HIBLUP: an integration of statistical models on the BLUP framework for efficient genetic evaluation using big genomic data.

Human diseases and agricultural traits can be predicted by modeling a genetic random polygenic effect in linear mixed models. To estimate variance components and predict random effects of the model efficiently with limited computational resources has always been of primary concern, especially when it involves increasing the genotype data scale in the current genomic era. Here, we thoroughly reviewed the development history of statistical algorithms used in genetic evaluation and theoretically compared their computational complexity and applicability for different data scenarios. Most importantly, we presented a computationally efficient, functionally enriched, multi-platform and user-friendly software package named 'HIBLUP' to address the challenges that are faced currently using big genomic data. Powered by advanced algorithms, elaborate design and efficient programming, HIBLUP computed fastest while using the lowest memory in analyses, and the greater the number of individuals that are genotyped, the greater the computational benefits from HIBLUP. We also demonstrated that HIBLUP is the only tool which can accomplish the analyses for a UK Biobank-scale dataset within 1 h using the proposed efficient 'HE + PCG' strategy. It is foreseeable that HIBLUP will facilitate genetic research for human, plants and animals. The HIBLUP software and user manual can be accessed freely at https://www.hiblup.com.

Both human diseases and agricultural traits can be predicted by incorporating phenotypic observations and a relationship matrix among individuals in a linear mixed model. Due to the great demand for processing massive data of genotyped individuals, the existing algorithms that require several repetitions of inverse computing on increasingly big dense matrices (e.g. the relationship matrix and the coefficient matrix of mixed model equations) have encountered a bottleneck. Here, we presented a software tool named 'HIBLUP' to address the challenges. Powered by our advanced algorithms (e.g. HE + PCG), elaborate design and efficient programming, HIBLUP can successfully avoid the inverse computing for any big matrix and compute fastest under the lowest memory, which makes it very promising for genetic evaluation using big genomic data.

Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses. METHODS: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms. RESULTS: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca2+ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment. CONCLUSIONS: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

Experimental Demonstration of Laser Guiding and Wakefield Acceleration in a Curved Plasma Channel.

Curved plasma channels have been proposed to guide intense lasers for various applications, such as x-ray laser emission, compact synchrotron radiation, and multistage laser wakefield acceleration [e.g. J. Luo et al., Phys. Rev. Lett. 120, 154801 (2018)PRLTAO0031-900710.1103/PhysRevLett.120.154801]. Here, a carefully designed experiment shows evidences of intense laser guidance and wakefield acceleration in a centimeter-scale curved plasma channel. Both experiments and simulations indicate that when the channel curvature radius is gradually increased and the laser incidence offset is optimized, the transverse oscillation of the laser beam can be mitigated, and the stably guided laser pulse excites wakefields and accelerates electrons along the curved plasma channel to a maximum energy of 0.7 GeV. Our results also show that such a channel exhibits good potential for seamless multistage laser wakefield acceleration.

Fusobacterium nucleatum facilitates proliferation and autophagy by activating miR-361-3p/NUDT1 axis through oxidative stress in hypopharyngeal squamous cell carcinoma.

BACKGROUND: To investigate how Fusobacterium nucleatum (Fn) promotes oxidative stress and mediates proliferation and autophagy in hypopharyngeal squamous cell carcinoma (HPSCC). METHODS: The prognosis for 82 HPSCC cases was retrospectively analyzed. HPSCC cell line FaDu was co-cultured with Fn. Knockdown of NUDT1 (shNUDT1 group) was done after observing DNA damage response. CCK8 and tumorigenesis assays for proliferation observation, mitochondria ROS (MitoROS) measurement to examine intracellular oxidative stress, and ELISA to analyze concentration of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in cells. Dual-luciferase reporter assays clarified miR-361-3p connection with NUDT1. Autophagy flow was observed using electron microscopy and related proteins. RESULTS: Fn was highly associated with NUDT1. The shNUDT1 group experienced lower proliferation compared with normal FaDu (NC group) in vivo and in vitro. The shNUDT1 group showed 8-oxo-dG and γH2AX to be elevated. Intracellular ROS decreased in shNUDT1Fn group when compared to Fn group. Upregulating miR-361-3p could suppress NUDT1 expression and downstream proliferation and autophagy. Fn modulated miR-361-3p via OH-, which could be proven by H2O2 assay and N-acetylcysteine. CONCLUSIONS: Higher Fn in HPSCC patients suggests poorer prognosis. NUDT1 might affect cell proliferation and autophagy and modulate DNA damage response. The oxidative stress induced miR-361-3p/NUDT1 axis is first introduced in microbiome-carcinoma research.

