tbuckley/cabot-search huggingface dataset:
Stromal Cells in Chronic Inflammation and Tertiary Lymphoid Organ Formation
Authors: Christopher D. Buckley, Francesca Barone, Saba Nayar, Cecile Bénézech, Jorge Caamaño
Journal: Annual Review of Immunology (2015)

Inflammation is an unstable state. It either resolves or persists. Why inflammation persists and the factors that define tissue tropism remain obscure. Increasing evidence suggests that tissue-resident stromal cells not only provide positional memory but also actively regulate the differential accumulation of inflammatory cells within inflamed tissues. Furthermore, at many sites of chronic inflammation, structures that mimic secondary lymphoid tissues are observed, suggesting that chronic inflammation and lymphoid tissue formation share common activation programs. Similarly, blood and lymphatic endothelial cells contribute to tissue homeostasis and disease persistence in chronic inflammation. This review highlights our increasing understanding of the role of stromal cells in inflammation and summarizes the novel immunological role that stromal cells exert in the persistence of inflammatory diseases.
Periampullary and duodenal carcinoid tumours
Authors: K. W. Warren, W. M. McDonald, C. J. H. Logan
Journal: Gut (1964)

EDITORIAL SYNOPSIS This is a study of nine patients with this rare tumour involving the duodenum.Radical resection is advocated.The relative rarity of this type of tumour as seen in description of nine patients seen at the Lahey Clinic the collected cases shown in Table I prompts over the years 1954-63.
Infliximab treatment results in significant improvement in the quality of life of patients with severe psoriasis: a double-blind placebo-controlled trial
Authors: S.R. Feldman, K.B. Gordon, M. Bala, R. Evans, S. Li, L.T. Dooley, C. Guzzo, K. Patel, A. Menter, A.B. Gottlieb
Journal: British Journal of Dermatology (2005)

Background Psoriasis is a chronic disease that significantly diminishes the health‐related quality of life (HRQOL). Infliximab is a chimeric, tumour necrosis factor α monoclonal antibody that has been shown to improve the signs and symptoms of plaque psoriasis. Objectives The objective of this study was to evaluate the effect of infliximab induction therapy on the HRQOL of patients with severe plaque psoriasis. Methods In this double‐blind, placebo‐controlled trial, 249 patients were randomly assigned to receive intravenous infusions of 3 or 5 mg kg−1 of infliximab or placebo and were treated at weeks 0, 2 and 6. Patients completed the Dermatology Life Quality Index (DLQI) at baseline and week 10. Results Infliximab induction therapy resulted in a substantial improvement in HRQOL. At week 10, patients in the infliximab 3‐ and 5‐mg kg−1 groups showed a median percentage improvement in DLQI scores of 84·0% and 91·0%, respectively, compared with 0% in the placebo group (P < 0·001). The median decrease from baseline in DLQI score at week 10 was 8·0 and 10·0 for the 3 and 5 mg kg−1 infliximab groups, respectively, compared with 0 in the placebo group (P < 0·001). Thirty‐three per cent and 40% of patients in the 3 and 5 mg kg−1 infliximab groups, respectively, had a DLQI score of 0 at week 10, compared with 2% in the placebo group (P < 0·001). There was a strong correlation between the percentage change from baseline at week 10 in Psoriasis Area and Severity Index (PASI) scores and the percentage change in DLQI scores during the same period (Spearman's correlation, 0·61, P < 0·001). When the infliximab and placebo treatment groups were combined, patients with at least 75% improvement in PASI scores between baseline and week 10 had a greater mean improvement in DLQI scores (81%) than those with 50–75% improvement in PASI during the same period (60%). Conclusions Infliximab induction therapy resulted in significant improvement in HRQOL in patients with severe psoriasis.
Human vascular adhesion protein 1 (VAP-1) is a unique sialoglycoprotein that mediates carbohydrate-dependent binding of lymphocytes to endothelial cells.
Authors: M Salmi, S Jalkanen
Journal: The Journal of Experimental Medicine (1996)

