tbuckley/cabot-search huggingface dataset:
Tumor-Infiltrating Lymphocytes Expressing the Tissue Resident Memory Marker CD103 Are Associated with Increased Survival in High-Grade Serous Ovarian Cancer
Authors: John R. Webb, Katy Milne, Peter Watson, Ronald J. deLeeuw, Brad H. Nelson
Journal: Clinical Cancer Research (2013)

The presence of CD8(+) tumor-infiltrating lymphocytes (TIL) is associated with prolonged survival in high-grade serous ovarian cancer (HGSC) and other epithelial cancers. Survival is most strongly associated with intraepithelial versus intrastromal CD8(+) TILs; however, the mechanisms that promote the intraepithelial localization of TILs remain poorly understood. We hypothesized that intraepithelial CD8(+) TILs, like normal mucosal intraepithelial lymphocytes, might express CD103, a subunit of αE/β7 integrin, which binds E-cadherin on epithelial cells.A large collection of primary ovarian tumors (HGSC, endometrioid, mucinous, and clear cell) was analyzed by immunohistochemistry for the presence of TIL-expressing CD103. The activation and differentiation status of CD103(+) TILs were assessed by flow cytometry. The prognostic significance of TIL subsets was evaluated by Kaplan-Meier analysis.CD103(+) TILs were present in all major ovarian cancer subtypes and were most abundant in HGSC. CD103(+) TILs were preferentially localized to epithelial regions of tumors and were comprised predominantly of CD8(+) T cells expressing activation (HLA-DR, Ki-67, PD-1) and cytolytic (TIA-1) markers, as well as CD56(+) NK cells. Tumor infiltration by CD103(+) TILs was strongly associated with patient survival in HGSC. Tumors containing CD8(+) TILs that were CD103(-) showed poor prognosis equivalent to tumors lacking CD8(+) TILs altogether.CD103(+) TILs comprise intraepithelial, activated CD8(+) T cells, and NK cells and are strongly associated with patient survival in HGSC. CD103 may serve as a useful marker for enriching the most beneficial subsets of TILs for immunotherapy.
Bone marrow-derived cells fail to induce positive selection in thymus reaggregation cultures.
Authors: B B Ernst, C D Surh, J Sprent
Journal: The Journal of Experimental Medicine (1996)

The requirements for inducing positive selection of T cells were examined in thymus reaggregation cultures, a system in which dispersed populations of immature CD4+8+ cells and purified thymic epithelial cells (TEC) are reaggregated in tissue culture. Studies with TEC from mice selectively lacking major histocompatibility complex (MHC) class I (I-II+), class II (I+II-), or both class I and II (I-II-) molecules showed that class II expression was essential for the differentiation of CD4+8+ cells into CD4+8- cells. Unexpectedly, the generation of TCRhi CD4-8+ cells from CD4+8+ cells was apparent with I-II+ TEC but not with I-II- TEC, perhaps reflecting cross-reactive specificity of CD4-8+ cells for class II molecules. Significantly, the failure of I-II- TEC to generate TCRhi CD4+8- or CD4-8+ cells could not be overcome by adding MHC+ bone marrow-derived cells. These findings, together with experiments on purified subsets of TEC, suggest that positive selection in thymus reaggregation cultures is an exclusive property of cortical TEC.
A longitudinal study investigating factors associated with changes in lung function over time in early life (age 3 to 11)
Authors: Danielle Belgrave, Lesley Lowe, Angela Simpsonn, Adnan Custovic
Journal: European Respiratory Journal (2011)

Background: Previous studies have investigated factors associated with poor lung function in children. However, these studies use a cross-sectional approach which ignores changes in lung function over time. In this study, we develop multilevel longitudinal models in order to investigate factors affecting developmental change in lung function in early life.

Methods: In a population-based birth cohort 1185 participants were recruited prenatally and followed prospectively (1, 3, 5, 8 and 11 years). At each time point, a validated questionnaire was administered to collect information on asthma-related symptoms, height and weight. We assessed atopy and lung function (Specific Airway Resistance (sRaw), plethysmography) at each follow-up.We use a longitudinal linear mixed models approach to determine predictors of change in sRaw over time.

Results: Univariate longitudinal analyses revealed marked deterioration in sRaw among children who were atopic (mean difference 2.85%, 95% CI 1.05%-9.84%, p=0.003). Children who wheezed also had poorer lung function (mean difference 5.20%, 95% CI 0.87%-2.54%, p<0.001). Boys had poorer lung function compared to girls (mean difference 3.48%, 95% CI 0.87%-6.52%, p=0.03) and also had a higher rate of deterioration of sRaw over time which increased by 0.011 units (p=0.012) per year. In a multivariate longitudinal model, the factors which best predicted diminished lung function were atopy, increased BMI, paternal atopy, gender and current wheeze.

