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Biomedical subjects

R Schiff

Publications and source records attributed to R Schiff.

At least 19 recordsLinked to original sources
PubMed2006

Takayasu's arteritis: a cause of prolonged arterial stiffness.

OBJECTIVES: Cardiovascular disease is a major cause of mortality and morbidity in patients with Takayasu's arteritis (TA). Increased arterial stiffness is an independent risk factor and predictor of cardiovascular mortality in a variety of diseases. Pulse wave velocity (PWV) and the augmentation index (AI) are used as clinical measurements of arterial stiffness. METHODS: Data are presented from 10 patients with TA and 11 normal controls obtained between 2000 and 2004. Arterial compliance was assessed non-invasively by measurement of PWV, using the Complior system, and calculation of the aortic AI. RESULTS: TA patients (mean age 40.8+/-13.2 yr) were compared with a control group of healthy women from a parallel study (mean age 32.3+/-5.5 yr). The mean carotid-femoral PWV (PWV-CF) was higher in TA patients (P = 0.03). In addition, both aortic AI derived from the radial artery (P = 0.002) and carotid AI (P = 0.03) were higher in TA patients compared with controls. PWV-CF did not correlate with CRP (r = - 0.23, P = 0.23) or ESR (r = - 0.19, P = 0.27). Similar results were obtained for the correlation of carotid-radial PWV with CRP (r = 0.15, P = 0.32) and ESR (r = 0.33, P = 0.14). CONCLUSIONS: Our data show that TA is associated with elevated arterial stiffness in the central aorta, which may persist when the disease is quiescent. These data suggest that PWV represents a means by which cardiovascular risk can be detected and monitored in TA, and highlights the importance of effective management of cardiovascular risk factors in these patients.

Adult↗
PubMed2005

Growth factor signalling and response to endocrine therapy: the Royal Marsden Experience.

De novo resistance to endocrine therapy is a near-universal feature of oestrogen receptor (ER)- negative breast cancer. Although many ER-positive breast cancers also show no response to tamoxifen or aromatase inhibitors on objective clinical grounds the large majority show reduced proliferation indicating that some oestrogen dependence is present in almost all ER-positive breast cancer. In neoadjuvant studies HER2 positivity is associated with poor response rates to tamoxifen but not aromatase inhibitors, consistent with preclinical models. Acquired resistance to tamoxifen is associated with decreases in ER positivity but most recurrent lesions remain ER-positive. A small proportion of these show increased HER2 expression and in these patients increased phospho-p38 may contribute to the tamoxifen-resistant phenotype. There is an unfortunate paucity of clinical and biological data on acquired resistance to aromatase inhibitors.

Antineoplastic Agents, Hormonal↗
PubMed2001

Estrogen receptor: current understanding of its activation and modulation.

Breast cancer development and progression are directly related to the effects of the female hormone estrogen. The nuclear receptor for estrogen (ER) functions as a transcription factor controlling estrogen-regulated genes. Receptor conformation on ligand binding, its interaction with various coregulators, and response elements in the promoter region of target genes all contribute to the net estrogenic effects in a cell. ER is an important diagnostic and therapeutic target in breast cancer. Various polypeptide growth factors and their membrane receptors also contribute to breast cancer development and progression. Pathways mediating cell survival, cell proliferation, and response to stress not only generate signals through various protein kinase pathways to enhance cell survival and proliferation, but these pathways also interact with ERs. Kinases in the growth factor cascade can phosphorylate and activate ER, and ER in turn activates and augments signaling through the growth factor pathways. Signaling through the growth factor pathways may contribute to hormonal resistance states by ligand-independent activation of ER. Targeting growth factor pathways, in addition to ER, is a developing strategy that hypothetically may represent optimal therapy by preventing the development of resistance to endocrine therapy.

Animals↗
PubMed2000

Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo.

