Baricitinib in patients with rheumatoid arthritis with inadequate response to methotrexate: results from a phase 3 study.

OBJECTIVES: This study evaluated the efficacy and safety of baricitinib, an oral Janus kinase (JAK)1/JAK2 inhibitor, in patients with moderately to severely active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX) therapy. METHODS: In this phase 3, double-blind, 52-week, placebo-controlled study, 290 patients with moderately to severely active RA and inadequate response to MTX were randomly assigned 1:1 to placebo or baricitinib 4-mg once daily, stratified by country (China, Brazil, Argentina) and presence of joint erosions. Primary endpoint measures included American College of Rheumatology 20% response (ACR20) at week 12. Secondary endpoints included changes in Health Assessment Questionnaire-Disability Index (HAQ-DI) and Disease Activity Score for 28-joint counts (DAS28)-high-sensitivity C-reactive protein (hsCRP), Simplified Disease Activity Index (SDAI) score ≤3.3, mean duration of morning joint stiffness, severity of morning joint stiffness numeric rating scale (NRS 0-10), worst tiredness NRS, and worst joint pain NRS at week 12. RESULTS: Most patients (approximately 80%) were from China. More patients achieved ACR20 response at week 12 with baricitinib than with placebo (58.6% vs. 28.3%; p<0.001). Statistically significant improvements were also seen in HAQ-DI, DAS28-hsCRP, morning joint stiffness, worst tiredness, and worst joint pain in the baricitinib group compared to placebo at week 12. Through week 24, rates of treatment-emergent adverse events, including infections, were higher for baricitinib compared to placebo, while serious adverse event rates were similar between baricitinib and placebo. CONCLUSIONS: In patients with RA who had an inadequate response to MTX, baricitinib was associated with significant clinical improvements as compared with placebo.

Linc-OIP5 in the breast cancer cells regulates angiogenesis of human umbilical vein endothelial cells through YAP1/Notch/NRP1 signaling circuit at a tumor microenvironment.

BACKGROUND: LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways. METHODS: A trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments. RESULTS: Overexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition. CONCLUSION: Hence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.

Linc-OIP5 in the breast cancer cells regulates angiogenesis of human umbilical vein endothelial cells through YAP1/Notch/NRP1 signaling circuit at a tumor microenvironment

BACKGROUND: LincRNAs have been revealed to be tightly associated with various tumorigeneses and cancer development, but the roles of specific lincRNA on tumor-related angiogenesis was hardly studied. Here, we aimed to investigate whether linc-OIP5 in breast cancer cells affects the angiogenesis of HUVECs and whether the linc-OIP5 regulations are involved in angiogenesis-related Notch and Hippo signaling pathways. METHODS: A trans-well system co-cultured HUVECs with linc-OIP5 knockdown breast cancer cell MDA-MB-231 was utilized to study the proliferation, migration and tube formation abilities of HUVECs and alterations of related signaling indicators in breast cancer cells and their conditioned medium through a series of cell and molecular experiments. RESULTS: Overexpressed linc-OIP5, YAP1, and JAG1 were found in breast cancer cell lines MCF7 and MDA-MB-231 and the expression levels of YAP1 and JAG1 were proportional to the breast cancer tissue grades. MDA-MB-231 cells with linc-OIP5 knockdown led to weakened proliferation, migration, and tube formation capacity of co-cultured HUVECs. Besides, linc-OIP5 knockdown in co-cultured MDA-MB-231 cells showed downregulated YAP1 and JAG1 expression, combined with a reduced JAG1 level in conditioned medium. Furthermore, a disrupted DLL4/Notch/NRP1 signaling in co-cultured HUVECs were also discovered under this condition. CONCLUSION: Hence, linc-OIP5 in MDA-MB-231 breast cancer cells may act on the upstream of the YAP1/Notch/NRP1 signaling circuit to affect proliferation, migration, and tube formation of co-cultured HUVECs in a non-cellular direct contact way through JAG1 in conditioned medium. These findings at least partially provide a new angiogenic signaling circuit in breast cancers and suggest linc-OIP5 could be considered as a therapeutic target in angiogenesis of breast cancers.

