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Biomedical subjects

J Kelley

Publications and source records attributed to J Kelley.

At least 19 recordsLinked to original sources
PubMed2002

Positron emission tomography/computed tomography imaging for the detection of recurrent ovarian and fallopian tube carcinoma: a retrospective review.

PURPOSE: Imaging modalities to evaluate ovarian/fallopian tube cancer patients for recurrence are limited. Positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound lack the sensitivity to consistently detect recurrence or measurable disease in these patients. A new technique combines PET and CT (PET/CT) images to identify increased metabolic activity and to locate that signal with improved anatomic specificity. The objective of this study is to compare PET/CT, CT, and histologic findings in patients with recurrent ovarian/fallopian tube cancers. METHODS: Retrospective chart review of eight patients with primary ovarian (n = 6) or fallopian tube (n = 2) cancer was performed. All eight patients underwent initial cytoreductive surgery. Five patients initially received chemotherapy, one received radioactive phosphorus ((32)P), one received tamoxifen, and one received no therapy. Seven of eight patients had a suspected recurrence based on clinical examination, elevated CA-125 level, and/or abnormal CT findings; one patient requested a PET/CT. Histologic findings from surgery were correlated with PET/CT and CT findings. RESULTS: All eight patients had positive histology, and of these, seven patients had a negative CT and five patients had lesions that were correctly identified by PET/CT. CONCLUSIONS: Five of the eight (62%) patients had recurrent disease based on correlative histology with a positive PET/CT and a negative CT. These preliminary findings suggest that combined PET/CT may be an effective means of identifying patients with recurrent ovarian/fallopian tube cancer. Such patients could potentially proceed to salvage treatment and avoid the morbidity and expense of surgical assessment. Pilot studies comparing CT, PET, PET/CT, and histologic findings are underway.

Aged↗
PubMed2001

The human mast cell: functions in physiology and disease.

Mast cells are multifunctional, tissue-dwelling cells capable of secreting a wide variety of mediators. They develop from bone marrow-derived progenitor cells, primed with stem cell factor (SCF), which mediates its actions by interacting with the SCF receptor or c-kit on the cell surface. Mast cells continue their maturation and differentiation in peripheral tissue, developing into two well described subsets of cells, MCT and MCTC cells, varying in content of tryptase and chymase as well as in immunobiology. Mast cells are activated by numerous stimuli, including antigen (acting via the high affinity IgE receptor, Fc?RI), superoxides, complement proteins, neuropeptides and lipoproteins resulting in activation and degranulation. Following activation, these cells express mediators such as histamine, leukotrienes and prostanoids, as well as proteases, and many cytokines and chemokines, pivotal to the genesis of an inflammatory response. Recent data suggests that mast cells may play an active role in such diverse diseases as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis. Mast cells directly interact with bacteria and appear to play a vital role in host defense against pathogens. Drugs, such as glucocorticoids, cyclosporine and cromolyn have been demonstrated to have inhibitory effects on mast cell degranulation or mediator release.

Arteriosclerosis↗
PubMed2001

A potential role for protein kinase C-epsilon in regulating megakaryocytic lineage commitment.

Multiple studies have shown that intracellular signal transduction by the protein kinase C (PKC) family participates in the initiation of megakaryocyte differentiation. In this study, multiple approaches addressed the functional contributions by specific PKC isozymes to megakaryocytic lineage commitment of two independent cell lines, K562 and human erythroleukemia (HEL). Pharmacologic profiles of induction and inhibition of megakaryocytic differentiation in both cell lines suggested a role for the calcium-independent novel PKCs, in particular PKC-epsilon. In transfection studies, the isolated variable domain of PKC-epsilon selectively blocked exogenous activation of the megakaryocyte-specific alpha IIb promoter. Constitutively active mutants of PKC-epsilon, but not of other PKC isozymes, cooperated with the transcription factor GATA-1 in the activation of the alpha IIb promoter. The functional cooperation between GATA-1 and PKC-epsilon displayed dependence on cellular milieu, as well as on the promoter context of GATA binding sites. In aggregate, the data suggest that PKC-epsilon specifically participates in megakaryocytic lineage commitment through functional cooperation with GATA-1 in the activation of megakaryocytic promoters.

