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Biomedical subjects

D L Longo

Publications and source records attributed to D L Longo.

At least 181 records · Page 10Linked to original sources
PubMed1994

LPS-inducible nuclear factor in human monocytes that binds the negative regulatory element of the HIV LTR.

We studied the constitutive and lipopolysaccharide (LPS)-induced expression of nuclear protein binding to the negative regulatory element (NRE) of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) in fresh human monocytes. We demonstrated the existence of a constitutive factor binding to the NRE 73-bp HpaII/HpaII fragment (-216 to -143) whose expression is up-regulated by LPS treatment. Competition experiments with overlapping oligonucleotides covering the HpaII/HpaII fragment and with mutated oligonucleotides mapped the binding within the TTTCATCAC region (-171 to -163). This binding pattern is unique to human monocytes.

Base Sequence↗
PubMed1994

Cytogenetic study of two cases with lymphoma of mucosa-associated lymphoid tissue.

Cytogenetic studies have been reported in fewer than 20 patients with lymphoma of mucosa associated lymphoid tissue (MALT). Two patients with this disease at the Clinical Center, National Institutes of health had numerical and structural chromosome abnormalities, including +12 in both cases. The clonal karyotypes observed were 48-49,XX,t(2;8)(q33;p23), +3, -10,del(10)(q23), +12, +18 [cp] and 47,X,-X,i(6p), +7, +inv(12)(p13q13). Review of cytogenetic studies from published data showed that all cases of MALT lymphoma reported to date also have both numerical and structural chromosome abnormalities, the most frequent being numerical involvement of chromosomes 3, 7, and 12. Identification of a clonal abnormality can help establish the diagnosis when differential diagnosis includes atypical hyperplasia. Although trisomy 12 has been associated with a poor prognosis in B-cell chronic lymphocytic lymphoma (B-CLL), both these patients with MALT lymphoma have had long survival: 8 and 11 years, respectively.

Chromosome Aberrations↗
PubMed1994

Induction of phosphocholine-specific antibodies in X-linked immune deficient mice: in vivo protection against a Streptococcus pneumoniae challenge.

X-linked immune deficient (XID) mice are susceptible to infection with Streptococcus pneumoniae because they fail to mount an immune response to the immunodominant phosphocholine (PC) epitope on the bacterial cell wall. It is difficult to induce PC-specific antibodies in XID mice because PC-specific B cells expressing the T15-, M167- and M603 idiotype (Id), which provide protection against S. pneumoniae, are deleted in these mice via an antigen-specific, receptor-mediated process. In addition, the standard PC hapten, p-diazophenylphosphocholine (DPPC), induces high affinity phenylphosphocholine (PPC)-specific antibodies in XID mice, which are not protective against S. pneumoniae. We have used a novel PC hapten, p-nitrophenyl-6-(O-phosphocholine)hydroxyhexanoate (EPC), to induce PC-specific antibodies in XID mice. The immune response to EPC-keyhole limpet hemacyanin (KLH) is dominated by IgG1, VH1+, T15-Id-, PC-inhibitable antibodies. A small IgM anti-PC response having a consistent T15-Id+ component is also induced in XID mice, whereas normal mice produce a large IgM response dominated by T15-Id+ antibodies. The immune response to EPC-KLH remains predominantly PC-inhibitable even after multiple immunizations, while the response to DPPC-KLH becomes dominated by PPC-specific antibodies. C.CBA/N mice immunized twice with EPC-KLH are protected against 10(4) S. pneumoniae while as few as 10 bacteria are 100% lethal for the unimmunized controls. The ability of EPC-protein to induce a long-lived, PC-specific response should make this hapten a potential TD vaccine candidate for S. pneumoniae.

Animals↗
PubMed1994

In murine AIDS, B cells are early targets of defective virus and are required for efficient infection and expression of defective virus in T cells and macrophages.

