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Whether peripheral immune cell subsets can predict pathological complete response (pCR) in breast cancer patients remains to be elucidated. We aimed to dissect the relationship between peripheral immune cell subsets and pCR.Two hundred and twenty-six eligible patients from two prospective clinical trials (SHPD001 and SHPD002) in China were randomly divided into a training cohort and a validation cohort. The breast cancer subtypes in this study included hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 95), HER2-positive (n = 100), and triple negative (n = 31) breast cancer. We defined the "Neo-Peripheral Adaptive Immune Score" for neoadjuvant chemotherapy (neoPAI Score) based on the percentages of CD4 + T cells, CD8 + T cells, B cells, and the CD4 + /CD8 + ratio in peripheral blood. We also evaluated the ability of the neoPAI Score derived from tumor-infiltrating immune cells (TIICs) to predict survival by employing The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) database.In the training cohort, multivariate analysis showed that HR status [odds ratio (OR) 0.325; 95% confidence interval (CI) 0.135-0.761; P = 0.010], HER2 status (OR 2.657; 95% CI 1.266-5.730; P = 0.011), Ki67 index (OR 3.191; 95% CI 1.509-6.956; P = 0.003), histological grade (OR 2.297; 95% CI 1.031-5.290; P = 0.045) and neoPAI Score (OR 4.451; 95% CI 1.608-13.068; P = 0.005) were independent predictors of pCR. In the validation cohort, histological grade (OR 3.779; 95% CI 3.793-1.136 × 10The neoPAI Score defined by the percentages of peripheral immune cell subsets could be used as a potential biomarker for neoadjuvant chemotherapy efficacy.

Longwang Chen,1,* Xinyong Liu,2,* Xuetao Wang,3 Zhongqiu Lu,1 Yumei Ye4 1Department of Emergency, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of China; 3Department of Intensive Care Unit, Wenzhou Longwan District First People’s Hospital, Wenzhou, Zhejiang, People’s Republic of China; 4Department of Ultrasound Imaging, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yumei Ye, Department of Ultrasound Imaging, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China, Tel +860577-5557-9410, Email 314894957@qq.comPurpose: A common complication of sepsis is acute lung injury (ALI), which is associated with an acute onset, rapid disease changes, and high mortality. Regulatory T (Treg) and T helper 17 (Th17) cells comprise CD4+ T cell subsets, which strongly influence inflammation during ALI. In this study, we investigated the effect of berberine (BBR), an antioxidant, anti-inflammatory, and immunomodulatory drug, on the inflammatory response and immune state in mice with sepsis.Methods: A mouse model of cecal ligation and puncture (CLP) was established. The mice were intragastrically administered 50 mg/kg BBR. We used histological techniques to evaluate inflammatory tissue injury and flow cytometry for analyzing Treg/Th17 levels. We also assessed NF-κB signaling pathways by Western blotting assays and immunofluorescence staining. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the content of cytokines.Results: Treatment with BBR considerably mitigated lung injury while improving survival, post-cecal ligation, and puncture (CLP). Treatment with BBR ameliorated pulmonary edema and hypoxemia in septic mice and inhibited the NF-κB signaling pathway. BBR also increased Treg cells and decreased Th17 proportions in the spleen and lung tissue of CLP-treated mice. Blocking Treg cells weakened the protective effect of BBR on sepsis-associated lung injury.Conclusion: Overall, these results suggested that BBR is a potential therapeutic agent for sepsis.Graphical Abstract: Keywords: berberine, sepsis, inflammation, cell differentiation, immunodeficiency, T lymphocyte

Purpose:Despite accumulating evidence on dual blockade of HER2 for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy.Patients and Methods:The phase II NeoATP trial included female patients with histologically confirmed stage IIA to IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel–cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathologic complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis, and safety.Results:Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor–negative and –positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00%, respectively, for those with and without PIK3CA mutation (P = 0.958). The most frequently reported Grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%), and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction 10 points drop from baseline to before surgery was reported.Conclusions:The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.

Supplementary Data from Neoadjuvant Trastuzumab and Pyrotinib for Locally Advanced HER2-Positive Breast Cancer (NeoATP): Primary Analysis of a Phase II Study