Carbazoles↗
PubMed2001

High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

We describe here a system for the rapid identification, assay development, and characterization of gene-based single nucleotide polymorphisms (SNPs). This system couples informatics tools that mine candidate SNPs from public expressed sequence tag resources and automatically designs assay reagents with detection by a chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform. As a proof of concept of this system, a genomewide collection of reagents for 9,115 gene-based SNP genetic markers was rapidly developed and validated. These data provide preliminary insights into patterns of polymorphism in a genomewide collection of gene-based polymorphisms.

Alleles↗
PubMed2001

A (1-->3)-beta-D-linked heptasaccharide is the unit ligand for glucan pattern recognition receptors on human monocytes.

Glucans are fungal cell wall polysaccharides which stimulate innate immune responses. We determined the minimum unit ligand that would bind to glucan receptors on human U937 cells using laminarin-derived pentaose, hexaose, and heptaose glucan polymers. When U937 membranes were pretreated with the oligosaccharides and passed over a glucan surface, only the heptasaccharide inhibited the interaction of glucan with membrane receptors at a K(d) of 31 microM (95% CI 20-48 microM) and 100% inhibition. However, the glucan heptasaccharide did not stimulate U937 monocyte NFkappaB signaling, nor did it increase survival in a murine model of polymicrobial sepsis. Laminarin, a larger and more complex glucan polymer (M(w) = 7700 g/mol), only partially inhibited binding (61 +/- 4%) at a K(d) of 2.6 microM (99% CI 1.7-4.2 microM) with characteristics of a single binding site. These results indicate that a heptasaccharide is the smallest unit ligand recognized by macrophage glucan receptors. The data also indicate the presence of at least two glucan-binding sites on U937 cells and that the binding sites on human monocyte/macrophages can discriminate between glucan polymers. The heptasaccharide and laminarin were receptor antagonists, but they were not receptor agonists with respect to activation of NFkappaB-dependent signaling pathways or protection against experimental sepsis.

Animals↗
PubMed2001

Early activation of IKKbeta during in vivo myocardial ischemia.

We have demonstrated that in vitro brief ischemia activates nuclear factor (NF)-kappaB in rat myocardium. We report in vivo ischemia-reperfusion (I/R)-induced NF-kappaB activation, IkappaB kinase -beta (IKKbeta) activity, and IkappaBalpha phosphorylation and degradation in rat myocardium. Rat hearts were subjected to occlusion of the coronary artery for up to 45 min or occlusion for 15 min followed by reperfusion for up to 3 h. Cytoplasmic and nuclear proteins were isolated from ischemic and nonischemic areas of each heart. NF-kappaB activation was increased in the ischemic area (680%) after 10 min of ischemia and in the nonischemic area (350%) after 15 min of ischemia and remained elevated during prolonged ischemia and reperfusion. IKKbeta activity was markedly increased in ischemic (1,800%) and nonischemic (860%) areas, and phosphorylated IkappaBalpha levels were significantly elevated in ischemic (180%) and nonischemic (280%) areas at 5 min of ischemia and further increased after reperfusion. IkappaBalpha levels were decreased in the ischemic (45%) and nonischemic (36%) areas after 10 min of ischemia and remained low in the ischemic area during prolonged ischemia and reperfusion. The results suggest that in vivo I/R rapidly induces IKKbeta activity and increases IkappaBalpha phosphorylation and degradation, resulting in NF-kappaB activation in the myocardium.

Animals↗
PubMed2000

A phase I/II study of hypofractionated whole abdominal radiation therapy in patients with chemoresistant ovarian carcinoma: Karnofsky score determines treatment outcome.

