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PubMed1997

Osteopontin and p53 expression are associated with tumor progression in a case of synchronous, bilateral, invasive mammary carcinomas.

OBJECTIVE: To examine the association between expression of osteopontin (OPN), p53, other molecular markers (Ki-67, c-erb B2, and estrogen receptor protein) and tumor progression in a case of synchronous, bilateral, invasive mammary carcinomas of the same histology. DESIGN: Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections. Plasma OPN level was determined by a quantitative antigen capture assay. SETTING: The patient was seen, treated, and followed up for a period of 5 years at the London Regional Cancer Centre, Ontario, Canada. PATIENT: A 60-year-old woman presented with bilateral infiltrating mammary carcinomas of the same histologic type and grade. Bilateral mastectomy and axillary node dissection showed involvement of 3 of 12 right axillary and 0 of 11 left axillary lymph nodes. She later developed a right chest wall recurrence, followed by widespread metastatic disease to the skull, liver, and left femur. RESULTS: The primary tumor of the right breast was OPN- and p53-positive, whereas the tumor of the left breast was negative for both markers. The development of right axillary lymph node metastases, chest wall recurrence, and distant metastases was associated in all instances with an immunohistochemical profile of high level expression of OPN and p53. Plasma assay for OPN at the time of last admission showed a markedly elevated OPN level. CONCLUSIONS: Increased p53 expression was found to be associated with increased tumor aggressiveness. The association of increased OPN expression with increased malignancy in breast cancer is a novel finding and raises the possibility of a role for OPN in tumor progression, as well as the potential for this marker in predicting clinical aggressiveness.

Biomarkers, Tumor↗
PubMed2005

Immune responses after local administration of IgY loaded-PLGA microspheres in gut-associated lymphoid tissue in pigs.

Oral vaccination of large animals using PLGA MS (poly(D,L-lactide-co-glycolide)microspheres) appeared to be more challenging than immunization of mice. The purpose of this study was to deliver to GALT an immunogenic model protein (IgY), free or encapsulated by spray-drying in PLGA MS, and to evaluate systemic immune response in SPF Large White pigs. Pigs were surgically processed for local administration of IgY in three sets of experiments. In two sets of experiments, administration was locally performed in temporary ligatured intestinal segments, in jejunal Peyer's patches and in mesenteric lymph nodes. In the third experiment, pigs received IgY via an intestinal cannula. Total IgY-specific antibodies were detected in the sera of pigs after a single local immunization, but not in the sera of cannulated pigs. The study of IgG1 and IgG2 isotypes indicated that PLGA MS are able to elicit a combined serum IgG2/G1 response with a predominance of IgG1 response when locally administered. PLGA MS can be a potential oral delivery system for antigen but our results underlined the difficulty to immunize large animals like pigs. Transposition of data between small and large animals appears to be complex and suggests that physiological features need to be considered to increase intestinal availability of oral encapsulated vaccines.

Animals↗
PubMed1999

Micrometastases in bone marrow: prognostic indicators for pancreatic cancer.

Minimal residual disease in patients with operable pancreatic carcinoma is frequently missed by current noninvasive tumour staging. We applied an immunocytochemical cytokeratin assay that allows identification of individual pancreatic carcinoma cells disseminated to bone marrow. Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages and an age-matched control group of 33 noncarcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1, and A45-B/B3 to epithelial cytokeratins (CK) using the alkaline phosphatase antialkaline phosphatase method. CK-positive cells were found in 14 (48.4%) of 31 cancer patients treated with curative intent and in 10 (58.8%) of 18 patients with extended disease. The overall frequency of these cells was 1 to 83 per 5x10(5) mononuclear cells with no significant differences between patients at different tumor stages and lymph node involvement. After a median follow-up of 22.8 months (range 3-48 months), 6 (40.0%) of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) had local relapse compared to none of 12 corresponding patients without such cells (p<0.05). Univariate survival analyses revealed that the presence of CK-positive cells was predictive of reduced overall survival. In conclusion, anticytokeratin mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus the described technique may help identify patients with pancreatic cancer and at potentially high risk of early metastatic relapse. The results promise to be of important assistance for determining prognosis and the consequences in therapy of early stage pancreatic cancer.

Adenocarcinoma↗
PubMed2004

Highly uneven distribution of tenofovir-selected simian immunodeficiency virus in different anatomical sites of rhesus macaques.

