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71.
Conservative surgery for early cancer of the distal rectum 总被引:6,自引:5,他引:6
Claudio Coco M.D. Paolo Magistrelli M.D. Pierluigi Granone M.D. Giuliano Roncolini M.D. Aurelio Picciocchi M.D. 《Diseases of the colon and rectum》1992,35(2):131-136
From 1967 through 1988, 36 patients underwent local excision of a distal rectal cancer as an initial operative procedure with curative intent. A diagnostic, preoperative protocol was performed to assess the histologic grade of the tumor, the depth of penetration in the rectal wall, and the presence of positive lymph nodes or distant metastases. All patients had a transanal local excision performed under general anesthesia. If preoperative criteria were not confirmed by histopathologic specimen examination, a major operation was advised. To increase the chance of local control, external adjuvant radiotherapy was used in T2 cancers. Postoperative mortality was 0 percent. The postoperative complication rate was 9.3 percent. The observed local recurrence rate was 3 percent, and the rectal cancer-specific death rate was 6 percent. We compared these results with those obtained in 70 concomitant patients operated on by us employing a traditional resection for Dukes' A rectal cancer. There are no statistically significant differences between groups. In light of our findings, a policy of curative local excision is justified in accurately selected cases of distal rectal cancer. 相似文献
72.
Calmodulin accelerates the rate of polymerization of human platelet actin and alters the structural characteristics of actin filaments. 总被引:3,自引:1,他引:3
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G A Piazza R W Wallace 《Proceedings of the National Academy of Sciences of the United States of America》1985,82(6):1683-1687
Calmodulin stimulated the rate of Mg2+-induced polymerization of human platelet actin. The stimulatory effect was due to an increase in the nucleation phase of the reaction; there was no effect on the steady-state viscosity. The calmodulin antagonist trifluoperazine blocked the stimulatory effect of calmodulin. Addition of EGTA to the reaction mixture also stimulated the rate of actin polymerization; however, the effect of calmodulin on actin polymerization is not due to Ca2+ chelation, as is presumed to be the case for EGTA. Electron microscopy revealed structural differences in the filaments prepared in the presence of calmodulin as compared to those prepared with trifluoperazine. In the presence of calmodulin, the filaments were thicker, suggesting that they consisted of multiple actin polymers. In addition, numerous projections were present perpendicular to the filaments, as well as localized areas of filament bundling. It was not possible to demonstrate a direct interaction between calmodulin and actin, which raises the possibility that the calmodulin effect may be indirect through a calmodulin-binding protein or calmodulin-dependent enzyme. Regardless of whether calmodulin is acting directly or indirectly, these results provide evidence that calmodulin may play a regulatory role in either the polymerization of actin or in determining the structural characteristics of actin filaments. 相似文献
73.
Ph.?MonnierEmail author F.?G.?Dikkers H.?Eckel C.?Sittel C.?Piazza G.?Campos M.?Remacle G.?Peretti 《European archives of oto-rhino-laryngology》2015,272(10):2885-2896
Adult and pediatric laryngotracheal stenoses (LTS) comprise a wide array of various conditions that require precise preoperative assessment and classification to improve comparison of different therapeutic modalities in a matched series of patients. This consensus paper of the European Laryngological Society proposes a five-step endoscopic airway assessment and a standardized reporting system to better differentiate fresh, incipient from mature, cicatricial LTSs, simple one-level from complex multilevel LTSs and finally “healthy” from “severely morbid” patients. The proposed scoring system, which integrates all of these parameters, may be used to help define different groups of LTS patients, choose the best treatment modality for each individual patient and assess distinct post-treatment outcomes accordingly. 相似文献
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Celine Valant Lauren T. May Luigi Aurelio Chung Hui Chuo Paul J. White Jo-Anne Baltos Patrick M. Sexton Peter J. Scammells Arthur Christopoulos 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(12):4614-4619
The concepts of allosteric modulation and biased agonism are revolutionizing modern approaches to drug discovery, particularly in the field of G protein-coupled receptors (GPCRs). Both phenomena exploit topographically distinct binding sites to promote unique GPCR conformations that can lead to different patterns of cellular responsiveness. The adenosine A1 GPCR (A1AR) is a major therapeutic target for cardioprotection, but current agents acting on the receptor are clinically limited for this indication because of on-target bradycardia as a serious adverse effect. In the current study, we have rationally designed a novel A1AR ligand (VCP746)—a hybrid molecule comprising adenosine linked to a positive allosteric modulator—specifically to engender biased signaling at the A1AR. We validate that the interaction of VCP746 with the A1AR is consistent with a bitopic mode of receptor engagement (i.e., concomitant association with orthosteric and allosteric sites) and that the compound displays biased agonism relative to prototypical A1AR ligands. Importantly, we also show that the unique pharmacology of VCP746 is (patho)physiologically relevant, because the compound protects against ischemic insult in native A1AR-expressing cardiomyoblasts and cardiomyocytes but does not affect rat atrial heart rate. Thus, this study provides proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins and tractable drug targets (1, 2). Unfortunately, there remains a high attrition rate associated with traditional GPCR-based drug