Conclusion: Multilevel longitudinal models allow us to predict factors associated with diminished lung function as well as factors associated with change in lung function over time.
Admission to Hospitals With On-Site Cardiac Catheterization Facilities
Authors: Harlan M. Krumholz, Jersey Chen, Jaime E. Murillo, David J. Cohen, Martha J. Radford
Journal: Circulation (1998)

Background —Admission to a hospital with a capability for cardiac procedures is associated with a higher likelihood of referral for a cardiac procedure but not with a better short-term clinical outcome. Whether there are differences in long-term mortality and resource consumption is not clear. We sought to determine whether elderly Medicare patients with acute myocardial infarction admitted to hospitals with on-site cardiac catheterization facilities have lower long-term hospital costs and better outcomes than patients admitted to hospitals without such facilities. Methods and Results —As part of the Cooperative Cardiovascular Project pilot in Connecticut, we conducted a retrospective cohort study using data from medical charts and administrative files. The study sample included 2521 patients with acute myocardial infarction covered by Medicare from 1992 to 1993. The cardiac catheterization rate was higher in the hospitals with facilities (38.6% versus 26.9%; P &lt;0.001), but the revascularization rate was similar (20.5% versus 19.5%) during the initial episode of care and at 3 years (29.7% versus 29.7%). Mortality rates were similar for patients admitted to the 2 types of hospitals at 30 days (OR, 1.08; 95% CI, 0.83 to 1.42) and at 3 years (OR, 1.02; 95% CI, 0.83 to 1.26). The adjusted readmission rates were significantly lower among patients admitted to hospitals with cardiac catheterization facilities (OR, 0.76; 95% CI, 0.61 to 0.94). However, the overall mean days in the hospital for the 3 years after admission was 25.9 for patients admitted to hospitals with facilities and 24.6 for the other patients ( P =0.234). Adjusting for baseline patient characteristics, there was no significant difference in the 3-year costs between patients admitted to the 2 types of hospitals. Conclusions —With higher rates of cardiac catheterization and lower readmission rates, patients admitted to hospitals with on-site cardiac catheterization facilities did not have significantly different hospital costs compared with patients admitted to hospitals without these facilities. There was also no significant difference in short- or long-term mortality rates.
Phase I Study of 506U78 Administered on a Consecutive 5-Day Schedule in Children and Adults With Refractory Hematologic Malignancies
Authors: J. Kurtzberg, T.J. Ernst, M.J. Keating, V. Gandhi, J.P. Hodge, D.F. Kisor, J.J. Lager, C. Stephens, J. Levin, T. Krenitsky, G. Elion, B.S. Mitchell
Journal: Journal of Clinical Oncology (2005)

Purpose A phase I study was conducted to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of a novel purine nucleoside, nelarabine, a soluble prodrug of 9-beta-D-arabinosylguanine (araG; Nelarabine), in pediatric and adult patients with refractory hematologic malignancies. Patients and Methods Between April 1994 and April 1997, 93 patients with refractory hematologic malignancies were treated with one to 16 cycles of study drug. Nelarabine was administered daily, as a 1-hour intravenous infusion for 5 consecutive days, every 21 to 28 days. First-cycle pharmacokinetic data, including plasma nelarabine and araG levels, were obtained on all patients treated. Intracellular phosphorylation of araG was studied in samples of leukemic blasts from selected patients. Results The MTDs were defined at 60 mg/kg/dose and 40 mg/kg/dose daily × 5 days in children and adults, respectively. Dose-limiting toxicity (DLT) was neurologic in both children and adults. Myelosuppression and other significant organ toxicities did not occur. Pharmacokinetic parameters were similar in children and adults. Accumulation of araGTP in leukemic blasts was correlated with cytotoxic activity. The overall response rate was 31%. Major responses were seen in patients with T-cell malignancies, with 54% of patients with T-lineage acute lymphoblastic leukemia achieving a complete or partial response after one to two courses of drug. Conclusion Nelarabine is a novel nucleoside with significant cytotoxic activity against malignant T cells. DLT is neurologic. Phase II and III trials in patients with T-cell malignancies are encouraged.
Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation
Authors: Alvaro Alonso, Faye L. Lopez, Kunihiro Matsushita, Laura R. Loehr, Sunil K. Agarwal, Lin Y. Chen, Elsayed Z. Soliman, Brad C. Astor, Josef Coresh
Journal: Circulation (2011)