BackgroundAchieving pathologic complete response (pCR) because of neoadjuvant therapy has been correlated with long-term clinical benefit, however, luminal-like tumors achieve a lower rate of pCR in comparison with other subtypes. The Shanghai Pudong (SHPD) 002 trial compares neoadjuvant chemotherapy concurrently with or with different estrogen deprivation therapy separately in premenopausal and postmenopausal patients with locally advanced breast cancer. MethodsIn this prospective, multicentre, neoadjuvant, phase III trial, 236 patients with locally advanced breast cancer were randomly assigned (2:1) to receive neoadjuvant chemotherapy (NCT) with gonadotropin-releasing hormone agonist (GnRHa) in premenopausal women or letrozole in postmenopausal women compared with chemotherapy alone. The primary endpoint was pCR (ypT0/is/ypN0). Secondary endpoints included disease-free survival, overall survival, and safety. This trial is registered with ClinicalTrials.gov, number NCT NCT02221999.Results A total of 236 patients were included. pCR was achieved by 20.4% in the chemotherapy plus ET group and 38.6% in the chemotherapy group. In postmenopausal patients, pCR was observed in 22.6% when treated with letrozole, 32.4% with NCT alone (p=0.276). Premenopausal patients with NCT and GnRHa achieved a significantly lower pCR of 18.8% than those of 42.9% in patients with NCT alone(p=0.003). A posthoc analysis showed CPS+EG score 0-3 was significantly more probable in patients with GnRHa (OR, 0.245; 95% CI, 0.072 to 0.832, P=0.024) than in those without GnRHa in the premenopausal patients who didn’t achieve near-pCR. After a median follow-up of 45 months, there was no significant difference concerning disease-free survival (DFS) (p=0.874) or overall survival (OS) (P =0.947) between the 2 postmenopausal groups. GnRHas significantly improved survival outcome in premenopausal patients (3-year OS, 100% with GnRHas, vs 88.2% without; log-rank p=0.034). Improved DFS (log-rank p = 0.001) and OS (log-rank p=0.003) were strongly associated with pCPS+EG score and GnRHa usage in premenopausal patients.ConclusionsConcurrent administration of GnRHas during neoadjuvant chemotherapy improves OS in premenopausal patients, though it does not increase the pCR rate. The adoption of the CPS+EG score may be a better surrogate endpoint for survival outcomes. The addition of letrozole to neoadjuvant chemotherapy confers no therapeutic advantage in terms of tumor response or survival outcome. Citation Format: Liheng Zhou, Shuguang Xu, Xiaohong Xue, Yinzhou Zhang, Bei Gu, Baoxing Lin, Junwen Bai, Hongwei Zhang, Kejin Wu, Yanping Lin, Yumei Ye, Yueyao Du, Xiaonan Sheng, Yaqian Xu, Jie Zhang, Wenjin Yin, Jinsong Lu. Efficacy, safety and survival of neoadjuvant chemotherapy with different estrogen deprivation stratified by menstrual status versus chemotherapy alone in locally advanced breast cancer (SHPD002)—— A randomized multicentre, open-label, phase 3 Triab [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-02.

Ischemic postconditioning (PostC), repetitive cycles of re-occlusion, and reperfusion of the infarct-related artery immediately after reperfusion have been shown to limit myocardial infarct size in various animal models. Yet, translating the model into the clinical setting was disappointing, several clinical trials showing neutral effect. We hypothesized that aspirin loading could explain the differences between the pre-clinical and clinical studies. Male Sprague Dawley rats were subjected to 30-min coronary artery ligation. At 25 min of ischemia, animals received intravenous aspirin (20 mg/kg) or vehicle. Upon reperfusion half of the rats were randomized to PostC (3 cycles of 10-s re-occlusion/10-s reperfusion. After 4-h reperfusion, rats were euthanized. Area at risk was assessed by blue dye and infarct size by 2,3,5-triphenyl-tetrazolium-chloride (TTC). Body weight and the size of the ischemic area at risk were comparable among groups. Infarct size expressed as a percentage of the ischemic area at risk was significantly smaller in the PostC group (13.9 ± 0.4%; p

Ticagrelor and dapagliflozin can suppress the activation of the NOD-like receptor 3 (NLRP3)-inflammasome and activate AMP-activated protein kinase (AMPK). The anti-inflammatory effects of dapagliflozin has been shown to depend on AMPK activation. Dapagliflozin and ticagrelor have been shown to have additive effects on the progression of diabetic cardiomyopathy in BTBR ob/ob mice with type-2 diabetes. We assessed whether dapagliflozin and ticagrelor have additive effects on the activation of the NLRP3-inflammasome and the progression of diabetic nephropathy in mice with type-2 diabetes. Eight-week-old BTBR received either no-drug, dapagliflozin (1.5 mg/kg/d), ticagrelor (100 mg/kg/d), or their combination for 12 weeks. Blood was assessed weekly for glucose and urine for glucose and albumin. After 12 weeks, blood creatinine, cystatin C, inflammasome activation, and insulin were assessed by ELISA. Renal cortex samples were assessed by hematoxylin and eosin and periodic acid-Schiff staining. RT-PCR and immunoblotting were used to evaluate fibrosis and the activation of Akt, AMPK and the inflammasome. Both ticagrelor and dapagliflozin reduced serum creatinine and cystatin C levels and urinary albumin. Both drugs attenuated the increase in glomerular area and mesangial matrix index. Both drugs decreased collagen-1 and collagen-3 expression and the activation of the NLRP3-inflammasome. Both drugs increased P-AMPK levels, but only dapagliflozin increased P-Akt levels. Overall, the protective effects of dapagliflozin and ticagrelor were additive. Dapagliflozin and ticagrelor attenuated the progression of diabetic nephropathy in BTBR ob/ob mice with additive effects of the combination. This was associated with AMPK activation and reduced activation of the NLRP3 inflammasome, whereas only dapagliflozin increased Akt activation.

