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The use of corticosteroids has been controversial in viral pneumonia. In most cases, application of methylprednisolone in severe and critical viral pneumonia patients can quickly alleviate the symptoms of dyspnea and prevent disease progression. However, some scholars have confirmed that corticosteroids delayed the body's clearance of the virus. In our retrospective non‐randomised study, 34 patients under 50 years old and diagnosed with coronavirus disease 2019 (COVID‐19) were included, according to given methylprednisolone treatment (n = 18) or not (n = 16), they were separated into 2 groups. By comparing the clinical data we concluded that corticosteroids therapy can effectively release COVID‐19 symptoms such as persistent fever and difficult breathing, improve oxygenation and prevent disease progression. However, it can prolong the negative conversion of nucleic acids. This article is protected by copyright. All rights reserved.

A major feature of neurodegeneration is disruption of central nervous system homeostasis, during which microglia play diverse roles. In the central nervous system, microglia serve as the first line of immune defense and function in synapse pruning, injury repair, homeostasis maintenance, and regulation of brain development through scavenging and phagocytosis. Under pathological conditions or various stimulations, microglia proliferate, aggregate, and undergo a variety of changes in cell morphology, immunophenotype, and function. This review presents the features of microglia, especially their diversity and ability to change dynamically, and reinterprets their role as sensors for multiple stimulations and as effectors for brain aging and neurodegeneration. This review also summarizes some therapeutic approaches for neurodegenerative diseases that target microglia.

Accumulating evidence shows that cellular and acellular components in tumor microenvironment (TME) can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Cancer research and treatment have switched from a cancer-centric model to a TME-centric one, considering the increasing significance of TME in cancer biology. Nonetheless, the clinical efficacy of therapeutic strategies targeting TME, especially the specific cells or pathways of TME, remains unsatisfactory. Classifying the chemopathological characteristics of TME and crosstalk among one another can greatly benefit further studies exploring effective treating methods. Herein, we present an updated image of TME with emphasis on hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, and mechanical microenvironment. We then summarize conventional drugs including aspirin, celecoxib, β-adrenergic antagonist, metformin, and statin in new antitumor application. These drugs are considered as viable candidates for combination therapy due to their antitumor activity and extensive use in clinical practice. We also provide our outlook on directions and potential applications of TME theory. This review depicts a comprehensive and vivid landscape of TME from biology to treatment.

A 12‐week feeding trial was conducted to assess the impact of fishmeal replacement with blood meal or dried porcine solubles on the growth performance, body composition and intestinal morphology of common carp (Cyprinus carpio). Fishmeal was 50% substituted with either blood meal or dried porcine solubles, or two‐third substituted with both alternative products, at a 1:1 ratio. There was no significant difference in survival, final weight, weight gain ratio, feed conversion ratio or condition factor between the control and experimental groups (p > .05), although the visceral somatic index of the blood meal group was higher than that of the control group (p .05). The amino acid composition of each experimental group was not significantly different from that of the control (p > .05). The intestinal villus height and fold depth of each experimental group were significantly lower than those of the control group (p

Ovarian cancer is the most common malignant tumors of the female reproductive system, and its standard treatments are cytoreductive surgery and platinum-based adjuvant chemotherapy. Great advances have been achieved in novel treatment strategies, including targeted therapy and immunotherapy. However, ovarian cancer has the highest mortality rate among gynecological tumors due to therapeutic resistance and the gap between preclinical data and actual clinical efficacy. Organoids are a 3D culture model that markedly affects gene analysis, drug screening, and drug sensitivity determination of tumors, especially when used in targeted therapy and immunotherapy. In addition, organoid can lead to advances in the preclinical research of ovarian cancer due to its convenient cultivation, good genetic stability, and high homology with primary tumors.

Stent migration is one of the common reasons for the failure of tracheal stent. An antitumor drug/tracheal stent combination can promptly relieve dyspnea caused by tracheal stenosis and locally treat malignant occupying lesion or tumor. To prevent stent migration for more effective treatment, we prepared a migration-preventing nitinol tracheal stent (TS) with a high dose of 5-fluorouracil or paclitaxel (5-FU/TS or PTX/TS) by stent surface coating with a bilayered film, which is composed of a drug-loaded layer containing Carbopol 974P as mucoadhesive matrix and a blank Carbopol 974P layer. The resulting stent had a similar mechanical performance with the nitinol tracheal stent itself. The bilayered film containing 30% PTX (PTX30) could keep adhesion to porcine mucosa for 221.7 ± 11.4 min in PBS at a stirring speed of 150 rpm, and the corresponding PTX30/TS was difficult to be moved in the porcine tracheal lumen with a pulling force less than 0.7 N, indicating its good migration-preventing ability. The migration-preventing ability of the 5-FU/TS or PTX/TS was related to the compositions of bilayered films. The 5-FU release from the 5-FU/TS was dominated by a relaxation mechanism, while the PTX release was mainly controlled by a diffusion mechanism. Moreover, the 5-FU permeation from the 5-FU loaded film through the porcine tracheal mucosa was determined by the 5-FU dissolution, and PTX permeation was limited by the trans-mucosa process. After the deployment of PTX30/TS, inflammatory responses were observed in the rabbit tracheas and gradually alleviated during the follow-up period.

