Role of apoptosis in Pseudomonas aeruginosa pneumonia.
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Animals↗
Biomedical subjects
C G Davis
Publications and source records attributed to C G Davis.
Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy.
Overexpression of epidermal growth factor receptor (EGFr) has been demonstrated on many human tumors, and the increase in receptor expression levels has been linked with a poor clinical prognosis. Blocking the interaction of EGFr and the growth factors could lead to the arrest of tumor growth and possibly result in tumor cell death. To this end, using XenoMouse technology, ABX-EGF, a human IgG2 monoclonal antibody (mAb) specific to human EGFr, has been generated. ABX-EGF binds EGFr with high affinity (5x10(-11) M), blocks the binding of both EGF and transforming growth factor-alpha (TGF-alpha) to various EGFr-expressing human carcinoma cell lines, and inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. In vivo ABX-EGF prevents completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice. More importantly, administration of ABX-EGF without concomitant chemotherapy results in complete eradication of established tumors. No tumor recurrence was observed for more than 8 months following the last antibody injection, further indicating complete tumor cell elimination by the antibody. Inhibition of human pancreatic, renal, breast and prostate tumor xenografts which express different levels of EGFr by ABX-EGF was also achieved. Tumor expressing more than 17000 EGFr molecules per cell showed significant growth inhibition when treated with ABX-EGF. ABX-EGF had no effect on EGFr-negative tumors. The potency of ABX-EGF in eradicating well-established tumors without concomitant chemotherapy indicates its potential as a monotherapeutic agent for treatment of multiple EGFr-expressing human solid tumors, including those where no effective chemotherapy is available. Utilization of mAbs directed to growth factor receptors as cancer therapeutics has been validated recently by the tumor responses obtained from clinical trials with Herceptin, the humanized anti-HER2 antibody, in patients with HER2 overexpressing metastatic breast cancer. Being a fully human antibody, ABX-EGF is anticipated to exhibit a long serum half-life and minimal immunogenicity with repeated administration, even in immunocompetent patients. These results demonstrate the potent anti-tumor activity of ABX-EGF and its therapeutic potential for the treatment of multiple human solid tumors that overexpress EGFr.
Animals↗
The human immunoglobulin loci introduced into mice: V (D) and J gene segment usage similar to that of adult humans.
Variable gene segments of the human immunoglobulin loci are represented in the human peripheral repertoire at different frequencies. XenoMouse strains contain approximately 2 megabases of the human immunoglobulin heavy and kappa light chain loci that functionally recapitulate the human humoral immune system. Analysis of human antibody transcripts from XenoMouse spleens and lymph nodes revealed that V, D and J gene segment utilization from these unimmunized animals were nearly identical to the gene segment utilization reported for humans with extensive antigenic histories.
Adult↗
Searching for meaning in loss: are clinical assumptions correct.
Three assumptions guiding research and clinical intervention strategies for people coping with sudden, traumatic loss are that (a) people confronting such losses inevitably search for meaning, (b) over time most are able to find meaning and put the issue aside, and (c) finding meaning is critical for adjustment or healing. We review existing empirical research that addresses these assumptions and present evidence from a study of 124 parents coping with the death of their infant and a study of 93 adults coping with the loss of their spouse or child to a motor vehicle accident. Results of these studies indicate that (a) a significant subset of individuals do not search for meaning and yet appear relatively well-adjusted to their loss; (b) less than half of the respondents in each of these samples report finding any meaning in their loss, even more than a year after the event; and (c) those who find meaning, although better adjusted than those who search but are unable to find meaning, do not put the issue of meaning aside and move on. Rather, they continue to pursue the issue of meaning as fervently as those who search but do not find meaning. Implications for both research and clinical intervention are discussed.
Adaptation, Psychological↗
Production of protective human antipneumococcal antibodies by transgenic mice with human immunoglobulin loci.