Chronic kidney disease is associated with the incidence of cardiovascular disease. Chronic kidney disease may also increase the risk of atrial fibrillation (AF), but existing studies have reported inconsistent results. We estimated cystatin C-based glomerular filtration rate (eGFR(cys)) and measured urinary albumin-to-creatinine ratio (ACR) in 10 328 men and women free of AF from the Atherosclerosis Risk in Communities (ARIC) Study in 1996 to 1998. Incidence of AF was ascertained through the end of 2007. During a median follow-up of 10.1 years, we identified 788 incident AF cases. Compared with individuals with eGFR(cys) ≥90 mL · min(-1) · 1.73 m(-2), multivariable hazard ratios and 95% confidence intervals (CIs) of AF were 1.3 (95% CI, 1.1 to 1.6), 1.6 (95% CI, 1.3 to 2.1), and 3.2 (95% CI, 2.0 to 5.0; P for trend <0.0001) in those with eGFR(cys) of 60 to 89, 30 to 59, and 15 to 29 mL · min(-1) · 1.73 m(-2), respectively. Similarly, the presence of macroalbuminuria (ACR ≥300 mg/g; hazard ratio, 3.2; 95% CI, 2.3 to 4.5) and microalbuminuria (ACR, 30 to 299 mg/g; hazard ratio, 2.0; 95% CI, 1.6 to 2.4) was associated with higher AF risk compared with those with ACR <30 mg/g. Risk of AF was particularly elevated in those with both low eGFR(cys) and macroalbuminuria (hazard ratio, 13.1; 95% CI, 6.0 to 28.6, comparing individuals with ACR ≥300 mg/g and eGFR(cys) of 15 to 29 mL · min(-1) · 1.73 m(-2) and those with ACR <30 mg/g and eGFR(cys) ≥90 mL · min(-1) · 1.73 m(-2)). In this large population-based study, reduced kidney function and presence of albuminuria were strongly associated with the incidence of AF independently of other risk factors.
Clinical profiling of recombinant follicle stimulating hormone (rFSH; Puregon): relationship between serum FSH and efficacy
Authors: B. Mannaerts
Journal: Human Reproduction Update (1996)

Single-dose and multiple-rising dose studies of recombinant follicle stimulating hormone (rFSH) in hypogonadotrophic male and female volunteers demonstrated that the rate of FSH absorption after i.m. injection is higher in men than in women. In the absence of endogenous FSH, a correlation between serum FSH and body weight became apparent. The elimination half-life of rFSH was not different between the sexes and was comparable with urinary FSH. However, the in-vitro bio:immuno ratio of serum FSH was significantly higher after the administration of rFSH than after urinary FSH. When rFSH was administered daily with a fixed dose, steady state levels were reached within 3-5 days. Serum FSH concentrations increased in a dose-dependent manner when the daily dose was increased weekly over 3 weeks from 75 to 225 IU. In hypogonadotrophic women, rFSH induced normal follicular growth whereas oestrogen synthesis was impaired. In women pituitary suppressed by a high-dose oral contraceptive, the daily administration of 150 IU rFSH for 1 week induced more and larger antral follicles than the same regimen with urinary FSH, whereas the serum immunoactive FSH concentrations measured 24 h after each dosing were similar. It is concluded that even though equal or lower serum immunoactive FSH concentrations were obtained following the administration of rFSH compared with urinary FSH, circulating bioactivity FSH concentrations were higher. Therefore, the conventional idea that serum immunoreactive FSH correlates positively with the magnitude of the ovarian response should be reconsidered.
Macrophages induce an allergen-specific and long-term suppression in a mouse asthma model
Authors: J. L. M. Vissers
Journal: European Respiratory Journal (2005)