BACKGROUND: Most breast cancers, even those that are initially responsive to tamoxifen, ultimately become resistant. The molecular basis for this resistance, which in some patients is thought to involve stimulation of tumor growth by tamoxifen, is unclear. Tamoxifen induces cellular oxidative stress, and because changes in cell redox state can activate signaling pathways leading to the activation of activating protein-1 (AP-1), we investigated whether tamoxifen-resistant growth in vivo is associated with oxidative stress and/or activation of AP-1 in a xenograft model system where resistance is caused by tamoxifen-stimulated growth. METHODS: Control estrogen-treated, tamoxifen-sensitive, and tamoxifen-resistant MCF-7 xenograft tumors were assessed for oxidative stress by measuring levels of antioxidant enzyme (e.g., superoxide dismutase [SOD], glutathione S-transferase [GST], and hexose monophosphate shunt [HMS]) activity, glutathione, and lipid peroxidation. AP-1 protein levels, phosphorylated c-jun levels, and phosphorylated Jun NH(2)-terminal kinase (JNK) levels were examined by western blot analyses, and AP-1 DNA-binding and transcriptional activities were assessed by electrophoretic mobility shift assays and a reporter gene system. All statistical tests are two-sided. RESULTS: Compared with control estrogen-treated tumors, tamoxifen resistant tumors had statistically significantly increased SOD (more than threefold; P=.004) and GST (twofold; P=.004) activity and statistically significantly reduced glutathione levels (greater than twofold; P<.001) and HMS activity (10-fold; P<.001). Lipid peroxides were not significantly different between control and tamoxifen-resistant tumors. We observed no differences in AP-1 protein components or DNA-binding activity. However, AP-1-dependent transcription (P=.04) and phosphorylated c-Jun and JNK levels (P<.001) were statistically significantly increased in the tamoxifen-resistant tumors. CONCLUSION: Our results suggest that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with oxidative stress and the subsequent antioxidant response and with increased phosphorylated JNK and c-Jun levels and AP-1 activity, which together could contribute to tumor growth.

Animals↗
PubMed1999

Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer.

It has been shown in previous studies that a variety of estrogen receptor (ER) beta mRNA transcripts are expressed in human breast cancer cell lines and tumors. To complement the RNA expression studies, we have developed ER-beta-specific antibodies to characterize ER-beta protein expression in breast cancer cell lines and tumors. Monoclonal antibodies were made against a peptide representing the first 18 amino acids of the longest ER-beta open reading frame reported to date, and polyclonal antibodies were made against a peptide within the ER-beta B domain. By Western blot analysis, we show that ER-beta protein is expressed in all cancer cell lines tested and in three of five breast tumor samples. The breast cancer cell lines showed variation in the size of the expressed ER-beta protein. The longest form detected was consistent with the 530-amino acid, full-length ER-beta sequence. Shorter ER-beta isoforms were detected in the ER-alpha-negative MDA-MB-231 and MDA-MB-435 breast cancer cell lines, likely corresponding to previously described COOH-terminal RNA variant isoforms.

Blotting, Western↗
PubMed1999

Statistical analysis of array expression data as applied to the problem of tamoxifen resistance.

