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J Ferrara

Publications and source records attributed to J Ferrara.

At least 37 records · Page 2Linked to original sources
PubMed1994

Highly potent transcriptional activation by 16-ene derivatives of 1,25-dihydroxyvitamin D3. Lack of modulation by 9-cis-retinoic acid of response to 1,25-dihydroxyvitamin D3 or its derivatives.

Although several studies have been performed on the biological activities of analogs of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3) at the whole animal and cellular levels, little work has been done to analyze their transcriptional activation properties. A highly inducible 1,25-(OH)2 D3-responsive promoter composed of three copies of the mouse osteopontin vitamin D3 response element (VDRE3) inserted upstream of a herpes simplex virus thymidine kinase promoter has been constructed, and its transcriptional properties have been analyzed by transient transfection into the monkey kidney cell line COS-7 and the rat osteoblast-like osteosarcoma line ROS 17/2.8. We have studied systematically transcriptional activation by a number of 1,25-(OH)2 D3 analogs, particularly those substituted at positions 16, 23, 26, and 27, sites that are targets for metabolism. Strikingly, except for derivatives that bind the 1,25-(OH)2 D3 receptor (VDR) very weakly, we find no parallel between the potency of action of a derivative as a transcriptional inducer and its affinity for the VDR. Derivatives substituted by multiple bonds at positions 16 and/or 23, although having varying affinities for the VDR, all stimulate transcription more potently than D3, in some cases at 100-fold lower concentrations. The peak transcriptional activity observed varies by only approximately 20% among different active analogs, indicating little difference in the activity of the VDR once bound to ligand. Gel retardation assays with ROS 17/2.8 nuclear extracts suggest that the VDR binds to the mouse osteopontin VDRE predominantly as a heterodimer with retinoid X receptor(s) (RXR(s)). We find that 9-cis-retinoic acid, the cognate ligand for RXRs, does not have a significant effect on the response of the VDRE3 promoter to 1,25-(OH)2 D3 or a number of its derivatives in ROS 17/2.8 or in COS-7 cells, under conditions in which promoters containing retinoid X response elements are activated. This suggests that 9-cis-retinoic acid may not act on the response to 1,25-(OH)2 D3 or its derivatives by directly influencing the transcriptional activity of VDR/RXR heterodimers. This promoter/reporter system should be useful for analyzing the tissue-specific transcriptional activity of 1,25-(OH)2 D3 and its derivatives in any cell type amenable to transient transfection.

Animals↗
PubMed1994

Prodepin: a new product of the adrenomedullin (ADM) gene has systemic vasodilator activity.

The purpose of the present study was to investigate the effects of products of the ADM gene other than ADM on systemic hemodynamics in the anesthetized rat, rabbit, piglet, cat and dog. Bolus intravenous (i.v.) injections of rat proADM22-41 (3-30 micrograms) significantly decreased systemic arterial pressure (SAP) and systemic vascular resistance in the anesthetized rat. Unlike ADM, rat proADM22-41 markedly increased cardiac output in the rat. Bolus i.v. injections of human proADM22-41 up to 500 micrograms had not effect in all species studied and rat proADM22-41 had no effect in species other than the rat. The present data suggest that rat proADM22-41 is a novel product of the ADM gene other than ADM and possesses marked systemic vasodilator activity. The present data also suggest that the hemodynamic activity of this peptide is species specific.

Adrenomedullin↗
PubMed1994

Synergistic effects of interleukin-11 with other growth factors on the expansion of murine hematopoietic progenitors and maintenance of stem cells in liquid culture.

The effect of interleukin-11 (IL-11), alone and in combination with other hematopoietic growth factors, was studied in liquid suspension cultures of murine bone marrow. Stem and progenitor cell contents of input bone marrow 2 days after 5-fluorouracil (5-FU) treatment (FU2dBM) and lineage-depleted, Sca-1-positive FU2dBM (Lin-Sca+Fu2dBM) were compared with output values obtained after 6 days in different growth factor combinations. Stem and progenitor cell recoveries were measured by long-term in vivo competitive repopulation, spleen colony-forming unit (CFU-S), and in vitro limiting dilution long-term bone marrow culture (cobblestone area-forming cell [CAFC]) assays. IL-11, IL-3, IL-6, and Steel factor (SF) were tested separately and in combinations of two, three, and four factors. IL-11 was incapable of maintaining the survival of stem or progenitor cells as a single agent but synergized with either IL-3 or SF to expand progenitor cell output in cultures of FU2dBM. IL-11 greatly enhanced progenitor cell expansion from FU2dBM when added to two- and three-factor combinations of SF, IL-3, and IL-6. The recovery of long-term repopulating ability was enhanced four-fold by incubation in SF plus IL-11 compared to SF alone. IL-11 in combination with SF, IL-3, and IL-6 stimulated a 24,000-fold expansion of progenitor cells from stem cell-enriched Lin-Sca+FU2dBM. Overall, the results indicate that IL-11 is a potent synergistic factor for stem cell proliferation and expansion of progenitors in liquid culture.

