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J Biggs

Publications and source records attributed to J Biggs.

14 recordsLinked to original sources
PubMed1992

A human Id-like helix-loop-helix protein expressed during early development.

The interaction of helix-loop-helix (HLH) proteins is known to regulate the differentiation of several different tissues, including mammalian muscle and the insect peripheral nervous system. In myoblasts, the products of myogenic HLH genes such as MyoD and ubiquitous HLH proteins such as E12 are present at constant levels throughout development. An E12 monomer and a MyoD monomer form a DNA binding heterodimer that activates muscle-specific genes. These two proteins are unable to dimerize in proliferating myoblasts because a negative regulator HLH protein, Id, is present. We now report the sequence and structure of a human HLH gene related to Id, which has been designated Id-2. Two prominent Id-2 RNA molecules of 2.5 and 1.3 kilobases were found in a number of different human normal and neoplastic tissues. We believe the larger RNA is a precursor of the 1.3-kilobase mRNA that encodes an Id-2 protein of 134 amino acids. The HLH region of the Id-2 protein is 90% homologous to that of myogenic Id, but the homology is much less extensive outside the HLH region. The Id-2 gene is highly expressed during early fetal development in several tissues, including those of the central nervous system, but is not expressed in the corresponding mature tissues. Id-2 expression is modulated in association with retinoic acid-induced ganglionic differentiation of the neuroblastoma cell line SMS-KCNR. These findings suggest that Id-2 is an inhibitor of tissue-specific gene expression, although its distinctive pattern of expression during development suggests a role different from that of Id.

Amino Acid Sequence↗
PubMed1992

Lung dose rate and interstitial pneumonitis in total body irradiation for bone marrow transplantation.

The effect of dose rate to the lungs and development of interstitial pneumonitis (IP) was evaluated in 114 bone marrow transplant patients receiving fractionated total body irradiation (TBI) (1200 rads TD in 6 fractions twice daily over 3 days) as part of their pre-conditioning regimen. The tumour dose (TD) was calculated as the mean lung dose as previously described (1). A 6MV linear accelerator at a mid-line dose rate of 7.5 rads/minute was used between March 1981 and June 1985 and a Co-60 source at 5 rads/minute thereafter. This resulted in a range of dose rates to the lung of between 6.9 and 8.9 rads/minute and 2.9 and 6.5 rads/minute respectively. In the majority of patients the aetiology of IP was investigated by lung biopsy with histology and culture. There was no statistically significant difference in the incidence of IP over the two sets of dose rates. Our study suggest that the incidence of IP using fractionated TBI is not influenced by dose rates below 8.9 rads per minute.

Adolescent↗
PubMed1992

Cytokine activity after allogeneic bone marrow transplantation. IV. Production of mRNA for IL-3 and GM-CSF by mitogen-stimulated circulating mononuclear cells.

The ability of circulating mononuclear cells from recipients of HLA identical sibling marrow transplants to generate messenger (m) RNA for the haemopoietic growth factors interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) upon mitogen stimulation was investigated. The amount of IL-3 mRNA per ml of blood and IL-3 mRNA per 10(7) mononuclear cells as well as the amount of GM-CSF mRNA per ml of blood was significantly lower in transplant recipients than in normal volunteers. Lower values for mRNA expression for both IL-3 and GM-CSF were associated with the use of immunosuppressive therapy post transplant. No correlation was found between the expression of message for either cytokine, or the presence or absence of acute graft-versus-host disease at the time of testing. While there was no correlation between the quantity of GM-CSF message produced and time elapsed post transplant, IL-3 message expression increased slightly with increasing time post transplant. These defects of haemopoietic regulators constitute another parameter of impaired cellular immunity occurring after allogeneic marrow transplantation.

Bone Marrow Transplantation↗
PubMed1991

In vivo administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF, interleukin-1 (IL-1), and IL-4, alone and in combination, after allogeneic murine hematopoietic stem cell transplantation.