Increasing evidence suggests that macrophages (Mphi) play a crucial downregulatory role in the initiation and progression of allergic asthma. Recently, the current authors demonstrated that ovalbumin (OVA)-loaded Mphi (OVA-Mphi) suppress subsequent OVA-induced airway manifestations of asthma and that this effect could be potentiated upon selective activation. In the present study, the authors further delineated the underlying pathway by which Mphi exert this immunosuppressive effect. To examine the migration of OVA-Mphi, cells were labelled with 5'chloromethylfluorescein diacetate (CMFDA) and were administered (i.v.) into OVA-sensitised BALB/c mice. After 20 h, the relevant organs were dissected and analysed using fluorescent microscopy. Allergen-specificity was investigated by treating OVA-sensitised mice with keyhole limpet haemocyanin (KLH)-Mphi activated with immunostimulatory sequence oligodeoxynucleotide (ISS-ODN). By lengthening the period between treatment and challenge to 4 weeks it was examined whether OVA-Mphi exerted an immunosuppressive memory response. Strikingly, CMFDA-labelled Mphi were not trapped in the lungs, but migrated to the spleen. ISS-ODN-stimulated KLH-Mphi failed to suppress OVA-induced airway manifestations of asthma. Moreover, treatment with ISS-ODN-stimulated OVA-Mphi was still effective after lengthening the period between treatment and challenge. These data demonstrate that allergen-loaded macrophages can induce an indirect immunosuppressive response that is allergen-specific and long lasting, which are both hallmarks of a memory lymphocyte response.
Improved transduction of human sheep repopulating cells by retrovirus vectors pseudotyped with feline leukemia virus type C or RD114 envelopes
Authors: M. Lee Lucas, Nancy E. Seidel, Christopher D. Porada, John G. Quigley, Stacie M. Anderson, Harry L. Malech, Janis L. Abkowitz, Esmail D. Zanjani, David M. Bodine
Journal: Blood (2005)
Rapid Interferon γ–dependent Clearance of Influenza A Virus and Protection from Consolidating Pneumonitis in Nitric Oxide Synthase 2–deficient Mice
Authors: Gunasegaran Karupiah, Jian-He Chen, Surendran Mahalingam, Carl F. Nathan, John D. MacMicking
Journal: The Journal of Experimental Medicine (1998)

Viral infection often activates the interferon (IFN)-gamma-inducible gene, nitric oxide synthase 2 (NOS2). Expression of NOS2 can limit viral growth but may also suppress the immune system and damage tissue. This study assessed each of these effects in genetically deficient NOS2(-/-) mice after infection with influenza A, a virus against which IFN-gamma has no known activity. At inocula sufficient to cause consolidating pneumonitis and death in wild-type control mice, NOS2(-/-) hosts survived with little histopathologic evidence of pneumonitis. Moreover, they cleared influenza A virus from their lungs by an IFN-gamma-dependent mechanism that was not evident in wild-type mice. Even when the IFN-gamma-mediated antiviral activity was blocked in NOS2(-/-) mice with anti-IFN-gamma mAb, such mice failed to succumb to disease. Further evidence that this protection was independent of viral load was provided by treating NOS2(+/+) mice with the NOS inhibitor, Nomega-methyl-L-arginine (L-NMA). L-NMA prevented mortality without affecting viral growth. Thus, host NOS2 seems to contribute more significantly to the development of influenza pneumonitis in mice than the cytopathic effects of viral replication. Although NOS2 mediates some antiviral effects of IFN-gamma, during influenza infection it can suppress another IFN-gamma-dependent antiviral mechanism. This mechanism was observed only in the complete absence of NOS2 activity and appeared sufficient to control influenza A virus growth in the absence of changes in cytotoxic T lymphocyte activity.
Mechanisms responsible for the heterogeneous coronary microvascular response to nitroglycerin.
Authors: M A Kurz, K G Lamping, J N Bates, C L Eastham, M L Marcus, D G Harrison
Journal: Circulation Research (1991)

