Predicting Blood-Brain Barrier Permeation of Erlotinib and JCN037 by Molecular Simulation.

Glioblastoma (GBM) is a highly malignant primary brain tumor, and epidermal growth factor receptor (EGFR) is a well characterized biomaker on GBM. Treatment of GBM with EGFR inhibitors achieved limited efficacy due to low blood-brain barrier (BBB) permeability, and BBB-penetrant drugs are required. In this study, the BBB penetration of erlotinib and JN037 were studied using molecular dynamics method with explicit membrane model. The free energy profiles indicate that JCN037 has a lower central energy barrier than erlotinib, and it has a local minimum at lipid-water interface while erlotinib has not. Unconstrained MD simulations found that erlotinib prefers staying in water while JCN037 tends to interact with lipid molecules. Further analysis reveals that the Br atom of JCN037 plays an important role in its interaction with lipid molecules, and the adjacent F atom enhances the interaction of Br. The two flexible methoxyethoxy chains of erlotinib are responsible for its poor penetration. Our computational results agree well with the experimental results, providing useful information in the design and improvement of drugs with good BBB permeation.

Synthesis and biological evaluation of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl)glycines as oral erythropoietin secretagogues.

Erythropoietin (EPO) is the predominant regulating factor in erythropoiesis. Herein we describe the identification of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl) glycine-based oral EPO secretagogues. Most of these compounds obviously increased the EPO level in Hep3B cells by stabilizing the hypoxia-inducible factor-α (HIF-α). Furthermore, their potential inhibitory activities against HIF prolyl hydroxylase domain (PHD) revealed their function as PHD inhibitors in PHD-HIF pathway. Compound 6i, with a biphenyl substituent on the sulfonamido group, particularly increased plasma EPO level in mice and could serve as a candidate of EPO stimulating agent for anemia treatment.

LncRNA-ROR/microRNA-185-3p/YAP1 axis exerts function in biological characteristics of osteosarcoma cells.

AIM: The co-expression network of long non-coding RNA ROR (lncRNA-ROR) and microRNA-185-3p (miR-185-3p) has not been focused on osteosarcoma. Therein, this work was initiated to uncover lncRNA-ROR and miR-185-3p functions in osteosarcoma. METHODS: LncRNA-ROR, miR-185-3p and Yes-associated protein 1 (YAP1) expression in osteosarcoma tissues and cells were detected. The screened cells (MG63 and U2OS) were transfected with decreased and/or increased lncRNA-ROR and miR-185-3p to explore osteosarcoma progression. Tumor growth was detected by tumor xenografts in mice. RESULTS: Up-regulated lncRNA-ROR and YAP1 and down-regulated miR-185-3p were found in osteosarcoma. LncRNA ROR knockdown or miR-185-3p overexpression inhibited osteosarcoma cell progression while lncRNA ROR elevation or miR-185-3p inhibition presented the opposite effects. Function of lncRNA ROR was rescued by miR-185-3p and regulated the growth and metastasis of osteosarcoma cells via modulating YAP1, the target gene of miR-185-3p. CONCLUSION: This work illustrates that lncRNA-ROR down-regulation or miR-185-3p up-regulation inhibits osteosarcoma progression via YAP1 repression.

Novel Sophoridine Derivatives Bearing Phosphoramide Mustard Moiety Exhibit Potent Antitumor Activities In Vitro and In Vivo.

Novel mustard functionalized sophoridine derivatives were synthesized and evaluated for their cytotoxicity against of a panel of various cancer cell lines. They were shown to be more sensitive to S180 and H22 tumor cells with IC50 values ranging from 1.01⁻3.65 µM, and distinctly were more cytotoxic to cancer cells than normal cell L929. In addition, compounds 7a, 7c, and 7e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Furthermore, they arrested tumor cells in the G1 phase and induced cellular apoptosis. Their potential binding modes with DNA-Top I complex have also been investigated.

[Efficacy of the Sentinel Mouse Method in Monitoring Schistosoma japonicum Infection in Key #br# Water Areas of Hanchuan City].

