Specific and gender differences between hospitalized and out of hospital mortality due to myocardial infarction

In this paper, the authors evaluate gender related differences of myocardial infarction mortality before and after hospital admittance. Myocardial infarction mortality in the Clinical Hospital Split in the seven years period between 2000 and 2006, have been analyzed together with out of hospital sudden death patients with acute myocardial infarction established during autopsy. During the seven year period between 2000 and 2006, 3434 patients were treated for myocardial infarction in the Split Clinical Hospital, 2336 (68%) males and 1098 (32%) females with a 12% total mortality (427 patients). The annual number of hospitalized persons has been increasing during that period (474 in yr. 2000 us. 547 in yr. 2006), while mortality decreased from 15% in 2000 to 9.6% in 2006. Female patients had significantly higher hospital mortality than male patients, (228 or 21% vs. 202 or 9%, p<0.05). Women also had significantly higher total AMI mortality (23.7% vs. 15,7%, p <0.05). Anterior myocardial infarction with ST elevation in precordial leads had significantly higher mortality (19%) compared to patients with lateral (11%), inferior (10%) myocardial infarction with ST elevation and also NSTEMI (4%) mortality p<0.05. Female patients more frequently die in hospital, 84% (230) than out of hospital 16% (43). From the total number of AMI deaths (388) in male patients, 56% (217) were in hospital and 44% (171) out of hospital (p<0.001). Men had significantly higher prehospital mortality rate than women (81% vs. 19%, p<0.05). Men also more frequently died from ventricular fibrillation (22% vs. 10%, p<0.05), while women died more frequently of heart failure, cardiogenic shock, and myocardial rupture (33% vs. 15% p<0.05). Regarding the total number of deaths from myocardial infarction men had significantly higher prehospital mortality compared to women (178 or 7.3% vs. 43 or 3.7%, p<0.05). Anterior myocardial infarction had a significantly higher rate in patients dying pre-hospital (58%), in contrast to inferior (36%) and lateral myocardial infarction with ST elevation (6%) p<0.05. We have concluded that male patients die more frequently within the first few hours of AMI mostly due to malignant arrhythmias, while female patients died in sub acute stage due to heart failure while being hospitalized. Nevertheless total mortality of AMI remains significantly higher in women.     

Amino Acid-Induced Translation of TOP mRNAs Is Fully Dependent on Phosphatidylinositol 3-Kinase-Mediated Signaling, Is Partially Inhibited by Rapamycin, and Is Independent of S6K1 and rpS6 Phosphorylation

Vertebrate TOP mRNAs contain an oligopyrimidine tract at their 5' termini (5'TOP) and encode components of the translational machinery. Previously it has been shown that they are subject to selective translational repression upon growth arrest and that their translational behavior correlates with the activity of S6K1. We now show that the translation of TOP mRNAs is rapidly repressed by amino acid withdrawal and that this nutritional control depends strictly on the integrity of the 5'TOP motif. However, neither phosphorylation of ribosomal protein (rp) S6 nor activation of S6K1 per se is sufficient to relieve the translational repression of TOP mRNAs in amino acid-starved cells. Likewise, inhibition of S6K1 activity and rpS6 phosphorylation by overexpression of dominant-negative S6K1 mutants failed to suppress the translational activation of TOP mRNAs in amino acid-refed cells. Furthermore, TOP mRNAs were translationally regulated by amino acid sufficiency in embryonic stem cells lacking both alleles of the S6K1 gene. Inhibition of mTOR by rapamycin led to fast and complete repression of S6K1, as judged by rpS6 phosphorylation, but to only partial and delayed repression of translational activation of TOP mRNAs. In contrast, interference in the phosphatidylinositol 3-kinase (PI3-kinase)-mediated pathway by chemical or genetic manipulations blocked rapidly and completely the translational activation of TOP mRNAs. It appears, therefore, that translational regulation of TOP mRNAs, at least by amino acids, (i) is fully dependent on PI3-kinase, (ii) is partially sensitive to rapamycin, and (iii) requires neither S6K1 activity nor rpS6 phosphorylation.     