Nitroglycerin dilates large (greater than or equal to 100 microns) but not small coronary arterial microvessels, and a putative metabolite of nitroglycerin, S-nitroso-L-cysteine, has been shown in vitro to dilate both large and small coronary microvessels. Based on this evidence, we tested the hypothesis that the lack of response of small coronary microvessels was due to an inability of small coronary microvessels to convert nitroglycerin into its vasoactive metabolite and examined possible explanations for this phenomenon. We studied left ventricular epicardial microvessels in vivo using video microscopy and stroboscopic epi-illumination in anesthetized, open-chest dogs. Diameters were determined while the epicardium was suffused with nitroglycerin, S-nitroso-L-cysteine, or S-nitroso-D-cysteine (all 10 microM) and nitroglycerin in the presence of L- or D-cysteine (100 microM). None of the agents affected systemic hemodynamics. Nitroglycerin dilated large arterioles (20 +/- 2%) but not small arterioles (1 +/- 1%). Both S-nitroso-L-cysteine and S-nitroso-D-cysteine were potent dilators of all size classes of microvessels. Concomitant application of L-cysteine and nitroglycerin evoked dilation in small microvessels (22 +/- 4%, p less than 0.5 versus nitroglycerin alone) and larger microvessels (27 +/- 6%, p = NS versus nitroglycerin alone). D-Cysteine did not alter the microvascular response to nitroglycerin in either small (7 +/- 4%, p = NS versus nitroglycerin alone) or large (18 +/- 3%, p = NS versus nitroglycerin alone) microvessels. Neither L-cysteine nor D-cysteine had a direct effect on microvascular diameter. These findings suggest that 1) sulfhydryl groups are required for the conversion of nitroglycerin to its vasoactive metabolite; 2) the interaction between nitroglycerin and sulfhydryl residues is a stereospecific process, indicating either an intracellular mechanism or a membrane-associated enzymatic reaction; and 3) a lack of available sulfhydryl groups may be responsible for the lack of response of small coronary arterioles to nitroglycerin.
Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study
Authors: G Greub, B Ledergerber, M Battegay, P Grob, L Perrin, H Furrer, P Burgisser, P Erb, K Boggian, J-C Piffaretti, B Hirschel, P Janin, P Francioli, M Flepp, A Telenti
Journal: The Lancet (2000)
Immune Parameters in High-risk Atopic Individuals during Early Childhood
Authors: HUUB F. J. SAVELKOUL
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The profile of cytokine production by peripheral blood mononuclear cells (PBMCs) from patients with bronchial asthma on stimulation with house dust mite was demonstrated to be compatible with that of helper T type 2 (Th2) cells (1). The number of Th2 cells was also shown to be increased in bronchial tissue and bronchoalveolar lavage fluid of patients with bronchial asthma. Also, the recruitment of allergen-specific Th2 cells from the peripheral blood into the bronchial tissue after an inhalant allergen challenge was demonstrated. Allergic asthma is therefore considered a Th2-driven disease in which the presence of Th2 cells correlates with IgE production, mast cell hyperplasia, and eosinophil infiltration, determining the severity of the disease (2). The Th2-derived cytokine interleukin 5 (IL-5) is a crucial cytokine, which accounts for the recruitment and activation of eosinophils, resulting in airway eosinophilia in patients with allergy (3). In animal models, depletion of CD4 1 T cells results in abrogation of airway eosinophilia and in subsequent reduction of airway hyperresponsiveness. Similarly, elevated IL-4-induced serum levels of IgE and allergen-specific IgE levels as observed in patients with atopic allergy can be explained in terms of excessive Th2 activation. Many, but not all, the pleiotropic effects of IL-4, which are of importance in allergic diseases, can be inhibited by interferon g (IFNg ). Thus, the balance between Th1/Th2 activation is generally established by determining the ratio between IL-4 and IFNg produced by activated PBMCs or purified T cells.
Gene Expression Analysis Identifies Potential Biomarkers of Neurofibromatosis Type 1 Including Adrenomedullin
Authors: Trent R. Hummel, Walter J. Jessen, Shyra J. Miller, Lan Kluwe, Victor F. Mautner, Margaret R. Wallace, Conxi Lázaro, Grier P. Page, Paul F. Worley, Bruce J. Aronow, Elizabeth K. Schorry, Nancy Ratner
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Plexiform neurofibromas (pNF) are Schwann cell tumors found in a third of individuals with neurofibromatosis type 1 (NF1). pNF can undergo transformation to malignant peripheral nerve sheath tumors (MPNST). There are no identified serum biomarkers of pNF tumor burden or transformation to MPNST. Serum biomarkers would be useful to verify NF1 diagnosis, monitor tumor burden, and/or detect transformation. Experimental Design: We used microarray gene expression analysis to define 92 genes that encode putative secreted proteins in neurofibroma Schwann cells, neurofibromas, and MPNST. We validated differential expression by quantitative reverse transcription-PCR, Western blotting, and ELISA assays in cell conditioned medium and control and NF1 patient sera. Results: Of 13 candidate genes evaluated, only adrenomedullin (ADM) was confirmed as differentially expressed and elevated in serum of NF1 patients. ADM protein concentrati on was further elevated in serum of a small sampling of NF1 patients with MPNST. MPNST cell conditioned medium, containing ADM and hepatocyte growth factor, stimulated MPNST migration and endothelial cell proliferation. Conclusions: Thus, microarray analysis identifies potential serum biomarkers for disease, and ADM is a serum biomarker of NF1. ADM serum levels do not seem to correlate with the presence of pNFs but may be a biomarker of transformation to MPNST. Clin Cancer Res; 16(20); 5048–57. ©2010 AACR.