Decreased plasma miR-140-3p is associated with coronary artery disease.

Background: Although many circulating miRNAs (c-miRNAs) are associated with coronary artery disease (CAD), they are far from being the biomarker for CAD diagnosis or risk prediction. Therefore, novel c-miRNAs discovery and validation are still required, especially evaluating their prediction capacity. Objectives: Identify novel CAD-related c-miRNAs and evaluate its risk prediction capacity for CAD. Methods: miRNAs associated with CAD were preliminarily investigated in three paired samples representing pre-CAD stage and CAD stage of three female individuals using the Applied Biosystems miRNA TaqMan® Low-Density Array (TLDA). Then, the candidate miRNAs were further verified in an independent case-control study including 129 CAD patients and 76 controls, and their potential practical value in prediction for CAD was evaluated using a machine learning (ML) algorithm. The accuracy of classification and prediction was assessed with the area under the receiver operating characteristic curve (AUC). Results: TLDA analysis shows that miR-140-3p decreased significantly in CAD-stage (FC = -3.01, P = 0.007). Further study shows that miR-140-3p was significantly lower in CAD group [1.26 (0.68, 2.01)] than in control group [2.07 (1.19, 3.21)] (P < 0.001) and independently associated with CAD (P < 0.001). The addition of miR-140-3p to the variables including smoking history, HDL-c, and APOA1 improved the accuracy of classification by logistic regression and of prediction for CAD by ML models. The ML models built with miR-140-3p and HDL-c, respectively, had a similar prediction accuracy. The feature importance of miR-140-3p and HDL-c in the ML models was also similar. Decision curve analysis showed that miR-140-3p and HDL-c had almost identical net benefits. Conclusion: Reduced levels of miR-140-3p is linked to CAD, and it is possible to use the plasma level of miR-140-3p as a means of evaluating the risk of CAD.

Corrigendum: Nitazoxanide, an antiprotozoal drug, reduces bone loss in ovariectomized mice by inhibition of RANKL-induced osteoclastogenesis.

[This corrects the article DOI: 10.3389/fphar.2021.781640.].

Comprehensive transcriptomics and metabolomics analyses reveal that hyperhomocysteinemia is a high risk factor for coronary artery disease in a chinese obese population aged 40-65: a prospective cross-sectional study.

BACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD. METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model. RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables. CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.

Apoe-knockout induces strong vascular oxidative stress and significant changes in the gene expression profile related to the pathways implicated in redox, inflammation, and endothelial function.

Apolipoprotein E (APOE) was recognized as a key regulator of lipid metabolism, which prompted the Apoe-knockout (Apoe-/-) mouse to be the most widely used atherosclerotic model. However, with more and more important physiological roles of APOE being revealed, it is necessary to reacquaint its comprehensive function in the aorta. In this study, we aimed to reveal how Apoe-knockout impacts the gene pathways and phenotypes in the aorta of mice. We performed transcriptome sequencing to acquire the gene expression profile (GEP) for C57BL/6J and Apoe-/- mouse aorta, and used enrichment analysis to reveal the signal pathways enriched for differentially expressed genes (DEGs). In addition, we used immunofluorescence and ELISA to detect the phenotypic differences of vascular tissues and plasma in the two-group mice. Apoe-knockout resulted in significant changes in the expression of 538 genes, among which about 75% were up-regulated and 134 genes were altered more than twice. In addition to the lipid metabolism pathways, DEGs were also mainly enriched in the pathways implicated in endothelial cell proliferation, migration of epithelial cells, immune regulatory, and redox. GSEA shows that the up-regulated genes are mainly enriched in 'immune regulation pathways' and 'signal regulation' pathways, while the down-regulated genes are enriched in lipid metabolism pathways, 'regulation_of_nitric_oxide_synthase_activity' and the pathways involved in redox homeostasis, including 'monooxygenase regulation', 'peroxisomes' and 'oxygen binding'. A significant increase of reactive oxygen species and a remarkable reduction of GSH/GSSG ratio were respectively observed in the vascular tissues and plasma of Apoe-/- mice. In addition, endothelin-1 significantly increased in the vascular tissue and the plasma of Apoe-/- mice. Taken together, our results suggest that besides functioning in lipid metabolism, APOE may be an important signal regulator that mediates the expression of the genes related to the pathways involved in redox, inflammation, and endothelial function. Apoe-knockout-induced strong vascular oxidative stress is also the key factor contributing to atherosclerosis.