The regulated interactions of leukocytes with vascular endothelial cells are crucial in controlling leukocyte traffic between blood and tissues. Vascular adhesion protein-1 (VAP-1) is a novel, human endothelial cell molecule that mediates tissue-selective lymphocyte binding. Two species (90 and 170 kD) of VAP-1 exist in lymphoid tissues. Glycosidase digestions revealed that the mature 170-kD form of VAP-1 expressed on the lumenal surfaces of vessels is a heavily sialylated glycoprotein. The sialic acids are indispensable for the function of VAP-1, since the desialylated form of VAP-1 no longer mediates lymphocyte binding. We also show that L-selectin is not required for binding of activated lymphocytes to VAP-1 under conditions of shear stress. The 90-kD form of VAP-1 was only seen in an organ culture model, and may represent a monomeric or proteolytic form of the larger species. These data indicate that L-selectin negative lymphocytes can bind to tonsillar venules via the VAP- 1-mediated pathway. Moreover, our findings extend the role of carbohydrate-mediated binding in lymphocyte-endothelial cell interactions beyond the known selectins. In conclusion, VAP-1 naturally exists as a 170-kD sialoglycoprotein that uses sialic acid residues to interact with its counter-receptors on lymphocytes under nonstatic conditions.
Cost-Effective Screening for Diabetic Retinopathy Using a Nonmydriatic Retinal Camera in a Prepaid Health-Care Setting
Authors: Anne L Peters, Mayer B Davidson, Frederick H Ziel
Journal: Diabetes Care (1993)

OBJECTIVE To assess the efficacy of using a nonmydriatic Polaroid retinal camera as a method for screening diabetic patients for treatable diabetic retinopathy. RESEARCH DESIGN AND METHODS All 522 diabetic patients followed in a health maintenance organization-affiliated diabetes program had retinal photos taken. Compliance with the routine referral to one of two retinal specialists (the examiners) was 74%. The results from the examiners were compared with the results of the reader of the retinal photos. RESULTS Sensitivity was 100% and specificity was 82% for the diagnosis of serious diabetic retinopathy (preproliferative or proliferative retinopathy or macular edema) by the examiners compared with the diagnosis of any diabetic retinopathy by the reader. No patient had serious diabetic retinopathy inside or outside the photographic field that was missed because all patients with serious diabetic retinopathy showed some diabetic retinopathy within the photographic field. The reader tended to underrate the severity of the diabetic retinopathy, but when the reader diagnosed serious diabetic retinopathy, it was always present on exam. CONCLUSIONS The nonmydriatic retinal camera is easy to use, inexpensive, and can be used as part of a general diabetes exam, independent of a physician, in patients who should, but may not, be referred to an ophthalmologist. Any patient with abnormal findings on photos should be referred to an ophthalmologist, and any patient with findings of serious diabetic retinopathy on the photos should be referred immediately for possible laser therapy.
Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes
Authors: Peter Gæde, Henrik Lund-Andersen, Hans-Henrik Parving, Oluf Pedersen
Journal: New England Journal of Medicine (2008)

Intensified multifactorial intervention — with tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents — has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes.
Efficacy and duration of action of the antileukotriene zafirlukast on cold air-induced bronchoconstriction
Authors: K. Richter, R.A. Jorres, H Magnussen
Journal: European Respiratory Journal (2000)

The objectives of the study were to assess the magnitude of the effect of the leukotriene receptor antagonist, zafirlukast, against cold air-induced bronchoconstriction following the first dose and to assess magnitude and duration after 5 days of dosing. Nineteen patients with asthma were included. In a randomized cross-over design, either zafirlukast 20 mg or 80 mg b.d. or placebo were given over 5 days. Challenges were performed 3 h post first dose and 3, 8, 12 and 24 h post last dose. The authors assessed the provocative ventilation rate necessary to achieve a 10% (PV10) and 20% (PV20) fall in forced expiratory volume in one second. The median PV20 3 h post first dose was 69.1 L x min-1 for zafirlukast 80 mg compared to 40 L x min-1 for placebo (p=0.004). The corresponding median value for zafirlukast 20 mg was 59.9 L x min-1 (p=0.06). At steady state the differences in PV20, between zafirlukast 80 mg and placebo were significant at 8 h and 12 h post last dose. The corresponding difference for zafirlukast 20 mg was statistically significant at 8 h post last dose. The analysis of PV10 yielded compatible results. There was no significant protection 24 h after last dose. This study has demonstrated that zafirlukast offers significant protection against cold air-induced bronchoconstriction in asthma. The degree and duration of protection were dose-dependent. However, there was a large interindividual variability for the protective effect of this leukotriene receptor antagonist.
Umbilical Cord Blood Transplantation and Banking
Authors: Claudio G. Brunstein, John E. Wagner
Journal: Annual Review of Medicine (2006)

