Prevalence and risk factors of significant fibrosis in chronic hepatitis B patients with concurrent metabolic dysfunction-associated steatotic liver disease.

INTRODUCTION AND OBJECTIVES: Significant fibrosis is an indicator of clinical intervention for both chronic hepatitis B (CHB) and metabolic dysfunction-associated steatotic liver disease (MASLD). There remains a paucity of data regarding the clinical impact of biopsy-defined MASLD on significant fibrosis in CHB patients. The current study aims to elucidate whether patients with concomitant MASLD are at higher risk of significant fibrosis in patients with CHB. PATIENTS AND METHODS: This retrospective research of two tertiary hospitals comprised 1818 patients between 2009 and 2021 with CHB and hepatic steatosis who had not received antiviral therapy. Pathologic findings by liver biopsy were contrasted between CHB group (n = 844) and CHB + MASLD (n = 974) group. METAVIR values of F≥2 were used to categorize significant fibrosis. RESULTS: Patients with CHB + MASLD had more significant fibrosis (35.5 % vs. 23.5 %, p < 0.001) than CHB group. The presence of MASLD [adjusted odds ratio (aOR) 2.055, 95 % confidence interval (CI) 1.635-2.584; p < 0.001] was strongly associated with significant fibrosis in all CHB patients. There was a trend for patients with more cardiometabolic risk factors (CMRFs) to have a higher prevalence of significant fibrosis: (25.7 % in CMRF1 subgroup v.s. 34.9 % in CMRF2 subgroup v.s. 53.7 % in CMRF≥ 3 subgroup, p < 0.001). Patients with CMRF≥3 had a three-fold higher significant fibrosis than those with just one CMRF. CONCLUSIONS: MASLD was associated with higher fibrosis stage in patients with CHB. Early detection and intervention are crucial to patients with three or more cardiometabolic risk factors.

Exploiting the CD200-CD200R immune checkpoint axis in multiple myeloma to enhance CAR T-cell therapy.

ABSTRACT: Patients with multiple myeloma (MM) treated with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells usually relapse with BCMA+ disease, indicative of CAR T-cell suppression. CD200 is an immune checkpoint that is overexpressed on aberrant plasma cells (aPCs) in MM and is an independent negative prognostic factor for survival. However, CD200 is not present on MM cell lines, a potential limitation of current preclinical models. We engineered MM cell lines to express CD200 at levels equivalent to those found on aPCs in MM and show that these are sufficient to suppress clinical-stage CAR T-cells targeting BCMA or the Tn glycoform of mucin 1 (TnMUC1), costimulated by 4-1BB and CD2, respectively. To prevent CD200-mediated suppression of CAR T cells, we compared CRISPR-Cas9-mediated knockout of the CD200 receptor (CD200RKO), to coexpression of versions of the CD200 receptor that were nonsignaling, that is, dominant negative (CD200RDN), or that leveraged the CD200 signal to provide CD28 costimulation (CD200R-CD28 switch). We found that the CD200R-CD28 switch potently enhanced the polyfunctionality of CAR T cells, and improved cytotoxicity, proliferative capacity, CAR T-cell metabolism, and performance in a chronic antigen exposure assay. CD200RDN provided modest benefits, but surprisingly, the CD200RKO was detrimental to CAR T-cell activity, adversely affecting CAR T-cell metabolism. These patterns held up in murine xenograft models of plasmacytoma, and disseminated bone marrow predominant disease. Our findings underscore the importance of CD200-mediated immune suppression in CAR T-cell therapy of MM, and highlight a promising approach to enhance such therapies by leveraging CD200 expression on aPCs to provide costimulation via a CD200R-CD28 switch.

From NAFLD to MASLD: When metabolic comorbidity matters.

