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901.
Zunino F Dallavalleb S Laccabuea D Berettaa G Merlinib L Pratesi G 《Current pharmaceutical design》2002,8(27):2505-2520
Camptothecins are cytotoxic agents with a wide spectrum of antitumor activity. The unique mechanism of action, the impressive preclinical efficacy and the clinical success of irinotecan and topotecan have stimulated intensive efforts to identify novel analogues. The development of novel camptothecins was recently rationalized on the basis of the detailed knowledge of mechanism of drug-target interaction and was aimed to overcome the major limitations of these drugs (i.e. lactone ring instability and reversibility of topoisomerase I-DNA cleavage complexes). The development of novel series of analogues (7-substituted camptothecins, silatecans and homocamptothecins) resulted in identification of promising compounds, which are currently in clinical development. Considering the lack of precise correlations between preclinical activity and clinical efficacy of camptothecins, the potential advantages of novel analogs in clinical therapy remains to be documented. However, a rational basis for drug selection and development is now provided by the recognition of major limitations of these agents and by a detailed knowledge of multiple interactions between drug, cellular target and serum albumin. Inhibition of the nuclear enzyme DNA topoisomerase I has proven to be a promising strategy in the design of antitumor agents, in spite of a limited cellular basis of selectivity in cytotoxic action of camptothecins (i.e., overexpression of the target enzyme in tumor cells, and increased sensitivity of proliferating cells). The interest in topoisomerase I as a therapeutic target promoted various efforts to identify other chemotypes effective as topoisomerase inhibitors and chemical/modelling efforts to rationally design specific analogs among known inhibitors. Additional approaches, including drug delivery/formulation, optimization of dose/schedule and route of administration, are expected to improve the therapy with camptothecins and other inhibitors. 相似文献
902.
Poletti P Pinotti G Rosati G Luppi G Ibrahim T Marinozzi C Pucci F Pancera G Biasco G Barni S Garufi C Martignoni G Visonà G Labianca R 《Tumori》2002,88(2):104-109
The "Misura" project is a retrospective survey, with the aim to evaluate how 5FU is used in the treatment of colorectal cancer in clinical practice in Italian oncology departments. Twenty-four centers participated. Patients seen in the second half of 1998 with colorectal cancer and treated with 5FU were analyzed. Observed patients were 664, 45.9% of patients presented metastatic disease. Biochemical modulation with folinic acid and bolus 5FU was the most used schedule (59%). The De Gramont (LV 5FU2) regimen, alone or with other cytotoxic drugs, was the second most chosen schedule (14%). The most frequent side effect observed was gastrointestinal toxicity. No hematological toxicity was demonstrated in 68.8% of patients. Cutaneous toxicity occurred in 21.1% of patients. 5FU is widely used independently by the stage of disease. In palliative treatment a variety of schedules were administered by the Italian centers, lacking a standard therapy. There are very few surveys investigating oncology clinical practice. A larger survey on this issue is auspicable. 相似文献
903.
Hepatitis A virus (HAV) protein 2A has been demonstrated to be involved in virus morphogenesis and suggested to be located on the surface of the particle. To determine whether this protein can function as a target structure to harbor and expose foreign epitopes on HAV particles, a full-length HAV cDNA, containing a seven amino acid stretch of human immunodeficiency virus type 1 (HIV-1) envelope protein gp41, was constructed. Following vaccinia virus MVA-T7-mediated expression of the cDNA in COS7 and Huh-T7 cells, chimeric HAV particles, exposing the foreign epitope gp41 on their surface, were produced. These particles were found to be empty capsids (70S), as judged by immunospecific enzyme linked immunosorbent assay (ELISA) on sucrose gradient fractions and immunoelectron microscopy. The immunological detection of VP1-2A harboring the gp41 epitope of HIV suggests that the 2A domain of HAV is suitable to present foreign antigenic epitopes. 相似文献
904.