Estimation of critical closing pressure using intravascular blood pressure of the common carotid artery.

PURPOSE: Radial artery, femoral artery, and aortic arterial blood pressures (ABPs) can be used to estimate cerebral critical closing pressure (CrCP) and resistance-area product (RAP). However, the use of the common carotid artery (CCA) intravascular blood pressure to estimate CrCP is unclear. Thus, using continuous ABP monitoring, we compared the CrCP and RAP estimated from CCA measurements with the corresponding values acquired from the radial artery. METHODS: In this retrospective cross-sectional study, we analyzed CrCP and RAP estimations from 21 patients with normal cerebral blood vessels between July 23, 2010, and February 9, 2011, using linear regression of the cerebral blood flow velocity-ABP relationship. RESULTS: Bland-Altman analysis showed that the average differences (95% limits of agreement) between the radial artery and the left CCA were -6.3 (-53.1 - 40.6) mmHg and -0.08 (-0.41 - 0.25) mmHg s cm-1 for CrCP and RAP, respectively. CONCLUSIONS: The CrCP and RAP estimated from the CCA measurements are consistent with the corresponding values obtained from the radial artery.

Effect of sex on the association between arterial partial pressure of oxygen and in-hospital mortality in ICU patients with cardiogenic shock: a retrospective cohort study.

Background: Maintaining tissue perfusion and oxygen supply are essential for cardiogenic shock (CS) treatment. Sex has been reported to be associated with mortality and oxygen use in patients with CS. Males and females respond differently to hypoxia. We designed this cohort study to evaluate the effects of sex on the association between the arterial partial pressure of oxygen (PaO2) and in-hospital mortality. Methods: We used the Medical Information Mart for Intensive Care (MIMIC) IV database for this cohort study. The outcome was in-hospital mortality. The relationship between the PaO2 and in-hospital mortality was compared with sex (via an interaction test) using multivariable Cox regression models. Presence of interaction between PaO2 and sex was tested by using inter interaction terms. Results: A total of 1,772 patients with CS were enrolled in this study. The association between PaO2 and in-hospital mortality appeared to differ between males and females [hazard ratio (HR): 0.997, 95% confidence interval (CI): 0.995-0.999 vs. HR: 1.002, 95% CI: 0.999-1.003, P for interaction =0.002]. We repeated the analyses, based on different PaO2 category (PaO2 <60 mmHg; PaO2 60-100 mmHg; PaO2 >100 mmHg) and the results remained stable, P for interaction =0.008. Conclusions: Sex affects the relationship between PaO2 and in-hospital mortality in CS patients. Our findings may lead to the development of individualized therapies that focus on the use of different target oxygen partial pressures in different sexes to treat patients with CS.

Nitazoxanide, an Antiprotozoal Drug, Reduces Bone Loss in Ovariectomized Mice by Inhibition of RANKL-Induced Osteoclastogenesis.

Nitazoxanide (NTZ) is an FDA-approved anti-parasitic drug with broad-spectrum anti-infective, anti-inflammatory, and antineoplastic potential. However, its regulatory effects on osteoclastogenesis and the underlying mechanisms remain unclear. The present study found that NTZ potently inhibited osteoclast formation at the early stage of receptor activator of NF-κB ligand-induced osteoclastogenesis in a concentration-dependent manner at a non-growth inhibitory concentration. NTZ suppressed actin ring formation and decreased osteoclast marker gene expression, including TRAP, MMP9, and cathepsin K. NTZ significantly impaired the bone resorption activity of osteoclasts. In vivo, ovariectomized mice were treated with 50, 100 and 200 mg/kg/d NTZ for 3 months. NTZ (100 mg/kg/d) administration markedly reduced ovariectomy-induced bone loss by suppressing osteoclast activity. Mechanistically, osteoclastogenesis blockade elicited by NTZ resulted from inhibition of STAT3 phosphorylation, and reduction of the Ca2+ fluorescence intensity and NFATc1 expression. NTZ weakened the binding between STAT3 and the NFATc1 promoter region. Furthermore, enforced NFATc1 expression partly rescued the impaired osteoclast differentiation in NTZ-treated RAW264.7 cells. In summary, NTZ could inhibit osteoclastogenesis and bone loss through modulation of the receptor activator of NF-κB ligand-induced STAT3-NFATc1 signaling pathway, which might be a potential alternative treatment regimen against bone destruction-related diseases including osteoporosis.

