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Biomedical subjects

A Haeffner

Publications and source records attributed to A Haeffner.

At least 19 recordsLinked to original sources
PubMed2003

Potentiation of tumour apoptosis by human growth hormone via glutathione production and decreased NF-kappaB activity.

In addition to its primary role as growth factor, human growth hormone (hGH) can also participate in cell survival, as already documented by its protective effect on human monocytes or human promyelocytic leukaemia U937 cells exposed to a Fas-mediated cell death signal. However, despite similarities in the molecular events following Fas and TNF-alpha receptor engagement, we report that U937 cells, genetically engineered to constitutively produce hGH, were made more sensitive to TNF-alpha-induced apoptosis than parental cells. This was due to overproduction of the antioxidant glutathione, which decreased the nuclear factor (NF)-kappaB activity known to control the expression of survival genes. These findings were confirmed in vivo, in nude mice bearing U937 tumours coinjected with recombinant hGH and the NF-kappaB -inducing anticancer drug daunorubicin, to avoid the in vivo toxicity of TNF-alpha. This study therefore highlights one of the various properties of hGH that may have potential clinical implications.

Animals↗
PubMed2002

Human growth hormone gene transfer into tumor cells may improve cancer chemotherapy.

Chemotherapy remains the main tool for the treatment of cancers, but is often hampered by tumor cell resistance. In this context, the transfer of genes able to accentuate the effect of anticancer drugs may constitute a useful approach, as exemplified by inactivation of nuclear factor (NF)-kappa B via direct transfer of a gene encoding a negative dominant of its natural inhibitor I kappa B, leading to improved response to cancer chemotherapy. Following our previous report that transfection of human growth hormone (hGH) gene into human monocytic cell lines may also inactivate NF-kappa B in another situation, we decided to test the consequences of hGH gene transfer on cancer treatments. We demonstrated that hGH-transfected human myeloid leukemia U937 cells were sensitized to an apoptotic signal mediated by the anticancer drugs. In parallel, we found that, by inhibiting degradation of I kappa B, hGH gene transfer diminished NF-kappa B entry into the nuclei of U937 cells exposed to daunorubicin. Finally, we report that hGH-transfected tumor cells engrafted in nude mice responded in vivo to chemotherapy with nontoxic doses of daunorubicin whereas, under the same conditions, control tumor cells remained insensitive. Overall, this study therefore suggests that hGH gene transfer may offer new therapeutic prospects in cancer therapy.

Antibiotics, Antineoplastic↗
PubMed2000

Teledermatology as a new tool in sub-saharan Africa: an experience from Tanzania.

Large areas of sub-Saharan Africa suffer a substantial lack of skin care. Hence teledermatology, meaning the online visual exchange of clinical and histologic data, could develop into a powerful medical resource. We report the first established teledermatologic connection in this area: between the Regional Dermatology Training Centre (RDTC) in Moshi, Northern Tanzania, and the Department of Dermatology, University Hospital of Zürich, Switzerland. This report illustrates local difficulties as well as the considerable potential of teledermatology in such a setting.

Dermatology↗
PubMed1999

Growth hormone prevents human monocytic cells from Fas-mediated apoptosis by up-regulating Bcl-2 expression.

Apoptosis and particularly Fas-mediated apoptosis has been proposed to play a key role in controlling monocyte homeostasis. We and others have documented the regulatory function of human growth hormone (hGH) on monocytic cells, which prompted us to investigate the role of hGH on their response to Fas antigen cross-linking. Using human promonocytic U937 cells constitutively producing hGH upon gene transfer and human primary monocytes cultured in the presence of recombinant hGH, we demonstrated that hGH diminished Fas-mediated cell death by enhancing the expression of the antiapoptotic oncoprotein Bcl-2 as well as the level of bcl-2alpha mRNA. In parallel, we established that overexpression of Bcl-2 through gene transfer into normal U937 cells also diminished Fas-induced apoptosis. Further, as a result of Bcl-2 overexpression, we found that hGH greatly depressed Fas-induced activation of the cysteine protease caspase-3 (CPP32), which in turn affected the cleavage of poly(ADP-ribose) polymerase. Altogether, these data provide evidence that hGH mediates its protective effect through a Bcl-2-dependent pathway, clearly a crucial step in enhanced survival of monocytic cells exposed to Fas-induced death.

