFe2As2 (Ba-122) superconducting wires or tapes for high-field applications. Herein, superconducting joints were fabricated by a simple cold-pressing method, and the joint resistance of the iron-based superconducting joint was estimated for the first time. The superconducting properties, microstructures, and elements distribution in the joint regions were investigated. At 4.2 K and 10 T, a transport critical current Ic of 105 A for the joint was obtained, and the critical current ratio (CCR= Ic-joint/Ic-tape) of the joint was 94.6%. On the other hand, the joint show very low joint resistance of 2.7x10^-13 ohm in self-field at 4.2 K. Among iron-based superconductors (IBS), this work is the first to successfully realize a superconducting joint with such high CCR and low joint resistance. This work shows great potential to apply Ba-122 in a range of practical applications, where superconducting joints are essential., 20 pages, 8 figures

BackgroundPARP inhibitor (PARPi) is an important progress in ovarian cancer treatment. The available evidence suggests that BRCA mutation and homologous recombination deficiency (HRD) are effective biological markers for PARPi. Here we investigated the relationship between adverse events (AEs) and efficacy of PARPi in ovarian cancer patients.MethodsSeventy-eight patients with ovarian cancer patients underwent Olaparib and Niraparib from July 2018 to July 2020 were analyzed. AEs were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Chi-square test or fisher exact tests was performed to observe the association between categorical variables. Logistic regression analysis was conducted to investigate the independent variables for disease control response (DCR). Progression-free survival (PFS) was compared between AEs variables by log-rank test.ResultsPatients with AEs in the first one week had a higher DCR compared with those after one week (86.11% versus 60.98%, p=0.013). Patients with serious AEs (SAEs) had a significantly higher DCR (81.40% versus 60.60%, p=0.045). There were associations between anemia and DCR in both occurrence (79.63% versus 56.52%, p=0.037) and grade (100% versus 73.17%, p=0.048). The median PFS of patients with hematological toxicity was longer than that of patients with no-hematological toxicity (30 versus 20 weeks, p=0.047). Patients with hematological toxicity within four weeks had prolonged median PFS than those with hematological toxicity after four weeks (40 versus 22 weeks, p=0.003).ConclusionsThe early presence of AEs and SAEs in hematological toxicity of PARPi were related to the antitumor efficacy, which might be a valid and easily measurable clinical marker in ovarian cancer patients.

Dong Guo,1 Liang Fang,2 Xuelai Yu,3 Congyang Wang,4 Yan Wang,4 Wenwen Guo4 1Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 2Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, People’s Republic of China; 3Department of Neurology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, People’s Republic of China; 4Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210011, People’s Republic of ChinaCorrespondence: Wenwen Guo; Yan WangDepartment of Pathology, The Second Affiliated Hospital of Nanjing Medical University, No. 121 Jiangjiayuan Road, Nanjing, 210011, Jiangsu, People’s Republic of ChinaTel +86-25-58509910; +86-25-58509909Email hguowen@163.com; wangyan_9999@sina.comObjective: The purpose of this study was to investigate the relationships between TP53 Pro72Arg (rs1042522) polymorphism and susceptibility to type 2 diabetes (T2DM) and its related complications.Methods: The TP53 Pro72Arg polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 206 T2DM patients and 446 healthy controls. Mitochondrial DNA (mtDNA) content, mtDNA transcriptional level and large-scale mtDNA deletion were evaluated in leukocytes of T2DM patients using fluorescence-based quantitative PCR (FQ-PCR), reverse transcriptase-quantitative PCR (RT-qPCR) and long-range PCR approaches, respectively. The data of our study were processed by GraphPad Prism software (version 7.00).Results: The distribution of TP53 Pro72Arg differed in T2DM patients from the controls, with a moderately increased proportion of TP53 Arg72 variant carriers (Pro/Arg and Arg/Arg genotypes) (88.3% vs 81.2%, p=0.022; OR=1.089, 95% CI=1.018– 1.164). T2DM patients with Arg/Arg genotype had significantly decreased prevalences of diabetic neuropathy and retinopathy compared to those without (6.5% vs 19.4%, p=0.018 and 14.8% vs 30.7%, p=0.018, respectively). T2DM patients with Arg/Arg genotype had higher mtDNA content and mtRNA expression level than those who were not Arg/Arg genotype (p< 0.05 for all), and we did not observe mtDNA 4977-base pair (bp) deletion mutations in the leukocytes of T2DM patients.Conclusion: There was a significant association of the TP53 Pro72Arg polymorphism with susceptibility to T2DM, and the homozygous Arg/Arg genotype of this gene locus might be a protective factor for diabetic complications. Those results suggested that the TP53 Arg72 variant had a different association with type 2 diabetes and its complications, and it might be related to mtDNA maintenance of the TP53 Arg72 variant under hyperglycemia-induced stress.Keywords: TP53, type 2 diabetes mellitus, complication, mtDNA content, mtRNA, mtDNA maintenance