Regulation of heavy metals accumulated by Acorus calamus L. in constructed wetland through different nitrogen forms.

Improving accumulation of heavy metals (HMs) by plants is an important pathway for constructed wetland (CW) to alleviate the environmental risks caused by their release. This study aims to regulate HMs (Cr, Ni, Cu, Zn, and Cd) accumulated by Acorus calamus L. in the sandy substrate CW with different nitrogen forms, including ammonia (NH4+), nitrate (NO3‾), and NH4+/NO3‾ (1:1) in synthetic tailwaters. In general, the removal efficiency of HMs by CW could reach 92.4% under the initial concentrations below 500 µg/L. Accumulation percentages of HMs in the shoots and roots of plants in CW with NH4+ and NH4+/NO3‾ influents increased by 52-395% and 15-101%, respectively, when compared with that of NO3‾ treatment. Influents with NH4+ promoted plant growth of Acorus calamus L. and metabolic functions, such as carbohydrate metabolism/amino acid metabolism, related to HMs mobilization of rhizosphere bacterial communities, which might induce more organic acids and amino acids secreted by plants and microbes during their metabolic processes. These are the main reasons for the enhancive mobilization of HMs from their precipitation fractions and their uptake by plants in CW with NH4+ treatments. Moreover, the enhancement of organics secreted from plants and microbes also led to the high denitrification efficiency and nitrogen removal in CW. Overall, this study could provide a feasible method for the enhancive accumulation of HMs by wetland plants via the regulation water treatment process to appropriately increase NH4+ for CW.

Aspirin-omitted dual antithrombotic therapy in non-valvular atrial fibrillation patients presenting with acute coronary syndrome or undergoing percutaneous coronary intervention: results of a meta-analysis.

AIMS: To investigate the effects of aspirin-omitted dual antithrombotic therapy (DAT) on myocardial infarction and stent thrombosis in non-valvular atrial fibrillation (NVAF) patients presenting with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: A systematic review and meta-analysis were performed using PubMed to search for randomized clinical trials comparing DAT with triple antithrombotic therapy (TAT) in this setting. Three trials involving 8845 patients were included (4802 and 4043 patients treated with DAT and TAT, respectively). There were no significant differences in all-cause death and stroke between the aspirin-omitted DAT group and TAT group. Otherwise, the incidence of myocardial infarction was significantly higher with aspirin-omitted DAT vs. TAT [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.02-1.63; P = 0.04; I2 = 0%]. Similarly, the incidence of stent thrombosis increased in patients treated with aspirin-omitted DAT vs. TAT (OR: 1.61, 95% CI: 1.02-2.53; P = 0.04; I2 = 0%). The occurrence of major bleeding and clinically relevant non-major bleeding events, as defined by the International Society on Thrombosis and Haemostasis, was significantly lower with aspirin-omitted DAT vs. TAT (OR: 0.61, 95% CI: 0.48-0.78; P = 0.02; I2 = 76%). Similar results were found according to the International Society on Thrombosis and Haemostasis major bleeding, Thrombolysis in Myocardial Infarction major or minor bleeding, and Thrombolysis in Myocardial Infarction major bleeding scales. CONCLUSION: Aspirin-omitted DAT reduces the occurrence of bleeding episodes, with a higher rate of myocardial infarction and stent thrombosis in NVAF patients presenting with ACS or undergoing PCI.

Efficacy and safety of oral pyrotinib in HER2 positive metastatic breast cancer: real-world practice / 北京大学学报(医学版)