BackgroundPhosphorylated CTD-interacting factor 1 (PCIF1) is identified as the only known methyltransferase of N6,2′-O-dimethyladenosine (m6Am) in mRNA. However, its oncogenic and immunogenic role in cancer research is at an initial stage.MethodsHerein, we carried out a pan-cancer analysis of PCIF1, with a series of datasets (e.g., TIMER2.0, GEPIA2, cBioPortal).ResultsPCIF1 expression was higher in most cancers than normal tissues and was discrepant across pathological stages. Highly expressed PCIF1 was positively correlated with overall survival (OS) or disease-free survival (DFS) of some tumors. PCIF1 expression had a positive correlation with CD4+ T-cell infiltration in kidney renal clear cell carcinoma (KIRC), CD8+ T cells, macrophages, and B cells in thyroid carcinoma (THCA), and immune checkpoint genes (ICGs) in LIHC but a negative correlation with CD4+ T cells, neutrophils, myeloid dendritic cells, and ICGs in THCA. It also affected tumor mutational burden (TMB) and microsatellite instability (MSI) of most tumors.ConclusionPCIF1 expression was correlated with cancer prognosis and immune infiltration, suggesting it to be a potential target for cancer therapy.

Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.

Objectives To characterize the mitochondrial respiratory chain complex IV(complex IV) activity and protein expression during polymicrobial sepsis. Material and methods Polymicrobial peritonitis, a clinically relevant mouse model of sepsis, was generated by cecum ligation and puncture (CLP) in Sprague- Dawley rats. The rats were randomly divided into 3 groups as follows: the sepsis without resuscitation (S), sepsis and fluid resuscitated (R) group, and a control (C) group. Twelve hours after the sepsis model was established, tissue specimens were obtained from the myocardium, liver and skeletal muscle. Mitochondrial respiratory chain complex IV activity of all tissue specimens was detected by spectrophotometry. Western blot was used to measure the liver mitochondrial respiratory chain complex IV protein content. The ultrastructure changes of mitochondria were detected by transmission electron microscopy. Results In myocardial cells, complex IV activity decreased significantly in the S and R groups as compared to the C group. There were no differences in complex IV activity between groups in skeletal muscle cells while in liver cells, complex IV activity and content was significantly decreased for the S group but no differences were observed between the C and R groups. Increased matrix volume and reduced density with generalized disruption of the normal cristae pattern was most extensive in the liver, followed by cardiac muscle cells with that in skeletal muscle cells been relatively mild in the S group. Mitochondrial fusion/fission and mitochondrial autophagy was also observed in the S group by transmission electron microscopy. Mitochondrial ultrastructure was preserved in the R-group and was similar to that seen in the C-group. Conclusions Changes in complex IV activity and mitochondrial ultrastructure, a manifestation of the mitochondrial dysfunction varied depending on cell type. These changes are partly reversed by fluid therapy. Therapies aimed at mitochondrial resuscitation should be explored.

Aim To assess the prevalence of the lesions in duodenal bulb mucosa and the relationship between duodenal lesions and upper gastrointestinal diseases, including helicobacter pylori infection. Methods Clinical, endoscopic and pathological data of the cases with duodenal bulb and gastric mucosal biopsy from January 2005 to May 2017 were analyzed retrospectively. Results A total of 3540 patients were enrolled. The biopsy from protuberant lesions with endoscopic morphology are mostly duodenal gastric heterotopia or adenoma. The biopsy from duodenal ulcers are often observed in inflammatory changes and gastric metaplasia. Patients with gastric heterotopia had a significantly lower prevalence of chronic atrophic gastritis, intestinal metaplasia, and gastric ulcer; and much higher prevalence of gastroesophageal reflux disease and gastric fundic polyps. Patients with gastric metaplasia had been positively associated with gastroesophageal reflux disease, and negatively associated with gastric fundic polyps. There were positive correlation between helicobacter pylori infection and duodenal active inflammation, Brunner gland hyperplasia, gastric metaplasia and duodenal ulcer. However, Patients with gastric heterotopia in bulb had been negatively associated with helicobacter pylori infection. Conclusions The mucosa lesions in duodenal bulb were associated with concurrent gastric fundic gland polyps, gastroesophageal reflux disease, duodenal ulcer, and helicobacter pylori infection.

Disparities at the major histocompatibility complex (MHC) antigens and associated minor antigens trigger harmful immune responses, leading to graft rejection after transplantation. We showed that MHC-silenced cells and tissues are efficiently protected against rejection. In complex vascularized organs, the endothelium is the major interface between donor and recipient. This study therefore aimed to reduce the immunogenicity of the lung by silencing MHC expression on the endothelium. In porcine lungs, short-hairpin RNAs targeting beta-2-microglobulin and class II-transactivator transcripts were delivered by lentiviral vectors during normothermic ex vivo perfusion to silence swine leukocyte antigen (SLA) I and II expression permanently. The results demonstrated the feasibility of genetically engineering all lung regions, achieving a targeted silencing effect for SLA I and II of 67% and 52%, respectively, without affecting cell viability or tissue integrity. This decrease in immunogenicity carries the potential to generate immunologically invisible organs to counteract the burden of rejection and immunosuppression.