Objective: To understand the water infectivity of schistosomes in key water areas of Hanchuan City, and explore the use of sentinel mice in surveillance and forecast of schistosomiasis. Methods: Surveillance and forecast sites were set up in North Han River, Diaocha Lake, and Miaowu Ditch in 2014. Sentinel mice （male Kunming mice, n=20 in each site） were placed there within the first ten-day period of June and September, respectively. Field detections lasted 4 h each, for a total of 2 days. The loss and death rates of mice were recorded. Humans and livestocks with activities in these sites were also examined for schistosome infection. The sentinel mice recovered were raised in laboratory for 35 days, dissected, and examined for liver granulomas and adult worm counting. The distribution of sites with positive detections and their infection status were analyzed. Emergency measures were taken in the positive sites. Results: A total of 13（5 sites in North Han River, 5 in Diaocha Lake, and 3 in Miaowu Ditch） surveillance and forecast sites were set up. No infected snail was detected in any of these sites in spring 2014. The detection rate of living snails in North Han River （18.7%, 224/1 201) was significantly higher than that in Diaocha Lake（12.8%, 852/6 644） and in Miaowu Ditch （6.4%, 202/3 147）（P<0.01）. Of the 520 mice placed, 6 were lost, and 514 were recovered, among which 4 mice died during laboratory raising. The remaining 510 sentinel mice were then dissected, revealing infection in 4 mice, with a positive rate of 0.8%. Twenty-seven Schistosoma japonicum worms were collected, and the mean worm burden of positive mice was 6.8 worms per mouse. Three sites (Sansi village, Kangjia village and Doubu village) were found to be positive sites of infection in September, with the detailed number of 2, 1 and 0 in North Han River, Diaocha Lake, and Miaowu Ditch respectively, with a positive rate of 1.5% （3/197）, 0.5% （1/195） and 0 （0/118） in sentinel mice （P>0.05）. In addition, among the 22 cattle found in the 13 sites, 2 were infected with schistosomes; and among the 62 fishermen and boatmen, 2 were infected. Emergency measures were taken in the three positive sites, and no high endemicity occurred. Conclusion: The monitoring of sentinel mice infections can improve the sensitivity of the surveillance and forecast system of schistosomiasis. The infected fishermen and cattle remain the major source of schistosomiasis transmission in Hanchuan City.

Synthesis of the alkylated active metabolite of tipidogrel.

Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr-derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented.

Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple-Negative Breast Cancer.

As a critical epigenetic modulator of gene expression, histone deacetylases (HDACs) have been involved in the pathogenesis and therapeutic investigation of cancer. Quinolizidine alkaloid sophoridine is known to have anticancer efficacy but with limited indication. By incorporating the pharmacophore of the HDAC inhibitor into the ring-opened sophoridine core, a new series of sophoridine hydroxamic acid derivatives were synthesized. After structure-activity studies, a selected compound was found to exert significant cytotoxicity in triple-negative breast cancer CAL-51 cells (IC50 1.17 µM), and demonstrated low nanomolar inhibitory potency toward HDAC1/3/6. Cellular functional assays indicated that this compound was able to induce apoptosis and cause accumulation of cells in the S phase of the cell cycle. Western blot analysis revealed it to decrease the expression of DNMT1, DNMT3a and DNMT3b by down-regulating phosphor-ERK1/2. Furthermore, treatment with this compound proved to block the PI3K/AKT/mTOR signaling in the PI3KCA and PTEN-mutant CAL-51 cells. Collectively, this work provides a novel lead compound for the development of potential therapeutics against triple-negative breast cancers, possibly mesenchymal-like subtype.

[Effects on Salvia miltiorrhiza hairy roots of tanshinones content accumulation after treated with fosmidomycin].

