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1.  Utility of progranulin and serum leukocyte protease inhibitor as diagnostic and prognostic biomarkers in ovarian cancer 
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death in females and leading gynecologic cause of cancer death. Despite the identification of a number of serum biomarkers, methods to identify early stage disease and predict prognosis remain scarce. We have evaluated two biologically connected serum biomarkers, serum leukocyte protease inhibitor (SLPI) and progranulin (PGRN).
200 frozen plasma samples were acquired from the Mayo Clinic Biospecimen Repository for Ovarian Cancer Research. Samples were obtained from 50 patients with benign conditions, 50 with AJCC stage I and II EOC, and 100 with AJCC stage III and IV EOC patients. Samples were obtained prior to surgical resection of a mass and were analyzed for absolute levels of SLPI and PGRN using enzyme-linked immunosorbent (ELISA) assays. Receiver-operator characteristic curves were generated for SLPI and PGRN. Median follow-up was 48 months.
Absolute levels of SLPI were significantly elevated in patients with EOC compared to benign disease and predicted the presence of EOC (AUC of 0.812. P = 0.04); SLPI remained elevated in the subset of patients with normal CA-125, PGRN levels were not significantly increased in early stage or late stage EOC patients as a whole, but an increase in PGRN levels was associated with decreased overall survival in advanced EOC.
SLPI levels are elevated in epithelial ovarian cancer, and SLPI shows promise as a diagnostic biomarker for patients with both elevated and normal CA-125 levels. An increase in PGRN is associated with decreased overall survival.
SLPI is elevated in EOC and warrants investigation in a screening study in women at risk for EOC.
PMCID: PMC3839679  PMID: 23878295
Ovarian neoplasms; GRN protein, human; SLPI protein, human; Biological Markers; Prognosis
2.  What is the most dangerous snake? 
Letter to Editor of Journal of Venomous Animals and Toxins.
PMCID: PMC3766188  PMID: 23981479
Snakes; Snake bites; Snake venoms; Snake envenomation
3.  Unusually High Levels of n-6 Polyunsaturated Fatty Acids in Whale Sharks and Reef Manta Rays 
Lipids  2013;48:1029-1034.
Fatty acid (FA) signature analysis has been increasingly used to assess dietary preferences and trophodynamics in marine animals. We investigated FA signatures of connective tissue of the whale shark Rhincodon typus and muscle tissue of the reef manta ray Manta alfredi. We found high levels of n-6 polyunsaturated fatty acids (PUFA), dominated by arachidonic acid (20:4n-6; 12–17 % of total FA), and comparatively lower levels of the essential n-3 PUFA—eicosapentaenoic acid (20:5n-3; ~1 %) and docosahexaenoic acid (22:6n-3; 3–10 %). Whale sharks and reef manta rays are regularly observed feeding on surface aggregations of coastal crustacean zooplankton during the day, which generally have FA profiles dominated by n-3 PUFA. The high levels of n-6 PUFA in both giant elasmobranchs raise new questions about the origin of their main food source.
PMCID: PMC3779593  PMID: 23975574
n-3 Fatty acids; Arachidonic acid; Planktivores; Zooplankton; Elasmobranch
4.  A pitfall in the reconstruction of fibre ODFs using spherical deconvolution of diffusion MRI data 
Neuroimage  2013;65(C):433-448.
Diffusion weighted (DW) MRI facilitates non-invasive quantification of tissue microstructure and, in combination with appropriate signal processing, three-dimensional estimates of fibrous orientation. In recent years, attention has shifted from the diffusion tensor model, which assumes a unimodal Gaussian diffusion displacement profile to recover fibre orientation (with various well-documented limitations), towards more complex high angular resolution diffusion imaging (HARDI) analysis techniques.
Spherical deconvolution (SD) approaches assume that the fibre orientation density function (fODF) within a voxel can be obtained by deconvolving a ‘common’ single fibre response function from the observed set of DW signals. In practice, this common response function is not known a priori and thus an estimated fibre response must be used. Here the establishment of this single-fibre response function is referred to as ‘calibration’. This work examines the vulnerability of two different SD approaches to inappropriate response function calibration: (1) constrained spherical harmonic deconvolution (CSHD)—a technique that exploits spherical harmonic basis sets and (2) damped Richardson–Lucy (dRL) deconvolution—a technique based on the standard Richardson–Lucy deconvolution.