Antiviral tenofovir monotherapy was used to determine whether drug-selected simian immunodeficiency virus (SIV) variants replaced their wild-type progenitors at the same rate in different tissues of six rhesus macaques. The relative frequencies of drug-resistant and wild-type genotypes were measured longitudinally in blood and in 23 lymphoid and nonlymphoid tissues collected at necropsy. The mutant/wild-type genotype ratio was measured using a heteroduplex tracking assay targeting tenofovir-selected SIV reverse transcriptase codons. After the initiation of tenofovir treatment in animals with high steady-state viremia levels, resistant genotypes emerged in the plasma within 1 to 8 weeks and in five of six cases reached frequencies of nearly 100% within 4 to 25 weeks. The appearance of tenofovir-resistant genotypes in peripheral blood mononuclear cell (PBMC) DNA was generally delayed by 1 to 2 weeks and in one case was completely absent. Necropsies performed 8 to 55 weeks after the initiation of tenofovir treatment showed the frequency of resistant SIV genotypes to be generally higher in tissue RNA than DNA fractions. The frequency of drug-resistant genotypes varied widely between anatomical sites, including different lymph nodes of the same animal. Except for the epidydimis, the tissues with the lowest rates of proviral replacement by tenofovir-resistant genotypes differed between animals. The highly uneven distribution of tenofovir-resistant genotypes in different tissues seen shortly after the initiation of tenofovir monotherapy may reflect differences in local antiviral drug selection pressures and/or the stochastic effect of small effective populations of drug-resistant variants randomly seeding different anatomical sites early in therapy.

Adenine↗
PubMed2003

Generation of a rat monoclonal antibody specific for importin alpha3/Qip1.

Importin alpha, which mediates the nuclear import of nuclear localization signal (NLS)-containing proteins, is a member of nuclear transport factors. Importin alpha binds directly NLS and functions as an adapter for accessing the importin beta-dependent import pathway. To date, several isoforms of importin alpha have been identified and classified into three subfamilies in higher eukaryotes. In this study, we report on the production of a rat monoclonal antibody (MAb) against importin alpha3/Qip1, a member of the importin alpha family, using a rat medial iliac lymph node method. The MAb 3D10 produced, reacted with both recombinant and endogenous importin alpha 3/Qip1. Immunoblotting analysis revealed that MAb 3D10 exclusively recognizes importin alpha3/Qip1 among members of the importin alpha family, in various mammalian cells.

Animals↗
PubMed2005

Mapping PrPSc propagation in experimental and natural scrapie in sheep with different PrP genotypes.

Twenty-one orally inoculated and seven naturally infected sheep with scrapie were examined for PrP(Sc) in peripheral tissues and in the central nervous system (CNS), using immunohistochemistry. In the inoculated group, VRQ (valine at codon 136, arginine at codon 154 and glutamine at codon 171)/VRQ sheep generally had a greater accumulation of the pathologic form of prion protein (PrP(Sc)) in peripheral tissues, as compared with VRQ/ARQ (alanine at codon 136, arginine at codon 154, and glutamine at codon 171) animals at corresponding time points after inoculation. PrP(Sc) was not detected in the ileal Peyer's patch, the spleen, the superficial cervical lymph node, and peripheral nervous tissues of several inoculated VRQ/ARQ animals. All inoculated VRQ/VRQ sheep, but only one of eight inoculated VRQ/ARQ animals, were PrP(Sc)-positive in the CNS. Thus, the propagation of PrP(Sc) seemed slower and more limited in VRQ/ARQ animals. Tissue and cellular localization of PrP(Sc) suggested that PrP(Sc) was disseminated through three different routes. PrP(Sc)-positive cells in lymph node sinuses and in lymphatics indicated spreading by lymph. The sequential appearance of PrP(Sc) in the peripheral nervous system and the CNS, with satellite cells as early targets, suggested the periaxonal transportation of PrP(Sc) through supportive cells. Focal areas of vascular amyloid-like PrP(Sc) in the brain of five sheep, suggested the hematogenous dissemination of PrP(Sc). There was a poor correlation between the amount of PrP(Sc) in the CNS and clinical signs. One subclinically affected sheep showed widespread PrP(Sc) accumulation in the CNS, whereas three sheep had early clinical signs without detectable PrP(Sc) in the CNS. A VV(136) (homozygous for valine at codon 136) sheep inoculated with ARQ/ARR (alanine at codon 136, arginine at codon 154, and arginine at codon 171) tissue succumbed to disease, demonstrating successful heterologous transmission. Less susceptible sheep receiving VRQ/VRQ or ARQ/ARR material were PrP(Sc)-negative by immunohistochemistry, enzyme-linked immunosorbent assay, and western blot.