To explore the clinical regularities in acupuncture-moxibustion treatment of cancer pain by reviewing the relevant studies published between 1985 and 2017. Based on the Chinese Medicine Acupuncture-moxibustion Information Database, quantitative analysis, correlation analysis and Chi-square test were applied to analyze the commonly used acupoints, meridian affiliations and body region distributions, commonly used methods and acupoint correlations, treatment method correlations, the efficacy of acupuncture- moxibustion plus the three-step analgesic ladder for cancer pain, and indicators. Zusanli (ST 36), Ashi point and Sanyinjiao (SP 6) ranked the top on the list of frequency; points from Bladder Meridian of Foot Taiyang and Stomach Meridian of Foot Yangming were often used; points from the lower limbs and back had high frequencies. The most commonly used treatment method was acupuncture-moxibustion plus medication. Acupuncture-moxibustion plus the three-step analgesic ladder showed certain advantage compared with the two methods used separately, and among the integrated methods, acupoint application plus the three-step analgesic ladder produced the most significant efficacy. It took (44.77±55.54) min for the analgesic effect to act and the effect lasted for (12.81±14.59) h. Numerical rating scale (NRS), visual analog scale (VAS) and Karnofsky performance status (KPS) scores all showed significant changes after interventions (all P 0.05). Zusanli (ST 36), Ashi point and Sanyinjiao (SP 6) are commonly selected in acupuncture-moxibustion treatment of cancer pain; acupuncture and acupoint application are often used; acupuncture-moxibustion plus the three-step analgesic ladder can boost the treatment efficacy.

Activated autophagy has been intensively observed in cerebrovascular diseases, including focal cerebral ischemia injury, but its molecular mechanisms remain unclear. TOM7, which is a component of the protein translocase of the outer mitochondrial membrane (TOM) complex, may modulate assembly of the TOM complex. However, an understanding of how TOM7 affects cerebral ischemia injury is limited. In this study, we demonstrate that the expression of TOM7 is up-regulated after a photothrombotic cerebral ischemic model in rats, peaking at 3 days. In addition, TOM7 knockdown may aggravate cerebral ischemic injury and inhibit autophagy after ischemic stroke. Mechanically, TOM7 may regulate autophagy through the PINK1/Beclin1 pathway after cerebral ischemia injury. These results demonstrate that TOM7 silencing may aggravate cerebral ischemia injury through inhibiting PINK1/Beclin1 pathway- mediated autophagy.

Goals The main aim of this study was to investigate the significance of a pale area via flexible spectral imaging color enhancement (FICE) in the diagnosis of esophageal dysplasia and cancer. Background The early diagnosis of esophageal squamous cancer is challenging, and the indication of Lugol's chromoendoscopy has not yet been well established. Study The esophageal mucosa of patients at our endoscopic center were sequentially evaluated with white-light endoscopy and FICE during insertion of the endoscope, followed by staining with Lugol's solution during withdrawal. Patients were divided into 2 groups depending on whether esophageal leukoplakia was detected by white-light endoscopy and 2 groups depending on whether a pale area was detected by FICE. We compared cases of patients with abnormal iodine staining, and cases of dysplasia or cancer in esophageal leukoplakia-or pale area-positive and negative groups. Results Cases of abnormal staining in the esophageal leukoplakia-or pale area-positive group were far more numerous than cases without esophageal leukoplakia or pale area, respectively (P=0.000). Cases of esophageal dysplasia and cancer in the esophageal leukoplakia-or pale area-positive group were far more numerous than cases without esophageal leukoplakia or pale area, respectively (P=0.000). Conclusions Iodine staining should be performed in patients with esophageal leukoplakia or pale areas. Esophageal dysplasia and early-stage cancer were more easily detected in those with esophageal leukoplakia or pale areas.

Background & Aims The natural course of gastric mild-moderate dysplasia in a country with high incidence of gastric cancer (GC) is relatively unknown. We aimed to determine the long-term cumulative incidence of and risk factors for advanced neoplasia in patients with gastric dysplasia. Methods This was a single center observational study including all consecutive patients diagnosed with gastric mild-moderate dysplasia between 2000 and 2017. Follow-up data were collected until December 2019. We determined the cumulative incidence of advanced neoplasia and identified risk factors with Cox regression. Results A total of 3489 consecutive participants were followed for a median of 4.19 years from initial mild-moderate dysplasia diagnosis. The median surveillance interval between index endoscopy and next follow-up endoscopy was 1.08 years, and more than half of patients had at least 3 surveillance gastroscopies. During the study period, the majority of participants did not show disease progression, with either dysplasia not detected (51.4%) or with persistent dysplasia (46.1%). There were 88 (2.9%) patients (5.13 per 1,000 patient-years) who progressed to advanced neoplasia within a median of 4.3 years. The annual incidence of advanced neoplasia and GC were 0.43% and 0.26%, respectively, within 5 years of mild-moderate dysplasia diagnosis. Increasing age, male gender, moderate dysplasia, dysplasia detected in fundus/cardia at index endoscopy, and persistent H.pylori infection during follow-up, were independent risk factors for developing advanced neoplasia . Conclusions Even in a country with high incidence of GC, the majority of patients with gastric mild-moderate dysplasia did not experience disease progression in the long-term. Intensified surveillance during the first 5 years after mild-moderate dysplasia detection is suggested.

