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Biomedical subjects

K Rosenberg

Publications and source records attributed to K Rosenberg.

At least 19 recordsLinked to original sources
PubMed2000

Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX.

Mutations in type 3 repeats of cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). We expressed recombinant wild-type COMP that showed structural and functional properties identical to COMP isolated from cartilage. A fragment encompassing the eight type 3 repeats binds 14 calcium ions with moderate affinity and high cooperativity and presumably forms one large disulfide-bonded folding unit. A recombinant PSACH mutant COMP in which Asp-469 was deleted (D469 Delta) and a MED mutant COMP in which Asp-361 was substituted by Tyr (D361Y) were both secreted into the cell culture medium of human cells. Circular dichroism spectroscopy revealed only small changes in the secondary structures of D469 Delta and D361Y, demonstrating that the mutations do not dramatically affect the folding and stability of COMP. However, the local conformations of the type 3 repeats were disturbed, and the number of bound calcium ions was reduced to 10 and 8, respectively. In addition to collagen I and II, collagen IX also binds to COMP with high affinity. The PSACH and MED mutations reduce the binding to collagens I, II, and IX and result in an altered zinc dependence. These interactions may contribute to the development of the patient phenotypes and may explain why MED can also be caused by mutations in collagen IX genes.

Achondroplasia↗
PubMed1998

Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen.

Cartilage and tendon extracellular matrices are composed of collagens, proteoglycans, and a number of noncollagenous proteins. Cartilage oligomeric matrix protein (COMP) is a prominent such protein, structurally related to the thrombospondins. We found that native COMP binds to collagen I/II and procollagen I/II and that the interaction is dependent on the divalent cations Zn2+ or Ni2+, whereas Ca2+, Mg2+, and Mn2+ did not promote binding. Using a solid phase assay, Scatchard analysis identified one class of binding site with a dissociation constant (Kd) close to 1.5 nM in the presence of Zn2+. The results were confirmed by studies using surface plasmon resonance. Furthermore, metal chelate chromatography demonstrated that COMP bound Zn2+ and Ni2+. Electron microscopy showed that the interaction occurred at four defined sites on the 300-nm collagen and procollagen molecules. Two were located close to each end, and two at 126 and 206 nm, respectively, from the C-terminal. COMP interacted via its C-terminal globular domain and significantly only in the presence of Zn2+.

Binding Sites↗
PubMed1996

The significance of heregulin in breast cancer tumor progression and drug resistance.

The erbB-2 receptor plays an important role in the prognosis of breast cancer and is expressed at high levels in nearly 30% of tumors in breast cancer patients. While evidence accumulates to support the relationship between erbB-2 overexpression and poor overall survival in human breast cancer, understanding of the biological consequence(s) of erbB-2 overexpression remains elusive. The discovery of heregulin has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2/4 receptor. These endpoints of growth, invasiveness, and differentiation have clear implications for the emergence, maintenance, and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in human breast cancer. Preliminary studies in vitro have shown that heregulin induces a biphasic growth effect on cells with erbB-2 overexpression. Interestingly, we observed that expression of heregulin correlates with a more aggressive/invasive, vimentin-positive phenotype in breast cancer cells lines. Therefore, we have postulated that heregulin is involved in breast cancer tumor progression. We have shown that heregulin induces in vitro chemoinvasion and chemotaxis of breast cancer cells as well as growth in an anchorage dependent and independent manner. Interestingly, a heregulin neutralizing antibody inhibits chemotaxis and results in cell growth inhibition and blockade of the invasive phenotype. Strikingly, genetically engineered cells which constitutively express heregulin demonstrate critical phenotypic changes that are associated with a more aggressive phenotype. Specifically, these cells are no longer dependent on estrogen for growth and are resistant to tamoxifen in vitro and in vivo, and moreover these cells metastasize to lymph nodes in athymic nude mice. These tumors appear to have lost bcl-2 expression as compared with the control tumors. In addition, presumably by activation/regulation of topoisomerase II, the heregulin-transfected cells become exquisitely sensitive to doxorubicin and VP-16. Clearly, mechanistic aspects of the erbB-2/4 and heregulin interaction need to be understood from a therapeutic standpoint which could provide additional insights into synergistic treatments for certain patients, or improve treatment regimens for a large number of women. The study of heregulin and its co-expression with erbB-2/4 receptor and the assessment of its involvement in the progression from the in situ stage of breast tumors to the invasive one will additionally increase the relevance of heregulin as a prognostic/diagnostic factor. We believe that our studies provide new insights into breast cancer diagnosis, prognosis, and treatment.

