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Introduction: Senile osteoporosis is one of the most common age-related diseases worldwide. Glucagon like peptide-2 (GLP-2), a naturally occurring gastrointestinal peptide, possesses therapeutic effects on bone loss in postmenopausal women and ovariectomized rats. However, the role of GLP-2 in senile osteoporosis and underlying mechanisms has not been explored. Methods: GLP-2 was subcutaneously injected into the 6-month-old male senile osteoporosis model of senescence-accelerated mouse prone 6 (SAMP6) mice for 6 weeks. SAMP6 subjected to normal saline and senescence-accelerated mouse resistant 1 served as control groups. Micro-computed tomography was performed to evaluate the bone mass and microarchitecture of the mice. Osteoblastic and osteoclastic activities were determined by biochemical, quantitative real-time PCR, histological, and histomorphometric analyses combined with hematoxylin-eosin, toluidine blue, and tartrate-resistant acid phosphatase staining. We also examined the proteins and structure of intestinal tight junction using immunohistochemical assay as well as a transmission electron microscope. Serum inflammation marker levels were measured using ELISA. Additionally, anti-oxidative enzymes GPX-4 and SOD-2 and receptors of GLP-2 and vitamin D expression in the ileum and colon were detected under immunofluorescence staining. Results: Six-week GLP-2 treatment attenuated bone loss in SAMP6 mice, as evidenced by increased bone mineral density, improved microarchitecture in femora, and enhanced osteogenic activities. In contrast, the activity of osteoclastic activity was not obviously inhibited. Moreover, GLP-2 ameliorated tight junction structure and protein expression in the intestinal barrier, which was accompanied by the reduction of TNF-α level. The expression of receptors of intestinal GLP-2 and vitamin D in the ileum was elevated. Furthermore, the oxidative stress in the intestines was improved by increasing the GPX-4 and SOD-2 signaling. Conclusion: Our findings suggest that GLP-2 could ameliorate age-associated bone loss, tight junction structure, and improved antioxidant enzyme activity in the gut in SAMP6 mice. Amelioration of gut barrier dysfunction may potentially contribute to improving bone formation and provide evidence for targeting the entero-bone axis in the treatment of senile osteoporosis.

To alleviate the dilemma of drug administration in Alzheimer's disease (AD) patients, it is of great significance to develop a new drug delivery system. In this study, a subcutaneously implanted microneedle (MN) device with a swellable gelatin methacryloyl (GelMA) needle body and a dissolvable polyvinyl alcohol (PVA) backing layer was designed. The backing layer quickly dissolved once the MN was introduced into the subcutaneous, and the hydrogel needles were implanted in the subcutaneous to enable prolonged drug release. Compared with oral administration, the MN system offers the benefits of a high administration rate, a fast onset of effect, and a longer duration of action. By detecting the concentration of acetylcholine (ACH) and Aβ 1-42, it was found that MN administration exhibited a stronger therapeutic effect. The biological safety of the MN system was also assessed, and no obvious signs of hemolysis, cytotoxicity, and inflammatory reaction were observed. Together, these findings suggested that the MN system is a convenient, efficient, and safe method of delivering donepezil hydrochloride (DPH) and may provide AD patients with a novel medicine administration option.

Maintaining proteostasis in the endoplasmic reticulum (ER) is critical for cell viability and plant survival under adverse conditions. The unfolded protein response (UPR) pathways interact with reactive oxygen species (ROS) to precisely trigger adaptive outputs or cell death under ER stress with varying degrees. However, little information is known about the relationship between UPR signalling and ROS regulation. Here, Arabidopsis GOLGI ANTI-APOPTOTIC PROTEIN1 (GAAP1)-GAAP4 were found to play redundant positive roles under ER stress. Genetic analysis showed that GAAP4 played a role in INOSITOL-REQUIRING ENZYME (IRE1)-dependent and -independent pathways. In addition, GAAPs played negative roles to activate the adaptive UPR under conditions of stress. Quantitative biochemical analysis showed that mutations in GAAP genes decreased the oxidised glutathione content and altered the pattern of ROS and glutathione in early ER stress. When plants were challenged with unmitigated ER stress, mutations in GAAP advanced ROS accumulation, which was associated with a decline in adaptive UPR. These data indicated that GAAPs resist cell death by regulating glutathione content to inhibit ROS accumulation and maintain UPR during ER stress. They provide a basis for further analysis of the regulation of cell fate decision under ER stress.