Umbilical cord blood transplantation (UCBT) is an expanding practice for both pediatric and adult patients. Rapid availability, low risk of infectious disease transmission, lower risk of graft-versus-host disease, and lack of risk for the donor makes UCB an attractive alternative source of hematopoietic stem cells for transplantation. We review the state of the art of pediatric and adult UCBT and important aspects of UCB banking. Current strategies to improve clinical results and expand access to UCBT to a larger number of adult patients are discussed. New approaches to enhance hematopoietic recovery by the use of accessory cells or direct intra-bone marrow injection are also reviewed.
In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction.
Authors: F Candotti, S A Oakes, J A Johnston, L D Notarangelo, J J O'Shea, R M Blaese
Journal: The Journal of Experimental Medicine (1996)

Mutations affecting the expression of the Janus family kinase JAK3 were recently shown to be responsible for autosomal recessive severe combined immunodeficiency (SCID). JAK3-deficient patients present with a clinical phenotype virtually indistinguishable from boys affected by X-linked SCID, a disease caused by genetic defects of the common gamma chain (gamma c) that is a shared component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15. The specific interaction of JAK3 and gamma c represents the biochemical basis for the similarities between these two immunodeficiencies. Both forms of SCID are characterized by recurrent, severe infections leading to death in infancy unless successfully treated by allogeneic bone marrow transplantation. Because of the potentially lethal complications associated with allogeneic bone marrow transplantation and the frequent lack of suitable marrow donors, the development of alternative forms of therapy is highly desirable. To this end, we investigated a retroviral-mediated gene correction approach for JAK3-deficiency. A vector carrying a copy of JAK3 cDNA was constructed and used to transduce B cell lines derived from patients with JAK3-deficient SCID. We demonstrate restoration of JAK3 expression and phosphorylation upon IL-2 and IL-4 stimulation. Furthermore, patients' cells transduced with JAK3 acquired the ability to proliferate normally in response to IL-2. These data indicate that the biological defects of JAK3-deficient cells can be efficiently corrected in vitro by retroviral-mediated gene transfer, thus providing the basis for future investigation of gene therapy as treatment for JAK3-deficient SCID.
Apoptosis in rheumatoid arthritis synovium.
Authors: G S Firestein, M Yeo, N J Zvaifler
Journal: Journal of Clinical Investigation (1995)

RA synovial tissue (ST) was studied to determine if and where apoptosis occurs in situ. Genomic DNA was extracted from 5 RA and 1 osteoarthritis ST samples. Agarose gel electrophoresis demonstrated DNA ladders characteristic for apoptosis from each tissue. In situ and labeling (ISEL) was used to identify DNA strand breaks consistent with apoptosis in frozen sections. 12 RA and 4 osteoarthritis ST were studied by ISEL and all were positive, but only 2 of 4 normal tissues were positive. The primary location of apopotic cells was the synovial lining. Some sublining cells were also positive, but lymphoid aggregate staining was conspicuously absent. Immunohistochemistry and ISEL were combined and showed that the lining cells with DNA strand breaks were mainly macrophages, although some fibroblastlike cells were also labeled. Sublining cells with fragmented DNA included macrophages and fibroblasts, but T cells in lymphoid aggregates, which expressed large amounts of bcl-2, were spared. DNA strand breaks in cultured fibroblastlike synoviocytes was assessed using ISEL. Apoptosis could be induced by actinomycin D, anti-fas antibody, IL-1, and TNF-alpha but not by IFN-gamma. Fas expression was also detected on fibroblast-like synoviocytes using flow cytometry. Therefore, DNA strand breaks occur in synovium of patients with arthritis. Cytokines regulate this process, and the cytokine profile in RA (high IL-1/TNF; low IFN-gamma) along with local oxidant injury might favor induction of apoptosis.
Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation
Authors: J. Lazovic, H. Soto, D. Piccioni, J. R. Lo Ru, S. Li, L. Mirsadraei, W. Yong, R. Prins, L. M. Liau, B. M. Ellingson, T. F. Cloughesy, A. Lai, W. B. Pope
Journal: Neuro-Oncology (2012)