BACKGROUND: Although the emerging complementary DNA (cDNA) array technology holds great promise to discern complex patterns of gene expression, its novelty means that there are no well-established standards to guide analysis and interpretation of the data that it produces. We have used preliminary data generated with the CLONTECH Atlas human cDNA array to develop a practical approach to the statistical analysis of these data by studying changes in gene expression during the development of acquired tamoxifen resistance in breast cancer. METHODS: For hybridization to the array, we prepared RNA from MCF-7 human breast cell tumors, isolated from our athymic nude mouse xenograft model of acquired tamoxifen resistance during estrogen-stimulated, tamoxifen-sensitive, and tamoxifen-resistant growth. Principal components analysis was used to identify genes with altered expression. RESULTS AND CONCLUSIONS: Principal components analysis yielded three principal components that are interpreted as 1) the average level of gene expression, 2) the difference between estrogen-stimulated gene expression and the average of tamoxifen-sensitive and tamoxifen-resistant gene expression, and 3) the difference between tamoxifen-sensitive and tamoxifen-resistant gene expression. A bivariate (second and third principal components) 99% prediction region was used to identify outlier genes that exhibit altered expression. Two representative outlier genes, erk-2 and HSF-1 (heat shock transcription factor-1), were chosen for confirmatory study, and their predicted relative expression levels were confirmed in western blot analysis, suggesting that semiquantitative estimates are possible with array technology. IMPLICATIONS: Principal components analysis provides a useful and practical method to analyze gene expression data from a cDNA array. The method can identify broad patterns of expression alteration and, based on a small simulation study, will likely provide reasonable power to detect moderate-sized alterations in clinically relevant genes.

Animals↗
PubMed1998

Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes.

Several lines of evidence indicate that the nuclear receptor corepressor (N-CoR) complex imposes ligand dependence on transcriptional activation by the retinoic acid receptor and mediates the inhibitory effects of estrogen receptor antagonists, such as tamoxifen, suppressing a constitutive N-terminal, Creb-binding protein/coactivator complex-dependent activation domain. Functional interactions between specific receptors and N-CoR or SMRT corepressor complexes are regulated, positively or negatively, by diverse signal transduction pathways. Decreased levels of N-CoR correlate with the acquisition of tamoxifen resistance in a mouse model system for human breast cancer. Our data suggest that N-CoR- and SMRT-containing complexes act as rate-limiting components in the actions of specific nuclear receptors, and that their actions are regulated by multiple signal transduction pathways.

Animals↗
PubMed1997

Spinal cord dysmyelination induced in vivo by IgM antibodies to three different myelin glycolipids.

It was shown previously (Rosenbluth et al.: J. Neurosci. 16:2635-2641, 1996) that implantation of hybridoma cells that produce an IgM antigalactocerebroside into the spinal cord of young rats results in the development of myelin sheaths with a repeat period approximately 2-3x normal, similar to the abnormal peripheral myelin sheaths seen in human IgM gammopathies. We now present evidence that this effect can be reproduced in the spinal cord by implanting either of two other hybridomas, O4 and A2B5, that secrete, respectively, antisulfatide and antiganglioside IgM antibodies. The formation of expanded CNS myelin thus does not depend on antibodies to galactocerebroside specifically but can be mediated by IgM antibodies that react with other myelin glycolipids as well.

Animals↗
PubMed1997

Xenotransplantation of transgenic oligodendrocyte-lineage cells into spinal cord-injured adult rats.

Spinal cord trauma is associated not only with loss of nerve cells and fibers but also with damage to oligodendrocytes and demyelination. In order to assess the potential of transplanted oligodendrocyte-lineage cells to repair the demyelination that follows spinal cord injury, we have used donor glia derived from a transgenic mouse line containing the LacZ transgene under control of the myelin basic protein promoter. Glia derived from fetal or neonatal transgenic mice were injected into the spinal cords of immunosuppressed adult rats at the site of an experimental traumatic lesion 1-16 days after injury. Cells expressing LacZ were identified 15-18 days later in cryosections rostral and caudal to the transplant site, most conspicuously within white matter defects. Some of these cells within the dorsal columns gave rise to approximately 30- to 60-microns processes, consistent with myelin segments, which are oriented parallel to the fiber tract. Glial transplantation may thus be a feasible means of replacing damaged host oligodendrocytes with donor oligodendrocyte-lineage cells capable of reforming myelin and potentially restoring functional lost as a result of demyelination associated with spinal cord injury.

Animals↗
PubMed1997

Hypothalamic-pituitary-adrenal function following cranial irradiation.