INTRODUCTION AND OBJECTIVES: In a recent development, a cohort of hepatologists has proposed altering the nomenclature of non-alcoholic fatty liver disease (NAFLD) to metabolic-associated steatotic liver disease (MASLD), accompanied by modified diagnostic criteria. Our objective was to investigate the effect of the revised definition on identifying significant hepatic fibrosis. PATIENTS AND METHODS: From Jan 2009 to Dec 2022, a total of 428 patients with biopsy-proven hepatic steatosis were diagnosed with NAFLD. Patients were classified into subgroups according to MASLD and Cryptogenic-SLD diagnostic criteria. The clinical pathological features were compared between these two groups. Risk factors for significant fibrosis were analysed in the MASLD group. In total, 329 (76.9 %) patients were diagnosed with MASLD, and 99 (23.1 %) were diagnosed with Cryptogenic-SLD. RESULTS: Those with MASLD exhibited a higher degree of disease severity regarding histology features than Cryptogenic-SLD. The prevalence of significant fibrosis increased from 13 % to 26.6 % for one and two criteria present to 42.5 % for meeting three or more cardiometabolic risk factor (CMRF) criteria (p = 0.001). ALB (aOR:0.94,95 %CI:0.90-1.00; p = 0.030), lower levels of PLT (aOR:0.99, 95 %CI:0.99-1.00; p < 0.001), and more metabolic comorbidities (aOR:1.42,95 %CI:1.14-1.78; p = 0.012) were independent risk factors of significant fibrosis in MASLD. CONCLUSIONS: The new nomenclature of MASLD and SLD is more applicable to identifying significant fibrosis than NAFLD. Patients with three or more cardiometabolic risk factors are at higher risk of fibrosis.

Safety and immunogenicity of SCB-2019, an adjuvanted, recombinant SARS-CoV-2 trimeric S-protein subunit COVID-19 vaccine in healthy 12-17 year-old adolescents.

We previously demonstrated the efficacy of the COVID-19 vaccine candidate, SCB-2019, in adults in the SPECTRA phase 2/3 efficacy study. We extended the study to include 1278 healthy 12-17-year-old adolescents in Belgium, Colombia, and the Philippines who received either two doses of SCB-2019 or placebo 21 days apart, to assess immunogenicity as neutralizing antibodies against prototype SARS-CoV-2 and variants of concern, and safety and reactogenicity as solicited and unsolicited adverse events with a comparator group of young adults (18-25 years). In participants with no evidence of prior SARS-CoV-2 infection SCB-2019 immunogenicity in adolescents was non-inferior to that in young adults; respective geometric mean neutralizing titers (GMT) against prototype SARS-CoV-2 14 days after the second vaccination were 271 IU/mL (95% CI: 211-348) and 144 IU/mL (116-178). Most adolescents (1077, 84.3%) had serologic evidence of prior SAR-CoV-2 exposure at baseline; in these seropositive adolescents neutralizing GMTs increased from 173 IU/mL (135-122) to 982 IU/mL (881-1094) after the second dose. Neutralizing titers against Delta and Omicron BA SARS-CoV-2 variants were also increased, most notably in those with prior exposure. SCB-2019 vaccine was well tolerated with generally mild or moderate, transient solicited and unsolicited adverse events that were comparable in adolescent vaccine and placebo groups except for injection site pain - reported after 20% of SCB-2019 and 7.3% of placebo injections. SCB-2019 vaccine was highly immunogenic against SARS-CoV-2 prototype and variants in adolescents, especially in those with evidence of prior exposure, with comparable immunogenicity to young adults. Clinical trial registration: EudraCT 2020-004272-17; ClinicalTrials.gov NCT04672395.

Validation studies on migraine diagnostic tools for use in nonclinical settings: a systematic review / Estudos de validação de ferramentas de diagnóstico de enxaqueca (migrânea) para uso em ambientes não clínicos: uma revisão sistemática

