Annexin-A1 controls an ERK-RhoA-NFκB activation loop in breast cancer cells.

Wound healing is critical for normal development and pathological processes including cancer cell metastasis. MAPK, Rho-GTPases and NFκB are important regulators of wound healing, but mechanisms for their integration are incompletely understood. Annexin-A1 (ANXA1) is upregulated in invasive breast cancer cells resulting in constitutive activation of NFκB. We show here that silencing ANXA1 increases the formation of stress fibers and focal adhesions, which may inhibit wound healing. ANXA1 regulated wound healing is dependent on the activation of ERK1/2. ANXA1 increases the activation of RhoA, which is dependent on ERK activation. Furthermore, active RhoA is important in NF-κB activation, where constitutively active RhoA potentiates NFκB activation, while dominant negative RhoA inhibits NFκB activation in response to CXCL12 stimulation and active MEKK plasmids. These findings establish a central role for ANXA1 in the cell migration through the activation of NFκB, ERK1/2 and RhoA.

Myocardial infarction in singapore: ethnic variation in evidence-based therapy and its association with socioeconomic status, social network size and perceived stress level.

BACKGROUND: Singapore is a multiethnic Asian country comprising predominantly Chinese, Malays, and Indians. We sought to study the disparities in evidence-based therapy for people from these three ethnic groups who were admitted to hospital with ST-segment elevation myocardial infarction (STEMI). We also examined its association with socioeconomic level and social network size and the influence on psychological stress level. METHODS: In a prospective study, patients admitted with STEMI were recruited for a questionnaire survey. Relevant demographic and clinical data were collected. RESULTS: A total of 364 patients were recruited and categorised based on ethnicity: Chinese (222 patients), Malays (72 patients), and Indians (70 patients). Malays and Indians were significantly younger than Chinese at the time of presentation with STEMI. Malays had significantly more children than the Chinese and Indians. Malays were in the lowest socioeconomic class, based on education level (P ≤ .02) and residential type (P ≤ .003). Most (87%) patients were treated with primary percutaneous coronary intervention. There were no significant differences between Chinese, Malays, and Indians in accessibility to primary percutaneous coronary intervention, symptom-to-balloon time, door-to-balloon time, and prescription of evidence-based medications. Malays had larger social networks for information support (P ≤ .05) and financial support (P ≤ .04) than Chinese and Indians. There were no significant differences between the three ethnic groups in satisfaction with social support. The perceived stress level was higher among Malays and Indians than Chinese. CONCLUSIONS: Although Malays were underprivileged in the socioeconomic level, no significant difference in healthcare disparities were observed among the three ethnic groups. This may be a reflection of the advancement in Singapore's healthcare system. The lower socioeconomic level may also explain the higher perceived stress level in Malays.

Angiographic and platelet reactivity outcomes with prasugrel 60 mg pretreatment and clopidogrel 600 mg pretreatment in primary percutaneous coronary intervention.

Pretreatment with 60 mg of prasugrel is more effective than 300 mg of clopidogrel in reducing thrombotic complications with primary percutaneous coronary intervention (PCI). We compared angiographic outcomes and platelet reactivity between treatment with 60 mg of prasugrel and 600 mg of clopidogrel administered before primary PCI. In this single centre non-randomized study, 65 consecutive Asian patients with ST-elevation myocardial infarction (STEMI) received 60 mg of prasugrel before primary PCI. The pre- and post-PCI corrected thrombolysis in myocardial infarction frame count (CTFC) and the 8-h post-treatment platelet vasodilator-stimulated phosphoprotein (VASP) index was compared with a matched historical Asian STEMI cohort (n = 65) receiving 600 mg of clopidogrel pretreatment. Comparing the prasugrel and clopidogrel groups, the mean age was 54.1 ± 10.2 versus 55.5 ± 11.8 years, P = 0.238, and the mean body mass index was 24.6 ± 2.0 versus 24.7 ± 2.8 kg m(-2), P = 0.393. The mean pre-PCI CTFC was 82.1 ± 30.2 versus 86.1 ± 27.6, P = 0.045, and the mean post-PCI CTFC was 21.1 ± 13.9 versus 20.1 ± 9.2, P = 0.309. Pre-PCI coronary thrombi were visualised in 6.3 versus 18.1 %, P = 0.038. The median VASP index was 22.2 ± 24.5 versus 70.5 ± 17.5 %, P < 0.001, and high on-treatment platelet reactivity (VASP index > 50 %) was observed in 13.8 versus 84.3 %, P = 0.001. Rescue intracoronary glycoprotein inhibitors were administered to 29.7 versus 51.0 %, P = 0.018, respectively. Treatment with 60 mg of prasugrel before primary PCI was associated with lower platelet reactivity, a modest trend towards better pre-PCI angiographic outcomes, less pre-PCI coronary thrombi and less rescue glycoprotein inhibitor use compared with 600 mg of clopidogrel. The very high frequency of high on-clopidogrel platelet reactivity with 600 mg of clopidogrel in this Asian STEMI cohort deserves further study.

Immigrant status and disparities in health care delivery in patients with myocardial infarction.

