ASYMMETRIC LEAVES 2 and ASYMMETRIC LEAVES 2-LIKE are partially redundant genes and essential for fruit development in tomato.

Fruit size and shape are controlled by genes expressed during the early developmental stages of fruit. Although the function of ASYMMETRIC LEAVES 2 (AS2) in promoting leaf adaxial cell fates has been well characterized in Arabidopsis thaliana, the molecular mechanisms conferring freshy fruit development as a spatial-temporal expression gene in tomato pericarp remain unclear. In the present study, we verified the transcription of SlAS2 and SlAS2L, two homologs of AS2, in the pericarp during early fruit development. Disruption of SlAS2 or SlAS2L caused a significant decrease in pericarp thickness as a result of a reduction in the number of pericarp cell layers and cell area, leading to smaller tomato fruit size, which revealed their critical roles in tomato fruit development. In addition, leaves and stamens exhibited severe morphological defects in slas2 and slas2l single mutants, as well as in the double mutants. These results demonstrated the redundant and pleiotropic functions of SlAS2 and SlAS2L in tomato fruit development. Yeast two-hybrid and split-luciferase complementation assays showed that both SlAS2 and SlAS2L physically interact with SlAS1. Molecular analyses further indicated that SlAS2 and SlAS2L regulate various downstream genes in leaf and fruit development, and that some genes participating in the regulation of cell division and cell differentiation in the tomato pericarp are affected by these genes. Our findings demonstrate that SlAS2 and SlAS2L are vital transcription factors required for tomato fruit development.

Anti-carbamylated protein antibodies drive AEC II toward a profibrotic phenotype by interacting with carbamylated TLR5.

OBJECTIVES: This study was to explore the role of Anti-carbamylated protein (Anti-CarP) antibodies in contributing to lung fibrosis in connective tissue disease (CTD)-associated interstitial lung disease (ILD) in an autoantigen-dependent manner. METHODS: ELISA tested serum samples, including 89 of CTD-ILD group and 170 of non-ILD CTD, for the anti-CarP levels. Male C57BL/6 mice were used for pulmonary fibrosis model and anti-CarP treatment in vivo (n = 5), and patient serum-derived or commercialized anti-CarP for cell treatment. We identified the carbamylated membrane protein via immunofluorescence (IF) and coimmunoprecipitation followed by mass spectrometry (MS) analysis. RT-qPCR, IF and western blot were performed to explore the antigen-dependent role of anti-CarP. Native electrophoretic mobility shift assay and MS analysis were used to verify direct interaction and carbamylation sites. RESULTS: A significantly higher serum anti-CarP level was observed in CTD with ILD than without ILD. In vivo, intrapulmonary delivery of anti-CarP induces epithelial-mesenchymal transition (EMT) and micro fibrotic foci. Carbamylation was enriched in type II alveolar epithelial cells (AEC II). A novel carbamylated membrane receptor, specifically recognized by anti-CarP, was identified as toll-like receptor 5 (TLR5). We found anti-CarP induces the nuclear translocation of NF-κB and downstream events, including EMT and expression of inflammatory cytokines in AEC II, which were reversed by TLR5 blocking or TLR5 knockdown. Moreover, up to 12 lysine carbamylation sites were found in TLR5 ectodomain, allowing the interaction of anti-CarP with carbamylated TLR5. CONCLUSIONS: Overall, we found anti-CarP drives aberrant AEC II activation by interacting with carbamylated TLR5 to promote ILD progress.

Prognosis in different subtypes of metaplastic breast cancer: a population-based analysis.