Varrone A Pappatà S Caracò C Soricelli A Milan G Quarantelli M Alfano B Postiglione A Salvatore M 《European journal of nuclear medicine and molecular imaging》2002,29(11):1447-1454
Characteristic patterns of regional cerebral blood flow (rCBF) reduction, as detected by technetium-99m hexamethylpropylene amine oxime ((99m)Tc-HMPAO) single-photon emission tomography (SPET), may help clinicians in differentiating patients with frontotemporal dementia (FTD) from those with Alzheimer's disease (AD). However, in some cases these patients may share common rCBF abnormalities and the visual analysis and/or the region of interest (ROI) approach may not sensitively detect more localised focal changes that could be more specific for each pathology. Recently, automated voxel-by-voxel statistical analysis of perfusion brain maps has been applied to SPET images. This method has the advantage of including the rCBF information for the whole brain for statistical analysis without any a priori hypothesis regarding the regions possibly involved. This could result in a better characterisation of rCBF differences in brain regions while also reducing the operator's subjectivity and the time required for data analysis. The purpose of this study was to apply such a technique to highlight the specific brain areas showing a relative functional involvement in FTD and AD. Thus, we compared the relative rCBF patterns obtained in eight FTD patients with those obtained in 21 AD patients using (99m)Tc-HMPAO SPET and statistical parametric mapping (SPM). When FTD patients were compared with AD patients, relatively lower rCBF was observed in right medial frontal cortex (BA 8, 9, 10), right anterior cingulate cortex (BA 32), right temporal cortex (BA 21/22), right orbitofrontal cortex (BA 11) and ventrolateral prefrontal cortex (BA 47); in BA 47 the reduction was evident bilaterally but was more marked on the right side. On the other hand, when AD patients were compared with FTD patients, a significant relative rCBF decrease was found in the bilateral superior parietal cortex (BA 7); this decrease was more extensive on the left side, where it also included the inferior parietal (BA 40), superior occipital (BA 19) and temporo-occipital regions (BA 39, 19). The results of this study confirm the preferential involvement of the frontotemporal regions in FTD patients and of the temporoparietal regions in AD patients. Furthermore, they highlight the networks that are more specifically impaired in these disorders and that could be implicated in the emotional-behavioural and cognitive disturbances that characterise FTD and AD respectively. 相似文献
905.
Influence of Mycobacterium bovis Bacillus Calmette Guérin on In Vitro Induction of CD1 Molecules in Human Adherent Mononuclear Cells
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906.
Mycobacterium tuberculosis diverts alpha interferon-induced monocyte differentiation from dendritic cells into immunoprivileged macrophage-like host cells 总被引:1,自引:0,他引:1
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Mariotti S Teloni R Iona E Fattorini L Romagnoli G Gagliardi MC Orefici G Nisini R 《Infection and immunity》2004,72(8):4385-4392
Dendritic cells (DCs) are critical for initiating a pathogen-specific T-cell response. During chronic infections the pool of tissue DCs must be renewed by recruitment of both circulating DC progenitors and in loco differentiating monocytes. However, the interaction of monocytes with pathogens could affect their differentiation. Mycobacterium tuberculosis has been shown to variably interfere with the generation and function of antigen-presenting cells (APCs). In this study we found that when alpha interferon (IFN-alpha) is used as an inductor of monocyte differentiation, M. tuberculosis inhibits the generation of DCs, forcing the generation of immunoprivileged macrophage-like cells instead. Cells derived from M. tuberculosis-infected monocyte-derived macrophages (M. tuberculosis-infected MoMphi) retained CD14 without acquiring CD1 molecules and partially expressed B7.2 but did not up-regulate B7.1 and major histocompatibility complex (MHC) class I and II molecules. They synthesized tumor necrosis factor alpha and interleukin-10 (IL-10) but not IL-12. They also showed a reduced ability to induce proliferation and functional polarization of allogeneic T lymphocytes. Thus, in the presence of IFN-alpha, M. tuberculosis may hamper the renewal of potent APCs, such as DCs, generating a safe habitat for intracellular growth. M. tuberculosis-infected MoMphi, in fact, showed reduced expression of both signal 1 (CD1, MHC classes I and II) and signal 2 (B7.1 and B7.2), which are essential for mycobacterium-specific T-lymphocyte priming and/or activation. These data further suggest that M. tuberculosis has the ability to specifically interfere with monocyte differentiation. This ability may represent an effective M. tuberculosis strategy for eluding immune surveillance and persisting in the host. 相似文献
907.
Annette Schmitt-Gräff Graziella Chakroun Giulio Gabbiani 《Virchows Archiv : an international journal of pathology》1993,422(2):99-107
Summary Hepatic perisinusoidal cells (PSCs) proliferate and are thought to be the principal source of extracellular matrix proteins during the development of liver fibrosis. We have studied the classical model of carbon tetrachloride induced liver fibrosis in order to evaluate the possible modulation of PSCs into a synthetically active and contractile cell: the myofibroblast (MF). At the ultrastructural level, this modulation was characterized by reduction of lipid vacuoles and appearance of a developed rough endoplasmic reticulum as well as of microfilament bundles. On investigating the cytoskeletal equipment of PSCs and MFs using light and electron microscopic immunohistochemistry, we found a heterogeneity of phenotypic features. While typical PSCs in normal and fibrotic livers always contained desmin, MFs expressed-smooth muscle (SM) actin in areas of tissue injury and active fibrogenesis. Cells co-expressing-SM actin and desmin were most prominent in the prevenular zone of the lobule (known to be vulnerable to carbon tetrachloride toxicity) and in developing fibrous septa. As demonstrated by immunogold electron microscopy, labelling of microfilament bundles by-SM actin antibody was noted in PSCs containing lipid droplets in early stages of fibrosis; here MFs gradually accumulated and showed-SM actin containing microfilament bundles. In scar tissue,-SM actin expression decreased in both PSCs and myofibroblasts. Our observations support the concept of phenotypic plasticity of PSCs and confirm, at the ultrastructural level, previous suggestions of modulation of these cells into MFs in the course of liver fibrosis. 相似文献
908.