Previous studies showed that B cells and CD4+ T cells are required for induction of a murine retrovirus-induced immunodeficiency syndrome, murine AIDS. Using B6 mice deficient in mature B cells as a result of a knockout of the transmembrane exon of the immunoglobulin M gene, we found that spleen and other tissues from murine AIDS virus-infected mice did not express the defective virus (BM5def) required for induction of disease, even though helper viruses were readily detectable and BM5def proviral DNA was present. This indicates that the B-lineage cells are the primary targets for infection and expression of the defective virus and that in the absence of mature B cells, there is inefficient infection of T cells and macrophages.

Actins↗
PubMed1994

Growth hormone promotes human T cell adhesion and migration to both human and murine matrix proteins in vitro and directly promotes xenogeneic engraftment.

Recombinant human growth hormone (rhGH) promotes human T cell engraftment in mice with severe combined immunodeficiency, suggesting that rhGH may have effects on T cell adhesion and migration in vivo. The ability of rhGH to directly affect the adhesion capacity of human T cells to a variety of human or murine adhesion molecules and extracellular matrix proteins was examined. rhGH induced significant human T cell adherence to both human and murine substrates via either beta 1 or beta 2 integrin molecules. rhGH was capable of inducing significant migration of resting and activated human T cells and their subsets. Most of the migratory response to rhGH was chemokinetic rather than chemotactic. In vivo engraftment studies in severe combined immunodeficiency mice receiving human T cells revealed that treatment with rhGH resulted in improved thymic engraftment, whereas treatment with non-human-reactive ovine GH demonstrated no significant effects. These data demonstrate that rhGH directly augments human T cell trafficking to peripheral murine lymphoid tissues. rhGH appears to be capable of directly altering the adhesive and migratory capacity of human T cells to molecules of either murine or human origin. Therefore, GH may, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation.

Animals↗
PubMed1994

Diffuse small noncleaved-cell, non-Burkitt's lymphoma in adults: a high-grade lymphoma responsive to ProMACE-based combination chemotherapy.

PURPOSE: To review the efficacy of cyclophosphamide, doxorubicin, etoposide, methotrexate with leucovorin, and prednisone (ProMACE)-based combination chemotherapy programs in the treatment of patients with diffuse small noncleaved-cell non-Burkitt's lymphoma. PATIENTS AND METHODS: Thirty-three patients with diffuse small noncleaved-cell non-Burkitt's lymphoma were accrued: eight with localized disease were treated with modified ProMACE-mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) plus involved-field radiation therapy, and 25 with advanced-stage disease were treated with ProMACE/MOPP flexitherapy (n = 8), ProMACE-MOPP (n = 9), or ProMACE-cytarabine, bleomycin, vincristine, and methotrexate with leucovorin (CytaBOM) (n = 8). The median follow-up duration is 10 years. RESULTS: All eight patients with localized disease achieved a complete response, none have relapsed, and one died of intercurrent illness. Among patients with advanced-stage disease, five of eight (63%) flexitherapy-treated patients, six of nine (67%) ProMACE-MOPP-treated patients, and eight of eight (100%) ProMACE-CytaBOM-treated patients achieved a complete response. If the two ProMACE-MOPP-based groups are considered together, disease-free and overall survival rates at 15 years are projected at 61% and 35%, respectively. In contrast, only one patient has relapsed from a ProMACE-CytaBOM-induced complete remission, and overall survival of ProMACE-CytaBOM-treated patients (88%) is significantly higher than that for flexitherapy and ProMACE-MOPP (P2 = .04). CONCLUSION: Adult patients with diffuse small non-cleaved-cell non-Burkitt's lymphoma may be effectively treated with regimens that are effective in other aggressive lymphomas (eg, diffuse large-cell lymphoma).

Adult↗
PubMed1994

Lymphomas.

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Hodgkin Disease↗
PubMed1994

Hodgkin's disease.

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Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Human insulin-like growth factor I exerts hematopoietic growth-promoting effects after in vivo administration.