A novel feature screening method is proposed to examine the correlation between latent responses and potential predictors in ultrahigh-dimensional data analysis. First, a confirmatory factor analysis (CFA) model is used to characterize latent responses through multiple observed variables. The expectation-maximization algorithm is employed to estimate the parameters in the CFA model. Second, R-Vector (RV) correlation is used to measure the dependence between the multivariate latent responses and covariates of interest. Third, a feature screening procedure is proposed on the basis of an unbiased estimator of the RV coefficient. The sure screening property of the proposed screening procedure is established under certain mild conditions. Monte Carlo simulations are conducted to assess the finite-sample performance of the feature screening procedure. The proposed method is applied to an investigation of the relationship between psychological well-being and the human genome.

In this paper, collected the operation data of a fuel cell vehicle (FCV) at - 30 ℃ by analyzing the vehicle CAN message. Took stack temperature, stack voltage, stack calorific value and battery SOC as the target objects, analyzed the control logic of fast cold start of the fuel cell vehicle stack at low temperature, and summarized the technical highlights of the fuel cell vehicle, which can be used to guide the product development of domestic automobile enterprises.

Objective The purpose of this study was to investigate the relationships between TP53 Pro72Arg (rs1042522) polymorphism and susceptibility to type 2 diabetes (T2DM) and its related complications. Methods The TP53 Pro72Arg polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 206 T2DM patients and 446 healthy controls. Mitochondrial DNA (mtDNA) content, mtDNA transcriptional level and large-scale mtDNA deletion were evaluated in leukocytes of T2DM patients using fluorescence-based quantitative PCR (FQ-PCR), reverse transcriptase-quantitative PCR (RT-qPCR) and long-range PCR approaches, respectively. The data of our study were processed by GraphPad Prism software (version 7.00). Results The distribution of TP53 Pro72Arg differed in T2DM patients from the controls, with a moderately increased proportion of TP53 Arg72 variant carriers (Pro/Arg and Arg/Arg genotypes) (88.3% vs 81.2%, p=0.022; OR=1.089, 95% CI=1.018–1.164). T2DM patients with Arg/Arg genotype had significantly decreased prevalences of diabetic neuropathy and retinopathy compared to those without (6.5% vs 19.4%, p=0.018 and 14.8% vs 30.7%, p=0.018, respectively). T2DM patients with Arg/Arg genotype had higher mtDNA content and mtRNA expression level than those who were not Arg/Arg genotype (p, Graphical Abstract

Yolk sac tumors (YSTs) of the endometrium and the broad ligament are very rare, with only 29 cases and one case of each other reported before in the English literature. Due to lack of standard guidelines, the treatment strategies of these diseases are controversial. Here, we share two cases of YSTs originating from the endometrium and the broad ligament respectively and review related literature. A 35-year-old woman was diagnosed with endometrial YST in our center and underwent surgery followed by chemotherapy with BEP (bleomycin, cisplatin and etoposide) regimen for six courses. After follow-up for 21 months, there is still no evidence of relapse. Another 36-year-old woman was admitted to our department with YST of the broad ligament. She was treated with surgery followed by chemotherapy with BEP regimen and was lost to follow-up after completing therapy. The case of endometrial YST we shared was similar to cases reported before, while the case with YST of the broad ligament we shared was the second case reported worldwide. Both of these two cases were treated with surgery combined with chemotherapy with BEP regimen.