Infections with Streptococcus pneumoniae remain a significant cause of morbidity and mortality. To gain insight into structure-function relationships for human antibodies to pneumococcal capsular polysaccharide (PPS), we studied the response of transgenic mice reconstituted with human immunoglobulin loci, XenoMouse, to PPS antigens in a pneumococcal vaccine. Enzyme-linked immunosorbent assays of sera from mice vaccinated with a 23-valent pneumococcal vaccine revealed that they produced serotype-specific human antibodies, with the greatest response being to the PPS of serotype 3 (PPS 3). Molecular sequence analysis of three monoclonal antibodies (MAbs) to PPS 3 generated from lymphoid cells from mice vaccinated with a 23-valent pneumococcal vaccine or a PPS 3-bovine serum albumin conjugate revealed that they all used heavy-chain immunoglobulin genes from the V(H)3 family, two expressed light chain genes from the human Vkappa1 family, and one expressed a mouse lambda light chain. The protective efficacy of the two MAbs was examined in mice. A 10-microgram dose of both, and a 1-microgram dose of one, significantly prolonged survival from a lethal serotype 3 infection in CBA/N mice. Our data show that XenoMouse mice produced protective, serotype-specific human antibodies to PPS 3, and they lend support to the proposal that these animals represent a useful model to study the human antibody response to PPS antigens.
Animals↗
Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy.
A fully human IgG2kappa monoclonal antibody (MAb), E7.6.3, specific to the human epidermal growth factor (EGF) receptor (EGFr) was generated from human antibody-producing XenoMouse strains engineered to be deficient in mouse antibody production and to contain the majority of the human antibody gene repertoire on megabase-sized fragments from the human heavy and kappa light chain loci. The E7.6.3 MAb exhibits high affinity (KD = 5 x 10(-11) M) to the receptor, blocks completely the binding of both EGF and transforming growth factor alpha (TGF-a) to various EGFr-expressing human carcinoma cell lines, and abolishes EGF-dependent cell activation, including EGFr tyrosine phosphorylation, increased extracellular acidification rate, and cell proliferation. The antibody (0.2 mg i.p. twice a week for 3 weeks) prevents completely the formation of human epidermoid carcinoma A431 xenografts in athymic mice. More importantly, the administration of E7.6.3 without concomitant chemotherapy results in complete eradication of established tumors as large as 1.2 cm3. Tumor eradication of A431 xenografts was achieved in nearly all of the mice treated with total E7.6.3 doses as low as 3 mg, administered over the course of 3 weeks, and a total dose of 0.6 mg led to tumor elimination in 65% of the mice. No tumor recurrence was observed for more than 8 months after the last antibody injection, which further indicated complete tumor cell elimination by the antibody. The potency of E7.6.3 in eradicating well-established tumors without concomitant chemotherapy indicates its potential as a monotherapeutic agent for the treatment of multiple EGFr-expressing human solid tumors, including those for which no effective chemotherapy is available. Being a fully human antibody, E7.6.3 is expected to exhibit minimal immunogenicity and a longer half-life as compared with mouse or mouse-derivatized MAbs, thus allowing repeated antibody administration, including in immunocompetent patients. These results suggest E7.6.3 as a good candidate for assessing the full therapeutic potential of anti-EGFr antibody in the therapy of multiple patient populations with EGFr-expressing solid tumors.
Animals↗
Fully human anti-interleukin-8 monoclonal antibodies: potential therapeutics for the treatment of inflammatory disease states.
Interleukin-8 (IL-8) is a potent chemotactic cytokine implicated in the pathogenesis of a number of inflammatory disease states. Agents that block the binding of IL-8 to its receptor have been shown to block inflammation in animal models of disease. This suggests that drugs specifically targeting IL-8 may prove efficacious in treating multiple human diseases. To this end, we developed a panel of fully human anti-IL-8 monoclonal antibodies (mAbs). These human antibodies were generated from XenoMouse strains, mice created by introducing megabase-size unrearranged human immunoglobulin heavy and kappa light chain loci into a mouse genome in which the corresponding endogenous loci have been inactivated. From the panel of more than 50 mAbs, two antibodies, K4.3 and K2.2, were further characterized and evaluated for their specificity, productivity, affinity, and biological activity. Both K4.3 and K2.2 bind human IL-8 with high affinity (Kd of K4.3 = 2.1x10(10) M; Kd of K2.2 = 2.5x10(-10) M). In vitro, in addition to blocking IL-8 binding to human neutrophils, K4.3 and K2.2 blocked a number of IL-8-dependent cellular functions including neutrophil activation, up-regulation of the cell adhesion receptor CD11b/CD18, and neutrophil chemotaxis, suggesting that the fully human anti-IL-8 mAbs derived from XenoMouse strains are potent anti-inflammatory agents. This was further supported by in vivo studies in which K4.3 and K2.2 significantly inhibited IL-8-induced skin inflammation in rabbits. A pharmacokinetic study in Cynomolgus monkeys demonstrated that the alpha phase half-life is 9.4 h and the beta phase 10.9 days, typical of human mAbs in monkeys. These data support advancing a fully human anti-IL-8 mAb into clinical trials to treat inflammatory diseases.