To assess the effects of electro-acupuncture (EA) on glycemic control, myocardial inflammation, and the progression of diabetic cardiomyopathy in mice with type 2 diabetes. Db/Db mice received EA at PC6+ST36 (DM-Acu), non-acupoint simulation (DM-Sham), or no treatment (DM). EA was applied for 30 min per day, 5 days a week for 4 weeks. Heart function was assessed by echocardiography. Myocardium was assessed by RT-PCR, immunoblotting, and histology. Serum TNF-α, IL-1α, IL-1β, IL-6, and IL-8 were measured. DM-Acu, but not DM-Sham, reduced fasting blood glucose without affecting body weight. DM decreased systolic function. DM-Acu, but not DM-Sham, attenuated the decrease in systolic function. Heart weight was significantly smaller in the DM-Acu than in the DM and DM-Sham groups. Percent fibrosis and apoptosis were reduced in the DM-Acu, but not the DM-Sham, group. Serum levels of IL-1α, IL-1β, IL-6, IL-8, ICAM-1, MCP-1, and TNF-α were significantly lower in the DM-Acu than in the DM or DM-Sham groups. Protein levels of P-Akt and P-AMPK and mRNA levels of phosphoinositide-3-kinase regulatory subunit 6 (PIK3r6) were significantly higher in the DM-Acu group. Myocardial mRNA and protein levels of insulin-like growth factor 1 receptor (IGF1R) were significantly lower in the DM and DM-Sham groups compared with the DM-Acu group. EA reduced serum glucose; prevented DM-induced hypertrophy and deterioration of systolic function, inflammation, and fibrosis; and restored IGF1R, P-Akt, and P-AMPK levels in mice with type 2 diabetes mellitus.

Background Neoadjuvant chemotherapy is usually used for treating locally advanced breast cancer. However, not all patients achieve pathologic complete response (pCR). In this study, we selected two epidermal growth factor receptor (EGFR) single nucleotide polymorphism (SNP) sites, rs1468727 and rs845552, to investigate the association between the genotypes and the response and toxicity derived from neoadjuvant chemotherapy for breast cancer. Methods All participants took part in clinical trial SHPD001 and SHPD002. For univariate analyses, the association between SNP and pCR or toxicity was analyzed by Chi-square or Fisher's exact test. For multivariate analyses, logistic regression was used instead. Results In all, one hundred and eighteen patients were enrolled. We found that the frequency of AA genotype in rs845552 was higher than that of other genotypes in HER2-positive breast cancer (AA vs. AG, P=0.039; AA vs. GG, P=0.005; AA vs. AG+GG, P=0.009). Multivariate logistic regression analyses showed that pCR was more difficult to be achieved in patients with a CT genotype in rs1468727 compared to those with a CC+TT genotype (OR =0.288, 95% CI: 0.109-0.762, P=0.012) or a CC genotype (OR =0.254, 95% CI: 0.076-0.849, P=0.026). Moreover, we demonstrated that both rs1468727 and rs845552 were associated with toxicity that results in complications such as increased total bilirubin, skin rash, peripheral neuropathy, and alopecia (P Conclusions Our study reported for the first time, that in treating breast cancer with neoadjuvant chemotherapy, EGFR SNP rs1468727 is associated with treatment response, and that both rs1468727 and rs845552 are related to treatment-derived toxicity. In addition, we also found that rs845552 may be related to the status of HER2 in breast cancer.

As one of the lifestyle interventions, respiratory training has a positive role in rehabilitation. This study summarizes the mechanism, intervention technique, effects and problems of respiratory training in patients with cardiovascular disease, so as to provide reference for the developing of the best respiratory training program of the clinicians.

Objective. To investigate the improvement of cognitive function and inflammatory response in perimenopausal patients with MCI by kidney-tonifying, blood-activating, and mind-nourishing. Methods. 80 perimenopausal patients with MCI who met the diagnostic criteria were divided into a therapy group (n = 40) and a control group (n = 40) according to the treatment method. The control group was given nimodipine (Bayer Pharmaceuticals) 30 mg, 3 times/day orally, while the therapy group was given a decoction of self-prepared Ningshen prescription on the top of the control group (glossy privet fruit, mulberry, aizoon stonecrop, dan-shen root, tuber fleeceflower stem, cyperus rotundus, citron). Patients in the 2 groups were assessed on the MocA scale, ADL scale, and TCM symptom score before and after 2 months of treatment, respectively, to observe whether there was any change in the scale scores and in the levels of inflammatory factors (hs-CRP, Hcy, and IL-1β) Pre- and posttherapy in the 2 groups. Observe the improvement of clinical symptoms and their safety in both groups (liver and kidney function indicators such as ALT, AST and Cr, dizziness, headache, decrease in blood pressure, flushing, and gastrointestinal reactions). Results. The efficacy of the therapy group was better than that of the control group; the MocA scale and ADL scale scores improved and the TCM symptom score decreased in both groups posttherapy, with the MocA scale and ADL scale scores improving more and the TCM symptom score decreasing more in the therapy group compared with the control group during the same period ( p < 0.05 ). The serum levels of hs-CRP, Hcy, and IL-1β decreased in both groups posttherapy, with the serum levels of hs-CRP, Hcy, and IL-1β decreasing more in the therapy group compared to the control group during the same period ( p < 0.05 ). The difference in adverse events between the two groups was not statistically significant when compared by a chi-square test ( p > 0.05 ). The differences in ALT, AST, and Cr levels between the control group and the treatment group before and after treatment were not significant ( p > 0.05 ). Conclusion. Ning Shen prescription can effectively prevent the continued development of cognitive dysfunction in perimenopausal patients with MCI, delay its natural course, and can improve the patients’ ability to perform daily activities and improve their TCM symptoms.