A water-cooled, stove-powered thermoelectric generator was designed and tested to provide electricity in off-grid areas and under emergency conditions. An Ω-shaped heat collector, which facilitates the compact incorporation of 20 thermoelectric modules and works under the radiation heat transfer mode, was proposed. A power load test was performed and compared with previous studies, thereby indicating that a standardization is required for future studies. Different aspects for evaluating the performance of a stove-powered thermoelectric generator were discussed, and appropriate parameters to qualify a stove-powered thermoelectric generator were suggested. Thermoelectric efficiency was measured and compared with a theoretical prediction. A simplified theoretical model, which was verified with experimental data, was developed to explore the temperature distribution inside the thermoelectric module and the power generation performance of the entire stove-powered thermoelectric generator. Special efforts were exerted to reveal the influences of thermal grease, ceramic substrate, and thermal contact on the effective temperature difference.

In this paper, I propose to read shame into Carson McCullers’s 1940 novel, The Heart is a Lonely Hunter, particularly into the characterization of the protagonist John Singer. Often conceived of as...

This paper is concerned with independence test in high-dimension. A new test statistic is proposed with two terms: one is based on the modified distance correlation statistic, the other is construc...

This study considers the block relocation and loading problem in container terminals. The optimal loading sequence and relocation location are simultaneously decided on the basis of the desired ship‐bay and initial yard space configuration. An integer linear programming model is developed to minimize the number of relocations in the yard space on the basis of no shifts in the ship bay. The accuracy of the model is tested on small‐scale scenarios by using CPLEX. Considering the problem size in the real world, we present a rule‐based heuristic method that is combined with a mathematical model for the removal, loading, and relocation operations. The influence of rules on algorithm performance is also analyzed, and the heuristic algorithm is compared with different types of algorithms in the literature. The extensive numerical experiments show the efficiency of the proposed heuristic algorithm.

Objective: The results of the study on the relationship between obesity and cord blood irisin were far apart. The aim of this study was to explore the relationship between cord blood irisin levels ...

In this work, near-infrared fluorescence (NIRF) and magnetic resonance (MR) dual-modality imaging probes are prepared by conjugating maleimide derivative cyanine dye (Mal-Cy5.5), gadolinium‐diethylenetriamine pentaacetic acid (Gd-DTPA), and RGD peptide (Mal-PEG2-RGD) on thioether-bridged mesoporous organosilica nanoparticles (MONs) via click reaction. Fourier transform infrared (FT-IR) spectra, zeta potentials, UV–vis spectra, and energy dispersive X-ray (EDX) spectrum confirm the successful modifications of the functional molecules on the MONs. The prepared MON-Gd-Cy5.5-RGD probes shows excellent NIRF and MR imaging properties, and the relaxivity rate (r1) is measured up to 2.85 mM−1 s −1. In addition, the MON-Gd-Cy5.5-RGD probes show excellent in vitro and in vivo biocompatibility. Confocal laser scanning microscopy and flow cytometry demonstrate that the MON-Gd-Cy5.5-RGD can efficiently target to MDA-MB-231 tumor cells. Additionally, ex vivo NIFR and in vivo MR imaging demonstrate that the MON-Gd-Cy5.5-RGD probes can accumulate in tumor and improve the signals of tumor.

Rosai-Dorfman disease (RDD) is a condition of unknown etiology, and characterized by the proliferation of histiocytes. RDD most commonly affects lymph nodes, and central nervous system (CNS) involvement is rare. Here, we describe the case of a 43-year-old man who presented with an intradural tumour of the thoracic spine. The patient underwent a laminectomy for tumour resection and pathology results diagnosed the tumour as a RDD. Two years later, brain magnetic resonance imaging (MRI) revealed multiple intracranial dural-based lesions. Prednisolone treatment was initiated and led to resolution of the disease. We reviewed the literature to the investigate clinical characteristics, imaging features, diagnosis and treatment protocols pertaining to such cases.

Background Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with an unknown etiology. Increased oxidative stress and mitochondrial dysfunction are thought to be involved in its pathogenesis. However, the effect of the AluYb8MUTYH polymorphism on IPF is not known. Results The mean age of onset for IPF in patients homozygous for the AluYb8MUTYH variant (P/P) was 66.5 years old, which was significantly earlier than that in patients with the wild-type (A/A, 70.45 years old). For the 97 male IPF patients with lung function data, the FVC% of the P/P patients was lower than that of the wild-type (A/A) or heterozygous (A/P) patients. The laboratory analysis indicated that an increased mtDNA content and impaired mitochondrial quality control were associated with the P/P genotype. We also confirmed that AluYb8 insertion into MUTYH caused decreased MUTYH1 expression in lung tissues. Methods We compared the lung function of IPF patients and observed the mtDNA content, mtDNA integrity and molecular expression of mitochondrial quality control among subjects with different AluYb8MUTYH genotypes. Additionally, immunoblotting and a reporter gene system were used to test whether altered mitochondrial MUTYH1 expression was linked to AluYb8MUTYH. Conclusions The AluYb8 insertion polymorphism in MUTYH impairs mtDNA stability and affects the age of onset of IPF.