BACKGROUND: Metaplastic breast cancer (MpBC) is a rare histological subtype of breast cancer recognized as a unique pathologic entity in 2000. However, the pathogenesis, optimal therapy, and prognosis of MpBC and the potential effect of systemic treatments on different subtypes of MpBC are not well defined. METHODS: A retrospective population-based study was performed to identify breast cancer patients with MpBC and other triple-negative breast cancers (TNBC) between 2010 and 2014 using the surveillance, Epidemiology, and End Results (SEER) database. Chi-square test was used to analyze characteristics between subgroups. Kaplan-Meier analysis and Multivariate Cox regressions were used to evaluate overall survival (OS) of MpBC, TNBC, and MpBC subgroups. Competing risk analysis and multivariate regression model of competing risk were used to assess breast cancer-specific survival (BCSS) of MpBC and TNBC RESULTS: We identified a study cohort of 22,433 patients (1112 MpBC and 21,321 TNBC). MpBC correlated with older population, larger tumor size and less lymph node involvement, and TNBC phenotype. Patients with MpBC especially with triple-negative subtype (TN-MpBC) had worse survival than the overall TNBC population. However, the prognosis of MpBC without triple-negative subtype (non-TN MpBC) was not different from that of TNBC. In Kaplan-Meier analysis, chemotherapy was not associated with significant difference in OS of TN-MpBC. In non-TN MpBC group, the 3-year OS was 79.8% for patients receiving chemotherapy and 70.5% in patients without chemotherapy, and chemotherapy was associated (P = 0.033) with improved OS. Within the MpBC patients, radiotherapy was significantly (HR 1.544; 95% CI 1.148-2.078; P = 0.004) associated with improved OS and (HR 1.474; 95% CI 1.067-2.040; P = 0.019) BCSS. CONCLUSIONS: Patients with TN-MpBC had worse prognosis than TNBC and chemotherapy was not associated with improved survival. In contrast, non-TN MpBC may derive survival benefit from chemotherapy and radiotherapy.

The physiological and molecular mechanism of brassinosteroid in response to stress: a review.

The negative effects of environmental stresses, such as low temperature, high temperature, salinity, drought, heavy metal stress, and biotic stress significantly decrease crop productivity. Plant hormones are currently being used to induce stress tolerance in a variety of plants. Brassinosteroids (commonly known as BR) are a group of phytohormones that regulate a wide range of biological processes that lead to tolerance of various stresses in plants. BR stimulate BRASSINAZOLE RESISTANCE 1 (BZR1)/BRI1-EMS SUPPRESSOR 1 (BES1), transcription factors that activate thousands of BR-targeted genes. BR regulate antioxidant enzyme activities, chlorophyll contents, photosynthetic capacity, and carbohydrate metabolism to increase plant growth under stress. Mutants with BR defects have shortened root and shoot developments. Exogenous BR application increases the biosynthesis of endogenous hormones such as indole-3-acetic acid, abscisic acid, jasmonic acid, zeatin riboside, brassinosteroids (BR), and isopentenyl adenosine, and gibberellin (GA) and regulates signal transduction pathways to stimulate stress tolerance. This review will describe advancements in knowledge of BR and their roles in response to different stress conditions in plants.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) activates p38 to affect pulmonary fibrosis.

Objective: We aimed to examine whether heparin-binding epidermal growth factor-like growth factor (HB-EGF) affects the lung fibrosis process through the activation of p38 protein in mitogen-activated protein kinases (MAPK) signaling pathway, as well as the expression of downstream inflammatory factors. Methods: The expression levels of HB-EGF, collagen type I (COL-I), and hexokinase 2 (HK2) in peripheral blood mononuclear cells (PBMCs) of patients with connective tissue disease-related interstitial lung disease (CTD-ILD) were examined by qPCR, Western blotting and ELISA. Results: In vitro experiments showed that HB-EGF was increased in almost all subtypes [rheumatoid arthritis (RA), systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIMs)] as well as in all groups (P < 0.05). For embryonic lung fibroblast (A549) cells, the expression levels of HK2 and α-smooth muscle actin (α-SMA) genes were elevated during 0-4 h and then plateaued. Transforming growth factor-ß1 (TGF-ß1) induced fibrosis in human embryonic lung fibroblasts (MRC-5) cells and A549 for a certain period of time, but the degree of induction varied, which may be related to the redifferentiability of cells at different spatial locations. Moreover, HB-EGF at concentrations above 1 ng/ml stimulation increased COL-I expression (P < 0.05), and for α-SMA gene, even 1 ng/ml concentration of HB-EGF had a stimulatory effect, and different concentrations of HB-EGF did activate the expression of p38 in a concentration-dependent manner within a certain concentration range, and by The qPCR results showed that for interleukin 6 (IL-6), an inflammatory factor regulated downstream of p38, the expression was significantly increased in A549 cells compared to control (P < 0.05), but tumor necrosis factor-α (TNF-α) expression was downregulated (P < 0.05), but for interleukin-1ß (IL-1ß) gene, there was no significant difference in A549 cells, and expression was downregulated in MRC-5 cells. Therefore, it is suggested that HB-EGF regulates the expression of inflammatory factors through p38 will be differential across cells. Conclusion: Our study shows that HB-EGF can suppress pulmonary fibrosis through downstream activation of p38/MAPK pathway activity, as well as the expression of various inflammatory factors downstream of it.