Through simulations, the impact of a discrepancy between the calibrated diffusion profiles and the observed (‘Target’) DW-signals in both single and crossing-fibre configurations was investigated. The results show that CSHD produces spurious fODF peaks (consistent with well known ringing artefacts) as the discrepancy between calibration and target response increases, while dRL demonstrates a lower over-all sensitivity to miscalibration (with a calibration response function for a highly anisotropic fibre being optimal). However, dRL demonstrates a reduced ability to resolve low anisotropy crossing-fibres compared to CSHD. It is concluded that the range and spatial-distribution of expected single-fibre anisotropies within an image must be carefully considered to ensure selection of the appropriate algorithm, parameters and calibration. Failure to choose the calibration response function carefully may severely impact the quality of any resultant tractography.
► We compare two spherical deconvolution based fODF retrieval techniques. ► We examine fODF error under inappropriate response function calibration. ► CSHD produces errors as response and target diffusion profiles diverge. ► dRL is poor against low FA targets but adequate across white matter. ► Manuscript updated to cover orientational dependence of CSHD errors.
PMCID: PMC3580290  PMID: 23085109
Spherical harmonic deconvolution; Richardson–Lucy; MRI; Calibration; Tractography; Diffusion tensor imaging
6.  Teaching Skeptical Inquiry 
CBE Life Sciences Education  2012;11(3):233-234.
PMCID: PMC3433294
7.  A randomised, phase II study of intetumumab, an anti-αv-integrin mAb, alone and with dacarbazine in stage IV melanoma 
British Journal of Cancer  2011;105(3):346-352.
αv integrins are involved in angiogenesis and melanoma tumourigenesis. Intetumumab (CNTO 95) is a fully human anti-αv-integrin monoclonal antibody.
In a multicentre, randomised, phase II study, stage IV melanoma patients were randomised 1 : 1 : 1 : 1 to 1000 mg m−2 dacarbazine+placebo (n=32), 1000 mg m−2 dacarbazine+10 mg kg−1 intetumumab (n=32), 10 mg kg−1 intetumumab (n=33), or 5 mg kg−1 intetumumab (n=32) q3w. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events, and pharmacokinetics.
No statistically significant differences in efficacy were observed between groups. In the dacarbazine+placebo, dacarbazine+intetumumab, 10 mg kg−1 intetumumab, and 5 mg kg−1 intetumumab groups, median PFS was 1.8, 2.5, 1.4, and 1.4 months; median OS was 8, 11, 15, and 9.8 months; and ORR of complete+partial response was 10, 3, 6, and 0%. Nonlinear intetumumab pharmacokinetics and potential intetumumab–dacarbazine interactions were observed. Transient, asymptomatic, nonrecurring, grade 1–2, uveitic reactions that resolved spontaneously or with topical steroids were seen in 22–30% of intetumumab-treated patients. Low-grade infusion-reaction symptoms (headache, fatigue, nausea, vomiting, fever, chills) were observed, as expected, in 16–73% of dacarbazine-treated patients. No intetumumab-related myelosuppression, laboratory/electrocardiogram abnormalities, or deaths occurred.
With its favourable safety profile and a nonsignificant trend towards improved OS, intetumumab merits further investigation in advanced melanoma.
PMCID: PMC3172894  PMID: 21750555
intetumumab; melanoma; αv integrins; dacarbazine; CNTO 95
8.  MHC class II epitope nesting modulates dendritic cell function and improves generation of antigen-specific CD4 helper T cells1 
CD4 T helper cells are critical to the development of coordinated immune responses to infections and tumors. T helper cells are activated through interactions of the TCR with MHC class II complexed with peptide. T cell activation is dependent on the density of MHC peptide complexes as well as the duration of interaction of the TCR with antigen presenting cells. In this study, we sought to determine whether MHC class II peptides could be modified with amino acid sequences that facilitated uptake and presentation with the goal of improving T helper cell activation in vitro and in vivo. A model epitope derived from the murine folate receptor alpha, a self and tumor antigen, was modified at its carboxy terminus with the invariant chain derived Ii-Key peptide and at its amino terminus with a peptide that enhances uptake of antigen by antigen presenting cells. Modification of peptide resulted in enhanced generation of high avidity murine folate receptor alpha T cells that persisted in vivo and homed to sites of antigen deposition. The nesting approach was epitope and species independent and specifically excluded expansion of CD4 regulatory T cells. The resulting T helper cells were therapeutic, enhanced in vivo helper activity, and had an increased ability to resist tolerizing immune microenvironments. In addition to improved immunoadjuvants, this epitope modification strategy may be useful for enhancing ex vivo and in vivo generation of T helper cells for preventing and treating diseases.