Animals↗
Transgenic mice as a source of fully human antibodies for the treatment of cancer.
The last two years have seen a renaissance of monoclonal antibodies for the treatment of disease. Of the eight antibodies currently approved for human therapy, two are for the treatment of cancer. In large part, the revival of antibodies has been driven by technology developments geared toward making antibodies less likely to elicit an anti-antibody response in humans. The development of transgenic mice, XenoMouse animals, capable of making fully human antibodies offers new opportunities for generating antibodies of therapeutic quality. Recently, this technology has been applied to the generation of a fully human antibody to the epidermal growth factor receptor. A description of the development of this antibody serves to illustrate the power and ease of use of XenoMouse technology.
Amino Acid Sequence↗
"Thanks for sharing that": ruminators and their social support networks.
Receiving positive social support after a trauma generally is related to better adjustment to the trauma. The personality of trauma survivors may affect the extent to which they seek social support, their perceived receipt of social support, and the extent to which they benefit from social support. The authors hypothesized that people with a ruminative coping style, who tended to focus excessively on their own emotional reactions to a trauma, compared to those without a ruminative coping style, would seek more social support, and would benefit more from social support, but would report receiving less social support. These hypotheses were confirmed in a longitudinal study of people who lost a loved one to a terminal illness.
Adaptation, Psychological↗
Making sense of loss and benefiting from the experience: two construals of meaning.
Theoretical models of the adjustment process following loss and trauma have emphasized the critical role that finding meaning plays. Yet evidence in support of these models is meager, and definitions of meaning have been too broad to facilitate a clear understanding of the psychological process involved. Using a prospective and longitudinal study of people coping with the loss of a family member, we differentiate 2 construals of meaning--making sense of the event and finding benefit in the experience--and demonstrate that both independently play roles in the adjustment process following the loss. Results indicate that making sense of the loss is associated with less distress, but only in the 1st year postloss, whereas reports of benefit finding are most strongly associated with adjustment at interviews 13 and 18 months postloss.
Adult↗
Childhood adversity and adult psychiatric disorder in the US National Comorbidity Survey.
BACKGROUND: Survey data are presented on the associations between retrospectively reported childhood adversities and subsequent onset and persistence of DSM-III-R disorders. METHODS: Data come from the US National Comorbidity Survey, a large survey of the US household population. RESULTS: Twenty-six adversities were considered, including loss events (e.g. parental divorce), parental psychopathologies (e.g. maternal depression), interpersonal traumas (e.g. rape) and other adversities (e.g. natural disaster). These adversities were consistently associated with onset, but not persistence, of DSM-III-R mood disorders, anxiety disorders, addictive disorders and acting out disorders. Most bivariate associations with onset attenuated in models that controlled for clustering of adversities and for lifetime co-morbidities among psychiatric disorders. Multivariate effects of adversities in logistic models were additive, which means that they have multiplicative effects on probability of disorder onset. Adversities showed little specificity. An analysis of time decay showed that the effects of childhood adversities on disorder onset persist beyond childhood. CONCLUSIONS: The existence of strong clustering among childhood adversities and lifetime co-morbidity among adult disorders means that caution is needed in interpreting the results of previous single-adversity single-disorder studies as documenting unique effects of specific childhood adversities on specific adult disorders. Future studies need to assess a broader range of adversities and disorders and to explore the existence and effects of commonly occurring adversity clusters. Replication is needed to verify that the effects of childhood adversities are mostly on first onset rather than on the creation of vulnerabilities that lead to increased risk of persistence.