Amino Acid Substitution↗
PubMed1996

Limited efficacy of preoperative computed tomographic scanning for the evaluation of lymph node metastasis in patients before radical prostatectomy.

OBJECTIVES: To evaluate the efficacy of preoperative computed tomographic (CT) scanning in patients with presumed localized prostatectomy prior to radical retropubic prostatectomy. METHODS: A retrospective study of 173 consecutive patients believed to be candidates for radical retropubic prostatectomy who underwent preoperative CT scanning regardless of preoperative prostate-specific antigen (PSA) value, clinical stage, or Gleason grade was undertaken. All patients underwent radical retropubic prostatectomy with bilateral pelvic lymph node dissection or aspiration needle biopsy of abnormal nodes on CT scanning. RESULTS: One hundred sixty-five of 173 patients (95.4%) were believed to have normal CT scans preoperatively. Of these 165 patients, 156 (94.5%) were found to have negative lymph nodes confirmed histologically at the time of lymphadenectomy. Nine patients (5.5%) were found to have lymph node metastases confirmed histologically, despite a negative CT scan. Computed tomographic scanning understaged 9 of 12 (75%) patients with proven metastases. Incidental abdominal pathology of clinical significance was documented in 4 patients (2.3%), including 2 with renal cell cancers, 1 with colon cancer, and 1 with a large (8 cm) abdominal aortic aneurysm. Prostate-specific antigen levels in patients with metastatic lymph nodes ranged from 0.7 to 130 ng/mL (Hybritech Tandem assay), with a mean level of 42 ng/mL. Although 9 of 33 patients (27.3%) with PSA levels greater than 25 ng/mL had node metastases, only 3 of these 33 patients (9.1%) were correctly diagnosed by CT scanning. CONCLUSIONS: Although additional numbers of patients with high PSA levels need to be evaluated, we could not find any justification for routine preoperative CT scanning in patients with a PSA of less than 25 ng/mL. These results suggest that significant savings can be realized by abandoning the practice of routine CT scanning for lymph node metastasis in all patients with newly diagnosed prostate cancer.

Humans↗
PubMed2004

[Variation of cytokines with administration of chemotherapeutic and immuno-therapeutic drugs for colorectal cancer].

Systemic and local immunological responses were studied in patients with or without preoperative administration of chemotherapeutic and/or immunotherapeutic drugs for colorectal cancer. The plasma TGFbeta and other cytokines such as IL-2, IL-4, IL-6, IL-10, IL-12, IFN-gamma in the supernatant fluid of culture of peripheral blood mononuclear cell (PBMC) and regional lymph node were measured by the ELISA method. A systemic response of cytokines was as follows: the production of plasma TGFbeta increased in many cases by chemotherapeutic drugs with a significant elevation of the mean production. Productions of IFN-gamma, IL-2, IL-12 in the supernatant fluid of culture of PBMC increased in many cases by immunotherapeutic drugs, and that of IL-4, IL-6 increased in many cases by chemotherapeutic drugs. A local response of cytokines was as follows: the production of IL-2 by immunotherapeutic drugs was greater than that without immunotherapeutic drugs whereas the production of IL-10 by immunotherapeutic drugs was smaller than that without immunotherapeutic drugs.

Adjuvants, Immunologic↗
PubMed2005

Expression profile of cancer-testis genes in 121 human colorectal cancer tissue and adjacent normal tissue.