Fosmidomycin (100 micromol x L(-1)) which is the effective inhibitor of DXR, key enzyme in terpenoid MEP pathway, was used to treat with hairy roots of Salvia miltiorrhiza. The treated roots were harvested at 2, 4, 6, 8, 10, 16 and 21 d, mRNA level of SmDXR and tanshinone content in treated and negative control groups were detected. Results found that, after treated with fosmidomycin, color of S. miltiorrhiza hairy roots grew pale gradually comparing with controls; mRNA level of SmDXR in hairy roots varied as a shape of parabolic and the highest value achieved at the sixth day after treatment, then it decreased gradually; Content of four kinds of tanshinones were detected. Among of the four kinds of tanshinones, Tanshinone I content changed relatively little, while content of dihydrotanshinone I, cryptotanshinone and tanshinone II (A) decreased gradually in 21 days. The content of total tanshinones in NC groups was 5, 63 times more than FOS-treated roots in the 21th day. The previous results showed that SmDXR played an important role in the accumulation of tanshinone content in MEP pathway. Once the mRNA level of SmDXR was suppressed, the accumulation of secondary metabolites will be significantly affected.

Effects of high-pressure argon and nitrogen treatments on respiration, browning and antioxidant potential of minimally processed pineapples during shelf life.

BACKGROUND: High-pressure (HP) inert gas processing causes inert gas and water molecules to form clathrate hydrates that restrict intracellular water activity and enzymatic reactions. This technique can be used to preserve fruits and vegetables. In this study, minimally processed (MP) pineapples were treated with HP (∼10 MPa) argon (Ar) and nitrogen (N) for 20 min. The effects of these treatments on respiration, browning and antioxidant potential of MP pineapples were investigated after cutting and during 20 days of storage at 4 °C. RESULTS: Lower respiration rate and ethylene production were found in HP Ar- and HP N-treated samples compared with control samples. HP Ar and HP N treatments effectively reduced browning and loss of total phenols and ascorbic acid and maintained antioxidant capacity of MP pineapples. They did not cause a significant decline in tissue firmness or increase in juice leakage. HP Ar treatments had greater effects than HP N treatments on reduction of respiration rate and ethylene production and maintenance of phenolic compounds and DPPH(•) and ABTS(•+) radical-scavenging activities. CONCLUSION: Both HP Ar and HP N processing had beneficial effects on MP pineapples throughout 20 days of storage at 4 °C.

1-(4,5,6,7-Tetra-hydro-thieno[3,2-c]pyridin-5-yl)-2-{4-[3-(trifluoro-meth-yl)phen-yl]piperazin-1-yl}ethanone.

In the title mol-ecule, C(20)H(22)F(3)N(3)OS, the piperazine ring has a chair conformation, and the N-C(=O)-C-N torsion angle is -59.42 (14)°. In the crystal, weak C-H⋯O and C-H⋯π inter-actions link the mol-ecules into layers parallel to (101).

Molecular dynamics simulations of a central nervous system-penetrant drug AZD3759 with lipid bilayer.

AZD3759 is an epidermal growth factor receptor inhibitor with good blood-brain barrier permeability, demonstrating encouraging activity against central nervous system metastases. However, the underlying mechanism was still unclear. In this study, the interaction between AZD3759 and membrane was studied with 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayer as a model lipid. Both the cationic and neutral state of AZD3759 were considered in the simulations, and the results show that cationic AZD3759 forms more hydrogen bonds with bilayer than neutral AZD3759, and Coulombic interaction has great effects in the transmembrane process of cationic AZD3759. AZD3759 prefers to reside in the interface between the hydrophilic headgroup region and hydrophobic region of bilayer, and the chloroflurobenzene moiety plays a crucial role in the insertion of AZD3759. PMF results suggest that the hydrophobic region of DMPC bilayer is permeable by AZD3759. Understanding the transmembrane mechanism of AZD3759 at molecular level may provide useful information to the design and optimization of anti-tumor drugs with improved BBB penetration. • The penetration mechanism of AZD3759 with DMPC bilayer was studied by molecular dynamics simulations. • Neutral AZD3759 could penetrate deeper into DMPC bilayer than protonated AZD3759. • The chloroflurobenzene moiety plays a significant role in the insertion of AZD3759 into DMPC bilayer. • The electrostatic interaction is the driving force for the initial binding of AZD3759 to DMPC bilayer. • Our findings may enhance the mechanism understanding of drugs with good BBB permeability.

Identification of candidate miRNA biomarkers correlated with the prognosis of cell carcinoma and endocervical adenocarcinoma via integrated bioinformatics analysis.