Abstract Background Migraine underdiagnosis and undertreatment are so widespread, that hence is essential to diagnose migraine sufferers in nonclinical settings. A systematic review of validation studies on migraine diagnostic tools applicable to nonclinical settings can help researchers and practitioners in tool selection decisions. Objective To systematically review and critically assess published validation studies on migraine diagnostic tools for use in nonclinical settings, as well as to describe their diagnostic performance. Methods A multidisciplinary workgroup followed transparent and systematic procedures to collaborate on this work. PubMed, Medline, and Web of Science were searched for studies up to January 17, 2022. The QUADAS-2 was employed to assess methodological quality, and the quality thresholds adopted by the Global Burden Disease study were used to tail signaling questions. Results From 7,214 articles identified, a total of 27 studies examining 19 tools were eligible for inclusion. There has been no high-quality evidence to support any tool for use of migraine diagnosis in nonclinical settings. The diagnostic accuracy of the ID-migraine, structured headache and HARDSHIP questionnaires have been supported by moderate-quality evidence, with sensitivity and specificity above 70%. Of them, the HARDSHIP questionnaire has been the most extensively validated. The remaining 16 tools have provided poor-quality evidence for migraine diagnosis in nonclinical populations. Conclusions Up till now, the HARDSHIP questionnaire is the optimal choice for diagnosing migraine in nonclinical settings, with satisfactory diagnostic accuracy supported by moderate methodological quality. This work reveals the crucial next step, which is further high-quality validation studies in diverse nonclinical population groups.

Resumo Antecedentes O sub-diagnóstico e o subtratamento da enxaqueca são tão difundidos que, portanto, é essencial para diagnosticar os portadores de enxaqueca em ambientes não-clínicos. Uma revisão sistemática dos estudos de validação das ferramentas de diagnóstico da enxaqueca aplicáveis a ambientes não-clínicos pode ajudar os pesquisadores e profissionais nas decisões de seleção de ferramentas. Objetivo Revisar sistematicamente e avaliar criticamente estudos de validação publicados sobre ferramentas de diagnóstico da enxaqueca para uso em ambientes não-clínicos, bem como descrever seu desempenho diagnóstico. Métodos Um grupo de trabalho multidisciplinar seguiu procedimentos transparentes e sistemáticos para colaborar neste trabalho. PubMed, Medline e Web of Science foram pesquisados por estudos até 17 de janeiro de 2022. O QUADAS-2 foi empregado para avaliar a qualidade metodológica, e os limites de qualidade adotados pelo estudo da Global Burden Disease foram usados para responder a questões de sinalização. Resultados De 7.214 artigos identificados, um total de 27 estudos examinando 19 ferramentas foram elegíveis para inclusão. Não houve evidência de alta qualidade para apoiar qualquer ferramenta para o uso de diagnóstico de enxaqueca em ambientes não clínicos. A precisão diagnóstica do ID-Migraine, questionário de dor de cabeça estruturada e questionário HARDSHIP foram apoiados por evidências de qualidade moderada, com sensibilidade e especificidade acima de 70%. Deles, o questionário HARDSHIP foi o mais amplamente validado. As 16 ferramentas restantes forneceram provas de má qualidade para o diagnóstico de enxaqueca em populações não-clínicas. Conclusões Até agora, o questionário HARDSHIP é a escolha ideal para o diagnóstico da enxaqueca em ambientes não-clínicos, com precisão diagnóstica satisfatória apoiada por uma qualidade metodológica moderada. Este trabalho revela o próximo passo crucial, que é a realização de mais estudos de validação de alta qualidade em diversos grupos populacionais não-clínicos.

Validation studies on migraine diagnostic tools for use in nonclinical settings: a systematic review.

BACKGROUND: Migraine underdiagnosis and undertreatment are so widespread, that hence is essential to diagnose migraine sufferers in nonclinical settings. A systematic review of validation studies on migraine diagnostic tools applicable to nonclinical settings can help researchers and practitioners in tool selection decisions. OBJECTIVE: To systematically review and critically assess published validation studies on migraine diagnostic tools for use in nonclinical settings, as well as to describe their diagnostic performance. METHODS: A multidisciplinary workgroup followed transparent and systematic procedures to collaborate on this work. PubMed, Medline, and Web of Science were searched for studies up to January 17, 2022. The QUADAS-2 was employed to assess methodological quality, and the quality thresholds adopted by the Global Burden Disease study were used to tail signaling questions. RESULTS: From 7,214 articles identified, a total of 27 studies examining 19 tools were eligible for inclusion. There has been no high-quality evidence to support any tool for use of migraine diagnosis in nonclinical settings. The diagnostic accuracy of the ID-migraine, structured headache and HARDSHIP questionnaires have been supported by moderate-quality evidence, with sensitivity and specificity above 70%. Of them, the HARDSHIP questionnaire has been the most extensively validated. The remaining 16 tools have provided poor-quality evidence for migraine diagnosis in nonclinical populations. CONCLUSIONS: Up till now, the HARDSHIP questionnaire is the optimal choice for diagnosing migraine in nonclinical settings, with satisfactory diagnostic accuracy supported by moderate methodological quality. This work reveals the crucial next step, which is further high-quality validation studies in diverse nonclinical population groups.