Elevated platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with polymyositis/dermatomyositis: a retrospective study.

OBJECTIVES: This study aimed to examine the diagnostic and prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in patients with polymyositis/dermatomyositis (PM/DM). METHOD: Clinical data of 200 patients with PM/DM and 204 healthy controls were retrospectively reviewed. We examined whether the PLR and NLR were associated with PM/DM. RESULTS: The PLR and NLR were higher in patients with PM/DM than in controls (both P < 0.001). The PLR and NLR were higher in patients with DM than in those with PM (both P < 0.01). The PLR was higher in the anti-melanoma differentiation-associated protein-5 (anti-MDA5) + PM/DM group than in the anti-MDA5- PM/DM group (P = 0.002). The NLR in non-survivors was higher than that in survivors (P = 0.01). The NLR was positively correlated with the occurrence of interstitial lung disease (ILD). The PLR and NLR were independent predictors of PM/DM, as well as risk factors (both P < 0.001). Moreover, the NLR had a predictive value for PM/DM-ILD and was closely related to mortality (P = 0.033, P = 0.003, respectively). CONCLUSIONS: Patients with PM/DM have a higher NLR and PLR than healthy controls, especially in those with anti-MDA5+. The PLR and NLR are independent risk factors for PM/DM and have some predictive value. The NLR is correlated with ILD and associated with an increased risk of mortality in patients with PM/DM. The NLR and PLR may be simple, economical, and accurate diagnostic and prognostic markers for patients with PM/DM. Key points • The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been studied in numerous inflammatory diseases as potential markers, but their clinical significance in polymyositis/dermatomyositis (PM/DM) remains unclear. • We examined the changes in the NLR and PLR between patients with PM/DM and healthy controls, as well as their association with mortality, interstitial lung disease, and anti-melanoma differentiation-associated protein-5. • Patients with PM/DM may benefit from using the NLR and PLR as simple, economical, and accurate diagnostic and prognostic markers.

Distribution and clinical significance of anti-carbamylation protein antibodies in rheumatological diseases among the Chinese Han population.

Objective: Several studies have demonstrated that anti-carbamylation protein antibodies (Anti-CarPA) are persistent in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSC), primary Sjögren's syndrome (pSS), and interstitial lung disease associated with RA (RA-ILD). However, the relationship between anti-CarPA and other rheumatic diseases (RDs) and non-RA-ILD is not known till now. This study sought to examine the presence of anti-CarPA in Chinese Han patients with RDs and its clinical significance. Methods: The study included 90 healthy controls (HCs) and 300 patients with RDs, including RA, SLE, polymyositis/dermatomyositis (PM/DM), pSS, SSC, spondyloarthritis (SpA), anti-neutrophil cytoplasmic autoantibodies associated with vasculitis (AAV), undifferentiated connective tissue disease (UCTD), and Behcet's disease (BD). Antibodies against carbamylated human serum albumin were detected using commercial enzyme-linked immunosorbent assay kits. Correlations between clinical and laboratory parameters were analyzed. Result: Serum levels of anti-CarPA in RA (34.43 ± 33.34 ng/ml), SLE (21.12 ± 22.23 ng/ml), pSS (16.32 ± 13.54 ng/ml), PM/DM (30.85 ± 17.34 ng/ml), SSC (23.53 ± 10.70 ng/ml), and UCTD (28.35 ± 21.91 ng/ml) were higher than those of anti-CarPA in the HCs (7.30 ± 5.05 ng/ml). The concentration of serum anti-CarPA was higher in patients with rheumatic disease-related interstitial lung disease (RD-ILD), especially RA-ILD, PM/DM-ILD, and pSS-ILD. Patients with RD-ILD who tested positive for anti-CarPA were more likely to have a more severe radiographic classification (grades II, p = 0.045; grades III, p = 0.003). Binary logistic regression analysis suggested that anti-CarPA had an association with ILD in RA (p = 0.033), PM/DM (p = 0.039), and pSS (p = 0.048). Based on receiver operating characteristics (ROC) analysis, anti-CarPA cutoffs best discriminated ILD in RA (>32.59 ng/ml, p = 0.050), PM/DM (>23.46 ng/ml, p = 0.038), and pSS (>37.08 ng/ml, p = 0.040). Moreover, serum levels of anti-CarPA were correlated with antibodies against transcription intermediary factor 1 complex (anti-TIF1) (R = -0.28, p = 0.044), antibodies against glycyl-transfer ribonucleic acid synthetase (anti-EJ) (R = 0.30, p = 0.031), and antibodies against melanoma differentiation-associated gene 5 (anti-MDA5) (R = 0.35, p = 0.011). Conclusion: Serum anti-CarPA could be detected in patients with RA, PM/DM, pSS, SSC, and UCTD among the Chinese Han population. And it may also assist in identifying ILD in patients with RA, PM/DM, and pSS, which emphasized attention to the lung involvement in anti-CarPA-positive patients.

