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Biomedical subjects

C Alexandre

Publications and source records attributed to C Alexandre.

At least 127 records · Page 7Linked to original sources
PubMed1991

Four regulatory elements in the human c-fos promoter mediate transactivation by HTLV-1 Tax protein.

Expression of the human c-fos proto-oncogene is activated in trans by the Tax protein encoded by human T-cell leukemia virus type-1 (HTLV-1). Indeed, we show here that a HeLa clone stably transfected by Tax expresses Fos at a high level. We also show that multiple elements of the human c-fos promoter, i.e. the v-sis conditioned medium inducible element (SIE), the dyad symmetry element (DSE) necessary for growth factor induction, the octanucleotide direct repeat element (DR), and the cyclic AMP response element (CRE) centred at -60, can all mediate Tax transactivation. In the DSE, the 10bp central core that binds the serum response factor (SRF) is, by itself, sufficient to mediate Tax transactivation. Moreover, a CRE-binding protein is involved in Tax activation through the CRE-60 element. Since Fos is a transregulator of cellular genes, our results suggest that the oncoprotein plays a crucial role in T-cell transformation by HTLV-1 in conjunction with other Tax-inducible genes.

Base Sequence↗
PubMed1991

Transactivation of Krox-20 and Krox-24 promoters by the HTLV-1 Tax protein through common regulatory elements.

The HTLV-1 Tax protein has been shown to induce the expression of host cellular genes, some of which play crucial roles in cell proliferation and differentiation. We have examined the effect of Tax on the expression of two immediate-early genes, Krox-20 and Krox-24, which encode transcription factors. Several HTLV-1-infected T-cell lines and a HeLa cell line that constitutively expresses the Tax protein have a high level of expression of the Krox-20 and Krox-24 genes. In addition, Tax transactivates the promoters of both Krox-20 and Knox-24 in a co-transfection assay. Tax-responsive elements in Krox-20 and Krox-24 include the serum response elements (SREs) and the putative cAMP-responsive element (CRE). A correlation exists between the ability of these elements to mediate Tax transactivation and their affinity for their cognate factors, the serum response factor (SRF) or the CRE-binding protein (CREB) respectively. Since Tax is also able to transactivate the human c-fos promoter through the SRE and the CRE-60, our findings support the idea that the HTLV-1 Tax protein uses common mechanisms for transactivation of these three immediate-early genes. Deregulation of their expression may contribute to malignant transformation associated with HTLV-1 infection.

Base Sequence↗
PubMed1991

Bone histomorphometric comparison of rat tibial metaphysis after 7-day tail suspension vs. 7-day spaceflight.

Using histomorphometric analysis, we compared the effects of 7 d spaceflight (Biocosmos 1667) and 7 d tail-suspension in tibiae of 12-13 weeks old male Wistar rats. The skeletal alterations induced by both true and simulated weightlessness in the proximal tibial metaphysis consisted of an inhibition of longitudinal growth as indicated by the reduction of the primary spongiosa thickness. In both primary and secondary spongiosae, the loss of trabecular bone was more extensive in flight rats than in suspended rats. Impairment in cancellous and endocortical osteoid surfaces occurred in microgravity and 1-G conditions but with greater magnitude in the spongy space in flight rats. In suspended rats, the cancellous mineralization rate was decreased, suggesting an alteration of the formation activity. Bone resorption remained unchanged in flight rats whereas a twofold increase occurred in simulated conditions. These data support the hypothesis that mechanisms of bone loss in space are not entirely identical to those of tail-suspension model on Earth. New experiments allowing comparison between actual spaceflight and spaceflight simulations must be developed in order to explore common alterations and to understand differential mechanisms in the bone system.

Animals↗
PubMed1990

Micro-osteoclast resorption as a characteristic feature of B-cell malignancies other than multiple myeloma.

