Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation.

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.

[Evaluation of the efficacy of medial open wedge high tibial osteotomy combined with anterior cruciate ligament reconstruction in the treatment of varus knee osteoarthritis with anterior cruciate ligament injury].

Objective: To evaluate the efficacy of medial open wedge high tibial osteotomy (MOWHTO) combined with anterior cruciate ligament (ACL) reconstruction in the treatment of varus knee osteoarthritis (OA) with ACL injury. Methods: A follow-up study. The study retrospectively analyzed the patients underwent MOWHTO combined with ACL reconstruction for treatment of varus knee OA with ACL injury in Tianjin Hospital between April 2018 and September 2022. The preoperative and postoperative posterior slope angle (PSA), hip-knee-ankle angle (HKA), visual analog scale (VAS) pain scores, Lysholm score, International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Tegner score were compared. The follow-up indicators were recorded at 6 weeks, 3 months and 1 year after operation, and the complications were recorded. Results: The study included 32 patients (23 males, 9 females) with a mean age of (50.7±8.4) years. The mean follow-up time was (21.2±4.8) months. PSA increased from 9.2°±1.8° preoperatively to 11.1°±2.4° postoperatively, and HKA increased from 168.7°±2.2° to 181.5°±2.2° (both P<0.01). The indicators such as VAS score (6.8±1.1 vs 1.8±0.4), Lysholm score (52.6±7.1 vs 82.0±6.4), IKDC score (64.7±6.2 vs 80.3±10.0), WOMAC score (51.8±6.3 vs 81.8±6.5), and Tegner score (1.9±0.6 vs 5.0±1.0) were all improved after the operation (all P<0.01). Complications occurred in 5 patients (15.6%), including hematomas, sensory abnormalities, intermuscular vein thrombosis and correction angle loss. Conclusion: MOWHTO combined with ACL reconstruction is a safe and effective approach for the treatment of varus knee OA with ACL injury.

Inflammation and neutrophil extracellular traps in cerebral cavernous malformation.

Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3iECKO mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3iECKO mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas  of patients with CCM confirms the clinical relevance of NETs in CCM.

[Comparison of three different measurement methods to determine resting energy expenditure in patients with decompensated hepatitis B cirrhosis].

Objective: To compare the differences to determine resting energy expenditure (REE) measured with indirect calorimetry and REE predicted by formula method and body composition analyzer in patients with decompensated hepatitis B cirrhosis, so as to provide theoretical guidance for the implementation of precision nutrition intervention. Methods: Patients with decompensated hepatitis B cirrhosis who were admitted to Henan Provincial People's Hospital from April 2020 to December 2020 were collected. REE was determined by the body composition analyzer and the H-B formula method. Results: were analyzed and compared to REE measured by the metabolic cart. Results A total of 57 cases with liver cirrhosis were included in this study. Among them, 42 were male, aged (47.93 ± 8.62) years, and 15 were female aged (57.20 ± 11.34) years. REE measured value in males was (1 808.14 ± 201.47) kcal/d, compared with the results calculated by the H-B formula method and the measured result of body composition, and the difference was statistically significant (P = 0.002 and 0.003, respectively). REE measured value in females was (1 496.60 ± 131.28) kcal/d, compared with the results calculated by the H-B formula method and the measured result of body composition, and the difference was statistically significant (P = 0.016 and 0.004, respectively). REE measured with the metabolic cart had correlation with age and area of visceral fat in men (P = 0.021) and women (P = 0.037). Conclusion: Metabolic cart use will be more accurate to obtain resting energy expenditure in patients with decompensated hepatitis B cirrhosis. Body composition analyzer and formula method may underestimate REE predictions. Simultaneously, it is suggested that the effect of age on REE in H-B formula should be fully considered for male patients, while the area of visceral fat may have a certain impact on the interpretation of REE in female patients.

[A multicenter study on the tolerance of intravenous low-dose cyclophosphamide in systemic lupus erythematosus].