Background: Metabolic reprogramming caused by SHMT1/2, as key enzymes in one-carbon metabolism, has been considered to play a critical role in occurrence and progression of hepatocellular carcinoma (HCC). However, the associations between single nucleotide polymorphisms (SNPs) in SHMT1/2 genes and susceptibility of HCC remains unknown. The purpose of this study was to investigate the relation between four candidate SNPs in SHMT1/2 and risk of HCC in Chinese population. Materials and methods: A case-control study including 514 HCC patients and 234 controls was performed to determine associations between SNPs of SHMT1/2 and HCC risk,isolated via mass spectrometry. Results: Our data revealed that SHMT2 rs2229717 was significantly associated with HCC risk when compared to healthy controls under multiple genetic models (Allele T: odds ratio (OR) = 0.73, P=0.023; Dominant Model: OR = 0.72, P=0.044). When our cohort was stratified by sex, male subjects with the T allele and TT genotype for rs2229717 exhibited a decreased risk for HCC risk (OR=0.67, 95%CI=0.50-0.91; OR=0.43, 95%CI=0.18-0.99). In addition, after age stratification was executed, the results showed that both the T allele and the GT genotype for rs2229717 were less common in HCC patients under 50 years old. Conclusion: These data indicate that rs2229717is a predisposing factor for HCC and may affect the occurrence of HCC in various age or sex subgroups, suggesting that SHMT2 rs2229717may be as a useful predictive or diagnostic tool for HCC in some populations.

Microneedles (MNs) have been developed for various applications such as drug delivery, cosmetics, diagnosis, and biosensing. To meet the requirements of MNs used in these areas, numerous materials have been used for the fabrication of MNs. However, MNs will be exposed to skin tissues after piercing the stratum corneum barrier. Thus, it is necessary to ensure that the matrix materials of MNs have the characteristics of low toxicity, good biocompatibility, biodegradability, and sufficient mechanical properties for clinical application. In this review, the matrix materials currently used for preparing MNs are summarized and reviewed in terms of these factors. In addition, MN products used on the market and their applications are summarized in the end. This work may provide some basic information to researchers in the selection of MN matrix materials and in developing new materials.

Background and aims Hepatic ischemia-reperfusion (I/R) injury, which mainly involves inflammatory responses and apoptosis, is a common cause of organ dysfunction in liver transplantation (LT). As a critical mediator of inflammation and apoptosis in various cell types, the role of tripartite motif-containing (TRIM) 27 in hepatic I/R injury remains worthy of study. Approach and results This study systemically evaluated the putative role of TRIM27/transforming growth factor β-activated kinase 1 (TAK1)/JNK (c-Jun N-terminal kinase)/p38 signaling in hepatic I/R injury. TRIM27 expression was significantly down-regulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Subsequently, using global Trim27 knockout mice (Trim27-KO mice) and hepatocyte-specific Trim27 transgenic mice (Trim27-HTG mice), TRIM27 functions to ameliorate liver damage, reduce the inflammatory response, and prevent cell apoptosis. In parallel in vitro studies, activating TRIM27 also prevented H/R-induced hepatocyte inflammation and apoptosis. Mechanistically, TRIM27 constitutively interacted with the critical components, TAK1 and TAK1 binding protein 2/3 (TAB2/3), and promoted the degradation of TAB2/3, leading to inactivation of TAK1 and the subsequent suppression of downstream JNK/p38 signaling. Conclusions TRIM27 is a key regulator of hepatic I/R injury by mediating the degradation of TAB2/3 and suppression of downstream TAK1-JNK/p38 signaling. TRIM27 may be a promising approach to protect the liver against I/R-mediated hepatocellular damage in transplant recipients.

Primula denticulata exhibits considerable variation in floral morphology and flowering phenology along elevational gradients in SW China. We isolated 30 microsatellite markers from P. denticulata to facilitate further investigation of population genetics and floral evolution in this species. We used the HiSeq X-Ten sequencing system to develop a set of markers, and measured polymorphism and genetic diversity in a sample of 72 individuals from three natural populations of P. denticulata subsp. denticulata. The markers displayed relatively high polymorphism, with the number of alleles ranging from two to seven (mean = 3.567). The observed and expected heterozygosity ranged from 0 to 1.000 and 0.041 to 0.702, respectively. Twenty-eight of the loci were also successfully amplified in P. denticulata subsp. sinodenticulata. The microsatellite markers we have identified will provide valuable tools for investigations of the population genetic structure, mating systems and phylogeography of the P. denticulata complex, and will help to address questions concerning the ecological and genetic mechanisms responsible for the evolution of reproductive traits in the species.

