Search PubMed⌕ Search

Biomedical subjects

R J Arceci

Publications and source records attributed to R J Arceci.

At least 37 records · Page 2Linked to original sources
PubMed1997

Diabetes insipidus secondary to Langerhans' cell histiocytosis: is radiation therapy indicated?

Langerhans' cell histiocytosis (LCH) is a proliferative disease of Langerhans' cells that has multiple clinical manifestations including diabetes insipidus (DI). This study reviews the effectiveness of hypothalamic-pituitary radiation therapy (HPRT) as a treatment of LCH-induced DI in the modern era. A retrospective review was done of 116 pediatric patients with LCH seen from 1975 to 1992. Seventeen of the 116 patients (15%) were diagnosed with complete or partial diabetes insipidus. Diagnosis was made either by water deprivation test or on clinical grounds. Fourteen patients received hypothalamic-pituitary irradiation as treatment for DI. The median interval from the onset of DI symptoms (polyuria and polydipsia) to treatment was 30 days. The median interval from the onset of diagnosis to treatment was 4 days. With a mean follow-up of 7.3 years (range, 2.4-14.3), only two patients had a complete response to therapy, as defined as no need for antidiuretic hormone (ADH) replacement therapy. No patient had a partial response, defined as a decrease in the dose of ADH replacement. Of the two responders, neither had a complete ADH deficiency, suggesting "early" disease. In addition, both received RT within 3 days. We feel that the standard treatment of RT to all patients with LCH-induced DI is no longer justified. Our series has shown no benefit in treating patients with a long history of DI. Rather, an improved rationale would be rapid initiation of hypothalamic-pituitary irradiation in patients with new symptoms of DI and an abnormal water deprivation test.

Adolescent↗
PubMed1997

Allelotype of pediatric rhabdomyosarcoma.

An allelotype covering all autosomes was constructed for the embryonal form of childhood rhabdomyosarcoma (ERMS) in order to identify regions encompassing tumorsuppressor genes (TSG) involved in ERMS. Thusfar most studies were focussed on chromosome 11p15.5, which frequently shows loss of heterozygozity (LOH) in embryonal tumors like RMS and Wilms' tumor (WT). In this study we show that, besides LOH of chromosome 11p15.5 (72%), LOH of chromosome 16q was present in 54% of the tumors analysed. Delineation of these two regions shows that the smallest region of overlap (SRO) for chromosome 11 was between D11S988 and D11S922. This region, estimated to be 7 cM and 3-5 Mb, is also the location of the putative Wilms' tumor WT2 TSG. It contains several genes including IGF2 and potential tumorsuppressor genes like H19 and p57kip2, which might contribute to the carcinogenesis of RMS. Analysis of chromosome 16q LOH defined the SRO between D16S752 and D16S413. LOH of chromosome 16 is also found in other tumors, including WT. Our data suggest that genes involved in the development of RMS and WT may not only be similar for chromosome 11 but also for chromosome 16.

Alleles↗
PubMed1996

Induction of embryonic vasculogenesis by bFGF and LIF in vitro and in vivo.

The de novo formation of blood vessels (vasculogenesis) is an integral part of embryogenesis. Elucidation of the role of cytokine cooperation in vasculogenesis may lead to a better understanding of organogenesis, blood vessel regulation during tumorigenesis, and tissue injury. We have used embryonic stem cells to derive an endothelial cell line, designated IEM, which expresses a range of endothelial markers, including Von Willibrand Factor VIII related antigen, vascular cell adhesion molecule, platelet-endothelial cell adhesion molecule (CD31), and receptors for acetylated low-density lipoprotein. More importantly, IEM cells can be induced upon exposure to combinations of basic fibroblast growth factor and leukemia inhibitory factor (LIF) to proliferate and undergo vasculogenesis in vitro, resulting in the formation of vascular tubes and microcapillary anastomoses. Moreover, exposure to both cytokines conditionally permits IEM cells to specifically chimerize microvascular endothelium in vivo following blastocyst injection. These results indicate that bFGF and LIF together contribute to the induction and support of embryonic vasculogenesis in an isolated endothelial cell line. Our results provide evidence that combined actions of bFGF/LIF may play a role in mechanisms controlling blood vessel development.

