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41.
Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors
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Hartley O Gaertner H Wilken J Thompson D Fish R Ramos A Pastore C Dufour B Cerini F Melotti A Heveker N Picard L Alizon M Mosier D Kent S Offord R 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(47):16460-16465
We have used total chemical synthesis to perform high-resolution dissection of the pharmacophore of a potent anti-HIV protein, the aminooxypentane oxime of [glyoxylyl1]RANTES(2-68), known as AOP-RANTES, of which we designed and made 37 analogs. All involved incorporation of one or more rationally chosen nonnatural noncoded structures, for which we found a clear comparative advantage over coded ones. We investigated structure-activity relationships in the pharmacophore by screening the analogs for their ability to block the HIV entry process and produced a derivative, PSC-RANTES [N-nonanoyl, des-Ser1[L-thioproline2, L-cyclohexylglycine3]-RANTES(2-68)], which is 50 times more potent than AOP-RANTES. This promising group of compounds might be optimized yet further as potential prophylactic and therapeutic anti-HIV agents. The remarkable potency of our RANTES analogs probably involves the unusual mechanism of intracellular sequestration of CC-chemokine receptor 5 (CCR5), and it has been suggested that this arises from enhanced affinity for the receptor. We found that inhibitory potency and capacity to induce CCR5 down-modulation do appear to be correlated, but that unexpectedly, inhibitory potency and affinity for CCR5 do not. We believe this study represents the proof of principle for the use of a medicinal chemistry approach, above all one showing the advantage of noncoded structures, to the optimization of the pharmacological properties of a protein. Medicinal chemistry of small molecules is the foundation of modern pharmaceutical practice, and we believe we have shown that techniques have now reached the point at which the approach could also be applied to the many macromolecular drugs now in common use. 相似文献
42.
Persistence of thyroid microsomal and thyroglobulin antigens in primary cultures of human thyroid epithelium 总被引:2,自引:0,他引:2
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The changes in the amount and distribution of thyroglobulin and thyroid `microsomal' antigens were studied in primary explant and monolayer cultures of human thyroid epithelium which were alive for about 60 days. Both explant and monolayer cultures produced thyroglobulin in vitro at all times during the 60-day period of observation. However, the number of cells containing the thyroid `microsomal' antigen and the amount of antigen in individual cells both diminished though the antigen was detectable in a proportion of viable cells in all cultures at all times during the 60-day period of observation of this report. 相似文献
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44.
Cerini R Faccioli N Barillari M De Iorio M Carner M Colletti V Pozzi Mucelli R 《La Radiologia medica》2008,113(2):265-277
PURPOSE: The aim of this study was to illustrate the different imaging features of middle and inner ear implants, brainstem implants and inferior colliculus implants. MATERIALS AND METHODS: We retrospectively reviewed the computed tomography (CT) images of 468 patients with congenital or acquired transmissive or neurosensory hearing loss who underwent surgery. The implants examined were: 22 Vibrant Soundbridge implants, 5 at the long limb of the incus and 17 at the round window, 350 cochlear implants, 95 brainstem implants and 1 implant at the inferior colliculus. All patients underwent a postoperative CT scan (single or multislice scanner) and/or a Dentomaxillofacial cone-beam CT scan (CBCT) (axial and multiplanar reconstruction), and/or a plain-film radiography to visualise the correct position of the implant. RESULTS: The CBCT scan depicts Vibrant site of implant better than plain-film radiography, with a lower radiation dose compared to CT. For cochlear implants, a single plain radiograph in the Stenvers projection can directly visualise the electrodes in the cochlea. All patients with brainstem or inferior colliculus implants underwent postoperative CT to exclude complications and the assess correct implantation, but the follow-up of these implants can be performed by plain radiography alone. CONCLUSIONS: CT and CBCT scans are reliable and relatively fast methods for precisely determining the location of middle ear implants. CBCT is preferable to CT because of the lower radiation dose administered; a single plain-film radiograph is enough to visualise and follow-up cochlear, brainstem and inferior colliculus implants. 相似文献
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Chiara Mameli Dario Dilillo Daniele Spiri Chiara Cerini Silvia Fasan Gian Vincenzo Zuccotti 《Pediatric neurology》2013,48(5):418-420
Posterior reversible encephalopathy syndrome is a recently described cliniconeuroradiological syndrome reported in children with several predisposing conditions such as transplantation, autoimmune, hematological, infectious, renal, and neoplastic diseases or administration of chemotherapeutic immunosuppressive drugs. Seizures are one of the most frequent manifestations of posterior reversible encephalopathy syndrome; status epilepticus has been described more frequently in adults but rarely in children. We report on the case of a 6-year-old healthy boy who presented status epilepticus as the main manifestation of posterior reversible encephalopathy syndrome in the absence of other underlying conditions. This is the first report of posterior reversible encephalopathy syndrome in a previously healthy child. Our case reminds us that pathogenesis of this condition is far from being completely understood and may include both genetic and environmental factors. Moreover, posterior reversible encephalopathy syndrome should always be suspected by clinicians in cases of status epilepticus with a prolonged neurological failure. 相似文献
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48.