PMCID: PMC3119756  PMID: 21613617
9.  TGFβ/TNFα-Mediated Epithelial-Mesenchymal Transition Generates Breast Cancer Stem Cells with a Claudin-Low Phenotype 
Cancer research  2011;71(13):4707-4719.
Breast cancer recurrence is believed to be caused by a sub-population of cancer cells that possess the stem cell attribute of treatment resistance. Recently, we and others have reported the generation of breast cancer stem cells (BCSCs) by epithelial to mesenchymal transition (EMT), although the physiological process by which these cells may arise in vivo remains unclear. We show here that exposure of tumor cells to TGFβ and TNFα induces EMT and, more importantly, generates cells with a stable BCSC phenotype which is demonstrated by increased self-renewing capacity, greatly increased tumorigenicity, and increased resistance to oxaliplatin, etoposide and paclitaxel. Furthermore, gene expression analyses found that the TGFβ/TNFα-derived BCSCs showed down regulated expression of genes encoding Claudin 3, 4 and 7 and the luminal marker, cytokeratin 18. These changes indicate a shift to the claudin low molecular subtype, a recently identified breast cancer subtype characterized by the expression of mesenchymal and stem cell-associated markers and correlated with a poor prognosis. Taken together, the data show that cytokine exposure can be used to generate stable BCSCs ex vivo, and suggest that these cells may provide a valuable tool in the identification of stem cell-directed biomarkers and therapies in breast cancer.
PMCID: PMC3129359  PMID: 21555371
10.  Tumor infiltrating PD-1+ dendritic cells mediate immune suppression in ovarian cancer 
Within the ovarian cancer microenvironment there are several mechanisms that suppress the actions of anti-tumor immune effectors. Delineating the complex immune microenvironment is an important goal towards developing effective immune-based therapies. A dominant pathway of immune suppression in ovarian cancer involves tumor-associated and dendritic cell-associated, B7-H1. The interaction of B7-H1 with PD-1 on tumor-infiltrating T cells is a widely cited theory of immune suppression involving B7-H1 in ovarian cancer. Recent studies suggest that the B7-H1 ligand, PD-1, is also expressed on myeloid cells complicating interpretations of how B7-H1 regulates dendritic cell (DC) function in the tumor. In this study we found that ovarian cancer-infiltrating DCs progressively expressed increased levels of PD-1 over time in addition to B7-H1. These dual-positive PD-1+B7-H1+ DCs have a classical DC phenotype (i.e. CD11c+CD11b+CD8−) but are immature, suppressive and respond poorly to danger signals. Accumulation of PD-1+B7-H1+ DC in the tumor was associated with suppression of T cell activity and decreased infiltrating T cells in advancing tumors. T cell suppressor function of these DCs appeared to be mediated by T cell associated PD-1. In contrast, ligation of PD-1 expressed on the tumor-associated DC suppressed NFκB activation, release of immune regulatory cytokines, and upregulation of co-stimulatory molecules. PD-1 blockade in mice bearing ovarian cancer substantially reduced tumor burden and increased effector antigen-specific T cell responses. Our results reveal a novel role of tumor infiltrating PD-1+B7-H1+ DCs in mediating immune suppression in ovarian cancer.
PMCID: PMC3110549  PMID: 21551365
Tolerance; tumor microenvironment; dendritic cells
Hypertension in Pregnancy  2010;29(4):399-409.
Evaluate association of the inflammatory marker C-reactive protein with recurrent preeclampsia.
Serum samples collected longitudinally in women with previous preeclampsia from the Maternal-Fetal Medicine Units Network trial of aspirin to prevent preeclampsia were assayed for CRP.
Of 255 women studied, 50 developed recurrence. Baseline C-reactive protein concentration was similar between women who did and did not recur. After adjusting for confounders, neither elevated baseline C-reactive protein nor its change over gestation was associated with recurrence.