PURPOSE: Radiation therapy can provide useful palliation in chemorefractory ovarian cancer patients. The purpose of this study was to prospectively study the palliative effect of a hypofractionated radiation treatment regimen. Change in quality-of-life scores (Functional Assessment of Cancer Therapy [FACT], Karnofsky scale), pain score, and tolerance to therapy were also assessed. METHODS AND MATERIALS: A single-institution Phase I/II trial was initiated in patients with chemoresistant recurrent or progressive ovarian cancer. All patients had symptomatic and measurable intra-abdominal disease. Patients were treated with a single radiation fraction (700 cGy) or two fractions (300 cGy twice a day) to the whole abdomen over 1 day. Quality-of-life scale (FACT G version 2) was assessed at baseline and 1 and 3 months following treatment. Karnofsky scale and pain score were also evaluated in the same time frame. RESULTS: Sixteen patients were prospectively entered into this protocol between February 1996 and September 1998. Twelve patients received a single 700 cGy fraction and four 300 cGy twice a day. All were heavily pretreated and 9 (56%) had a poor performance status prior to treatment. Symptoms needing palliation included pain (14), ascites (10), and bleeding (2). Symptomatic improvement occurred in all patients with pain (5 complete response [CR] and 7 partial response [PR], all patients with bleeding (CR 2), and two (20%) with ascites. Five patients (31%) had a reduction in lesion size documented radiologically in three. The mean duration of response was 22 weeks in patients with a Karnofsky score >70. Thirteen patients developed transient nausea and vomiting which resolved in 48 hours in all. All patients developed a transient lymphopenia. Thirteen patients completed a follow-up quality-of-life scale. There was an improvement in the physical and functional components of the scale in patients with Karnofsky score of 90-100. There was no improvement in quality of life in patients with Karnofsky score <90 despite symptomatic response. Median survival was 3 months from the date of treatment. CONCLUSION: Hypofractionated radiation therapy is an effective palliative treatment for end-stage ovarian cancer patients. Karnofsky score can help determine the duration of response and survival for this high-risk population.

Adult↗
PubMed2000

Inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands. 2. 4-(2-Malonyl)phenylalanine as a potent phosphotyrosyl mimetic.

Nonhydrolyzable phosphotyrosyl (pTyr) mimetics serve as important components of many competitive Grb2 SH2 domain inhibitors. To date, the most potent of these inhibitors have relied on phosphonate-based structures to replace the 4-phosphoryl group of the parent pTyr residue. Reported herein is the design and evaluation of a new pTyr mimetic, p-malonylphenylalanine (Pmf), which does not contain phosphorus yet, in Grb2 SH2 domain binding systems, approaches the potency of phosphonate-based pTyr mimetics. When incorporated into high affinity Grb2 SH2 domain-directed platforms, Pmf is 15-20 times more potent than the closely related previously reported pTyr mimetic, O-malonyltyrosine (OMT). Pmf-containing inhibitors show inhibition constants as low as 8 nM in extracellular Grb2 binding assays and in whole cell systems, effective blockade of both endogenous Grb2 binding to cognate erbB-2, and downstream MAP kinase activation. Evidence is provided that use of an N(alpha)()-oxalyl auxiliary enhances effectiveness of Pmf and other inhibitors in both extracellular and intracellular contexts. As one of the most potent Grb2 SH2 domain-directed pTyr mimetics yet disclosed, Pmf may potentially have utility in the design of new chemotherapeutics for the treatment of various proliferative diseases, including breast cancer.

Adaptor Proteins, Signal Transducing↗
PubMed2000

The effects of HIV infection on endothelial function.

Endothelial dysfunction and/or injury is pivotal to the development of cardiovascular and inflammatory pathology. Endothelial dysfunction and/or injury has been described in Human Immunodeficiency Virus (HIV) infection. Elaboration of circulating markers of endothelial activation, such as soluble adhesion molecules and procoagulant proteins, occurs in HIV infection. Certain endothelial cells, such as those lining liver sinusoids, human umbilical vein endothelial cells, bone marrow stromal endothelial cells or brain microvascular endothelial cells, have been shown to be variably permissive for HIV infection. Entry of virus into endothelial cells may occur via CD4 antigen or galactosyl-ceramide receptors. Other mechanisms of entry including chemokine receptors have been proposed. Nevertheless, endothelial activation may also occur in HIV infection either by cytokines secreted in response to mononuclear or adventitial cell activation by virus or else by the effects of the secreted HIV-associated proteins, gp 120 (envelope glycoprotein) and Tat (transactivator of viral replication) on endothelium. Enhanced adhesiveness of endothelial cells, endothelial cell proliferation and apoptosis as well as activation of cytokine secretion have all been demonstrated. Synergy between select inflammatory cytokines and viral proteins in inducing endothelial injury has been shown. In HIV infection, dysfunctional or injured endothelial cells potentiate tissue injury, inflammation and remodeling, and accelerate the development of cardiovascular disease.