Luman, also known as cAMP-response element-binding protein 3, is an endoplasmic reticulum stress-related protein that has been identified as a novel transcriptional coregulator of a variety of nuclear receptors. Herein, immunohistochemistry results showed that Luman was specifically expressed in mouse Leydig cells in an age-dependent increase manner, from prepuberty to sexual maturation. Luman was not detected in Sertoli cells within the seminiferous tubules at any developmental period. The immunofluorescent experiment indicated that Luman was mainly located within the cytoplasm of murine Leydig tumor cells (MLTC-1) and primary Leydig cells (PLCs). To investigate the physiological function of Luman, experiments were conducted to examine the consequences of short hairpin RNA- and small interfering RNA-mediated Luman knock-down in MLTC-1 and PLCs, respectively. Luman knock-down significantly upregulated the expression of steroidogenic acute regulatory, cytochrome P450 cholesterol side-chain cleavage enzymes, 3β-hydroxysteroid dehydrogenase, and 17-α-hydroxylase/C17-20 lyase in MLTC-1 cells and PLCs. Luman knock-down caused an increase in human chorionic gonadotropin-stimulated testosterone production in vitro and in vivo. The nuclear receptors SF-1 and Nur-77 were significantly increased upon Luman knock-down in MLTC-1. By contrast, the level of the nuclear receptor SHP decreased. Luciferase reporter assay results demonstrated that Luman knock-down upregulated the activity of SF-1 and Nur-77 promoters. These data suggested that Luman expressed in mouse Leydig cells in an age-dependent increase manner. Luman knock-down upregulated the activity of SF-1 and Nur-77 promoters, which lead to the increase of testosterone synthesis and steroidogenesis genes expression. In conclusion, these findings provide us with new insights into the role Luman played in male reproduction.

A bio-based phosphorus-containing benzoxazine monomer (CBz) was successfully synthesized through the reaction between cardanol and DOPO-based diamine. In order to simultaneously improve the toughness and flame retardancy of epoxy resin (EP), various contents of CBz in combination with boron-doped graphene (BG) nanosheets were incorporated into EP to obtain boron-doped graphene/cardanol derived benzoxazine-epoxy composites (EP/CBz/BG). By comparison, cardanol derived benzoxazine-epoxy co-polymers (EP/CBz) were also fabricated. Results show that the addition of the as-prepared CBz into EP not only endowed EP with excellent flame retardancy, but also improved the glass transition temperature and impact strength. Specifically, the peak heat release rate of EP composite with 13 wt% CBz and 2 wt% BG decreased by 48% compared to that of neat EP, accompanying with an increase of impact strength by 22%. These favorable features of EP/CBz/BG composites are attributed to the unique structure of CBz and high resistance to thermal decomposition of BG.

Testing the existence of low-dimensional perturbations or signals is very important, e.g., in factor analysis and signal processing. This paper aims to develop new tests for high-dimensional spiked covariance matrices based on a projection approach. The asymptotic distribution of the proposed tests is obtained under regularity conditions. We further explore a power enhancement technique under covariance matrix sparsity. The finite-sample enhanced power performance of the proposed tests is shown through simulations. A microarray dataset is used for illustration purposes.

This paper proposed an improved optimization algorithm for engineering optimization problems. This improved optimization algorithm, namely, gravitational search strategy-assisted rider optimization algorithm (GSSROA), combines the gravitational search strategy (GSS) with the rider optimization algorithm (ROA). In the GSSROA, the search step can be adaptively adjusted in each iteration. The performance of the GSSROA has been verified with three benchmark engineering design problems. The results indicate that the proposed GSSROA has the feasibility and good robustness. Then, the GSSROA is applied to optimize the weight of the front axle of an automobile under the non-linear constraints. The results show that the GSSROA can achieve the optimal structure with a weight that is reduced by 16.82% compared with the initial design.

Inflammable characteristic produces an inevitable challenge for the corn storage, which endangers the food demand of human being. We investigated the combustion behavior evolvement of corn under di...