We assessed the effect of cranial irradiation on hypothalamic-pituitary (HP)-adrenal function in 17 patients (12 females, 5 males) treated with cranial/ craniospinal irradiation for acute leukemia (2 patients) or tumors distant from the hypothalamus and pituitary (8 medulloblastoma, 3 astrocytoma, 3 rhabdomyosarcoma, 1 ependymoma). Estimated doses of radiation (RT) to the HP region ranged from 18 to 72 Gy. Thirteen of seventeen patients were also treated with chemotherapy. Patients were a median of 3.75 years of age (1.5-19 years) at diagnosis and were studied at a median of 5 years (0.1-20 years) after RT. Patients received corticotropin-releasing factor (oCRF, 1 microgram/kg i.v.), and sampling for cortisol and ACTH levels was performed at -15, 0, 15, 30, 60, 90 and 120 min. The-5- and 0-min levels were combined for a standardized baseline value (Base). Cortisol levels at 0, Base, 30 and 120 min, as well as the peak cortisol response, were significantly lower in the patients. Twelve of seventeen patients' peak cortisol levels fell below the normal range. The patients' mean integrated values for cortisol (area under the curve) were not, however, different from controls. The ACTH responses to oCRF did not differ between patients and controls. No relationship was observed between ACTH or cortisol responses and the time elapsed from treatment or dose of HP RT. Further, in 10 of 12 patients, 0-min dehydroepiandrosterone sulfate levels were lower than the expected normal mean levels for age, sex and pubertal status, and in 4 of these 10 patients the values were below the normal range. These data suggest that some patients treated with HP RT may be at risk for adrenal insufficiency.

Adolescent↗
PubMed1996

Myelin structure in proteolipid protein (PLP)-null mouse spinal cord.

Fixed preparations of proteolipid protein (PLP)-null mouse spinal cord show myelin sheaths which in some regions consist of typical alternating major dense lines (MDLs) and intermediate lines (ILs) with a repeat period of 10.3 nm. More commonly, the lamellar structure consists of what appears to be a single population of dense lines, having a repeat period of 5.2 nm. These apparently equivalent lines are, however, sometimes distinguishable as MDLs or ILs based on continuity with cytoplasmic or extracellular regions. Focal separations of lamellae at the intermediate line are common. MDLs too may be replaced focally by cytoplasmic pockets, sometimes in the same quadrant over several lamellae, resembling Schmidt-Lanterman clefts. Occasional densities reminiscent of the "radial component" can be seen. Otherwise, this structure, which is prominent in wild-type myelin, is conspicuously absent. Redundant folding of some lamellae but not others may occur in the same sheath. These observations conform to those made previously on the isolated myelin segments that occur in the myelin-deficient rat central nervous system (CNS), which also lacks PLP. Thus, a compact lamellar structure can be seen in fixed PLP-null myelin, but defects in the apposition of both the extracellular and the cytoplasmic surfaces of the myelin membranes are common. The abnormalities seen suggest a lack of firm intermembrane bonding, resulting in structural instability. PLP-null myelin may therefore be more susceptible than normal myelin to disruption by mechanical or osmotic stresses. Although PLP is not essential for the formation of either major dense lines or intermediate lines, it may play a role in stabilizing the compact structure.

Animals↗
PubMed1996

Expanded CNS myelin sheaths formed in situ in the presence of an IgM antigalactocerebroside-producing hybridoma.

When O1 hybridoma cells, which produce an IgM antigalacto-cerebroside, are implanted into the dorsal columns of 4-8 d rat spinal cord, some of the myelin that subsequently develops in the immediate vicinity displays an abnormal periodicity. The spacings that are seen cluster at approximately 19 nm and 31 nm, roughly two and three times the normal 11 nm spacing. In the expanded sheaths, major dense lines are separated by broad extracellular spaces containing a dense material in which single or double rows of approximately 10 nm circular profiles can be identified, consistent with the "central rings" of IgM molecules. Because IgM is multivalent, it may serve to link adjacent lamellae together in place of intrinsic myelin molecules that normally interact at close range. Extensive direct contact between myelin components of successive myelin lamellae is thus not essential to signal the growth of the oligodendrocyte membrane or the spiral wrapping of that membrane around axons during myelinogenesis, or to stabilize the myelin spiral that forms.

