tbuckley/cabot-search huggingface dataset:
Expression of HCLCA1 in cystic fibrosis lungs is associated with mucus overproduction
Authors: H.P. Hauber, A. Tsicopoulos, B. Wallaert, S. Griffin, N.G. McElvaney, P. Daigneault, Z. Mueller, R. Olivenstein, K.J. Holroyd, R.C. Levitt, Q. Hamid
Journal: European Respiratory Journal (2004)

Mucus overproduction is typical in cystic fibrosis (CF) airway disease. The human calcium-activated chloride channel, hCLCA1, has been reported to be upregulated by interleukin (IL)-9 and to regulate the expression of mucins. Therefore, the expression of IL-9, IL-9 receptor (IL-9R) and hCLCA1 between the lungs of CF patients and healthy control subjects was compared. Endoscopic biopsy samples of bronchial mucosa from 10 CF patients and six control subjects were stained with periodic acid-Schiff. IL-9, IL-9R and hCLCA1 expression was determined by immunocytochemistry. Expression of hCLCA1 mRNA was also determined by in situ hybridisation. The present study found significant increases in IL-9, IL-9R and hCLCA1 immunoreactivity, hCLCA1 mRNA expression, and numbers of mucus-producing cells in the mucosa of CF patients compared to control subjects. Positive correlations were found between IL-9R-positive-cells with IL-9-positive cells and hCLCA1-positive cells, and between PAS-positive cells with hCLCA1-positive cells and IL-9R-positive cells. Expression of hCLCA1 mRNA was colocalised with IL-9R expression and PAS-positive staining in epithelial cells. Increased expression of interleukin-9 and interleukin-9 receptor, as well as an upregulation of the human calcium-activated chloride channel, hCLCA1, in mucus-producing epithelium of cystic fibrosis patients, support the hypothesis that interleukin-9 contributes to mucus overproduction in cystic fibrosis airway disease.
Diagnostic Procedures in Patients With Superior Vena Cava Syndrome
Authors: Alvin S. Teirstein
Journal: JAMA (1981)

Understandably, the swollen plethoric face, the conjunctival edema of chemosis, and the distended neck veins and collaterals that indicate superior vena cava syndrome (SVCS) provoke visions of impending catastrophe. Usually, the radiotherapist or oncologist is summoned to administer emergency treatment, frequently in patients without a proved diagnosis of neoplastic disease. Thereafter, diagnostic procedures may be complicated by radiation reaction, and tissue alterations owing to cytotoxic therapy may impair histological interpretation. If the same patient had presented with a mediastinal mass, but no SVCS, his physician would have embarked on a careful plan of investigation. Perhaps he would employ one or more radiological and radionuclide procedures, but eventually a biopsy would be performed to establish specific histological diagnosis. At least 50% of all patients with SVCS have primary carcinoma of the lung (increasingly, small cell carcinoma). Approximately 15% have lymphoma, 15% have other malignant neoplasms, and 15% have benign disease such
Inactivation of the Quinone Oxidoreductases NQO1 and NQO2 Strongly Elevates the Incidence and Multiplicity of Chemically Induced Skin Tumors
Authors: Jun Shen, Roberto J. Barrios, Anil K. Jaiswal
Journal: Cancer Research (2010)

The cytosolic quinone oxidoreductases NQO1 and NQO2 protect cells against oxidative stress by detoxifying quinones and preventing redox cycling. In this study, we used double knockout (DKO) mice deficient for NQO1 and NQO2 to investigate the role of these antioxidative enzymes in a two-stage model of inflammatory skin carcinogenesis. In this model, tumors are caused by exposure to topical carcinogen dimethylbenz(a)anthracene or benzo(a)pyrene (BP) followed by twice weekly application of proinflammatory phorbol 12-myristate 13-acetate. On this classic chemical carcinogenesis protocol, DKO mice showed a significantly higher skin tumor frequency and multiplicity compared with control wild-type or single knockout mice. Analysis of skin from wild-type and DKO mice exposed to BP for 6, 12, or 24 hours revealed a relative delay in the activation of p53, p63, p19ARF, and apoptosis in DKO mice, consistent with a negative modifier role for NQO1/NQO2 in carcinogenesis. Our findings offer genetic evidence of the significance of quinone oxidoreductases NQO1 and NQO2 in limiting chemical skin carcinogenesis.
Targeting canine bladder transitional cell carcinoma with a human bladder cancer-specific ligand
Authors: Tzu-yin Lin, Hongyong Zhang, Sisi Wang, Li Xie, Bin Li, Carlos O Rodriguez, Ralph de Vere White, Chong-xian Pan
Journal: Molecular Cancer (2011)