Efficacy and Safety of Anti-Tumor Necrosis Factor-Alpha Agents for Patients with Intestinal Behcet's Disease: A Systematic Review and Meta-Analysis.

PURPOSE: Intestinal Behcet's disease (BD) is a systemic autoimmune disease for which treatment options are limited. As a prospective therapeutic strategy for intestinal BD, anti-tumor necrosis factor-alpha (anti-TNF-α) agents have received increasing attention. In this study, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of anti-TNF-α agents for patients with intestinal BD. MATERIALS AND METHODS: We searched PubMed, Embase, and Cochrane Library databases up to July 1, 2021 and articles that met the eligibility criteria were further assessed. Pooled rates were synthesized by a randomized effects model using Stata software. RESULTS: Eleven clinical trials covering 671 patients with intestinal BD were included. According to compositive data, the pooled rate for remission was 39% [95% confidence interval (CI) 26-52] in patients receiving anti-TNF-α agents. Intestinal symptoms were cured in 70% (95% CI 53-84) of the patients, and the rate for endoscopic healing was 65% (95% CI 52-78). Corticosteroid discontinuation was achieved in 43% (95% CI 28-58) of the patients, and the dose reduction of corticosteroid was 20.43 mg (95% CI 13.4-27.46). There were 239 adverse events and 80 serious adverse events during follow-up. CONCLUSION: Our study indicated that anti-TNF-α agents may serve as an effective treatment with acceptable safety for patients with intestinal BD. However, more robust evidence from randomized controlled trials is urgently needed to assess the long-term efficacy and safety of anti-TNF-α agents for those patients.

The Role of Anti-U1 RNP Antibody in Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis.

Connective tissue disease (CTD) patients may suffer from pulmonary arterial hypertension (PAH), a serious complication, and anti-U1 ribonucleoprotein (RNP) antibodies can be used as a potential indicator for the development and prognosis of CTD-associated PAH (CTD-PAH). However, there are still some controversies; thus, a systematic review and meta-analysis were performed. We searched PubMed, Embase, Cochrane Library, and Scopus for eligible studies and assessed their quality using Newcastle−Ottawa scales or Agency for Healthcare Research and Quality indicators according to the type of research. Odds ratio (OR) was adopted as a measure of effect in risk factor analysis, and hazard ratio (HR) was adopted for prognostic factor analysis. Publication bias was evaluated using the Egger's test. Thirteen studies were finally included. Anti-U1 RNP antibody was proved as a risk factor for PAH among CTD patients (OR = 5.30, 95%CI 2.96−9.48, p < 0.05) and a protective factor against mortality among CTD-PAH patients (HR = 0.55, 95%CI 0.36−0.83, p < 0.05). CTD patients with positive anti-U1 RNP antibodies are at high risk for PAH, so routine screening examinations, including echocardiography, are recommended. Additionally, anti-U1 RNP positivity has been linked to decreased mortality in patients with CTD-PAH.

Establishment of Multiple Parameter Reference Intervals for Different Age Groups in Qingdao, China.