OBJECTIVE@#Pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, showed promising antitumor activity and acceptable tolerability in phase II and phase III randomized clinical trials. We assessed the activity and safety of oral pyrotinib for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer patients in the real world.@*METHODS@#We retrospectively analyzed 72 HER2 positive metastatic breast cancer (MBC) patients who received oral pyrotinib based regimens at Beijing Cancer Hospital and other four hospitals (Peking University First Hospital, China-Japan Friendship Hospital, General Hospital of PLA, Peking University Third Hospital) from August 2018 to September 2019. Progression free survival (PFS), objective response rate (ORR), adverse events (AE) of pyrotinib were investigated.@*RESULTS@#Seventy-two patients with HER2 positive MBC were enrolled. The median age of the patients was 55 years (range: 32-79 years). Sixty-nine (95.8%) patients had received anti-HER2 treatment in the metastatic and/or (neo) adjuvant settings; 61 (84.7%) patients had received anti-HER2 treatments in the metastatic setting in terms of trastuzumab 56 (77.8%) patients, lapatinib 36 (50.0%) patients, and T-DM1 4 (5.6%) patients. Among these 72 patients who received oral pyrotinib based regimens, 62 (86.1%) patients received pyrotinib (±trastuzumab) in combination with chemotherapy, 6 (8.3%) patients received pyrotinib (± trastuzumab) in combination with endocrine therapy and 4 (5.6%) patients received pyrotinib (±trastuzumab). Sixty-five (90.3%) patients received 400 mg pyrotinib once daily as initial dose, and 7 (9.7%) patients received 320 mg. OBJECTIVE response and safety to pyrotinib based therapy were evaluable in all the 72 patients. One (1.4%) patient achieved complete response (CR), 18 (25.0%) patients achieved partial response (PR), 41 (56.9%) patients had stable disease (SD), and 12 (16.7%) patients had progressive disease (PD). The ORR (CR+PR) was 26.4% and the median PFS was 7.6 months (95%CI: 5.5-9.7 months). Among the 36 patients with prior lapatinib therapy, the median PFS was 7.9 months (95%CI: 4.1-11.7 months). Among the 15 patients with brain metastasis, the median PFS was 6.0 months (95%CI: 2.2-9.8 months). The main toxicities related to pyrotinib were diarrhea in 57 (79.2%) cases, and 48 (66.7%) cases with grade 1-2 as well as 9 (12.5%) cases with grade 3.@*CONCLUSION@#Pyrotinib based therapy is an effective treatment for patients with HER2 positive MBC, including patients with lapatinib treatment failure and brain metastasis, and the toxicities can be tolerated.

Wolbachia localization during Laodelphax striatellus embryogenesis.

Wolbachia are intracellular bacteria carried by thousands of arthropod species. The success of Wolbachia is due to efficient vertical transmission by the host maternal germline. Wolbachia's behavior during host oogenesis is well characterized, although their behavior during embryogenesis is unclear. Vertical transmission of Wolbachia wStri in the small brown planthopper, Laodelphax striatellus is extraordinarily efficient. To understand why, we investigated its localization and dynamics in L. striatellus embryos. Microscopic observations indicated that the Wolbachia were mainly localized at the anterior region of the embryo during early embryogenesis. The distribution of Wolbachia within the anterior region was established during oogenesis, and according to a phylogenetic analysis, may be due to intrinsic factors in Wolbachia. We observed that wStri migrated to the posterior part cells during late embryogenesis, in the region where gonads were formed. An expression profile of Wolbachia-infected host embryonic development genes revealed Ddx1 mRNAs, which is required for host viability and in the germ line, accumulated in the posterior region of 3-day-old embryos, while other development genes mRNAs were significantly more abundant in the posterior region of 6-day-old embryos. These genes thus appear to be associated with the localization of Wolbachia wStri in the anterior region, although their functions remain unclear. These results can explain Wolbachia wStri high prevalence in L. striatellus.

Vertical Transmission of Wolbachia Is Associated With Host Vitellogenin in Laodelphax striatellus.

Wolbachia in host germ lines are essential for their vertical transmission to the next generation. It is unclear how the regulation of host oocyte development influences Wolbachia location and the mechanistic basis of transmission. Here, we investigated whether vitellogenin influences Wolbachia transmission in Laodelphax striatellus. Wolbachia increased in density and spread from the anterior tropharium to developing oocytes as ovaries developed. Microscopic observations indicated that Wolbachia invaded ovarioles from the tropharium of its anterior side rather than the pedicel side. Wolbachia utilized the host Vg transovarial transportation system to enter the ovaries and were transmitted from the tropharium into the developing oocytes through nutritive cords. These observations were supported by knocking down the Vg transcript, in which low Wolbachia titers were detected in ovaries and fewer Wolbachia were transmitted into oocytes. Our findings establish a link between the Vg-related mode of transovarial transmission and efficient maternal transmission of Wolbachia.

miR-10a rejuvenates aged human mesenchymal stem cells and improves heart function after myocardial infarction through KLF4.

