Association Between Antihypertensive Medication Use and Breast Cancer: A Systematic Review and Meta-Analysis.

Background: The prevalence rate of hypertension and breast cancer increases with advancing age. Renin-angiotensin system inhibitors (RASIs), ß-blockers (BBs), calcium channel blockers (CCBs), and diuretics are widely used to treat patients with hypertension. Although, the association between the use of antihypertensive medication and breast cancer has been highly debated, recent evidence supporting this association remains controversial. Objective: To evaluate the association between the use of antihypertensive medication and the risk of breast cancer and its prognosis. Methods: This study was conducted using data from the PubMed, Embase, and Cochrane Library databases retrieved for the period from January 2000 to April 2021. Articles and their references were checked and summary effects were calculated using random- and fixed-effects models. Heterogeneity test and sensitivity analysis were also performed. Results: This meta-analysis included 57 articles, which were all related to breast cancer risk or prognosis. Assessment of breast cancer risk using the pooled data showed that the use of BBs or CCBs or diuretics was associated with increased cancer risk [BB: relative risk (RR) = 1.20, 95% confidence interval (CI) = 1.09-1.32; CCBs: RR = 1.06, 95% CI 1.03-1.08; diuretics: RR = 1.06, 95% CI 1.01-1.11]. Long-term use of diuretic increased the risk of breast cancer (RR = 1.10, 95% CI 1.01-1.20), whereas long-term RASIs treatment reduced the risk (RR = 0.78, 95% CI 0.68-0.91). In addition, we found that diuretic users may be related to elevated breast cancer-specific mortality [hazard ratio (HR) = 1.18, 95% CI 1.04-1.33], whereas using other antihypertensive medications was not associated with this prognosis in patients with breast cancer. Conclusion: Using CCBs, BBs, and diuretics increased the risk of breast cancer. In addition, diuretics may elevate the risk of breast cancer-specific mortality. The long-term use of RASIs was associated with a significantly lower breast cancer risk, compared with non-users. Thus, this analysis provides evidence to support the benefits of the routine use of RASIs in patients with hypertension, which has important public health implications.

Corrigendum: TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation.

[This corrects the article DOI: 10.3389/fphar.2020.00010.].

TSG-6 Inhibits Oxidative Stress and Induces M2 Polarization of Hepatic Macrophages in Mice With Alcoholic Hepatitis via Suppression of STAT3 Activation.

Tumor necrosis factor (TNF)-α-stimulated protein 6 (TSG-6) is a secreted protein with diverse tissue protective and anti-inflammatory properties. We aimed to investigate its effective in treating mice with alcoholic hepatitis (AH) and the associated mechanisms. AH was induced in 8-10 week female C57BL/6N mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) injection of recombinant mouse TSG-6 or saline were performed in mice on day 10. Blood samples and hepatic tissues were collected on day 11. Biochemistry, liver histology, flow cytometry, and cytokine measurements were conducted. Compared to the normal control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic macrophage infiltration, serum and hepatic interleukin (IL)-6, and tumor necrosis factor (TNF)-α, which were markedly reduced by i.p. injection of rmTSG-6. Compared to the normal control mice, the hepatic glutathione (GSH), accumulation of M2 macrophages, serum, and hepatic IL-10 and TSG-6 were prominently reduced in the AH mice, which were significantly enhanced after i.p. injection of rmTSG-6. Compared to the normal control mice, hepatic activation of signal transducer and activator of transcription 3 (STAT3) was significantly induced, which was markedly suppressed by rmTSG-6 treatment. TSG-6 were effective for the treatment of AH mice, which might be associated with its ability in inhibiting hepatic oxidative stress and inducing hepatic M2 macrophages polarization via suppressing STAT3 activation.

Mesenchymal stem cells reduce alcoholic hepatitis in mice via suppression of hepatic neutrophil and macrophage infiltration, and of oxidative stress.