BALB/c mice (H-2d) given 10 Gy total body irradiation (TBI) followed by 10(7) bone marrow (BM) and 10(6) spleen cells from C57BL/6 (H-2b) donor mice received recombinant cytokines intraperitoneally (IP) twice daily. The effect on neutrophil recovery rate, graft-v-host disease (GVHD), and survival was assessed. Four reagents were used: granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin-1 (IL-1) and IL-4, both alone and in combination. The most effective combination for increasing the circulating absolute neutrophil account (ANC) above the control value at day 7 posttransplant was the combination of G-CSF and IL-1 (mean ANC 2.4 +/- 1.6 x 10(9)/L as compared with control value of 0.07 +/- 0.05, P less than .02), followed by G-CSF alone (mean ANC 1.1 +/- 0.2, P less than .0001), the combination of GM-CSF plus IL-1 (mean ANC 0.8 +/- 0.3, P less than .002), and the combination of G-CSF plus GM-CSF (mean ANC 0.8 +/- 0.3, p less than .005). At day 10 posttransplant, the most effective combination in raising the ANC was the combination of G-CSF plus GM-CSF (mean ANC 7.5 +/- 2.3 as compared with control value of 3.5 +/- 1.1, P less than .01), followed by G-CSF alone (mean ANC 6.9 +/- 2.1, P less than .02). At the doses used, neither G-CSF nor GM-CSF had a deleterious effect on the incidence or severity of GVHD; indeed, GM-CSF was associated with improved survival. In contrast, IL-1 at doses greater than or equal to 100 ng twice daily caused marked early mortality, and there was a suggestion that IL-4 at doses of 500 ng twice daily resulted in increased late mortality, possibly owing to exacerbation of GVHD. This model appears to be of value for exploring the use of hematopoietic growth factors before they are used clinically in marrow allograft recipients.

Animals↗
PubMed1991

Prophylactic use of ganciclovir in allogeneic bone marrow transplantation: absence of clinical cytomegalovirus infection.

Ganciclovir was given prophylactically to 25 patients receiving allogeneic bone marrow transplants for haematological malignancy. Patients who were seropositive for cytomegalovirus (CMV) pre-transplant were given ganciclovir both pre- and post-transplant. Those who were CMV seronegative, but who received marrow from a CMV seropositive donor, received ganciclovir post-transplant. No nonhaemopoietic toxicity was observed. Toxicity was restricted to late reversible haematological toxicity in four of the 19 evaluable patients (one thrombocytopenia, one pancytopenia, two leucopenia). No CMV interstitial pneumonitis (IP) was observed, nor were any other clinically manifest CMV infections detected. Sixteen patients remain alive at greater than 84 to greater than 518 d post-transplant. In a retrospective comparison of 152 recipients of allogeneic transplants for haematological malignancy not given prophylactic ganciclovir, and in whom either the recipient or the donor or both were CMV seropositive, the incidence of all clinically manifest CMV infections was 23% (P = 0.02) and that of CMV IP 17% (P = 0.05). If only patients in the study group and the control group receiving the same cyclosporin/short methotrexate prophylactic immune suppressive regimen, the same prophylactic acyclovir regimen and the same CMV and leucocyte-filtered blood product transfusion strategy were considered, the incidence of all clinically manifest CMV infections in the control group was 24% (P = 0.01) and that of CMV IP 13% (P = 0.07). Ganciclovir appears to reduce the incidence of CMV infections in allogeneic marrow transplant recipients even in those given immune suppressive regimens associated with adequate control of acute graft-versus-host disease.

Acute Disease↗
PubMed1991

The toxicity of busulphan and cyclophosphamide as the preparative regimen for bone marrow transplantation.