Apoptosis↗
PubMed1997

Inhibitory effect of growth hormone on TNF-alpha secretion and nuclear factor-kappaB translocation in lipopolysaccharide-stimulated human monocytes.

Several studies have pointed to a link between immune and endocrine systems, including a regulatory function of GH on monocyte activation. The present study demonstrates that human THP-1 promonocytic cells, engineered by gene transfer to constitutively produce human growth hormone (hGH), secreted depressed amounts of TNF-alpha in response to challenge by LPS. The effect of GH appears to occur in an autocrine fashion, since the inhibitory effect on TNF-alpha secretion by constitutive GH production could be abolished in the presence of anti-hGH mAb. The GH-induced inhibitory effect was also observed using normal human monocytes and monocyte-derived macrophages. Inhibition of TNF-alpha production by THP-1-hGH-transfected cells cultured in the presence of LPS is dependent on a selective pathway, since no inhibition of TNF-alpha production was observed when cells were cultured in the presence of PMA. Inhibition of TNF-alpha secretion by LPS-stimulated THP-1-hGH cells was associated with a decrease in nuclear translocation of nuclear factor-kappaB. The capacity of GH to inhibit LPS-induced TNF-alpha production by monocytes without altering other pathways leading to TNF-alpha production may be of potential relevance in septic shock, since GH is available for clinical use.

CD4 Antigens↗
PubMed1997

Oligotyping for HLA-DQA, -DQB, and -DPB in idiopathic nephrotic syndrome.

Associations of human leukocyte antigens (HLA) with the idiopathic nephrotic syndrome (NS) have mainly been described for alleles of the HLA-DR locus. In the present study the polymorphism of HLA-DQ and -DP at the molecular level was investigated in 167 children with NS (129 steroid-sensitive) using the polymerase chain reaction and sequence-specific oligonucleotides in a French and a German cohort. HLA-DR typing was also performed by classical serology. In steroid-sensitive patients we observed an increased frequency of the alleles HLA-DQA1*0201 and -DQB1*0201 in both populations with relative risks ranging from 3.8 to 8.5 (Pb < 0.01 to Pb < 0.00001 after Bonferoni's correction). In contrast, the frequency of HLA-DQA1*0102 and DQB1*0602 was significantly decreased. In children with frequent relapses the HLA associations were generally more pronounced than in those with infrequent or no relapses. Applying logistic regression analysis, a nephrotic child bearing DQA1*0201 or DR7 was five times more likely to be in the steroid-sensitive group of patients than in the steroid-resistant group compared with nephrotic children not bearing one of these alleles. These HLA alleles therefore seem to be useful indicators of a steroid-sensitive frequently relapsing course of NS. No associations with DPB alleles were observed, which narrows the region genetically involved in the disease susceptibility to the DR-DQ region. Steroid-resistant NS was not associated with HLA.

Adolescent↗
PubMed1996

Mitochondrial permeability transition is a central coordinating event of apoptosis.

In a number of experimental systems, the early stage of the apoptotic process, i.e., the stage that precedes nuclear disintegration, is characterized by the breakdown of the inner mitochondrial transmembrane potential (delta psi m). This delta psi m disruption is mediated by the opening of permeability transition (PT) pores and appears to be critical for the apoptotic cascade, since it is directly regulated by Bcl-2 and since mitochondria induced to undergo PT in vitro become capable of inducing nuclear chromatinolysis in a cell-free system of apoptosis. Here, we addressed the question of which apoptotic events are secondary to mitochondrial PT. We tested the effect of a specific inhibitor of PT, bongkrekic acid (BA), a ligand of the mitochondrial adenine nucleotide translocator, on a prototypic model of apoptosis glucocorticoid-induced thymocyte death. In addition to abolishing the apoptotic delta psi m disruption, BA prevents a number of phenomena linked to apoptosis: depletion of nonoxidized glutathione, generation of reactive oxygen species, translocation of NF kappa B, exposure of phosphatidylserine residues on the outer plasma membrane, cytoplasmic vacuolization, chromatin condensation, and oligonucleosomal DNA fragmentation. BA is also an efficient inhibitor of p53-dependent thymocyte apoptosis induced by DNA damage. These data suggest that a number of apoptotic phenomena are secondary to PT. In addition, we present data indicating that apoptotic delta psi m disruption is secondary to transcriptional events. These data connect the PT control point to the p53- and ICE/ Ced 3-regulated control points of apoptosis and place PT upstream of nuclear and plasma membrane features of PCD.