Mafic magmatism within deep crustal hot zones plays an important role in the crustal formation and evolution. High-pressure garnet crystallization drives magma differentiation and Fe isotope fractionation at the base of the lower crust. The ∼840 Ma intrusion and the associated ∼830 Ma dikes from the Tongde region in South China consist mainly of gabbro and diorite, which record complicated magmatic processes of the deep crustal zones and provide new insights into the Fe isotope fractionation. Rocks from the Tongde intrusion have high Sr/Y ratios (61–163) and variable δ57Fe values (+0.07 to +0.21‰ relative to IRMM-014) that initially increase then decrease with progressive magmatic differentiation. All samples do not display obvious imprint of deuteric fluid exsolution, and residual garnet in the mantle source did not fractionate the Fe isotope compositions of the primary magmas significantly. The variable Fe isotope signatures in this study can be reproduced by sequential fractional crystallization of olivine/pyroxene and garnet in the deep crust followed by amphibole saturation in the upper section. The host rocks of the intrusion underwent diffusive exchange with the dikes. Removal of both isotopically light- and heavy-Fe minerals well explains the small Fe isotope fractionation in mafic and intermediate rocks. The high-Sr/Y suites of the intrusion and dikes have an average δ57Fe of +0.11 ± 0.02‰ (2SD), similar to the value of arc crust at convergent continental margins. Therefore, garnet fractionation is an important process in arc roots, which drives the melts evolving to calc-alkaline series. Fractional crystallization of hydrous basaltic magmas under high pressures in deep crustal hot zones makes a significant contribution to the formation and evolution of continental crust.

By using the prominent merit of poly(N-isopropylacrylamide) (PNIPAm) that can reversibly switch from a linear state to a coiled state with the change in temperature, in this work, gelatin was grafted with carboxylic end-capped PNIPAm as the matrix material to fabricate a physical entanglement crosslinked hydrogel microneedles (MNs) patch that can control drug release after application on the skin. The crystallization of the drug during the fabrication process of MNs was decreased due to the thermo-reversible sol-gel transition of the matrix materials. In addition, to increase the mechanical strength of the MNs and to decrease the application time, the gelatin-g-PNIPAm (GP) MNs patch was mounted onto solid MNs to fabricate a rapidly separating MNs system (RS-GP-MNs). The combination of the rapidly separating technique and the thermosensitive hydrogel provides the combined ability to efficiently deliver drug-loaded MNs into the skin within few seconds and to control drug release within the skin. Through a series of tests, we found that RS-GP-MNs showed suitable lower critical solution temperature and adequate crosslinking speed for practical application. The hypoglycemic effect in diabetic mice was characteristically controlled by insulin release through RS-GP-MNs as compared to the MNs made from unmodified gelatin. The proposed RS-GP-MNs system is potentially applicable to various hydrophilic small molecular and peptide medicines that require frequent dosing, thus providing an effective, noninvasive, and painless administration method with minimal safety concerns. STATEMENT OF SIGNIFICANCE: 1. Hydrogel microneedles that can be reversibly triggered and controllably release drugs at body temperature were fabricated. 2. Hydrogel microneedles prepared from gelatin-g-PNIPAm can avoid the use of a molecular crosslinker that is toxic and difficult to be completely removed. 3. Gelatin-g-PNIPAm with thermosensitive property showed appropriate molecular interactions with the drug and slowed down the crystallization speed of the drug in the solution.