Recombinant apyrase (AZD3366) increases adenosine production and ticagrelor inhibits adenosine reuptake. We investigated whether intravenous AZD3366 before reperfusion reduces myocardial infarct size (IS) and whether AZD3366 and ticagrelor have additive effects.Sprague-Dawley rats underwent 30 min ischemia. At 25 min of ischemia, animals received intravenous AZD3366 or vehicle. Additional animals received intravenous CGS15943 (an adenosine receptor blocker) or intraperitoneal ticagrelor. At 24 h reperfusion, IS was assessed by triphenyltetrazolium chloride. Other rats were subjected to 30 min ischemia followed by 1 h or 24 h reperfusion. Myocardial samples were assessed for adenosine levels, RT-PCR, and immunoblotting.AZD3366 and ticagrelor reduced IS. The protective effect was blocked by CGS15943. The effect of AZD3366 + ticagrelor was significantly greater than AZD3366. One hour after infarction, myocardial adenosine levels significantly increased with AZD3366, but not with ticagrelor. In contrast, 24 h after infarction, adenosine levels were equally increased by AZD3366 and ticagrelor, and levels were higher in the AZD3366 + ticagrelor group. One hour after reperfusion, AZD3366 and ticagrelor equally attenuated the increase in interleukin-15 (an early inflammatory marker after ischemic cell death) levels, and their combined effects were additive. AZD3366, but not ticagrelor, significantly attenuated the increase in RIP1, RIP3, and P-MLKL (markers of necroptosis) 1 h after reperfusion. AZD3366, but not ticagrelor, significantly attenuated the increase in IL-6 and GSDMD-N (markers of pyroptosis) 1 h after reperfusion. At 24 h of reperfusion, both agents equally attenuated the increase in these markers, and their effects were additive.AZD3366 attenuated inflammation, necrosis, necroptosis, and pyroptosis and limited IS. The effects of AZD3366 and ticagrelor were additive.

Purpose: Despite accumulating evidence on dual blockade of HER2 for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy. Patients and Methods: The phase II NeoATP trial included female patients with histologically confirmed stage IIA to IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel–cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathologic complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis, and safety. Results: Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor–negative and –positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00%, respectively, for those with and without PIK3CA mutation (P = 0.958). The most frequently reported Grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%), and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction 10 points drop from baseline to before surgery was reported. Conclusions: The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.

Although the emerging of immunotherapy conferred a new landscape of gastric cancer (GC) treatment, its response rate was of significant individual differences. Insight into GC immune microenviroment may contribute to breaking the dilemma. To this end, the enrichment score of NF

A number of criteria have been developed to aid with the diagnosis of occlusion myocardial infarction (OMI) in patients with left bundle branch block (LBBB) and ventricular paced rhythms (VPR). The current guidelines do not provide clear preference for any specific ECG criteria in LBBB and paced rhythm patients. This review delineates the difficulties of electrocardiographic diagnosis of OMI in both LBBB and VPR patients. We describe the original Sgarbossa and the newer criteria and their diagnostic performances. We highlight the expected changes of newer pacing modalities and how they may interfere with the electrocardiographic diagnosis of OMI. We recommend utilizing the Cai et al. algorithm, which combines clinical assessment with the Smith Modified Sgarbossa ECG criteria, for both LBBB and right ventricular pacing patients with suspected OMI. There is limited data concerning ECG changes of OMI in patients with the newer pacing modalities, such as biventricular, His-bundle, or left bundle branch pacing.

Background SGLT2 inhibitors increase plasma ketone concentrations. It has been suggested that insulinopenia, along with an increase in the counter-regulatory hormones epinephrine, corticosterone, glucagon and growth hormone, can induce ketoacidosis, especially in type-1 diabetes (T1DM). Dehydration precipitates SGLT2 inhibitor-induced ketoacidosis in type-2 diabetes. We studied the effects of dapagliflozin and water deprivation on the development of ketoacidosis and the associated signaling pathways in T1DM mice. Methods C57BL/6 mice were fed a high-fat diet. After 7 days, some mice received intraperitoneal injection of streptozocin + alloxan (STZ/ALX). The treatment groups were control + water at lib; control + dapagloflozin + water at lib; control + dapagloflozin + water deprivation; STZ/ALX + water at lib; STZ/ALX + water deprivation; STZ/ALX + dapagloflozin + water at lib; STZ/ALX + dapagloflozin + water deprivation. Dapagliflozin was given for 7 days. In the morning of day 18, food was removed, and water was removed in the water deprivation groups. ELISA, rt-PCR, and immunoblotting were used to assess blood, heart, liver, white and brown adipose tissues. Results The T1DM mice had ketoacidosis even without water deprivation. Water deprivation increased plasma levels of β-hydroxybutyrate, acetoacetate, corticosterone, and epinephrine and reduced the levels of adiponectin in T1DM mice. Interleukin (IL) 1β, IL-6, IL-8, and TNFα were also increased in the T1DM mice with water deprivation. Dapagliflozin attenuated the changes in the T1DM mice without and with water deprivation. Likewise, water deprivation increased the activation of the inflammasome in the heart, liver, and white fat of the T1DM mice and dapagliflozin attenuated these changes. Dapagliflozin reduced the mRNA levels of glucagon receptors in the liver and the increase in GPR109a in white and brown fat. In the liver, dapagliflozin increased AMPK phosphorylation, and attenuated the phosphorylation of TBK1 and the activation of NFκB. Conclusions Dapagliflozin reduced ketone body levels and attenuated the activation of NFκB and the activation of the inflammasome in T1DM mice with ketoacidosis.

