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Biomedical subjects

A Sobel

Publications and source records attributed to A Sobel.

At least 19 recordsLinked to original sources
PubMed2005

Beneficial effect of highly active antiretroviral therapy on the prognosis of AIDS-related systemic non-Hodgkin lymphomas.

The influence of HAART on the survival of patients with AIDS-related lymphoma (ARL) was evaluated. A retrospective analysis of 73 HIV-1-infected patients with proven ARL diagnosed between 1992 and 2000 was conducted. Patients received uniformly the same chemotherapy regimen according to CD4 cell counts at NHL diagnosis:, patients with CD4 cells below or above 100 cells x 10(6)/liter received CHOP or ACVBP regimens, respectively. Event-free survival (EFS) and survival were estimated by the Kaplan-Meir method and a Cox model was used to evaluate the effect of different variables on survival. At diagnosis of ARL, the median age was 37 years and 22 patients (30%) had prior AIDS-defining events. Median CD4 cell count was 99 x 10(6)/liter. The median follow-up was 60 months. Ann Arbor stage 3-4 was noted in 60 patients (82%) and bone marrow or meningeal involvement was present in 13 (17%) and 12 (16%) patients, respectively. Two groups were identified: group 1 (n = 38) included patients who had never received HAART and group 2 (n = 35) included those who received HAART either before the diagnosis or following ARL. There was no statistical significant differences in lymphoma extensive stage, presence of B symptoms, meningeal involvement, CD4 cell count at diagnosis, prior AIDS events, or chemotherapy regimens between the two groups. Median survival (MS) of the whole cohort of patients was 8 months. Estimated EFS was significantly higher (30 months) in group 2 compared to group 1 (6.1 months) (p = 0.03). In the multivariate Cox model HAART has an independent significant effect on EFS (p = 0.0085). No influence on outcome was found for other variables except for prior AIDS and bone marrow involvement. HAART has significantly improved the survival and EFS in patients with ARL, independently of chemotherapy regimen.

Adult↗
PubMed2003

Evaluation of buprenorphine maintenance treatment in a French cohort of HIV-infected injecting drug users.

BACKGROUND: Buprenorphine was approved in France for treating opiate dependence in July 1995 and can be prescribed by general practitioners (GPs). Most studies assessing buprenorphine maintenance treatment (BMT) outcomes have taken place in GP settings. An evaluation of BMT outcomes in patients already followed for their HIV-infection could supply additional information about the changes in addictive practices in a non-GP setting. METHODS: We assessed BMT discontinuations and the course of self-reported addictive behaviours and characteristics associated with buprenorphine-injection misuse in 114 HIV-infected patients on BMT who were followed in a hospital-based outpatient department. RESULTS: The continuous series of follow-up visits at which these 114 patients reported regular buprenorphine prescriptions accounted for 237.5 person-years of observation, i.e. 475 follow-up visits. Of the 114 patients on BMT, 43% continued BMT throughout the follow-up, 40% stopped it, and results for 17% were not available either because they did not answer the self-administered questionnaire (5%) or because they were lost to follow-up (12%). Addictive behaviours declined but buprenorphine injection misuse remained stable. Depression measured by the CESD score (RR=1.04 95%CI [1.01-1.06]), cocaine use (RR=2.48 95%CI [1.31-4.68]) and alcohol consumption exceeding 4 alcohol units (AU) per day (RR=2.29, 95%CI [1.17-4.46]) were independently associated with buprenorphine injection misuse among stabilised BMT patients. CONCLUSIONS: Despite the reduction in drug injection after starting BMT, buprenorphine injection misuse mainly involves patients with characteristics of severe addiction. Better monitoring of the illicit drug use patterns of patients on BMT may suggest new medical strategies for GPs to improve BMT outcomes.

Adult↗
PubMed2003

[The stathmin-tubulin interaction and the regulation of the microtubule assembly].

Stathmin family proteins interact with tubulin and negatively regulate its assembly in microtubules. One stathmin molecule forms a complex with two alphabeta tubulin heterodimers in an interaction that is weakened upon stathmin phosphorylation. The X-ray structure of crystals of the complex reveals a head-to-tail arrangement of the two tubulins which are connected by a long stathmin alpha helix. By holding tubulins in a curved complex that is not incorporated in microtubules, stathmin lowers the pool of "assembly competent" tubulin. An alternate mechanism has been also proposed to account for the stathmin action in vivo; it involves a direct interaction of stathmin with microtubule (+) ends. More experiments are needed to evaluate the relative contribution of this alternative mechanism to the regulation of tubulin assembly by stathmin.

Dimerization↗
PubMed2003

Failure to maintain adherence to HAART in a cohort of French HIV-positive injecting drug users.