Cancer immunotherapy has achieved great advancement in the past decades. Whereas, its response is largely limited in immunologically cold tumors, in an urgent need to be solve. In recent years, an increasing number of studies have shown that inducing immunogenic cell deaths (ICDs) is an attractive approach to activate antitumor immunity. Upon specific stress, cancer cells undergo ICDs and dying cancer cells release danger associated molecular patterns (DAMPs), produce neoantigens and trigger adaptive immunity. ICDs exert a cancer vaccine-like effect and Inducement of ICDs mimics process of cancer vaccination. In this review, we propose a concept of ICD-based cancer vaccines and summarize sources of ICD-based cancer vaccines and their challenges, which may broaden the understandings of ICD and cancer vaccines in cancer immunotherapy.

Rongli Cui,* Zhiqiang Song,* Baojun Suo, Xueli Tian, Yan Xue, Lingmei Meng, Zhanyue Niu, Zhu Jin, Hejun Zhang, Liya Zhou Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liya ZhouDepartment of Gastroenterology, Peking University Third Hospital, 49 Road Garden, Haidian District, Beijing, 100191, People’s Republic of ChinaTel +86-13911827827Fax +86-10-82265021Email zhouliya123456@163.comBackground: It has not been fully confirmed whether the detection of Helicobacter pylori resistance gene mutation can replace antibiotic drug sensitivity test to guide the clinical individualized treatment. Therefore, we have studied this aspect and discussed the application value of antibiotic sensitivity gene test.Materials and Methods: The biopsy specimen of gastric mucosa from the patients examined by endoscopy and positive for rapid urease test were collected continuously for histopathological analysis, H. pylori culture, antibiotic drug sensitivity test (E-test drug sensitivity test), and antibiotic sensitivity gene test (high-throughput nucleotide sequencing). The participants received triple plus bismuth solution eradication treatment (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg, twice daily for 14 days) for follow-up, and the eradication effect was determined.Results: The 551/602 subjects, who met the inclusion criteria, were subjected to culture for H. pylori and antibiotic drug sensitivity determination; among them 506 were cultured successfully. The results showed that the resistance rates of H. pylori were 38.9% for clarithromycin and 31.0% for levofloxacin. In 489 H. pylori strains, the mutations were detected in clarithromycin and levofloxacin resistance genes, indicating the genotype resistance. The resistance genes of clarithromycin and levofloxacin were consistent with phenotype resistance with respect to sensitivity (81.2% and 69.7% for clarithromycin and levofloxacin, respectively) and specificity (88.9% and 93.7% for clarithromycin and levofloxacin, respectively). The eradication rate of H. pylori in the clarithromycin-resistant group was significantly lower than that in the sensitive group (ITT: 52.1% vs 85.0%, P < 0.001).Conclusion: A correlation was established between the resistance genes of clarithromycin and levofloxacin and their phenotypic resistance and clinical efficacy. The detection of H. pylori resistance genes has a good clinical application prospect.Keywords: Helicobacter pylori, drug resistance, clarithromycin, levofloxacin, mutation, high-throughput nucleotide sequencing

Excessive growth of tumor within biliary wall and formation of biofilm on inner surface of stent can cause restenosis or even obstruction after stent implantation. Therefore, it is important and valuable to develop a new biliary stent for anti-cholangiocarcinoma and anti-biofilm formation. Herein, we designed, prepared and primarily evaluated a new trilayered film for biliary stents consisting of one poly (lactic acid) (PLA) layer loaded with anti-tumor paclitaxel (PTX layer), one middle PLA isolation layer (isolation layer) and one PLA layer loaded with antimicrobial ofloxacin (OFLX layer). It is postulated that the PTX layer releases drug towards biliary wall with tumor, the OFLX layer releases drug towards lumen of bile duct and the isolation layer is used to separate from the PTX layer and the OFLX layer and facilitate drug release in unidirectional way. The prepared trilayered films were characterized in terms of morphology, microstructure, crystallinity and biodegradability. It was found that the films could effectively tune drug release by addition of different amounts of drug or PEG, release PTX and OFLX in opposite directions, effectively inhibit the proliferation of human cholangiocarcinoma RBE cells, the adherence of E. coli and S. aureus and the formation of biofilm in vitro. It is potential that the trilayered films can be used to fabricate a new biliary stent with a dual function of anti-cholangiocarcinoma and anti-biofilm formation.

There is a wide range of oesophageal diseases, the most general of which are inflammation, injury and tumours, and treatment methods are constantly being developed and updated. With an increasingly comprehensive understanding of stem cells and their characteristics of multilineage differentiation, self-renewal and homing as well as the combination of stem cells with regenerative medicine, tissue engineering and gene therapy, stem cells are playing an important role in the treatment of a variety of diseases. Mesenchymal stem cells have many advantages and are most commonly applied; however, most of these applications have been in experimental studies, with few related clinical trials for comparison. Therefore, the methods, positive significance and limitations of stem cells in the treatment of oesophageal diseases remain incompletely understood. Thus, the purpose of this paper is to review the current literature and summarize the efficacy of stem cells in the treatment of oesophageal diseases, including oesophageal ulceration, acute radiation-induced oesophageal injury, corrosive oesophageal injury, oesophageal stricture formation after endoscopic submucosal dissection and oesophageal reconstruction, as well as gene therapy for oesophageal cancer.