In this group of women with previous preeclampsia, neither baseline C-reactive protein concentration nor change in concentration over gestation was associated with recurrent preeclampsia.
PMCID: PMC3339658  PMID: 20701468
Pregnancy; Preeclampsia; C-Reactive Protein; Inflammation; Acute-Phase Reaction
12.  Mite dispersal among the Southern Ocean Islands and Antarctica before the last glacial maximum 
It has long been maintained that the majority of terrestrial Antarctic species are relatively recent, post last glacial maximum, arrivals with perhaps a few microbial or protozoan taxa being substantially older. Recent studies have questioned this ‘recolonization hypothesis’, though the range of taxa examined has been limited. Here, we present the first large-scale study for mites, one of two dominant terrestrial arthropod groups in the region. Specifically, we provide a broad-scale molecular phylogeny of a biologically significant group of ameronothroid mites from across the maritime and sub-Antarctic regions. Applying different dating approaches, we show that divergences among the ameronothroid mite genera Podacarus, Alaskozetes and Halozetes significantly predate the Pleistocene and provide evidence of independent dispersals across the Antarctic Polar Front. Our data add to a growing body of evidence demonstrating that many taxa have survived glaciation of the Antarctic continent and the sub-Antarctic islands. Moreover, they also provide evidence of a relatively uncommon trend of dispersals from islands to continental mainlands. Within the ameronothroid mites, two distinct clades with specific habitat preferences (marine intertidal versus terrestrial/supralittoral) exist, supporting a model of within-habitat speciation rather than colonization from marine refugia to terrestrial habitats. The present results provide additional impetus for a search for terrestrial refugia in an area previously thought to have lacked ice-free ground during glacial maxima.
PMCID: PMC3049079  PMID: 20943685
ameronothroid mites; biogeography; dispersal; glacial refugia; vicariance
13.  Casp8p41 expression in primary T cells induces a proinflammatory response 
AIDS (London, England)  2010;24(9):1251-1258.
HIV infection of CD4 T cells can lead to HIV protease-mediated cleavage of procaspase 8 generating a novel, HIV-specific peptide called Casp8p41. Casp8p41 has at least two biologic functions: induction of cell death via mitochondrial depolarization and release of cytochrome C, as well as activation of nuclear factor kappa B (NFκB). We have previously shown that Casp8p41-induced NFκB activation enhances HIV LTR transcription and consequently increases HIV replication. Herein, we questioned whether Casp8p41-induced NFκB activation impacts the cytokine profile of cells expressing Casp8p41.
Analysis of cells expressing Casp8p41 and HIV-infected T cells.
We assessed whether host genes are transcriptionally activated following Casp8p41 production, using microarray analysis, cytokine quantification, followed by western blot and flow cytometry.
Microarray analysis identified 259 genes significantly upregulated following expression of Casp8p41. Furthermore, Casp8p41 expression in primary CD4 T cells results in increased production of interleukin (IL)-2, IL-15 and tumor necrosis factor (TNF), as well as IL-1RA; whereas levels of granulocyte macrophage colony-stimulating factor and interferon (IFN)-γ were reduced in the Casp8p41 expressing cells. Intra-cellular flow cytometry confirmed the co-association of Casp8p41 with elevated TNF in HIV-infected cells.
These data indicate that the expression of Casp8p41 in HIV-infected CD4 T cells in addition to promoting apoptosis and enhancing HIV replication also promotes a proinflammatory cytokine milieu, which is characteristic of untreated HIV infection.
PMCID: PMC3150465  PMID: 20299954
apoptosis; Casp8p41; HIV; inflammation; protease; tumor necrosis factor
14.  Dynamics of maternal and paternal effects on embryo and seed development in wild radish (Raphanus sativus) 
Annals of Botany  2010;106(2):309-319.
Background and Aims
Variability in embryo development can influence the rate of seed maturation and seed size, which may have an impact on offspring fitness. While it is expected that embryo development will be under maternal control, more controversial hypotheses suggest that the pollen donor and the embryo itself may influence development. These latter possibilities are, however, poorly studied. Characteristics of 10-d-old embryos and seeds of wild radish (Raphanus sativus) were examined to address: (a) the effects of maternal plant and pollen donor on development; (b) the effects of earlier reproductive events (pollen tube growth and fertilization) on embryos and seeds, and the influence of embryo size on mature seed mass; (c) the effect of water stress on embryos and seeds; (d) the effect of stress on correlations of embryo and seed characteristics with earlier and later reproductive events and stages; and (e) changes in maternal and paternal effects on embryo and seed characteristics during development.