The study, carried out in the French MANIF 2000 cohort of HIV positive patients contaminated through injecting drug use, assessed the impact of patients' sociodemographic and psychological characteristics, behaviors toward drug abuse, and antiretroviral treatment characteristics on the maintenance of adherence to HAART (highly active antiretroviral therapies). A total of 96 patients (30 men and 66 women), who were initially adherent at their first visit after HAART prescription, were considered for analysis. Among these 96 patients, 22 (22.9%) experienced adherence failure defined as a self-reported, non-adherence behavior at any visit before the 18th month of treatment. Logistic regression showed that lack of a stable relationship, active drug injection, and depression were independently associated with adherence failure. Patients' counseling for facilitating maintenance of adherence to HAART over time should focus on prevention of drug use, provision of social support and consider the potential impact of difficulties with treatment on psychological well-being.

Adult↗
PubMed2001

Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy.

In a sample of 277 patients included in the French APROCO cohort study who were initially adherent at follow-up visit 4 months after initiation of a protease inhibitor-containing regimen, 76.4% self-reported at least one lipodystrophy-related symptom and 30.0% failed to maintain adherence behaviour 20 months after enrolment. After multiple adjustment for other related factors, such as younger age, alcohol consumption and poor housing conditions, the number of self-reported lipodystrophy symptoms was independently associated with adherence failure.

Adult↗
PubMed2001

Mortality in a cohort of HIV-infected adults started on a protease inhibitor-containing therapy: standardization to the general population.

Death rates in the APROCO cohort of 1,157 HIV-1 infected adults starting for the first time a protease inhibitor-containing therapy were standardized to the 1996 French general population mortality rates stratified by age and gender. Median follow-up was 23 months and mortality rate was 2.2% person-years (95% confidence interval [CI] = 1.6-2.9). Overall mortality was 7.8 times higher than in the general population (95% CI = 5.7-10.4), 4.7 in men and 19.5 in women. Among the 144 patients considered complete responders, the death rate was 1.2% person-years (95% CI = 0.2-3.5) and mortality remained 5.1 times higher (95% CI = 1.0-14.9) than in the general population. Failure of treatment, long-term adverse effects, or less favorable socio-demographic status could explain these trends.

Adult↗
PubMed2001

Differential effect of two stathmin/Op18 phosphorylation mutants on Xenopus embryo development.

Stathmin/Op18 destabilizes microtubules in vitro and regulates microtubule polymerization in vivo. Both a microtubule catastrophe-promoting activity and a tubulin sequestering activity were demonstrated for stathmin in vitro, and both could contribute to microtubule depolymerization in vivo. Stathmin activity can be turned down by extensive phosphorylation on its four phosphorylatable serines, and down-regulation of stathmin activity by phosphorylation is necessary for cells to proceed through mitosis. We show here that microinjection of a nonphosphorylatable Ser to Ala (4A) quadruple mutant in Xenopus two-cell stage embryos results in cell cleavage arrest in the injected blastomeres and aborted development, whereas injection of a pseudo-phosphorylated Ser to Glu quadruple mutant (4E) does not prevent normal development. Addition of these mutants to mitotic cytostatic factor-arrested extracts in which spindle assembly was induced led to a dramatic reduction of spindle size with 4A stathmin, and to a moderate increase with 4E stathmin, but both localized to spindle poles. Interestingly, the microtubule assembly-dependent phosphorylation of endogenous stathmin was abolished in the presence of 4A stathmin, but not of 4E stathmin. Altogether, this shows that the phosphorylation-mediated regulation of stathmin activity during the cell cycle is essential for early Xenopus embryonic development.

Animals↗
PubMed2001

Stathmin family proteins display specific molecular and tubulin binding properties.

Stathmin family phosphoproteins (stathmin, SCG10, SCLIP, and RB3/RB3'/RB3") are involved in signal transduction and regulation of microtubule dynamics. With the exception of stathmin, they are expressed exclusively in the nervous system, where they display different spatio-temporal and functional regulations and hence play at least partially distinct and possibly complementary roles in relation to the control of development, plasticity, and neuronal activities. At the molecular level, each possesses a specific "stathmin-like domain" and, with the exception of stathmin, various combinations of N-terminal extensions involved in their association with intracellular membrane compartments. We show here that each stathmin-like domain also displays specific biochemical and tubulin interaction properties. They are all able to sequester two alpha/beta tubulin heterodimers as revealed by their inhibitory action on tubulin polymerization and by gel filtration. However, they differ in the stabilities of the complexes formed as well as in their interaction kinetics with tubulin followed by surface plasmon resonance as follows: strong stability and slow kinetics for RB3; medium for SCG10, SCLIP, and stathmin; and weak stability and rapid kinetics for RB3'. These results suggest that the fine-tuning of their stathmin-like domains contributes to the specific functional roles of stathmin family proteins in the regulation of microtubule dynamics within the various cell types and subcellular compartments of the developing or mature nervous system.