Hepatic ischemia-reperfusion (HIR) injury, a common clinical complication of liver transplantation and resection, affects patient prognosis. Ring finger protein 5 (RNF5) is an E3 ubiquitin ligase that plays important roles in endoplasmic reticulum stress, unfolded protein reactions, and inflammatory responses; however, its role in HIR is unclear.RNF5 expression was significantly down-regulated during HIR in mice and hepatocytes. Subsequently, RNF5 knockdown and overexpression of cell lines were subjected to hypoxia-reoxygenation challenge. Results showed that RNF5 knockdown significantly increased hepatocyte inflammation and apoptosis, whereas RNF5 overexpression had the opposite effect. Furthermore, hepatocyte-specific RNF5 knockout and transgenic mice were established and subjected to HIR, and RNF5 deficiency markedly aggravated liver damage and cell apoptosis and activated hepatic inflammatory responses, whereas hepatic RNF5 transgenic mice had the opposite effect compared with RNF5 knockout mice. Mechanistically, RNF5 interacted with phosphoglycerate mutase family member 5 (PGAM5) and mediated the degradation of PGAM5 through K48-linked ubiquitination, thereby inhibiting the activation of apoptosis-regulating kinase 1 (ASK1) and its downstream c-Jun N-terminal kinase (JNK)/p38. This eventually suppresses the inflammatory response and cell apoptosis in HIR.We revealed that RNF5 protected against HIR through its interaction with PGAM5 to inhibit the activation of ASK1 and the downstream JNK/p38 signaling cascade. Our findings indicate that the RNF5-PGAM5 axis may be a promising therapeutic target for HIR.

A nitrate-promoted Pd-catalysed mild cross-dehydrogenative C(sp2)-H bond oxidation of oximes or azobenzenes with diverse carboxylic acids has been developed. In contrast to the previous catalytic systems, this protocol features mild conditions (close to room temperature for most cases) and a broad substrate scope (up to 64 examples), thus constituting a versatile method to directly prepare diverse O-aryl esters. Moreover, the superiority of the nitrate additive in this mild transformation was further determined by experimental and computational evidence.

BACKGROUND Acute liver failure (ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver (BAL) support systems have the potential to provide temporary support to bridge patients with ALF to liver transplantation or spontaneous recovery. In the past decades, several BAL support systems have been conducted in clinical trials. More recently, concerns have been raised on the renovation of high-quality cell sources and configuration of BAL support systems to provide more benefits to ALF models in preclinical experiments. AIM To investigate the characteristics of studies about BAL support systems for ALF, and to evaluate their effects on mortality. METHODS Eligible clinical trials and preclinical experiments on large animals were identified on Cochrane Library, PubMed, and EMbase up to March 6, 2019. Two reviewers independently extracted the necessary information, including key BAL indicators, survival and indicating outcomes, and adverse events during treatment. Descriptive analysis was used to identify the characteristics of the included studies, and a meta-analysis including only randomized controlled trial (RCT) studies was done to calculate the overall effect of BAL on mortality among humans and large animals, respectively. RESULTS Of the 30 selected studies, 18 were clinical trials and 12 were preclinical experiments. The meta-analysis result suggested that BAL might reduce mortality in ALF in large animals, probably due to the recent improvement of BAL, including the type, cell source, cell mass, and bioreactor, but seemed ineffective for humans [BAL vs control: relative risk (95% confidence interval), 0.27 (0.12-0.62) for animals and 0.72 (0.48-1.08) for humans]. Liver and renal functions, hematologic and coagulative parameters, encephalopathy index, and neurological indicators seemed to improve after BAL, with neither meaningful adverse events nor porcine endogenous retrovirus infection. CONCLUSION BAL may reduce the mortality of ALF by bridging the gap between preclinical experiments and clinical trials. Clinical trials using improved BAL must be designed scientifically and conducted in the future to provide evidence for transformation.

BACKGROUND Current diagnostic testing methods for peanut allergy, including serum specific immunoglobulin E (sIgE) and skin-prick testing (SPT), have low specificity, whereas oral food challenge (OFC) carries significant risk of provoking adverse events. Mucosal brush biopsy (MBB) from the oral cavity is currently being studied as a new diagnostic test for peanut allergy, but normative data is not yet available with which to begin measuring specificity and predictive value. METHODS Twenty individuals with no history of adverse reactions from eating peanuts underwent oral MBB and serum testing for peanut sIgE. These data were then compared with previously published data from 10 individuals with a history of clinical peanut allergy, in order to generate receiver operating characteristic (ROC) curves and calculate the sensitivity, specificity, and positive and negative predictive values for both testing modalities. RESULTS The optimal cutoff levels for oral MBB and sIgE testing were 0.12 kU/L and 1.0 kU/L, respectively. At 0.12 kU/L, the sensitivity of oral MBB testing was 80% and the specificity was 85%, whereas at 1.0 kU/L, the sensitivity of sIgE testing was 50% and the specificity was 100%. From the ROC curves, the areas under the ROC curve (AUC) for oral MBB and sIgE were 0.91 (p