Rita Fossaceca Giuseppe Guzzardi Paolo Cerini Claudio Cusaro Alessandro Stecco Giuseppe Parziale Marco Perchinunno Marco De Bonis Alessandro Carriero 《Cardiovascular and interventional radiology》2013,36(3):637-644
Purpose
To evaluate the efficacy of percutaneous transluminal angioplasty (PTA) in a selected population of diabetic patients with below-the-knee (BTK) disease and to analyze the reliability of the angiosome model.Methods
We made a retrospective analysis of the results of PTA performed in 201 diabetic patients with BTK-only disease treated at our institute from January 2005 to December 2011. We evaluated the postoperative technical success, and at 1, 6, and 12 months’ follow-up, we assessed the rates and values of partial and complete ulcer healing, restenosis, major and minor amputation, limb salvage, and percutaneous oximetry (TcPO2) (Student’s t test). We used the angiosome model to compare different clinicolaboratory outcomes in patients treated by direct revascularization (DR) from patients treated with indirect revascularization (IR) technique by Student’s t test and the χ2 test.Results
At a mean ± standard deviation follow-up of 17.5 ± 12 months, we observed a mortality rate of 3.5 %, a major amputation rate of 9.4 %, and a limb salvage rate of 87 % with a statistically significant increase of TcPO2 values at follow-up compared to baseline (p < 0.05). In 34 patients, treatment was performed with the IR technique and in 167 by DR; in both groups, there was a statistically significant increase of TcPO2 values at follow-up compared to baseline (p < 0.05), without statistically significant differences in therapeutic efficacy.Conclusion
PTA of the BTK-only disease is a safe and effective option. The DR technique is the first treatment option; we believe, however, that IR is similarly effective, with good results over time. 相似文献49.
Mandalà M Colletti L Carner M Barillari M Cerini R Mucelli RP Colletti V 《Auris, nasus, larynx》2011,38(4):547-550
Pneumolabyrinth due to late complications of stapes surgery is a rare entity. Symptoms may include various degrees of hearing loss, tinnitus and dizziness. We report the case of a 67-year-old patient who developed a unique pneumolabyrinth variant affecting the vestibule, cochlea and semicircular canals 28 years after stapedectomy. The patient presented with intractable paroxysmal positional vertigo of the lateral semicircular canal. The pneumolabyrinth was visualized by means of high resolution computed tomography. Exploratory tympanotomy findings were consistent with a perilymphatic fistula. One year after surgical treatment the subject was free of vertigo spells. Pathogenetic mechanisms are discussed. 相似文献
50.
Peiman Nazerian Gabriele Cerini Simone Vanni Chiara Gigli Maurizio Zanobetti Maurizio Bartolucci Stefano Grifoni Giovanni Volpicelli 《Critical Ultrasound Journal》2016,8(1):17