Glutamate decarboxylase (GAD) has the potential of converting L-glutamate to gamma-aminobutyric acid (GABA), which is an important non-proteinogenic amino acid that has a potential use as food additive or dietary supplement for its physiological functions. A novel pyridoxal 5'-phosphate (PLP)-dependent glutamate decarboxylase (LsGAD) was cloned from GRAS (generally recognized as safe) Lactobacillus senmaizukei by genome mining and efficiently expressed in Escherichia coli BL21. The LsGAD displayed excellent temperature property, pH property and kinetic parameters compared with the probe LbGAD and the other GADs. By increasing the copy number of the LsGAD encoding gene, the expression level of LsGAD and the biosynthesis yield of GABA were increased, which was near to 2 times of that was expressed in single copy. These results established a solid foundation for increasing the added value of L-glutamate and the biosynthesis of GABA.

Prolyl-4-hydroxylase subunit 2 (P4HA2), as a member of collagen modification enzymes, is induced under hypoxic conditions with essential roles in the collagen maturation, deposition as well as the remodeling of extracellular matrix(ECM). Mounting evidence has suggested that deregulation of P4HA2 is common in cancer. However, the expression pattern and molecular mechanisms of P4HA2 in glioma remain unknown. Here, we demonstrate that P4HA2 is overexpressed in glioma and inversely correlates with patient survival. Knockdown of P4HA2 inhibits proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT)-like phenotype of glioma cellsin vitroand suppressed tumor xenograft growthin vivo. Mechanistically, bioinformatics analysis shows that ECM-receptor interaction and PI3K/AKT pathway are the most enriched pathways of the co-expressed genes with P4HA2. Furthermore, P4HA2 mRNA was positively correlated with mRNA expressions of a series of collagen genes, but not mRNA of PI3K or AKT1/2. Conversely, both the protein expressions of collagens and phosphorylated PI3K/AKT could be downregulated either by silencing of P4HA2 expression or inhibition of its prolyl hydroxylase. Moreover, the inhibitory effects on the migration, invasion and the EMT-related molecules by P4HA2 knockdown can be recapitulated by the Akt phosphorylation activator. Taken together, our findings for the first time reveal an oncogenic role of P4HA2 in the glioma malignancy. By regulating the expression of fibrillar collagens and the downstream PI3K/AKT signaling pathway, it may serve as a potential anti-cancer target for the treatment of glioma.HighlightsP4HA2 is overexpressed and correlated with poor prognosis in glioma.P4HA2 depletion inhibits glioma proliferation, migration, invasion and EMT-like phenotype in vitro and tumorigenesis in vivo.P4HA2 depletion attenuates the PI3K/AKT signaling pathway in a collagen-dependent manner.

Supplemental material, Supplementary_1 for Network pharmacology-based identification of the antitumor effects of taraxasterol in gastric cancer by Wei Chen, Jingwei Li, Chen Li, Hui-Ning Fan, Jing Zhang and Jin-Shui Zhu in International Journal of Immunopathology and Pharmacology

This study evaluated the anesthetic and sedative effects of tricaine methanesulfonate (MS-222) on yellow catfish (Pelteobagrus fulvidraco), and determined its effectiveness for the simulated transportation. In the anesthesia induction and recovery experiment, the adult fish (87.5 ± 13.9 g) were treated with five concentrations of MS-222 (0, 40, 60, 90 and 110 mg L−1), respectively. The results showed that the effective concentration of MS-222 for short-term anesthesia induction was between 90 and 110 mg L−1, according to the principle of anesthesia within 3 min and recovery within 10 min. In the simulated transportation experiment, the fish (86.7 ± 11.4 g) were stored in tanks containing 40 mg L−1 MS-222 solution for 12 h. The results revealed that the content of water ammonia nitrogen in the MS-222 group was significantly lower than that of control group . The fish in the anesthetized transportation group showed a significant decrease in serum cortisol levels (43.11 ± 3.74 ng mL−1) compared with the control group (50.12 ± 0.65 ng mL−1), whereas the levels of serum glucose in fish exposed to MS-222 significantly increased . The hsp70 mRNA expression in the liver of anesthetized yellow catfish was found to significantly upregulate after transportation . Thus, it is concluded that the effective concentrations of MS-222 for sedation and anesthesia in adult yellow catfish were from 90 to 110 mg L−1, and while 40 mg L−1 MS-222 has the potential to be used for the transportation of yellow catfish within 12 h.