OBJECTIVE: To compare the safety of low-dose cyclophosphamide and high-dose cyclophosphamide in the treatment of systemic lupus erythematosus (SLE). METHODS: A total of 1 022 patients with systemic lupus erythematosus from 24 hospitals in China between March 2017 to July 2018 were enrolled. Their clinical manifestations, laboratory tests, adverse events, reasons for stopping receiving intravenous cyclophosphamide and comorbidities were collected. Among them, 506 SLE patients received short-interval low-dose intravenous cyclophosphamide therapy (SILD IV-CYC, 400 mg every two weeks), and 256 patients underwent high-dose cyclophosphamide therapy (HD IV-CYC, 500 mg/m2 of body surface area every month), the side effects between the two groups were compared, the remaining 260 SLE patients were treated with IV-CYC irregularly. Moreover, a total of 377 patients in SILD IV-CYC group and 214 patients in HD IV-CYC group had medical records of the reasons for stopping recei-ving IV-CYC. The reasons for stopping receiving IV-CYC in these two groups were analyzed. RESULTS: In this study, only 40.27%(238/591)of the SLE patients stopped receiving intravenous cyclophosphamide for the causes of disease improvement, however, up to 33.67% (199/591) of the patients for the reason of drug-related side effects. There were 83 patients out of 214 (38.79%) with high-dose intravenous cyclophosphamide treatment who stopped receiving IV-CYC for the drug-related side effects, which was significantly higher than that in the low-dose cyclophosphamide group (30.77%, 116/337, P=0.048). Of theses 506 patients in SILD IV-CYC group, 88 (17.39%) patients experienced gastrointestinal reactions, 66 (13.04%) suffered from infections, 49 (9.68%) had myelosuppression and 68 (13.44%) had alopecia, respectively. Among the 256 patients in the HD IV-CYC group, 80 (31.25%) experienced gastrointestinal reactions, 57 (22.27%) suffered from infections, 51 (19.92%) had myelosuppression and 49 (19.14%) had alopecia. Moreover, 71 (25.18%) of 282 female patients with age between 16 to 45 years in SILD IV-CYC group had abnormal menstruation, while menstrual disorder occurred in 39.72% (56/141) patients of HD IV-CYC group. There was no difference of drug-induced hepatic injury, hemorrhagic cystitis and fatigue between the two groups. CONCLUSION: Low-dose cyclophosphamide showed a lower prevalence of adverse events than high-dose cyclophosphamide in systemic lupus erythematosus patients.

[Research advances in the relationship of dietary factors and prostate cancer risk].

Prostate cancer is the second most common malignancy in men worldwide. An increasing trend for prostate cancer incidence was observed in China. Enormous studies have been conducted to investigate the association between dietary factors and prostate cancer, however conflicted results were obtained. Red meat, processed meat, and dairy products consumption were reported to be associated with the increased prostate cancer risk, while tomatoes, soybeans and green tea might reduce the risk of prostate cancer occurance. However, no consensus could be reached without strong evidence. Furthermore, further studies are needed to investigate the association between vitamin and mineral supplements and prostate cancer risk. Some studies reported that men with higher dietary inflammatory index scores increased prostate cancer risk. There may be a long susceptible period when dietary factors affect prostate cancer risk, which poses challenges for collecting exposure and the follow-up. Measure bias and detection bias are the main reasons which impair the authenticity of studies on the relationship of dietary factors and prostate cancer risk. Researchers should apply various methods to measure participants' dietary consumption levels and ascertain essential outcomes, such as prostate cancer death. This article reviews updated epidemiological evidences on the association of dietary factors and prostate cancer, aims to benefit future nutritional epidemiology studies focus on the prostate cancer prevention.

[Practice of laparoscopic anatomical adrenalectomy].

On the basis of existing laparoscopic transabdominal adrenalectomy, this article described a safe and reliable surgical method for the treatment of small adrenal lesions-laparoscopic anatomical adrenalectomy (LAA), and retrospectively analyzed the clinical data of 74 patients who had undergone LAA. All patients had no signs of recurrence on imaging. LAA has high safety and feasibility, clear intraoperative anatomical layers, good spatial operability, and low postoperative complications. LAA provides a more reliable option for the treatment of small adrenal diseases.