Animals↗
PubMed1996

Allograft inflammatory factory-1. A cytokine-responsive macrophage molecule expressed in transplanted human hearts.

Allograft inflammatory factor-1 (AIF-1), a cytokine-responsive macrophage molecule, was originally identified and cloned from rat cardiac allografts with chronic cardiac rejection. We performed the present study to determine whether AIF-1 was also involved in the inflammatory response associated with human cardiac transplant rejection. AIF-1 gene transcripts were identified by the reverse-transcriptase polymerase chain reaction in endomyocardial biopsy specimens from human heart transplants and in macrophage cell lines. In the 441-base pair coding region of the human and rat cDNAs, the nucleotide sequences were 86% identical and the deduced amino acid sequences were 90% identical. Consistent with our studies in the rat. AIF-1 was selectively expressed in human macrophage-like cell lines, and immunostaining in human heart allografts localized the AIF-1 gene product to a subset of CD68+ macrophages in the interstitial and perivascular spaces. The parallels between rat and human AIF-1 expression suggest that AIF-1 may have a common effect on the function of activated macrophages in cardiac allografts.

Animals↗
PubMed1996

Irradiated B7-1 transduced primary acute myelogenous leukemia (AML) cells can be used as therapeutic vaccines in murine AML.

Recent studies have shown that tumor cells genetically modified by transduction of B7-1, a natural ligand for the T-cell costimulatory molecules CD28 and CTLA-4, are rejected in syngeneic hosts. In these reports, transformed cell lines and drug-selected cells have been used for vaccinations. To determine the effectiveness of B7-1-transduced primary acute myelogenous leukemia (AML) cells on the induction of antitumor immunity, we have studied a murine AML model in which primary AML cells were retrovirally transduced with the murine B7-1 cDNA. A defective retroviral producer clone expressing B7-1 and secreting a high titer of virus was used for infection of AML cells. Unselected transduced AML cells, expressing a high level of B7-1, were used for in vivo vaccinations. Our results show that one intravenous (IV) injection of irradiated B7-1-positive (B7-1+) AML cells can provide long-lasting (5 to 6 months) systemic immunity against subsequent challenge with wild-type AML cells. Furthermore, one exposure to irradiated B7-1+ AML cells results in rejection of leukemia by leukemic mice when the vaccination occurs in the early stages of the disease. The antileukemia immunity is CD8+ T-cell-dependent and B7/CD28-mediated, since in vivo treatment of mice with anti-CD8 monoclonal antibody or CTLA-4 Ig leads to abrogation of the specific antileukemia immune response. These results emphasize that B7-1 vaccines may have therapeutic usefulness for patients with AML.

Animals↗
PubMed1996

P-glycoprotein is expressed in the mineralizing regions of the skeleton.

Using oligonucleotide primers specific for the human MDR 1 gene, we were able to identify a specific amplicon using RT-PCR from total bovine growth plate chondrocyte RNA. The identification of MDR mRNA in growth plate chondrocytes led us to examine the precise distribution of MDR P-glycoprotein in bone and cartilage. We applied two monoclonal antibodies (C219 and C494) to human fetal, neonatal, and childhood growth plates and bone. In growth plates, P-glycoprotein was detected at high levels in a perilacunar distribution in the calcifying zone and at lower levels in hypertrophic, but not proliferative or reserve zone, chondrocytes. P-glycoprotein was also observed in perichondrial chondrocytes, in perivascular chondrocytes and matrix in the fetal cartilage anlage, and in osteoblasts and the surface osteoid matrix of newly formed bone trabeculae in the primary spongiosa. The recently described chloride channel of P-glycoprotein suggests a potential role of P-glycoprotein in growth plate chondrocyte hypertrophy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Absence of colony-stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects.

Previous studies have shown that the mononuclear phagocyte growth factor, colony-stimulating factor-1 (CSF-1), has an important role in female reproduction. Mating experiments with osteopetrotic (csfmop/csfmop) mice, which possess an inactivating mutation in the CSF-1 gene, suggested that there are male, as well as female, reproductive defects. In the present study, we have shown that male csfmop/csfmop mice have a sevenfold lower concentration of circulating testosterone (T) and a significantly lower intratesticular T concentration than wild-type mice. These lowered T concentrations were associated with a reduction in mating capability and a reduction in the number of viable sperm. Reconstitution of male csfmop/csfmop mice with either circulating T in the adult or circulating CSF-1 throughout the postnatal period completely restored viable sperm numbers and significantly restored sexual behavior. These observations, coupled with the close association of Leydig cells with testicular macrophages and the proposed function of these macrophages in the regulation of Leydig cell steroidogenesis, suggest that CSF-1-regulated testicular macrophages play an important role in male reproduction.

