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J Biggs

Publications and source records attributed to J Biggs.

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

Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes.

Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53-/-) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1-restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53-/- transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53-/- and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53-/- mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

Animals↗
PubMed1997

Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis.

Proteins with glycosylphosphatidylinositol (GPI) anchors exhibit a range of activities and some of these proteins exist in both a membrane-associated and a soluble form. CD48 is a 47-kd GPI-linked glycoprotein which is expressed on T and B lymphocytes, monocytes, and many lymphoid malignancies. The biological function of CD48 is unknown. We describe the detection of a soluble form of CD48 in plasma and serum. Its level was quantified by an immunoenzymometric assay (IEMA) specific for soluble CD48. While soluble CD48 was detected in the plasma of healthy individuals (median = 29 ng/ml; range, 15-48 ng/ml), elevated levels were detected in some patients with lymphoproliferative disease (median = 41 ng/ml; range, 9-213 ng/ml, arthritis (median = 42 ng/ml; range, 13-67 ng/ml), and acute EBV infection (174 ng/ml). Soluble CD48 was also detectable in tissue culture supernatants from the Raji lymphoid cell line. The mechanism of CD48 release from cells is unclear. The finding of significant levels of soluble CD48 in plasma and the development of a sensitive IEMA for its measurement will facilitate further studies on its normal function and its role in disease.

Adult↗
PubMed1997

Managing TMD.

Explore the source record for details and available documents.

American Dental Association↗
PubMed1997

Code generation through annotation of macromolecular structure data.

The maintenance of software which uses a rapidly evolving data annotation scheme is time consuming and expensive. At the same time without current software the annotation scheme itself becomes limited and is less likely to be widely adopted. A solution to this problem has been developed for the macromolecular Crystallographic Information File (mmCIF) annotation scheme. The approach could be generalized for a variety of annotation schemes used or proposed for molecular biology data. mmCIF provides a highly structured and complete annotation for describing NMR and X-ray crystallographic data and the resulting macromolecular structures. This annotation is maintained in the mmCIF dictionary which currently contains over 3,200 terms. A major challenge is to maintain code for converting between mmCIF and Protein Data Bank (PDB) annotations while both continue to evolve. The solution has been to define a simple domain specific language (DSL) which is added to the extensive annotation already found in the mmCIF dictionary. The DSL calls specific mapping modules for each category of data item in the mmCIF dictionary. Adding or changing the mapping between PDB and mmCIF items of data is straightforward since data categories (and hence mapping modules) correspond to elements of macromolecular structure familiar to the experimentalist. Each time a change is made to the macromolecular annotation the appropriate change is made to the easily located and modifiable mapping modules. A code generator is then called which reads the mapping modules and creates a new executable for performing the data conversion. In this way code is easily kept current by individuals with limited programming skill, but who have an understanding of macromolecular structure and details of the annotation scheme. Most important, the conversion process becomes part of the global dictionary and is not open to a variety of interpretations by different research groups writing code based on dictionary contents. Details of the DSL and code generator are provided.

Crystallography, X-Ray↗
PubMed1996

Hepatic dysfunction following busulfan and cyclophosphamide myeloablation: a retrospective, multicenter analysis.

Veno-occlusive disease continues to be a significant cause of morbidity and early mortality following bone marrow transplantation. This study retrospectively analyzes the incidence and risk factors for severe VOD in 350 patients treated with 4 days of busulfan (total 16 mg/kg) and 2 days of cyclophosphamide (120 mg/kg) at four marrow transplant centers. Using the criteria defined by McDonald et al (Hepatology 1984; 4: 116-122), 93/350 (27%) developed VOD (11% mild, 5% moderate and 11% severe). Multivariate analysis revealed the following risk factors to be significantly associated with severe VOD: pretransplant transaminase and alkaline phosphatase elevation, ciprofloxacin antibiotic prophylaxis, use of estrogen/progestins or vancomycin during the peritransplant period and methotrexate for GVHD prophylaxis. Mild to moderate grades of VOD were not associated with significantly increased mortality but mortality was higher in patients with severe VOD (31%, P = 0.0013). These data suggest that risk factors for VOD may depend on the preparative regimen used and suggest that use of these risk factors may identify a subgroup of patients that can be targetted for studies of prevention of VOD.