Candidate loci for breeding compact plant-type soybean varieties.

Plant height and node number are important agronomic traits that influence yield in soybean (Glycine max L.). Here, to better understand the genetic basis of the traits, we used two recombinant inbred line (RIL) populations to detect quantitative trait loci (QTLs) associated with plant height and node number in different environments. This analysis detected 9 and 21 QTLs that control plant height and node number, respectively. Among them, we identified two genomic regions that overlap with Determinate stem 1 (Dt1) and Dt2, which are known to influence both plant height and node number. Furthermore, different combinations of Dt1 and Dt2 alleles were enriched in distinct latitudes. In addition, we determined that the QTLs qPH-13-SE and qPH-13-DW in the two RIL populations overlap with genomic intervals associated with plant height and the QTL qNN-04-DW overlaps with an interval associated with node number. Combining the dwarf allele of qPH-13-SE/qPH-13-DW and the multiple-node allele of qNN-04-DW produced plants with ideal plant architecture, i.e., shorter main stems with more nodes. This plant type may help increase yield at high planting density. This study thus provides candidate loci for breeding elite soybean cultivars for plant height and node number. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-022-01352-2.

Fabrication and Performance Evaluation of Gelatin/Sodium Alginate Hydrogel-Based Macrophage and MSC Cell-Encapsulated Paracrine System with Potential Application in Wound Healing.

A gelatin/sodium alginate-based hydrogel microsphere has been fabricated after reaction condition optimization. Macrophages (RAW246.7) and adipose mesenchymal stem cells (ADSC) have been subsequently encapsulated in the microsphere in order to construct a 3D paracrine system for wound healing treatment. The synthesized microsphere displayed neglectable cytotoxicity toward both encapsulated cells until 10 days of incubation, indicating promising biocompatibility of the microsphere. A qRT-PCR and ELISA experiment revealed positive regulation of cytokines (Arg-1, IL-6, IL-8, IL-10, bFGF, HGF, VEGF, TLR-1, and CXCL13) expression regarding macrophage phenotype transformation and anti-inflammatory performance both inside the microsphere and in the microenvironment of established in vitro inflammatory model. Additionally, positive tendency of cytokine expression benefit wound healing was more pronounced in a fabricated 3D paracrine system than that of a 2D paracrine system. Furthermore, the 3D paracrine system exhibited more efficiently in the wound healing rate compared to the 2D paracrine system in an in vitro model. These results suggested the current paracrine system could be potentially used as a robust wound healing dressing.

MMAP: a cloud computing platform for mining the maximum accuracy of predicting phenotypes from genotypes.

Accurately predicting phenotypes from genotypes holds great promise to improve health management in humans and animals, and breeding efficiency in animals and plants. Although many prediction methods have been developed, the optimal method differs across datasets due to multiple factors, including species, environments, populations and traits of interest. Studies have demonstrated that the number of genes underlying a trait and its heritability are the two key factors that determine which method fits the trait the best. In many cases, however, these two factors are unknown for the traits of interest. We developed a cloud computing platform for Mining the Maximum Accuracy of Predicting phenotypes from genotypes (MMAP) using unsupervised learning on publicly available real data and simulated data. MMAP provides a user interface to upload input data, manage projects and analyses and download the output results. The platform is free for the public to conduct computations for predicting phenotypes and genetic merit using the best prediction method optimized from many available ones, including Ridge Regression, gBLUP, compressed BLUP, Bayesian LASSO, Bayes A, B, Cpi and many more. Users can also use the platform to conduct data analyses with any methods of their choice. It is expected that extensive usage of MMAP would enrich the training data, which in turn results in continual improvement of the identification of the best method for use with particular traits. AVAILABILITY AND IMPLEMENTATION: The MMAP user manual, tutorials and example datasets are available at http://zzlab.net/MMAP. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Asymmetric Core-Expanded BOPYOs: Facile Synthesis and Optical Properties.