In this article, we have explored the establishment of multiple parameter reference intervals for different age groups in Qingdao, China. According to the age of subjects, the healthy adult population of different ages in Qingdao was randomly selected as the research object. According to the age of subjects, they were divided into 18-24-year-old, 25-39-year-old, 40-49-year-old, 50-64-year-old, and >65-year-old groups, respectively. The sample size of each age group was 120 male and female samples, and 60 male and female samples of >65-year-old subjects were selected. The data of subjects were collected, a questionnaire survey was completed, serum samples were collected, and the parameters of male and female groups of different ages in Qingdao were compared. The parameters of the male and female groups were compared in the same age group. The reference intervals of parameters of the male and female groups were compared in different ages. There were significant differences in the levels of FBG, AST, BUN, Cr, Hb, FT3, TT3, FT4, TT4, VB12, PROG, CYFRA 21-1, and SCC among men of different ages (P < 0.05). Among them, the levels of FBG, AST, BUN, VB12, CYFRA 21-1, and SCC in >65-year-old men were significantly higher than those in 18-24-years-old men, and the levels of Hb, FT3, TT3, FT4, TT4 in >65-year-old men were significantly lower than those in 18-24-year-old men (P < 0.05). There were significant differences in FBG, ALT, AST, BUN, Cr, Hb, TSH, FT3, TT3, FT4, TT4, VB12, CYFRA 21-1, anti-TPO, and ferritin levels among women of different ages (P < 0.05). Among them, the levels of FBG, ALT, AST, BUN, and ferritin in women aged >65 were significantly higher than those in women aged 18-24 (P < 0.05). The levels of FBG, ALT, AST, BUN, Cr, Hb, FT3, TT3, FT4, TT4, and VB12 in women aged 50-64 were significantly higher than those in women aged 25-39, and the levels of TSH were significantly lower than those in women aged 25-39 and significantly higher than those of the female population aged 40-49 (P < 0.05). The levels of ALT, AST, BUN, Cr, Hb, FT3, TT3, FT4 and ferritin in males aged 18-24 were significantly higher than those in females, while the levels of TSH, VB12 in males aged 18-24 were significantly lower than those in females (P < 0.05). The levels of FBG, ALT, AST, BUN, Cr, Hb, FT3, TT3, FT4 and ferritin in males aged 25-39 were significantly higher than those in females, while the levels of TSH, VB12, CYFRA 21-1 in males aged 25-39 were significantly lower than those in females (P < 0.05). The levels of FBG, ALT, AST, BUN, Cr, Hb, FT3, TT3, FT4, CYFRA 21-1 and ferritin in males aged 40-49 were significantly higher than those in females, and the levels of VB12, anti-TG, anti-TPO in males aged 40-49 were significantly lower than those in females (P < 0.05). The levels of FBG, ALT, BUN, Cr, FT3, TT3 and ferritin in males aged 50-64 were significantly higher than those in females, while the levels of VB12, anti-TG in males aged 50-64 were significantly lower than those in females (P < 0.05). The levels of Cr, Hb and ferritin in males >65 years old were significantly higher than those in females (P < 0.05). The reference intervals of various parameters are different among different ages and genders. The establishment of multiparameter reference intervals for different age groups in Qingdao, China, is of great significance for the early diagnosis and evaluation of various diseases in Qingdao, China, so as to reduce the missed diagnosis rate of diseases and improve people's quality of life.

Yellow Tea Stimulates Thermogenesis in Mice through Heterogeneous Browning of Adipose Tissues.

SCOPE: Large-leaf yellow tea (YT) exhibits interesting beneficial metabolic effects in previous studies. Here, the authors elucidated the actions of YT on thermogenesis, energy metabolism, and adipocyte metabolic conversion. METHODS AND RESULTS: Five-week-old male C57BL/6 mice are fed low-fat diet, high-fat diet (HFD), and HFD supplemented with 0.5% or 2.5% YT. After treatment for 10 or 14 weeks, YT enhances energy expenditure, O2 consumption and CO2 production. YT strongly boosts thermogenic program in brown adipose tissue (BAT) and subcutaneous adipose tissue (SAT), while only weakly in epididymal adipose tissue (EAT). These are accompanied by higher body temperature, increased mitochondrial copy numbers, and upregulation of thermogenic genes (Ucp1, Pgc1α, etc.) and proteins. The classic brown adipocyte markers (Eva1, Zic1) are induced only in BAT, while beige adipocyte markers (Tbx1, Tmem26) are boosted only in SAT. Furthermore, subcutaneous-originated preadipocytes are induced by YT in vitro to differentiate to brown-like adipocytes - a browning effect. CONCLUSION: Dietary YT induces adaptive thermogenesis through increasing mitochondrial biogenesis in EAT, inducing beigeing in SAT and enhancing browning in the BAT.

Prognosis of ovarian clear cell cancer compared with other epithelial cancer types: A population-based analysis.