Recombinant human insulin-like growth factor I (rhIGF-I) was administered to mice to determine its effect on hematopoiesis. Mice given intraperitoneal (IP) injections of 5 micrograms rhIGF-I for 7 days exhibited a significant increase in bone marrow (BM) hematopoietic progenitor cells, suggesting that rhIGF-I acts as a hematopoietic growth factor. Treatment with rhIGF-I also resulted in increases in erythroid precursor cells. Mice were then placed on azidothymidine (AZT), which produces significant myelotoxic effects. Splenic and BM progenitor cell content and hematocrit values were all significantly increased if rhIGF-I (5 micrograms injected IP every day for 28 days) was concurrently administered with AZT. Additionally, when mice were initially myelosuppressed by several weeks of AZT treatment, the subsequent administration of rhIGF-I resulted in an increase in hematopoietic progenitor cell content. No significant pathologic effects or weight changes were observed in mice receiving repeated injections of rhIGF-I at this dose and schedule. Thus, rhIGF-I exerts hematopoietic growth-promoting effects in vivo and may be of potential clinical use in promoting hematopoiesis in the face of myelotoxic therapy.

Animals↗
PubMed1994

Cloning and characterization of human and murine homologues of the Drosophila polo serine-threonine kinase.

We have cloned both human and murine complementary DNAs that are homologous to the Drosophila serine/threonine polo kinase and the recently cloned murine polo related kinase (PLK). Both the human and murine clones are about 2.1 kilobases with open reading frames of 1.8 kilobases, encoding proteins of 603 amino acids with a predicted size of 66 kilodaltons and an apparent size of 67 kilodaltons by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. During embryonic development of the mouse, the mRNA was expressed in all tissues examined, whereas in adult tissues, expression was limited to thymus and ovaries. All cell lines examined also expressed mRNAs of similar size. Microinjection of in vitro transcribed sense mRNA into serum-starved murine NIH3T3 cells induced tritiated thymidine incorporation, whereas microinjection of antisense RNA into growing NIH3T3 cells blocked tritiated thymidine incorporation. When PC12 rat cells were induced to differentiate with nerve growth factor, gene expression of PLK was greatly reduced. Together, these results suggest that PLK expression is restricted to, and is perhaps required by, proliferating cells.

3T3 Cells↗
PubMed1994

Non-Hodgkin's lymphoma.

The increasing incidence of lymphomas is related to environmental factors including occupational exposures and HIV infection. Molecular and immunologic studies have recently defined some new clinico-pathologic entities such as mantle cell lymphoma and lymphoma of mucosal-associated lymphatic tissue. However, the most prevalent lymphomas are follicular lymphomas and diffuse aggressive-histology lymphomas. Follicular lymphomas are curable with radiation therapy when they are localized to lymph nodes. Efforts to improve treatment results in patients with advanced follicular lymphoma are focusing primarily on the use of additional therapy (eg, interferon, high-dose chemoradiotherapy, and immunologic therapy) after induction of a complete response by combination chemotherapy. Aggressive-histology lymphoma is curable in more than 85% of patients when it is localized and in more than 50% of patients when it is disseminated. Efforts to improve treatment results are focusing primarily on delivering therapy with higher-dose intensity.

Humans↗
PubMed1993

Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma.

Cancer patients and mice bearing tumors develop a progressive immunosuppression manifested by a decreased delayed-type hypersensitivity, decreased T-cell lytic activity, diminished production of lymphokines, and a reduced T-cell proliferative response. The mechanisms underlying these changes are incompletely understood. We recently reported the presence of marked alterations in signal transduction in T-cells from mice bearing long-term (28-day) tumours. We hypothesized that a soluble product produced by the tumor or resulting from the immune response to tumor might be responsible for inducing the changes in T-cells. Tumor-infiltrating lymphocytes from patients with renal cell carcinoma tested here showed, in 10 of 11 cases, a marked decrease in the expression of the T-cell receptor zeta chain and in p56lck tyrosine kinase. The presence of major alterations in the tumor-infiltrating lymphocytes with only minor changes in the peripheral blood leukocyte T-cells supports the notion that the defects are induced by exposure to tumor. These results suggest that tumor-infiltrating lymphocytes may be compromised in their antitumor efficacy in patients with renal cell cancer.