N,O-bidentate BF2 complexes with five- and six-membered core rings have been thoroughly investigated. However, the development of seven-membered N,O-boron complexes is still an area to be explored. We have developed BF3 ⋅ OEt2 -induced self-condensation and coordination reactions based on a single starting material, which had been elucidated by experiment and calculation. This parent asymmetric core-expanded borondifluoride-(Z)-1,3-di(1H-pyrrol-2-yl)but-2-en-1-one (BOPYO) showed reactivity with a wide range of aldehydes, thus providing a series of conjugation BOPYOs. Moreover, a BOPYO derivative with a dimethylamino group was developed as a new NIR dye that responds to acid with favorable photophysical properties based on intramolecular charge transfer effect.

Management and prevention of brachial plexus injury caused by surgical suture of neck dissection induced chylous fistula.

BACKGROUND: The complication of brachial plexus injury (BPI) after surgical suture of chylous fistula caused by neck dissection is extremely rare. For the first time, we investigated the treatment and prevention strategy of BPI caused by surgical suture of neck dissection induced chylous fistula. METHODS: Forty-two patients undergoing surgical suture of neck dissection induced chylous fistula were identified between January 2015 to March 2022 at a single tertiary academic center. All patients were divided into two groups, medial anterior scalene muscle (MASM) group (24 patients) and lateral anterior scalene muscle (LASM) group (18 patients), according to the location of fistula regarding scalene muscle described in the surgical records. The incidence of BPI between the two groups after surgical suture was summarized and compared. RESULTS: There was significant difference in the incidence of different degrees of BPI between the two groups. In the MASM group, the incidence of BPI was 0 % (0/24), while in the LASM group, 6 cases suffered different degrees of BPI immediately after operation and the incidence of BPI was 33.3 % (6/18) (p < 0.05). The neurological function of all BPI cases recovered within 1-3 months after the suture was removed in time. CONCLUSION: The incidence of BPI in patients of LASM group was significantly higher than that of MASM group. When suturing this kind of fistula, the depth of the needle should be properly controlled to avoid BPI. In case of BPI, the suture should be removed as soon as possible to promote the recovery of neurological function.

Protein functional module identification method combining topological features and gene expression data.

BACKGROUND: The study of protein complexes and protein functional modules has become an important method to further understand the mechanism and organization of life activities. The clustering algorithms used to analyze the information contained in protein-protein interaction network are effective ways to explore the characteristics of protein functional modules. RESULTS: This paper conducts an intensive study on the problems of low recognition efficiency and noise in the overlapping structure of protein functional modules, based on topological characteristics of PPI network. Developing a protein function module recognition method ECTG based on Topological Features and Gene expression data for Protein Complex Identification. CONCLUSIONS: The algorithm can effectively remove the noise data reflected by calculating the topological structure characteristic values in the PPI network through the similarity of gene expression patterns, and also properly use the information hidden in the gene expression data. The experimental results show that the ECTG algorithm can detect protein functional modules better.

BODIPY-Appended Pt(II) Complexes with High Toxicities and Anti-chemoresistance Performances in a Cisplatin Resistant In Vivo Model.

Two novel fluorophore (BODIPY)-bearing complexes, pyriplatin (mCBP) and pyrimidine-chelated cisplatin (dCBP), were synthesized and characterized. The additional BODIPY-pyridine/pyridimine motifs of the two Pt(II) complexes resulted in stronger interactions with DNA in comparison with those of cisplatin. mCBP and cisplatin caused relative decreases in life span and body length in a cisplatin resistant in vivo model, N2 (wild-type) Caenorhabditis elegans. In contrast, dCBP resulted in a dramatic reduction in the two physiological parameters in N2 C. elegans, indicating high toxicity and sensitivity. The resistance factors (RF) of cisplatin, mCBP, and dCBP were determined to be 2.46, 1.04, and 0.91, respectively. The increasing RF folds for mCBP and dCBP against cisplatin were 2.36 and 2.70, respectively. This suggested they were featured with improved anti-chemoresistance capabilities. It is noteworthy that dCBP showed lowest lethal concentration (LC50) values of 0.56 and 0.61 mM in cisplatin resistant and sensitive in vivo models, respectively. Upregulation of several evolutionary conservation genes that regulate cisplatin chemoresistance through cisplatin effluxing, the DNA damage response, the unfolded protein response, and detoxification (asna-1, parp-1, enpl-1, and skn-1) was observed upon exposure to cisplatin but not to mCBP and dCBP. This could explain the improved anti-chemoresistance performances of synthesized Pt(II) complexes.

Molecular Insights into the Recruiting Between UCP2 and DDX5/UBAP2L in the Metabolic Plasticity of Non-Small-Cell Lung Cancer.