Abstract Objective To determine if a human bladder cancer-specific peptide named PLZ4 can target canine bladder cancer cells. Experimental Design The binding of PLZ4 to five established canine invasive transitional cell carcinoma (TCC) cell lines and to normal canine bladder urothelial cells was determined using the whole cell binding assay and an affinitofluorescence assay. The WST-8 assay was performed to determine whether PLZ4 affected cell viability. In vivo tumor-specific homing/targeting property and biodistribution of PLZ4 was performed in a mouse xenograft model via tail vein injection and was confirmed with ex vivo imaging. Results PLZ4 exhibited high affinity and specific dose-dependent binding to canine bladder TCC cell lines, but not to normal canine urothelial cells. No significant changes in cell viability or proliferation were observed upon incubation with PLZ4. The in vivo and ex vivo optical imaging study showed that, when linked with the near-infrared fluorescent dye Cy5.5, PLZ4 substantially accumulated at the canine bladder cancer foci in the mouse xenograft model as compared to the control. Conclusions and Clinical Relevance PLZ4 can specifically bind to canine bladder cancer cells. This suggests that the preclinical studies of PLZ4 as a potential diagnostic and therapeutic agent can be performed in dogs with naturally occurring bladder cancer, and that PLZ4 can possibly be developed in the management of canine bladder cancer.
INFLAMMATORY HEART DISEASE: Pathogenesis, Clinical Manifestations, and Treatment of Myocarditis
Authors: Kurt D. Olinde, M.D, John B. O'Connell, M.D
Journal: Annual Review of Medicine (1994)

▪ Abstract Myocarditis is an uncommon cause of cardiac disease that can result in arrhythmia, congestive heart failure, and death. Myocardial injury in myocarditis is due in part to activated cellular and humoral immune components directed toward normal cardiac tissue. Although numerous therapies for myocarditis, including corticosteroids and immunosuppressive agents, have been applied in animal experiments and in human studies, none have demonstrated survival benefit over untreated controls. In many patients, myocarditis may spontaneously resolve. Information about myocarditis pathogenesis, manifestations, and treatment has been useful in disease management. Further research into the inflammatory nature of myocarditis may provide the basis for more favorable outcomes of intervention in this disease.
Chemokines and asthma: redundancy of function or a coordinated effort?
Authors: Nicholas W. Lukacs, Sandra H.P. Oliveira, Cory M. Hogaboam
Journal: Journal of Clinical Investigation (1999)

Peribronchial inflammation (1–3) and exaggerated bronchospastic responses to antigen-specific and nonspecific stimuli (airways hyperresponsiveness [AHR]) are the pathologic and physiologic cornerstones of the asthmatic syndrome. Eosinophils are believed to play an important role in these responses, as tissue eosinophilia is a common feature in asthmatic airways, and eosinophils have been demonstrated to cause mucosal injury and likely contribute to the generation of altered lung physiology. The initiation and maintenance of allergic airway inflammation is mediated by poorly defined mechanisms. Even more confounding is the appreciation that different immunologic processes mediate different facets of asthma and that various types of inflammatory responses differentially contribute to the multiple features manifested by asthmatic patients. This is reflected in studies that suggest that, in addition to eosinophils, other cells — including mast cells, lymphocytes, and neutrophils — contribute to asthma pathogenesis (4–6). As a result, it has been difficult to design specific, inflammation-based therapeutic interventions for this disorder. Recent studies, however, have added to our understanding of the role of chemokines and chemokine receptors in the generation of eosinophilic and noneosinophilic airway inflammatory responses. This has begun to provide an appreciation of the complex levels of organization of airway inflammatory responses, and may help to identify novel therapeutic options.
Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization
Authors: Beatrice Bornholz, Stefanie Weidtkamp-Peters, Stephanie Schmitmeier, Claus A. M. Seidel, Lars R. Herda, Stephan B. Felix, Horst Lemoine, Jürgen Hescheler, Filomain Nguemo, Christoph Schäfer, Morten O. Christensen, Christian Mielke, Fritz Boege
Journal: Cardiovascular Research (2012)