[The potential application of a three-dimensional visualization technique in adrenal vein sampling].

Objective: To explore the potential application of a three-dimensional visualization technique in adrenal vein sampling (AVS). Methods: The clinical data were retrospectively analyzed, which included 76 patients with primary aldosteronism (PA) who have undergone AVS in Guizhou Provincial People's Hospital from December 2017 to May 2020. All cases were examined by adrenal thin-section enhanced CT and blood was drawn by bilateral AVS. Among them, the adrenal vein blood of 46 cases was sampled with the help of three-dimensional (3D) visualization processing of CT data, while that of 30 cases was without 3D visualization processing. The rate of the catheter in place, the successful rate of AVS, the time of blood collection, the dosage of the contrast agent, and surgical complications were compared between the two groups. Results: There were 76 cases included, while 38 were male and 38 were female. The average age was 45 (25-57) years. Compared with the patients without the aid of 3D visualization, the success rate of right AVS of the patients with the aid of 3D visualization technology increased from 43% to 78% (P<0.05). The success rate of adrenal vein blood collection increased from 53% to 83%. The dose of contrast agent decreased [the M(Q1,Q3) were78 (59, 89) ml vs 28 (16, 51) ml, P<0.05], and the time of blood sampling from the right adrenal vein approximately decreased [the M（Q1，Q3） were 70 (66, 88) min vs 44 (22, 61) min, P<0.05]. Compared with the case without the aid of 3D visualization, the left adrenal vein catheterization rate of patients in the 3D visualization group increased from 97% to 98%, the success rate of adrenal vein blood collection increased from 97% to 98%, and the differences of the time of blood sampling and the dosage of the contrast were not statistically significant between the two groups. Among all the cases experienced bilateral AVS, only one patient without 3D reconstruction had contrast extravasation, and the others had no obvious complications. Conclusions: Before AVS, 3D visualization processing of adrenal vein from CT data is capable of increasing the success rate of blood sampling from the right adrenal vein, as well as reducing the dosage of contrast agent and the time of adrenal vein blood sampling. Therefore, it has a potential clinical value of the application.

VE-Cadherin-Mediated Epigenetic Regulation of Endothelial Gene Expression.

RATIONALE: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE: We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS: We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and ß-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/ß-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS: These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

Nanographene oxides carrying antisense walR RNA regulates the Enterococcus faecalis biofilm formation and its susceptibility to chlorhexidine.

Enterococcus faecalis is the dominant pathogen for persistent periapical periodontitis. The chlorhexidine (CHX) is used as conversional irrigation agents during endodontic root canal therapy. It was reported that the antisense walR RNA (ASwalR) suppressed the biofilm organization. The aim of this study was to investigate the antimicrobial effects of novel graphene oxide (GO)-polyethylenimine (PEI)-based antisense walR (ASwalR) on the inhibition of E. faecalis biofilm and its susceptibility to chlorhexidine. The recombinant ASwalR plasmids were modified with a gene encoding enhanced green fluorescent protein (ASwalR-eGFP) as a reporter gene so that the transformation efficiency could be evaluated by the fluorescence intensity. The GO-PEI-based ASwalR vector transformation strategy was developed to be transformed into E. faecalis and to over-produce ASwalR in biofilms. Colony forming units (CFU) and confocal laser scanning microscopy were used to investigate whether the antibacterial properties of antisense walR interference strategy sensitize E. faecalis biofilm to the CHX. The results indicated that overexpression of ASwalR by GO-PEI-based transformation strategy could inhibit biofilm formation, decrease the EPS synthesis and increase the susceptibility of E. faecalis biofilms to CHX. Our reports demonstrated that antisense walR RNA will be a supplementary strategy in treating E. faecalis with irrigation agents.