Jackie W. Lu Victor B. Fenik Jennifer L. Branconi Graziella L. Mann Irma Rukhadze Leszek Kubin 《The Journal of physiology》2007,582(2):553-567
Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABAA receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABAA receptor antagonist, bicuculline (20 nl, 1 m m ), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABAA receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABAA receptor-expressing PF neurones may cause narcolepsy/cataplexy. 相似文献
909.
Cosma MP Pepe S Parenti G Settembre C Annunziata I Wade-Martins R Di Domenico C Di Natale P Mankad A Cox B Uziel G Mancini GM Zammarchi E Donati MA Kleijer WJ Filocamo M Carrozzo R Carella M Ballabio A 《Human mutation》2004,23(6):576-581
Multiple sulfatase deficiency (MSD) is a rare disorder characterized by impaired activity of all known sulfatases. The gene mutated in this disease is SUMF1, which encodes a protein involved in a post-translational modification at the catalytic site of all sulfatases that is necessary for their function. SUMF1 strongly enhances the activity of sulfatases when coexpressed with sulfatase in Cos-7 cells. We performed a mutational analysis of SUMF1 in 20 MSD patients of different ethnic origin. The clinical presentation of these patients was variable, ranging from severe neonatal forms to mild phenotypes showing mild neurological involvement. A total of 22 SUMF1 mutations were identified, including missense, nonsense, microdeletion, and splicing mutations. We expressed all missense mutations in culture to study their ability to enhance the activity of sulfatases. Of the predicted amino acid changes, 11 (p.R349W, p.R224W, p.L20F, p.A348P, p.S155P, p.C218Y, p.N259I, p.A279V, p.R349Q, p.C336R, p.A177P) resulted in severely impaired sulfatase-enhancing activity. Two (p.R345C and p.P266L) showed a high residual activity on some, but not all, of the nine sulfatases tested, suggesting that some SUMF1 mutations may have variable effects on the activity of each sulfatase. This study compares, for the first time, clinical, biochemical, and molecular data in MSD patients. Our results show lack of a direct correlation between the type of molecular defect and the severity of phenotype. 相似文献
910.
Köhler B Lumbroso S Leger J Audran F Grau ES Kurtz F Pinto G Salerno M Semitcheva T Czernichow P Sultan C 《The Journal of clinical endocrinology and metabolism》2005,90(1):106-111
Androgen insensitivity syndrome (AIS) is caused by numerous mutations of the androgen receptor (AR) gene. The phenotype may range from partial AIS (PAIS) with ambiguous genitalia to complete AIS (CAIS) with female genitalia. In 70% of the cases, AR mutations are transmitted in an X-linked recessive manner through the carrier mothers, but in 30%, the mutations arise de novo. When de novo mutations occur after the zygotic stage, they result in somatic mosaicisms, which are an important consideration for both virilization in later life-because both mutant and wild-type receptors are expressed-and genetic counseling. We report here six patients with AIS due to somatic mutations of the AR and one mother with somatic mosaicism who transmitted the mutation twice. Of the four patients with PAIS, three presented spontaneous or induced virilization at birth or puberty. These cases underline the crucial role of the remnant wild-type AR for virilization because the same mutations, when they are inherited, lead to CAIS. We also report two novel mutations of the AR, with somatic mosaicism, detected in patients with CAIS. Thus, the remnant wild-type receptor does not always lead to virilization. In one of these patients, a high ratio of wild-type to mutant AR expression was found in the gonads and genital skin fibroblasts. Although no prenatal virilization occurred, the possibility of virilization at puberty could not be excluded, and early gonadectomy was performed. A seventh patient had a CAIS with a novel germline AR mutation. The mutation was inherited from the mother, in whom mosaicism was detected in blood and who transmitted the mutation to a second, XX, offspring. The detection of somatic AR mutations is particularly important for the clinical management and genetic counseling of patients with AIS. Before definite sex assignment, a testosterone treatment trial should be performed in all patients with PAIS, but it becomes crucial when an AR mosaicism has been detected. In patients with CAIS or severe PAIS raised as female, there is no consensus about when (early childhood or puberty) gonadectomy should be performed. When somatic AR mutations are detected, however, gonadectomy should be performed earlier because of the risk of virilization during puberty. When a germline de novo mutation is identified in the index case, the risk of transmission to a second child due to a possible germ cell mosaicism in the mother cannot be excluded. However, given the high number of AR de novo mutations and the rarity of such reports, this risk appears to be very low. 相似文献