Autoantibodies against second extracellular loops of β1-adrenergic receptors frequent in dilated cardiomyopathy confer myocardial dysfunction presumably via cAMP stimulation. Here, we investigate the autoantibody impact on receptor conformation and function. IgG was prepared from patients with dilated cardiomyopathy, matched healthy donors (10 each) or commercial IgG preparations (2). IgG binding to β1-adrenergic receptor peptides was detected in 5 of 10 patients and 2 of 10 controls. IgG colocalization with the native receptor was detected in 8 of 10 patients and 1 of 10 controls (10 of 10 patients and 7 of 10 controls at >30 mg IgG/L). All IgGs exhibiting receptor colocalization triggered changes in receptor conformation (determined with fluorescent sensors) not stringently correlated to cAMP stimulation, suggesting the induction of more or less active receptor conformations. Receptor-activating IgG was detected in 8 of 10 patients but only 1 of 10 controls. In addition, IgG from 8 of 10 patients and 3 of 10 controls attenuated receptor internalization (measured by total internal reflection fluorescence microscopy). IgG-inducing inactive receptor conformations had no effect on subsequent cAMP stimulation by isoproterenol. IgG-inducing active receptor conformations dampened or augmented subsequent cAMP stimulation by isoproterenol, depending on whether receptor internalization was attenuated or not. Corresponding IgG effects on the basal beating rate and chronotropic isoproterenol response of embryonic human cardiomyocytes were observed. (i) Autoantibodies trigger conformation changes in the β1-adrenergic receptor molecule. (ii) Some also attenuate receptor internalization. (iii) Combinations thereof increase the basal beating rate of cardiomyocytes and optionally entail dampening of their chronotropic catecholamine responses. (iv) The latter effects seem specific for patient autoantibodies, which also have higher levels.
Investigation of Cortical Thickness Abnormalities in Lithium-Free Adults With Bipolar I Disorder Using Cortical Pattern Matching
Authors: Lara C. Foland-Ross, Paul M. Thompson, Catherine A. Sugar, Sarah K. Madsen, Jim K. Shen, Conor Penfold, Kyle Ahlf, Paul E. Rasser, Jeffrey Fischer, Yilan Yang, Jennifer Townsend, Susan Y. Bookheimer, Lori L. Altshuler
Journal: American Journal of Psychiatry (2011)

Although several lines of evidence implicate gray matter abnormalities in the prefrontal cortex and anterior cingulate cortex in patients with bipolar disorder, findings have been largely inconsistent across studies. Differences in patients' medication status or mood state or the application of traditional volumetric methods that are insensitive to subtle neuroanatomical differences may have contributed to variations in findings. The authors used MRI in conjunction with cortical pattern matching methods to assess cortical thickness abnormalities in euthymic bipolar patients who were not receiving lithium treatment.Thirty-four lithium-free euthymic patients with bipolar I disorder and 31 healthy comparison subjects underwent MRI scanning. Data were processed to measure cortical gray matter thickness. Thickness maps were spatially normalized using cortical pattern matching and were analyzed to assess illness effects and associations with clinical variables.Relative to healthy comparison subjects, euthymic bipolar patients had significantly thinner gray matter in the left and right prefrontal cortex (Brodmann's areas 11, 10, 8, and 44) and the left anterior cingulate cortex (Brodmann's areas 24/32). Thinning in these regions was more pronounced in patients with a history of psychosis. No areas of thicker cortex were detected in bipolar patients relative to healthy comparison subjects.Using a technique that is highly sensitive to subtle neuroanatomical differences, significant regional cortical thinning was found in lithium-free euthymic patients with bipolar disorder.
SELECTIVE REVERSIBLE INHIBITION OF MICROBIAL GROWTH WITH PYRITHIAMINE
Authors: D. W. Woolley, A. G. C. White
Journal: The Journal of Experimental Medicine (1943)