[Study on mechanism of Fangji Huangqi Decoction on hypouricemic effect and renal protection in hyperuricemia mice].

The aim of this paper was to study the specific mechanism of Fangji Huangqi Decoction(FHT) in decreasing uric acid and improving renal function in mice with hyperuricemia(HUA) induced by potassium oxonate, so as to provide theoretical basis for the research and development of drugs for clinical prevention and treatment of HUA and the modernization of traditional Chinese medicine. Sixty Kunming male mice were randomly divided into 6 groups, with 10 mice in each group, namely normal group, model group(250 mg·kg~(-1) potassium oxonate), FHT high, medium and low-dose groups(10 920, 5 460, and 2 730 mg·kg~(-1)) and positive drug allopurinol group(5 mg·kg~(-1)). Drug administration was given once a day for 7 days. On the 6 th day, mice of each group were kept in metabolic cages, and their urine was collected for 24 hours for determination of uric acid, creatinine, and ß2-microglobulin(ß2-MG) levels. After 7 days, the animals were sacrificed to determine serum uric acid, creatinine ß2-MG and interleukin-1ß(IL-1ß) levels, and their liver and kidney tissues were collected. The liver tissues were used for subsequent determination of xanthine oxidase(XOD) activity, and the kidney tissues were used for subsequent determination of IL-1ß levels, pathological tests and related Western blot experiments. In the cell transfection experiment, the cells were divided into blank group, model group(4.8 mmol·L~(-1) uric acid treatment), FHT administration group(4.8 mmol·L~(-1) uric acid+200 µg·mL~(-1) FHT), leucine-rich repeat kinase 1(LRRK1)-small interfering RNA(siRNA) group(4.8 mmol·L~(-1) uric acid+LRRK1-siRNA transfection) and LRRK1-siRNA+FHT group(4.8 mmol·L~(-1) uric acid+LRRK1-siRNA transfection+200 µg·mL~(-1) FHT). After 24 h incubation, the level of IL-1ß in the cell supernatant was detected, and the cellular proteins were extracted and used to determine LRRK1, epidermal growth factor receptor(EGFR), PDZ kinase 1(PDZK1) and nuclear factor-kappa B(NF-κB) protein expression levels. The results showed that, FHT could significantly reduce the uric acid, creatinine and ß2-MG levels in serum and ß2-MG levels in urine, increase the uric acid and creatinine levels in urine, and improve the renal pathological results of the HUA mice, but showed no effect on liver XOD activity; at the same time, we found that the expression level of IL-1ß in serum and kidney, NF-κB, LRRK1 and EGFR protein levels in kidney of HUA mice were significantly increased, and the expression level of PDZK1 protein was significantly decreased, while FHT could significantly improve the abnormal expression of these proteins, and FHT increased protein expression of renal organic anion transporter 1(OAT1), OAT3 and ATP bin-ding transporter G2(ABCG2) in HUA mice, but FHT had no effect on the expression of urate transporter 1(URAT1). In the cell transfection experiment, after transfection of LRRK1-siRNA, the levels of IL-1ß, EGFR and NF-κB in supernatant were significantly reduced, and the expression of PDZK1 protein was significantly increased. As compared with the LRRK1-siRNA group, the levels of IL-1ß, EGFR, PDZK1 and NF-κB did not change significantly with the additional FHT. This study showed that FHT may regulate the renal uric acid transport system through LRRK1 gene, improve the capacity of uric acid excretion, so as to reduce the level of serum uric acid. At the same time, FHT can not only protect the kidney directly, but also in an indirect manner by reducing the level of uric acid.

Genetic polymorphisms in IL1B predict susceptibility to steroid-induced osteonecrosis of the femoral head in Chinese Han population.