Animals↗
PubMed1996

Langerhans cell histiocytosis: an uncommon disease commonly manifesting in the craniofacial skeleton.

Langerhans cell histiocytosis is an infrequent and enigmatic proliferative disorder that commonly presents in the head and neck region. This is an analysis of 77 patients with Langerhans cell histiocytosis treated at Children's Hospital and Dana Farber Cancer Institute from 1974 through 1993. The study focused on clinical findings, anatomic location and extent of disease, therapy, and outcome. The patients were, on average, under 5 years of age at initial presentation. Over 62 percent of the patients had signs and symptoms referred to the craniofacial skeleton. Osteolytic lesions of the cranium were the most common, followed, in frequency, by scalp rash, osteolytic mandibular tumor(s), enlarged nodes, and gingival swelling or ulceration. Single bony lesions usually were treated with curettage or radiotherapy. Chemotherapy was used commonly for advanced disease with multifocal or disseminated presentation. Initial therapy included moderate doses of single agents; other agents were added if no response was achieved. The natural history of Langerhans cell histiocytosis varied from an acute fulminant course, a waxing and waning chronic disease, to spontaneous regression. Young age at presentation and organ dysfunction predicted a poor prognosis. Statistical analysis showed that there was no significant relationship between outcome and extent of skeletal involvement when controlling for age or organ dysfunction.

Bone Diseases↗
PubMed1996

Tumor cell survival and resistance to therapy.

The primary reason for the failure to cure patients with cancer remains the development of multiple mechanisms of resistance to cytotoxic agents. The two major effectors of tumor cell killing include genotoxic agents and cell-mediated immunity. Genotoxic agents function primarily by initiating pathways leading to apoptosis or programmed cell death, whereas immune-mediate cytotoxicity utilizes both programmed cell death-promoting as well as cytolytic processes. The mechanisms leading to treatment resistance initially involve alterations in the way tumor cells transport, metabolize, and provide substrates for cytotoxic agents. Beyond these specific mechanisms, tumor cells may also express alterations in the regulators and effectors of apoptotic death, thus creating a more generalized resistance pattern. Through a variety of other mechanisms, tumor cells may also decrease specific antigen expression or the ability to costimulate T lymphocytes. The result of antigen recognition in the absence of costimulation can lead to antigen-specific tolerance, which may also represent a major form of escape from immune-mediated killing. The elucidation of these mechanisms of resistance to therapy and tumor cell survival should form the basis for the development of more effective therapies.

Apoptosis↗
PubMed1995

Anti-B4-blocked ricin synergizes with doxorubicin and etoposide on multidrug-resistant and drug-sensitive tumors.

Anti-B4-blocked ricin (anti-B4-bR) is an immunotoxin directed against CD19-positive cells that is currently being tested in several B-cell leukemia/lymphoma clinical trials. To explore the possibility of using anti-B4-bR in combination with chemotherapy protocols, we investigated the in vitro and in vivo cytotoxic effects of combining it with doxorubicin or etoposide using the lymphoma cell line Namalwa and a P-glycoprotein-expressing cell line, Namalwa/mdr-1, obtained by retroviral infection of Namalwa cells with the mdr-1 gene. Namalwa/mdr-1 cells were slightly more sensitive to anti-B4-bR than Namalwa cells; IC37 values were approximately 4 pmol/L and 8 pmol/L, respectively. When anti-B4-bR was combined simultaneously with doxorubicin or etoposide, additive to supra-additive killing of Namalwa and Namalwa/mdr-1 cells was observed. In xenografts of Namalwa/mdr-1 cells in severe combined immunodeficiency (SCID) mice, doxorubicin and etoposide at their maximum tolerated doses (3 mg/kg x 3 or 15 mg/kg x 3) showed no therapeutic effect. However, treatment with 5 daily bolus injections of anti-B4-bR (50 micrograms/kg) followed by treatment with doxorubicin or etoposide significantly increased the life span of the mice by 129% and 115%, respectively. After treatment with anti-B4-bR, the Namalwa/mdr-1 population expressed lower levels of P-glycoprotein, and this decrease may account for the synergistic action of the drug combinations. These results suggest that anti-B4-bR could be used to good effect in combination with current treatment regimens and further hint at a promising role for this immunotoxin in treatment of disease at the minimal residual disease stage, where cells may be resistant to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Mechanisms of resistance to therapy and tumor cell survival.