ANTECEDENTES: O sub-diagnóstico e o subtratamento da enxaqueca são tão difundidos que, portanto, é essencial para diagnosticar os portadores de enxaqueca em ambientes não-clínicos. Uma revisão sistemática dos estudos de validação das ferramentas de diagnóstico da enxaqueca aplicáveis a ambientes não-clínicos pode ajudar os pesquisadores e profissionais nas decisões de seleção de ferramentas. OBJETIVO: Revisar sistematicamente e avaliar criticamente estudos de validação publicados sobre ferramentas de diagnóstico da enxaqueca para uso em ambientes não-clínicos, bem como descrever seu desempenho diagnóstico. MéTODOS: Um grupo de trabalho multidisciplinar seguiu procedimentos transparentes e sistemáticos para colaborar neste trabalho. PubMed, Medline e Web of Science foram pesquisados por estudos até 17 de janeiro de 2022. O QUADAS-2 foi empregado para avaliar a qualidade metodológica, e os limites de qualidade adotados pelo estudo da Global Burden Disease foram usados para responder a questões de sinalização. RESULTADOS: De 7.214 artigos identificados, um total de 27 estudos examinando 19 ferramentas foram elegíveis para inclusão. Não houve evidência de alta qualidade para apoiar qualquer ferramenta para o uso de diagnóstico de enxaqueca em ambientes não clínicos. A precisão diagnóstica do ID-Migraine, questionário de dor de cabeça estruturada e questionário HARDSHIP foram apoiados por evidências de qualidade moderada, com sensibilidade e especificidade acima de 70%. Deles, o questionário HARDSHIP foi o mais amplamente validado. As 16 ferramentas restantes forneceram provas de má qualidade para o diagnóstico de enxaqueca em populações não-clínicas. CONCLUSõES: Até agora, o questionário HARDSHIP é a escolha ideal para o diagnóstico da enxaqueca em ambientes não-clínicos, com precisão diagnóstica satisfatória apoiada por uma qualidade metodológica moderada. Este trabalho revela o próximo passo crucial, que é a realização de mais estudos de validação de alta qualidade em diversos grupos populacionais não-clínicos.

Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Sirolimus Can Increase the Disappearance Rate of Cardiac Rhabdomyomas Associated with Tuberous Sclerosis: A Prospective Cohort and Self-Controlled Case Series Study.

OBJECTIVES: To investigate the efficacy and safety of sirolimus in the treatment of cardiac rhabdomyomas associated with tuberous sclerosis complex and the specific benefits in different subgroups. STUDY DESIGN: The study was a prospective cohort and self-controlled case series study. Based on the prevalence of cardiac rhabdomyoma at different ages, we estimated the natural tumor disappearance rate. The subgroup analysis was done by Cox regression. Self-controlled case series method was used to assess the magnitude and duration of the drug effect. Adverse events were described. RESULTS: A total of 217 patients were included in the cohort study. Tumor disappearance rate was higher in younger age groups (hazard ratio = 0.99, P = .027) and female patients (hazard ratio = 2.08, P = .015). The age-adjusted incidence ratio showed that the disappearance of rhabdomyomas between 3 and 6 months was more related to sirolimus. Adverse events were observed 60 times in 42 of 217 children, mainly stomatitis. CONCLUSIONS: Sirolimus can increase the disappearance rate of cardiac rhabdomyoma in the tuberous sclerosis complex population. Efficacy varies by sex and age: female and younger patients have higher tumor disappearance rate. Sirolimus is well-tolerated.