The arginine 132 (R132) mutation of isocitrate dehydrogenase -1 (IDH1(R132)) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1(R132), whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1(R132) or IDH1 wild-type (IDH1(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1(R132) showed a resonance at 2.25 ppm corresponding to the 2-HG peak described for human IDH1(R132) gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T(2), apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1(WT) tumors. The IDH1(R132) mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma.
A Sensitized Screen of N-ethyl-N-nitrosourea–Mutagenized Mice Identifies Dominant Mutants Predisposed to Diabetic Nephropathy
Authors: Elena E Tchekneva, Eugene M Rinchik, Dina Polosukhina, Linda S Davis, Veronika Kadkina, Yassir Mohamed, Steve R Dunn, Kumar Sharma, Zhonghua Qi, Agnes B Fogo, Matthew D Breyer
Journal: Journal of the American Society of Nephrology (2006)

Diabetic nephropathy (DN) is a late diabetic complication that comprises progressively increasing albuminuria, declining GFR, and increased cardiovascular risk. Only a minority of patients with diabetes (25 to 40%) develop nephropathy, and there is evidence that heritable genetic factors predispose these "at-risk" individuals to DN. Comparing variability among inbred mouse strains with respect to a specific phenotype can model interhuman variability, and each strain represents a genetically homogeneous system with a defined risk for nephropathy. C57BL/6 mice, which are relatively resistant to DN, were mutagenized using N-ethyl-N-nitrosourea and screened for mutants that developed excess albuminuria on a sensitizing type 1 diabetic background contributed by the dominant Akita mutation in insulin-2 gene (Ins2(Akita)). Two of 375 diabetic G1 founders were found to exhibit albumin excretion rates persistently 10-fold greater than albumin excretion rates in nonmutagenized Ins2(Akita) controls. This albuminuria trait was heritable and transmitted to approximately 50% of Ins2(Akita) G2 and G3 progeny, consistent with a simple, dominantly inherited trait, but was never observed in nondiabetic offspring. During the course of 1 yr, albuminuric Ins2(Akita) G2 and G3 progeny developed reduced inulin clearance with elevated blood urea nitrogen and plasma creatinine. Glomerular histology revealed mesangial expansion, and glomerular basement membrane thickening as determined by electron microscopy was enhanced in diabetic mutant kidneys. Hereditary albuminuric N-ethyl-N-nitrosourea-induced mutants were redesignated as Nphrp1 (nephropathy1) and Nphrp2 (nephropathy2) mice for two generated lines. These novel mutants provide new, robust mouse models of DN and should help to elucidate the underlying genetic basis of predisposition to DN.
Redox-Sensitive Signaling by Angiotensin II Involves Oxidative Inactivation and Blunted Phosphorylation of Protein Tyrosine Phosphatase SHP-2 in Vascular Smooth Muscle Cells From SHR
Authors: Fatiha Tabet, Ernesto L. Schiffrin, Glaucia E. Callera, Ying He, Guoying Yao, Arne Östman, Kai Kappert, Nicholas K. Tonks, Rhian M. Touyz
Journal: Circulation Research (2008)