Adolescent↗
PubMed1995

Targeting p53 as a general tumor antigen.

A major barrier to the design of immunotherapeutics and vaccines for cancer is the idiosyncratic nature of many tumor antigens and the possibility that T cells may be tolerant of broadly distributed antigens. We have devised an experimental strategy that exploits species differences in protein sequences to circumvent tolerance of high-affinity T cells. HLA transgenic mice were used to obtain cytotoxic T lymphocytes specific for peptides from the human p53 tumor-suppressor molecule presented in association with HLA-A2.1. Although such p53-specific cytotoxic T cells did not recognize nontransformed human cells, they were able to lyse a wide variety of human tumor cells lines, thus confirming the existence of broadly distributed determinants that may serve as targets for immunotherapy.

Amino Acid Sequence↗
PubMed1995

Inhibition of leukemic cell growth by the protein kinase C activator bryostatin 1 correlates with the dephosphorylation of cyclin-dependent kinase 2.

Bryostatin 1 is a natural antineoplastic agent that activates protein kinase C. Treatment of U937 human leukemic cells with bryostatin 1 caused a 60% reduction in cell growth, whereas another protein kinase C activator, phorbol myristate acetate (PMA), completely inhibited U937 cell growth. Both bryostatin 1 and PMA induced inhibition of cyclin-dependent kinase 2 (cdk2) activity. The first phase of cdk2 inhibition correlated with the transient induction of p21, a known inhibitor of cdk2. In contrast, the second phase of cdk2 inhibition correlated with the dephosphorylation of cdk2 on threonine-160, which must be phosphorylated for cdk2 activity. The level of growth inhibition induced by these two compounds correlated with the degree of cdk2 dephosphorylation as follows: bryostatin 1, 60%; PMA, 100%.

Antineoplastic Agents↗
PubMed1995

The human glioma pathogenesis-related protein is structurally related to plant pathogenesis-related proteins and its gene is expressed specifically in brain tumors.

We report the cloning of a cDNA encoding GliPR (glioma pathogenesis-related protein), a protein that is structurally similar to plant pathogenesis-related proteins. The GLIPR gene is highly expressed in the human brain tumor, glioblastoma multiforme/astrocytoma, but neither in normal fetal or adult brain tissue, nor in other nervous system tumors. GliPR shares up to 50% amino acid (aa) homology with plant pathogenesis-related proteins, group 1, over a region that comprises almost two thirds of the protein. We speculate that there may be functional similarities between the human and plant proteins as well.

Amino Acid Sequence↗
PubMed1994

Conformational differences in major histocompatibility complex-peptide complexes can result in alloreactivity.

Mutations within the class I major histocompatibility complex (MHC) molecule that affect a peptide binding can result in strong allogeneic responses. It is believed this reflects, in part, binding of a different set of endogenous peptides by each MHC molecule. We have examined the representation of allopeptides recognized by Kb-specific cytotoxic T lymphocytes (CTL) clones among targets that express either the Kb or the Kbm8 mutant. These class I molecules mutationally differ by several residues at the base of the peptide binding groove resulting in lack of recognition of bm8 targets by most Kb-specific CTL, and in strong mutual alloreactivity. Since these differences involve pockets in the base of the peptide binding groove that are presumed to contribute to the affinity of peptide binding, and there is evidence for differences in peptide binding by the mutant and wild type molecule, it was considered most likely that alloreactivity was due to binding of different sets of peptides by each of these molecules. Surprisingly, the allopeptides recognized by Kb-specific clones from a variety of responders, including bm8, are often found associated with both the wild type and mutant class I molecules. Although for some allopeptides the amount of peptide normally found associated with bm8 is less than that associated with Kb, reactivity could not be restored by increasing the amount of the relevant peptide. Thus, the basis for much of the alloreactivity observed in this particular mutant and wild type combination is not the presence or absence of the relevant allopeptide but rather the different conformation adapted by the peptide-MHC complex. These results allow us to conclude that strong alloreactive responses can result from T cell recognition of conformational differences between the stimulation and responder MHC molecules.