Animals↗
PubMed1993

Effect of peritoneal and gastric irrigation with ozonated saline on arterial and venous blood gas values.

Ozone, a proven in vitro antiseptic agent, has been shown in vivo to reduce infectious morbidity when used as a lavage solution in rodent fecal peritonitis. As concern that absorption of hydroxyl radical byproducts of ozone breakdown might be deleterious to blood buffering capacity, the effects of a 5 minute intragastric or peritoneal lavage with ozonated saline on rodent arterial and venous blood gas values were determined. Compared to values obtained following lavage with oxygenated saline or normal saline, ozonated saline irrigation produced no appreciable alterations in arterial or venous pH, pO2, and pCO2 over a 1 hour observation period. Short-term ozonated saline peritoneal lavage does not appreciably effect rodent blood buffering capacity.

Analysis of Variance↗
PubMed1993

In vitro alloreactivity against host antigens in an adult HLA-mismatched bone marrow transplant recipient despite in vivo host tolerance.

An adult recipient of an HLA-DR, DQ-mismatched, T cell-depleted bone marrow graft, who remains without graft versus host disease and who is not maintained on immunosuppressive therapy, was studied at 23 months posttransplantation for in vitro reactivity against the mismatched antigens of the host. The donor's PBMC's proliferated vigorously against the recipient's stimulators in the pretransplant mixed lymphocyte cultures (MLC). After transplant reconstitution, MLCs demonstrated that the in vitro response of engrafted donor T cells against host MHC class II antigens was equivalent to control allogeneic responses, while there was no detectable response against the donor's antigens. Posttransplantation limiting dilution analysis showed no difference between the precursor frequencies of antihost responders among populations of fresh donor PBMCs and among the engrafted cells of donor origin that are found circulating in the patient. This result suggests that clonal deletion is, at best, incomplete and that peripheral tolerance is essential in protecting this patient from GVHD. These findings also support the conclusion that bone marrow-derived thymic elements may be important for clonal deletion in human chimeras.

Adult↗
PubMed1993

Hematopoietic stem cell deficit of transplanted bone marrow previously exposed to cytotoxic agents.

High-dose chemotherapy and/or total body irradiation followed by autologous bone marrow rescue has improved the survival of patients with a variety of malignancies. Candidates for autologous bone marrow transplantation (ABMT) often have received prior exposure to cytotoxic agents, some of which may damage primitive stem cells. We have developed an in vivo murine model to evaluate the effects of a number of individual cytotoxic agents on the ability of syngeneic donor marrow to provide long-term hematopoiesis in recipients following high-dose total body irradiation. Marrow was experimentally obtained by giving donor mice 6 weekly injections of saline, cytosine arabinoside, cyclophosphamide, cisplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), or busulfan, drugs known to have differing effects on primitive hematopoietic stem cells. After time to allow recovery of marrow and peripheral blood counts, 1 x 10(7) marrow cells from these mice were transplanted into lethally irradiated syngeneic recipients. Five to 6 months after marrow transplantation, the quality of long-term hematopoietic recovery was measured by WBC counts, marrow cellularity, CFU-S content, and determinations of stem cell self-renewal. Abnormalities were noted with the use of donor marrow exposed to all cytotoxic agents. Recipients of marrow previously exposed to cytosine arabinoside, an agent that spares the most primitive stem cells, were the least affected. Recipients of marrow previously exposed to busulfan, an agent known to damage primitive stem cells, were most affected with a decrease in peripheral blood counts, marrow cellularity, stem cell content, self-renewal capacity, and long-term survival. A decrease in hematopoietic stem cell self-renewal was seen in recipients of marrow previously exposed to cyclophosphamide, cisplatin, and BCNU even when marrow cellularity and CFU-S content were normal. These data suggest that the capacity of syngeneic donor marrow to provide long-term hematopoiesis in lethally irradiated recipients is dependent on its donor marrow primitive stem cell content. Long-term hematopoiesis may be severely compromised in recipients of donor stem cells previously exposed to cytotoxic agents which damage primitive stem cells.

Animals↗
PubMed1991

Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies.

