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991.
Gopi H Umashankara M Pirrone V LaLonde J Madani N Tuzer F Baxter S Zentner I Cocklin S Jawanda N Miller SR Schön A Klein JC Freire E Krebs FC Smith AB Sodroski J Chaiken I 《Journal of medicinal chemistry》2008,51(9):2638-2647
Structure-activity correlations were investigated for substituted peptide conjugates that function as dual receptor site antagonists of HIV-1 gp120. A series of peptide conjugates were constructed via click reaction of both aryl and alkyl acetylenes with an internally incorporated azidoproline 6 derived from the parent peptide 1 (12p1, RINNIPWSEAMM). Compared to 1, many of these conjugates were found to exhibit several orders of magnitude increase in both affinity for HIV-1 gp120 and inhibition potencies at both the CD4 and coreceptor binding sites of gp120. We sought to determine structural factors in the added triazole grouping responsible for the increased binding affinity and antiviral activity of the dual inhibitor conjugates. We measured peptide conjugate potencies in both kinetic and cell infection assays. High affinity was sterically specific, being exhibited by the cis- but not the trans-triazole. The results demonstrate that aromatic, hydrophobic, and steric features in the residue 6 side-chain are important for increased affinity and inhibition. Optimizing these features provides a basis for developing gp120 dual inhibitors into peptidomimetic and increasingly smaller molecular weight entry antagonist leads. 相似文献
992.
Daniel Suez Mark Stein Sudhir Gupta Iftikhar Hussain Isaac Melamed Kenneth Paris Amy Darter Christelle Bourgeois Sandor Fritsch Heinz Leibl Barbara McCoy David Gelmont Leman Yel 《Journal of clinical immunology》2016,36(7):700-712
Patients with primary immunodeficiency disease (PIDD) typically require life-long intravenous (IV) or subcutaneous (SC) immunoglobulin (Ig) replacement therapy to prevent recurrent infections. The efficacy, safety, and pharmacokinetics of a highly concentrated (20 %) Ig preparation for SC administration (IGSC 20 %) were evaluated in a prospective trial in patients with PIDD. A total of 74 patients (aged 3–83 years) received 4327 IGSC 20 % infusions over a median of 380.5 days. The rate of validated serious bacterial infections was 0.012 event/patient-year (p?<?0.0001 compared with the historical control), and the annualized rate of infection was 2.41 events/patient. Median IgG trough levels were >14.5 g/l. The median maximum infusion rate was 60 ml/h/site (range 4.4–180), resulting in a median infusion duration of 0.95 h. A volume ≥30 ml was infused per site in 74.8 % of IGSC 20 % infusions. Most (84.9 %) infusions were administered using ≤2 infusion sites; for 99.8 % of infusions, there was no need to interrupt/stop administration or reduce the infusion rate. No related serious adverse event (AE) occurred during IGSC 20 % treatment; related non-serious AEs occurred at a rate of 0.036 event/infusion. The incidence of related local AEs was 0.015 event/infusion and of related systemic AEs was 0.021 event/infusion; most were mild in severity, none severe. Increased infusion rates or volumes were not associated with higher AE rates. The investigated IGSC 20 % treatment was shown to be effective and safe, enabling higher infusion rates and volumes per site compared to conventional SC treatments, resulting in fewer infusion sites and shorter infusion durations. 相似文献
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George A. K. van Voorn Pepijn Vemer Dominique Hamerlijnck Isaac Corro Ramos Geertruida J. Teunissen Maiwenn Al Talitha L. Feenstra 《Applied health economics and health policy》2016,14(2):129-133
Evaluations of healthcare interventions, e.g. new drugs or other new treatment strategies, commonly include a cost-effectiveness analysis (CEA) that is based on the application of health economic (HE) models. As end users, patients are important stakeholders regarding the outcomes of CEAs, yet their knowledge of HE model development and application, or their involvement therein, is absent. This paper considers possible benefits and risks of patient involvement in HE model development and application for modellers and patients. An exploratory review of the literature has been performed on stakeholder-involved modelling in various disciplines. In addition, Dutch patient experts have been interviewed about their experience in, and opinion about, the application of HE models. Patients have little to no knowledge of HE models and are seldom involved in HE model development and application. Benefits of becoming involved would include a greater understanding and possible acceptance by patients of HE model application, improved model validation, and a more direct infusion of patient expertise. Risks would include patient bias and increased costs of modelling. Patient involvement in HE modelling seems to carry several benefits as well as risks. We claim that the benefits may outweigh the risks and that patients should become involved. 相似文献