PURPOSE: Among tumor antigens identified to date, cancer-testis (CT) antigens, which are coded by CT genes, are identified as a group of highly attractive targets for cancer vaccines. This study is the first to analyze the mRNA expression and possible correlation with pathologic characteristics of multiple CT genes in a large cohort of colorectal cancer (CRC) patients. EXPERIMENTAL DESIGN: The expression of 10 individual CT genes in 121 CRC and adjacent tissues were analyzed by RT-PCR method. The presence of autologous antibodies against NY-ESO-1 was examined in serum samples by ELISA. To confirm the protein expression, immunohistochemistry was done for detecting the NY-ESO-1 antigen in mRNA-positive CRC tissues. RESULTS: The CT genes were detected with various frequencies in CRC tissue, SCP-1, 1.7%; SSX-2, 2.5%; SSX-4, 2.5%; SSX-1, 5.0%; CT10, 6.6%; NY-ESO-1, 9.9%; MAGE-1, 11.6%; LAGE-1, 15.7%; MAGE-4, 22.3%; and MAGE-3, 27.3%. In 56.2% of tumor tissues examined in this study, at least one CT gene was detected. In contrast, no CT gene expression was found in cancer adjacent tissues. Among 10 CT genes investigated, NY-ESO-1 and LAGE-1 are of particular interest because their mRNA expression in CRC was rarely reported before. In our study, NY-ESO-1 mRNA was found to express in 9.9% of the samples, and also correlated significantly with stages (P = 0.041) and local lymph node metastasis (P = 0.002). In addition, we also identified one NY-ESO-1 antibody-positive serum sample. MAGE-4 mRNA was expressed at a high frequency in tumor tissues with vessel emboli samples (P = 0.025). CONCLUSIONS: These results suggested that CT genes, especially NY-ESO-1 and LAGE-1, do express in CRC. More than 50% of the CRC patients in this study express at least one CT gene, making them eligible for CT vaccination. NY-ESO-1 gene may serve as a marker for local metastasis and advanced disease. MAGE-4 gene is significantly associated with the vessel emboli.

Adult↗
PubMed1996

Local intestinal immune responses to infections with Trichinella spiralis. Real-time, continuous assay of cytokines in the intestinal (afferent) and efferent thoracic duct lymph of rats.

Levels of IL-4, IL-5, TNF-alpha, and IFN-gamma were quantitated in the intestinal (afferent) and efferent thoracic duct lymph of rats during the course (0 to 289 h) of an infection with Trichinella spiralis. Intestinal lymph was collected by cannulating thoracic ducts of mesenteric lymphadenectomized animals. These studies showed that cytokines typical of a Th2 type (IL-4 and IL-5) and a Th1 type (IFN-gamma) were simultaneously detected in the intestinal lymph during the first 8 days after infection. Worm expulsion (day 11 to 12) was associated with increased levels of IL-4 and IL-5 in the intestinal lymph. IL-5 levels rose as early as 15 to 20 h and remained elevated throughout the infection. IL-4 activity appeared in intestinal lymph 60 h after infection and reached peak levels during worm expulsion. Despite the predominantly Th2 nature of cytokine response, IFN-gamma levels showed several cycles of high and low production during the course of infection. A comparison of cytokine levels between intestinal and efferent lymph values showed no significant differences in IL-4 or IL-5 levels suggesting no contribution by the mesenteric node to efferent lymph. However, IFN-gamma and TNF-alpha levels were lower in efferent lymph compared with intestinal lymph suggesting mesenteric node consumption. Adoptive transfer experiments showed that protective CD4+CD45RC- cells primed the gut for a more rapid TH2-type response that was faster than in a primary infection. In contrast, adoptive transfer of CD4+CD45RC+ cells primed the gut for a more rapid Th1-type(IFN-gamma) response. These studies demonstrate a novel method for measuring real-time changes in cytokine levels in the gut during the course of an active infection.

Animals↗
PubMed2003

VEGF and endostatin levels in wound fluid and plasma after breast surgery.

Angiogenesis is essential for wound repair after surgical trauma. Vascular endothelial growth factor (VEGF) and endostatin are endogenous angiogenic factors involved in the initiation and completion of angiogenesis. The aim of this study was to examine the local and systemic VEGF and endostatin profiles in patients undergoing surgery for benign and malignant breast processes. A total of 16 patients with or without cancer underwent breast surgery. Group I: eight patients with primary breast cancer underwent a simple or radical mastectomy according to Madden including dissection of axillary lymph nodes. Group II: eight healthy female-to-male transsexuals underwent subcutaneous mastectomy. VEGF and endostatin levels in plasma and wound fluid were determined. In both groups VEGF levels in wound fluid were significantly higher compared to postoperative plasma levels, whereas wound fluid endostatin levels were lower than plasma levels and decreased progressively after surgery. In both groups plasma VEGF and endostatin levels did not change significantly before and after surgery. The local VEGF increase and endostatin decrease observed immediately after surgery appears to be a physiological response to operative trauma, which can be studied more profoundly in locally generated fluid than in blood. This process did not seem to be influenced by the type of process (cancerous or non-cancerous) involved in the surgical intervention.