BACKGROUND: Neoadjuvant chemotherapy is usually used for treating locally advanced breast cancer. However, not all patients achieve pathologic complete response (pCR). In this study, we selected two epidermal growth factor receptor (EGFR) single nucleotide polymorphism (SNP) sites, rs1468727 and rs845552, to investigate the association between the genotypes and the response and toxicity derived from neoadjuvant chemotherapy for breast cancer. METHODS: All participants took part in clinical trial SHPD001 and SHPD002. For univariate analyses, the association between SNP and pCR or toxicity was analyzed by Chi-square or Fisher’s exact test. For multivariate analyses, logistic regression was used instead. RESULTS: In all, one hundred and eighteen patients were enrolled. We found that the frequency of AA genotype in rs845552 was higher than that of other genotypes in HER2-positive breast cancer (AA vs. AG, P=0.039; AA vs. GG, P=0.005; AA vs. AG+GG, P=0.009). Multivariate logistic regression analyses showed that pCR was more difficult to be achieved in patients with a CT genotype in rs1468727 compared to those with a CC+TT genotype (OR =0.288, 95% CI: 0.109–0.762, P=0.012) or a CC genotype (OR =0.254, 95% CI: 0.076–0.849, P=0.026). Moreover, we demonstrated that both rs1468727 and rs845552 were associated with toxicity that results in complications such as increased total bilirubin, skin rash, peripheral neuropathy, and alopecia (P

Ticagrelor, a P2Y12 receptor antagonist, and dapagliflozin, a sodium–glucose-cotransporter-2 inhibitor, suppress the activation of the NLRP3 inflammasome. The anti-inflammatory effects of dapagliflozin depend on AMPK activation. Also, ticagrelor can activate AMPK. We assessed whether dapagliflozin and ticagrelor have additive effects in attenuating the progression of diabetic cardiomyopathy in T2DM mice. Eight-week-old BTBR and wild-type mice received no drug, dapagliflozin (1.5 mg/kg/day), ticagrelor (100 mg/kg/day), or their combination for 12 weeks. Heart function was evaluated by echocardiography and heart tissue samples were assessed for fibrosis, apoptosis, qRT-PCR, and immunoblotting. Both drugs attenuated the progression of diabetic cardiomyopathy as evident by improvements in left ventricular end-systolic and end-diastolic volumes and left ventricular ejection fraction, which were further improved by the combination. Both drugs attenuated the activation of the NOD-like receptor 3 (NLRP3) inflammasome and fibrosis. The effect of the combination was significantly greater than each drug alone on myocardial tissue necrotic factorα (TNFα) and interleukin-6 (IL-6) levels, suggesting additive effects. The combination had also a greater effect on ASC, collagen-1, and collagen-3 mRNA levels than each drug alone. While both drugs activated adenosine mono-phosphate kinase (AMPK), only dapagliflozin activated mTOR and increased RICTOR levels. Moreover, only dapagliflozin decreased myocardial BNP and Caspase-1 mRNA levels, and the effects of dapagliflozin on NLRP3 and collagen-3 mRNA levels were significantly greater than those of ticagrelor. Both dapagliflozin and ticagrelor attenuated the progression of diabetic cardiomyopathy, the activation of the NLRP3 inflammasome, and fibrosis in BTBR mice with additive effects of the combination. While both dapagliflozin and ticagrelor activated AMPK, only dapagliflozin activated mTOR complex 2 (mTORC2) in hearts of BTBR mice.

We assessed whether the SGLT-2 inhibitor dapagliflozin (Dapa) attenuates the upregulation of the cardiac Na+/H+ exchanger (NHE-1) in vitro in mouse cardiofibroblasts stimulated with lipopolysaccharides (LPS) and whether this effect is dependent on adenosine monophosphate kinase (AMPK) activation. Mouse cardiofibroblasts were exposed for 16 h to Dapa (0.4 μM), AMPK activator (A769662 (10 μM)), AMPK inhibitor (compound C (CC) (10 μM)), an SGLT-1 and SGLT-2 inhibitor (phlorizin (PZ) (100 μM)), Dapa+CC, or Dapa+PZ, and then stimulated with LPS (10 ng/ml) for 3 h. NHE-1 mRNA levels were assessed by rt-PCR and total AMPK, phosphorylated-AMPK (P-AMPK), NHE-1, and heat shock protein-70 (Hsp70) protein levels in the whole cell lysate by immunoblotting. In addition, NHE-1 protein levels attached to Hsp70 were assessed by immunoprecipitation. Exposure to LPS significantly reduced P-AMPK levels in the cardiofibroblasts. A769662 and Dapa equally increased P-AMPK. The effect was blocked by CC. Phlorizin had no effect on P-AMPK. LPS exposure significantly increased NHE-1 mRNA levels. Both Dapa and A769662 equally attenuated this increase. The effect of Dapa was blocked with CC. Interestingly, none of the compounds significantly affected NHE-1 and Hsp70 protein levels in the whole cell lysate. However, LPS significantly increased the concentration of NHE-1 attached to Hsp70. Both Dapa and A69662 attenuated this association and CC blocked the effect of Dapa. Again, phlorizin had no effect and did not alter the effect of Dapa. Dapa increases P-AMPK in cardiofibroblasts exposed to LPS. Dapa attenuated the increase in NHE-1 mRNA and the association between NHE-1 and Hsp70. This effect was dependent on AMPK.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 inhibitors (DPP4I) are used to treat type 2 diabetes (T2DM). DPP4 inhibitors (DPP4) attenuate Nlrp3 inflammasome activation in the kidney. SGLT2 inhibition reduces inflammation and attenuates the progression of diabetic nephropathy (DN). The effects of dapagliflozin (Dapa) on the activation of the Nlrp3 inflammasome and the combined effect of SGLT2 and DPP4 on T2DM-induced inflammasome activation and progression of DN have not been previously studied. We assessed whether Dapa attenuates the inflammasome activation and progression of DN in T2DM mice and whether these effects can be augmented by adding DPP4I saxagliptin (Saxa). METHODS AND RESULTS: Male BTBR ob/ob and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Serum BUN in the WT mice was 16.9 ± 0.8 mg/dl. It increased to 55.7 ± 2.8 mg/dl in the BTBR mice. Dapa alone reduced BUN to 31.4 ± 1.2 mg/dl. A greater effect was seen in the Dapa+Saxa combination (24.8 ± 0.8 mg/dl). Serum creatinine was 0.16 ± 0.02 and 1.01 ± 0.04 mg/dl in the WT and BTBR mice, respectively. Dapa and Dapa+Saxa attenuated the increase of creatinine to 0.65 ± 0.02 and 0.40 ± 0.03 mg/dl, respectively. Serum cystatin C was elevated in the BTBR mice (3.9 ± 0.1 vs. 0.6 ± 0.2 ng/ml) as compared to WT mice. Dapa (2.4 ± 0.1) and Dapa+Saxa (1.4 ± 0.1) attenuated this increase. Kidney weight was higher in the BTBR than that of WT mice. Dapa reduced the kidney/body weight ratio in the BTBR mice. Dapa+Saxa tended to have greater effect, but the difference was not significant. mRNA levels of NALP3, ASC, IL-1β, IL-6, caspase-1, TNF-α, collagen-1, and collagen-3 significantly increased in the kidneys of the BTBR compared to the WT mice. Dapa alone and to a greater extent, Dapa+Saxa, attenuated the activation of the inflammasome. Yet, the combination did not result in greater attenuation of the collagen-1 and collagen-3 mRNA levels. The P-AMPK/total AMPK ratio was lower in the BTBR mice than in the WT mice. Dapa and Dapa+ Saxa equally increased the ratio.Dapa attenuates T2DM-induced activation of the inflammasome and progression of DN in BTBR ob/ob mice. Adding Saxa to Dapa augmented attenuation of the inflammasome, but had no significant effect on kidney weight or collagen-1 and collagen-3 mRNA levels. Future clinical trials are necessary to study the effect of combined SGLT2 inhibitor and incretin therapy on renal outcomes in patients with T2DM.