Hormonal regulation and cell-specific expression of endothelin-converting enzyme 1 isoforms in bovine ovarian endothelial and steroidogenic cells

Endothelin-converting enzyme 1 (ECE-1) is a key enzyme in the biosynthesis of endothelin 1 (ET-1), a potent regulator of ovarian function. Different ECE-1 isoforms are localized in distinct intracellular compartments. Thus, the spatial and temporal pattern of ECE-1 expression determines the site of big ET-1 activation and the bioavailability of ET-1. This study was undertaken to investigate the hormonal regulation and cell-specific expression of ECE-1 isoforms in endothelial and steroidogenic cells of bovine follicles and corpora lutea (CL). Using enriched follicular and luteal cell subpopulations and in situ hybridization techniques, we showed that the ECE-1 gene is expressed by both endothelial and steroidogenic cells; however, the intracellular ECE-1a isoform was present only in ET-1-expressing endothelial cells. Steroidogenic cells in follicles or in CL, deficient in ET-1, expressed only the plasma membrane ECE-1b isoform. The intensity of antisense ECE-1 labeling in the granulosa cell layer increased with follicular size; insulin-like growth factor I and insulin upregulated ECE-1 expression when cultured with granulosa cells, suggesting that these growth factors may increase ECE-1 in growing follicles. In contrast, ET-1 and LH downregulated ECE-1 in steroidogenic cells. This effect could account for low ECE (and ET-1) levels, which characterize the early luteal phase. These findings suggest that ECE-1 is regulated during different stages of the cycle in a physiologically relevant manner. The hormonal regulation and intracellular localization of bovine ECE-1 isoforms revealed in this study may provide new insights into ET-1 biosynthesis and mode of action in different cellular microenvironments within the ovary.     

Phospho-regulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p

The Aurora kinase Ipl1p plays a crucial role in regulating kinetochore-microtubule attachments in budding yeast, but the underlying basis for this regulation is not known. To identify Ipl1p targets, we first purified 28 kinetochore proteins from yeast protein extracts. These studies identified five previously uncharacterized kinetochore proteins and defined two additional kinetochore subcomplexes. We then used mass spectrometry to identify 18 phosphorylation sites in 7 of these 28 proteins. Ten of these phosphorylation sites are targeted directly by Ipl1p, allowing us to identify a consensus phosphorylation site for an Aurora kinase. Our systematic mutational analysis of the Ipl1p phosphorylation sites demonstrated that the essential microtubule binding protein Dam1p is a key Ipl1p target for regulating kinetochore-microtubule attachments in vivo.     

Synthesis, cytotoxicity, QSAR, and intercalation study of new diindenopyridine derivatives

Seven new derivatives of diindenopyridine were synthesized by Hantsch pyridine synthesis. Their biological activity to inhibit cell proliferation was assessed by MTT assay on seven cell lines. 11-(4-Fluoro-phenyl)-diindeno[1,2-b;2',1'-e]pyridine-10,12-dione and 11-(2-nitro-phenyl)-diindeno[1,2-b;2',1'-e]pyridine-10,12-dione were active on K-562 cell line with IC50 values of 79.66 and 78.2 microM, respectively. Effect of structural parameters on the cytotoxicity was evaluated by quantitative structure activity relationship (QSAR) analysis and a linear relationship was found between the -logIC15 of these compounds and their surface area and molar refractivity. To model the DNA-intercalator complex, force field molecular mechanic calculation was employed and the binding energy of the reaction between the intercalating agent and each reasonable double base pairs of DNA was calculated. It was found that these molecules could intercalate into the DNA. Also, it was observed that 11-(2-nitro-phenyl)-diindeno[1,2-b;2',1'-e]pyridine-10,12-dione, which showed the highest activity in K-562 cell line, produced the most negative binding energy with a moderate selectivity toward A-G/T-C double base pairs.     

