Biomedical subjects

V Goffin

Publications and source records attributed to V Goffin.

At least 55 records · Page 3Linked to original sources

PubMed1999

Should prolactin be reconsidered as a therapeutic target in human breast cancer?

Although prolactin (PRL) has been long suspected to be involved in the progression of human breast cancer, the failure of clinical improvement by treatment with dopamine agonists, which lower circulating levels of PRL, rapidly reduced the interest of oncologists concerning a potential role of this pituitary hormone in the development of breast cancer. Within the last few years, however, several studies reported first, that PRL is also synthesized in the mammary gland, and second that it exerts its proliferative action in an autocrine/paracrine manner. These observations have led to a reconsideration of the role of PRL as an active participant in breast cancer and are an impetus to search for alternative strategies aimed at inhibiting the proliferative effects of PRL on tumor mammary cells. In this report, we discuss the three possible levels that can be targeted for this purpose: the mammary synthesis of PRL, the interaction of the hormone with its receptor at the surface of mammary cells, and the intracellular signaling cascades triggered by the activated receptor. For each of these steps, we discuss the molecular event(s) that can be targeted, our understanding of the mechanisms involving these putative targets as well as the tools currently available for their inhibition. Besides its proliferative effect, PRL is also involved in the control of angiogenesis through one of its cleaved fragments, named PRL 16K, which has been shown to inhibit the angiogenic process. In view of this biological activity, we discuss first the cleavage of PRL with respect to the human mammary gland and, second, the hypothesis speculating that a balance between the proliferative effect of intact PRL and the anti-angiogenic activity of its 16K-like fragments might be physiologically relevant in the evolution of mammary tumors. If true, our hypothesis would suggest that the enzymatic cleavage of PRL could represent a new molecular target in the search for alternative strategies in the treatment of breast cancer.

Breast Neoplasms↗

PubMed1999

Opposing actions of intact and N-terminal fragments of the human prolactin/growth hormone family members on angiogenesis: an efficient mechanism for the regulation of angiogenesis.

Angiogenesis, the process of development of a new microvasculature, is regulated by a balance of positive and negative factors. We show both in vivo and in vitro that the members of the human prolactin/growth hormone family, i.e., human prolactin, human growth hormone, human placental lactogen, and human growth hormone variant are angiogenic whereas their respective 16-kDa N-terminal fragments are antiangiogenic. The opposite actions are regulated in part via activation or inhibition of mitogen-activated protein kinase signaling pathway. In addition, the N-terminal fragments stimulate expression of type 1 plasminogen activator inhibitor whereas the intact molecules have no effect, an observation consistent with the fragments acting via separate receptors. The concept that a single molecule encodes both angiogenic and antiangiogenic peptides represents an efficient model for regulating the balance of positive and negative factors controlling angiogenesis. This hypothesis has potential physiological importance for the control of the vascular connection between the fetal and maternal circulations in the placenta, where human prolactin, human placental lactogen, and human growth hormone variant are expressed.

Allantois↗

PubMed1999

From the molecular biology of prolactin and its receptor to the lessons learned from knockout mice models.

Prolactin (PRL), a polypeptide hormone secreted mainly by the pituitary and, to a lesser extent, by peripheral tissues, affects more physiological processes than all other pituitary hormones combined since it is involved in > 300 separate functions in vertebrates. Its main actions are related to lactation and reproduction. The initial step of PRL action is the binding to a specific membrane receptor, the PRLR, which belongs to the class 1 cytokine receptor superfamily. PRL-binding sites have been identified in a number of tissues and cell types in adult animals. Signal transduction by this receptor is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases and signal transducers and activators of transcription (STATs). Disruption of the PRLR gene has provided a new mouse model with which to identify actions directly associated with PRL or any other PRLR ligands, such as placental lactogens. To date, several different phenotypes have been analyzed and are briefly described in this review. Coupled with the SAGE technique, this PRLR knockout model is being used to qualitatively and quantitatively evaluate the expression pattern of hepatic genes in two physiological situations: transcriptomes corresponding to livers from both wild type and PRLR KO mice are being compared, and following statistical analyses, candidate genes presenting a differential profile will be further characterized. Such a new approach will undoubtedly open future avenues of research for PRL targets. To date, no pathology linked to any mutation in the genes encoding PRL or its receptor have been identified. The development of genetic models provides new opportunities to understand how PRL can participate to the development of pathologies throughout life, as for example the initiation and progression of breast cancer.

Adult↗

PubMed1999

Passive sustainable hydration of the stratum corneum following surfactant challenge.