discovery that, in part, reflects an emphasis on the endogenous agonist binding (orthosteric) site as the predominant means of achieving selective GPCR drug targeting (3). Over the last decade, substantial breakthroughs have occurred in the exploitation of topographically distinct GPCR allosteric sites as a means for attaining greater selectivity, especially in those instances where there is high sequence similarity in the orthosteric site across GPCR subtypes (4–6). However, there are increasing examples where both the therapeutic effect and adverse effects are mediated by the same GPCR target (7). In these situations, the desired selectivity needs to be attained at the level of the intracellular signaling pathways linked to a given receptor subtype.GPCRs are highly dynamic proteins, fluctuating between different conformations; these conformations can be linked to different cellular outcomes (8). Thus, chemically distinct ligands, interacting with either orthosteric or allosteric sites, have the potential to stabilize different interaction networks within a GPCR to promote a subset of signaling pathways linked to the receptor at the expense of others. This phenomenon has been termed biased agonism (7, 9, 10). The overall promise of biased agonism is the ability to design GPCR ligands that selectively engage therapeutically relevant signaling pathways while sparing pathways that contribute to undesirable side effects mediated by the same target.The adenosine receptor (AR) family is an important class of physiologically and therapeutically relevant GPCRs that can benefit substantially from more selective drug targeting. Although all four AR subtypes are expressed in the mammalian heart (11, 12), the well-known protective effects of adenosine in this tissue are predominantly mediated by the adenosine A1 receptor (A1AR) subtype, especially under conditions of ischemia and reperfusion injury (13–17). Unfortunately, the transition of A1AR agonists into the clinic has been severely hindered because of high doses causing on-target bradycardia, atrioventricular block, and hypotension (13, 18). As a consequence, clinical trials of AR agonists have had limited success because of the suboptimal dose of agonist that can be used (19–22). It is possible that this problem may be overcome through the exploitation of biased agonism at the A1AR.Although no study has identified biased orthosteric A1AR ligands, we recently showed that the 2-amino-3-benzoylthiophene allosteric modulator (VCP171) could promote biased signaling in the activity of the prototypical orthosteric agonist, R(-)N6-(2-phenylisopropyl) adenosine (R-PIA) (23). Thus, we hypothesized that the rational design of a bitopic ligand (i.e., a class of hybrid molecule containing both orthosteric and allosteric pharmacophores) (24–26) may be able to achieve high efficacy and biased agonism at the A1AR in a single molecule. Herein, we report proof of concept that it is possible to use this approach as a means to dissociate on-target efficacy from on-target side effects. 相似文献
76.
Rehab H. Abd El‐Aleam Riham F. George Kevin J. Lee Adam B. Keeton Gary A. Piazza Amr A. Kamel Mahmoud E. El‐Daly Ghaneya S. Hassan Hamdy M. Abdel‐Rahman 《Archiv der Pharmazie》2019,352(8)
A series of 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC50 values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC50 = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity. 相似文献
77.
Gregory Piazza Samuel Z. Goldhaber Aimee Kroll Robert J. Goldberg Catherine Emery Frederick A. Spencer 《The American journal of medicine》2012,125(10):1010-1018
ObjectiveOur aim was to compare the clinical characteristics, prophylaxis, treatment, and outcomes of venous thromboembolism in patients with and without previously diagnosed chronic obstructive pulmonary disease.MethodsWe analyzed the population-based Worcester Venous Thromboembolism Study of 2488 consecutive patients with validated venous thromboembolism to compare clinical characteristics, prophylaxis, treatment, and outcomes in patients with and without chronic obstructive pulmonary disease.ResultsOf 2488 patients with venous thromboembolism, 484 (19.5%) had a history of clinical chronic obstructive pulmonary disease and 2004 (80.5%) did not. Patients with chronic obstructive pulmonary disease were older (mean age 68 vs 63 years) and had a higher frequency of heart failure (35.5% vs 12.9%) and immobility (53.5% vs 43.3%) than patients without chronic obstructive pulmonary disease (all P < .0001). Patients with chronic obstructive pulmonary disease were more likely to die in hospital (6.8% vs 4%, P = .01) and within 30 days of venous thromboembolism diagnosis (12.6% vs 6.5%, P < .0001). Patients with chronic obstructive pulmonary disease demonstrated increased mortality despite a higher frequency of venous thromboembolism prophylaxis. Immobility doubled the risk of in-hospital death (adjusted odds ratio, 2.21; 95% confidence interval, 1.35-3.62) and death within 30 days of venous thromboembolism diagnosis (adjusted odds ratio, 2.04; 95% confidence interval, 1.43-2.91).ConclusionPatients with chronic obstructive pulmonary disease have an increased risk of dying during hospitalization and within 30 days of venous thromboembolism diagnosis. Immobility in patients with chronic obstructive pulmonary disease is an ominous risk factor for adverse outcomes. 相似文献
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79.
Maggio A Vitrano A Lucania G Capra M Cuccia L Gagliardotto F Pitrolo L Prossomariti L Filosa A Caruso V Gerardi C Campisi S Cianciulli P Rizzo M D'Ascola G Ciancio A Di Maggio R Calvaruso G Pantalone GR Rigano P 《American journal of hematology》2012,87(7):732-733
A multicenter randomized open-label long-term sequential deferiprone–deferoxamine (DFP-DFO) versus DFP alone trial (sequential DFP-DFO) performed in patients with thalassemia major (TM) was retrospectively reanalyzed to assess the variation in the left ventricular ejection fraction (LVEF) [1]. 相似文献
80.