In this paper, superfine waste sand generated in waterway regulation engineering was used as the main raw material to produce sand concrete. The effects of ground granulated blast-furnace slag (GGBS) and fly ash (FA) on the mechanical properties, abrasion resistance, and microstructure of sand concrete were measured and compared. The results show that the mechanical properties of sand concrete increase and then decrease with increasing filler content. The optimal filler/sand (F/S) ratios of sand concrete using GGBS and FA fillers are 0.13 and 0.11, respectively. With 300 kg/m3 of cement content, the incorporation of 200 kg/m3 and 150 kg/m3 of GGBS and FA filler, respectively, results in maximum compressive strengths of 36.1 MPa and 30.5 MPa, respectively, at 28 days, and the corresponding splitting tensile strengths are 3.03 MPa and 2.15 MPa, respectively. This optimum mix with weight losses of 6.58% and 8.01% for GGBS and FA fillers, respectively, presents an excellent abrasion resistance. Furthermore, the test results of scanning electron microscopy and mercury intrusion porosimeter indicate that sand concrete with the GGBS filler has higher amount of hydrate products and lower porosity than that with FA. These findings verify the potential usage of sand concrete made with superfine waste sand as a substitute for ordinary concrete in local hydraulic engineering.

Nacre mimetic coatings are attractive candidates for food packaging, electronics, textiles, protective insulation, and flame retardant materials. Inspired by the hierarchical structure of nacre, we present an environmentally friendly strategy to construct robust and flame retardant films using chitin, which is an abundantly available biopolymer. Chitin was phosphorylated to make it water-soluble. Multilayered films were constructed by assembling poly (vinyl alcohol) (PVA), graphene oxide (GO) nanosheets, phosphorylated chitin (p. chitin), and laponite (LAP) via Layer-by-Layer (LbL) and vacuum-assisted filtration (VAF) assemblies. SEM micrographs revealed the nacre-like layered structure while photographic images showed a similar sheen to that of the mother of pearl. The fabricated coatings possess good mechanical properties with a reduced modulus of 25.53 GPa and hardness of 1.45 GPa. In addition, multilayered films exhibited iridescence and attractive flame retardancy. We believe that our strategy of embedding chitin offers cost-effective and environmentally friendly coatings for textiles, food packaging, barrier, and electronic materials.

Background Niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for first/second-line maintenance treatment of ovarian cancer patients with complete or partial response to platinum-based chemotherapy, and multi-line monotherapy in BRCAmt patients or platinum-sensitive recurrence patients with homologous recombination deficiency (HRD). We present real-world experience from a single center of China. Methods Patients treated with niraparib in Jiangsu Cancer Hospital between June 2019 to July 2020 were recruited. The initial dose was given according to individualization. Response and adverse events (AEs) were analyzed by Response Evaluation Criteria in Solid Tumors v1.1. and National Cancer Institute Common Terminology Criteria for Adverse Events v5.0, respectively. HRD testing (AmoyDx®) was detected in most patients. Treatment was given until unequivocal progression or intolerable toxicity. Results Twenty-two patients all received niraparib at a bolus of 200 mg/d. Fifty percent of patients with high-grade serous ovarian cancer are HRD-positive. Six patients underwent first-line maintenance therapy. Sixteen patients received exploratory therapy. Ultimately image evaluation revealed that two patients achieved partial response (PR) and one patient achieved stable disease (SD), yielding objective response rate (ORR) of 33.3% (95%CI = 0.060–0.759) and disease control rate (DCR) of 50% (95%CI = 0.140–0.861) in the exploratory multi-line monotherapy group. The most common AEs were nausea, thrombocytopenia, and anemia. Grade 3–4 thrombocytopenia were managed by dose reduction and interruption. Leg swelling was observed as a new adverse event. Conclusion It is feasible that patients receiving a bolus of 200 mg/d in patients from Chinese population can acquire promising efficacy and tolerance. This is the first real-world data about niraparib in ovarian cancer patients with available HRD status from China.