Primula denticulata exhibits considerable variation in floral morphology and flowering phenology along elevational gradients in SW China. We isolated 30 microsatellite markers from P. denticulata to facilitate further investigation of population genetics and floral evolution in this species. We used the HiSeq X-Ten sequencing system to develop a set of markers, and measured polymorphism and genetic diversity in a sample of 72 individuals from three natural populations of P. denticulata subsp. denticulata. The markers displayed relatively high polymorphism, with the number of alleles ranging from two to seven (mean = 3.567). The observed and expected heterozygosity ranged from 0 to 1.000 and 0.041 to 0.702, respectively. Twenty-eight of the loci were also successfully amplified in P. denticulata subsp. sinodenticulata. The microsatellite markers we have identified will provide valuable tools for investigations of the population genetic structure, mating systems and phylogeography of the P. denticulata complex, and will help to address questions concerning the ecological and genetic mechanisms responsible for the evolution of reproductive traits in the species.

Herein we report a novel Cu-catalyzed regioselective C2-H alkylation of benzimidazoles with aromatic alkenes. The reaction features exclusive regioselectivity and broad substrate scope in the intermolecular alkylation of benzimidazoles with terminal and internal aromatic alkenes, constituting a modular access toward benzimidazole-containing 1,1-di(hetero)aryl alkanes. The intramolecular C2-H alkylation of benzimidazoles with aromatic alkenes has been achieved in an endo-selective manner. The enantioselective C2 alkylation of benzimidazoles has also been realized with moderate to good stereocontrol.

A nitrate-promoted Pd-catalysed mild cross-dehydrogenative C(sp

The role of cytoskeleton-associated membrane protein 4 (CKAP4) in hepatocellular carcinoma (HCC) is controversial. The present study aimed to investigate the association between tumor CKAP4 mRNA expression and clinicopathological characteristics and prognosis in patients with HCC. Data relating to CKAP4 mRNA expression in HCC tumor and normal adjacent liver tissues, and clinicopathological characteristics, were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The CKAP4 mRNA levels in tumor tissues were compared with those in normal adjacent liver tissues, their association with clinicopathological parameters was analyzed, and diagnostic and prognostic values were evaluated in patients with HCC. In all 4 datasets (total samples, n=693), CKAP4 mRNA levels were significantly higher in tumor tissues compared with adjacent tissues (all P3 years (P=0.003). The high-level CKAP4 mRNA group also exhibited lower overall survival (OS) and disease-free survival (DFS) rates compared with the low-level group [hazard ratio (HR)=1.494; 95% confidence interval (CI), 1.044–2.138; P=0.028] for OS and (HR=1.616; 95% CI, 1.022–2.555; P=0.040) for DFS. The results of the present study suggest that CKAP4 mRNA is upregulated in HCC tumor tissues compared with normal adjacent tissues, and is associated with poor clinical prognosis, pathological features and survival in patients with HCC. Thus, CKAP4 is a potential biomarker for HCC diagnosis and prognosis.

Background The pathogenesis of eosinophilic esophagitis (EoE) is currently unknown, but evidence suggests that allergic sensitization to food and airborne allergens may play a key role. This retrospective study examines the rate of sensitization to both food and airborne allergens in EoE patients, and compares their sensitivity patterns to control groups. Methods We identified 103 patients with a diagnosis of EoE via esophageal eosinophilia (≥15 eosinophils/high-power field [hpf]), who had undergone comprehensive food and/or airborne allergen testing through either skin or in vitro methods. Food and airborne allergen sensitization was defined as positive testing in at least 1 food subgroup (milk, peanut, tree nut, seafood/fish, soy, grain, egg) or airborne subgroup (tree, grass, weed, mite/cockroach, animal, mold), respectively. The same sensitization criterion was applied to allergic rhinitis (AR) patients, with and without a clinical suspicion of food allergy (FA), in order to create control groups. Results Sensitization in the EoE group to at least 1 subgroup of food allergen and airborne allergen was seen in 77.1% (64/83) and 71.7% (38/53), respectively (p = 0.82). There were significant differences in sensitization between EoE and control groups for tree nut, soy, grain, and egg, but no differences noted in any of the other food or airborne allergen subgroups, even after accounting for age and gender. Conclusion EoE and control groups had similar airborne allergen sensitization patterns, yet dissimilar food allergen sensitization patterns, suggesting that specific allergens may play a more prominent role in the pathogenesis of EoE. The EoE group had a more uniform distribution pattern for food allergens, compared to controls.