In order to compare the clinicopathological characteristics and survival outcomes of patients with ovarian clear cell carcinoma (CCC) to other epithelial cancer types, a total of 27,290 patients were analyzed, including 2,424 patients with CCC (8.9%), 3,505 patients with endometrioid cancer (EC) (12.8%), 2,379 patients with mucinous cancer (MC) (8.7%) and 18,982 patients with serous cancer (SC) (69.6%). Patients with EC had the most favorable prognosis and patients with SC had the poorest prognosis among all epithelial ovarian cancers. Among patients with stage I cancer, patients with CCC had a more favorable prognosis compared with patients with SC, especially after 60 months (landmark analysis results, HR=2.079, P=0.001) and had a poorer prognosis compared with patients with MC [restricted mean survival time (RMST) difference, -3.434 months]. Among patients at stages III and IV, patients with CCC had a poorer prognosis compared with patients with SC (RMST difference in stage III, -7.588 months; RMST difference in stage IV, -15.445 months) and had a more favorable prognosis compared with patients with MC (RMST difference in stage III, 10.850 months; RMST difference in stage IV, 8.430 months). The present results suggested that most patients with CCC exhibited, high grade, an early stage, unilateral status and were of a young age. In general, patients with SC presented the poorest prognosis among all patients with epithelial ovarian cancer and no significant survival difference was found between patients with CCC and MC. However, after adjusting for stage using pairwise comparisons, the prognosis of patients with CCC was found to be more favorable compared with the patients with SC and worse compared with patients with MC at stage I; the results at stage III-IV were opposite and the prognosis of patients with CCC was worse compared with the patients with SC and more favorable compared with the patients with MC.

Evaluating overall survival and competing risks of survival in patients with early-stage breast cancer using a comprehensive nomogram.

BACKGROUND: Patients with early-stage breast cancer (BC) live long but have competing comorbidities. This study aimed to estimate the effect of cancer and other causes of death in patients with early-stage BC and further quantify the survival differences. MATERIALS AND METHODS: Data of patients diagnosed with BC between 2010 and 2016 were collected from the Surveillance, Epidemiology, and End Results database. The cumulative incidence function for breast cancer-specific mortality (BCSM) and other cause-specific mortality (OCSM) was estimated, and the differences were tested using the Gray test. The nomogram for estimating 3-, 4-, and 5-year overall survival (OS), breast cancer-specific survival, and other cause-specific survival was established based on Cox regression analysis and Fine and Gray competing risk analysis. The discriminative ability, calibration, and precision of the nomogram were evaluated and compared using C statistics, calibration plots, and area under the receiver operating characteristic curve. RESULTS: A total of 196 304 eligible patients with early-stage BC were identified in this study. Of these, 12 417 (6.3%) patients died: 5628 (45.3%) due to BC and 6789 (54.7%) due to other causes. Five validated variables were incorporated to develop the prognostic nomogram: age, grade, tumor size, subtype, and surgery of primary site (Figure 3). Age was a strong predictive factor, which was more obvious in OCSM. The effect of surgery was more prominent in BCSM. Increased tumor size was correlated with OS and BCSM and slightly correlated with OCSM. Grade and subtype differences were more predominant in BCSM than in OCSM. The established nomogram was well calibrated and displayed good discrimination. CONCLUSIONS: We evaluate OS and competing risks of death in patients with early-stage BC, establishing the first comprehensive prognostic nomogram.

The evolving role of trastuzumab emtansine (T-DM1) in HER2-positive breast cancer with brain metastases.

Approximately 30-50% of advanced human epidermal growth factor receptor 2 (HER2) positive breast cancer patients will develop brain metastases (BMs) during the disease course. Brain metastases may become a main limitation of life expectancy and a half of them will die from brain progression. Even in patients with early HER2-positive breast cancer managed with curative therapy, the risk of brain metastases is also increased. Central nervous system (CNS) may usually present as the first site of recurrence in HER2-positive breast cancer. Local treatments including radiotherapy and surgery are essential while new chemotherapy and biological agents appear to contribute a significant role in the future treatment field of CNS metastases. This article will review recent progresses in HER2-positive breast cancer with BM, with a focus on the efficacy of the HER2 targeted agents-trastuzumab emtansine (T-DM1).

Predictive value of a nomogram for melanomas with brain metastases at initial diagnosis.