A morphological classification for vocal fold leukoplakia / Classificação morfológica das leucoplasias de prega vocal

Abstract Introduction: There is still no general method for discriminating between benign and malignant leukoplakia and identifying vocal fold leukoplakia. Objective: To evaluate the reliability of a morphological classification and the correlation between morphological types and pathological grades of vocal fold leukoplakia. Methods: A total of 375 patients with vocal fold leukoplakia between 2009 and 2015 were retrospectively reviewed. Two observers divided the vocal fold leukoplakia into flat and smooth, elevated and smooth, and rough type on the basis of morphological appearance. The inter-observer reliability was evaluated and the results of classification from both observers were compared with final pathological grades. Clinical characteristics between low risk and high risk group were also analyzed. Results: The percentage inter-observer agreement of the morphological classification was 78.7% (κ = 0.615, p < 0.001). In the results from both observers, the morphological types were significantly correlated with the pathological grades (p1 < 0.001, p2 < 0.001, Kruskal-Wallis test; r1 = 0.646, p1 < 0.001, r2 = 0.539, p2 < 0.001, Spearman Correlation Analysis). Multivariate analysis showed patient's age (p = 0.018), the size of lesion (p < 0.001), and morphological type (p < 0.001) were significantly different between low risk group and high risk group. Combined receiver operating characteristic curve analysis of significant parameters revealed an area under the receiver operating characteristic curve of 0.863 (95% CI 0.823-0.903, p < 0.001). Conclusions: The proposed morphological classification of vocal fold leukoplakia was consistent between observers and morphological types correlated with pathological grades. Patient's age, the size of lesion, and morphological type might enable risk stratification and provide treatment guidelines for vocal fold leukoplakia.

Resumo Introdução: Ainda não há um método universal estabelecido para diferenciar entre a leucoplasia benigna e maligna ou identificar as leucoplasias das pregas vocais. Objetivo: Avaliar a confiabilidade de uma classificação morfológica e a correlação entre os tipos morfológicos e os graus histopatológicos das leucoplasias de pregas vocais. Método: Os registros de 375 pacientes com leucoplasia da prega vocal assistidos entre 2009 e 2015 foram revisados retrospectivamente. Dois observadores dividiram a leucoplasia da prega vocal entre tipo plano e liso, elevado e liso, e rugoso, com base na aparência morfológica. A confiabilidade interobservador foi avaliada e os resultados de classificação de ambos os observadores foram comparados com os graus histopatológicos finais. As características clínicas entre os grupos de baixo risco e alto risco também foram analisadas. Resultados: A porcentagem da concordância interobservador da classificação morfológica foi de 78,7% (κ = 0,615, p < 0,001). Nos resultados de ambos os observadores, os tipos morfológicos correlacionaram-se significativamente com os graus histopatológicos (p1 < 0,001, p2 < 0,001, teste de Kruskal-Wallis; r1 = 0,646, p1 < 0,001, r2 = 0,539, p2 < 0,001, análise de correlação de Spearman). A análise multivariada mostrou que a idade do paciente (p = 0,018), o tamanho da lesão (p < 0,001) e o tipo morfológico (p < 0,001) foram significativamente diferentes entre o grupo de baixo risco e o de alto risco. A análise da curva ROC (Receiver Operating Characteristic) combinada de parâmetros significativos revelou uma área sob a curva de 0,863 (IC 95%: 0,823 ± 0,903, p < 0,001). Conclusões: A classificação morfológica proposta para leucoplasia de prega vocal foi consistente entre observadores e os tipos morfológicos correlacionaram-se com os graus histopatológicos. A idade do paciente, o tamanho da lesão e o tipo morfológico podem permitir a estratificação de risco e fornecem diretrizes de tratamento para a leucoplasia da prega vocal.

A morphological classification for vocal fold leukoplakia.