Based on the characteristics of biological supramolecules and the law of " imprinting template",the research status and common problems in " maintaining medicinal properties after carbonisatus" in traditional Chinese medicine( TCM) were analyzed,and the further countermeasures were put forward. According to the historical evolution of " maintaining medicinal properties after carbonisatus" in TCM processing,the origin of its common problems was clarified by using the theory of biosupramolecular chemistry. TCM is a megacomplex biological supramolecular system,so TCM processing is just the processing of megacomplex biological supramolecular system,and its essence is a TCM pharmaceutical technology with chemical changes in host and guest of biological supramolecular system with or without adjuvant material under high temperature and humidity. In this study on pharmaceutical technology,host molecule was destructed in the process of carbonizing,but guest molecule was retained. The changing law of the host and guest molecule was controlled by the " imprinting template",which was reflected in the degree of change in the drug properties and efficacy of the decoction pieces. Supramolecular chemistry ran through the whole process,and the " imprinting template" of charcoal medicine was characterized by the supramolecular topological structure characteristics and imprinting behavior. After being combined with the quantitative mathematical model of heating degree in processing,it can realize the accurate processing of " maintaining medicinal properties after carbonisatus" from the source,quantitatively control the quality of carbonic herbs,and formulate stable and controllable quality standards.

Objective. Asthma is a syndrome that incorporates many immune phenotypes. The immunologic effects of subcutaneous immunotherapy (SCIT) exerts on allergic asthma remain still largely unknown. Here, we investigated the effects of SCIT on cytokine production and peripheral blood levels of lymphocyte subtypes in children with mite-induced moderate and severe allergic asthma. Methods. The study included 60 kids with mite-induced allergic asthma from 5 to 10 years old. All subjects had received antiasthmatic pharmacologic for 3 months at baseline. Half of the children were treated with SCIT combined with pharmacologic treatment named the SCIT group and the other half only with pharmacologic therapy named the no-SCIT group. Total asthma symptom score (TASS) and total medication score (TMS) were recorded. Flow cytometry was used to identify lymphocyte subtypes: type 2 innate lymphocytes (ILC2s), type 1 (Th1) and type 2 (Th2) helper T cells, T helper 17 (Th17) cells, and regulatory T (Treg) cells. ELISA, flow cytometry, and cytometric bead array were used to assess cytokines IL-13, IFN-γ, IL-4, IL-17, and TGF-β, at baseline and 3 and 6 months after study treatment in both groups of patients. Results. Both groups can significantly improve clinical symptoms in children with asthma. SCIT can significantly reduce asthma medication after 6 months of treatment. SCIT induced a significantly higher and progressive reduction in ILC2 percentage and IL-13 levels after 3 and 6 months of treatment compared with baseline and compared with no-SCIT patients. Significant differences were detected in the Th1/Th2 cell ratio and IFN-γ/IL-4 cytokine ratio between groups after 6 months of treatment. Similarly, the Th17/Treg ratio and IL-17/TGF-β ratio in the SCIT group were much lower than those in the no-SCIT group after 3-6 months of treatment. Conclusion. SCIT is a promising option to reduce the percentage of ILC2 and regulate Th1/Th2 and Th17/Treg immune balance in the peripheral blood of children with asthma.

Hepatocellular carcinoma (HCC) is a common type of malignant tumor with an extremely poor prognosis. Because many HCC patients are diagnosed with advanced disease, surgical treatment is typically not possible, and other currently available treatments are often ineffective. Immunotherapy is being explored as a new treatment method for a variety of cancers, including HCC. However, there have been no systematic reports about the relationship between immune-related genes and HCC patient prognosis. In this study, we established and verified a gene set-based model to examine the relationship between immune-related genes and prognosis in HCC patients. The model was based on a dataset from The Cancer Genome Atlas (TCGA), and its stability and reliability was confirmed in four verification datasets. In addition, we performed multivariate Cox regression analyses to identify the independent risk factors affecting HCC patient prognoses. We found that this new model based on immune-related genes was effective for predicting prognosis, evaluating disease state, and identifying treatment options for HCC patients.