Multiple myeloma (MM) is characterized by the presence of lytic bone lesion and frequent hypercalcaemia. These are due to an excessive osteoclastic resorption in association with a low bone formation, as demonstrated by bone histomorphometry. Conversely, B-cell malignancies other than MM are rarely associated with lytic bone lesion and/or hypercalcaemia. In this study we have analysed quantitative bone histology in 65 patients with B-cell malignancies other than MM at diagnosis: chronic lymphocytic leukaemia (CLL, n = 20), non-Hodgkin's lymphoma (NHL, n = 25), Waldenström's disease (WD, n = 14), hairy cell leukaemia (HCL, n = 6). Fifty patients presented no clinical evidence of increased bone resorption, including no lytic bone lesions radiologically detectable and/or no hypercalcaemia. 80% of these patients (40/50) had increased bone resorption parameter using quantitative bone histology, including 19/29 (65.5%) patients with CLL or WD and 21/21 (100%) patients with NHL or HCL (P less than 0.01). As a control group, seven patients lacking bone marrow involvement on bone sample presented no excessive bone resorption. However, eight patients presented lytic bone lesions and/or hypercalcaemia. All of these patients had increased resorption parameters with high numbers of osteoclasts per surface trabecular bone (mean = 35.3), as opposed to the patients lacking lytic bone lesions and/or hypercalcaemia (mean = 6.6, n = 28) and to normal individuals (mean +/- SD = 3.8 +/- 1.7 and 6.3 +/- 2.6, respectively before and after 60 years). In all the cases, excessive histologic bone resorption was mediated by mononuclear small osteoclasts (mean osteoclast length +/- SD = 27.3 +/- 4.1 as compared to normal range = 35.0 +/- 1.0, P less than 0.001). In different in vitro models, these small mononuclear osteoclasts are considered as progenitors. These data suggest an abnormal osteoclast differentiation in B-cell malignancies other than MM, probably due to differences in the production of local factors acting on bone remodelling.

Adult↗
PubMed1990

Osteoblast stimulation in multiple myeloma lacking lytic bone lesions.

The reasons why some patients with multiple myeloma (MM) do not develop severe bone loss, or even develop sclerotic bone lesions, remain unclear. In order to answer this question at the cellular and tissue level, we evaluated the histological bone condition of 10 patients with MM who never developed lytic bone lesions during the course of their disease (including two patients with sclerotic MM). Myeloma-induced bone changes in the close vicinity of myeloma cells were evaluated by quantitative histology (bone histomorphometry). All 10 patients presented a significantly increased osteoblastic activity. This was associated with an increased bone resorption in seven of the 10 cases. Three patients had a pure osteoblastic presentation. These features were the reverse of the pattern observed in seven patients with lytic bone lesions: increased bone resorption with decreased bone formation. Almost all of these 10 patients showing excessive osteoblastic activity had increased serum bone gla protein levels, a specific marker of bone formation. Finally, 90% of these patients were lambda MM (70% of them were IgG lambda MM), an immunoglobulin subtype previously associated with the sclerotic MM variants. In conclusion, a subset of patients with MM never develop severe bone loss because of the stimulation of osteoblastic activity. These patients belong to the same family as osteosclerotic MM, presenting more frequently the IgG type and lambda subtype.

Aged↗
PubMed1990

Effect of human T-cell leukemia virus type I tax protein on activation of the human vimentin gene.

We report that the expression of the vimentin gene, a cytoskeletal growth-regulated gene, is activated in trans by the Tax (p40x) transactivator protein encoded by the human T-cell leukemia virus type I. Expression of the Tax protein activates a number of cellular genes, such as those coding for the alpha chain of the high-affinity interleukin-2 receptor and interleukin-2. These findings indicate that the Tax protein is involved in the unregulated T-cell growth associated with human T-cell leukemia virus type I infection. Higher levels of vimentin mRNA were expressed in two human T-cell leukemia virus type I-transformed T cell lines, C91/PL and C81-66/45, when compared with that in Jurkat T cells. We demonstrate that this activation is conferred by the vimentin upstream flanking sequences. Indeed, enhanced activity was detected when constructs with the vimentin promoter linked to the chloramphenicol acetyltransferase gene were transfected in HeLa cells and in two cell lines of hematopoietic origin (Jurkat T lymphoblastoid cells and U937 promonocytic cells) together with a Tax expression plasmid. By introducing a series of deletions in the vimentin promoter, we further restrict these sequences to 30 base pairs, located between 241 and 210 base pairs upstream of the mRNA cap site. A 40-base-pair oligonucleotide containing this regulatory region proved sufficient to confer Tax inducibility upon a heterologous promoter linked to chloramphenicol acetyltransferase. Importantly, this segment includes an 11-base-pair promoter segment that has homology with the binding site for the NF-kappa B transactivating factor. Our findings indicate that constitutive expression of the vimentin gene under the control of the Tax protein may be relevant in understanding the progression of the lymphoproliferative process associated with human T-cell leukemia virus type I infection.

Base Sequence↗
PubMed1990

Osteoclast cytomorphometry and scanning electron microscopy of bone eroded surfaces during leukemic disorders.

