Metformin reverses mesenchymal phenotype of primary breast cancer cells through STAT3/NF-κB pathways.

BACKGROUND: Breast cancer currently is the most frequently diagnosed neoplasm and the leading cause of death from cancer in women worldwide, which is mainly due to metastatic disease. Increasing our understanding of the molecular mechanisms leading to metastasis might thus improve the pharmacological management of the disease. Epithelial-mesenchymal transition (EMT) is a key factor that plays a major role in tumor metastasis. Some pro-inflammatory cytokines, like IL-6, have been shown to stimulate phenotypes consistent with EMT in transformed epithelial cells as well as in carcinoma cell lines. Since the EMT is one of the crucial steps for metastasis, we studied the effects of metformin (MTF) on EMT. METHODS: Cytotoxic effect of MTF was evaluated in eight primary breast cancer cell cultures by crystal violet assay. EMT markers and downstream signaling molecules were measured by Western blot. The effect of MTF on cell proliferation and cell migration were analyzed by MTT and Boyden chamber assays respectively. RESULTS: We observed that the response of cultured breast cancer primary cells to MTF varied; mesenchymal cells were resistant to 10 mM MTF and expressed Vimentin and SNAIL, which are associated with a mesenchymal phenotype, whereas epithelial cells were sensitive to this MTF dose, and expressed E-cadherin but not mesenchymal markers. Further, exposure of mesenchymal cells to MTF down-regulated both Vimentin and SNAIL as well as cell proliferation, but not cell migration. In an in vitro IL-6-induced EMT assay, primary breast cancer cells showing an epithelial phenotype underwent EMT upon exposure to IL-6, with concomitant activation of STAT3 and NF-κB; addition of MTF to IL-6-induced EMT reversed the expression of the mesenchymal markers Vimentin and SNAIL, decreased pSTAT3 Y705 and pNF-κB S536 and increased E-cadherin. In addition, downregulation of STAT3·activation was dependent on AMPK, but not NF-κB phosphorylation. Further, MTF inhibited cell proliferation and migration stimulated by IL-6. CONCLUSION: These results suggest that MTF inhibits IL-6-induced EMT, cell proliferation, and migration of primary breast cancer cells by preventing the activation of STAT3 and NF-κB. STAT3 inactivation occurs through AMPK, but not NF-κB.

Dental changes induced by a modified Herbst appliance followed by fixed appliances: A digital dental model analysis.

BACKGROUND: Herbst therapy is an effective treatment for Class II malocclusions. However, the maintenance of the effects after fixed appliances treatment remains questionable. This retrospective study aimed to assess, using digital dental models, the sagittal and transverse dental arch changes in young patients during two Class II Division 1 treatment phases, first with modified Herbst appliance (HA) and then with fixed appliances. METHODS: The treated group (TG) comprised 32 patients (17 boys, 15 girls; mean age, 12.85 ± 1.16 years) treated with HA and fixed appliances. The control group comprised 28 patients (13 boys, 15 girls; mean age, 12.21 ± 1.35 years) with untreated Class II malocclusions. Digital models were obtained immediately before and after HA therapy and after fixed appliances. Data were statistically analyzed. RESULTS: Compared with the control group, the TG showed an increase in maxillary and mandibular arch perimeters and in intercanine and intermolar arch widths, a decrease in overjet and overbite, and an improvement in canine and molar relationships. In the time after HA therapy until the end of fixed appliances treatment, the TG showed a decrease in maxillary and mandibular arch perimeters, overjet, upper and lower intermolar widths; an increase in molar Class II relationship; and no changes in canine relationship, overbite, and upper and lower intercanine widths. CONCLUSIONS: In this sample of patients treated with HA, on average, there was an improvement in the Class II relationship, which seemed to remain after fixed appliances. The transverse dental changes achieved in HA phase relapsed after treatment with fixed appliances.

Clinical profile and prognosis of young patients with ST-elevation myocardial infarction managed by the emergency-intervention Codi IAM network.

INTRODUCTION AND OBJECTIVES: Data on the clinical profile and outcomes of younger patients with ST-elevation myocardial infarction (STEMI) is scarce. This study compared clinical characteristics and outcomes between patients aged<45 years and those aged ≥ 45 years with STEMI managed by the acute myocardial infarction code (AMI Code) network. Sex-based differences in the younger cohort were also analyzed. METHODS: This multicenter study collected individual data from the Catalonian AMI Code network. Between 2015 and 2020, we enrolled patients with an admission diagnosis of STEMI. Primary endpoints were all-cause mortality within 30 days, 1 year, and 2 years. RESULTS: Overall, 18 933 patients (23% female) were enrolled. Of them, 1403 participants (7.4%) were aged<45 years. Younger patients with STEMI were more frequently smokers (P<.001) and presented with cardiac arrest and TIMI flow 0 before pPCI (P<.05), but the time from first medical contact to wire crossing was shorter than in the older group (P<.05). All-cause mortality rates were lower in patients aged<45 years (P<.001). Among younger patients, cardiogenic shock was most prevalent in women than in their male counterparts (P=.002), with the time from symptom onset to reperfusion being longer (P<.05). Compared with men aged<45 years, younger women were less likely to undergo pPCI (P=.004). CONCLUSIONS: Despite showing high-risk features on admission, young patients exhibit better outcomes than older patients. Differences in ischemia times and treatment were observed between men and women.