Mitochondrial uncoupling protein 2 (UCP2) is distributed in tumor cells with a link to the support of systemic metabolic deregulation, and the downregulation of UCP2 has been unveiled as a biomarker of oncogenesis and chemoresistance in non-small-cell lung cancer (NSCLC) cells. However, the underlying mechanism of how UCP2 cooperates with other proteins in this metabolic reprogramming remains largely unsolved. We employed a combined computational and experimental strategy to explore into the recruiting of DDX5 with other proteins, and we unraveled the underlying structural mechanisms. We found that recruiting by ATP-dependent RNA helicase DDX5 (DDX5)/ubiquitin-associated protein 2-like (UBAP2L) might help UCP2 to play the pathological roles in NSCLC cells. According to the view of thermodynamics in physics, UCP2 tends to recruit DDX5 rather than UBAP2L, as shown by the ensemble-based docking, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM/GBSA) approach. Cellular immunofluorescence assays further demonstrated that UCP2 associate with DDX5, and the recruiting of DDX5 with UCP2 at least partially contribute to the metabolic plasticity of NSCLCs via the AKT/mTOR pathway. Our study proposed an efficient way for detecting the protein-protein association via the experimentally validated molecular simulation. Our results shed light on the functional annotation of UCP and DDX family proteins in dysregulated metabolism, and the identification of candidate therapeutic targets for NSCLC.

Molecular insights into the binding variance of the SARS-CoV-2 spike with human, cat and dog ACE2 proteins.

SARS-CoV-2 has recently caused an epidemic in humans and poses a huge threat to global public health. As a primary receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) exists in different hosts that are in close contact with humans, especially cats and dogs. However, the underlying mechanism of how the spike receptor binding domain (RBD) of SARS-CoV-2 cooperates with human ACE2 (hACE2), cat ACE2 (cACE2) and dog ACE2 (dACE2) and the variation in binding remains largely unsolved. Therefore, we explored the binding behavior of the spike RBD with cACE2, dACE2 and hACE2 via all-atom molecular dynamics simulations. In accordance with the binding free energies and residue interactions, the spike RBD has respective binding specificities with cACE2, dACE2 and hACE2, and the binding affinities decrease in the order of hACE2, cACE2, dACE2, mainly due to changes in the amino acids Q24L, H34Y, and M82T in cACE2 or dACE2. Furthermore, alanine scanning analysis results validated some key residues of the spike RBD interact with ACE2 and provided clues to the variation of amino acid that could influence the transmissibility or immune responses of SARS-CoV-2. Decreasing dynamic correlations strengths of ACE2 with the RBD were found in all hACE2-RBD, cACE2-RBD and dACE2-RBD systems. The ACE2 protein shows variable motion modes across the zinc metallopeptidase domain, which induces different interactions between ACE2 and the RBD. Our studies reveal that the motion pattern of the zinc metallopeptidase domain is critical to the binding behavior of RBD with ACE2. These findings could aid our understanding of selective recognition involving various ACE2 with the SARS-CoV-2 spike and shed further light on the binding mechanisms.

A nomogram for predicting occult lymph node metastasis in early hypopharyngeal cancer with cN0.

PURPOSE: To explore the risk factors of cervical occult lymph node metastasis (OLNM) in early cN0 hypopharyngeal squamous cell carcinoma (HPSCC), and construct a nomogram model to predict the risk of OLNM in patients with early cN0 HPSCC. METHODS: 78 cases of early (T1-T2) HPSCC patients who underwent hypopharyngectomy were retrospectively analyzed. Univariate and multivariate logistic regression analyses were used to determine independent risk factors and a nomogram was constructed according to the results of the multivariate logistic regression analysis. Model performance was assessed by constructing a receiver operating characteristic (ROC) curve, and discriminatory capacity assessed using the area under the curve (AUC). Calibration was completed using a plotted calibration curve accompanied by the Hosmer-Lemeshow test. RESULTS: Multivariate logistic regression analysis revealed that age (OR 0.928, 95% CI 0.863-0.997), history of drinking (OR 6.668, 95% CI 1.724-25.788), histological differentiation of tumor (OR 7.269, 95% CI 1.000-52.820), depth of invasion (OR 5.046, 95% CI 1.281-19.874) were independent risk factors of OLNM in early cN0 HPSCC. The ROC curve had an AUC of 0.811 (95% CI 0.713-0.909), which implies good discriminate capacity. The calibration curve and the Hosmer-Lemeshow test (P = 0.972) demonstrated good model fitted and high calibration. CONCLUSION: A nomogram model based on age, drinking history, histological differentiation of tumor, and depth of tumor invasion was successfully developed to predict occult cervical lymph node metastasis in patients with early cN0 hypopharyngeal cancer.