Tartrate resistant acid phosphatase (TRAP) is a reliable histochemical marker of osteoclasts when used on tissue sections of undecalcified bone. This paper presents an original morphometric analysis which can be done after histochemical identification of osteoclasts. These bone resorbing cells were demonstrated on undecalcified bone biopsies from control subjects and patients presenting a malignant disease of the lymphocyte B lineage. Computerized analysis of the osteoclastic population revealed that: (1) all TRAP positive cells along bone trabeculae belong to a osteoclastic population; (2) that B cell malignancies had an increased bone resorption. At the scanning electron microscopic level small resorption bays (about 10 microns in diameter) were observed either associated or separated from eroded surfaces presenting abnormal appearance; TRAP staining of histological sections of undecalcified bone, coupled with morphometric studies, may help in the understanding of bone disease pathobiology.

Acid Phosphatase↗
PubMed1989

Evaluation of the osteoclastic population in iliac crest biopsies from 36 normal subjects: a histoenzymologic and histomorphometric study.

After histochemical staining of tartrate-resistant acid phosphatase (TRAP) activity, the total and active trabecular resorption surfaces and the number of osteoclasts were determined by histomorphometry on iliac crest biopsies from 36 healthy volunteers. The subjects were separated into three groups according to age and sex. Total trabecular resorption surface showed no significant variation in any group, but the fraction of active resorption surface was significantly higher in the older population. The number of TRAP cells per mm2 of section area, related to trabecular bone volume or surface, showed a significant increase in elderly subjects. The mean osteoclast interface was similar in all the groups. We found a significant decrease in resorption depth between young and old populations. These results are consistent with a reduced activity of bone-resorbing cells in advancing age. These normal values, established after histochemical identification of osteoclasts, may be applied for evaluating abnormal bone-resorbing cell activity in metabolic bone diseases.

Adult↗
PubMed1989

Effects of a bisphosphonate (1-hydroxy ethylidene-1,1 bisphosphonic acid) on osteoclast number during prolonged bed rest in healthy humans.

Acute osteoporosis is known to occur after immobilization in spinal cord injured patients and is related to an early increase in osteoclastic bone resorption. Whether osteoporosis develops in healthy immobilized human patients is still a matter of controversy. Furthermore, acute osteoporosis was thought to be a good model to study the effects of weightlessness on the human skeleton and to adapt preventive procedures. A bed rest experiment was developed in the USSR on 15 healthy human volunteers to determine the precise effects on bone structure and cell activities. A preventive protocol, including an anti-osteoclastic drug (1-hydroxyethylidene-1,1 bisphosphonic acid; K salt) was investigated. Two transiliac bone biopsies were performed on the 15 individuals before and at the end of the 120-day bed rest period. Undecalcified bone biopsies were studied with automatic and semi-automatic image analyzers specially devoted to bone histomorphometry. Trabecular bone volume, osteoid amount, and eroded surfaces were measured. Osteoclast number was measured after histochemical identification of tartrate-resistant acid phosphatase. After the bed rest period, an insignificant bone loss was observed in healthy humans while osteoclast number was highly increased. In bisphosphonate-treated subjects, osteoclast number was markedly reduced and so was osteoid amount. Bisphosphonates were shown to present a highly cytotoxic activity on osteoclasts, a finding that has never been demonstrated in normal subjects.

Adult↗
PubMed1989

Bone changes in alcoholic cirrhosis of the liver. A histomorphometric study.

The effects of alcoholic liver cirrhosis on the calcium, calciotropic hormones (parathyroid hormone and 25 hydroxy vitamin D) and testosterone were examined in twenty men. A transiliac bone biopsy was performed in each patient. A double tetracycline labeling was done in 17 patients. Radiological signs of osteoporosis (crushed vertebrae and rib fractures) were rarely observed but a low trabecular bone volume (BV/TV) was consistently encountered (BV/TV = 14.2 +/- 4.6; normal 18.8 +/- 4.8; p less than .001). Osteomalacic signs were never observed in spite of very low calcium and 25 hydroxy vitamin D levels in the blood. Increased osteoclastic eroded surfaces (ES/BS = 8.1 +/- 5.2; normal 3.7 +/- 1.1; p less than .001) were not related with an hyperparathyroidism but a significant correlation was found with testosterone levels (r = .45; p less than .05). Histodynamic measurements indicate a drastically decreased osteoblastic activity with a very low bone formation rate (BFR/BS = .009 +/- .001; normal .0175 +/- .0125; p less than .001). This could explain the net increase of eroded surfaces and that osteomalacia cannot be observed even in the presence of profound calcium and vitamin D changes in alcoholics.

Aged↗
PubMed1989

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

Bone Diseases↗