Breast Neoplasms↗
PubMed1996

Induction of ductal morphogenesis and lobular hyperplasia by amphiregulin in the mouse mammary gland.

As the juvenile mouse mammary gland matures, it undergoes extensive epithelial proliferation, leading to a network of ductal branching that transverses the organ. Recent evidence suggests that the epidermal growth factor-related peptide amphiregulin (AR) may play multiple roles in the proliferation, differentiation, and neoplastic conversion of the mouse mammary gland. Using a dual approach of recombinant AR in slow-release pellets and retroviral expression of AR, we explored the roles of this growth factor in the mouse mammary gland in vivo. We first noted that recombinant AR can reestablish longitudinal ductal proliferation in growth quiescent mammary glands of ovariectomized mice. Furthermore, retrovirally transduced mammary transplants overexpressing AR developed into hyperplastic tertiary ducts and hyperplastic lobules with increased lateral branching, apparent 9 weeks after transplantation into cleared mammary fat pads. This is the first study to demonstrate that AR can reestablish the early developmental activity of ductal mammary epithelium and induce hyperplasia in vivo. These data, coupled with previous findings that demonstrated nearly universal overexpression of AR in human breast cancer and rodent mammary tumorigenesis, suggest that AR may be an important intermediary in glandular maturation and early malignant progression.

Adipose Tissue↗
PubMed1995

Interaction between erbB-receptors and heregulin in breast cancer tumor progression and drug resistance.

The type I growth factor receptor family is increasingly recognized as important in the development and maintenance of breast cancer. The family currently consists of four closely related members: the epidermal growth factor receptor (EGF-R/erbB-1), erbB-2, erbB-3 and erbB-4. Putative ligands which bind directly to or indirectly activate erbB-2/3/4 have been characterized recently. This still growing family of EGF-related growth factors includes gp30, its homolog heregulin (HRG), the rat homolog neu differentiation factor (NDF), glial growth factors (GLIA), ARIA and a 50 kDa factor from COLO 16 cells. The understanding of the function, biology and interactions of these growth factor receptors and their ligands will have far-reaching implications for the prognosis and treatment of breast cancer. This review focuses on advances and future directions for further investigations intended to clarify the mechanism and significance of erbB/ligand interactions in breast cancer.

Animals↗
PubMed1994

Safety characteristics of the conically sculpted Nd:YAG laser fiber for operative laparoscopy.

The objective of this study was to define the effects and safety margins of available Nd:YAG laser fibers with flat and conically sculpted tips for operative laparoscopy. An in vitro agar base model was designed to define the effect of the conically sculpted fiber at distances of 5 and 10 mm beyond the fiber tip, and an in vivo rat model was used to assess similar effects in the contact mode, as well as at 1, 3, 5, and 10 mm beyond the tip. The beam divergence emitted through conically sculpted tips demonstrated significant reduction in power density at 3-5 mm beyond the tip, which is suggestive of minimal risk of undesired effects. Threshold energy levels required for thermal effects are lower for darker organs than for light-colored objects. The Nd:YAG laser cutting effect is satisfactory when the conically sculpted tips are in contact with soft tissue, and subjacent organs are relatively more protected when compared to the flat tips. The potential advantages of this tool over other laser and conventional accessories for operative laparoscopy has yet to be determined.