The failure to cure patients with cancer continues to be primarily because of the development of treatment resistance. Both normal and malignant cells die by either programmed cell death (apoptosis) or by cytolysis. Malignant cells have developed mechanisms of resistance that prevent them from entering the programmed cell death pathway as well as mechanisms of escaping immune recognition and cytolysis. These mechanisms include specific protective adaptations involving drug transport, metabolism, and target interactions. Malignant cells may also become resistant to therapy through alterations in genes encoding proteins involved in the initiation of apoptotic pathways. Finally, tumor cells may develop mechanisms to escape immune recognition, making them resistant to T-cell destruction. This article provides an overview of these mechanisms, with emphasis on published articles reported within the past year.

Adaptation, Physiological↗
PubMed1995

Cloning and characterization of allograft inflammatory factor-1: a novel macrophage factor identified in rat cardiac allografts with chronic rejection.

The development of arteriosclerotic lesions in the Lewis to F344 rat model of chronic cardiac rejection is characterized by macrophage adhesion to the vessel lumen and macrophage infiltration in the neointima prior to smooth muscle cell accumulation. We report the cloning and characterization of allograft inflammatory factor-1 (AIF-1), a novel cDNA that is expressed early and persistently in chronically rejecting cardiac allografts but is absent in cardiac syngrafts and host hearts. The full-length cDNA codes for a hydrophilic polypeptide of 17 kD that contains a 12-amino acid region similar to an EF-hand (calcium-binding) domain. In cardiac allografts AIF-1 transcripts and protein localized to infiltrating mononuclear cells. Analysis of isolated cell populations confirmed that AIF-1 was selectively expressed in macrophages and neutrophils and demonstrated that AIF-1 transcripts could be upregulated by sixfold after stimulation with the T cell-derived cytokine IFN-gamma. Treatment with a diet deficient in essential fatty acids (which attenuates arteriosclerosis) or CTLA-4 Ig (which blocks lymphocyte activation) significantly decreased AIF-1 transcript levels. Upregulation of AIF-1 in the setting of T cell activation suggests that it may play a role in macrophage activation and function.

Amino Acid Sequence↗
PubMed1994

Identification and upregulation of galactose/N-acetylgalactosamine macrophage lectin in rat cardiac allografts with arteriosclerosis.

Using differential mRNA display to uncover potential mediators associated with chronic rejection, we identified a cDNA fragment induced in Lewis to F344 rat cardiac allografts with arteriosclerosis but not Lewis syngrafts. The full-length cDNA (1.4 kb) isolated from a rat cardiac allograft cDNA library was 99% identical to galactose/N-acetylgalactosamine (Gal/GalNAc) macrophage lectin, a cell-surface receptor. This cDNA hybridized in Northern analysis with total RNA from eight cardiac allografts but not with host hearts, syngrafts, or other organs. There was a significant allograft-specific increase in transcript levels measured by reverse transcriptase PCR at days 7, 14, 28, and 75 in comparison with paired F344 host hearts (subject to same circulation but histologically normal), day-0 hearts, and syngrafts (P < 0.008, n = 4 at each time). Transcript levels in cardiac allografts were higher than those in paired host spleens (a major source of inflammatory cells) (P < 0.0001), indicating the localized nature of Gal/GalNAc lectin induction. By in situ hybridization and immunostaining, Gal/GalNAc lectin expression localized to a subset of inflammatory cells in cardiac allografts. These findings link Gal/GalNAc macrophage lectin to the chronic rejection process, as a possible mediator of macrophage infiltration.

Acetylgalactosamine↗
PubMed1994

P-glycoprotein mediates profound resistance to bisantrene.

