Low protein expression of LZTR1 in hepatocellular carcinoma triggers tumorigenesis via activating the RAS/RAF/MEK/ERK signaling.

LZTR1 is a substrate specific adaptor for E3 ligase involved in the ubiquitination and degradation of RAS GTPases, which inhibits the RAS/RAF/MEK/ERK signaling to suppress the pathogenesis of Noonan syndrome and glioblastoma. However, it's still unknown whether LZTR1 destabilizes RAS GTPases to suppress HCC progression by inhibiting these signaling pathway. Lenvatinib is the first-line drug for the treatment of advanced HCC, however, it has high drug resistance. To explore the roles of LZTR1 in HCC progression and the underlying mechanisms of lenvatinib resistance, techniques such as bioinformatics analysis, immunohistochemical staining, RT-qPCR, Western blot, cell functional experiments, small interfering RNA transfection and cycloheximide chase assay were applied in our study. Among these, bioinformatics analysis and immunohistochemical staining results indicated that LZTR1 protein was aberrantly expressed at low levels in HCC tissues, and low protein expression of LZTR1 was associated with poor prognosis of HCC patients. In vitro functional experiments confirmed that low expression of LZTR1 promoted HCC cell proliferation and migration via the aberrant activation of the RAS/RAF/MEK/ERK signaling due to the dysregulation of LZTR1-induced KRAS ubiquitination and degradation. Transwell assays revealed that blocking of LZTR1-mediated KRAS degradation could induce lenvatinib resistance in HCC cells. In conclusion, our study revealed that LZTR1 knockdown promoted HCC cell proliferation and migration, and induced lenvatinib resistance via activating the RAS/RAF/MEK/ERK signaling, which may provide new ideas for HCC treatment.

Self-referenced electro-optic response measurement of dual-parallel Mach-Zehnder modulators employing single-tone level control and low-frequency bias swing.

A self-referenced method is proposed to characterize the electro-optic frequency response of dual-parallel Mach-Zehnder modulators (DPMZMs) based on single-tone level control and low-frequency bias swing. The single-tone driving signal and the low-frequency bias signal of the DPMZM mix with each other after photodetection, and a low-frequency beat note is generated in the electrical domain. The functional relationship between the desired low-frequency amplitude and the single-tone driving level is investigated and established, from which the modulation depth and half-wave voltage are extracted with the help of regression analysis. We experimentally demonstrate the feasibility of the proposed method and compare it with the conventional ones to check the consistency. The self-referenced method features single-tone modulation and low-frequency detection for measuring high-speed DPMZMs, which avoids the use of a broadband photodetector (PD) and the influence of the uneven response of the PD.

Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma.

The tumor microenvironment (TME) is a complex multicellular functional compartment that includes fibroblasts, myofibroblasts, endothelial cells, immune cells, and extracellular matrix (ECM) elements. The microenvironment provides an optimum condition for the initiation, growth, and dissemination of hepatocellular carcinoma (HCC). As one of the critical and abundant components in tumor microenvironment, cancer-associated fibroblasts (CAFs) have been implicated in the progression of HCC. Through secreting various growth factors and cytokines, CAFs contribute to the ECM remodeling, stem features, angiogenesis, immunosuppression, and vasculogenic mimicry (VM), which reinforce the initiation and development of HCC. In order to restrain the CAFs-initiated HCC progression, current strategies include targeting specific markers, engineering CAFs with tumor-suppressive phenotype, depleting CAFs' precursors, and repressing the secretions or downstream signaling. In this review, we update the emerging understanding of CAFs in HCC, with particular emphasis on cellular origin, phenotypes, biological functions and targeted strategies. It provides insights into the targeting CAFs for HCC treatment.

A meta-analysis of secondary osteoporosis in systemic lupus erythematosus: prevalence and risk factors.