OBJECTIVES: This study was designed to explore MicroRNAs (miRNAs) associated with the prognosis of cell carcinoma and endocervical adenocarcinoma (CESC) to search for biomarkers of CESC and provide guidelines for the clinical treatment. METHODS: mRNAs of CESC patients were downloaded from The Cancer Genome Atlas (TCGA), and miRNA expression and clinical data of the patients were preprocessed. Key miRNAs associated with the prognosis of cervical cancer were identified by weighted gene co-expression network (WGCNA). The corresponding target genes were intersected with differentially expressed genes (DEGs) acquired from variation analysis, and the pathways and functional enrichment of genes were analyzed. Key genes were screened by Kaplan-Meier (K-M) survival analysis. Risk models were constructed using Cox proportional hazard regression model and the Least Absolute Shrinkage and Selection Operator (LASSO) method, and the predictive value of the models was evaluated by time-associated receiver operating characteristic (ROC) curves. Finally, independent prognostic factors were identified by COX analysis. RESULTS: The hsa-miR-3150b-3p associated with the prognosis of CESC was identified by WGCNA. A total of 136 target genes were differentially expressed in CESC tissue and were associated with biological processes such as phylogeny, multicellular organism development and cell development. CBX7, ENPEP, FAIM2, IGF1, NUP62CL and TSC22D3 were associated with the prognosis of CESC, and a prognostic prediction model was constructed using these six genes, which had a good predictive value for the prognosis of cervical cancer within 1, 3 and 5 years (AUC: 0.784, 0.680 and 0.683, respectively). Among them, ENPEP (hazard ratio = 1.3996, 95% confidence interval: 1.0552-1.8565) was identified as an independent prognostic factor. CONCLUSIONS: In this study, a highly accurate prognostic model consisting of six gene signatures was developed to predict the prognosis of patients with cervical cancer, which provides a reference for developing individualized treatment plans for patients.

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple-Negative Breast Cancer through Inhibition of mTOR Signaling.

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.

Nomogram for Prediction of Postoperative Delirium after Deep Brain Stimulation of Subthalamic Nucleus in Parkinson's Disease under General Anesthesia.

Introduction: Postoperative delirium can increase cognitive impairment and mortality in patients with Parkinson's disease. The purpose of this study was to develop and internally validate a clinical prediction model of delirium after deep brain stimulation of the subthalamic nucleus in Parkinson's disease under general anesthesia. Methods: We conducted a retrospective observational cohort study on the data of 240 patients with Parkinson's disease who underwent deep brain stimulation of the subthalamic nucleus under general anesthesia. Demographic characteristics, clinical evaluation, imaging data, laboratory data, and surgical anesthesia information were collected. Multivariate logistic regression was used to develop the prediction model for postoperative delirium. Results: A total of 159 patients were included in the cohort, of which 38 (23.90%) had postoperative delirium. Smoking (OR 4.51, 95% CI 1.56-13.02, p < 0.01) was the most important risk factor; other independent predictors were orthostatic hypotension (OR 3.42, 95% CI 0.90-13.06, p=0.07), inhibitors of type-B monoamine oxidase (OR 3.07, 95% CI 1.17-8.04, p=0.02), preoperative MRI with silent brain ischemia or infarction (OR 2.36, 95% CI 0.90-6.14, p=0.08), Hamilton anxiety scale score (OR 2.12, 95% CI 1.28-3.50, p < 0.01), and apolipoprotein E level in plasma (OR 1.48, 95% CI 0.95-2.29, p=0.08). The area under the receiver operating characteristic curve (AUC) was 0.76 (95% CI 0.66-0.86). A nomogram was established and showed good calibration and clinical predictive capacity. After bootstrap for internal verification, the AUC was 0.74 (95% CI 0.66-0.83). Conclusion: This study provides evidence for the independent inducing factors of delirium after deep brain stimulation of the subthalamic nucleus in Parkinson's disease under general anesthesia. By predicting the development of delirium, our model may identify high-risk groups that can benefit from early or preventive intervention.

N-(5-Ethylsulfanyl-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyri-din-5-yl)acetamide.