Amino Acid Sequence↗
PubMed2001

Expression of stathmin and SCG10 proteins in the olfactory neurogenesis during development and after lesion in the adulthood.

Stathmin and SCG10 belong to a family of phosphoproteins associated to cell proliferation and differentiation. In the present study, we have analyzed immunocytochemically the distribution of these proteins during neurogenesis in the mouse olfactory system, from midgestation to adulthood. Data show that already at embryonic day 12, stathmin and SCG10 immunoreactivities were present in the olfactory and vomeronasal neurons, and their number increased greatly, colocalizing with neuronal specific tubulin, a marker of immature neurons. Later on up to adulthood, the distribution of stathmin and SCG10 became progressively restricted to a few immature receptor and chemosensory neurons. Significantly, in the olfactory epithelium, stathmin was seen in immature neurons and also in basal cells representing precursors of neuronal elements. Interestingly, before birth stathmin and SCG10 immunopositive cells were seen outside the olfactory epithelium, seemingly migrating toward the olfactory bulb. After regeneration in the adult following peripheral lesion of the olfactory epithelium, stathmin and SCG10 were again strongly expressed and generally colocalized with neuronal specific tubulin immunoreactivity. Overall these results indicate that stathmin and SCG10 are expressed in immature olfactory neurons as well as in the migrating cells generated from the olfactory epithelium, supporting the role of these proteins in neurogenesis and cell migration.

Animals↗
PubMed2001

Stathmin/Op18 phosphorylation is regulated by microtubule assembly.

Stathmin/Op 18 is a microtubule (MT) dynamics-regulating protein that has been shown to have both catastrophe-promoting and tubulin-sequestering activities. The level of stathmin/Op18 phosphorylation was proved both in vitro and in vivo to be important in modulating its MT-destabilizing activity. To understand the in vivo regulation of stathmin/Op18 activity, we investigated whether MT assembly itself could control phosphorylation of stathmin/Op18 and thus its MT-destabilizing activity. We found that MT nucleation by centrosomes from Xenopus sperm or somatic cells and MT assembly promoted by dimethyl sulfoxide or paclitaxel induced stathmin/Op18 hyperphosphorylation in Xenopus egg extracts, leading to new stathmin/Op18 isoforms phosphorylated on Ser 16. The MT-dependent phosphorylation of stathmin/Op18 took place in interphase extracts as well, and was also observed in somatic cells. We show that the MT-dependent phosphorylation of stathmin/Op18 on Ser 16 is mediated by an activity associated to the MTs, and that it is responsible for the stathmin/Op18 hyperphosphorylation reported to be induced by the addition of "mitotic chromatin." Our results suggest the existence of a positive feedback loop, which could represent a novel mechanism contributing to MT network control.

Animals↗
PubMed2000

Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16.

We have identified a rapid protein phosphorylation event at residue serine 16 of stathmin using two-dimensional gel electrophoresis coupled to matrix-assisted laser desorption/ionization mass spectrometry in combination with post-source decay analysis, which is induced by the epidermal growth factor receptor. Phosphorylation is specifically mediated by the small GTPases Rac and Cdc42 and their common downstream target, the serine/threonine kinase p65PAK. Both GTPases have previously been shown to regulate the dynamics of actin polymerization. Because stathmin destabilizes microtubules, and this process is inhibited by phosphorylation at residue 16, Rac and Cdc42 can potentially regulate both F-actin and microtubule dynamics.

Cell Line↗
PubMed2000

The 4 A X-ray structure of a tubulin:stathmin-like domain complex.

Phosphoproteins of the stathmin family interact with the alphabeta tubulin heterodimer (tubulin) and hence interfere with microtubule dynamics. The structure of the complex of GDP-tubulin with the stathmin-like domain of the neural protein RB3 reveals a head-to-tail assembly of two tubulins with a 91-residue RB3 alpha helix in which each copy of an internal duplicated sequence interacts with a different tubulin. As a result of the relative orientations adopted by tubulins and by their alpha and beta subunits, the tubulin:RB3 complex forms a curved structure. The RB3 helix thus most likely prevents incorporation of tubulin into microtubules by holding it in an assembly with a curvature very similar to that of the depolymerization products of microtubules.

Amino Acid Sequence↗
PubMed2000

Probing the native structure of stathmin and its interaction domains with tubulin. Combined use of limited proteolysis, size exclusion chromatography, and mass spectrometry.