Animals↗
PubMed1999

Vulnerable plaque.

Explore the source record for details and available documents.

Arteriosclerosis↗
PubMed1999

Equatorius: a new hominoid genus from the Middle Miocene of Kenya.

A partial hominoid skeleton just older than 15 million years from sediments in the Tugen Hills of north central Kenya mandates a revision of the hominoid genus Kenyapithecus, a possible early member of the great ape-human clade. The Tugen Hills specimen represents a new genus, which also incorporates all material previously referable to Kenyapithecus africanus. The new taxon is derived with respect to earlier Miocene hominoids but is primitive with respect to the younger species Kenyapithecus wickeri and therefore is a late member of the stem hominoid radiation in the East African Miocene.

Animals↗
PubMed1999

Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands.

Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell membrane penetration. Work presented in the current study examines a variety of pTyr mimetics in the context of a high-affinity Grb2 binding platform. Among the analogues studied are new non-phosphorus-containing pTyr mimetics 23a and 23b which, when incorporated into tripeptide structures 18f and 20f, are able to inhibit Grb2 SH2 domain binding with affinities among the best yet reported for non-phosphorus-containing SH2 domain inhibitors (IC50 values of 6.7 and 1.3 microM, respectively). The present study has also demonstrated the usefulness of the Nalpha-oxalyl group as an auxiliary which enhances the binding potency of both phosphorus- and non-phosphorus-containing pTyr mimetics. When combined with the (phosphonomethyl)phenylalanine (Pmp) residue to give analogues such as L-20d, potent inhibition of Grb2 SH2 domain binding can be achieved both in extracellular assays using isolated Grb2 SH2 domain protein and in intracellular systems measuring the association of endogenous Grb2 with its cognate p185erbB-2 ligand. These latter effects can be achieved at micromolar to submicromolar concentrations without prodrug derivatization. The oxalyl-containing pTyr mimetics presented in this study should be of general usefulness for the development of other Grb2 SH2 domain antagonists, independent of the beta-bend-mimicking platform utilized for their display.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The paleoenvironment of Sivapithecus parvada.

Remains of the hominoid Sivapithecus parvada and a diversity of mammalian taxa are preserved at locality Y311 (ca. 10 Ma) in the Siwalik Nagri Formation of northern Pakistan. Bovids (Bovidae, Artiodactyla) are the most abundant mammals next to tragulids (Tragulidae, Artiodactyla) at locality Y311 and provide a means for reconstructing the paleoenvironments that would have been available to Sivapithecus parvada. A functional model indicates a linkage between habitat and several femoral characters among extant bovids. Based on this model, we infer that forested habitats predominated at locality Y311 but that some less densely covered areas may also have been present. Paleoenvironments in the earlier Chinji Formation appear comparable to those at locality Y311, although the presence of a continuous canopy in the former is more certain. Thus, adaptive changes in the bovid fauna from the Chinji through the Nagri Formations appear to have preceded the shift to predominantly C4 grasslands which, based on other lines of evidence, occurred locally (and possibly globally) between 8 and 6 Ma. The paleoenvironments of locality Y311 and the Chinji Formation localities appear different from the paleoenvironment of Kenyapithecus at Fort Ternan in Kenya, where the presence of continuous canopy is unlikely. The Fort Ternan fauna is dominated by two genera of bovids. One of these is adapted to light cover while the other appears better adapted to heavy cover. Sivapithecus and Kenyapithecus lived in different ecological settings probably characterized by varying degrees of vegetative cover.

Animals↗
PubMed1999

Human endothelium as a source of multifunctional cytokines: molecular regulation and possible role in human disease.