The purpose of this research was to examine if the IL1B gene polymorphism has impact on the risk of steroid-induced ONFH in Chinese population. We found that IL1B rs1143630 decreased the SANFH's risk and IL1B rs2853550 increased the risk of steroid-induced ONFH. So, we guess that IL1B gene influences the genetic susceptibility of steroid-induced ONFH. INTRODUCTION: Genetic polymorphisms in IL1B gene could be related in the pathogenesis of osteonecrosis. Discusses on the relationship between the IL1B gene and steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is still less in Chinese Han population. So, in this research, we want to examine whether the IL1B gene polymorphism has impact on the risk of steroid-induced ONFH in Chinese population. METHODS: A total of 286 steroid-induced ONFH patients and 441 controls were recruited, and seven SNPs (rs2853550, rs1143643, rs3136558, rs1143630, rs1143627, rs16944, and rs1143623) in IL1B gene were selected; unconditional logistic regression analysis was used to research the influence on the risk of steroid-induced ONFH. Functional annotations of IL1B variants were performed by RegulomeDB and HaploReg. RESULTS: rs1143630 (A>C) in the IL1B gene decreased the risk of steroid-induced ONFH in the allele model (OR = 0.69, 95%CI 0.51-0.93, p = 0.014). Further genetic model analyses found that IL1B rs2853550 AG genotype increased the risk of steroid-induced ONFH compared with the people who are carriers of the IL1B rs2853550 GG genotype (OR = 1.69, 95%CI 1.16-2.46, p = 0.012). In the dominant model, IL1B rs1143630 GG-GT genotype decreased the risk of steroid-induced ONFH (OR = 0.62, 95%CI 0.44-0.87, p = 0.0051). And further haplotype analysis was performed, while the result was not significant. Using RegulomeDB and HaploReg, rs2853550 is likely to affect TF binding, any motif and DNase peak. CONCLUSIONS: We guess that IL1B gene influences the genetic susceptibility of steroid-induced ONFH.

Chewing lice from high-altitude and migrating birds in Yunnan, China, with descriptions of two new species of Guimaraesiella.

In total, 366 birds representing 55 species in 24 families and eight orders, were examined for chewing lice (Phthiraptera: Amblycera, Ischnocera) in two high-altitude localities in Yunnan Province, China. In Ailaoshan, almost all of the birds examined were resident passeriforms, of which 36% were parasitized by chewing lice. In Jinshanyakou, most birds were on migration, and included both passerine and non-passerine birds. Of the passerine birds caught in Jinshanyakou, only one bird (0.7%) was parasitized by chewing lice. The prevalence of Myrsidea and Brueelia-complex lice on birds caught in Ailaoshan was higher than in previous reports. Of the chewing lice identifiable to species level, three represent new records for China: Actornithophilus hoplopteri (Mjöberg, 1910), Maculinirmus ljosalfar Gustafsson & Bush, 2017 and Quadraceps sinensis Timmermann, 1954. In total, 17 new host records are included, of which we describe two as new species in the Brueelia-complex: Guimaraesiella (Cicchinella) ailaoshanensis sp. nov. ex Schoeniparus dubius dubius (Hume, 1874) and G. (C.) montisodalis sp. nov. ex Fulvetta manipurensis tonkinensis Delacour & Jabouille, 1930. This published work has been registered in ZooBank, http://zoobank.org/urn:lsid:zoobank.org:pub:9FC3D8EE-2CED-4DBE-A1DB-471B71260D27.

Comparative studies of mucosal humoral and cellular immune responses to 2009 pandemic H1N1 influenza virus in mice.