Mesenchymal stem cells (MSCs) are a population of pluripotent cells that have been tested for the treatment of many inflammatory diseases. It remains unclear whether MSCs were effective in treating mice with alcoholic hepatitis (AH) and its underlying mechanism. In the present study, MSCs were isolated from bone marrow of 4-6 week-old C57BL/6N male mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) transplantation of MSCs or saline were performed in mice on day 10. Blood samples and hepatic tissues were harvested on day 11. Biochemical, liver histological and flow cytometric analyses were performed. Compared to the control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic neutrophil and macrophage infiltration (P<0.001), which were markedly reduced by i.p. transplantation of MSCs (P<0.01). Compared to the control mice, the hepatic glutathione (GSH) was prominently lower in the AH mice (P<0.001), which was markedly enhanced after i.p. injection of MSCs (P<0.001). MSCs were effective for the treatment of AH mice, which might be associated with their ability in inhibiting hepatic neutrophil and macrophage infiltration, and alleviating oxidative stress.

Mesenchymal stem cells alleviate liver injury induced by chronic-binge ethanol feeding in mice via release of TSG6 and suppression of STAT3 activation.

BACKGROUND: Mesenchymal stem cells (MSCs) are a population of pluripotent cells that might be used for treatment of liver disease. However, the efficacy of MSCs for mice with alcoholic hepatitis (AH) and its underlying mechanism remains unclear. METHODS: MSCs were isolated from the bone marrow (BM) of 4-6-week-old male C57BL/6 N mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. The mice were given intraperitoneal injections of MSCs with or without transfection or AG490, recombinant mouse tumor necrosis factor (TNF)-α-stimulated gene/protein 6 (rmTSG-6), or saline at day 10. Blood samples and hepatic tissues were collected at day 11. Various assays such as biochemistry, histology, and flow cytometry were performed. RESULTS: MSCs reduced AH in mice, decreasing liver/body weight ratio, liver injury, blood and hepatic lipids, malondialdehyde, interleukin (IL)-6, and TNF-ɑ, but increasing glutathione, IL-10, and TSG-6, compared to control mice. Few MSCs engrafted into the inflamed liver. Knockdown of TSG-6 in MSCs significantly attenuated their effects, and injection of rmTSG-6 achieved similar effects to MSCs. The signal transducer and activator of transcription 3 (STAT3) was activated in mice with AH, and MSCs and rmTSG-6 inhibited the STAT3 activation. Injection of MSCs plus AG490 obtained more alleviation of liver injury than MSCs alone. CONCLUSIONS: BM-MSCs injected into mice with AH do not engraft the liver, but they secrete TSG-6 to reduce liver injury and to inhibit STAT3 activation.

Early tumor shrinkage served as a prognostic factor for patients with stage III non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND: Lung cancer is the most common cause of cancer death. About 80% of patients are diagnosed at stage III in the non-small cell lung cancer (NSCLC). It is extremely important to understand the progression of this disease which has low survival times despite the advancing treatment modalities. We aimed to investigate the relationship between early tumor shrinkage (ETS) after initial concurrent chemoradiotherapy (C-CRT) and survival outcome in patients with stage III (NSCLC). METHODS: A retrospective review of 103 patients with stage III NSCLC who had received C-CRT from January 2006 to October 2011 was performed. Patients were treated with systemic chemotherapy regimen of Cisplatin/Vp-16 and concurrent thoracic radiotherapy at a median dose of 66 Gy (range 60-70 Gy). All patients received a computed tomography (CT) examination before treatment. Also subsequently, chest CT scans were performed with the same imaging parameters at approximately 5 weeks after the initiation of treatment. ETS is here stratified by a decrease in tumor size ≥30% and <30% in the longest dimension of the target lesion within 5 weeks. RESULTS: Of the 103 patients, 59 ones showed a 30% decrease in tumor size, and the rest displayed a decrease of <30%. ETS showed no significant correlation with age, T classification, N classification, histological classification, smoking status, G classification, EGFR status, or acute pulmonary toxicity. In the current retrospective clinical study, Kaplan-Meier curves showed that patients with ETS ≥ 30% had a better progression-free survival and overall survival. The univariate and multivariate Cox regression analyses indicated that ETS < 30% was associated with a significantly increased risk of cancer-related death (P < .05) in stage IIINSCLC. CONCLUSIONS: ETS may be served as a useful prognostic factor to predict the outcome of stage III NSCLC patients treated with CCRT.