In the title compound, C(13)H(16)N(4)OS(3), a thienopyridine-derivative, the tetra-hydro-pyridine ring exhibits a half-chair conformation, and the folded conformation of the mol-ecule is defined by the N-C-C-N torsion angle of -78.85 (16)°. The crystal packing features inter-molecular C-H⋯N, N-H⋯N and C-H⋯O hydrogen bonds.

[A case-control study on the risk factors for lower respiratory tract infection by Stenotrophomonas maltophilia in a medical intensive care unit].

OBJECTIVE: To explore the risk factors for lower respiratory tract infection by Stenotrophomonas maltophilia in the medical intensive care unit (MICU) in Fujian Provincial Hospital. METHODS: A 1:4 matched case-control study was carried out in the MICU in Fujian Provincial Hospital. Thirty-five patients with hospital-acquired lower respiratory tract infection by Stenotrophomonas maltophilia from 2007 to 2010 were included as cases, and 140 patients without lower respiratory tract infection served as controls. The case group included 22 cases with respiratory diseases, 4 with cerebrovascular diseases, 4 with cardiovascular diseases, 1 with hemorrhage of the digestive tract, 1 with acute pancreatitis, 1 with chronic kidney disease, 1 with cervical cancer and 1 with Alzheimer's disease. While the control group included 30 cases with respiratory diseases, 44 with cerebrovascular diseases, 14 with cardiovascular diseases, 2 with malignant tumors and 50 with others. Patients' information, general situation before being admitted to MICU, drug therapy, invasive procedures and hospital-acquired infection were analyzed. Conditional logistic regression was performed to identify independent risk factors. RESULTS: Univariate analysis showed that factors such as more than 4 underlying diseases (OR = 4.63), APACHE-II score ≥ 20(OR = 10.29), stay in the general ward more than 1 week before being admitted to MICU, treatment with more than 3 kinds of antibiotics (OR = 8.03), endotracheal intubation (OR = 4.10) or tracheotomy (OR = 50.29) and mechanical ventilation (OR = 7.95) were risk factors for hospital-acquired lower respiratory tract infection by Stenotrophomonas maltophilia. Multivariate logistic regression showed that variables such as APACHE-II score (OR = 8.39), kinds of antibiotics used (OR = 5.96) and tracheotomy (OR = 28.92) were independent risk factors (P < 0.01). CONCLUSIONS: Underlying diseases, the severity of diseases, tracheotomy, mechanical ventilation, and the use of wide-spectrum antibiotics are important risk factors for lower respiratory tract infection by Stenotrophomonas maltophilia in MICU. To identify these factors and take preventive measures earlier may be useful for decreasing Stenotrophomonas maltophilia infection-related mortality.

WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner.

N6-methyladenosine (m6A) regulators are involved in the progression of various cancers via regulating m6A modification. However, the potential role and mechanism of the m6A modification in osteosarcoma remains obscure. In this study, WTAP was found to be highly expressed in osteosarcoma tissue and it was an independent prognostic factor for overall survival in osteosarcoma. Functionally, WTAP, as an oncogene, was involved in the proliferation and metastasis of osteosarcoma in vitro and vivo. Mechanistically, M6A dot blot, RNA-seq and MeRIP-seq, MeRIP-qRT-PCR and luciferase reporter assays showed that HMBOX1 was identified as the target gene of WTAP, which regulated HMBOX1 stability depending on m6A modification at the 3'UTR of HMBOX1 mRNA. In addition, HMBOX1 expression was downregulated in osteosarcoma and was an independent prognostic factor for overall survival in osteosarcoma patients. Silenced HMBOX1 evidently attenuated shWTAP-mediated suppression on osteosarcoma growth and metastasis in vivo and vitro. Finally, WTAP/HMBOX1 regulated osteosarcoma growth and metastasis via PI3K/AKT pathway. In conclusion, this study demonstrated the critical role of the WTAP-mediated m6A modification in the progression of osteosarcoma, which could provide novel insights into osteosarcoma treatment.

lncRNA Xist Regulates Osteoblast Differentiation by Sponging miR-19a-3p in Aging-induced Osteoporosis.