We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia-reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1β, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1β, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1β, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.

Reusable spacecraft can significantly reduce the cost of space travel, while evaluation of the structural health of the craft between flights becomes one of the key issues. A digital twin framework is proposed in this paper to track the life of spacecraft structures. A digital twin is a digital representation of an engineering system. It can simulate, monitor, diagnose, predict states and optimize operations of the real engineering system in real time. The proposed framework can be divided into offline and online stages. It has the functions of diagnosis, model updating, performance evaluation and data storage. To demonstrate the prognosis and decision support capabilities of the framework, a numerical example considering fatigue crack growth in a load-bearing frame is carried out. The method of manufactured solutions is employed for validation. Information entropy and relative entropy are used for measuring the uncertainties in crack length prediction. The results show that through the framework, crack growth model can be updated to have a lower uncertainty. Future crack growth and reusable life can be predicted more accurately using the improved model. With the structural life of the spacecraft quantified by the framework, mission success rates for repeated flights can be maximized at a lower cost.

We assessed whether the SGLT-2 inhibitor dapagliflozin (Dapa) attenuates the upregulation of the cardiac NaMouse cardiofibroblasts were exposed for 16 h to Dapa (0.4 μM), AMPK activator (A769662 (10 μM)), AMPK inhibitor (compound C (CC) (10 μM)), an SGLT-1 and SGLT-2 inhibitor (phlorizin (PZ) (100 μM)), Dapa+CC, or Dapa+PZ, and then stimulated with LPS (10 ng/ml) for 3 h. NHE-1 mRNA levels were assessed by rt-PCR and total AMPK, phosphorylated-AMPK (P-AMPK), NHE-1, and heat shock protein-70 (Hsp70) protein levels in the whole cell lysate by immunoblotting. In addition, NHE-1 protein levels attached to Hsp70 were assessed by immunoprecipitation.Exposure to LPS significantly reduced P-AMPK levels in the cardiofibroblasts. A769662 and Dapa equally increased P-AMPK. The effect was blocked by CC. Phlorizin had no effect on P-AMPK. LPS exposure significantly increased NHE-1 mRNA levels. Both Dapa and A769662 equally attenuated this increase. The effect of Dapa was blocked with CC. Interestingly, none of the compounds significantly affected NHE-1 and Hsp70 protein levels in the whole cell lysate. However, LPS significantly increased the concentration of NHE-1 attached to Hsp70. Both Dapa and A69662 attenuated this association and CC blocked the effect of Dapa. Again, phlorizin had no effect and did not alter the effect of Dapa.Dapa increases P-AMPK in cardiofibroblasts exposed to LPS. Dapa attenuated the increase in NHE-1 mRNA and the association between NHE-1 and Hsp70. This effect was dependent on AMPK.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to exert benefit on cardiac outcomes. In this review, we provide updates on available clinical data, studies on potential mechanisms for the CV effects, as well as discuss potential clinical implications of these new findings. Since the publications of the EMPA-REG and CANVAS trials, large multi-national cohort studies have further shown the cardioprotective effects of SGLT2i. Moreover, new studies examining SGLT2i action on sodium-hydrogen exchanger proteins in both the heart and the kidney, on myocardial energetics and impact on inflammation and atherosclerosis continue to shed light on the multitude of pleotropic effects of these agents. Though more data is needed to substantiate the safety and efficacy, SGLT2i should be considered as a valuable therapy to help reduce CV risk in patients with diabetes. Ultimately, SGLT2i may have utility in preventing progression to diabetes or providing CV protection in patients who do not have diabetes.

Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials.

Objective— In addition to P2Y 12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. Approach and Results— Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks. (1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P P 4 levels. Conclusions— Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect.

The aim of this study is to examine the cardioprotective properties of Glucagon-like peptide-1 receptor agonist, a class of antihyperglycemic therapy, via meta-analysis of four recently published cardiovascular outcomes trials. Meta-analysis was performed pooling data from the ELIXA, LEADER, SUSTAIN-6 and EXSCEL trials. A random effects model was used to generate risk ratio with 95% confidence interval for cardiovascular and safety outcomes. A total of 33,457 patients were included in the meta-analysis. Based on the study, GLP-1R agonists significantly reduced all-cause mortality (RR 0.89; 95% CI 0.82 to 0.96) and cardiovascular mortality (RR 0.88; 95% CI 0.80 to 0.97) when compared to placebo. When long-acting agents were analyzed alone, reduction in major adverse cardiac events (RR 0.88; 95% CI 0.81 to 0.97) and non-fatal strokes (RR 0.87; 95% CI 0.76 to 0.99) also showed significance. Overall, GLP-1R agonists appear to have cardioprotective properties likely via modification of metabolic parameters such as glycemic control, weight loss, and improvement in blood pressure. Additional studies are warranted to compare cardiovascular outcomes among the different agents.

We explored the effects of rosuvastatin, aspirin, ticagrelor, and clopidogrel, alone or in combinations on the progression of atherosclerosis and inflammasome activation in diabetic mice. Statins and ticagrelor increase the production of 15-epi-lipoxin A4 via cyclooxygenase-2. Aspirin alone increases 15-epi-lipoxin A4, but when combined with statins, cyclooxygenase-2 is completely blocked. ApoE−/−/db+/db+ double-knockout mice received rosuvastatin (5 mg/kg/day), aspirin (25 mg/kg/day), ticagrelor (300 mg/kg/day), clopidogrel (75 mg/kg/day), or their combination for 14 weeks. Serum 15-epi-lipoxin A4 levels and aortic wall cholesterol content, IL-1β, IL-6, and TNF-α levels, and plaque area were assessed. Aspirin, ticagrelor, and rosuvastatin increased 15-epi-lipoxin A4 levels. The combination of rosuvastatin + ticagrelor provided an additive effect. Aspirin attenuated the effect of both ticagrelor and rosuvastatin. Aspirin, ticagrelor, and rosuvastatin reduced the area of the atherosclerotic plaque. The combination of ticagrelor + rosuvastatin provided additive effects. There was a negative interaction when aspirin was combined with ticagrelor or rosuvastatin. Aspirin, ticagrelor, and rosuvastatin decreased serum IL-1β and IL-6 levels. There was no interaction between aspirin and ticagrelor or aspirin and rosuvastatin, whereas combining rosuvastatin and ticagrelor provided an additive effect. Aspirin, ticagrelor, and rosuvastatin all decreased TNF-α levels. Aspirin attenuated the effect of both ticagrelor and rosuvastatin, and there was no additive effect of combining ticagrelor + rosuvastatin. We found an intricate interaction between aspirin, ticagrelor, and rosuvastatin, as aspirin reduced both ticagrelor and rosuvastatin ability to ameliorate inflammation and atherosclerosis. In contrast, we found additive effects when ticagrelor and rosuvastatin were combined.

Background/Aims: Chronic heavy alcohol consumption may result in alcoholic cardiomyopathy. This study was designed to screen differentially expressed microRNAs and circular RNAs in heart tissue of mice with alcoholic cardiomyopathy to reveal the underlying molecular mechanism. Methods: Having established a murine alcoholic cardiomyopathy model, we screened differentially expressed microRNAs and circular RNAs in three heart samples from the alcohol-treated and control groups by high-throughput microarray analysis. We analyzed the function and biological signaling pathways of differentially expressed non-coding RNAs closely related to alcoholic cardiomyopathy using bioinformatics software to identify some mRNAs and their biological signaling pathways closely related to alcoholic cardiomyopathy. Results: Nineteen microRNAs and 265 circular RNAs were differentially expressed in the alcohol-treated group compared with the control group. After analyzing gene function and signaling pathways by bioinformatics software, we found that the differentially expressed mRNAs were associated with carbohydrate metabolism. Conclusions: Chronic alcohol consumption can change the non-coding RNA profile of heart tissue, which is closely related to the pathological mechanisms of alcoholic cardiomyopathy.