BACKGROUND: Estimation of incidence and prognosis of melanomas with brain metastases (MBM) at initial diagnosis based on a large cohort is lacking in current research. This study aims to construct an effective prognostic nomogram for newly diagnosed MBM. MATERIALS AND METHODS: Patients diagnosed with melanomas from Surveillance, Epidemiology, and End Results program between 2010 and 2014 were enrolled in our study. Risk factors predicting brain metastases (BM) were identified using logistic regression analysis. Cox regression analysis was performed to identify prognostic factors of overall survival (OS). Nomogram for estimating 6-, 9-, and 12-month OS was established based on Cox regression analysis. The discriminative ability and calibration of the nomogram were tested using C statistics, calibration plots, and Kaplan-Meier curves. RESULTS: Sixty-two thousand three hundred and sixty-nine melanoma patients were enrolled, including 928 with BM. Sex, marital status, insurance status, subsite, surgery of primary sites, radiation, chemotherapy, bone metastases, liver metastases, and lung metastases were associated with MBM at initial diagnosis. On multivariable Cox regression, the following eight variables were incorporated in the prediction of OS: age, unmarried status, absence of surgery to primary sites or unknown, absence of radiation or unknown, absence of chemotherapy or unknown, with bone metastases, with liver metastases, and with lung metastases. The nomogram showed good predictive ability as indicated by discriminative ability and calibration, with the C statistics of 0.716 (95% CI, 0.695-0.737). CONCLUSIONS: The incidence and prognosis of MBM patients were well estimated in this study based on a large cohort. The nomogram performed well and could be a useful tool to predict prognosis.

Primary spinal mucosa-associated lymphoid tissue lymphoma: A case report.

RATIONALE: Mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent B-cell lymphoma which occurs mainly in the organs having mucosal layer and owns a fairly good prognosis. To date, 7 cases of spinal primary MALT has been reported before. However, there is no consensus on the optimal adjuvant treatment modalities for primary spinal MALT. The aim of this study was to add a new case of MALT which responded well to systemic therapy to the literature and to review the current literature. PATIENT CONCERNS: A 68-year-old woman visited to our hospital due to back pain and progressive bilateral lower extremity weakness for 2 months. Magnetic resonance imaging (MRI) of the spine revealed a diffusely contrast-enhancing epidural mass extending from vertebral body T6 to T8 with compression of the spinal cord. Due to the spinal cord compression, patient underwent surgical resection. Histological examination indicated monocytoid small B-cells. Immunochemical study demonstrates that most tumor cells were positive for CD20, CD21, CD45, CD79a, CD43, bcl-2 with Ki-67 labing index was 15%, but were negative for CD3, CD5 cyclin D1, BCL6, and CD23. The positron emission tomography/computer tomography (PET/CT) revealed that right iliac wing and right liver were metastases for the standard uptake value (SUV) were 9.05 and 8.35, respectively. DIAGNOSES: Based on these findings, final diagnosis of spinal MALT lymphoma was made. INTERVENTIONS: After the diagnosis, the patient received 6 cycles of immuno-chemotherapy and repeated intrathecal methotrexate and intrathecal cytarabine. OUTCOMES: At 1 year follow up, no recurrence or other dissemination was detected. LESSONS: Chemotherapy and/or radiation have been employed in larger case series. While there is no defined treatment guideline for this rare disease entity, our reported case suggests a favorable prognosis when combining both surgical and adjuvant systemic approach.

Exogenous supplement of N-acetylneuraminic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND AND AIMS: Previous studies investigating the correlation between plasma sialic acid and the severity of atherosclerosis present conflicting results. In atherosclerosis patients, plasma levels of N-acetylneuraminic acid (NANA) are increased; however, the underlying mechanisms have not yet been clarified. We assume the increased NANA level may be a compensatory mechanism due to oxidative stress and/or inflammation. The aim of this study is to investigate whether supplementation of NANA could attenuate the progression of atherosclerosis. METHODS: Exogenous NANA was used to determine its effect on apolipoprotein E-deficient (apoE(-/-)) mice taking natural quercetin as a positive control. The effect of NANA on lipid lowering, antioxidant activity and anti-inflammation was investigated by methods of molecular biology. RESULTS: 1) NANA administration decreased 18.9% of the atherosclerotic plaque formation in the aorta and 26.7% of the lipid deposition in the liver of high-fat diet apoE(-/-) mice; 2) notably, NANA treatment reduced 62.6% of the triglyceride by improving lipoprotein lipase activity; 3) NANA lowered 17.5% of the plasma total cholesterol by up-regulating reverse cholesterol transport (RCT)-related protein expression such as ATP-binding cassette transporter (ABC) G1 and ABCG5 in liver or small intestine; 4) NANA administration notably decreased oxidative stress by increasing antioxidant enzymes activity and protein expression of paraoxonase 1 and 2; 5) NANA markedly reduced tumour necrosis factor-α and intercellular adhesion molecule-1 expression in aorta and liver. CONCLUSIONS: NANA exhibited triglyceride lowering, anti-oxidation, and RCT promoting activities, and therefore NANA supplementation may be a new strategy for prevention and treatment of atherosclerosis.