Bisantrene, mitoxantrone, and anthracyclines are anthracene derivatives that interact with DNA and are used for the treatment of cancers. The mechanisms of resistance to bisantrene are unknown. Here we show that cells that overexpress low levels of P-glycoprotein or are transfected with human MDR1 have approximately 10-fold greater resistance to bisantrene compared to vinblastine, doxorubicin, or colchicine. Furthermore, bisantrene can be used to select for high-level P-glycoprotein-mediated multiple drug resistance in a human colon carcinoma cell line, LS 174T, and the drug blocks photoaffinity labeling of P-glycoprotein. The data suggest that bisantrene is an excellent substrate for P-glycoprotein. These findings could influence subsequent clinical evaluation of bisantrene for the treatment of cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Treatment options--commentary.

Although effective treatments are available for many children with LCH, there are many others for whom no definitive therapy yet exists. These patients include those with 1) multisystem disease and associated organ dysfunction, 2) chronic, relapsing disease, 3) new onset pituitary involvement associated with diabetes insipidus and 4) long-term complications such as pulmonary fibrosis, liver fibrosis or CNS involvement. This introductory paper discusses these clinical problem areas and then reviews several new therapeutic approaches including novel chemotherapeutic agents, immunosuppressive strategies, bone marrow transplantation and gene therapy.

Antibodies, Monoclonal↗
PubMed1993

Binding properties of monoclonal antibodies recognizing external epitopes of the human MDR1 P-glycoprotein.

Monoclonal antibodies (MAbs) recognizing external epitopes of the human MDR1 P-glycoprotein have been used both for the detection of multidrug-resistant cells and as specific inhibitors of P-glycoprotein-mediated multidrug resistance. Using a panel of recently developed transfected or transgenic cell lines containing variants of the human MDR1 and MDR3 P-glycoproteins, we have compared the specificity and binding properties of the previously isolated MAbs MRK16, HYB-241, UIC2 and 4E3, and of the newly isolated MAb 7G4. The removal of 1, 2 or all 3 of the N-glycosylation sites present in the first extracellular loop of MDR1 P-glycoprotein did not significantly affect the binding of these MAbs. In contrast, 20 amino acid deletion in the first extracellular loop of MDR1 P-glycoprotein completely abolished binding of UIC2, whereas the binding of all other MAbs was hardly affected. None of the MAbs tested bound detectably to cell lines containing a high level of the human MDR3 P-glycoprotein. The differences in the binding specificity between UIC2 and the other tested antibodies parallel the reported functional differences in the ability of these antibodies to inhibit P-glycoprotein-mediated drug efflux.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Monoclonal antibody to an external epitope of the human mdr1 P-glycoprotein.

A membrane glycoprotein, termed P-glycoprotein, has been shown to be responsible for cross-resistance to a broad range of structurally and functionally distinct cytotoxic agents. P-glycoprotein, encoded in humans by the mdr1 gene, functions as an energy-dependent efflux pump to exclude these cytotoxic agents from the resistant cell. In order to study the phenomenon of multidrug resistance in both normal and neoplastic cells, we have generated a mouse monoclonal antibody directed to an external epitope of the human P-glycoprotein. This monoclonal antibody, 4E3, is an IgG2a class antibody which specifically recognizes the human mdr1 P-glycoprotein but not the mdr3 gene product. The 4E3 monoclonal antibody immunoprecipitates both the glycosylated and nonglycosylated forms of P-glycoprotein under mild denaturation conditions. In addition, 4E3 can detect P-glycoprotein in immunocytochemical analysis of fixed tissue-cultured cells and in analysis of frozen sections of human tissue. Binding of the monoclonal antibody to multidrug-resistant cells does not significantly affect the intracellular accumulation or potentiate the cytotoxicity of daunomycin in multidrug-resistant cells. However, at high concentrations of antibody, 4E3 produces a mild potentiation of vinblastine and actinomycin cytotoxicity in multidrug-resistant cells. This monoclonal antibody will be useful both for analyzing P-glycoprotein expression in normal and neoplastic cells and for isolating live cells expressing the P-glycoprotein without significantly affecting the efflux functions of the transporter.

ATP Binding Cassette Transporter, Subfamily B, Mem↗