Adolescent↗
Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice.
We constructed two megabase-sized YACs containing large contiguous fragments of the human heavy and kappa (kappa) light chain immunoglobulin (Ig) loci in nearly germline configuration, including approximately 66 VH and 32 V kappa genes. We introduced these YACs into Ig-inactivated mice and observed human antibody production which closely resembled that seen in humans in all respects, including gene rearrangement, assembly, and repertoire. Diverse Ig gene usage together with somatic hypermutation enables the mice to generate high affinity fully human antibodies to multiple antigens, including human proteins. Our results underscore the importance of the large Ig fragments with multiple V genes for restoration of a normal humoral immune response. These mice are likely to be a valuable tool for the generation of therapeutic antibodies.
Amino Acid Sequence↗
The familial aggregation of common psychiatric and substance use disorders in the National Comorbidity Survey: a family history study.
BACKGROUND: Most family studies of psychiatric disorders examine one syndrome at a time, and identify probands in clinical rather than epidemiological settings. METHOD: In the National Comorbidity Survey, 5877 respondents were asked about the history of five psychiatric disorders in their parents: major depression (MD), generalised anxiety disorder (GAD), antisocial personality disorder (ASP), alcohol abuse/dependence (AAD) and drug abuse/dependence (DAD). RESULTS: Significant familial aggregation was seen for all disorders. Controlling for other disorders produced only modest reductions in the odds ratios for MD, GAD and AAD and larger reductions for ASP and DAD. The familial transmission of these disorders can be explained by underlying vulnerabilities to internalising and to externalising disorders transmitted across generations with moderate fidelity. CONCLUSIONS: Familial aggregation of common psychiatric and substance use disorders is substantial in epidemiologic samples. The examined environmental adversities account for little of the observed parent-offspring transmission of these conditions.
Adolescent↗
Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors.
Interleukin-12 (IL-12) promotes specific and long-lasting anti-tumor immunity mediated by T cells in a variety of murine tumor models. IL-12 also synergizes with B7.1 (CD80) co-stimulation to induce proliferation and cytokine production by both human and murine T cells in vitro. We evaluated the combined anti-tumor efficacy of IL-12 and B7.1 gene delivery in two apparently poorly immunogenic tumor models (TS/A and MCA207). In both of these models, expression of B7.1 and production of IL-12 in the inoculum led to improved anti-tumor immunity, with up to 80% long-term tumor-free animals (vs 0-20% of mice remaining tumor free when inoculated with either B7.1- or IL-12-transfected tumors alone). Tumor-free mice were capable of rejecting a subsequent rechallenge with the wild-type tumor in 66% of the cases. Cooperativity was dependent upon the level of IL-12 secreted by engineered cells. IL-12 delivery required B7 expression of therapeutic effects to be observed in these models. Vaccines provided at a site distal to a control, non-transfected tumor slowed (TS/A) or abrogated (MCA207) the progression of wild-type tumors. The synergistic anti-tumor effects associated with combined application of B7.1- and IL-12-transfected tumors were partially negated by systemic administration of the CD28-B7.1/B7.2 antagonist CTLA4-Ig or by inoculation with neutralizing antibodies directed against murine interferon-gamma or tumor necrosis factor-alpha, two cytokines elicited in response to IL-12 stimulation. These data support the potential clinical utility of combined gene therapy using IL-12- and B7.1-engineered autologous cells (tumor or fibroblasts) as a vaccine to elicit specific anti-tumor immunity.
Abatacept↗
Spinal cord ischemia and reperfusion metabolism: the effect of hypothermia.