BACKGROUND: We investigated the differences in socioeconomic status and quality health care between Singapore-born citizens and immigrants presenting with ST-segment elevation myocardial infarction (STEMI). METHODS: In a prospective study, patients admitted with STEMI were recruited for a questionnaire survey. The recruited patients were categorized based on their immigration status into Singapore-born citizens (SBC), foreign-born citizens (FBC), permanent residents (PR) and non-residents (NR). RESULTS: Among the 374 recruited patients, 286 (76.5%) patients were categorized as SBC, and the remaining 88 (23.5%) as immigrants. Further breakdown of the immigrants revealed that 33 were FBC (median duration of living in Singapore, 53 years), 22 were PR (18 years), and 33 were NR (11 years). Significant differences in socioeconomic status among SBC, FBC, PR and NR were detected. NR were in the lowest, while PR in the highest, socioeconomic class based on occupation (p=0.003), education level (p<0.001), and average monthly household income (p=0.020). There were no disparities in the proportion of patients treated with primary PCI (SBC 88%, FBC 82%, PR 91%, NR 79%, p=0.555). Median door-to-balloon times were similar among the four groups (56, 52, 60, 56min, p=0.614). Compared with SBC, PR was associated with longer symptom-to-balloon times (median difference 54.1 min; 95% CI 9.0 to 99.2). CONCLUSION: There were major differences in the socioeconomic status among SBC, FBC, PR and NR who presented with STEMI. Although there were no major disparities in access to high quality health care to these patients with different immigration status, symptom-to-balloon time differed substantially among the different migrant classes.

Adiponectin profile in Asian patients undergoing coronary revascularization and its association with plaque vulnerability: IDEAS-ADIPO study.

Despite potent insulin-sensitizing, anti-inflammatory, and antiatherogenic effects in animal studies, the relationship between serum adiponectin level and coronary artery disease in patients remains unclear. We determined the adiponectin profile in a cohort of multiethnic Asian patients with coronary artery disease, and the association between serum adiponectin level and culprit lesion necrotic core (NC) content. Ninety-four Asian patients (BMI, 25.3 ± 3.7 kg/m(2)) undergoing percutaneous coronary intervention were recruited. The serum adiponectin level was measured (n = 94), and the baseline virtual histology intravascular ultrasound examination was analyzed (n = 88). The median level of adiponectin was 3.7 µg/ml (interquartile range, 2.8-4.5 µg/ml). The serum adiponectin level was below 10 µg/ml in 90 patients (95.7%) and below 6 µg/ml in 80 patients (85.1%). There was a significant association between ethnicity and serum adiponectin level (P = 0.048). The median adiponectin level was highest among the Chinese, followed by the Malay and the Indians. Serum adiponectin levels were positively associated with culprit lesion NC content. A 1-µg/ml increase in log adiponectin was associated with a 3.04% (95% confidence interval: 0.33-5.44) increase in culprit lesion NC content. This association remains significant after adjusting for age, sex, ethnicity, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and procedural indication. We found a low serum level of adiponectin in Asian patients and a significant ethnic effect on serum adiponectin level. Increased serum adiponectin levels were independently associated with increased culprit lesion NC burden, suggesting a role for adiponectin in modulating coronary plaque vulnerability.

CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects.

UNLABELLED: AIM, MATERIALS & METHODS: We investigated the functional significance of CYP2C19*2, *3, *17 and PON1 Q192R SNPs in 89 consecutive Asian patients on clopidogrel treatment and the prevalence of functionally significant polymorphisms among 300 Chinese, Malays and Asian Indians. RESULTS: Both CYP2C19 loss-of-function alleles (*2 or *3) were associated with higher platelet reactivity while the CYP2C19 gain-of-function allele (*17) had lower platelet reactivity. For PON1, the median PRI was not significantly different between the QQ, QR and RR groups. The allele frequencies of CYP2C19*2, CYP2C19*3 and CYP2C19*17 were 0.280, 0.065 and 0.010 (rare) for Chinese, 0.310, 0.050 and 0.025 for Malays, and 0.375, 0.010 (rare) and 0.165 for Indians, respectively. CONCLUSION: Our data suggest that genotyping studies to investigate clopidogrel response should include CYP2C19*2 and *3 but not *17 polymorphisms in Chinese, and CYP2C19*2 and *17 polymorphisms but not *3 in Indians. All three polymorphisms should preferably be genotyped in Malays.

Severe obstructive sleep apnea and outcomes following myocardial infarction.

STUDY OBJECTIVE: We sought to determine the effect of severe obstructive sleep apnea (OSA) on long-term outcomes after myocardial infarction. We hypothesized that severe OSA was associated with lower event-free survival rate after ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 120 patients underwent an overnight sleep study during index admission for STEMI. Severe OSA was defined as apnea hypopnea index (AHI) ≥ 30, and non-severe OSA defined as AHI < 30. RESULTS: Among the 105 patients who completed the study, 44 (42%) had severe OSA and 61 (58%) non-severe OSA. The median creatine kinase level and mean left ventricular systolic function were similar between the 2 groups. None of the 105 study patients had received treatments for OSA. Between 1- and 18-month follow-up, the severe OSA group incurred 1 death, 2 reinfarctions, 1 stroke, 6 unplanned target vessel revascularizations, and 1 heart failure hospitalization. In contrast, there were only 2 unplanned target vessel revascularizations in the non-severe OSA group. The incidence of major adverse events was significantly higher in the severe OSA group (15.9% versus 3.3%, adjusted hazard ratios: 5.36, 95% CI: 1.01 to 28.53, p = 0.049). Kaplan-Meier event-free survival curves showed the event-free survival rates in the severe OSA group was significantly worse than that in the non-severe OSA group (p = 0.021, log-rank test). CONCLUSION: 42% of the patients admitted with STEMI have undiagnosed severe OSA. Severe OSA carries a negative prognostic impact for this group of patients. It is associated with a lower event-free survival rate at 18-month follow-up.