Surfactants exhibit a protein-denaturating potency which is responsible for water uptake and swelling of the stratum corneum. There is also an increased transepidermal water loss related to the alteration of the barrier function. In the present prospective study, we evaluated sodium lauryl sulphate (SLS)-dependent changes in electrometric properties of skin. Single and iterative SLS challenges were performed. Measurements were made using a NOVA DPM on continuous mode for 5 min in order to assess both the baseline surface hydration and the rate of changes during probe occlusion. The present noninvasive instrumental evaluation of surfactant irritancy shows high sensitivity in each subject, but suffers from large inter-individual variability in the skin response following single and iterative sodium lauryl sulphate (SLS) challenges. The baseline surface hydration, that is almost unaffected 1 h after removing SLS patches, significantly decreases after a lag time of 24 h. The rate of water accumulation in the stratum corneum during the probe occlusion is significantly increased by SLS and is proportional to the SLS concentration and the number of iterative patches. Single water- or SLS-patch-tests fail to predict the skin response to cumulative SLS challenges and inter-individual variability is large for all electrometric variables.

Adult↗

PubMed1999

Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice.

Bone development is a multistep process that includes patterning of skeletal elements, commitment of hematopoietic and/or mesenchymental cells to chondrogenic and osteogenic lineages, and further differentiation into three specialized cell types: chondrocytes in cartilage and osteoblasts and osteoclasts in bone. Although PRL has a multitude of biological actions in addition to its role in the mammary gland, very little is known about its effect on bone. Mice carrying a germline null mutation for the PRL receptor gene have been produced in our laboratory and used to study the role of PRL in bone formation. In -/- embryos, we observed an alteration in bone development of calvaria. In adults, histomorphometric analysis showed that the absence of PRL receptors leads to a decrease in bone formation rate using double calcein labeling and a reduction of bone mineral density, measured by dual energy x-ray absorptiometry. In addition, serum estradiol, progesterone, testosterone, and PTH levels were analyzed. We also established that osteoblasts, but not osteoclasts, express PRL receptors. This suggests that an effect of PRL on osteoblasts could be required for normal bone formation and maintenance of bone mass. Thus, the PRL receptor knockout mouse model provides a new tool to investigate the involvement of PRL in bone metabolism.

Absorptiometry, Photon↗

PubMed1999

The human growth hormone antagonist B2036 does not interact with the prolactin receptor.

The human growth hormone (hGH) antagonist B2036 combines a single amino acid substitution impairing receptor binding site 2 (G120K) with eight additional amino acid substitutions that improve binding site 1 affinity. This hGH antagonist is being tested for treating pathologies linked to excess hGH levels. B2036-PEG is a polyethylene glycol (PEG) conjugated form of B2036 that has an increased half-life due to reduced renal clearance. It is currently in phase III trials for acromegaly. Human GH is also able to bind to the receptor of prolactin (PRLR). Since activation of PRLR can promote an array of pathological states (reproduction disorders, breast cancer), the ability of B2036-PEG to interact with the PRLR had to be determined. In this study, we compared four hGH antagonists (G120K, G120K-PEG, B2036 and B2036-PEG) in three bioassays: proliferation of rat Nb2 cells, binding to the human PRLR and activation of human PRLR-mediated signaling in a cell line stably expressing this receptor and a luciferase reporter gene. Agonistic and antagonistic properties were characterized. Our data show that B2036-PEG does not bind, activate or antagonize PRLRs, either from rat or human origin. These observations further demonstrate that the eight amino acid substitutions within binding site 1 provide binding specificity directed towards the human GH receptor.

Animals↗

PubMed1999

[Cutaneous melanomas, a spectrum of emerging cancers in women of Wallonia. Outlook by the Mosan Study Group of Pigmented Neoplasms].

The Mosan Study Group of Pigmented Neoplasms was founded about 15 years ago. It has collected more than 20,000 cutaneous malignancies including melanomas and basal and squamous cell carcinomas. The incidence of these cancers is on the rise in Wallonia. In particular, malignant melanomas represent a spectrum of emerging cancers characterized by a proteiform biological outcome. They mostly affect young women. The major risk factor appears to be iterative and unwise ultraviolet exposures. The prevention of melanomas is basically founded on such a dogma and accordingly relies on sunscreens. However, controversies about their beneficial effects are rife and fueled by axiomas and contradictory sophisms. At the exception of surgery, the therapeutic options for the diverse types of melanomas do not yet fulfill the scope of evidence-based medicine.

Carcinoma, Squamous Cell↗

PubMed1999

[Do you have a good nose? Small lexicon of bromhidroses and other body odors].