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Maharrish Chelladurai Dan Xu Sivan Izraely Shlomit Ben-Menachem Roman Bengaiev Orit Sagi-Assif Weirong Yuan Metsada Pasmanik Chor Dave S. Hoon Wuyuan Lu Isaac P. Witz 《International journal of cancer. Journal international du cancer》2024,154(3):561-572
Metastatic (as well as tumor) microenvironments contain both cancer-promoting and cancer-restraining factors. The balance between these opposing forces determines the fate of cancer cells that disseminate to secondary organ sites. In search for microenvironmental drivers or inhibitors of metastasis, we identified, in a previous study, the beta subunit of hemoglobin (HBB) as a lung-derived antimetastatic factor. In the present study, exploring mechanisms regulating melanoma brain metastasis, we discovered that brain-derived factors restrain proliferation and induce apoptosis and necrosis of brain-metastasizing melanoma cells. Employing various purification procedures, we identified a heterodimer composed of hemoglobin alpha and beta chains that perform these antimetastatic functions. Neither the alpha nor the beta subunit alone was inhibitory. An alpha/beta chain dimer chemically purified from human hemoglobin inhibited the cell viability of primary melanomas, melanoma brain metastasis (MBM), and breast cancer cell lines. The dimer-induced DNA damage, cell cycle arrest at the SubG1 phase, apoptosis, and significant necrosis in four MBM cell lines. Proteomic analysis of dimer-treated MBM cells revealed that the dimer downregulates the expression of BRD4, GAB2, and IRS2 proteins, playing crucial roles in cancer cell sustainability and progression. Thus, we hypothesize that the hemoglobin dimer functions as a resistance factor against brain-metastasizing cancer cells. 相似文献
1000.
Isabel B. Cruz Peter J. F. Snijders Chris J. Meijer Boudewijn J. Braakhuis Gordon B. Snow Jan M. Walboomers Isaac van der Waal 《The Journal of pathology》1998,184(4):360-368
Epithelial dysplasia is usually used to establish the prognosis of oral premalignant lesions. Its assessment, however, is subjective and does not always correctly predict the outcome of the lesions in terms of malignant transformation. Early molecular alteration(s) that dictate the development of cancer should be identified and used to evaluate oral premalignant lesions. In this context, alterations in the expression of p53 were investigated. Thirty-five oral premalignant lesions and 11 carcinomas that developed from them in a period of 16 years were investigated for p53 expression by immunohistochemistry. Normal oral mucosa from healthy individuals and oral benign lesions were used as controls. In benign lesions and normal mucosa, p53 staining, when present, was confined to the basal cell layer. Seven out of 35 (20 per cent) premalignant lesions showed p53 expression clearly above the basal cell layer and six of these (86 per cent) developed carcinomas. Suprabasal p53 expression was found in three lesions with no or mild dysplasia that developed carcinomas. All carcinomas derived from premalignant lesions with p53 suprabasal expression showed p53 expression in neoplastic cells. The combined use of histological parameters (presence of moderate or severe dysplasia) with p53 expression patterns (p53 staining above the basal cell layer) showed the highest sensitivity for the detection of lesions that progressed to carcinoma (91 per cent). When used individually, the p53 expression pattern showed higher specificity than assessment of dysplasia (96 per cent vs. 54 per cent) and higher positive predictive value (86 per cent vs. 44 per cent) for correct prediction of the malignant transformation of the lesions. The results suggest that clear expression of p53 above the basal cell layer is an early event in oral carcinogenesis and an indicator of a developing carcinoma, even preceding morphological tissue alterations. However, since immunohistochemistry cannot always detect changes in p53 expression in lesions preceding carcinoma, p53 immunohistochemical analysis is strongly recommended in conjunction with histological parameters, to increase the sensitivity of detection of cases that will progress to carcinoma. © 1998 John Wiley & Sons, Ltd. 相似文献