Animals↗
PubMed1995

Distribution of myelin lipid antigens in adult and developing rat spinal cord.

We examined the distribution of myelin antigens recognized by monoclonal antibodies (mAbs) 01 and 04 in the developing ventral white matter of the cervical spinal cord of the rat using immunogold-labeled ultrathin cryosections. From the beginning of myelination after birth to multilamellar myelin in adult animals, we observed colocalization of 04 and 01 label in myelin. In the oligodendrocyte soma, immunolabel was found primarily over Golgi cisternae. In the oligodendrocyte processes, immunolabeling was also found in the cytoplasm and along the plasmalemma. More cytoplasmic 04 and 01 label was found in the external loop of myelin than in the internal loop. The amount of 01 and 04 label increased over compact myelin in proportion to the number of lamellae, but the label density per unit length of membrane remained approximately the same in compact myelin as in oligodendrocyte plasmalemma. We did not see a concentration gradient for either 04 or 01 label across, or along multilamellar myelin sheaths.

Aging↗
PubMed1995

Paranodal structural abnormalities in rat CNS myelin developing in vivo in the presence of implanted O1 hybridoma cells.

O1 hybridoma cells, which produce a monoclonal IgM antigalactocerebroside, were implanted into the spinal cords of immature and mature rats and the cords examined 5-24 days later. Study of the younger group, in which myelin was developing at the time of implantation, revealed examples of abnormal myelin sheaths in which the repeat period was markedly increased. The paranodal regions of these abnormal sheaths were superficially normal in configuration; i.e. myelin lamellae terminated one by one as 'terminal loops' that indented the axolemma and formed normal axoglial junctions displaying periodic 'transverse bands'. Neighbouring terminal loops are normally joined by tight junctions that block passage of tracers from the paranodal periaxonal space into the compact myelin, as seen after implantation of a control hybridoma. In the abnormal sheaths that developed after O1 implantation, in contrast, terminal loops were usually widely separated from each other. As a result, multiple pathways from the paranodal periaxonal space into the myelin sheath remained patent, forming potential routes for shunting nodal action currents. This subtle abnormality could thus compromise conduction, even though the sheaths might appear to be normally myelinated at the histological level. Equivalent abnormalities in human neurological diseases, including multiple sclerosis and paraproteinemic neuropathies, could underlie functional loss in the absence of frank demyelination.

Animals↗
PubMed1994

Effects of cerebellar lesions on tonic seizures, tremor and lifespan in myelin-deficient rats.

In common with other dysmyelinating mutants, the myelin-deficient rat displays an action tremor and tonic seizures culminating in the death of the animals at approximately 23-26 days. We find that deep lesions of the cerebellar vermis alleviate the manifestations of the myelin deficiency significantly. Such lesions introduced at 20 days or later eliminate both tremor and seizures for periods up to 10 days. Lifespan is prolonged to nearly 30 days, on average, and to 35 days in some cases. Shallow lesions of the vermis or lateral lobe lesions have relatively little effect. Based on these observations we suggest that the cerebellum contributes not only to the action tremor but also to the tonic seizures characteristic of central myelin deficiency. Spontaneous activity originating in myelin-deficient fiber tracts may be carried to the cerebellum and processed there to produce a highly amplified and/or synchronized output to broad areas of the neuraxis. Deep lesions of the vermis presumably interfere with cerebellar output and compromise the cerebellar contribution to the seizures. Tonic seizures and other 'paroxysmal attacks' also occur commonly in human demyelinating diseases including multiple sclerosis [11]. Manipulation of cerebellar output offers a potential approach to the control of such spontaneous activity.

Animals↗