PURPOSE: The metabolic and neurologic functional effects of regional hypothermia induced by cold (4 degrees C) heparinized saline perfusion on spinal cord ischemia were evaluated in 35 rabbits. METHODS: Spinal cord ischemia was induced for 20 minutes by infrarenal aortic occlusion in anesthetized animals. Regional spinal cord hypothermia was obtained by perfusing the lumbar arteries supplying the spinal cord through an infrarenal aortic catheter. The lumbar spinal cord was "snap frozen" in situ with liquid nitrogen and harvested immediately at the conclusion of the ischemic period or after 24 hours of normothermic reperfusion and neurologic observation. Spinal cord metabolic studies included determination of the energy charge and the intracellular concentrations of adenosine triphosphate, glucose, lactate, glutamate, and aspartate. RESULTS: Postoperative neurologic function was normal in all but one animal treated with hypothermia, while normothermic ischemia resulted in paralysis in all animals (p = 0.002). Spinal cord temperature during 20 minutes of ischemia and hypothermic perfusion decreased from 37.5 degrees +/- 0.43 degrees C to 22.8 degrees +/- 0.00 degrees C (p = 0.0001) compared to a fall in systemic temperature from 38.8 to 36.1 (p = 0.0001). Hypothermia reduced the decline in energy charge, adenosine triphosphate concentration and glucose concentration during ischemia but had no effect on markedly elevated levels of lactate acid. High-energy phosphates were restored after reperfusion in both normothermic and hypothermic animals and were not predictive of postoperative paraplegia. Intracellular glutamate and aspartate concentrations were unchanged during normothermic ischemia but decreased after reperfusion in all paralyzed animals. Intracellular glutamate and aspartate concentrations increased during hypothermic perfusion and remained elevated after reperfusion in animals with a normal or mildly abnormal neurologic examination result. CONCLUSIONS: We conclude that spinal cord hypothermia induced by cold heparinized saline perfusion is a simple technique that prevents paraplegia after 20 minutes of ischemia and preserves intracellular concentrations of important metabolites.
Adenosine Triphosphate↗
The cytoplasmic tail of CD4 targets chimeric molecules to a degradative pathway.
Many different cell surface receptors undergo endocytosis via coated pits. Once having entered the cell, the receptors are sorted into diverse pathways. Which path a given receptor will follow is determined by signals inherent in the receptor's structure. The nature of these structural features is not yet known. In this study, we have taken the approach of constructing chimeric molecules to localize the domain of the T-cell surface molecule CD4 which is responsible for targeting it for degradation. Chimeric molecules bearing the cytoplasmic domain of CD4 and the extracellular domain of either the low-density lipoprotein receptor or a major histocompatibility complex (MHC) class I molecule were both internalized in response to phorbol 12-myristate 13-acetate and were subsequently degraded, indicating that the cytoplasmic tail of CD4 contains all the information required for both processes. The ability to modulate the level of MHC class I molecules on the cell surface offers an approach to investigating quantitative aspects of antigen presentation, the initial possibilities of which are explored herein.
CD4 Antigens↗
The value of psychosocial Level II fieldwork.
The shortage of occupational therapists choosing to practice in mental health and the increase of therapists electing to specialize in other areas led to a pilot study designed to gather information regarding the value of psychosocial Level II fieldwork. A survey was mailed to 152 practicing occupational therapists who had graduated from Colorado State University in Fort Collins between 1983 and 1988; of the surveys returned, 116 were used in this study. The results indicate that the psychosocial Level II fieldwork experience provides therapists with valuable training and experience regardless of their current area of practice or specialization. The results also suggest that to preserve the holistic approach that occupational therapists offer their clients, psychosocial Level II fieldwork must remain a requirement of occupational therapy programs.
Holistic Health↗
The many faces of epidermal growth factor repeats.
Epidermal growth factor (EGF) is a short peptide with a distinctive motif of six cysteines. This motif is found in many different proteins of diverse functions. One approach to determining the functional utility of EGF repeats is to undertake a methodical analysis of each individual protein. While this approach has met with some success, it has been applied to only a small fraction of all the EGF repeat-bearing proteins. A second approach is to consider all these proteins as a whole but give particular attention to structural and functional similarities. This review attempts a broad, although not comprehensive, survey of the families of proteins containing EGF repeats, with particular emphasis on the relative distribution of calcium-binding and noncalcium-binding EGF repeats.
Amino Acid Sequence↗