Objective: This study aimed to develop and validate a simple-to-use nomogram for early hepatocellular carcinoma (HCC) patients undergoing a preoperative consultation and doctors conducting a postoperative evaluation.Methods: A total of 2,225 HCC patients confirmed with stage I or II were selected from the Surveillance, Epidemiology, and End Results database between January 2010 and December 2015. The patients were randomly divided into two groups: a training group (n = 1,557) and a validation group (n = 668). Univariate and multivariate hazards regression analyses were used to identify independent prognostic factors. The Akaike information criterion (AIC) was used to select variables for the nomogram. The performance of the nomogram was validated concerning its ability of discrimination and calibration and its clinical utility.Results: Age, alpha-fetoprotein (AFP), race, the degree of differentiation, and therapy method were significantly associated with the prognosis of early HCC patients. Based on the AIC results, five variables (age, race, AFP, degree of differentiation, and therapy method) were incorporated into the nomogram. The concordance indexes of the simple nomogram in the training and validation groups were 0.707 (95% CI: 0.683–0.731) and 0.733 (95% CI: 0.699–0.767), respectively. The areas under the receiver operating characteristic (ROC) curve of the nomogram in the training and validation groups were 0.744 and 0.764, respectively, for predicting 3-year survival, and 0.786 and 0.794, respectively, for predicting 5-year survival. Calibration plots showed good consistency between the predictions of the nomogram and the actual observations in both the training and validation groups. Decision curve analysis (DCA) showed that the simple nomogram was clinically useful, and the overall survival significantly differed between low- and high-risk groups divided by the median score of the nomogram in the training group (P < 0.001).Conclusion: A simple-to-use nomogram based on a large population-based study is developed and validated, which is a conventional tool for doctors to facilitate the individual consultation of preoperative patients and the postoperative personalized evaluation.

Whipple’s disease (WD), caused by infection with the organism Tropheryma whipplei, is a rare disease that classically presents with diarrhea, weight loss, and polyarthralgia. Less commonly, Whipple’s Disease can presentation with endocarditis or neurologic infections. The authors report a patient with Whipple’s Disease endocarditis whose initial presentation was acute lower extremity arterial occlusion, and review current literature regarding the epidemiology, diagnosis, treatment, and prognosis of Whipple’s Disease endocarditis.

Background Extrahepatic metastasis is the independent risk factor of poor survival of primary hepatic carcinoma (PHC), and most occurs in the chest and abdomen. Currently, there is still no available method to predict thoracoabdominal extrahepatic metastasis in PHC. In this study, a novel nomogram model was developed and validated for prediction of thoracoabdominal extrahepatic metastasis in PHC, thereby conducted individualized risk management for pretreatment different risk population. Methods The nomogram model was developed in a primary study that consisted of 330 consecutive pretreatment patients with PHC. Large-scale datasets were extracted from clinical practice. The nomogram was based on the predictors optimized by data dimension reduction through Lasso regression. The prediction performance was measured by the area under the receiver operating characteristic (AUROC), and calibrated to decrease the overfit bias. Individualized risk management was conducted by weighing the net benefit of different risk population via decision curve analysis. The prediction performance was internally and independently validated, respectively. An independent-validation study using a separate set of 107 consecutive patients. Results Four predictors from 55 high-dimensional clinical datasets, including size, portal vein tumor thrombus, infection, and carbohydrate antigen 125, were incorporated to develop a nomogram model. The nomogram demonstrated valuable prediction performance with AUROC of 0.830 (0.803 in internal-validation, and 0.773 in independent-validation, respectively), and fine calibration. Individual risk probability was visually scored. Weighing the net benefit, threshold probability was classified for three-independent risk population, which was 71.8%, respectively. According to this classification, pretreatment risk management was based on a treatment-flowchart for individualized clinical decision-making. Conclusions The proposed nomogram is a useful tool for pretreatment risk management of thoracoabdominal extrahepatic metastasis in PHC for the first time, and may handily facilitate timely individualized clinical decision-making for different risk population. Electronic supplementary material The online version of this article (10.1186/s12967-019-1861-z) contains supplementary material, which is available to authorized users.