Dataset on inflammatory proteins expressions and sialic acid levels in apolipoprotein E-deficient mice with administration of N-acetylneuraminic acid and/or quercetin.

The data presented in this article describe an effect of N-acetylneuraminic acid and/or quercetin on the inflammatory proteins expressions (TNF-α, ICAM-1, VCAM-1 and MOMA-2) and the N-acetylneuraminic acid (NANA) levels of apolipoprotein E-deficient mice that are given a high-fat diet. Protein expression was performed by immunohistochemical imaging and NANA was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) or semi-quantified using Image-Pro Plus software after ligation with fluorescein-5-thiosemicarbazide (FTSC). Further interpretation and discussion could be found at our research article entitled "Exogenous supplement of N-acetylneuraminic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice" (Guo et al., 2016) [1].

Knockdown of hippocampal cysteinyl leukotriene receptor 1 prevents depressive behavior and neuroinflammation induced by chronic mild stress in mice.

RATIONALE: Numerous studies have demonstrated that neuroinflammation is associated with depression-like symptoms and neuropsychological disturbances, and cysteinyl leukotriene receptor 1 (CysLT1R) was reported to be involved in neuroinflammation. The pathophysiological role of CysLT1R has been reported in several types of brain damage. However, the role of CysLT1R in depression remains to be elucidated. OBJECTIVES: We aimed to investigate the effect of hippocampal CysLT1R downregulation on depressive behaviors and neuroinflammatory responses in mice exposed to chronic mild stress (CMS). RESULTS: We firstly found that expression of hippocampal CysLT1R was gradually increased over CMS exposure, while 3 weeks treatment with fluoxetine reversed the increment of hippocampal CysLT1R expression. Hippocampal CysLT1R knockdown suppressed CMS-induced depressive-like behaviors as evidenced by decreases in immobility time in tail suspension test (TST), decreased latency to feed in novelty-suppressed feeding (NSF) test, and by increase in the number of entries and decrease in time spent in the open arm in elevated plus maze (EPM) test. Increments of hippocampal NF-κB p65, IL-1ß, and TNF-α induced by CMS were also prevented by hippocampal CysLT1R knockdown beforehand. CONCLUSIONS: Hippocampal CysLT1R participates in depression, and knockdown of hippocampal CysLT1R prevents CMS-induced depressive-like behaviors and neuroinflammation, suggesting that suppression of CysLT1R could prevent the development of depression.

[Investigation of Toxoplasma gondii infection in pregnant women in Qingdao area].

OBJECTIVE: To understand the status of Toxoplasma gondii (TOX) infection in pregnant women in Qingdao area. METHODS: Antibody capture ELISA was used to detect the TOX-IgM, IgG and TOX-DNA in 1 341 pregnant women and 201 infertility, miscarriage, stillbirth pregnant women from June 2011 to July 2013. RESULTS: Among 201 abnormal pregnant women, 43 cases were TOX antibody positive, accounting for 22.39%, and among the normal pregnant women, 84 cases were TOX antibody positive, accounting for 6.26%, and there was a significant difference (X2 =10.60, P <0.05). The TOX positive rate of 20-29 years old women was higher than that of the women aged over 30 years (X2 =21.9, P < 0.05). The TOX antibody positive rates of families with pets and families without pets were 26.63% and 8.77% respectively (X2 =10.93, P <0.05). The TOX antibody positive rates were 10.94%(22/201)in unemployed women, 3.98% (8/201) in farmers, 3.98%(8/201) in staff, and 3.48%(7/201) in workers. CONCLUSIONS: The TOX infection rate in abnormal pregnant women is significantly higher than that in normal pregnancy women; therefore, the health education should be strengthened. In addition, in young women, especially 20-29 years old women, and some special occupation women, the control measures should be enhanced.