Seventy-one patients with hematologic malignancies received bone marrow from a histocompatible sibling (n = 48) or a partially matched relative (n = 23) that had been depleted of CD5+ T cells with either an anti-CD5 mooclonal antibody (MoAb) plus complement (anti-Leu1 + C) or an anti-CD5 MoAb conjugated to ricin A chain (ST1 immunotoxin [ST1-IT]). These patients received intensive chemoradiotherapy consisting of cytosine arabinoside, cyclophosphamide, and fractionated total body irradiation. Both anti-Leu1 + C and ST1-IT ex vivo treatments effectively depleted bone marrow of T cells (97% and 95%, respectively). Overall, primary and late graft failure each occurred in 4% of evaluable patients. The diagnosis of myelodysplasia was a significant risk factor for graft failure (P less than .001), and if myelodysplastic patients were excluded, there were no graft failures in major histocompatibility complex (MHC)-matched patients and 2 of 23 (8.7%) in MHC-mismatched patients. The actuarial risk of grade 2 to 4 acute graft-versus-host disease (GVHD) was 23% in MHC-matched patients and 50% in MHC-mismatched patients. In MHC-matched patients, acute GVHD tended to be mild and treatable with corticosteroids. Chronic GVHD was observed in 6 of 36 (17%) MHC-matched patients and none of 11 MHC-mismatched patients. There were no deaths attributable to GVHD in the MHC-matched group. Epstein-Barr virus-associated lymphoproliferative disorders were observed in 3 of 23 MHC-mismatched patients. The actuarial event-free survival was 38% in the MHC-matched patients versus 21% in the MHC-mismatched patients. However, if outcome is analyzed by risk of relapse, low-risk patients had a 62% actuarial survival compared with 11% in high-risk patients. These data indicate that the use of anti-CD5 MoAbs can effectively control GVHD in histocompatible patients, and that additional strategies are required in MHC-mismatched and high-risk patients.

Adolescent↗
PubMed1990

Prospective evaluation of clinical and pathologic detection of axillary metastases in patients with carcinoma of the breast.

Complete axillary dissection was performed in 287 patients undergoing modified radical mastectomy between 1984 and 1987 to identify patterns of axillary node metastases, as well as discontinuous axillary node ("skip") metastases. Positive pathologic findings were compared with preoperative clinical examinations in 266 patients and showed only 60 cases (22.6%) clinically suspicious for tumor, in contrast to 131 (45.6%) with pathologically confirmed positive lymph nodes. Axillary contents were classified level I, II, or III based on their relationship to the pectoralis minor muscle. An average of 24.2 nodes was resected per patient (level I, 10; level II, 8.1; and level III, 5.3). Tumors ranged in size from 0.5 to 12.0 cm (mean, 2.6 cm), and increasing tumor size was associated with an increased likelihood of positive nodes. The data on 204 patients with complete clinical and pathologic data show that of 119 patients with negative level I nodes a limited axillary dissection (level I only) would fail to identify 6 with positive level II and 2 with positive level III nodes, whereas of 85 patients with positive level I nodes limited axillary dissection would fail to identify 17 with positive level II nodes, 7 with positive level III nodes, and 27 with positive levels II and III nodes. Complete axillary dissection (levels I, II, and III) should be performed to stage patients accurately, as well as to remove tumor-involved nodes and diminish local axillary recurrences. Clinical examination of the axilla appears to be a poor means of identifying axillary metastatic cancer.

Adult↗
PubMed1989

Stem cell self-renewal considerations in bone marrow transplantation.

Autologous bone marrow transplantation is being used for an increasing number of patients with malignant diseases including Hodgkin's disease, non-Hodgkin's lymphomas, and leukemia. As the success of this procedure improves, there will be continuing concern for the consequences of such treatment. One such concern is the long-term hematopoietic function of recipients following marrow transplantation. There is evidence that bone marrow stem cells are limited in self-renewal capacity. Under circumstances of exposure to certain cytotoxic agents or to great proliferative stress, and following transplantation of marrow into lethally irradiated recipients, bone marrow stem cells undergo a permanent loss of self-renewal capacity. This loss is not initially reflected in peripheral blood counts or in marrow cellularity, but can be determined by a decrease in marrow stem cell content and by assays measuring self renewal. Animal work suggests that survival may be decreased following this loss in self-renewal. In order to limit the adverse effect of this phenomenon, efforts should be made to optimize both the quantity and quality of donor marrow engrafted. This should be possible by transplanting the largest number of marrow cells feasible, and by avoiding prior exposure to cytotoxic agents that are known to damage early stem cells in those patients who are possible candidates for autologous marrow transplantation. The use of lymphokines and peripheral stem cell harvests in transplantation should be carefully monitored as self renewal of engrafted marrow may also be decreased following these new techniques.

Animals↗
PubMed1987

Relationship of the genes for Chediak-Higashi syndrome (beige) and the T-cell receptor gamma chain in mouse and man.