Eight maternal plants (two each from four families) and four pollen donors were crossed and developing gynoecia were collected at 10 d post-pollination. Half of the maternal plants experienced water stress. Characteristics of embryos and seeds were summarized and also compared with earlier and later developmental stages.
Key Results
In addition to the expected effects of the maternal plants, all embryo characters differed among pollen donors. Paternal effects varied over time, suggesting that there are windows of opportunity for pollen donors to influence embryo development. Water-stress treatment altered embryo characteristics; embryos were smaller and less developed. In addition, correlations of embryo characteristics with earlier and later stages changed dramatically with water stress.
The expected maternal effects on embryo development were observed, but there was also evidence for an early paternal role. The relative effects of these controls may change over time. Thus, there may be times in development when selection on the maternal, paternal or embryo contributions to development are more and less likely.
PMCID: PMC2908165  PMID: 20519237
Raphanus sativus; embryo development; maternal effects; paternal effects; seed development; seed size; water stress; wild radish
15.  “The A-Word” Made Easy 
CBE Life Sciences Education  2010;9(4):392-393.
PMCID: PMC2995752
16.  Flight Modes in Migrating European Bee-Eaters: Heart Rate May Indicate Low Metabolic Rate during Soaring and Gliding 
PLoS ONE  2010;5(11):e13956.
Many avian species soar and glide over land. Evidence from large birds (mb>0.9 kg) suggests that soaring-gliding is considerably cheaper in terms of energy than flapping flight, and costs about two to three times the basal metabolic rate (BMR). Yet, soaring-gliding is considered unfavorable for small birds because migration speed in small birds during soaring-gliding is believed to be lower than that of flapping flight. Nevertheless, several small bird species routinely soar and glide.
Methodology/Principal Findings
To estimate the energetic cost of soaring-gliding flight in small birds, we measured heart beat frequencies of free-ranging migrating European bee-eaters (Merops apiaster, mb∼55 g) using radio telemetry, and established the relationship between heart beat frequency and metabolic rate (by indirect calorimetry) in the laboratory. Heart beat frequency during sustained soaring-gliding was 2.2 to 2.5 times lower than during flapping flight, but similar to, and not significantly different from, that measured in resting birds. We estimated that soaring-gliding metabolic rate of European bee-eaters is about twice their basal metabolic rate (BMR), which is similar to the value estimated in the black-browed albatross Thalassarche (previously Diomedea) melanophrys, mb∼4 kg). We found that soaring-gliding migration speed is not significantly different from flapping migration speed.
We found no evidence that soaring-gliding speed is slower than flapping flight in bee-eaters, contradicting earlier estimates that implied a migration speed penalty for using soaring-gliding rather than flapping flight. Moreover, we suggest that small birds soar and glide during migration, breeding, dispersal, and other stages in their annual cycle because it may entail a low energy cost of transport. We propose that the energy cost of soaring-gliding may be proportional to BMR regardless of bird size, as theoretically deduced by earlier studies.
PMCID: PMC2978710  PMID: 21085655
17.  Effect of Smoking on Circulating Angiogenic Factors in High Risk Pregnancies 
PLoS ONE  2010;5(10):e13270.
Changes in maternal concentrations of the anti-angiogenic factors, soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), and the pro-angiogenic placental growth factor (PlGF) precede the development of preeclampsia in healthy women. The risk of preeclampsia is reduced in women who smoke during pregnancy. The objective of this study was to investigate whether smoking affects concentrations of angiogenic factors (sFlt1, PlGF, and sEng) in women at high risk for developing preeclampsia.