BACKGROUND: Aging is one of the key factors that regulate the function of human bone marrow mesenchymal stem cells (hBM-MSCs) and related changes in microRNA (miRNA) expression. However, data reported on aging-related miRNA changes in hBM-MSCs are limited. METHODS: We demonstrated previously that miR-10a is significantly decreased in aged hBM-MSCs and restoration of the miR-10a level attenuated cell senescence and increased the differentiation capacity of aged hBM-MSCs by repressing Krüpple-like factor 4 (KLF4). In the present study, miR-10a was overexpressed or KLF4 was downregulated in old hBM-MSCs by lentiviral transduction. The hypoxia-induced apoptosis, cell survival, and cell paracrine function of aged hBM-MSCs were investigated in vitro. In vivo, miR-10a-overexpressed or KLF4-downregulated old hBM-MSCs were implanted into infarcted mouse hearts after myocardial infarction (MI). The mouse cardiac function of cardiac angiogenesis was measured and cell survival of aged hBM-MSCs was investigated. RESULTS: Through lentivirus-mediated upregulation of miR-10a and downregulation of KLF4 in aged hBM-MSCs in vitro, we revealed that miR-10a decreased hypoxia-induced cell apoptosis and increased cell survival of aged hBM-MSCs by repressing the KLF4-BAX/BCL2 pathway. In vivo, transplantation of miR-10a-overexpressed aged hBM-MSCs promoted implanted stem cell survival and improved cardiac function after MI. Mechanistic studies revealed that overexpression of miR-10a in aged hBM-MSCs activated Akt and stimulated the expression of angiogenic factors, thus increasing angiogenesis in ischemic mouse hearts. CONCLUSIONS: miR-10a rejuvenated aged hBM-MSCs which improved angiogenesis and cardiac function in injured mouse hearts.

Resveratrol inhibits angiotensin II­induced proliferation of A7r5 cells and decreases neointimal hyperplasia by inhibiting the CaMKII­HDAC4 signaling pathway.

Resveratrol has been reported to inhibit vascular smooth muscle cell proliferation and neointimal hyperplasia following arterial injury; however, the underlying mechanisms remain unclear. The present study was designed to investigate the effects of resveratrol on angiotensin II (AngII)­induced proliferation of A7r5 cells and explore the molecular mechanisms responsible for the observed effects. Resveratrol inhibited cell proliferation and migration, and decreased the AngII­induced protein expression of α­smooth muscle actin (α­SMA), proliferating cell nuclear antigen (PCNA) and cyclin­dependent kinase 4 (CDK4). Resveratrol inhibited AngII­induced activation of intracellular Ca2+/calmodulin­dependent protein kinase II (CaMKII) and histone deacetylases 4 (HDAC4), as well as blocking AngII­induced cell cycle progression from the G0/G1 to S­phase. In vivo, 4­weeks of resveratrol treatment decreased the neointima area and the neointima/media area ratio in rats following carotid balloon injury. Resveratrol also inhibited the protein expression of total and phosphorylated CaMKII and HDAC4 in the injured arteries. In conclusion, the present study demonstrated that resveratrol attenuated AngII­induced cell proliferation and neointimal hyperplasia by inhibiting the CaMKII­HDAC4 signaling pathway. These findings suggest that resveratrol may potentially prevent arterial restenosis.

Association between HLA-DQB1 alleles and susceptibility to coronary artery disease in Southern Han Chinese.