Breast Neoplasms↗
PubMed1997

Cytokine responses in mice infected with Angiostrongylus cantonensis.

For determination of the kinetics of cytokine production and its possible role in host resistance to Angiostrongylus cantonensis in the mouse, Th1 [interleukin 2 (IL-2) and interferon gamma (IFN-gamma] and Th2 (IL-5 and IL-4) cytokine production in the cerebrospinal fluid (CSF), sera, and culture supernatants of spleen cells (SC) or cervical lymph-node cells (CLNC) of infected BALB/c and C57BL/6 mice was assessed by a sandwich enzyme-linked immunosorbent assay (ELISA). IL-5 and IL-4 were detected in CSF of both strains, with a peak response occurring at around days 12-15 and 20 postinfection (p.i.), respectively. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay also revealed prominent IL-5 and IL-4 mRNA expression in T-cells but not in eosinophils in CSF. SC and CLNC stimulated with A. cantonensis young adult-worm antigen released IL-5 in vitro at and after day 20 p.i. Contrarily, IFN-gamma production in CSF and SC or CLNC culture supernatants was almost negligible before day 30 p.i. IL-5, IL-4, and IL-2 production in culture supernatants was rather prominent in resistant C57BL/6 mice as opposed to susceptible BALB/c mice as assessed by the magnitude of increase over preinfection levels. Antigen-specific IgG1 (but not IgG2a) responses were more prominent in C57BL/6 mice than in BALB/c mice. These data suggest that systemic and local Th2 cytokine responses, especially those involving IL-5, are predominant in A. cantonensis-infected mice and that IL-5 is an important cytokine underlying the innate resistance of the mouse against A. cantonensis.

Angiostrongylus cantonensis↗
PubMed2006

Inconsistencies between cytokine profiles, antibody responses, and respiratory hyperresponsiveness following dermal exposure to isocyanates.

Cytokine profiling of local lymph node responses has been proposed as a simple test to identify chemicals, such as low molecular weight diisocyanates, that pose a significant risk of occupational asthma. Previously, we reported cytokine messenger RNA (mRNA) profiles for dinitrochlorobenzene (DNCB) and six isocyanates: toluene diisocyanate, diphenylmethane-4,4'-diisocyanate, dicyclohexylmethane-4,4'-diisocyanate, isophorone diisocyanate, p-tolyl(mono)isocyanate, and meta-tetramethylene xylene diisocyanate. The present study was conducted to test the hypothesis that relative differences in the cytokine profile are predictive of relative differences in total serum immunoglobulin (Ig) E and respiratory responses to methacholine (Mch) following dermal exposure to the chemicals. After a preliminary experiment to determine an exposure regimen sufficient to achieve responses to Mch following dermal diisocyanate exposure, BALB/c mice received nine dermal exposures over a period of 28 days to one of six isocyanates, DNCB, or vehicle. Mice were then challenged with increasing doses of Mch and responsiveness was assessed using whole-body plethysmography. Serum antibody responses and cytokine mRNA profiles in the draining lymph node were also assessed. In separate experiments, cytokine protein assays were performed after five dermal exposures over a 14-day period. The response pattern for interleukin (IL)-4, IL-10, and IL-13 for the different isocyanates was highly reproducible as determined by RNAse protection assay, reverse transcription-PCR, or cytokine protein levels. However, the relative differences in T-helper cytokine profiles were not predictive of relative differences in either total serum IgE or respiratory responses to Mch following dermal exposure. The data suggest that the cytokine profiling approach needs to be further developed and refined before adoption and that other approaches to hazard identification should be pursued as well. Based on the weight of evidence from all the assays performed, it appears that all six isocyanates tested have some potential to cause respiratory hypersensitivity following dermal exposure.

Administration, Cutaneous↗
PubMed2004

Co-delivery of pro-apoptotic BAX with a DNA vaccine recruits dendritic cells and promotes efficacy of autoimmune diabetes prevention in mice.