Endothelial cells, by virtue of their capacity to express adhesion molecules and cytokines, are intricately involved in inflammatory processes. Endothelial cells have been shown to express interleukin-1 (IL-1), IL-5, IL-6, IL-8, IL-11, IL-15, several colony-stimulating factors (CSF), granulocyte-CSF (G-CSF), macrophage CSF (M-CSF) and granulocyte-macrophage CSF (GM-CSF), and the chemokines, monocyte chemotactic protein-1 (MCP-1), RANTES, and growth-related oncogene protein-alpha (GRO-alpha). IL-1 and tumor necrosis factor-alpha (TNF-alpha) produced by infiltrating inflammatory cells can induce endothelial cells to express several of these cytokines as well as adhesion molecules. Induction of these cytokines in endothelial cells has been demonstrated by such diverse processes as hypoxia and bacterial infection. Recent studies have demonstrated that adhesive interactions between endothelial cells and recruited inflammatory cells can also signal the secretion of inflammatory cytokines. This cross-talk between inflammatory cells and the endothelium may be critical to the development of chronic inflammatory states. Endothelial-derived cytokines may be involved in hematopoiesis, cellular chemotaxis and recruitment, bone resorption, coagulation, and the acute-phase protein synthesis. As many of these processes are critical to the maturation of an inflammatory and reparative state, it appears likely that endothelial-derived cytokines play a crucial role in several diseases, including atherosclerosis, graft rejection, asthma, vasculitis, and sepsis. Genetic and pharmacologic manipulation of endothelial-derived cytokines provides an additional approach to the management of chronic inflammatory diseases.

Arteriosclerosis↗
PubMed1999

Association of HIV viral load with oral diseases.

OBJECTIVE: The measurement of HIV viral load as a predictor of disease progression has revolutionized the medical management of HIV patients. In this study, oral diseases as measured by DMFT (decayed, missing and filled teeth), periodontal assessment and oral Candidacolonization, were related to HIV viral load. Also correlated was HIV status assessments, including CD4+ count, a history of intravenous drug abuse (IVDA) and the use of protease inhibitor drugs. MATERIALS AND METHODS: Oral and periodontal examination, dental radiographs, and tongue swab for fungal culture was accomplished over a 2-month period on 39 HIV positive patients attending the University of Maryland Dental School. Twenty-eight (71. 8%) of these patients had a history of IVDA. Viral load was measured by a quantitative RT-PCR. RESULTS: Among the patients with high viral load (>10 000 copies ml-1), 92.3% were found to have a history of IVDA. Also, patients with high viral load demonstrated average CD4+ counts of 136 mm-3 while moderate viral load (400-10 000 copies ml-1) corresponded to average counts of 271 mm-3. Periodontal pocket depths (PPD) of >5 mm at a minimum of two oral sites were found in 76.9% of the patients with high viral load. Among the high viral load patients, 69.2% had DMFT >20, 69.2% were culture positive for Candida and 81.5% of patients on protease inhibitors demonstrated moderate or low viral loads. CONCLUSION: These data demonstrated that elevated viral load levels correlate well with oral disease prevalence in this predominantly IVDA population of HIV-infected dental patients.

Adult↗
PubMed1998

The impact of adjuvant radiotherapy on carcinosarcoma of the uterus.

BACKGROUND: The role of adjuvant radiotherapy in the setting of uterine carcinosarcoma has not been clearly established. METHODS: A retrospective review of 60 patients receiving definitive therapy for carcinosarcoma of the uterus was undertaken at a single institution. Twenty-nine of 60 patients were treated with adjuvant radiotherapy. RESULTS: The addition of radiotherapy significantly reduced the local recurrence rate from 55% (17 patients) to 3% (1 patient). Adjuvant radiotherapy reduced the risk of distant failure and death in patients with disease confined to the uterus but did not impact distant recurrence or survival in stage III patients. Increasing stage and depth of myometrial tumor invasion were negatively associated with overall survival and disease-free survival but had no impact on local recurrence rates. The nuclear grade of the epithelial component was predictive of local recurrence (P = 0.0592), but epithelial architectural grade, grade of stromal component, and stromal versus epithelial predominance did not provide prognostic information. The relative risk of local recurrence of unirradiated patients versus irradiated patients was 17.54 (P = 0.0055) after adjusting for nuclear grade of the epithelial component. CONCLUSIONS: Local failure represents a significant site of failure in the absence of adjuvant radiotherapy. The improvement in local failure rates with the addition of radiotherapy translates into an improvement in distant failure rates and survival only for patients with stage I/II disease. Epithelial nuclear grade, in addition to depth of myometrial invasion and stage, provides important prognostic information. Epithelial architectural grade, stromal grade, type of stromal component (homologous versus heterologous), and predominance of either stromal or epithelial component were not found to be significant prognostic factors.

Aged↗