Gastric hyperplastic polyp (GHP) commonly arises in the abnormal surrounding mucosa, including autoimmune metaplastic atrophic gastritis (AMAG). We aimed to compare clinicopathological features in patients with GHPs associated with AMAG with those in patients with GHPs associated with non-AMAG.A total of 1170 patients with GHP(s) were enrolled, and their clinical and pathological data were analyzed, retrospectively.The GHP patients were divided into 181 A-GHP (type A GHP, AMAG-associated GHP) participants, 312 B-GHP (type B GHP, Helicobacter pylori infection-associated GHP) participants, and 677 other GHP participants (non-A-GHP and non-B-GHP) based on pathological status of the surrounding non-polypoid mucosa. The A-GHP patients were older and predominantly female (p .05). Gastroscopically, A-GHPs showed less distal and more multiple-region distribution in the stomach (p .001). In addition, the A-GHPs were observed to be usually numerous (55.8%), larger (mean maximum diameter 12.3 mm), and more pedunculated or sub-pedunculated (45.3%) (p .001). Histopathologically, the intestinal metaplasia, intraepithelial neoplasia, and carcinomatous transformation within GHPs were present in 24.3%, 9.9%, and 2.8% of AMAG patients, respectively, which were significantly higher than those in the B-GHPs and other GHPs (p .05). However, the differences of intraepithelial neoplasia and adenocarcinoma in surrounding non-polypoid mucosa did not reach statistical significance (p .05).The GHP(s) arising in AMAG patients is a distinct subgroup of GHP(s) and was an important precancerous lesion. The biopsy from surrounding non-polypoid mucosa was essential to evaluate the underlying etiology of the GHPs, and endoscopists should pay attention to these.

Cancer immunotherapies have shown sustained clinical success in treating primary non-small-cell lung cancer (NSCLC). However, patients with brain metastasis are excluded from the trials because the brain is viewed traditionally as an immune-privileged organ. The composition and properties of tumor-infiltrating myeloid cells in metastatic brain tumors are mostly unknown. To depict the baseline landscape of the composition, gene signature, and functional states of these immune cells, we performed - single-cell RNA sequencing (scRNAseq) for 12,196cellsafter data preprocessing, including 2,241 immunecells from three surgically removed brain lesions of treatment-naïve NSCLC patients. We found a lack of T lymphocyte infiltration and activation, as well as the vast expansion of tumor-associated macrophage(TAM) in the brain lesions of NSCLC patients. By comparing our scRNAseq dataset with published data from early and late-stage primary NSCLC tumors, we showed that this compromised T cell response is unique to brain lesions. We identified a unique alternative activation (M2) gene expression pattern of the TAM in the brain metastasis and a lack of known T cell co-stimulator expression. Accumulation of M2 polarized TAM may, therefore, cause the comprised anti-tumor T cell response in metastatic brain lesions. These findings can contribute to the design of new immunotherapy strategies for NSCLC patients with brain metastasis.

Inflammation and fibrosis caused by inserting cochlear implants into the inner ear are of great concern in clinical treatment. To address these issues, we studied new cochlear implant electrode analogs, polydimethylsiloxane (PDMS) filaments loaded with anti-inflammation/fibrosis dexamethasone (Dex) and coated with hyaluronic acid (HA) as a surface modifier. The PDMS filaments were prepared by incorporating Dex into PDMS that contained different amounts of poloxamer 188 (P188) as a drug release enhancer. HA coatings were performed to prevent protein adsorption by treating the surfaces of the PDMS filaments with O2 plasma, 3-aminopropyltriethoxysilane and HA in sequence. The prepared PDMS filaments were investigated by attenuated total reflection Fourier transform infrared spectroscopy, contact angle measurement and atomic force microscopy. Their protein adsorption and drug release behaviors were examined as well. L929 mouse fibroblast cells were used to evaluate the anti-cell adhesion/proliferation effects of the PDMS filaments. The results showed that the prepared PDMS filaments had the expected structure, good surface properties and excellent anti-fibroblast cell proliferation effects. The HA coatings provided filament surfaces that were more hydrophilic, smoother and more protein-repelling. Dex release was significantly facilitated by adding P188 and slightly slowed down by the HA coatings. The PDMS filaments that contained 5% Dex and 5% P188 and that were coated with HA showed a significant decrease in the fibroblast cell number by approximately 51%, with obviously reduced cell adhesion on the surfaces.

Ubiquitin-specific protease 22 (USP22) is a member of the "death-from-cancer" signature, which plays a key role in cancer progression. Previous evidence has shown that USP22 is overexpressed and correlates with poor prognosis in glioma. The effect and mechanism of USP22 in glioma malignancy, especially cancer stemness, remain elusive. Herein, we find USP22 is more enriched in stem-like tumorspheres than differentiated glioma cells. USP22 knockdown inhibits cancer stemness in glioma cell lines. With a cell-penetrating TAT-tag protein, B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), a robust glioma stem-cell marker, is found to mediate the effect of USP22 on glioma stemness. By immunofluorescence, USP22 and BMI1 are found to share similar intranuclear expression in glioma cells. By analysis with immunohistochemistry and bioinformatics, USP22 is found to positively correlate with BMI1 at the post-translational level only rather than at the transcriptional level. By immunoprecipitation and in vivo deubiquitination assay, USP22 is found to interact with and deubiquitinate BMI1 for protein stabilization. Microarray analysis shows that USP22 and BMI1 mutually regulate a series of genes involved in glioma stemness such as POSTN, HEY2, PDGFRA and ATF3. In vivo study with nude mice confirms the role of USP22 in promoting glioma tumorigenesis by regulating BMI1. All these findings indicate USP22 as a novel deubiquitinase of BMI1 in glioma. We propose a working model of the USP22-BMI1 axis, which promotes glioma stemness and tumorigenesis through oncogenic activation. Thus, targeting USP22 might be an effective strategy to treat glioma especially in those with elevated BMI1 expression.