COVID-19 Detection from X-ray Images using Multi-Kernel-Size Spatial-Channel Attention Network.

Novel coronavirus 2019 (COVID-19) has spread rapidly around the world and is threatening the health and lives of people worldwide. Early detection of COVID-19 positive patients and timely isolation of the patients are essential to prevent its spread. Chest X-ray images of COVID-19 patients often show the characteristics of multifocality, bilateral hairy glass turbidity, patchy network turbidity, etc. It is crucial to design a method to automatically identify COVID-19 from chest X-ray images to help diagnosis and prognosis. Existing studies for the classification of COVID-19 rarely consider the role of attention mechanisms on the classification of chest X-ray images and fail to capture the cross-channel and cross-spatial interrelationships in multiple scopes. This paper proposes a multi-kernel-size spatial-channel attention method to detect COVID-19 from chest X-ray images. Our proposed method consists of three stages. The first stage is feature extraction. The second stage contains two parallel multi-kernel-size attention modules: multi-kernel-size spatial attention and multi-kernel-size channel attention. The two modules capture the cross-channel and cross-spatial interrelationships in multiple scopes using multiple 1D and 2D convolutional kernels of different sizes to obtain channel and spatial attention feature maps. The third stage is the classification module. We integrate the chest X-ray images from three public datasets: COVID-19 Chest X-ray Dataset Initiative, ActualMed COVID-19 Chest X-ray Dataset Initiative, and COVID-19 radiography database for evaluation. Experimental results demonstrate that the proposed method improves the performance of COVID-19 detection and achieves an accuracy of 98.2%.

Visual SLAM for robot navigation in healthcare facility.

The COVID-19 pandemic has affected many countries, posing a threat to human health and safety, and putting tremendous pressure on the medical system. This paper proposes a novel SLAM technology using RGB and depth images to improve hospital operation efficiency, reduce the risk of doctor-patient cross-infection, and curb the spread of the COVID-19. Most current visual SLAM researches assume that the environment is stationary, which makes handling real-world scenarios such as hospitals a challenge. This paper proposes a method that effectively deals with SLAM problems for scenarios with dynamic objects, e.g., people and movable objects, based on the semantic descriptor extracted from images with help of a knowledge graph. Specifically, our method leverages a knowledge graph to construct a priori movement relationship between entities and establishes high-level semantic information. Built upon this knowledge graph, a semantic descriptor is constructed to describe the semantic information around key points, which is rotation-invariant and robust to illumination. The seamless integration of the knowledge graph and semantic descriptor helps eliminate the dynamic objects and improves the accuracy of tracking and positioning of robots in dynamic environments. Experiments are conducted using data acquired from healthcare facilities, and semantic maps are established to meet the needs of robots for delivering medical services. In addition, to compare with the state-of-the-art methods, a publicly available dataset is used in our evaluation. Compared with the state-of-the-art methods, our proposed method demonstrated great improvement with respect to both accuracy and robustness in dynamic environments. The computational efficiency is also competitive.

Computational Simulation of HIV Protease Inhibitors to the Main Protease (Mpro) of SARS-CoV-2: Implications for COVID-19 Drugs Design.

SARS-CoV-2 is highly homologous to SARS-CoV. To date, the main protease (Mpro) of SARS-CoV-2 is regarded as an important drug target for the treatment of Coronavirus Disease 2019 (COVID-19). Some experiments confirmed that several HIV protease inhibitors present the inhibitory effects on the replication of SARS-CoV-2 by inhibiting Mpro. However, the mechanism of action has still not been studied very clearly. In this work, the interaction mechanism of four HIV protease inhibitors Darunavir (DRV), Lopinavir (LPV), Nelfinavir (NFV), and Ritonavire (RTV) targeting SARS-CoV-2 Mpro was explored by applying docking, molecular dynamics (MD) simulations, and MM-GBSA methods using the broad-spectrum antiviral drug Ribavirin (RBV) as the negative and nonspecific control. Our results revealed that LPV, RTV, and NFV have higher binding affinities with Mpro, and they all interact with catalytic residues His41 and the other two key amino acids Met49 and Met165. Pharmacophore model analysis further revealed that the aromatic ring, hydrogen bond donor, and hydrophobic group are the essential infrastructure of Mpro inhibitors. Overall, this study applied computational simulation methods to study the interaction mechanism of HIV-1 protease inhibitors with SARS-CoV-2 Mpro, and the findings provide useful insights for the development of novel anti-SARS-CoV-2 agents for the treatment of COVID-19.