Bronchial asthma, a common chronic respiratory disease in children, is traditionally regarded as a noninfectious disease. Current hypotheses, however, argue that asthma can be caused by microbial infection. We, therefore, hypothesize that a variety of microbes are more commonly found in the sputum of children with asthma, and these microbes may contribute to the occurrence and development of asthma. The present study proposes to use metagenomic approach to explore microbial diversity and to identify the microbial community characteristics of sputum from children with asthma. We found that microbial communities in the sputum of children differed significantly between asthmatics and controls. Kruskal-Wallis testing showed that 16 phyla, 104 genera, and 159 species were significantly downregulated, whereas two phyla including Platyhelminthes phylum and Chordata phylum, two genera including Spirometra genus and Homo sapiens, and the Spirometra erinaceieuropaei species were significantly upregulated in asthma patients compared with controls (P < 0.05). Among them, H. sapiens and S. erinaceieuropaei exhibited 2.3- and 2.0-fold overabundance in asthmatics vs controls, respectively. Meanwhile, metastats assay demonstrated that 31 phyla, 400 genera, and 813 species were significantly downregulated, whereas two phyla, 10 genera, and 16 species were significantly upregulated in asthma patients compared with controls (P < 0.05). Among them, Tetrahymena thermophila and Candidatus Zinderia insecticola exhibited 4.7-fold overabundance in asthmatics vs controls. Our study establishes a link between microbial infection and the mechanisms leading to asthma development, which will be useful for developing novel diagnostic biomarkers and aiding in the prevention and control of asthma.

Aim Despite the perceived importance of frailty, few studies focus on its impact on rural patients undergoing chronic dialysis. Comparison of different self-report questionnaires in assessing frailty among these patients has not been attempted before. Methods A prospectively enrolled chronic dialysis cohort from a rural centre was recruited for analysis. Six types of self-report questionnaires were administered to these patients. Clinical and dialysis-related laboratory parameters were collected. Correlation analyses between questionnaire results and dialysis complications were performed, and variables demonstrating significant correlations were entered into multivariate regression models to determine their independent associations. Results Six types of questionnaire (Strawbridge questionnaire, Edmonton Frail Scale, simple FRAIL scale, Groningen Frail Indicator, G8 questionnaire, and Tilburg Frail Indicator) were provided to rural patients undergoing chronic dialysis. Scores from each questionnaire showed significant association with each other, except the G8 questionnaire. Scores from the simple FRAIL scale correlated significantly with age (P = 0.02), female gender (P = 0.03), higher Liu's comorbidity index (P = 0.02), lower serum albumin (P = 0.03) and creatinine levels (P

The pathogenesis of eosinophilic esophagitis (EoE) is currently unknown, but evidence suggests that allergic sensitization to food and airborne allergens may play a key role. This retrospective study examines the rate of sensitization to both food and airborne allergens in EoE patients, and compares their sensitivity patterns to control groups.We identified 103 patients with a diagnosis of EoE via esophageal eosinophilia (≥15 eosinophils/high-power field [hpf]), who had undergone comprehensive food and/or airborne allergen testing through either skin or in vitro methods. Food and airborne allergen sensitization was defined as positive testing in at least 1 food subgroup (milk, peanut, tree nut, seafood/fish, soy, grain, egg) or airborne subgroup (tree, grass, weed, mite/cockroach, animal, mold), respectively. The same sensitization criterion was applied to allergic rhinitis (AR) patients, with and without a clinical suspicion of food allergy (FA), in order to create control groups.Sensitization in the EoE group to at least 1 subgroup of food allergen and airborne allergen was seen in 77.1% (64/83) and 71.7% (38/53), respectively (p = 0.82). There were significant differences in sensitization between EoE and control groups for tree nut, soy, grain, and egg, but no differences noted in any of the other food or airborne allergen subgroups, even after accounting for age and gender.EoE and control groups had similar airborne allergen sensitization patterns, yet dissimilar food allergen sensitization patterns, suggesting that specific allergens may play a more prominent role in the pathogenesis of EoE. The EoE group had a more uniform distribution pattern for food allergens, compared to controls.

Silicate glass irradiated by γ-rays was investigated in this study using spectroscopic analyses which included ultraviolet–visible (UV–Vis) absorption, electron paramagnetic resonance (EPR), and nuclear magnetic resonance (NMR). The phenomenon of coloration on γ-ray-irradiated silicate glass was analyzed and the effect of annealing on the silicate coloration was also investigated. The results revealed that the coloration originates from the creation of hole-centers ( HC ) caused by radiation. The shade of the coloration highly correlates to the amount of these HC -related defects but can be reversed by thermal annealing. The variation in coloration is an effective predictive factor in understanding radiation damage on silicate glass. Therefore, this study is relevant in the development of radiation detectors using silicate material as well as in the permanent disposal of high-level nuclear waste in glass form.