BACKGROUND: Cephalosporin C acylase (CA) plays a key role in the one‐step enzymatic catalysis of 7‐aminocephalosporanic acid (7‐ACA) from Cephalosporin C (CPC). However, the synthesis of 7‐ACA needs low‐temperature conditions: unless catalyzed at 13 °C, it will produce large amounts of undesired products. Unfortunately, cephalosporin CA catalyzes CPC to 7‐ACA directly at a very low efficiency at 13 °C or below. RESULTS: In this work, multiple techniques including molecular docking, multi‐site random‐directed mutagenesis and high‐throughput screening were adopted and combined into an engineering strategy to improve the cold adaptability of CA. Thus, the best‐hit mutant 9H9 containing mutations of P238G, P449G and P582G was screened revealing a specific activity of 1.94 U mg⁻¹ at 13 °C, which is 1.3‐fold higher than that of the parent. Compared with the parent, the mutant 9H9 shows a slight decline in the Kₘ value and significant improvement in the Vₘₐₓ value. In addition, the yield of 7‐ACA catalyzed by 9H9 was obviously higher than that of the parent at low temperature. CONCLUSION: A new and viable strategy was established for improving the cold adaptability of CA and investigations were made into enhancing its conformational flexibility. This might lay a solid foundation for future study and industrial application of CAs. © 2018 Society of Chemical Industry

Non-small cell lung carcinoma is the predominant type of lung cancer, and shows an easily developable tolerance to radiotherapy. Cancer stem cells are suggested to be involved in the resistance against therapies. Onzin might be accumulated during the process tumor overcoming the radiation stress. To address the relationship between Onzin, stemness and radiation resistance, we treated the lung cancer tumor bearing mice with radiaotherapy and observed the differences between radiation sensitive (RS) and resistant (RR) tumors. Immunohistochemistry and HE staining were used to observe Onzin and POU5F1 expression in tumor tissues. Quantitative realtime-PCR and Western blot were applied for Onzin and POU5F1 in tumors and cells. In-vitro cellular viability was assessed by CCK8 methods for tumor derived cells. The stably transfected A549 cell lines overexpressing Onzin were generated through lentivirus transfection. After radiotherapy, those RR adenocarcinoma tumors and cells derived from them showed an increased Onzin expression. Further, RR cells were found upregulated stemness, indicated by increased sphericity and proliferation, as well as POU5F1 expression. Next, we overexpressed Onzin in the A549 cells and found an elevated POU5F1 expression, increased proliferation, and enhanced sphericity. Moreover, this could be suppressed by the AKT inhibitor MK-2260. In vivo, the A549 cells overexpressing Onzin showed not only higher tumor formation capability and growth, but also a significant resistance to radiation. Taken together, RR tumors have upregulated Onzin and POU5F1 expression. Ectopic expression of Onzin promotes the POU5F1 expression as well as stemness functions, and confers adenocarcinomas the resistance to radiotherapy.

Diet sources are closely involved in the pathogenesis of diverse neuropsychiatric disorders and cancers, in addition to inherited factors. Currently, natural products or nutraceuticals (commonly called medical foods) are increasingly employed for adjunctive therapy of these patients. However, the potential molecular mechanisms of the nutrient efficacy remain elusive. In this review, we summarized the neuroprotective and anti-cancer mechanisms of nutraceuticals. It was concluded that the nutraceuticals exerted neuroprotection and suppressed tumor growth possibly through the differential modulations of redox homeostasis. In addition, the balance between reactive oxygen species (ROS) production and ROS elimination was manipulated by multiple molecular mechanisms, including cell signaling pathways, inflammation, transcriptional regulation and epigenetic modulation, which were involved in the therapeutic potential of nutraceutical antioxidants against neurological diseases and cancers. We specifically proposed that ROS scavenging was integral in the neuroprotective potential of nutraceuticals, while alternation of ROS level (either increase or decrease) or disruption of redox homeostasis (ROS addiction) constituted the anti-cancer property of these compounds. We also hypothesized that ROS-associated ferroptosis, a novel type of lipid ROS-dependent regulatory cell death, was likely to be a critical mechanism for the nutraceutical antioxidants. Targeting ferroptosis is advantageous to develop new nutraceuticals with more effective and lower adverse reactions for curing patients with neuropsychiatric diseases or carcinomas.