Study Design
We performed a secondary analysis of serum samples from 993 high-risk women (chronic hypertension, diabetes, multifetal gestation, and previous preeclampsia) in a preeclampsia prevention trial. sFlt1, sEng and PlGF were measured in serum samples obtained at study entry, which was prior to initiation of aspirin (median 19.0 weeks' [interquartile range of 16.0–22.6 weeks']). Smoking status was determined by self-report.
sFlt1 was not significantly different in smokers from any high-risk groups compared to their nonsmoking counterparts. PlGF was higher among smokers compared to nonsmokers among diabetic women (142.7 [77.4–337.3] vs 95.9 [48.5–180.7] pg/ml, p = 0.005) and women with a history of preeclampsia (252.2 [137.1–486.0] vs 152.2 [73.6–253.7] pg/ml, p = 0.001). sEng was lower in smokers with multifetal gestations (5.8 [4.6–6.5] vs 6.8 [5.5–8.7] ng/ml, p = 0.002) and trended lower among smokers with diabetes (4.9 [3.8–5.6] vs 5.3 [4.3–6.3] ng/ml, p = 0.05). Smoking was not associated with a lower incidence of preeclampsia in any of these groups.
In certain high-risk groups, smoking is associated with changes in the concentrations of these factors towards a pro-angiogenic direction during early pregnancy; however, there was no apparent association between smoking and the development of preeclampsia in our cohort.
PMCID: PMC2953508  PMID: 20967275
18.  Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PlGF) in Preeclampsia among High Risk Pregnancies 
PLoS ONE  2010;5(10):e13263.
Differences in circulating concentrations of antiangiogenic factors sFlt1 and soluble endoglin (sEng) and the pro-angiogenic growth factor PlGF are reported to precede the onset of preeclampsia weeks to months in low-risk pregnant women. The objective of this study was to investigate whether similar changes can be detected in pregnant women at high-risk to develop the syndrome.
This study is a secondary analysis of the NICHD MFMU trial of aspirin to prevent preeclampsia in high-risk pregnancies. Serum samples were available from 194 women with pre-existing diabetes, 313 with chronic hypertension, 234 with multifetal gestation, and 252 with a history of preeclampsia in a previous pregnancy. Samples collected across pregnancy were analyzed in a blinded fashion for sFlt1, sEng and PlGF.
The odds of developing preeclampsia were significantly increased among women with multiple fetuses for each 2-fold elevation in sFlt1, sEng and the ratio of angiogenic factors (e.g. OR 2.18, 95% CI 1.46-3.32), and significantly decreased for each 2-fold elevation in circulating PlGF (OR 0.50, 95% CI 0.30-0.82) between 7 and 26 weeks' gestation. Cross-sectional analysis of the angiogenic factors across gestation showed significant differences during the third trimester in women who develop preeclampsia compared with appropriate controls in all high-risk groups. However, when data were examined in relation to the gestational week when preeclampsia was diagnosed only sFlt1 was significantly higher 2 to 5 weeks before the clinical onset of preeclampsia and only in women with previous preeclampsia.
The pattern of elevated concentrations of sFlt1 and sEng, and low PlGF in high-risk pregnant subjects who develop preeclampsia is similar to that reported in low-risk pregnant women. However, differences in these factors among high-risk women who do and do not develop preeclampsia are modest, and do not appear to be clinically useful predictors in these high-risk pregnant women.
PMCID: PMC2952583  PMID: 20948996
19.  Angiogenic dysfunction in molar pregnancy 
Molar pregnancy is associated with very early-onset preeclampsia. Since excessive circulating anti-angiogenic factors may play a pathogenic role in preeclampsia, we hypothesized that molar placentas produce more anti-angiogenic proteins than normal placentas.
Study design
This retrospective case-control study utilized a semiquantitative immunohistochemical technique to compare histological sections of molar placentas to normal controls. Tissue slides were treated with two antisera: one recognized the anti-angiogenic markers fms-like tyrosine kinase receptor 1 (Flt1) and its soluble form (sFlt1), while the other recognized vascular endothelial marker CD31. Stain intensity was graded from 1+ (strong focal staining) to 4+ (91%–100% staining).
Molar placentas (n=19) showed significantly more staining than controls (n=16) for Flt/sFlt1 (P < 0.0001).
There was a significant difference in Flt1/sFlt1 immunostaining intensity when molar placentas were compared to controls. This supports a hypothesis that the phenotype of preeclampsia in molar pregnancy may result from trophoblasts overproducing at least one anti-angiogenic protein.