4'-O-ß-D-glucosyl-5-O-methylvisamminol ameliorates imiquimod-induced psoriasis-like dermatitis and inhibits inflammatory cytokines production by suppressing the NF-κB and MAPK signaling pathways.

Psoriasis is a chronic inflammatory skin disorder in humans, and the inflammatory reaction plays an important role in development and onset of psoriasis. 4'-O-ß-D-glucosyl-5-O-methylvisamminol (4GMV) is one of the major active chromones isolated from Saposhnikoviae divaricata (Turcz.) Schischk, which has been reported to exhibit excellent anti-inflammatory activities. However, the possible therapeutic effect on psoriasis and underlying mechanism has not been reported. Thus, the aim of this study was to investigate the protective effect of 4GMV on the imiquimod (IMQ)-induced psoriasis-like lesions in BALB/c mice and the anti-inflammatory effect on the lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. The results demonstrated that 4GMV decreased IMQ-induced keratinocyte proliferation and inflammatory cell infiltration. Moreover, 4GMV treatment significantly inhibited the production of NO, PEG 2, and cytokines such as interleukin (IL)-1ß, IL-6, interferon (IFN)-γ, and IL-22 in LPS-stimulated RAW264.7 macrophages. 4GMV also suppressed the LPS-upregulated protein expressions of iNOS and COX-2 in a dose-dependent manner. Furthermore, qRT-PCR analysis showed that 4GMV down-regulated the mRNA level of IL-1ß and IL-6 expression. Further studies by western blot indicated that 4GMV inhibited the activation of upstream mediator NF-κB by suppressing the expression of TLR4 and the phosphorylation of IκBα and p65. The phosphorylation of JNK, p38, and ERK were also markedly reversed by 4GMV in LPS-treated RAW264.7 macrophages. Taken together, these results demonstrated that 4GMV showed a protective effect in IMQ-induced psoriasis-like mice and inhibited inflammation through the NF-κB and MAPK signaling pathways, indicating that 4GMV might be a potential therapeutic drug for psoriasis.

The effect of regions-of-interest and elasticity modulus selection on differentiating benign and malignant cervical lymph nodes with shear wave elastography.

OBJECTIVE: Imaging diagnosis of cervical lymphadenopathy has conventionally used ultrasonography. Shear wave elastography (SWE) is a recent ultrasound technological advancement that has shown promise in the important medical problem of differentiating between benign and malignant cervical lymph nodes based on quantitative measurements of elasticity modulus. However, widely varying elasticity modulus metrics and regions-of-interest (ROIs) were used in existing studies, leading to inconsistent findings and results that are hard to compare with each other. METHODS: Using a large dataset of 264 cervical lymph nodes from 200 patients, we designed a study comparing three elasticity modulus metrics (Emax, Emean, and standard deviation-SD) with three different ROIs to evaluate the effect of such selections. The metric values were compared between the benign and malignant node groups. The different ROI and metric selections were also compared through receiver operating characteristics curve analysis. RESULTS: For all ROIs, all metric values were significantly different between the two groups, indicting their diagnostic potential. This was confirmed by the ≥0.80 area under the curve (AUC) values achieved with these metrics. Different ROIs had no effect on Emax, whereas all ROIs achieved high performance at 0.88 AUC. For Emean, the smallest ROI focusing on the area of the highest elasticity achieved the best diagnostic performance. In contrast, the larger ROIs achieved higher performances for SD. CONCLUSIONS: This study illustrated the effect of elasticity modulus and ROI selection on the diagnostic performance of SWE on cervical lymphadenopathy. These new findings help guide relevant future studies and clinical applications of this important quantitative imaging modality.

The complete chloroplast genome sequence of Gynostemma yixingense and comparative analysis with congeneric species.