Animals↗
PubMed1991

Characterization of leukotriene C4 binding in anterior pituitary membrane preparations.

Pituitary cells produce leukotrienes (LTs) and respond to exogenous administration of LTs by releasing gonadotropins. Specific high affinity leukotriene C4 (LTC4) binding has been found in membrane preparations of bovine anterior pituitaries. Unlabelled LTC4 displaced specific [3H]LTC4 binding. Other leukotrienes (LTB4, LTD4, LTE4, LTF4) did not compete with [3H]LTC4 for binding sites when administered at increasing concentrations together with a constant amount of radioligand indicating that the binding is highly specific for LTC4. Scatchard analysis of binding data obtained from saturation studies revealed a single binding site for [3H]LTC4 with a Kd of 8.95 +/- 5.53 nM and a B max of 15.44 +/- 6.93 pmol per mg of membrane protein. Glutathione S-transferase, a possible LTC4 binding site, did not display activity in the membrane fraction although the two glutathione derivates S-octylglutathione and S-decylglutathione competed with LTC4 in binding experiments. As leukotrienes are potent stimulators of gonadotropin secretion and modulators of gonadotropin-releasing hormone (GnRH)-induced gonadotropin release it is concluded that leukotrienes may be involved in the signal transduction pathway of GnRH and that they may act via a specific and high affinity receptor.

Animals↗
PubMed1991

Teenage pregnancy in Scotland: trends and risks.

Teenage pregnancy, considered to be associated with social and medical risks, is seen as a growing problem. Population based information from the Registrar General (Scotland) and Notification of Abortion permitted an analysis of the trends in the numbers, rates and outcomes of pregnancies among women aged less than 20 years. In addition, clinical information is available on all deliveries in Scottish hospitals from the standard hospital discharge document permitting analysis of the association of defined complications with age. Contrary to current perceptions, pregnancies and births among teenagers are not more frequent in 1988 when compared to 1975. There has been, however, a large increase in births to single women, a group with particular problems. The obstetric risks when compared to older women, are small and probably socially, not age related. These include a slightly higher rate of pre-term delivery and low birthweight and a later presentation for specialist antenatal care. The proportion of pregnancies affected by neural tube defects which are terminated is lower among women under 20. These medical risks are small, however, compared to the well-documented social and economic problems which will have long term and indirect effects on health.

Abortion, Induced↗
PubMed1990

Screening and surveillance of pregnancy hypertension--an economic approach to the use of daycare.

Frequent measurement of blood pressure is an accepted part of routine outpatient antenatal care. Women found to have mild hypertension may be further monitored for signs of progressive disease, while women with proteinuria or severe hypertension may be admitted for more intensive surveillance or treatment. In practice, the course and ultimate severity of this disorder are unpredictable and women with mild hypertension are frequently admitted. Recently, daycare has grown as an option for assessing women with hypertension as it offers the advantage of more extensive evaluation than is possible at an outpatient clinic and is widely assumed to be more cost-effective than conventional management. However, its use in obstetrics has not been subject to a formal economic appraisal. Such an evaluation is currently being carried out in two hospitals in Scotland, one of which uses daycare and inpatient admissions in the management of hypertension and one of which uses domiciliary midwife visits as well as hospital beds. Preliminary results suggest that the pregnancy outcome in terms of birthweight, gestation at delivery, admission to a special unit, etc., are the same in the two units for women with mild hypertension (diastolic 90-99 mmHg, no proteinuria). The costs per patient were less in the hospital with a daycare unit. These lower individual costs, however, do not mean that the overall costs to the health service are less in a hospital with daycare. This will depend on the average number of visits to daycare for women with mild hypertension, the proportion of hypertensive women receiving daycare, whether freed inpatient beds are closed or redeployed, and the capital costs of establishing a day unit. Data has also been collected on women's costs and views which will ultimately be presented and should play a part in any decision to implement or continue daycare.