Animals↗
PubMed1995

Triggering of complement receptors CR1 (CD35) and CR3 (CD11b/CD18) induces nuclear translocation of NF-kappa B (p50/p65) in human monocytes and enhances viral replication in HIV-infected monocytic cells.

Monocyte/macrophages may harbor HIV in a nonproductive fashion for prolonged periods of time. Viral gene expression may be reactivated by stimulation of the cells with LPS or cytokines such as TNF-alpha in vitro. The effect of LPS and TNF-alpha is mediated by their ability to induce nuclear translocation of the DNA-binding heterodimer NF-kappa B (p50/p65), which binds to a specific sequence in the HIV-long terminal repeat. The present study demonstrates that triggering of complement receptors CR1 (CD35) and CR3 (CD11b/CD18) enhances viral replication in HIV-infected human monocytic cells. Monocytic cell lines and normal peripheral blood monocytes were infected with HIV-1 in vitro and cultured in the presence or absence of F(ab')2 fragments of monoclonal anti-CR1 or anti-CR3 Abs or with C3 fragments. Stimulation of CR1 or CR3 induces a two- to fourfold increase in the amount of cell-associated and released p24 Ag in cell cultures that was equivalent to that observed in control cultures triggered with LPS. We further observed that stimulation of CR1 or CR3 induces the nuclear translocation of NF-kappa B p50/p65 in infected cells. Translocation of NF-kappa B p50/p65 was also observed following stimulation of CR1 or CR3 of uninfected peripheral blood monocytes from HIV-seronegative donors. The amount of protein translocated was similar to that observed when cells were stimulated with rhTNF-alpha. TNF-alpha did not mediate the translocation of NF-kappa B p50/p65 induced by triggering of complement receptors. Taken together, these observations suggest that HIV gene expression may be activated in infected monocytes through interaction of the cells with complement-opsonized particles and that enhanced viral replication is associated with C3 receptor-mediated nuclear translocation of the NF-kappa B complex.

Biological Transport↗
PubMed1994

Molecular biology techniques for the diagnosis of cutaneous T-cell lymphoma.

The molecular biologic analysis of TCR gene rearrangements by Southern blot analysis and various PCR-based assays has contributed significantly to the understanding of CTCL. It is now known that CTCL is a monoclonal T-cell disorder like other T-cell neoplasms and that the same tumor clone is generally present in all sites of tissue involvement. Relative to histopathologic examination, the enhanced sensitivity of molecular biologic assays has allowed the diagnosis of CTCL at an early stage in many cases. In fact, molecular biologic analysis of TCR gene rearrangements suggests that CTCL may contain a dominant monoclonal tumor cell population from the time of its earliest clinically recognizable lesions, such as the cutaneous patches once termed large plaque parapsoriasis and now generally regarded as early CTCL. Furthermore, available data indicate that, at least in some cases, tumor cells are distributed widely among cutaneous and extracutaneous tissues at a time long before this involvement can be appreciated morphologically. It is apparent that, in addition to their value in the early diagnosis and staging of cutaneous lymphomas, these molecular biologic assays are valuable in monitoring the response to therapy, detecting early relapse, and improving understanding of the compartmentalization and trafficking of tumor cells. In order to reap the full clinical benefit from this new information, however, it is important to perform prospective long-term studies designed to determine the clinical significance of molecular biologic data. In addition, the complexity of cutaneous lymphoproliferative disorders dictates that molecular biologic clonality data should never be interpreted in a vacuum. In skin disease, dominant clonality does not always equate with clinical malignancy. The proper diagnosis of CTCL and other cutaneous lymphoproliferative diseases requires the thoughtful integration of molecular biologic data with the clinicopathologic and immunophenotypic findings.

Blotting, Southern↗