Accumulated evidence indicates that polymorphisms in human leukocyte antigens (HLA) are associated with susceptibility to coronary artery disease (CAD). However, whether HLA-DQB1 alleles are correlated with susceptibility to CAD is unclear. In this study, significantly lower frequencies of the allele groups (DQB1*03:01:01G and DQB1*05:03:01G) and the genotypes (DQB1*03:01:01G/DQB1*03:01:01G and DQB1*03:01:01G/DQB1*05:03:01G) were observed in the CAD group compared with that in the controls. However, notably higher frequencies of DQB1*04:01:01G and genotype DQB1*05:01:01G/DQB1*03:01:01G were observed in the CAD patients than in the controls. Further analysis in subgroups showed that DQB1*03:01:01G was present at a significantly lower frequency in both female and male CAD patients compared with the corresponding controls; however, DQB1*04:01:01G was overtly high only in male CAD patients. CAD patients with diabetes showed a negative association with DQB1*03:01:01G and DQB1*05:03:01G and a positive association with DQB1*04:01:01G, DQB1*03:02:01G and DQB1*03:03:02G. Results of logistic regression analysis indicated that DQB1*03:01:01G and DQB1*05:03:01G were significantly associated with reduced susceptibility to CAD, but DQB1*04:01:01G, DQB1*03:02:01G and DQB1*03:03:02G had no correlation with CAD. Together, these findings indicate that CAD in Southern Han Chinese is negatively associated with HLA-DQB1*03:01:01G and DQB1*05:03:01G, and males with HLA-DQB1*04:01:01G are likely to have high risk for CAD.

Clinical observation of peripheral nerve injury in 2 patients with cancer after radiotherapy.

AIM OF THE STUDY: This study aims to analyze the clinical manifestations and sequelae of peripheral nerve radiation damage of two cases of cancer patients after radiotherapy at the corresponding sites in clinical practice and to summarize experiences and lesions in order to provide a reference for future tumor radiotherapy. MATERIAL AND METHODS: Some data of two cases of patients, such as doses of radiotherapy, clinical manifestations and damage occurrence time, were collected and examinations were conducted to define diagnosis. Afterwards, therapies and follow-up were conducted. RESULTS: Case 1 (rectal cancer) was diagnosed as mild left lower extremity nerve damage. After the symptomatic treatment, the disease condition was improved, and there was no tumor recurrence sign. Case 2 (breast cancer) was diagnosed as left brachial plexus damage, and left upper extremity movement function was lost completely. While the analgesic treatment was conducted, anti-tumor relevant treatments were being carried out. CONCLUSIONS: Radiotherapy can cause different extents of radioactive nerve damage. In practice, it is necessary to constantly improve the radiotherapy technology level and actively prevent the occurrence of complications. Once symptoms appear, the diagnosis and treatment should be conducted as early as possible in order to avoid aggravating damage to cause dysfunction and cause lifetime pain to patients.

Prediction of recurrence risk in early breast cancer using human epidermal growth factor 2 and cyclin A2.

BACKGROUND: Human epidermal growth factor 2 (HER2) is one of the most important prediction factors, but only 25% - 30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular markers that could be used to predict prognosis and recurrence in HER2 negative patients. This study investigated correlations of cyclin A2 and HER2 levels with clinical outcomes in 281 patients with invasive breast cancer in order to identify whether cyclin A2 can serve as a prognostic factor in HER2 negative patients. METHODS: Immunohistochemical staining was used to detect cyclin A2 and HER2 expression in 281 patients. Cyclin A2 and HER2 gene amplifications were analyzed using gene analysis and RT-PCR in 12 patients. Risk and survival estimates were analyzed using Log-rank, Kaplan-Meier, and Cox regression analysis; cyclin A2 and HER2 consistency with survival were analyzed using Kappa analysis. RESULTS: Patients with higher cyclin A2 and HER2 expressions had significantly shorter disease-free survival periods (P = 0.047 and P = 0.05, respectively). Kappa analysis performed that cyclin A2 and HER2 showed a low Kappa index (kappa = 0.37), allowing us to conclude that cyclin A2 and HER2 detect different pathologies. Gene analysis and RT-PCR showed that cyclin A2 was upregulated in patients with early relapse; the average increase was 3.69 - 2.74 fold. CONCLUSIONS: Cyclin A2 and HER2 are associated with proliferation and high recurrence, particularly when combined. Cyclin A2 is easily detected by nuclear staining and might be a useful biomarker for recurrence risk in HER2 negative patients.