The toxicity of the conditioning regimen of high dose busulphan (Bu) (16 mg/kg) and cyclophosphamide (Cy) (120 mg/kg) has been compared to cyclophosphamide (Cy) (120 mg/kg) and fractionated total body irradiation (TBI) 12-14 Gy. Since 1985, 67 patients have received conditioning of Bu and Cy for HLA-identical sibling bone marrow transplants. 166 patients have received Cy and TBI since 1981. Veno-occlusive disease of the liver occurred in 19% in the Bu-Cy group and was fatal in 1/12 cases, but only in 1.3% of Cy-TBI group (P less than 0.0005) and was fatal in 1/2. 30% of evaluable patients developed haemorrhagic cystitis in the Bu-Cy group and 14% in the Cy-TBI group (P = 0.008). A multiple logistic regression analysis demonstrated the preparative regimen as the only significant risk factor for the development of veno-occlusive disease or haemorrhagic cystitis. Interstitial pneumonia was diagnosed in 12/56 evaluable patients (21%) in the Bu-Cy group and was fatal in 75%. It occurred in 39/137 evaluable patients (28%) in the Cy-TBI group with a 54% case mortality. Within the Bu-Cy group, the incidence of veno-occlusive disease and haemorrhagic cystitis was similar in chronic myeloid leukaemia (CML) and acute leukaemia (AL) groups, but there was a significant (P = 0.003) incidence of interstitial pneumonia in the CML group 36% as compared to 7% in the AL group. Preparative regimen and age were significant risk factors in the development of interstitial pneumonia in patients with CML. A flexural and acral rash ranging from pigmentation to severe erosion was noted in the Bu-Cy group, but not in the Cy-TBI group. Thus, veno-occlusive disease, haemorrhagic cystitis and cutaneous changes were more common in patients receiving Bu-Cy. Interstitial pneumonia was more common in patients receiving Bu-Cy for CML than for AL.

Adolescent↗
PubMed1991

A prospective randomised trial of cyclosporin and methotrexate versus cyclosporin, methotrexate and prednisolone for prevention of graft-versus-host disease after HLA-identical sibling marrow transplantation for haematological malignancy.

A prospective randomised trial was performed in patients given HLA-identical sibling bone marrow transplants for haematological malignancy comparing the combination of cyclosporin and methotrexate (CM) (n = 20) with the combination of cyclosporin, methotrexate and prednisolone (CMP) (n = 21) as prophylaxis for graft-versus-host disease (GVHD). There was no significant differences between the two arms for the incidence of acute GVHD grades I-IV, acute GVHD grades II-IV, chronic GVHD, interstitial pneumonitis, relapse, survival and disease-free survival. The actuarial incidence of acute GVHD grades II-IV in the CMP group was 10% and in the CM group 15% (ns). The incidence of leukaemic relapse in good risk patients was 42% in the CMP group and 40% in the CM group (ns), although the majority of these relapses were cytogenetic relapses only in patients with chronic myeloid leukaemia. The incidence of acute GVHD grades II-IV in both arms of the current trial was significantly lower than in our previous trial comparing cyclosporin and methotrexate as single agents. Leukaemic relapse is now the principal cause of treatment failure in this patient population. We conclude that prednisolone should not be included as part of the prophylactic GVHD regime and that further improvement in therapeutic outcome is dependent upon better control of the underlying malignancy.

Actuarial Analysis↗
PubMed1990

A Drosophila gene that is homologous to a mammalian gene associated with tumor metastasis codes for a nucleoside diphosphate kinase.

The product of the abnormal wing discs (awd) gene of Drosophila is 78% identical to the product of the nm23 gene of mammals, which is differentially expressed in certain metastatic tumors. We present evidence that the awd gene codes for a nucleoside diphosphate kinase (NDP kinase) and that this Awd/NDP kinase is microtubule associated. Neuroblasts in Drosophila larvae homozygous for a null mutation in the awd gene are arrested in metaphase, indicating that microtubule-associated Awd/NDP kinase plays a critical role in spindle microtubule polymerization.