Long-Term Intracoronary Structural and Vasomotor Assessment of the ABSORB Bioresorbable Vascular Scaffold.

We systematically categorized the longer-term (≥3 years) structural and functional characteristics of the ABSORB bioresorbable vascular scaffold (BVS) using optical coherence tomography imaging and coronary vasomotor reactivity testing and further compared the functional characteristics of BVS stented versus remote coronary segments. A total of 92 patients (mean age 56.4 ± 9.7 years, 22.8% women) who underwent percutaneous coronary intervention (76% with acute coronary syndrome) using the ABSORB BVS (112 lesions) were included. Optical coherence tomography analysis (38,790 visible struts) comprised in-segment quantitative lumen/plaque and semiquantitative plaque composition analysis of the neointimal pattern. Epicardial endothelium-dependent and-independent vasomotion was defined as any vasodilatation at low/intermediate intracoronary dose of acetylcholine (ACh) and nitroglycerine, assessed using quantitative coronary angiography. At a median time of 3.2 years follow-up, 79.8% of BVS segments still demonstrated visible struts with a predominant neointimal fibrotic healing pattern in 84% of BVS segments, with 99.5% of struts demonstrating coverage with apposition. Compared with remote segments, BVS segments demonstrated less endothelium-dependent vasodilatation at low (p = 0.06) and intermediate ACh doses (p = 0.04). Hypertension, longer time interval from index percutaneous coronary intervention, and the degree of in-BVS segment neointimal volume (p <0.03 for all) were each independently associated with abnormal BVS endothelium-dependent vasomotor function. Endothelium-independent function was more likely preserved in non-BVS (remote) segments compared with BVS segments (p = 0.06). In conclusion, at 3+ years post-ABSORB BVS insertion, the rate of complete scaffold resorption was low and residual strut presence was high, with a dominant fibrous healing response contributing toward neointimal hyperplasia and endothelium-dependent and-independent vasomotor dysfunction.

Differences in 30-day complications and 1-year mortality by sex in patients with a first STEMI managed by the Codi IAM network between 2010 and 2016.

INTRODUCTION AND OBJECTIVES: ST-segment elevation myocardial infarction (STEMI) emergency care networks aim to increase reperfusion rates and reduce ischemic times. The influence of sex on prognosis is still being debated. Our objective was to analyze prognosis according to sex after a first STEMI. METHODS: This multicenter cohort study enrolled first STEMI patients from 2010 to 2016 to determine the influence of sex after adjustment for revascularization delays, age, and comorbidities. End points were 30-day mortality, the 30-day composite of mortality, ventricular fibrillation, pulmonary edema, or cardiogenic shock, and 1-year all-cause mortality. RESULTS: From 2010 to 2016, 14 690 patients were included; 24% were women. The median [interquartile range] time from electrocardiogram to artery opening decreased throughout the study period in both sexes (119 minutes [85-160] vs 109 minutes [80-153] in 2010, 102 minutes [81-133] vs 96 minutes [74-124] in 2016, both P=.001). The rates of primary PCI within 120 minutes increased in the same period (50.4% vs 57.9% and 67.1% vs 72.1%, respectively; both P=.001). After adjustment for confounders, female sex was not associated with 30-day complications (OR, 1.06; 95%CI, 0.91-1.22). However, female 30-day survivors had a lower adjusted 1-year mortality than their male counterparts (HR,0.76; 95%CI, 0.61-0.95). CONCLUSIONS: Compared with men, women with a first STEMI had similar 30-day mortality and complication rates but significantly lower 1-year mortality after adjustment for age and severity.

Comparison of C Reactive Protein and Procalcitonin Levels in Cerebrospinal Fluid and Serum to Differentiate Bacterial from Viral Meningitis.

GOALS: It is unclear whether C reactive protein (CRP) and procalcitonin (PCT) levels in cerebrospinal fluid (CSF) improve the accuracy compared to their serum levels for the differential diagnosis of infectious meningitis. The aim of this study was to compare the accuracy of CRP and PCT levels in CSF and serum in order to differentiate between bacterial and viral meningitis. PROCEDURES: CRP and PCT levels were measured in CSF and serum from patients with bacterial or viral meningitis. The diagnostic accuracy was determined using receiver operating characteristic curves (ROC), calculating the area under the ROC curve (AUC). RESULTS: Thirty patients were included in this study, 18 of whom had bacterial meningitis and 12 viral meningitis. The AUCs to differentiate bacterial from viral meningitis using serum CRP, CSF CRP, serum PCT and CSF PCT were 0.926; 0.898; 0.963; and 0.694 respectively. Serum CRP and PCT exhibited 100% and 88.9% sensitivity, 83.3% and 100% specificity with a cut-off =14.0 mg/L and 0.18 µg/L respectively. CONCLUSIONS: Levels of CRP and PCT in CSF did not present greater accuracy in differentiating bacterial from viral meningitis compared to serum levels. Serum CRP and PCT showed a high diagnostic accuracy, therefore its quantification is recommended in all patients with suspected infectious meningitis.