Radiosynthesis and biological evaluation of 18F-labeled 4-anilinoquinazoline derivative (18F-FEA-Erlotinib) as a potential EGFR PET agent.

Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy. In this study, a novel fluorine-18 labeled 4-anilinoquinazoline based PET tracer, 1N-(3-(1-(2-18F-fluoroethyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (18F-FEA-Erlotinib), was synthesized and biological evaluation was performed in vitro and in vivo. 18F-FEA-Erlotinib was achieved within 50min with over 88% radiochemical yield (decay corrected RCY), an average specific activity over 50GBq/µmol, and over 99% radiochemical purity. In vitro stability study showed no decomposition of 18F-FEA-Erlotinib after incubated in PBS and FBS for 2h. Cellular uptake and efflux experiment results indicated the specific binding of 18F-FEA-Erlotinib to HCC827 cell line with EGFR exon 19 deletions. In vivo, Biodistribution studies revealed that 18F-FEA-Erlotinib exhibited rapid blood clearance both through hepatobiliary and renal excretion. The tumor uptake of 18F-FEA-Erlotinib in HepG2, HCC827, and A431 tumor xenografts, with different EGFR expression and mutations, was visualized in PET images. Our results demonstrate the feasibility of using 18F-FEA-Erlotinib as a PET tracer for screening EGFR TKIs sensitive patients.

[Comparison of anterior chamber angle examination by UBM, SL-OCT and gonioscopy].

OBJECTIVE: To compare the agreement of anterior chamber angle examination by ultrasound biomicroscope (UBM), slit lamp optical coherence tomography (SL-OCT), and gonioscopy in angle recession and angle closure. METHODS: The anterior chamber angle was measured with UBM, SL-OCT and gonioscopy in turns for temporal, nasal, superior and inferior quadrant in the same dark room. The results were compared with the agreement of the three methods in angle recession and angle closure by χ2 test and Kappa test. RESULTS: There were no statistically significant differences of the three methods in testing angle closure and angle recession (P>0.05). The consistency of UBM and gonioscopy was better (Kappa value of 0.882) than that of SL-OCT and gonioscopy (Kappa value of 0.624). CONCLUSION: When testing angle recession, UBM is better than SL-OCT with gonioscopy as the standard. When testing angle closure, UBM, SL-OCT and gonioscopy have good agreement.

Increased survival time in mice vaccinated with a branched lysine multiple antigenic peptide containing B- and T-cell epitopes from T. gondii antigens.

To develop a multiple antigenic peptide (MAP) vaccine against toxoplasmosis, tri-epitope MAP constructs were made in dimeric fashion. The constructs included one B-cell and two T-cell epitopes derived from Toxoplasma gondii antigens (SAG1, GRA4 and GRA1) situated in tandem through the GGG spacer sequence, with the latter positioned adjacent to a polylysine core. Immunization of BALB/c and Kunming mice with the MAP construct in Freund's adjuvant induced not only humoral immunes response but cellular responses. These responses were accompanied by significant levels of splenocyte proliferation and interferon gamma (IFN-γ) in vitro. After lethal challenge, vaccinated mice had increased survival time in comparison to unvaccinated controls. Our data demonstrate that a MAP construct could trigger strong humoral and cellular responses against T. gondii, and that this MAP is a vaccine candidate worth further development.

[Etiology analysis for hospitalized hypertensive patients: 10 years report from the department of hypertension (1999 - 2008)].