The switch between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) plays a key role in aging-induced osteoporosis. In this study, miR-19a-3p was obviously downregulated in BMSCs from aged humans and mice. Overexpressed miR-19a-3p evidently reduced aging-induced bone loss in mice and promoted osteogenic differentiation of BMSCs, while silenced miR-19a-3p manifestly increased aging-induced bone loss in mice and repressed osteogenic differentiation of BMSCs. Hoxa5 was significantly downregulated in the BMSCs from aged mice and contribute to miR-19a-3p-induced osteoblast differentiation as a direct target gene of miR-19a-3p. Furthermore, lncRNA Xist was found as a sponge of miR-19a-3p to repress BMSCs osteogenic differentiation. In conclusion, our study reveals the critical role of the lncRNA Xist/miR-19a-3p/Hoxa5 pathway in aging-induced osteogenic differentiation of BMSCs, indicating the potential therapeutic target for osteoporosis.

Differences in pathologic characteristics between ductal carcinoma in situ (DCIS), DCIS with microinvasion and DCIS with invasive ductal carcinoma.

In order to further our understanding of pathologic features in various ductal carcinoma in situ (DCIS) related breast ductal cancers, including DCIS, DCIS with microinvasion (DCIS-Mi) and DCIS with invasive ductal carcinoma (DCIS-IDC), a retrospective study including 453 cases of DCIS, 88 cases of DCIS-Mi, and 269 cases of DCIS-IDC was conducted. Statistical analysis showed significant pathological differences were found in DCIS, DCIS-Mi, and DCIS-IDC. Compared with DCIS, DCIS-IDC was significantly more associated with high nuclear grade, large tumor size, high Ki67 index, and lymph node metastasis (all P<0.05). Higher expression of steroid receptors was shown in DCIS-IDC than in DCIS (all P<0.05), but the status of HER2 between the two groups was similar (P=0.269). Compared with DCIS, DCIS-Mi was significantly more associated with high nuclear grade, large tumor size, comedonecrosis, absence of steroid receptors, HER2 overexpression, and high Ki67 index (all P<0.05). These features remain consistently even when compared with DCIS-IDC. According to the immunohistochemistry surrogate classification, the dominant types of DCIS and DCIS-IDC were luminal types (luminal A and luminal B, respectively), while the dominant type of DCIS-Mi was HER2 overexpression. These findings suggest that DCIS-Mi represents a distinct entity, and DCIS with features including high nuclear grade, large tumor size, comedonecrosis, steroid receptors negativity, HER2 positivity, and high Ki67 expression was more likely to have microinvasion than DCIS without these features.

[Expression of COX-2 and pregnancy associate plasma protein A in coronary arteries and their relationship with acute coronary syndrome: an autopsy study of 42 cases].

OBJECTIVE: To study the expression of COX-2 and pregnancy associate plasma protein A (PAPP-A) in coronary arteries and their relationship with acute coronary syndrome. METHODS: Twenty-one autopsy cases with acute coronary syndrome encountered during the period from 2002 to 2007 were enrolled into the study. Another 21 autopsy cases without evidence of acute coronary syndrome were used as the controls. The right and left coronary arteries of each group were dissected, embedded and processed as paraffin sections. Immunohistochemical study for CD68 and alpha-actin was performed to highlight the presence of macrophages and smooth muscle cells, respectively. The expression of COX-2 and PAPP-A was evaluated. RESULTS: In the acute coronary syndrome group, COX-2 was localized mainly in the cytoplasm of endothelial cells, macrophages and smooth muscle cells. COX-2 expression in the cytoplasm of smooth muscle cells (28.60%) was significantly higher than that in the control group (4.76%, chi(2) = 14.13, P< 0.05). There was a positive correlation on COX-2 and PAPP-A expression in smooth muscle cells of the media layer of coronary arteries in acute coronary syndrome group (r = 0.88, P < 0.05). The expression of PAPP-A in smooth muscle cells of the media layer in coronary arteries not associated with plaque formation, was higher than that when there were atherosclerotic plaques (chi(2) = 10.36, P < 0.05). CONCLUSION: In coronary arteries, COX-2 and PAPP-A play certain roles in the pathogenesis of acute coronary syndrome.