Design and synthesis of methyl 2-methyl-7,7-dihalo-5-phenyl-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity

A group of methyl 2-methyl-7,7-dihalo-5-(substituted-phenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX2, X = Br, Cl) with methyl 1-methyl-4-(substituted-phenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10(-5)-10(-6)M range) than the reference drug nifedipine (1.4 x 10(-8)M). Structure-activity relationship studies showed that the position of a nitro substituent on the C-5 phenyl ring where the relative potency order was ortho > meta > para, and the size and/or electronegativity of the C-7 geminal-dihalo substituents (Br > Cl), were determinants of calcium channel antagonist activity. This class of compounds did not exhibit any inotropic effect on guinea pig left atria. A dihalocyclopropyl moiety is a potential bioisostere for the 2-methyl-3-methoxycarbonylvinyl moiety present in the calcium channel antagonist nifedipine.     

Otx/otd homeobox genes specify distinct sensory neuron identities in C. elegans

The mechanisms by which the diverse functional identities of neurons are generated are poorly understood. C. elegans responds to thermal and chemical stimuli using 12 types of sensory neurons. The Otx/otd homolog ttx-1 specifies the identities of the AFD thermosensory neurons. We show here that ceh-36 and ceh-37, the remaining two Otx-like genes in the C. elegans genome, specify the identities of AWC, ASE, and AWB chemosensory neurons, defining a role for this gene family in sensory neuron specification. All C. elegans Otx genes and rat Otx1 can substitute for ceh-37 and ceh-36, but only ceh-37 functionally substitutes for ttx-1. Functional substitution in the AWB neurons is mediated by activation of the same downstream target lim-4 by different Otx genes. Misexpression experiments indicate that although the specific identity adopted upon expression of an Otx gene may be constrained by the cellular context, individual Otx genes preferentially promote distinct neuronal identities.     

Direct Transesterification of Castor and Jatropha Seeds for FAME Production by Microwave and Ultrasound Radiation Using a SrO Catalyst

In the present study, we report on an optimized method for fatty acid methyl esters (FAME) production from castor and jatropha seeds. In order to identify the most effective biodiesel production method, we have compared three two-stage methods, each consisting of oil extraction (the first step) and FAME production by transesterification (the second step), with the same three techniques each conducted in one stage, i.e., direct transesterification. The three techniques are conventional heating, sonochemistry, and microwave radiation. The FAME product was analyzed by ¹H NMR spectroscopy and GC-MS. The SrO catalyst was reused successfully, together with seeds containing oil residues, for 10 cycles. The highest yield of FAME, 57.2?% of the total weight of the castor seeds, and a conversion of castor oil to FAME of 99.95?% were achieved in a one-stage method lasting 5?min using microwave radiation as a heat source. Using jatropha seeds leads to a yield of 41.1?% and a 99.7?% conversion of triglyceride to FAME under microwave irradiation in a one-stage method. The direct transesterification by sonication resulted in yields of 48.2?% and 32.9?%, and a 93.6?% conversion from castor and jatropha seeds, respectively.     

Breast cancer is marked by specific,Public T-cell receptor CDR3 regions shared by mice and humans

The partial success of tumor immunotherapy induced by checkpoint blockade, which is not antigen-specific, suggests that the immune system of some patients contain antigen receptors able to specifically identify tumor cells. Here we focused on T-cell receptor (TCR) repertoires associated with spontaneous breast cancer. We studied the alpha and beta chain CDR3 domains of TCR repertoires of CD4 T cells using deep sequencing of cell populations in mice and applied the results to published TCR sequence data obtained from human patients. We screened peripheral blood T cells obtained monthly from individual mice spontaneously developing breast tumors by 5 months. We then looked at identical TCR sequences in published human studies; we used TCGA data from tumors and healthy tissues of 1,256 breast cancer resections and from 4 focused studies including sequences from tumors, lymph nodes, blood and healthy tissues, and from single cell dataset of 3 breast cancer subjects. We now report that mice spontaneously developing breast cancer manifest shared, Public CDR3 regions in both their alpha and beta and that a significant number of women with early breast cancer manifest identical CDR3 sequences. These findings suggest that the development of breast cancer is associated, across species, with biomarker, exclusive TCR repertoires.