PMCID: PMC2832058  PMID: 19922899
Anti-angiogenic factors; fms-like tyrosine kinase receptor; hydatidiform mole; molar pregnancy; sFlt1
Circulating tumor necrosis factor-alpha (TNF-α), a potent pro-inflammatory cytokine, capable of activating endothelial cells, as well as its soluble receptors (sTNF-R1 and sTNF-R2), is increased during overt preeclampsia, consistent with hypotheses that enhanced systemic inflammatory response and endothelial cell dysfunction are important in the pathophysiology of the preeclamptic syndrome. If so, such increases in levels should precede the onset of the disease. This study was designed to examine whether plasma concentrations of sTNF-R1 and sTNF-R2 are elevated prior to the onset of preeclampsia.
This was a retrospective biomarker study of stored maternal plasma from an NICHD preeclampsia prevention trial conducted in patients with risk factors for developing preeclampsia to test the effectiveness of low dose aspirin compared with placebo. The first sample was collected at 13–26 weeks’ gestation and the second at 24–28 weeks’ gestation. Serial sTNF-R1 and sTNF-R2 concentrations were assessed using sensitive and specific immunoassays in 1,004 patients in whom both samples were collected.
The incidence of preeclampsia was 21.3% (214/1004). Median plasma levels of the sTNF-R2, but not sTNF-R1, were significantly higher at 13–26 weeks (sample 1) and at 24–28 weeks (sample 2) in patients who developed preeclampsia than in those who did not (sample 1: sTNF-R2: median 2,678 pg/ml, range 934–7,835 vs. median 2,535 pg/ml, range 1,022–13,000, p=0.02; sTNF-R1: median 936 pg/ml, range 449–3,239 vs. median 913 pg/ml, range 359–5,060, p=0.19). There was a significantly increased odds of preeclampsia for an increase in sTNF-R2 from sample 1 to sample 2 (OR=1.23 per 1,000 unit increase). Women in the fourth quartile of sTNF-R2 at 24–28 weeks, had a significantly increased adjusted odds of preeclampsia (OR=1.55, 95%CI=1.02–2.35, p=0.04), compared with women in the first quartile. This association, however, varied by treatment group (aspirin or placebo). No association was observed for sTNF-R1. The sensitivity and positive predictive values were low for sTNF-R2, as well as sTNF-R1.
An increase in maternal plasma sTNF-R2 concentration precedes clinical manifestation of preeclampsia. These observations demonstrate that levels of proinflammatory cytokines rise well before development of overt disease and could be operative in the pathogenic mechanisms responsible for preeclampsia.
PMCID: PMC2862352  PMID: 19306961
21.  First Trimester Prediction of Early Preeclampsia - a Possibility at Last! 
Hypertension  2009;53(5):747-748.
PMCID: PMC2679993  PMID: 19273735
22.  Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells 
Cancer research  2009;69(7):2887-2895.
The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T cell-dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24−/loCD44+ phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to re-establish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse.
PMCID: PMC2664865  PMID: 19276366
EMT; breast cancer stem cells; generation in vivo; chemoresistance; radioresistance
PMCID: PMC2121665  PMID: 17403396
25.  B cells are important as antigen presenting cells for induction of MHC-restricted arthritis in transgenic mice. 
Molecular immunology  2007;44(11):2988-2996.
Rheumatoid arthritis and its animal model, collagen-induced arthritis, are known as a T and B cell dependent disease. To analyze the role of B cells in arthritis, we generated B cell deficient (muMT) mice carrying HLA-DQ8 as transgene, Aβo.DQ8.μmt mice. HLA-DQ8 transgenic mice (Aβo.DQ8) are susceptible to collagen induced arthritis, an animal model for inflammatory arthritis. Deletion of IgM gene led to the absence of B cells while T cells were comparable to Aβo.DQ8 mice. Arthritis and autoantibodies was completely abrogated in B cell deficient DQ8 mice. T cell response and proinflammatory cytokine production in response to type II collagen and its derived peptides in vitro was significantly decreased despite an increased number of Mac-1 positive cells in DQ8.μmt mice compared to DQ8 mice suggesting B cells could be important for antigen presentation as well. In vitro substitution of B cells from wild type mice restored the response in DQ8.umt mice. B cells could also present CII-derived peptides to antigen-specific DQ8-restricted hybridomas reinforcing the role of B cells in presentation of antigens to T cells. The data suggest that B cells can be involved in pathogenesis of arthritis by producing autoantibodies and antigen presentation.
PMCID: PMC1995074  PMID: 17303243
B cells; transgenic/knockout mice; antigen presentation; rheumatoid arthritis; autoantibodies

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