Amino Acid Sequence↗
PubMed1994

Genetic and molecular analysis of hyperplastic discs, a gene whose product is required for regulation of cell proliferation in Drosophila melanogaster imaginal discs and germ cells.

The hyperplastic discs (hyd) gene (formerly called l(3)c43) is located at 85E1-10 on the third chromosome of Drosophila melanogaster. It was originally identified by a temperature-sensitive mutation that causes imaginal disc overgrowth in mutant larvae raised at a restrictive temperature. Twenty new alleles of hyperplastic discs have been recovered in gamma ray, ethyl methanesulfonate and hybrid dysgenesis screens, and the molecular lesions have been identified for several of the alleles. The null phenotype appears to be lethality at or before the second instar. Adults that can be obtained in crosses of temperature-sensitive alleles maintained at permissive temperatures are sterile with one exception and have defects in germ tissue morphology. The hyperplastic discs locus has been cloned by chromosome walking from the alpha-tubulin-2 gene and encodes a 9.5-kb messenger RNA, containing a 2897-amino-acid open reading frame. Sequence analysis of HYD reveals strong similarity to a portion of the C-terminus of poly(A) binding protein and to the RAT 100-kDa PROTEIN, whose function is unknown. Developmental Northern and Western analyses show coincident accumulation of the 9.5-kb transcript and the 280-kDa protein at all stages of development, with high levels at the embryonic and pupal stages. The 280-kDa HYD protein accumulates at decreased levels in mutant alleles and at restrictive temperatures in ts alleles. Examination of relative levels of HYD protein in mutant animals support the idea that less severe mutations are those that result in disc overgrowth, while more severe mutations result in variable disc growth phenotypes.

Alleles↗
PubMed1993

What do inventories of students' learning processes really measure? A theoretical review and clarification.

Research into student learning has been based on two main theoretical sources: information processing (IP), and contextually based work on students' approaches to learning (SAL). The cross-fertilisation has been valuable, but it has led to ambiguities and misunderstandings, evident in the recent literature, about constructs, methodology, and of particular concern here, the development and interpretation of inventories of learning/study processes. The basic issue revolves around a conception of student learning as taking place within-the-student, as IP models appear to assume, or within-the-teaching/learning-context, as the SAL tradition emphasises. It is suggested that student learning is best construed within a teaching/learning context that functions as an 'open system', a model that brings some clarity to the use and interpretation of study process inventories, and that locates their value in yielding functionally useful data to researchers, teachers, and staff developers.

Child↗
PubMed1993

Ribozyme-mediated cleavage of the bcr/abl transcript expressed in chronic myeloid leukemia.

The bcr/abl transcript is specifically expressed in the hematopoietic cells of patients with chronic myeloid leukemia (CML). The Haseloff and Gerlach model was used to design a ribozyme targeted to this transcript. When tested against a synthetic substrate covering the translocation sequence, the ribozyme exhibited site specificity and an absolute requirement for divalent metal ions. Cleavage of the normal bcr was also noted but at a reduced efficiency compared to that exhibited for the bcr/abl substrate. Importantly, cleavage of the full-length bcr/abl mRNA was achieved at physiologic temperature, demonstrating effective ribozyme-mediated cleavage.

Base Sequence↗
PubMed1993

Management of abusive behaviour in a hemodialysis unit.

Occasionally in hemodialysis units there are situations where registered nurses are unable to assist an individual whose behaviour is abusive or escalating in that direction, and the person cannot re-establish self-control and appropriate behaviour. Such abusive behaviour may arouse concern for the physical and psychological safety or security of the nurse and that of other patients and visitors. Interdisciplinary conferences were held to develop a policy document and guidelines to aid caregivers should abusive situations occur. These were the result of collaboration between physicians, nurses, social workers, a dietician and the clinical nurse specialist from psychiatry. The policy statement and guidelines include nursing actions, physician interventions and recommendations for follow-up conferences.

Dangerous Behavior↗
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↗