Carcinoma, Renal Cell↗
PubMed1993

Activated natural killer cells and interleukin-2 promote granulocytic and megakaryocytic reconstitution after syngeneic bone marrow transplantation in mice.

Purified populations of natural killer (NK) cells were obtained from mice with severe combined immune deficiency (SCID). SCID spleen cells were cultured and activated with recombinant human interleukin-2 (rhIL-2) in vitro. The activated NK cells were then transferred with syngeneic BALB/c bone marrow cells (BMC) and rhIL-2 into lethally irradiated syngeneic recipients to determine their effect on long-term hematopoietic reconstitution. On analysis, the transfer of rhIL-2-activated NK cells along with BMC resulted in significant increases in splenic and BM hematopoietic progenitor cells when compared with those for mice not receiving NK cells. Histologic and flow cytometric analysis showed a marked increase in granulocytic and megakaryocytic lineage cells present in the spleens of the mice receiving activated NK cells. Analysis of the peripheral blood indicated that the transfer of activated NK cells with BMC also significantly improved platelet and total white blood cell counts, with increases in segmented neutrophils. Erythroid recovery was not affected. Finally, lethally irradiated mice receiving activated NK cells and rhIL-2 along with limiting numbers of syngeneic BMC showed a marked increase in survival rate. These results show that the use of populations enriched for activated NK cells after syngeneic BM transplantation (BMT) has a profound enhancing effect on engraftment primarily affecting megakaryocytic and granulocytic cell reconstitution. Therefore, the transfer of activated NK cells and rhIL-2 may be of clinical use to promote hematopoietic reconstitution after BMT.

Animals↗
PubMed1993

p53 mutation is associated with progression in follicular lymphomas.

The majority of low-grade follicular lymphomas will eventually transform to an aggressive intermediate, or high-grade lymphoma. The molecular mechanisms responsible for this transformation have not been determined. We studied serial biopsies from 34 patients with follicular lymphomas that underwent histologic transformation, for abnormalities of the p53 tumor suppressor gene by a combination of immunohistochemistry, single strand conformation polymorphism analysis (SSCP), and sequencing. We found overexpression of p53 in 10 of the 34 transformed aggressive lymphomas, 9 of which contained mutations identified by SSCP analysis and subsequent sequencing. Matched pretransformation low-grade follicular lymphoma biopsies were available for 7 of the 10 cases. None of six studied by immunohistochemistry showed overexpression of p53 and only 1 of 4 studied by SSCP/sequencing showed the presence of mutation in the pretransformation biopsy. Interestingly, an eighth p53 positive transformed lymphoma recurred with a clonally related, p53 negative low-grade lymphoma 5 years after the patient had achieved a complete remission. Immunohistochemistry also showed that several pretransformation biopsies from p53 positive transformed cases showed rare p53 positive cells and in one case we could document an increase in their number over time. Twenty-five additional low-grade follicular lymphoma biopsies were also examined. Three patients had lymphomas positive for p53 mutation. One of the three subsequently transformed within a year of the biopsy studied; the second patient had an earlier (unavailable) biopsy at a different site that showed transformed histology. The third patient was treated with ProMACE-MOPP combination chemotherapy and attained a complete remission. We conclude that (1) mutations of p53 are associated with histologic transformation in approximately 25% to 30% of follicular lymphomas and (2) p53 positive cells can be detected before histologic transformation, but do not comprise a significant percentage of the neoplastic cell population (identifiable by SSCP) until late in the disease, just before or after histologic progression. Finally, the data also suggest that p53 positive low-grade lymphomas are at risk for progression and that in this subset, aggressive therapy may be warranted.