The genetic linkage of Chediak-Higashi syndrome and its murine analog, beige (bg), to the T-cell receptor (TCR-gamma) gamma chain gene is further defined. Previous studies using recombinant inbred strains of mice demonstrated that the murine bg gene is genetically linked to a murine TCR-gamma gene. We report that in the mouse the frequency of recombination between these two markers is 0.025. Further, we tested the hypothesis that these two genes are linked in the human genome by analyzing restriction fragment length polymorphisms (RFLPs) in five families with children afflicted with Chediak-Higashi syndrome. In three families, RFLPs in TCR-gamma genes were inherited discordantly from Chediak-Higashi syndrome, demonstrating nonlinkage. We postulate that there is an evolutionary chromosomal breakpoint between the bg gene and the TCR-gamma gene.

Animals↗
PubMed1987

Engraftment following T-cell-depleted marrow transplantation. I. The role of major and minor histocompatibility barriers.

These experiments describe a murine model for survival and engraftment of bone marrow transplantation across differing histocompatibility barriers. Anti-Thy-1.2 antibody and complement-treated C57BL/6 (B6) marrow was transplanted at varying cell dose levels into syngeneic (B6), major histocompatibility complex congenic (A.BY), semiallogeneic (B6AF1), and fully allogeneic (A/J) recipients. Survival was monitored and engraftment determined by hemoglobin and lymphocyte phenotype. Survival was cell-dose dependent and was equivalent in B6, A.BY, and B6AF1 recipients. Survival was poor in allogeneic A/J recipients due to bone marrow failure even at high marrow dose levels. Survival posttransplant did not always correlate with stable donor engraftment, and competitive host marrow repopulation was frequently seen in B6AF1 recipients but rarely in A.BY recipients. This repopulation could be prevented by transplanting a larger marrow dose.

Animals↗
PubMed1986

Cutaneous acute graft-versus-host disease to minor histocompatibility antigens in a murine model: histologic analysis and correlation to clinical disease.

Graft-versus-host disease (GVHD) can occur in bone marrow-transplant recipients even when donor and host are identically matched at the major histocompatibility complex. GVHD in this context presumably arises because of differences in minor histocompatibility antigens. Murine GVHD to minor histocompatibility antigens has been studied in an effort to determine whether skin is a target of the immune response in this model system. T cell-depleted marrow cells (10(7)) from B10.BR (H-2k) mice were supplemented with varying numbers of nylon wool-enriched splenic B10.BR T cells and transplanted intravenously into irradiated (1100 R) CBA (H-2k) mice. Sequential biopsies of ear skin were obtained at weekly intervals over a 7-week period. Histopathologic evaluation revealed basal cell layer vacuolization, exocytosis, and satellitosis of mononuclear cells in the epidermis. Dyskeratosis was observed only in animals receiving T cells, and proved to be the most reliable histologic parameter of disease with the number of dyskeratotic cells per linear millimeter of epidermis correlating both with severity of clinical disease and with the number of transplanted T cells. Ultrastructural examination revealed exocytosis of mononuclear cells into the epidermis where they were frequently apposed to degenerating and necrotic keratinocytes. These data indicate that the skin is an informative target organ for study of experimental GVHD to minor histocompatibility antigens.

Acute Disease↗
PubMed1986

Acute cutaneous graft-versus-host disease to minor histocompatibility antigens in a murine model. Evidence that large granular lymphocytes are effector cells in the immune response.

We studied the morphologic and immunophenotypic characteristics of inflammatory infiltrates in the skin of mice with acute graft-versus-host disease induced by bone marrow transplantation between strains differing only in minor histocompatibility antigens. The strain combinations employed (B10.Br - greater than CBA) have been shown to produce a lethal graft-versus-host disease with clinical severity proportional to the number of T lymphocytes added to the donor marrow inoculum. Transplant recipients developed pronounced clinical signs of graft-versus-host disease, including copious diarrhea and weight loss, and histologic alterations in skin strikingly similar to this disease in humans. Our findings indicate that the preponderant mononuclear cell in lesional skin from these animals has phenotypic characteristics of a natural killer cell. This cell was often found in apposition with necrotic epidermal cells. The origin, function, and potential relevance of natural killer cells in lesion formation in this experimental model are discussed.

Acute Disease↗
PubMed1985

A simple method for identifying and testing the recurrent laryngeal nerve.

Simultaneous stimulation of the recurrent laryngeal nerve and palpation of an impulse in the homolateral cricothyroid area was performed upon 20 patients. Electrical stimulation of the recurrent laryngeal nerve with currents of 2 milliamperes caused no postoperative deficits in any of the patients studied. This is a simple and reproducible method to help identify the RLN and to confirm that the recurrent nerve is intact and viable at the completion of a surgical procedure. The technique is simpler than checking cord motion at the conclusion of surgical procedures upon the thyroid or parathyroid glands. Due to the variability of the response in some of the patients, we believe that the procedure should be tried on more patients before it is recommended as a conclusive test.

Electric Stimulation↗