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1.
N. S. Hari Narayana Moorthy Sergio F. Sousa Maria J. Ramos Pedro A. Fernandes 《Medicinal chemistry research》2016,25(7):1340-1357
Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets. 相似文献
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Milena Soares Santos Guilherme de Sousa Ribeiro Tainara Queiroz Oliveira Renan Cardoso Nery Santos Edilane Gouveia Kátia Salgado Daniele Takahashi Cleuber Fontes Leila Carvalho Campos Mitermayer Galvão Reis Albert Icksang Ko Joice Neves Reis 《International journal of infectious diseases》2009,13(4):456-461
5.
ME BURGE AM JOSHUA CM McNEIL R HUI MJ BOYER R ABRAHAM 《Asia-Pacific Journal of Clinical Oncology》2005,1(1):47-52
Background: Pemetrexed and cisplatin have recently been shown to significantly improve survival compared with cisplatin alone. However, there are only limited data reflecting teaching hospital experience outside a clinical trial. Pemetrexed has only been available in Australia on a restricted basis since 2002. We reviewed our experience of patients treated on the Australian ‘Special Access Scheme’ at three major thoracic oncology units. Methods: Charts were reviewed for all patients enrolled on the scheme. Data was extracted on age, World Health Organization (WHO) performance status, histology, prior therapy, time from diagnosis to starting pemetrexed, chemotherapy (pemetrexed alone or with a platinum), cycle number, response rate, actuarial progression‐free and overall survival. Doses were cisplatin 75 mg/m2 or carboplatin AUC = 5 and pemetrexed 500 mg/m2 every 21 days. Results: 52 patients (32 male and 20 female) were reviewed. Median age was 58 years and 88% were WHO 0–1. Histology included 54% epithelial, 17% biphasic (epithelial and sarcomatoid) and 21% undefined. The median time from diagnosis to administration of pemetrexed was 145 days. Sixty‐five percent had minimal surgical intervention with video assisted thoracoscopy, pleurodesis and biopsy, while 19% had received prior palliative radiation. Seventy‐one percent were chemotherapy naïve, the remaining 29% having received previous platinum and/or gemcitabine regimens. Twenty‐three percent had pemetrexed alone, 35% in combination with carboplatin and 42% with cisplatin. The median number of cycles was 4 (range 1–13). The response rate was 33%. No toxicity was observed in 20% grade 3–4 toxicity in 10% (majority nausea/vomiting). The median progression‐free and overall survival times from starting pemetrexed were 184 days and 298 days, respectively. Conclusions: Pemetrexed‐based regimens are safe and effective in a community setting in malignant mesothelioma. 相似文献
6.
Marco Antonio Botelho Rinaldo Araujo dos Santos Jose Galberto Martins Cintia Oliveira Carvalho Mabel Calina Paz Cláudio Azenha Ronaldo Sousa Ruela Dinalva Brito Queiroz Wagner Sousa Ruela Gloria Marinho Francisca Isabel Ruela 《Phytotherapy research : PTR》2009,23(9):1214-1219
An open, randomized, controlled study with two parallel treatment groups was done to evaluate the efficacy of a Lippia sidoides essential oil (EO) 1% mouthrinse compared with chlorhexidine 0.12% mouthrinse, applied two times daily for 1 week, in the treatment of dental plaque and gingivitis. Fifty‐five patients were included in the study. The efficacy variables were the colony count of Streptococcus mutans from the stimulated saliva and periodontal indices on days 0, 7 and 30 after commencement of therapy. Twenty eight patients received chlorhexidine mouthrinse (Periogard®) and 27 Lippia sidoides essential oil mouthrinse (Cepakill®). The clinical and microbiological parameters were significantly reduced by both mouthrinses. No significant difference was seen between the two groups (p > 0.05). There was a significant reduction in the colony count of S. mutans in both groups (p < 0.05). Chlorhexidine treatment reduced more efficiently than L. sidoides, however, no statistical difference was seen, the efficacy of both groups was similar (p = 0.3). The results indicate that Chlorhexidine mouthrinse reduced plaque index, gingival bleeding and the number of CFU (colonies forming units) more efficiently than L. sidoides but did not reach statistical significance. This study demonstrated that Lippia sidoides EO mouthrinse is effective in reducing microbial plaque and gingival inflammation. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
7.
A. B. Soares P. R. Faria L. A. Magna M. E. P. Correa C. A. de Sousa O. P. Almeida M. L. Cintra 《Journal of oral pathology & medicine》2005,34(6):368-373
BACKGROUND: Graft-vs.-host disease (GVHD) is the major cause of morbidity and mortality in patients undergoing allogeneic Bone Marrow Transplantation (BMT). The aim of our study was to identify the most relevant histological features for diagnosis of chronic Graft-vs.-Host Disease (cGVHD) in oral mucosa and minor salivary glands of 25 patients, as well as to evaluate the immunophenotype of the inflammatory cells. METHODS: Sixteen patients that were submitted to allogeneic BMT but did not present cGVHD were selected as a control group. The sections were studied on H & E and CD68, CD45, CD4, CD8, CD20 staining. RESULTS: The most frequent histologic findings in oral mucosa at the day of diagnosis of cGVHD were: hydropic degeneration of the basal layer of the epithelium, apoptotic bodies, lymphocytic infiltration, and focal or total cleavage between the epithelial and connective tissue. In the labial salivary glands (LSG), lymphocytic infiltration, acinar loss and fibrosis were the main alterations. Cytotoxic CD8-T cells and macrophages were predominant both in the epithelium and connective tissue, as well as in minor salivary glands. CONCLUSIONS: Histological features were useful in the diagnosis of oral cGVHD. It is suggested that CD8-T cells and macrophages play important role in the pathogenesis of the disease. 相似文献
8.