INTRODUCTION: There is still no general method for discriminating between benign and malignant leukoplakia and identifying vocal fold leukoplakia. OBJECTIVE: To evaluate the reliability of a morphological classification and the correlation between morphological types and pathological grades of vocal fold leukoplakia. METHODS: A total of 375 patients with vocal fold leukoplakia between 2009 and 2015 were retrospectively reviewed. Two observers divided the vocal fold leukoplakia into flat and smooth, elevated and smooth, and rough type on the basis of morphological appearance. The inter-observer reliability was evaluated and the results of classification from both observers were compared with final pathological grades. Clinical characteristics between low risk and high risk group were also analyzed. RESULTS: The percentage inter-observer agreement of the morphological classification was 78.7% (κ=0.615, p<0.001). In the results from both observers, the morphological types were significantly correlated with the pathological grades (p1<0.001, p2<0.001, Kruskal-Wallis test; r1=0.646, p1<0.001, r2=0.539, p2<0.001, Spearman Correlation Analysis). Multivariate analysis showed patient's age (p=0.018), the size of lesion (p<0.001), and morphological type (p<0.001) were significantly different between low risk group and high risk group. Combined receiver operating characteristic curve analysis of significant parameters revealed an area under the receiver operating characteristic curve of 0.863 (95% CI 0.823-0.903, p<0.001). CONCLUSIONS: The proposed morphological classification of vocal fold leukoplakia was consistent between observers and morphological types correlated with pathological grades. Patient's age, the size of lesion, and morphological type might enable risk stratification and provide treatment guidelines for vocal fold leukoplakia.

Quorum sensing LuxS/autoinducer-2 inhibits Enterococcus faecalis biofilm formation ability.

OBJECTIVE: To investigate the relation between biofilm formation ability and quorum sensing gene LuxS/AI-2. MATERIALS AND METHODS: Enterococcus faecalis (E. faecalis) standard strain ATCC 29212 was used in the study. Long flanking homology polymerase chain reaction method was used to build the LuxS gene knockout strain. Sequential culture turbidity measurement and CFU counting were used to assess the proliferation ability of E. faecalis after the depletion of LuxS. 96-well plate assay was used to quantify the biofilm formation ability; CLSM was used to observe the attached bacteria areas, while scanning electron microscopy (SEM) was performed to observe biofilm microstructure conditions. RESULTS: LuxS gene knockout strains were successfully constructed and identified. The results showed that proliferation ability of E. faecalis was not affected by the depletion of the luxS gene, and the biofilm formation ability of ΔLuxS 29212 significantly decreased (P<0.05). CONCLUSIONS: Collectively, our studies provide the LuxS gene's key role in controlling biofilm formation of E. faecalis, which presented a negative regulation, and furthermore, providing us a possible way to conquer the persistent apical periodontitis.

Quorum sensing LuxS/autoinducer-2 inhibits Enterococcus faecalis biofilm formation ability

Abstract Objective: To investigate the relation between biofilm formation ability and quorum sensing gene LuxS/AI-2. Materials and Methods: Enterococcus faecalis (E. faecalis) standard strain ATCC 29212 was used in the study. Long flanking homology polymerase chain reaction method was used to build the LuxS gene knockout strain. Sequential culture turbidity measurement and CFU counting were used to assess the proliferation ability of E. faecalis after the depletion of LuxS. 96-well plate assay was used to quantify the biofilm formation ability; CLSM was used to observe the attached bacteria areas, while scanning electron microscopy (SEM) was performed to observe biofilm microstructure conditions. Results: LuxS gene knockout strains were successfully constructed and identified. The results showed that proliferation ability of E. faecalis was not affected by the depletion of the luxS gene, and the biofilm formation ability of ΔLuxS 29212 significantly decreased (P<0.05). Conclusions: Collectively, our studies provide the LuxS gene's key role in controlling biofilm formation of E. faecalis, which presented a negative regulation, and furthermore, providing us a possible way to conquer the persistent apical periodontitis.