Gynostemma yixingense, an important medicinal member of the Cucurbitaceae family, is an endemic herbaceous species distributed in East China. It is morphologically similar to the plants in the same genus, which resulted in some confusion in identification and application. Meanwhile, there are still some controversies in taxonomy. Herein, the complete chloroplast genome sequence of G. yixingense was obtained by Illumina paired-end sequencing technology and compared to other chloroplast genome sequences of congeneric species. The complete chloroplast genome of G. yixingense is 157,910 bp in length with 36.94% GC content and contains a large single-copy (LSC) region of 86,791 bp, a small single-copy (SSC) region of 18,635 bp and a pair of inverted repeat (IR) regions of 26,242 bp. The whole genome contains 133 unique genes, including 87 protein-coding genes, 37 tRNA genes, eight rRNA genes and one pseudogene. In addition, 74 simple sequence repeats (SSRs) were identified, most of which were A/T rich. The phylogenetic analysis indicated that G. yixingense had the closest relationship to G. laxiflorum. The result of this study provided an important theoretical basis for chloroplast genome and phylogenetic analysis of G. yixingense.

New model predicting gastroesophageal varices and variceal hemorrhage in patients with chronic liver disease.

INTRODUCTION AND OBJECTIVES: The predictors for gastroesophageal varices (GOV) and hemorrhage development have not been well studied in different liver diseases or different population. This study aimed to evaluate whether a new algorithm focusing on chronic hepatitis B (CHB) patients is also applicable to other chronic liver diseases (CLDs) in Chinese population. PATIENTS OR MATERIALS AND METHODS: We retrospectively analyzed 659 CHB patients and 386 patients with other CLDs. A total of 439 CHB patients were included in training set, the other 220 CHB patients and other patients with CLDs were included in validation set. A new algorithm for diagnosing GOV was established and its sensitivity and specificity for predicting the varices was verified. RESULTS: Multivariable logistic regression revealed that the rough surface of the liver (p<0.001), splenic thickness (p<0.001), and liver stiffness (p=0.006) were independent predictors of GOV. The new algorithm was considered to be a reliable diagnostic model to evaluate the presence of varices. The AUROC was 0.94 (p<0.001) in CHB validation set and 0.90 (<0.001) in non-CHB validation set. When the cut-off value was chosen as -1.048, the sensitivity and specificity in diagnosing GOV in CHB population were 89.1% and 82.5%, respectively. Importantly, the new algorithm accurately predicted the variceal hemorrhage not only in CHB patients, but also in patients with other CLDs. CONCLUSION: The new algorithm is regarded as a reliable model to prognosticate varices and variceal hemorrhage, and stratified not only the high-risk CHB patients, but also in patients with other CLDs for developing GOV and variceal bleeding.

Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC50 = 3.2-23.2 µg/mL) and PTP1B (IC50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na3VO4 (IC50 = 2.7 µg/mL) and oleanolic acid (IC50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

Nesiritide protects endothelial function after balloon-induced trauma in the iliac artery in rabbits

To assess the effect of nesiritide on the endothelial function of iliac arteries following endothelia trauma. Right iliac artery trauma was created with a balloon catheter. Ten rabbits were treated with a 4-week subcutaneous injection of nesiritide at a fixed daily dose of 0.1mg/kg. Ten rabbits received daily normal saline injection. Plasma endothelin 1 (ET-1), nitric oxide (NO), and Von Willebrand Factor (vWF) were measured before and after the therapies. Tissue proliferating cell nuclear antigen (PCNA) was measured after the treatment. After the treatment, in the therapeutic group, the area under internal elastic membrane and the residual lumen area were higher than in the normal saline group (P <0.05). The plasma levels of ET-1 (91.6±6.8 vs 114.9±6.3 ng/L, P =0.001), vWF (134.6±10.8% vs 188.8±10.4%, P =0.001) and the ratio of PCNA positive expression (11.7±4.2% vs 36.2±11.4%, P =0.005) in the therapeutic group was lower than in the normal saline group, while the plasma levels of NO was higher (89.7±9.3 vs 43.5±5.3 µmol/L, P =0.001). Nesiritide inhibited remodeling of rabbit iliac artery following endothelial trauma. The inhibition of vascular remodeling may be related to the alleviated endothelial dysfunction and reduced expression of tissue proliferating cell nuclear antigen

4'-O-ß-D-glucosyl-5-O-methylvisamminol ameliorates imiquimod-induced psoriasis-like dermatitis and inhibits inflammatory cytokines production by suppressing the NF-κB and MAPK signaling pathways