Intestinal intraepithelial lymphocytes (iIEL) are primarily CD8 cells and most of them have a CD28? phenotype, the phenotype of effector cytotoxic T cells. We asked whether the predominance of CD8+ CD28? T cells in the gut may result from peripheral blood T cells preferentially migrating to the iIEL compartment and adhering to iEC. Compared with CD4 cells, adhesion of resting CD8+ T cells to iEC cell lines was significantly higher. Adhesion could be blocked with a MoAb to gp180, a molecule expressed on iEC which is known to interact with CD8/lck. No significant difference in the level of adhesion was observed between CD8+ CD28+ and CD8+ CD28? T cells. Thus CD8 cells may preferentially migrate to the iIEL compartment, but loss of CD28 expression could occur in situ after migration. Consistent with this hypothesis, the CD8+ CD28? cells became enriched after co-culturing T cells with iEC cell lines and primary iEC. Induction of the CD8+ CD28? phenotype in cord blood and adult T cells was observed in co-cultures with iEC and also with mitogens and superantigens. In the latter case, CD28 down-modulation was seen specifically in the Vβ subset targeted by the superantigen, indicating that loss of CD28 expression is a direct result of T cell receptor (TCR)-mediated stimulation. The combined results suggest that CD8+ CD28? T cells are antigen experienced T cells, and that they may have a survival advantage in the presence of gut epithelial cells in vitro. This may contribute to the predominance of CD8+ CD28? T cells in the iIEL compartment. 相似文献
9.
Cecatti JG Souza JP Parpinelli MA de Sousa MH Amaral E 《Reproductive Health Matters》2007,15(30):125-133
The occurrence of complications during pregnancy depends less on the degree of human development than differences in the way complications in pregnancy are detected and managed. It is the quick diagnosis and correct management that really contribute to the enormous differences in maternal mortality ratios between countries and regions. Understanding of the determinants of maternal mortality may be improved by studying cases of severe maternal morbidity. In this paper, various approaches to the concept of severe maternal morbidity and near-misses are discussed, and the relationship between these and maternal deaths. Although no consensus has been reached on a strict definition of near-miss or severe maternal morbidity, we show that the definitions used may be tailored to support diverse objectives, including monitoring progress, epidemiological surveillance and auditing of health care. We conclude that the versatility of the concept, the greater frequency of cases available for study and the possibility of interviewing the survivors of severe complications all support the value of studying severe maternal morbidity to help guide local efforts to reduce maternal mortality. Although this may almost be a reality in developed countries, it continues to represent an important and difficult challenge to overcome in places where its benefits would be most evident. 相似文献
10.
Mário Martins Oliveira Nogueira da Silva Ana Teresa Timóteo Joana Feliciano Lídia de Sousa Sofia Santos Fernando Marques Rui Ferreira 《Revista portuguesa de cardiologia》2007,26(7-8):691-702
Atrial electrical remodeling plays a part in recurrence of atrial fibrillation (AF). It has been related to an increase in heterogeneity of atrial refractoriness that facilitates the occurrence of multiple reentry wavelets and vulnerability to AF. AIM: To examine the relationship between dispersion of atrial refractoriness (Disp_A) and vulnerability to AF induction (A_Vuln) in patients with clinical paroxysmal AF (PAF). METHODS: Thirty-six patients (22 male; age 55+/-13 years) with > or =1 year of history of PAF (no underlying structural heart disease--n=20, systemic hypertension--n=14, mitral valve prolapse--n=1, surgically corrected pulmonary stenosis--n=1), underwent electrophysiological study (EPS) while off medication. The atrial effective refractory period (AERP) was assessed at five different sites--high (HRA) and low (LRA) lateral right atrium, high interatrial septum (IAS), proximal (pCS) and distal (dCS) coronary sinus--during a cycle length of 600 ms. AERP was taken as the longest S1-S2 interval that failed to initiate a propagation response. Disp_A was calculated as the difference between the longest and shortest AERP. A_Vuln was defined as the ability to induce AF with 1-2 extrastimuli or with incremental atrial pacing (600-300 ms) from the HRA or dCS. The EPS included analysis of focal electrical activity based on the presence of supraventricular ectopic beats (spontaneous or with provocative maneuvers). The patients were divided into group A--AF inducible (n=25) and group B--AF not inducible (n=11). Disp_A was analyzed to determine any association with A_Vuln. Disp_A and A_Vuln were also examined in those patients with documented repetitive focal activity. Logistic regression was used to determine any association of the following variables with A_Vuln: age, systemic hypertension, left ventricular hypertrophy, left atrial size, left ventricular function, duration of PAF, documented atrial flutter/tachycardia and Disp_A. RESULTS: There were no significant differences between the groups with regard to clinical characteristics and echocardiographic data. AF was inducible in 71% of the patients and noninducible in 29%. Group A had greater Disp_A compared to group B (105+/-78 ms vs. 49+/-20 ms; p=0.01). Disp_A was >40 ms in 50% of the patients without A_Vuln and in 91% of those with A_Vuln (p=0.05). Focal activity was demonstrated in 14 cases (39%), 57% of them with A_Vuln. Disp_A was 56+/-23 ms in this group and 92+/-78 ms in the others (p=0.07). Using logistic regression, the only predictor of A_Vuln was Disp_A (p=0.05). CONCLUSION: In patients with paroxysmal AF, Disp_A is a major determinant of A_Vuln. Nevertheless, the degree of nonuniformity of AERP appears to be less important as an electrophysiological substrate for AF due to focal activation. 相似文献