The nasal-associated lymphoid tissues (NALTs), embedded in the submucosa of murine upper respiratory tract, represents an important site of induction for local mucosal immune responses to airborne pathogens and intranasal vaccines. Here, we systematically investigated the mucosal humoral and cellular immune responses of NALTs in mice infected with A/Beijing/501/2009 (BJ501) and A/Puerto Rico/8/1934 (PR8) viruses. Compared with PR8 infection, BJ501 induced a more rapid increase of virus-specific IgA and IgG antibodies in the nasal lavage fluid and a higher ratio of IgG1/IgG2a, indicating a stronger Th2 response to BJ501 in mucosal immunity. In addition, using virus-specific enzyme-linked immunospot assay (ELISpot assay), we observed higher and earlier responses of virus-specific IgA and IgG antibody-secreting cells (ASCs) and IFN-γ and IL-4 cytokine-secreting cells (CSCs) in NALTs of mice intranasally infected with BJ501 virus. In particular, the frequency of BJ501-specific IFN-γ-CSCs significantly correlated with the kinetics of BJ501 virus load in NALTs, suggesting an important role of IFN-γ-CSCs-associated mucosal cellular immune responses in BJ501 virus clearance. Collectively, BJ501 induced a more comprehensive and rapid mucosal immune responses in NALTs of mice, providing further understanding of the immune responses elicited by 2009 pandemic H1N1 virus in upper respiratory tract. Keywords: nasal-associated lymphoid tissues (NALTs); influenza virus; mucosal immune response; Th1/Th2 response.

[Advances in the study of programmed cell death protein 1 and its ligand inhibitors in the treatment of late stage HCC].

The treatment of late stage hepatocellular carcinoma (HCC) presently remains a great challenge. A very few drugs have been recently approved for clinical use except sorafenib and lenvatinib. After decades of failure and experience with molecular targeted and immunosuppressive therapy, immune checkpoint inhibitors are becoming one of the potentially effective therapies for patients with HCC, whose tumor is in the middle and late stages. Moreover, immune checkpoint is one of the main mechanisms of tumor immune evasion; of which programmed cell death protein 1 and its ligand (PD1/PD-L1) are important immune checkpoint targets, and its related pathway has shown to have an antitumor effect in a variety of solid or hematologic tumors and its inhibitors can effectively exert antitumor immunosuppressive effects. This review summarizes the current role of PD1/PD-L1 inhibitors in the treatment of late stage HCC, and explores the forecasting value of combined therapy strategy for HCC.

Necroptosis in the periodontal homeostasis: Signals emanating from dying cells.

Periodontal tissues are constantly exposed to microbial stimuli. The equilibrium between microbes and host defense system helps maintain the homeostasis in the periodontal microenvironment. Growth of pathogenic bacteria in dental biofilms may induce proinflammatory cytokine production to recruit sentinel cells, mainly neutrophils and monocytes into the gingival sulcus or the periodontal pocket. Moreover, dysbiosis with overgrowth of anaerobic pathogens, such as Porphyromonas gingivalis and Tannerella forsythia, may induce death of both immune cells and host resident cells. Necroptosis is one newly characterized programmed cell death mediated by receptor-interacting protein kinase (RIPK)-1, RIPK3, and mixed lineage kinase like (MLKL). With its release of death-associated molecular patterns (DAMPs) into extracellular environment, necroptosis may help transmit the danger signal and amplify the inflammatory responses. In this review, we present recent advances on how necroptosis influences bacterial infection progression and what a role necroptosis plays in maintaining the homeostasis in the periodontal niche. Until we fully decipher the signals emanated from dying cells, we cannot completely understand the mechanism of disease progression.

[mRNA genomics change and significance of important ion channel proteins in patients with atrial fibrillation].

Objective: To investigate the mRNA genomics changes and significance of important ion channel proteins in patients with atrial fibrillation (AF), to reveal the mechanism of electrical remodeling in AF. Methods: Ninety patients with AF were chosen to receive the radiofrequency ablation (AF-RFA), 90 healthy subjects were included as the normal control group.The coronary sinus blood and peripheral venous blood were taken from each AF patient during the operation of AF-RFA.The genome-wide mRNA expression profile was analyzed with mRNA microarray chip, and the mRNA expression difference results for the major ion channel gene was further validated using Real-time PCR test. Results: The expression of twelve ion channel protein mRNA increased ≥2.0-fold, expression of 10 mRNA decreased ≥2.0-fold, among which K(+) channel gene KCNE4, KCND2, KCNN4 declined obviously, KCNA5 dropped 11.54-fold (P< 0.01); KCNS3, KCNS1, KCNG1, KCNG7 and Ca(+ +) channel gene CACNA2D3 increased significantly.Compared with autologous peripheral blood, 12 mRNAs of ion channel protein in coronary sinus blood of AF patients was differentially expressed ≥2.0-fold.Compared with control group in peripheral blood, 7 ion channel protein mRNA expression differences was ≥2.0-fold, and the KCNA5 gene expression was down by 8.13-fold.RT-PCR confirmed that the trend and extent of differential expression were consistent with the chip results.The results of myocardial tissue RT-PCR showed that CACNA1C, KCNC3, KCNG1 and KCNK7 mRNA were up-regulated in AF (P<0.05), and other ion channel mRNA expressions were down-regulated (P<0.05). KCNA5 was down-regulated most obvious. Conclusion: The down-regulation of KCNA5 gene expression in AF patients is most obvious, and more potassium ion channel expression differences are also significant, so that the potassium ion channel reconstruction may play a dominant or much more important role in AF electrical remodeling.