We assessed whether (1) dapagliflozin (Dapa, an SGLT2-inhibitor) attenuates the deterioration of heart function Nlrp3 and inflammasome activation in diabetic mice. (2) The effects can be augmented with saxagliptin (Saxa), a DDP4-inhibitor. (3) Dapa effect is possibly SGLT2-independent on cardiofibroblasts in vitro. Type 2 diabetic (BTBR ob/ob) and wild-type (WT) mice received vehicle, Dapa, or Dapa+Saxa for 8 weeks. Glucose tolerance test and echocardiogram were performed. Cardiofibroblasts from WT and BTBR hearts were incubated with Dapa and exposed to LPS. Left ventricular ejection fraction (LVEF) was 81 ± 1% in the WT and 53 ± 1% in the T2D-cont mice. Dapa and Dapa+Saxa improved LVEF to 68 ± 1 and 74.6 ± 1% in the BTBR mice (p

Objective— In a phase III clinical trial (PLATelet inhibition and patient Outcomes, PLATO), ticagrelor provided better clinical outcomes than clopidogrel in patients with acute coronary syndromes. In addition to P2Y 12 -receptor antagonism, ticagrelor prevents cell uptake of adenosine and has proven able to augment adenosine effects. Adenosine protects the heart against ischemia–reperfusion injury. We compared the effects of clopidogrel and ticagrelor on myocardial infarct size (IS). Approach and Results— Rats received oral ticagrelor (0, 75, 150, or 300 mg/kg/d) or clopidogrel (30 or 90 mg/kg/d) for 7 days and underwent 30-minute coronary artery ligation and 24-hour reperfusion. Area at risk was assessed by blue dye and IS by 2,3,5-triphenyl-tetrazolium-chloride. Cyclooxygenase-2 (COX2) enzyme activity was assessed by ELISA and expression by real-time polymerase chain reaction. Mechanism responsible was explored using adenosine-receptor antagonist (CGS15943, an A 2A /A 1 antagonist) or cyclooxygenase inhibition by either aspirin (5, 10, or 25 mg/kg) or specific cyclooxygenase-1 (SC560) or COX2 (SC5815) inhibitors. Ticagrelor, dose-dependently, reduced IS, whereas clopidogrel had no effect. Adenosine-receptor antagonism blocked the ticagrelor effect and COX2 inhibition by SC5815, or high-dose aspirin attenuated the IS-limiting effect of ticagrelor, whereas cyclooxygenase-1 inhibition or low-dose aspirin had no effect. Ticagrelor, but not clopidogrel, upregulated COX2 expression and activity. Also this effect was blocked by adenosine-receptor antagonism. Ticagrelor, but not clopidogrel, increased Akt and endothelial nitric oxide synthase phosphorylation. Conclusions— Ticagrelor, but not clopidogrel, reduces myocardial IS. The protective effect of ticagrelor was dependent on adenosine-receptor activation with downstream upregulation of endothelial nitric oxide synthase and COX2 activity.

Both HIF1α (hypoxia-inducible factor alpha) and VEGF (vascular endothelial growth factor) are implicated in the pathogenesis of diabetic retinopathy (DR). Competitive endogenous RNAs (ceRNAs) are messenger RNA (mRNA) molecules that affect each other expression through competition for their shared microRNAs (miRNA). However, little is known about the role of ceRNAs in DR. We assess whether the expression of HIF1α and VEGF in DR is interdependent through sequestration of common miRNAs. We used bioinformatics to identify potential miRNAs that affect both genes and validated the interdependence of the genes by silencing or overexpression of the genes and assessed the luciferase-HIF1α 3'UTR activity. We found that HIF1α and VEGF are targeted by 12 common miRNAs. Silencing either HIF1α or VEGF increased the availabilities of the shared miRNAs, therefore suppressed the luciferase-HIF1α 3'UTR activity, whereas over-expressing HIF1α or VEGF increased the luciferase activity. HIF1α was co-expressed with VEGF in-vivo and in-vitro in DR models. Silencing HIF1α transcripts resulted in a significant reduction in VEGF protein levels and vice versa. This interdependence was miRNA- and 3'UTR-dependent, as silencing Dicer abolished the interdependence. Over-expression of a common miRNA (miR-106a) significantly reduced the expression of HIF1α and VEGF and prevented high glucose-induced increased permeability. There is a cross-talk between HIF1α and VEGF through interactions with their common miRNAs. miRNA based therapy can affect the expression of both HIF1α and VEGF and may represent a therapeutic potential for the treatment of DR.

Nebivolol is a selective β1-blocker with nitric oxide–enhancing effects. MicroRNAs are small noncoding RNA molecules that downregulate gene expression. We compared the effects of nebivolol and atenolol, a first generation β1-selective blocker, on left ventricular hypertrophy, fibrosis, and function and microRNA expression in a rodent model of hypertension. Dahl salt-sensitive rats received either low-salt chow (control) or AIN-76A high-salt (8% NaCl) diet and randomized to vehicle (high-salt), nebivolol (20 mg/kg per day), or atenolol (50 mg/kg per day) for 8 weeks. High-salt induced left ventricular hypertrophy and fibrosis and decreased the expression of miR-27a, -29a, and -133a. Nebovolol attenuated deterioration of left ventricular systolic function, remodeling, and fibrosis more than atenolol, despite similar effects on heart rate and blood pressure. Nebivolol, but not atenolol, prevented the decrease in miR-27a and -29a induced by high-salt. Nebivolol and atenolol equally attenuated the decrease in miR-133a. In vitro overexpression of miR-27a,-29a, and -133a inhibited cardiomyocyte hypertrophy and reduced collagen expression. Both miR-27a and -29a target Sp1, and miR-133a targets Cdc42. Pharmacological inhibition of Sp1 and Cdc42 decreased myocardial fibrosis and hypertrophy. Our data support a differential microRNAs expression profile in salt-induced hypertension. Nebivolol substantially attenuated cardiac remodeling, hypertrophy, and fibrosis more than atenolol. These effects are related to attenuation of the hypertension-induced decrease in miR-27a and -29a (with a subsequent decrease in Sp1 expression) and miR-133a (with a subsequent decrease in Cdc42).