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.

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.

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.

Antidiabetic drugs restore abnormal transport of amyloid-ß across the blood-brain barrier and memory impairment in db/db mice.

Previous studies have shown significant changes in amyloid-ß (Aß) transport across the blood-brain barrier (BBB) under diabetic conditions with hypoinsulinemia, which is involved in diabetes-associated cognitive impairment. Present study employed db/db mice with hyperinsulinemia to investigate changes in Aß transport across the BBB, hippocampal synaptic plasticity, and restorative effects of antidiabetic drugs. Our results showed that db/db mice exhibited similar changes in Aß transport across the BBB to that of insulin-deficient mice. Chronic treatment of db/db mice with antidiabetic drugs such as metformin, glibenclamide and insulin glargine significantly decreased Aß influx across the BBB determined by intra-arterial infusion of (125)I-Aß(1-40), and expression of the receptor for advanced glycation end products (RAGE) participating in Aß influx. Insulin glargine, but not, metformin or glibenclamide increased Aß efflux across the BBB determined by stereotaxic intra-cerebral infusion of (125)I-Aß(1-40), and expression of the low-density lipoprotein receptor related protein 1 (LRP1) participating in Aß efflux. Moreover, treatment with these drugs significantly decreased hippocampal Aß(1-40) or Aß(1-42) and inhibited neuronal apoptosis. The drugs also ameliorated memory impairment confirmed by improved performance on behavioral tasks. However, insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation (LTP). Further study found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the BBB in db/db mice. Our data indicate that the antidiabetic drugs can partially restore abnormal Aß transport across the BBB and memory impairment under diabetic context.

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.