PURPOSE: This study aimed to evaluate the prevalence and risk factors of secondary osteoporosis (OP) in patients with systemic lupus erythematosus (SLE) and provide a theoretical basis for clinical prevention and treatment of SLE. METHODS: Take systematic review and meta-analysis of relevant studies. Data sources are CINAHL databases, PubMed, Embase, Wan Fang, Weipu, and CNKI databases. Eligibility criteria are cross-sectional or case-control studies which analyzed the prevalence and risk factors of OP in SLE. Two authors independently screened all studies; a third author verified and identify controversial studies. The quality of the included articles was evaluated. Stata 11 and Rev-Man 5.2 software were used for data processing. RESULTS: Thirty-one articles were included, with a total sample size of 3089 SLE, including 529 OP cases and 2560 non-OP cases. Meta-analysis showed that the prevalence of OP among SLE was 16% (95% CI (0.12, 0.19)). The risk of OP in SLE cases compared with controls was significantly greater with OR of 2.03 (95% CI 1.33-3.10, P = 0.001). Age, disease duration, cumulative glucocorticoid dose, duration of glucocorticoid therapy, SLICC, and menopause had significant differences between two groups. No statistical differences of daily glucocorticoid dose, SLEDAI, and BMI were found between OP and non-OP cases. CONCLUSIONS: Our study found a statistically significant increased risk of OP in SLE patients compared with controls. SLE patients should be actively screened for OP and its consequences. Larger longitudinal studies are needed to confirm this possible association. The prevalence of OP in SLE was 16%. Compared with controls, the risk of OP in SLE was 2.03. There were significant differences of age, disease duration, cumulative glucocorticoid dose, time of glucocorticoid, SLICC, and menopause, while daily glucocorticoid dose, SLEDAI, and BMI had no statistical differences between OP and non-OP cases.

Periodontal disease in Chinese patients with rheumatoid arthritis: A case-control study.

OBJECTIVE: To evaluate the prevalence and severity of periodontal disease in Chinese rheumatoid arthritis patients. SUBJECTS AND METHODS: This cross-sectional study included 128 RA and 109 healthy controls. Two dentists conducted periodontal status including Plaque index (PI), Gingival index (GI), pocket probing depths (PPDs), Clinical attachment level (CAL) and Bleeding on probing (BOP) independently. Sociodemographic, lifestyle, clinical parameters and use of medication were assessed. Data were analyzed by Student's t test, χ2 test, Wilcoxin-Mann- Whitney's test, Correlational Analysis, univariate or multivariate logistic regression. RESULTS: The periodontal status was significantly worse in RA, especially the condition of dental and gingival status. RA had 4.68-fold. After adjusted potential risk factors, RA had 10.26-fold. The independent variable related to GI was DAS28 (p = .05) negatively, to the contrary, ESR (p = .013) was positively associated; the independent variable positively and related to periodontitis was educational level (p = .021) and anti-CCP positivity (p = .002). Through multivariate logistic regression, age and swollen joint were the independent variable related to periodontitis of RA (OR 1.087, p = .044) and (OR 1.560, p = .008) respectively. CONCLUSIONS: Chinese RA patients show higher odds of PD. It is important to take early interventions in combination with medical therapy.

The impact of systemic lupus erythematosus on health-related quality of life assessed using the SF-36: a systematic review and meta-analysis.

To identify the impact of systemic lupus erythematosus (SLE) on health-related quality of life (HRQoL) domains compared with the results of healthy controls by systematically reviewing the literature. A systematic literature search was performed on MEDLINE, Web of Science and EMBASE until April, 2018 to obtain eligible studies reporting mean and standard deviation scores for each domain of the 36-item Short-Form Health Survey (SF-36) in SLE patients and healthy controls. Random effect model was performed to summarize the scores of each domain. The forest plot was used to compare the scores of SLE patients with healthy controls. Review Manager (version 5.3) was adopted in the meta-analysis. In all, 13 studies were included in the work, including 1279 SLE patients and 1466 healthy controls. Compared with controls, patients with SLE had lower scores in all SF-36 dimensions (physical function, physical role function, body pain, general health, vitality, social function, emotional role function, mental health), especially in the physical role function. SLE does impair HRQoL to varying degrees. It is indispensable to measure and assess HRQoL of SLE patients regularly, which contributes to formulate targeted interventions appropriately and provide effective ways of management of the disease positively.