Biological characteristics of staphylococcal enterotoxin Q and its potential risk for food poisoning.

AIMS: To elucidate the biological characteristics and stability of a newly identified staphylococcal enterotoxin Q (SEQ) against heating and digestive enzymes and to evaluate the risk of seq-harbouring Staphylococcus aureus in food poisoning. METHODS AND RESULTS: Purified SEQ was treated with heating, pepsin and trypsin which are related to food cooking, stomach and intestine conditions, respectively. Superantigenic activity of SEQ was assessed by determining the ability of IL-2 induction in mouse spleen cells. The emetic activity of SEQ was assessed using house musk shrew, a small emetic animal model. The results revealed that SEQ exhibits a remarkable resistance to heat treatment and pepsin digestion and has significant superantigenic and emetic activities. Furthermore, a sandwich ELISA for detection of SEQ production was developed, and the results showed that seq-harboring S. aureus isolates produce a large amount of SEQ. CONCLUSIONS: The newly identified SEQ had remarkable stability to heat treatment and digestive enzyme degradation and exhibited significant superantigenic and emetic activities. In addition, seq-harbouring S. aureus isolated from food poisoning outbreaks produced a large amount of SEQ, suggesting that seq-harbouring S. aureus could potentially be a hazard for food safety. SIGNIFICANCE AND IMPACT OF THE STUDY: This study found, for the first time, that SEQ, a nonclassical SE, had remarkable stability to heat treatment and enzyme degradation and exhibited significant emetic activity, indicating that SEQ is a high-risk toxin in food poisoning.

Reevaluation of Two Quantitative Trait Loci for Type II Resistance to Fusarium Head Blight in Wheat Germplasm PI 672538.

Fusarium head blight (FHB), mainly caused by Fusarium graminearum, is a destructive disease in wheat. A population consisting of 229 F2 and F2:3 plants derived from the cross PI 672538 × L661 was used to evaluate the reactions to FHB. The FHB resistance data distribution in the F2 population indicates that some quantitative trait loci (QTLs) were controlling the FHB resistance in PI 672538. We further detected two major QTLs (Qfhs-2B, Qfhs-3B) from analysis of the resistance data and the PCR-amplified results using WinQTLCart 2.5 software. Qfhs-2B, flanked by Xbarc55-2B and Xbarc1155-2B, explained more than 11.6% of the phenotypic variation of the percentage of diseased spikelets (PDS), and Qfhs-3B, flanked by Xwmc54-3B and Xgwm566-3B, explained more than 10% of the PDS phenotypic variation in the F2:3 population. In addition, Qfhs-3B was different from Fhb1 in terms of the pedigree, inheritance, resistance response, chromosomal location, and marker diagnosis. We also detected QTLs for other disease resistance indices, including the percentage of damaged kernels and 1,000-grain weight, in similar chromosomal regions. Therefore, the FHB resistance of PI 672538 was mainly controlled by two major QTLs, mapped on 2B (FhbL693a) and 3B (FhbL693b). PI 672538 could be a useful germplasm for improving wheat FHB resistance.