Cost-Benefit Analysis↗
PubMed1989

An evaluation of community antenatal care.

A study to ascertain how the community based antenatal services in the East End of Glasgow related to the guidelines set by a Working Party on Ante-Natal and Intrapartum Care (Royal College of Obstetricians and Gynaecologists, 1982) is reported. All community based clinics were visited and described. The socio-economic status of the sample population was defined and users' views and preferences sought. The women sampled were often socially and economically disadvantaged. Unemployment was high. They received their community antenatal care from midwives, general practitioners and consultants in both health centres and general practitioner surgeries. Women were generally satisfied with the care they received. Answers to more specific questions indicated, however, that more information and individualised care would be appreciated.

Adult↗
PubMed1989

Recent trends in the prevalence and secondary prevention of Down's syndrome.

Examination of data from the Glasgow Registry of Congenital Anomalies indicated that 184 infants with Down's syndrome were born (live or still) to mothers residing in the Greater Glasgow Health Board area between 1974 and 1986 inclusive. This represents a period prevalence of 1.1 per 1000 total births. Despite a strongly positive correlation between prevalence and maternal age, most of the Down's syndrome infants were born to mothers aged under 35 years. There was no evidence either of a recent decline in the annual prevalence rate or of a changing pattern of risk in relation to maternal age. Antenatal diagnosis resulted in the termination of less than a tenth of all Down's syndrome pregnancies. These findings point to a need for further aetiological research, for continued epidemiological monitoring, for an improvement in the relatively low uptake of amniocentesis by older mothers, and for the development of a screening test which can be offered to the entire pregnant population.

Adult↗
PubMed1988

In vivo acoustic attenuation in liver: correlations with blood tests and histology.

Results of in vivo attenuation measurements in the liver have been obtained in 26 normal controls and in 51 patients with chronic diffuse liver disease. A modified real-time sector scanner was used for narrow-band amplitude attenuation examination. In the control group (people without apparent liver disease), a statistically significant correlation was found between acoustic attenuation in liver and two blood tests reflecting liver function: serum albumin (n = 24, r = 0.67, p = 0.002) and prothrombin time (n = 23, r = 0.63, p = 0.019). There was a statistically significant positive correlation between attenuation and fat for all biopsied patients (n = 51, r = 0.32, p = 0.023) and for patients with minimal fibrosis (n = 25, r = 0.45, p = 0.027). Although no correlation with fibrosis was found for all patients, in the group of patients with minimal fat there was a correlation with portal fibrosis (n = 33, r = 0.37, p = 0.035). This double blind prospective study shows that in the liver: (1) attenuation estimates appear correlated with clinical parameters (blood tests) in normal volunteers, and (2) large changes in fat affect narrow-band acoustic attenuation estimates to a greater degree than severe portal fibrosis in patients with chronic diffuse liver disease. Further research is needed before these estimates can become a clinical tool.

Fatty Liver↗
PubMed1988

Screening for congenital neural tube defects in a high-risk area: an epidemiological perspective.

Data from the Glasgow Register of Congenital Malformations were used to investigate the extent of the recent decline in the prevalence of anencephaly and spina bifida, and the contribution of antenatal screening to it. Over the period 1974-85 inclusive, 303 pregnancies with an anencephalic foetus were diagnosed, representing an "adjusted" prevalence of 1.9 per 1000 total births, of which 179 (59%) were terminated following antenatal screening. There were 364 pregnancies with a spina bifida foetus representing an "adjusted" prevalence of 2.3 per 1000 total births, of which 84 (23%) were terminated. Over the study period, the "adjusted" prevalence of anencephaly fell by 50% while the birth prevalence fell by 89%; the "adjusted" prevalence of spina bifida fell by 38% while the birth prevalence fell by 76%. It was concluded that although the birth prevalence of both defects (particularly anencephaly) would have declined substantially in the absence of screening, the West of Scotland programme should continue.

Anencephaly↗