Body odours have a semiological significance in dermatology and in internal medicine and pediatrics as well. Most of them are brought by the eccrine or apocrine sweat. The term bromhidrosis refers to such conditions. Body odours originate from metabolic disorders, ingestion of food, toxic elements and drugs, and from contact with various xenobiotics. Specific bacterial infections and contaminations also release volatile smelling compounds without the intervention of sweat.

Dermatology↗

PubMed1998

Prolactin: a hormone at the crossroads of neuroimmunoendocrinology.

Prolactin (PRL), secreted by the pituitary, decidua, and lymphoid cells, has been shown to have a regulatory role in reproduction, immune function, and cell growth in mammals. The effects of PRL are mediated by a membrane-bound receptor that is a member of the superfamily of cytokine receptors. Formation of a trimer, consisting of one molecule of ligand and two molecules of receptor, appears to be a necessary prerequisite for biological activity. The function of these receptors is mediated, at least in part, by two families of signaling molecules: Janus tyrosine kinases (JAKs) and signal transducers and activators of transcription (STATs). To study these receptors, we have used two approaches: mutational analysis of their cytoplasmic domains coupled with functional tests and inactivation (knockout) of the receptor gene by homologous recombination in mice. We have produced mice by gene targeting in embryonic stem cells carrying a germline null mutation of the prolactin receptor gene. Heterozygous (+/-) females show almost complete failure to lactate, following their first, but not subsequent pregnancies. Homozygous (-/-) females are infertile as a result of multiple reproductive abnormalities, including ovulation of premiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Half of the homozygous males are infertile or show reduced fertility. In view of the wide-spread distribution of PRL receptors, other phenotypes including those on the immune system, are currently being evaluated in -/- animals. This study establishes the prolactin receptor as a key regulator of mammalian reproduction and provides the first total ablation model to further study the role of the prolactin receptor and its ligands.

Animals↗

PubMed1998

Sensitive skin at menopause; dew point and electrometric properties of the stratum corneum.

OBJECTIVE: A number of menopausal women experience skin sensitive to various environmental threats. METHOD: Two panels of 15 menopausal women on or without HRT were compared. We studied the response of their stratum corneum to variations in environmental humidity, either in air or in response to an emollient. Environment dew point and electrometric measurements on the skin were recorded to search for correlations. RESULTS: Data show that the baseline stratum corneum hydration is influenced by the dew point. HRT improves the barrier function of the skin. The use of emollient further extends the improvement in the functional properties of skin in menopausal women. CONCLUSION: Both HRT and an emollient can counteract in part some of the deleterious effects of cold and dry weather.

Epidermis↗

PubMed1998

Homodimerization of IL-2 receptor beta chain is necessary and sufficient to activate Jak2 and downstream signaling pathways.

Cytokine receptor signaling involves the Jak/Stat pathways. Heterotrimeric IL-2R (alpha, beta, gamma[c] chains) activates Jak1 and Jak3, whereas homodimeric PRLR activates Jak2. The requirements directing such specificity of Jak activation are unknown. We show that chimeric receptors containing the intracellular domain of IL-2Rbeta chain fused to the extracellular domain of either EPOR or Kit, a non-cytokine receptor, activate Jak2. This observation provides evidence that IL-2Rbeta intrinsically possesses the ability to activate Jak2, but that this property is only displayed in homodimerized complexes. Our data suggest a role for the stoichiometry of cytokine receptors in selective activation of Janus kinases.

Animals↗

PubMed1998

A pilot study on bacterial viability in acne. Assessment using dual flow cytometry on microbials present in follicular casts and comedones.

BACKGROUND: Antibiotic therapy is one of the main methods of acne treatment, however, bacterial resistance is on the rise and can affect the treatment outcome. Quantitative bacteriologic cultures are the gold standard methodology for the assessment of such a problem; however, certain important biological aspects remain uncovered. OBJECTIVE: The purpose of this study was to compare the antibacterial activity of minocycline and lymecycline in sebaceous follicle infundibula and comedones of acne patients. METHOD: We used a recently introduced flow cytometric method, allowing a distinction to be made between viable, injured (presumably resistant), and dead microorganisms. RESULTS: Minocycline (100 mg) proved to be superior to lymecycline (600 mg) in abating the microflora harboring in the sebaceous follicles of acne patients. CONCLUSIONS: The dissimilar bioavailability and antimicrobial efficacy between the two bacteriostatic agents may impart different clinical efficacy.

Acne Vulgaris↗

PubMed1998

Podophyllotoxin-induced acantholysis and cytolysis in a skin equivalent model.