Angiotensin II (Ang II) signaling in vascular smooth muscle cells (VSMCs) involves reactive oxygen species (ROS) through unknown mechanisms. We propose that Ang II induces phosphorylation of growth signaling kinases by redox-sensitive regulation of protein tyrosine phosphatases (PTP) in VSMCs and that augmented Ang II signaling in spontaneously hypertensive rats (SHRs) involves oxidation/inactivation and blunted phosphorylation of the PTP, SHP-2. PTP oxidation was assessed by the in-gel PTP method. SHP-2 expression and activity were evaluated by immunoblotting and by a PTP activity assay, respectively. SHP-2 and Nox1 were downregulated by siRNA. Ang II induced oxidation of multiple PTPs, including SHP-2. Basal SHP-2 content was lower in SHRs versus WKY. Ang II increased SHP-2 phosphorylation and activity with blunted responses in SHRs. Ang II—induced SHP-2 effects were inhibited by valsartan (AT 1 R blocker), apocynin (NAD(P)H oxidase inhibitor), and Nox1 siRNA. Ang II stimulation increased activation of ERK1/2, p38MAPK, and AKT, with enhanced effects in SHR. SHP-2 knockdown resulted in increased AKT phosphorylation, without effect on ERK1/2 or p38MAPK. Nox1 downregulation attenuated Ang II–mediated AKT activation in SHRs. Hence, Ang II regulates PTP/SHP-2 in VSMCs through AT 1 R and Nox1-based NAD(P)H oxidase via two mechanisms, oxidation and phosphorylation. In SHR Ang II–stimulated PTP oxidation/inactivation is enhanced, basal SHP-2 expression is reduced, and Ang II–induced PTP/SHP-2 phosphorylation is blunted. These SHP-2 actions are associated with augmented AKT signaling. We identify a novel redox-sensitive SHP-2–dependent pathway for Ang II in VSMCs. SHP-2 dysregulation by increased Nox1-derived ROS in SHR is associated with altered Ang II–AKT signaling.
A Comparison of Lithium and T <sub>3</sub> Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report
Authors: Andrew A Nierenberg, Maurizio Fava, Madhukar H Trivedi, Stephen R Wisniewski, Michael E Thase, Patrick J McGrath, Jonathan E Alpert, Diane Warden, James F Luther, George Niederehe, Barry Lebowitz, Kathy Shores-Wilson, A John Rush
Journal: American Journal of Psychiatry (2006)

Objective: More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine (T 3 ) augmentation as a third-step treatment for patients with major depressive disorder. Method: A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 mg/day; N=69) or with T 3 (up to 50 μg/day; N=73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score ≤7 on the 17-item Hamilton Depression Rating Scale. Results: After a mean of 9.6 weeks (SD=5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with T 3 augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p=0.027). Conclusions: Remission rates with lithium and T 3 augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of T 3 augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.
Glucocorticoids Modulate Tumor Radiation Response through a Decrease in Tumor Oxygen Consumption
Authors: Nathalie Crokart, Bénédicte F. Jordan, Christine Baudelet, Gregory O. Cron, Julie Hotton, Kim Radermacher, Vincent Grégoire, Nelson Beghein, Philippe Martinive, Caroline Bouzin, Olivier Feron, Bernard Gallez
Journal: Clinical Cancer Research (2007)

Abstract Purpose: We hypothesized that glucocorticoids may enhance tumor radiosensitivity by increasing tumor oxygenation (pO2) through inhibition of mitochondrial respiration. Experimental Design: The effect of three glucocorticoids (hydrocortisone, dexamethasone, and prednisolone) on pO2 was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO2 (tmax, 30 min after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO2 measurements were done using electron paramagnetic resonance. The oxygen consumption rate of tumor cells after in vivo glucocorticoid administration was measured using high-frequency electron paramagnetic resonance. Tumor perfusion and permeability measurements were assessed by dynamic contrast-enhanced magnetic resonance imaging. Results: All glucocorticoids tested caused a rapid increase in pO2. At tmax, tumor perfusion decreased, indicating that the increase in pO2 was not caused by an increase in oxygen supply. Also at tmax, global oxygen consumption decreased. When irradiation (25 Gy) was applied at tmax, the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7). Conclusion: These results show the potential usefulness of the administration of glucocorticoids before irradiation.