Stathmin is a cytosoluble phosphoprotein proposed to be a regulatory relay integrating diverse intracellular signaling pathway. Its interaction with tubulin modulates microtubule dynamics by destabilization of assembled microtubules or inhibition of their polymerization from free tubulin. The aim of this study was to probe the native structure of stathmin and to delineate its minimal region able to interact with tubulin. Limited proteolysis of stathmin revealed four structured domains within the native protein, corresponding to amino acid sequences 22-81 (I), 95-113 (II), 113-128 (III), and 128-149 (IV), which allows us to propose stathmin folding hypotheses. Furthermore, stathmin proteolytic fragments were mixed to interact with tubulin, and those that retained affinity for tubulin were isolated by size exclusion chromatography and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The results indicate that, to interact with tubulin, a stathmin fragment must span a minimal core region from residues 42 to 126, which interestingly corresponds to the predicted alpha-helical "interaction region" of stathmin. In addition, an interacting stathmin fragment must include a short N- or C-terminal extension. The functional significance of these interaction constrains is further validated by tubulin polymerization inhibition assays with fragments designed on the basis of the tubulin binding results. The present results will help to optimize further stathmin structural studies and to develop molecular tools to target its interaction with tubulin.

Chromatography, Gel↗
PubMed2000

Specific Ser-Pro phosphorylation by the RNA-recognition motif containing kinase KIS.

We present here a first appraisal of the phosphorylation site specificity of KIS (for 'kinase interacting with stathmin'), a novel mammalian kinase that has the unique feature among kinases to possess an RNP type RNA-recognition motif (RRM). In vitro kinase assays using various standard substrates revealed that KIS has a narrow specificity, with myelin basic protein (MBP) and synapsin I being the best in vitro substrates among those tested. Mass spectrometry and peptide sequencing allowed us to identify serine 164 of MBP as the unique site phosphorylated by KIS. Phosphorylation of synthetic peptides indicated the importance of the proline residue at position +1. We also identified a tryptic peptide of synapsin I phosphorylated by KIS and containing a phosphorylatable Ser-Pro motif. Altogether, our results suggest that KIS preferentially phosphorylates proline directed residues but has a specificity different from that of MAP kinases and cdks.

Animals↗
PubMed2000

Overexpression of stathmin in breast carcinomas points out to highly proliferative tumours.

We recently discovered that stathmin was overexpressed in a subgroup of human breast carcinomas. Stathmin is a cytosolic phosphoprotein proposed to act as a relay integrating diverse cell signalling pathways, notably during the control of cell growth and differentiation. It may also be considered as one of the key regulators of cell division for its ability to destabilize microtubules in a phosphorylation-dependent manner. To assess the significance of stathmin overexpression in breast cancer, we evaluated the correlation of stathmin expression, quantified by reverse transcription polymerase chain reaction, with several disease parameters in a large series of human primary breast cancer (n = 133), obtained in strictly followed up women, whose clinico-pathological data were fully available. In agreement with our preliminary survey, stathmin was found overexpressed in a subgroup of tumours (22%). In addition, overexpression was correlated to the loss of steroid receptors (oestrogen, P = 0.0006; progesterone, P = 0.008), and to the Scarff-Bloom-Richardson histopathological grade III (P= 0.002), this latter being ascribable to the mitotic index component (P= 0.02). Furthermore studies at the DNA level indicated that stathmin is overexpressed irrespective of its genomic status. Our findings raise important questions concerning the causes and consequences of stathmin overexpression, and the reasons of its inability to counteract cell proliferation in the overexpression group.

Adult↗
PubMed1999

Upregulation and redistribution of cadherins reveal specific glial and muscle cell phenotypes during wallerian degeneration and muscle denervation in the mouse.

In the present work, we investigated the expression of cadherin mRNAs in the adult neuromuscular system either under normal conditions or following experimental neurotomy. Cadherin-6, a marker of Schwann cell precursors, was not expressed in the adult peripheral nerve, while M-cadherin, cadherin-11, and N-cadherin were expressed both by glial and conjunctive cells. Moreover, the three transcripts were transiently upregulated in the distal stump of neurotomized sciatic nerve during Wallerian degeneration: N-cadherin was abundant in myelinating Schwann cells during myelin degradation, while M-cadherin and cadherin-11 may be upregulated in proliferating Schwann cells. M-cadherin, cadherin-11, and N-cadherin were also detected in myofibres and endomysium of adult gastrocnemius muscle. Following neurotomy, cadherin-11 was only transiently increased in denervated myofibres, while M-cadherin was increased and sustained for at least 21 days postoperation. In contrast, N-cadherin was not upregulated in denervated myofibres. Thus, we defined here a combination of cadherins expressed in the adult nerve and muscle, and modulated during Wallerian degeneration and muscle denervation. The comparison of the expression pattern of this combination of cadherins to the one previously described during embryonic development shows that chronically denervated Schwann and muscle cells do not reverse to embryonic state (recapitulative hypothesis), but present specific phenotypic features.

Animals↗