Base Sequence↗
PubMed1993

Natural killer cells and bone marrow transplantation.

Bone marrow transplantation is currently used in the treatment of a variety of neoplastic and nonneoplastic diseases. However, significant obstacles still limit the efficacy of this procedure. These include the occurrence of graft-versus-host disease, the failure of the marrow to engraft, the susceptibility of patients to opportunistic infections during the period of immunodeficiency after transplantation before full recovery of immune function, and finally, the recurrence of the cancer. Natural killer (NK) cells are lymphoid cells responsible for mediating a variety of immunologic and homeostatic functions. Initially described almost 20 years ago, the full range of functions carried out by these enigmatic cells continues to unfold. NK cells may be both beneficial and deleterious in bone marrow transplantation, depending on their genotype and activation status. Resting host-derived NK cells appear capable of mediating resistance to both autologous and allogeneic bone marrow cell grafts. At the other end of the spectrum, the transfer of activated NK cells of donor type appears to produce multiple beneficial effects during both syngeneic and allogeneic bone marrow transplantation. Here, we review and attempt to reconcile the literature concerning the basic biology of NK cells and their effects on hematopoiesis, both in vitro and in vivo. We also discuss the current issues in bone marrow transplantation and the potential role NK cells may play in determining the outcome of the marrow graft, the occurrence of graft-versus-host disease, and the generation of a graft-versus-tumor response when bone marrow transplantation is used for the treatment of cancer.

Animals↗
PubMed1993

Molecular analysis of the BCL-3 locus at chromosome 17q22 in B-cell neoplasms.

To better understand the role of the BCL-3 locus at chromosome 17q22 in the pathogenesis and progression of leukemias and lymphomas, we examined its genomic configuration in 264 B-cell malignancies and its expression in a smaller subset. Cases studied included 39 chronic lymphocytic leukemias, 58 low-grade follicular lymphomas, 20 mantle cell lymphomas, 30 small noncleaved cell lymphomas, 25 acute lymphoblastic leukemias, 10 acquired immunodeficiency syndrome--related non-Hodgkin's lymphomas, and 44 diffuse mixed- or diffuse large-cell lymphomas. In addition, 38 aggressive lymphomas (transformed follicular lymphomas) derived from previously indolent follicular lymphomas were examined. Southern blot analysis showed BCL-3 locus rearrangement in 4 cases (1.5%), ie, in 3 transformed follicular lymphomas and in 1 indolent follicular lymphoma. All 4 also had BCL-2 rearrangements consistent with their follicular center cell origin. None of the BCL-3 rearranged cases showed MYC gene rearrangement, as reported for the original leukemia that led to the discovery of BCL-3. Pretransformation specimens of all three transformed follicular lymphomas showed the presence of the BCL-3 alteration before histologic progression. In 1 case, serial pretransformation biopsies showed that the BCL-3 rearrangement was acquired during the indolent follicular phase of the patient's disease. Thirty lymphomas, including 2 of the 4 with BCL-3 rearrangement, were also examined for BCL-3 message. All 30, including the 2 with BCL-3 rearrangements, expressed the normal 1.7-kb BCL-3 transcript, at approximately equivalent levels. The data indicate that, although BCL-3 locus alterations are found in only a small fraction of B-cell lymphoid malignancies, they occur primarily in a subset of follicular center cell lymphomas. Interestingly, these alterations appear to be acquired during the indolent (follicular) phase of the disease and they are maintained when histologic transformation takes place. The data also suggest that BCL-3 locus alterations do not result in gross changes of BCL-3 gene expression and do not necessarily involve the MYC gene. Although the preferential involvement of BCL-3 alterations in a small subset of follicular lymphomas that transform suggests a possible link between these abnormalities and progression, further studies are needed to ensure that these alterations are biologically relevant and not simply a manifestation of genomic instability.

B-Cell Lymphoma 3 Protein↗