Prediction of recurrence risk in early breast cancer using human epidermal growth factor 2 and cyclin A2 / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Human epidermal growth factor 2 (HER2) is one of the most important prediction factors, but only 25% - 30% of breast cancer patients HER2 are positive. It is unknown whether there are other molecular markers that could be used to predict prognosis and recurrence in HER2 negative patients. This study investigated correlations of cyclin A2 and HER2 levels with clinical outcomes in 281 patients with invasive breast cancer in order to identify whether cyclin A2 can serve as a prognostic factor in HER2 negative patients.</p><p><b>METHODS</b>Immunohistochemical staining was used to detect cyclin A2 and HER2 expression in 281 patients. Cyclin A2 and HER2 gene amplifications were analyzed using gene analysis and RT-PCR in 12 patients. Risk and survival estimates were analyzed using Log-rank, Kaplan-Meier, and Cox regression analysis; cyclin A2 and HER2 consistency with survival were analyzed using Kappa analysis.</p><p><b>RESULTS</b>Patients with higher cyclin A2 and HER2 expressions had significantly shorter disease-free survival periods (P = 0.047 and P = 0.05, respectively). Kappa analysis performed that cyclin A2 and HER2 showed a low Kappa index (kappa = 0.37), allowing us to conclude that cyclin A2 and HER2 detect different pathologies. Gene analysis and RT-PCR showed that cyclin A2 was upregulated in patients with early relapse; the average increase was 3.69 - 2.74 fold.</p><p><b>CONCLUSIONS</b>Cyclin A2 and HER2 are associated with proliferation and high recurrence, particularly when combined. Cyclin A2 is easily detected by nuclear staining and might be a useful biomarker for recurrence risk in HER2 negative patients.</p>

[Clinical study of aromatase inhibitors in advanced breast cancer].

OBJECTIVE: To assess the antitumor activity and safety of aromatase inhibitors in advanced breast cancer. METHODS: Fifty-two advanced and female breast cancer patients with measurable and /or bone valuable tumor lesions were observed from June 2003 to September 2006. They were treated by aromatase inhibitors for at least 24 weeks, of whom 11 were treated less than 24 weeks because of disease progress; their age range was from 37 to 75 years (median 58); 8 patients were pre-menopausal, 6 with ovarian ablation and 2 with Goserelin to suppress ovarian function. Thirty-six patients were treated with exemestane, 13 with anastrozole and 3 with letrozole. Major items were observed including objective response rate (ORR=CR+PR), clinical benefit rate (CBR=CR+PR+SD>or=24 weeks), time to progress (TTP), time to failure (TTF), safety and toxicity. RESULTS: CR were 6 cases (11.5%) , with 1 case going on for 152 weeks, 1 case for 96 weeks, and other 4 cases for longer than 60 weeks; PR were 19 cases (36.5%), lasting 32-96 weeks; 16 cases obtained SD>or=24 weeks(30.8%); and 11 cases PD (progress of disease)+SD<24 weeks (21.2%). ORR were 48%, CBR 78.8%, and TTP 78.87 weeks (95% CI 61.13%-96.61%); although the patients who did not achieve objective response (group B) were treated with chemotherapy, radiotherapy or another kind of aromatase inhibitor, but their survival time was significantly different from that of the patients who achieved objective response (group A) when defined by Kaplan-Meier survival estimate. The over survival was 92% in group A, and 81.5% in group B when patients follow up more than 24 weeks [Log Rank (Mantel-Cox) analysis, chi2=3.85, P=0.047]; side effects were observed such as arthralgia, sweating, hot flash, and 2 patients developed heart failure with uncertain related drug before recovery. CONCLUSION: The single agent effective rate of aromatase inhibitor was 48%. The patients had long term survival if they obtained CR or PR, and the side effects were well tolerated.

[Expression of epidermal growth factor receptor-2 in Chinese breast cancer patients: a meta-analysis].

OBJECTIVE: To study the expression of cerbB-2 and its clinical biology value in Chinese breast cancer patients by evidence based medical analysis. METHODS: All the published studies about cerbB-2 and breast cancer for the last 10 years were reviewed and standard techniques of meta-analysis to combined with the results of these studies were used to produce a more precise estimate of the prognostic significance expression of cerbB-2. RESULTS: The mean of cerbB-2 positive expression was 50% (95% confidence interval 48%-54%), cerbB-2 positive expression was related with node metastasis, recurrence after surgery and survival time; the RR values were 1.71, 2.14 and 2.32 respectively; tumor size, nuclear grade and pathology type were also the important factors that were related with the expression of cerbB-2, while the expression was not related with age; cerbB-2 was a special and sensitive prognostic factor for breast cancer. CONCLUSION: cerbB-2 can be used as an independent molecular marker for definitive prognosis of breast cancer, as well as a reliable marker for choice of standard and individual therapy.