Genetic vaccines encoding pancreatic beta cell antigens can prevent autoimmune (type 1) diabetes when delivered into murine model systems, but there is a need to improve their efficacy. Here, we investigated the effects of intramuscular delivery of DNA coding for the pro-apoptotic protein BAX together with an intracellular or a secreted form of the beta cell antigen glutamic acid decarboxylase (GAD) on diabetes onset and immune responses in non-obese diabetic (NOD) mice. We hypothesized that induction of apoptosis in vaccine-containing cells could lead to GAD tolerance and disease suppression. Remarkably, monitoring of spontaneous diabetes onset indicated that only delivery of DNA coding for secreted GAD and BAX resulted in significant prevention of the disease. Using GFP as a model plasmid-encoded antigen revealed that co-delivery of BAX resulted in the recruitment of GFP-containing dendritic cells (DCs) in the draining lymph nodes and spleen of NOD mice. Furthermore, data indicated that subcellular localization of GAD had an effect on both the number and function of antigen presenting cells (APCs) recruited by BAX as well as on IFN-gamma secretion, and that diabetes suppression was unlikely to be caused by increased T helper 2 (Th2)-like activity. Our results indicate that, under certain conditions, co-delivery of DNA encoding BAX can improve the efficacy of genetic vaccination for prevention of pathogenic autoimmunity via a mechanism likely to involve modulation of antigen presenting cell function. In addition, our data also suggest that properties associated with subcellular localization of an antigen in apoptotic cells can have a significant effect on induced immune responses.

Animals↗
PubMed1998

Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion.

The localization of circulating leukocytes within inflamed tissues occurs as the result of interactions with and migration across vascular endothelium, and is governed, in part, by the expression of adhesion molecules on both cell types. Recently, we have described a novel primary adhesion interaction between the structurally activated form of the adhesion molecule CD44 on lymphocytes and its major ligand hyaluronan on endothelial cells under physiologic laminar flow conditions, and have proposed that this interaction functions in an extravasation pathway for lymphocytes in vascular beds at sites of inflammation. While the regulation of activated CD44 on leukocytes has been characterized in depth, regulation of hyaluronate (HA) on endothelial cells has not been extensively studied. Here we demonstrate that the expression of HA on cultured endothelial cell lines and primary endothelial cultures is inducible by the proinflammatory cytokines TNFalpha and IL-1beta, as well as bacterial lipopolysaccharide. In addition, this inducibility appears strikingly restricted to endothelial cells derived from microvascular, but not large vessel, sources. The elevated HA levels thus induced result in increased CD44-dependent adhesive interactions in both nonstatic shear and laminar flow adhesion assays. Changes in mRNA levels for the described HA synthetic and degradative enzymes were not found, suggesting other more complex mechanisms of regulation. Together, these data add to the selectin and immunoglobulin gene families a new inducible endothelial adhesive molecule, hyaluronan, and help to further our understanding of the potential physiologic roles of the CD44/HA interaction; i.e., local cytokine production within inflamed vascular beds may enhance surface hyaluronan expression on endothelial cells, thereby creating local sites receptive to the CD44/HA interaction and thus extravasation of inflammatory cells.

Animals↗
PubMed1995

Murine macrophage scavenger receptor: in vivo expression and function as receptor for macrophage adhesion in lymphoid and non-lymphoid organs.

Macrophage scavenger receptors are trimeric integral membrane glycoproteins which have been implicated in various macrophage functions including uptake of oxidized lipoprotein and the serum-dependent, divalent cation-independent adhesion of macrophages to tissue culture-treated plastic. In this study we have used a recently defined monoclonal antibody (2F8) which recognizes murine macrophage scavenger receptor, to explore its expression in lymphoid and non-lymphoid organs of the normal adult. Scavenger receptor was detected in the red pulp and marginal zone of normal adult mouse spleen, medulla of the thymus and subcapsular region of lymph nodes. Kupffer cells in the liver, alveolar macrophages in the lung and lamina propria macrophages in the gut all reacted with 2F8 monoclonal antibody. The antigen was not detected on any non-macrophage cells, with the exception of sinusoidal endothelial cells in the liver. In the spleen, lymph node and liver, scavenger receptor antigen expression was associated specifically with phagocytic cells which had taken up colloidal carbon. To examine macrophage adhesion in a context relevant to the interactions occurring within lymphoid and non-lymphoid organs, and the contribution of macrophage scavenger receptor to this adhesion, we designed an assay of macrophage adhesion to frozen tissue sections. Adhesion to most tissues was high and uniform in the absence of any chelating agents. The chelation of Ca2+ and Mg2+ revealed specific patterns of macrophage adhesion in lymphoid and non-lymphoid organs which was completely inhibited by 2F8. The ability of this antibody to block the EDTA-resistant adhesion correlated with tissue expression of the antigen in some tissues. Unlike adhesion to tissue culture-treated plastic, macrophage scavenger receptor-dependent adhesion of macrophages to frozen tissue sections did not exhibit an absolute requirement for exogenous fetal bovine serum indicating the presence of an endogenous ligand for scavenger receptor within the tissues. We propose that macrophage scavenger receptor is a candidate homing or retention molecule for macrophage localization within ligand-rich tissues.