Psoriasis is a chronic inflammatory skin disorder in humans, and the inflammatory reaction plays an important role in development and onset of psoriasis. 4'-O-β-D-glucosyl-5-O-methylvisamminol (4GMV) is one of the major active chromones isolated from Saposhnikoviae divaricata (Turcz.) Schischk, which has been reported to exhibit excellent anti-inflammatory activities. However, the possible therapeutic effect on psoriasis and underlying mechanism has not been reported. Thus, the aim of this study was to investigate the protective effect of 4GMV on the imiquimod (IMQ)-induced psoriasis-like lesions in BALB/c mice and the anti-inflammatory effect on the lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. The results demonstrated that 4GMV decreased IMQ-induced keratinocyte proliferation and inflammatory cell infiltration. Moreover, 4GMV treatment significantly inhibited the production of NO, PEG 2, and cytokines such as interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and IL-22 in LPS-stimulated RAW264.7 macrophages. 4GMV also suppressed the LPS-upregulated protein expressions of iNOS and COX-2 in a dose-dependent manner. Furthermore, qRT-PCR analysis showed that 4GMV down-regulated the mRNA level of IL-1β and IL-6 expression. Further studies by western blot indicated that 4GMV inhibited the activation of upstream mediator NF-κB by suppressing the expression of TLR4 and the phosphorylation of IκBα and p65. The phosphorylation of JNK, p38, and ERK were also markedly reversed by 4GMV in LPS-treated RAW264.7 macrophages. Taken together, these results demonstrated that 4GMV showed a protective effect in IMQ-induced psoriasis-like mice and inhibited inflammation through the NF-κB and MAPK signaling pathways, indicating that 4GMV might be a potential therapeutic drug for psoriasis.

The effect of regions-of-interest and elasticity modulus selection on differentiating benign and malignant cervical lymph nodes with shear wave elastography

OBJECTIVE: Imaging diagnosis of cervical lymphadenopathy has conventionally used ultrasonography. Shear wave elastography (SWE) is a recent ultrasound technological advancement that has shown promise in the important medical problem of differentiating between benign and malignant cervical lymph nodes based on quantitative measurements of elasticity modulus. However, widely varying elasticity modulus metrics and regions-of-interest (ROIs) were used in existing studies, leading to inconsistent findings and results that are hard to compare with each other. METHODS: Using a large dataset of 264 cervical lymph nodes from 200 patients, we designed a study comparing three elasticity modulus metrics (Emax, Emean, and standard deviation-SD) with three different ROIs to evaluate the effect of such selections. The metric values were compared between the benign and malignant node groups. The different ROI and metric selections were also compared through receiver operating characteristics curve analysis. RESULTS: For all ROIs, all metric values were significantly different between the two groups, indicting their diagnostic potential. This was confirmed by the ≥0.80 area under the curve (AUC) values achieved with these metrics. Different ROIs had no effect on Emax, whereas all ROIs achieved high performance at 0.88 AUC. For Emean, the smallest ROI focusing on the area of the highest elasticity achieved the best diagnostic performance. In contrast, the larger ROIs achieved higher performances for SD. CONCLUSIONS: This study illustrated the effect of elasticity modulus and ROI selection on the diagnostic performance of SWE on cervical lymphadenopathy. These new findings help guide relevant future studies and clinical applications of this important quantitative imaging modality.

[Research progress on chemical constituents and bioactivities of Lepidium meyenii].

Maca( Lepidium meyenii) known as the " national treasure of Peru" and " South American ginseng",is annual or biennial herbs of the genus Lepidium in Cruciferae. It mainly contains proteins,amino acids,polysaccharides,alkaloids( including:macamides,imidazoles,hydroxypyridines,carbazoles,organic amines and so on),glucosinolates,macaenes,thioethylurea,sterols and other chemical constituents. In recent years,more and more studies have found that it could treat osteoporosis and improve prostatehyperplasia,and possessed anti-cancer,female climacteric syndrome,rheumatism,antioxidant and other pharmacological effects. In this paper,the chemical constituents and bioactivity of Maca were reviewed,which could provide the basis for the further development and utilization of Maca.