OBJECTIVE: To analyze etiology of hospitalized hypertensive patients in the department of hypertension from 1999 to 2008. METHODS: This retrospective study was performed to analyze the etiology of hospitalized hypertensive patients in department of hypertension and to show the distribution change of hypertension from 1999 to 2008. RESULTS: (1) There were 5867 (75.1%) patients with essential hypertension and 1942 (24.9%) patients with secondary hypertension (SH). (2) The prevalence rate of SH increased significantly during the 10 years (χ(2) = 387.621, P < 0.001) and was higher in 2008 than in 1999 (39.3% vs. 9.5%, P < 0.05). The prevalence of obstructive sleep apnea syndrome (OSAS) and primary aldosteronism (PA) in 2008 increased 38.3 and 1.8 times respectively than in 1999 (χ(2) = 304.025, P < 0.001; χ(2) = 42.845, P < 0.001) and other SH remained unchanged. (3) The prevalence of PA complicated with OSAS increased significantly in recent five years (χ(2) = 26.376, P < 0.001). Incidence of OSAS was 23.9% in PA patients and incidence of PA was 6.7% in OSAS patients. CONCLUSIONS: With the insights gained on hypertension mechanism and the development of new diagnostic technology, percent of diagnosed SH increased remarkably in recent years in hospitalized hypertensive patients in our department of hypertension. OSAS and PA are the leading causes of SH.

Comparison of methimazole/hydrocortisone ointment with oral methimazole in patients with graves disease: A prospective, randomized, open-label, parallel-group, 18-month study.

BACKGROUND: Thionamide antithyroid drugs (ATDs) have certain disadvantages and are associated with some adverse events (AEs). To overcome the problems associated with ATDs, a compound antithyroid ointment (CATO) containing methimazole (MMI) and hydrocortisone has been developed for use as a local thyroid treatment (LTT). OBJECTIVE: The aim of this study was to assess the clinical effectiveness and tolerability of CATO LTT in patients with Graves disease (GD). METHODS: This was a prospective, randomized, open-label, parallel-group clinical trial conducted at the Provincial Hospital Affiliated to Shandong University (Jinan, China). Patients with GD aged 19 to 65 years were randomized to receive either CATO LTT 0.3 g/d or oral MMI 37.5 mg/d (control group) treatment for 18 months, with a 4-year follow-up period. Hyperthyroid symptoms, thyroid function, granulocyte count, liver function, and AEs were assessed at baseline and every 2 weeks until serum thyroid hormone (TH) concentration normalized, at which point patients were assessed monthly. The primary efficacy end points were the duration of treatment required for serum TH concentration to normalize and the remission rate after completing the 18-month treatment regimen. RESULTS: A total of 154 patients (133 women, 21 men; mean [SD] age, 39.6 [11.8] years; all Han Chinese) participated in the study; all patients completed the 18-month treatment period. Compared with the MMI group (n 76), the CATO- treated group (n 78) had a significantly shorter median (range) time to restoration of normal serum thyroid hormone concentration (43 [12-150] vs 22 [7-60] days; P < 0.001), a significantly lower rate of recurrence of hyperthyroidism (309/1520 [20.3%] vs 193/1368 [14.1%] person-time; P < 0.001), a significantly lower drug hypothyroidism rate (185/1520 [12.2%] vs 54/1368 [3.9%] person-time; P < 0.001), and a higher remission rate (year 1:46/69 [66.7%] vs 65/72 [90.3%] patients, P 0.001; year 2:40/69 [58.0%] vs 60/72 [83.3%] patients, P - 0.001; year 3:34/69 [49.3%] vs 57/72 [79.2%] patients, P < 0.001; and year 4:30/69 [43.5%] vs 55/72 [76.4%] patients, P < 0.001). Systemic AEs occurred in 6 patients (7.9%) in the MMI group (drug neutropenia, 2 patients [2.6%]; epistaxis, 1 [1.3%]; hepatopathy, 1 [1.3%]; and other systemic AEs, 2 [2.6%]), while no systemic AEs were observed/reported in the CATO group. CONCLUSION: This study suggests that CATO LTT was well tolerated and more effective than oral MMI treatment in controlling thyrotoxicosis and promoting remission of GD in these Han Chinese patients.

Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in chinese patients with non-small cell lung cancer.

PURPOSE: Studies have shown that mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are associated with response of lung cancer to gefitinib (Iressa, AstraZeneca Corp., Shanghai, China). A higher incidence of EGFR mutation was observed in non-small cell lung cancer (NSCLC) patients of Japanese origin compared with those of American origin. However, no data about such mutations in Chinese patients with NSCLC could be obtained. METHODS: Primary NSCLC tissues were obtained for analysis of mutations in exons 18 to 21 of EGFR from a total of 76 patients, of whom 54 did not receive gefitinib therapy and 22 did. PCR products were sequenced directly and mutations were confirmed by an independent PCR and sequence analysis. All types of mutation were cloned and sequenced. RESULTS: A total of 10 types of mutation were found in the series of patients, including two different silent mutations in exon 20 from 11 patients. More than half of the silent mutations (6 of 11) in exon 20 coexisted with other mutations. Mutations were more frequent in adenocarcinoma (17 of 35; 48.6%) compared with squamous carcinoma (1 of 19; 5.3%) among untreated patients. Similar mutations were observed in all seven gefitinib-treated patients with partial response, and no mutations were detected in all eight patients with progressive disease (P < 0.001), except two silent mutations. Three mutations were observed in seven patients with stable disease. CONCLUSIONS: Mutations in the epidermal growth factor receptor tyrosine kinase domain in lung adenocarcinomas from Chinese patients were more frequent than reported previously in lung adenocarcinomas from American patients. Such mutations were well correlated with tumor response to gefitinib.

[Humidification during mechanical ventilation].

This review aims to emphasize the importance of humidification and to identify humidification method the most effective in the intubated or ventilated patients. Some details are also discussed on how to perform humidification.

[Study on protective effect of monosialoganglioside (GM1) on injury induced by oxygen glucose deprivation/reperfusion in rat hippocampal slices].

AIM: To investigate the protective effect of monosialoganglioside (GM1) on injury induced by oxygen glucose deprivation/reperfusion (OGD/Rep) in rat hippocampal slices. METHODS: The protective effects of GM1 on hippocampal slices after OGD/Rep were observed by detecting the light transmittance (LT) changes of rat hippocampal slices and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining of rat hippocampal slices. RESULTS: (1) In four groups treated with 0 (control), 0.1, 1.0, 10 micromol/L GM1, the peak of light transmittance (LT) in the slices treated with 1.0 micromol/L GM1 was significantly lower than that of the control and the group treated with 0.10 micromol/L GM1 (P < 0.01, ANOVA), while the peak of LT in the slices treated with 10.0 micromol/L GM1 was significantly lower than that of the other groups (P < 0.01, ANOVA). The time to reach the peak of LT in four groups was significantly different from each other (P < 0.05, Kruskal-Wallis test). The time to reach the peak of LT in the group treated with 1 micromol/L GM1 was the significantly longer than that in the control (P < 0.01, Mann-Whitney U test). (2) There was characteristic dose-response relationship between GM1 and TTC staining of rat hippocampal slices. In the five groups, treated with 0 (control), 0.01, 0.1, 1.0, 10 micromol/L GM1 respectively, TTC staining in the group treated with 1 micromol/L GM1 was the deepest (P < 0.05 vs. control, 0.01 and 0.1 micromol/L GM1 group, ANOVA), and the next was in the group treated with 10 micromol/L GM1 (P < 0.05 vs. control and 0.01 micromol/L GM1 group, ANOVA). CONCLUSION: GM1 could protect injury induced by OGD/Rep in rat hippocampal slices effectively in vitro.