Animals↗
PubMed1996

Molecular in situ localization techniques in diagnosis and pathogenicity studies of enteroviral heart disease.

BACKGROUND: Enteroviruses, including coxsackieviruses of group B (CVB), are considered to be the most common agents of viral myocarditis. As demonstrated by in situ hybridization for the detection of viral RNA in endomyocardial biopsies and autopsy hearts, such infections are also detectable in patients with 'idiopathic' dilated cardiomyopathy, indicating the possibility of myocardial enterovirus persistence. Persistent enterovirus infection of the human heart is supported by the recent discovery in various murine models of chronic myocarditis, demonstrating that CVB3, typically a cytolytic virus, is capable of evading immunological surveillance in a host-dependent manner. METHODS: In order to investigate mechanisms underlying acute and persistent enterovirus infection in the myocardium, diverse tissues from CVB3 infected immunocompetent mice were processed in in situ hybridization for the detection of viral RNA. In addition, virus-host interactions were analyzed at the subcellular level in the myocardium in the course of the infection by means of an electron microscopic in situ hybridization assay. RESULTS: A close spatial and temporal relationship between viral replication and inflammatory lesions was observed during the acute as well as persistent phase of myocardial infection. A multiorgan study revealed that, in addition to heart muscle cells, lymphoid cells of spleen and lymph nodes are persistently infected. The results obtained at the ultrastructural level demonstrate that loss of host cell integrity is a direct consequence of acute viral replication and confirm that chronic myocarditis may be associated with persistent heart muscle infection. CONCLUSIONS: Viral replication plays a central role in the pathogenesis of acute and chronic myocarditis. Immune cells are important targets of the infection and provide a non-cardiac viral reservoir.

Journal Article↗
PubMed1994

Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States.

BACKGROUND: In the United States, prognosis and survival after the diagnosis of breast cancer is poorer among black patients and, to a lesser extent, among Hispanic patients, compared with white patients. Patients who are black or Hispanic have been reported to present with higher stage or more advanced disease. Even after adjusting for stage, however, survival rates are lower for blacks but not for Hispanics. PURPOSE: Our purpose was to compare survival, age, tumor size, nodal status, estrogen-receptor (ER) and progesterone-receptor (PgR) status, histologic type, S-phase fraction, DNA ploidy status, HER-2/neu protein expression, and p53 protein status, along with systemic treatment, in a large group of white, black, and Hispanic U.S. women. METHODS: From 1970 to 1991, breast tumor specimens were submitted to The University of Texas Health Science Center from 31 contributing hospitals throughout the United States for ER and PgR assay. A total of 4885 white, 1016 black, and 777 Hispanic women were eligible for this study. Median follow-up was 57 months. RESULTS: Overall, white women were significantly more likely to be older and to have smaller tumors, have less lymph node involvement, have tumors with positive ER and PgR status, and have a lower S-phase fraction compared with Hispanic or black women. There were no clinically important differences in DNA ploidy, histologic type, HER-2/neu, and p53 expression among the three groups. Considering all stages, white women had the best overall survival (date of diagnosis to date of death) at 5 years--75% +/- 1% (means +/- SE), with a median survival of 166 months, but Hispanic women had an intermediate survival--70% +/- 2% (median survival, 156 months), and black women had the worst survival--65% +/- 2% (median survival, 117 months) (P < .0001). For node-negative patients, there was no significant difference in disease-free survival (date of diagnosis to date of first recurrence) or overall survival, although blacks tended to have a worse prognosis. For node-positive or locally advanced disease and for metastatic disease, blacks had significantly (P < .0001) worse disease-free and overall survival than did white or Hispanic women. Differences in the use of systemic therapy did not explain these outcomes. CONCLUSION: A number of biologic factors associated with poor prognosis are found with a significantly increased frequency in breast tumors from Hispanic and, particularly, from black women. Tumors with a more aggressive biology could lead to a higher stage at diagnosis and a poorer survival for the group as a whole.

Adult↗