Alleles↗
PubMed1989

Widespread pulmonary fibrosis as a major clinical manifestation of chronic graft-versus-host disease.

A 20-year-old Chinese male given an HLA-identical sibling bone marrow transplant for severe aplastic anemia, who had previously had chronic graft-versus-host disease (GVHD) of the mouth, developed myasthenia gravis and widespread pulmonary infiltrates with cough and exertional dyspnea at day 820 post-transplant. There was nothing to suggest aspiration pneumonia. Lung histology at day 940 showed some areas of dense pulmonary fibrosis, some areas of normal parenchyma, and some areas of widening of the interstitium and a mild lymphocytic infiltrate. Evidence of infection was not found. Treatment with cyclosporin and prednisone resulted in slow partial resolution of the infiltrates over 5 months. The myasthenia gravis was controlled with pyridostigmine. In view of the association with myasthenia gravis, of the absence of infectious agents and the response to immunosuppression, we conclude that widespread pulmonary fibrosis can be a major clinical manifestation of chronic GVHD. Examination of lung tissue to distinguish this from infective interstitial pneumonitis is essential.

Adult↗
PubMed1989

Recipients of HLA-identical sibling marrow transplants with severe aplastic anemia engraft more quickly, and those with chronic myeloid leukemia more slowly, than those with acute leukemia.

An analysis of the rate of leukocyte reconstitution in 164 recipients of HLA-identical sibling marrow transplants showed two factors to be independently influential. These were the underlying diagnosis and the type of prophylactic regimen used to minimize the risk of graft-versus-host disease. Patients with severe aplastic anemia had a faster rate of reconstitution of the total white blood cell count to levels of both 500 and 1000 x 10(6)/l than patients with acute non-lymphoblastic leukemia (ANL), acute lymphoblastic leukemia (ALL) or chronic myeloid leukemia (CML). Patients with severe aplastic anemia (SAA), however, did not show a faster rate of reconstitution of blood neutrophils. As well as being slower than patients with SAA for total leukocyte reconstitution, patients with CML were slower than patients with ANL and ALL in attaining a neutrophil count of 500 x 10(6)/l, and slower than patients with ANL in attaining a neutrophil count of 1000 x 10(6)/l. Patients given cyclosporin as the sole immunosuppressant prophylactic regimen post-transplant had faster reconstitution to total leukocyte counts of 500 and 1000 x 10(6)/l and to neutrophils of 1000 x 10(6)/l than patients given methotrexate alone, methotrexate and cyclosporin, or cyclosporin and T cell depletion of the donor marrow. No other factors (including the pretransplant preparative regimen) were significant in influencing the rate of leukocyte or neutrophil reconstitution. When only patients given cyclosporin were analysed, those with severe aplastic anemia continued to show a faster rate of leukocyte reconstitution to WBC 500 x 10(6)/l compared to patients with ANL, ALL or CML, and a faster rate to WBC 1000 x 10(6)/l than patients with CML.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Aplastic↗
PubMed1976

Antibody-dependent cell-mediated cytotoxicity against melanoma cells induced by plasmapheresis.

Patients with disseminated melanoma were treated by repeated plasmapheresis using a continuous-flow blood-cell separator, as part of a study to investigate methods of removing factors from tissue fluids which block cell-mediated immunity. Using 51Cr release cytotoxic assays, it was found that plasmapheresis resulted in removal of serum blocking activity. Post-plasmapheresis sera taken from several patients also increased cell-mediated cytotoxicity by induction of antibody-dependent cell-mediated killing. This effect may have resulted from removal or alteration of circulating immune complexes in the serum. It is not known whether cytotoxic activity induced in this way improves the patient's immune response against their tumours. However, the procedure is well tolerated and these preliminary in-vitro results indicate that this form of therapy could act as an adjunct to other forms of treatment of advanced melanoma.

Antigen-Antibody Complex↗