Abdominal paracentesis drainage attenuates severe acute pancreatitis by enhancing cell apoptosis via PI3K/AKT signaling pathway.

Our previous studies have shown that abdominal paracentesis drainage (APD) is a safe and effective strategy for patients with severe acute pancreatitis (SAP). However, the underlying mechanisms behind APD treatment remain poorly understood. Given that apoptosis is a critical pathological response of SAP, we here aim to investigate the effect of APD on cell apoptosis in pancreatic tissues during SAP and to explore its potential molecular mechanism. SAP was induced by 5% sodium-taurocholate retrograde while APD group was inserted a drainage tube into the right lower abdomen of rats immediately after SAP induction. Histopathological staining, serum amylase, endotoxin and inflammatory mediators were measured. Cell apoptosis, apoptosis-related proteins and signaling pathway were also evaluated. Our results demonstrated that APD treatment significantly attenuated pancreatic damage and decreased the serum levels of amylase, endotoxin, TNF-α, IL-1 and IL-6 in rats with SAP. Notably, APD treatment enhanced cell apoptosis and reduced necrosis in pancreatic tissues, as evidenced by Tunnel staining, the increased pro-apoptosis proteins (Cleaved-caspase-3 and bax) and decreased anti-apoptosis protein (Bcl-2). Moreover, the effect of APD on cell apoptosis was further confirmed by the regulatory pathway of PI3K/AKT and NF-kB signaling pathway. These results suggest that APD attenuates the severity of SAP by enhancing cell apoptosis via suppressing PI3K/AKT signaling pathway. Our findings provide new insights for understanding the effectiveness of APD in patients with SAP.

Tumor-associated antigen-based personalized dendritic cell vaccine in solid tumor patients.

Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).

Throat Microbial Community Structure and Functional Changes in Postsurgery Laryngeal Carcinoma Patients.

The microbial community structure in the throat and its shift after laryngectomy in laryngeal squamous cell carcinoma (LSCC) patients were investigated. Thirty swab samples taken prior to laryngectomy (SLC), 18 samples 1 week after laryngectomy (SLCA1w), and 30 samples 24 weeks after laryngectomy (SLCA24w) from 30 LSCC patients were examined. Microbial diversity was profiled through sequencing the V3-V4 variable region of the 16S rRNA gene. Quantitative real-time PCR (qPCR) was used to validate the 16S rRNA sequence data for the V3-V4 region. The community structure and function of throat microbiota were assessed by PICRUSt (phylogenetic investigation of communities by reconstruction of unobserved states) analysis. Both alpha and beta diversity results showed significant differences in the throat microbiota of LSCC patients before and after laryngectomy (P < 0.05). The drinking index of the SLC group was positively associated with the genus abundance of Prevotella (P < 0.05). The SLCA1w group had lower abundances of Fusobacterium, Leptotrichia, Lachnoanaerobaculum, and Veillonella than the SLC group (P < 0.05). The SLCA24w group had higher abundances of Streptococcus and Leptotrichia as well as lower abundances of Fusobacterium and Alloprevotella than the SLC group (P < 0.05). The throat microbiomes of the SLC group could be implicated in human cancer signaling pathways, as evidenced by PICRUSt analysis (P < 0.05). Our study clarifies alterations in throat microbial community structure and function in LSCC patients during the perioperative period and postoperative recovery period.IMPORTANCE Laryngeal squamous cell carcinoma greatly impacts patients' lives, and noninvasive means of prognostic assessment are valuable in determining the effectiveness of laryngectomy. We set out to study the microbial structure changes in the throat before and after laryngectomy and found the gene functions of several throat bacteria to be associated with human cancer signaling pathways. Our findings may offer insights into the disease management of patients with laryngeal squamous cell carcinoma. We hope to provide a means of using molecular mechanisms to improve the prognosis of laryngeal cancer treatment and to facilitate relevant research.