Background As part of a long-standing line of research regarding how peer density affects health, researchers have sought to understand the multifaceted ways that the density of contemporaries living and interacting in proximity to one another influence social networks and knowledge diffusion, and subsequently health and well-being. This study examined peer density effects on oral health for racial/ethnic minority older adults living in northern Manhattan and the Bronx, New York, NY. Methods Peer age-group density was estimated by smoothing US Census data with 4 kernel bandwidths ranging from 0.25 to 1.50 mile. Logistic regression models were developed using these spatial measures and data from the ElderSmile oral and general health screening program that serves predominantly racial/ethnic minority older adults at community centers in northern Manhattan and the Bronx. The oral health outcomes modeled as dependent variables were ordinal dentition status and binary self-rated oral health. After construction of kernel density surfaces and multiple imputation of missing data, logistic regression analyses were performed to estimate the effects of peer density and other sociodemographic characteristics on the oral health outcomes of dentition status and self-rated oral health. Results Overall, higher peer density was associated with better oral health for older adults when estimated using smaller bandwidths (0.25 and 0.50 mile). That is, statistically significant relationships (p

It has been recently reported that CD38 was highly expressed in adipose tissues from obese people and CD38‐deficient mice were resistant to high‐fat diet (HFD)‐induced obesity. However, the role of CD38 in the regulation of adipogenesis and lipogenesis is unknown. In this study, to explore the roles of CD38 in adipogenesis and lipogenesis in vivo and in vitro, obesity models were generated with male CD38−/− and WT mice fed with HFD. The adipocyte differentiations were induced with MEFs from WT and CD38−/− mice, 3T3‐L1 and C3H10T1/2 cells in vitro. The lipid accumulations and the alternations of CD38 and the genes involved in adipogenesis and lipogenesis were determined with the adipose tissues from the HFD‐fed mice or the MEFs, 3T3‐L1 and C3H10T1/2 cells during induction of adipocyte differentiation. The results showed that CD38−/− male mice were significantly resistant to HFD‐induced obesity. CD38 expressions in adipocytes were significantly increased in WT mice fed with HFD, and the similar results were obtained from WT MEFs, 3T3‐L1 and C3H10T1/2 during induction of adipocyte differentiation. The expressions of PPARγ, AP2 and C/EBPα were markedly attenuated in adipocytes from HFD‐fed CD38−/− mice and CD38−/− MEFs at late stage of adipocyte differentiation. Moreover, the expressions of SREBP1 and FASN were also significantly decreased in CD38−/− MEFs. Finally, the CD38 deficiency‐mediated activations of Sirt1 signalling were up‐regulated or down‐regulated by resveratrol and nicotinamide, respectively. These results suggest that CD38 deficiency impairs adipogenesis and lipogenesis through activating Sirt1/PPARγ‐FASN signalling pathway during the development of obesity.

Fatigue life prediction is very important for the reliability and safety design of rubber isolators. As there is still no precise and credible theoretical or simulation method on fatigue life prediction for the kind of rubber isolators whose shape may change with time during the whole useful life, it means that the experimental method is still the best solution for the problem. A force-controlled temperature-accelerated fatigue experiment is designed for these long-life rubber isolators. The experiment introduced essential factors such as the equipment demands, stress condition, data collection and data processing. Compared with the traditional way, there are four advantages of the new experiment: the time cost of the experiment, the authenticity of the experiment data, the quantity of valid data and the control method of the mechanical load. By calculating the real-time vertical displacement, global stiffness and dissipated energy of the tested sample, the new experiment can improve the quantity of valid data for further researches. Moreover, Arrhenius model is proved accurately to estimate the accelerated life.

Tumors are comprised of highly heterogeneous populations of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumors in vivo. These rare cancer stem cells (CSCs) have been regarded as the "bad seeds" accounted for tumor initiation, progression, metastasis, relapse and therapeutic resistance. CSC-targeted therapy seems to be a better avenue for radical cure of cancer. Deubiquitinases (DUBs), specifically disassembling ubiquitin chains, have been demonstrated to play an important role in rigidly maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis in normal circumstances. Dysfunction or deregulation of DUBs always leads to a series of disorders, even malignant transformation. Despite the accumulative evidence that DUB inhibitors in cancer remedy mainly target the tumor bulk, side effects like toxicity and resistance are still hard nuts to crack. In this article, we review the concept of ubiquitin proteasome system (UPS) and hallmarks of CSCs related to tumor obstinacy. We primarily summarize the CSC-related factors and signaling pathways and focus on the function of DUBs on biological traits of CSCs. We also illustrate the opportunities and challenges for the application of DUB inhibitors in the CSC-targeted therapy. Finally, we discuss the complexity of cancer stem cell hierarchy complexity and argue that a combination therapy for both CSCs and non-CSCs should be a desirable option.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of numerous biological processes, especially in cancer development. Aberrantly expressed and specifically located in tumor cells, they exert distinct functions in different cancers via regulating multiple downstream targets such as chromatins, RNAs, and proteins. Differentiation antagonizing non-protein coding RNA (DANCR) is a cytoplasmic lncRNA that generally works as a tumor promoter. Mechanically, DANCR promotes the functions of vital components in the oncogene network by sponging their corresponding microRNAs or by interacting with various regulating proteins. DANCR's distinct expression in tumor cells and collective involvement in pro-tumor pathways make it a promising therapeutic target for broad cancer treatment. Herein, we summarize the functions and molecular mechanism of DANCR in human cancers. Furthermore, we introduce the use of CRISPR/Cas9, antisense oligonucleotides and small interfering RNAs as well as viral, lipid, or exosomal vectors for onco-lncRNA targeted treatment. Conclusively, DANCR is a considerable promoter of cancers with a bright prospect in targeted therapy.