Skin equivalent models are used for a wide variety of pharmacotoxicological trials. The present study was performed to assess morphologically the effect of podophyllotoxin on human bioengineered skin. The untreated model exhibited many resemblances with the parent tissues, although the epidermal differentiation was slightly impaired at the ultrastructural level. The penetration of podophyllotoxin and its biological effects inside the model appeared largely increased compared to the clinical experience with the drug. Acantholysis and cytolytic changes were prominent mimicking the effect of cantharidin. The exaggerated response of many skin equivalents to various compounds shed some doubts on the validity of the model when it is used to show efficacy rather than toxicity. This might apply to claims of efficacy for cosmetic compounds. The effect of cosmetic additives cannot be validated by such approach alone.

Acantholysis↗

PubMed1998

Shielded corneosurfametry and corneoxenometry: novel bioassays for the assessment of skin barrier products.

OBJECTIVES: One of the most frequent occupational and environmental insults to the skin is linked to chronic exposure to weak irritants. There is a need for new predictive tests assessing the efficacy of barrier creams. METHODS: Shielded variants of corneosurfametry and corneoxenometry are introduced as novel ex vivo bioassays applicable for comparing protection to surfactants and organic solvents. RESULTS: Both bioassays showed good reproducibility for each offending agent and skin-protective products. Significant differences in efficacy were indicated between the presumptive barrier products. CONCLUSIONS: Shielded corneosurfametry and corneoxenometry may be convenient bioassays to compare the protection afforded by topical products against specific offending compounds to the skin. They avoid animal testing and toxicological hazards in human testing. In addition, they are cheap, rapid and reproducible.

Biological Assay↗

PubMed1998

Modulation of human stratum corneum properties by salicylic acid and all-trans-retinoic acid.

Topical all-trans-retinoic acid (RA) has been reported to decrease the in vivo skin response to sodium lauryl sulfate (SLS). The converse was also shown with a synergistic effect of RA following prior applications of SLS. The reason for such effects is not clear. We employed measures of transepidermal water loss (TEWL), squamometry and sequential corneosurfametry to explore the protective activity of a 0.05% RA cream at the level of the stratum corneum. Nonionic oil-in-water emulsions with or without 5% salicylic acid (SA) served as test product references. Data indicated that the RA formulation was responsible for a stochastic impairment in the TEWL and for an increased intercorneocyte cohesion. SA and the unmedicated emulsion did not lead to similar TEWL changes. The squamometry test proved to be very sensitive to disclose the effects of SA and RA without, however, allowing to distinguish the difference in the physiological processes involved. The corneosurfametry bioassay did not show any protection or synergistic effect between RA or SA and SLS challenge on the stratum corneum. This is in contrast to a previous work showing a positive protective effect afforded by retinol against SLS. The combined effects of irritant compounds affecting the stratum corneum are complex. The precise reason for some of their biological consequences remains a conundrum. On balance, products such as SA and RA do not appear to afford protection or impairment to a surfactant challenge at the level of the stratum corneum.

Adult↗

PubMed1998

Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice.

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Animals↗

PubMed1998

[Dermoscopy: magnified imaging of pigmented cutaneous tumors].

The early clinical identification of malignant melanoma is important. Pigmented neoplasms are sometimes difficult to diagnose by visual inspection alone. Dermoscopy increases the reliability of the clinical assessment. Dermoscopic criteria of malignancy are well defined on a descriptive ground. They allow an optimal interpretation of the clinical aspect without, however, reaching the sensitivity and specificity of the microscopic examination.

Diagnosis, Differential↗

PubMed1997

Selective modification at the N-terminal region of human growth hormone that shows antagonistic activity.

A new analogue of recombinant human growth hormone (hGH), hGH des(1-6,14) was expressed in Escherichia coli, refolded and purified to homogeneity. The mutation decreased the hormone's ability to bind lactogenic and somatogenic receptors through its site 1, and almost completely abolished its ability to bind these receptors through site 2, as evidenced by both binding and gel-filtration experiments. More specifically, the binding to prolactin receptors (PRLRs) from various species or their soluble recombinant extracellular domains (ECDs) was decreased 1.5-4-fold, whereas the binding to hGH receptor (hGHR) was decreased 10-85-fold. These changes caused an almost total loss of hormone agonistic activity in several in vitro bioassays and subsequently, the hGH des(1-6,14) analogue acquired antagonistic properties. This antagonistic activity was dependent upon modification of site 1. In those cases in which the binding was reduced only slightly, e.g. binding to rabbit PRLRs, hGH des(1-6,14) acted as a strong antagonist, whereas in others in which the binding of site 1 was reduced to a higher degree, such as other PRLRs and, in particular, hGHR, the antagonistic activity was correspondingly weaker. Circular dichroism spectra of the analogue suggested that these changes do not result from a decrease in overall alpha-helix content, but rather from minor local structural modifications at the N-terminus.

Animals↗