The fibroblast growth factor (FGF) pathway plays an important role in epithelial-mesenchymal interactions during tooth development. Nevertheless, how the ligands, receptors, and antagonists of the FGF pathway are involved in epithelial-mesenchymal interactions remains largely unknown. Miniature pigs exhibit tooth anatomy and replacement patterns like those in humans and hence can serve as large animal models. The present study investigated the spatiotemporal expression patterns of critical genes encoding FGF ligands (FGF3, FGF4, FGF7, and FGF9), antagonists (SPRY2 and SPRY4) and receptors (FGFR1, FGFR2, and FGFR3) in the third deciduous molars of miniature pigs at the cap (embryonic day 40, E40), early bell (E50), and late bell (E60) stages. The results of in situ hybridization (ISH) with tyramide signal amplification and of qRT-PCR analysis revealed increased expression of FGF7, FGFR1, FGFR2, and SPRY4 in dental epithelium and of FGF7 and FGFR1 in mesenchyme from E40 to E50. In contrast, the results revealed decreased expression of FGF3, FGF4, FGF9, and FGFR3 in dental epithelium and of FGF4, FGF9, FGFR2, and FGFR3 in the mesenchyme from E40 to E60. Mesenchyme signals of FGF3, FGF4, FGF7, SPRY2, FGFR2, and FGFR3 were concentrated in the odontoblast layer from E50 to E60. The distinct expression patterns of these molecules indicated elaborate regulation during dental morphogenesis. Our results provide a foundation for further investigation into fine-tuning dental morphogenesis and odontogenesis by controlling interactions between dental epithelium and mesenchyme, thus promoting tooth regeneration in large mammals.

Background The fibroblast growth factor (FGF) pathway plays important role in epithelial-mesenchymal interactions during tooth development. However, how the ligands, receptors, and inhibitors of the FGF pathway get involved into the epithelial-mesenchymal interactions are largely unknown in miniature pigs, which can be used as large animal models for similar tooth anatomy and replacement patterns to humans. Results In this study, we investigated the spatiotemporal expression patterns of critical genes encoding FGF ligands, receptors, and inhibitors in the third deciduous molar of the miniature pig at the cap, early bell, and late bell stages. With the methods of fluorescence in situ hybridization and real time RT-PCR, it was revealed that the expression of Fgf3, Fgf4, Fgf7, and Fgf9 mRNAs were located mainly in the dental epithelium and underlying mesenchyme at the cap stage. The expression levels of Fgf3 and Fgf7 in the mesenchyme were upregulated in the early bell stage and then concentrated in the odontoblasts layer in the late bell stage. In contrast, the expression levels of Fgf4 and Fgf9 in the mesenchyme were downregulated from the cap to bell stage. Gene expression analysis also suggested that Fgfr1 and Fgfr3 were the major receptors regulating dental calcification. Furthermore, the inhibitor-coding genes Sprouty 2 and Sprouty 4 were expressed in the epithelium and mesenchyme in the three stages, indicating that elaborate regulation occurred during dental morphogenesis. Conclusions The spatiotemporal expression pattern of FGF signaling provides the foundation for future studies aiming to fine-tune dental morphogenesis and odontogenesis by controlling the interactions between the dental epithelium and mesenchyme, thereby promoting tooth regeneration in large mammals.

Background: Immunotherapy has dramatically changed the treatment landscape of cancer. Immunotherapies targeting the programmed death 1/programmed death ligand 1 pathway have been shown to lead to durable responses in patients with a variety of cancers. However, combination approaches are required to extend this benefit beyond a subset of patients. Studies have suggested that anti-angiogenic therapy can elicit or enhance tumor immunity response.Therefore, we hypothesised that combining immunotherapy with anti-angiogenic treatment may have a synergistic effect and may enhance the efficacy of both treatments.Methods: We evaluated the combination of bevacizumab (anti-vascular endothelial growth factor monoclonal antibody) and pembrolizumab (anti-programmed death 1 monoclonal antibody) in two mouse models of human non-small cell lung cancer cell lines (H1299 and A549). We monitored tumour growth and examined changes in the tumour vasculature, along with the frequency and phenotype of tumour-infiltrating lymphocytes.Results: The combination of bevacizumab and pembrolizumab synergistically inhibited tumour growth in vivo without overt toxicity in both cell lines. Combination therapy reprogrammed the immune microenvironment by increasing CD8+ cytotoxic T cell infiltration, thereby turning tumours with different phenotypes into inflamed (‘hot’) tumours. This is potentially mediated by vascular normalisation and endothelial cell activation, as demonstrated by a reduction in the number of microvessels and an increase in adhesion molecules.Conclusions: Taken together, our preclinical studies demonstrate that the combination of bevacizumab and pembrolizumab had a synergistic anti-tumour effect and provides a theoretical basis for translating basic research into clinical applications.