Growth of many microbial species was inhibited by pyrithiamine, the pyridine analog of thiamine. Growth of many other species was not influenced. In a series of bacteria, yeasts, and molds, it was found that inhibition of growth occurred only in those in which growth was stimulated by thiamine or its component pyrimidine and thiazole portions. The amount of pyrithiamine required for inhibition was correlated with the type of thiamine requirements of various species. The least amount was needed to inhibit organisms which required intact thiamine. Those which could use the pyrimidine and thiazole portions were not so readily inhibited. In the case of the former organisms, half maximal inhibition was produced by as little as 0.03 gamma per cc. In all instances, the inhibition was overcome by sufficient amounts of thiamine. The synthesis of thiamine by insusceptible species was studied, and it was concluded that formation of thiamine or other antagonistic substance did not provide an adequate explanation of the resistance of these species to the action of pyrithiamine.
Natural History of Kidney Graft Survival, Hypertrophy, and Vascular Function in End-Stage Renal Disease Type 1 Diabetic Kidney-Transplanted Patients
Authors: Paolo Fiorina, Massimo Venturini, Franco Folli, Claudio Losio, Paola Maffi, Claudia Placidi, Stefano La Rosa, Elena Orsenigo, Carlo Socci, Carlo Capella, Alessandro Del Maschio, Antonio Secchi
Journal: Diabetes Care (2005)

OBJECTIVE—Diabetes, hypertension, infections, and nephrotoxicity of certain immunosuppressive drugs (i.e., calcineurin inhibitors) can reduce functional survival of the kidney graft. Our aim was to evaluate survival, hypertrophy, and vascular function of the kidney graft in end-stage renal disease (ESRD) type 1 diabetic patients after transplant. RESEARCH DESIGN AND METHODS—The study population consisted of 234 ESRD type 1 diabetic patients who underwent kidney-pancreas (KP; 166 patients), successful kidney-islet (KI-s; 24 patients), and kidney (KD; 44 patients) transplant. Kidney size, graft survival, vascular function, and microalbuminuria were evaluated prospectively yearly for 6 years. Sixty-eight protocol kidney biopsies were performed routinely between 1993 and 1998 cross-sectionally (3.2 ± 0.3 years from kidney transplant). RESULTS—The KP and KI-s groups had better cumulative kidney graft survival at 6 years than did the KD group (KP: 73%; KI-s: 86%; KD: 42%, P &amp;lt; 0.01). The KP group but not the KI-s/KD groups showed a persistent kidney graft hypertrophy up to 6 years of follow-up. A significant increase in creatinine levels from baseline to year 6 was evident in the KD group (1.58 ± 0.08 to 2.78 ± 0.44 mg/dl, P &amp;lt; 0.05) but not in the KP/KI-s groups. The KP/KI-s groups only showed a reduction of renal resistance index from baseline to year 6 (KP at baseline: 0.74 ± 0.01 to 0.68 ± 0.01%, P &amp;lt; 0.01; KI-s at baseline: 0.72 ± 0.02 to 0.69 ± 0.02%, P &amp;lt; 0.05). At year 6, an increase from baseline in urinary albumin excretion was observed only in the KD group (31.4 ± 9.0 to 82.9 ± 33.6 mg/l, P &amp;lt; 0.05). Preliminary data suggested that graft nitric oxide (NO) expression was higher in the KP/KI-s groups than in the KD group (data not shown). CONCLUSIONS—In ESRD type 1 diabetic patients, KP and KI-s compared with KD resulted in enhanced kidney graft survival, hypertrophy, and vascular function.
A subset of dendritic cells induces CD4+ T cells to produce IFN-γ by an IL-12–independent but CD70-dependent mechanism in vivo
Authors: Helena Soares, HaeNa Waechter, Nicholas Glaichenhaus, Evelyne Mougneau, Hideo Yagita, Olga Mizenina, Diana Dudziak, Michel C. Nussenzweig, Ralph M. Steinman
Journal: The Journal of Experimental Medicine (2007)

Interferon (IFN)-γ, a cytokine critical for resistance to infection and tumors, is produced by CD4+ helper T lymphocytes after stimulation by cultured dendritic cells (DCs) that secrete a cofactor, interleukin (IL)-12. We have identified a major IL-12–independent pathway whereby DCs induce IFN-γ–secreting T helper (Th)1 CD4+ T cells in vivo. This pathway requires the membrane-associated tumor necrosis family member CD70 and was identified by targeting the LACK antigen from Leishmania major within an antibody to CD205 (DEC-205), an uptake receptor on a subset of DCs. Another major DC subset, targeted with 33D1 anti-DCIR2 antibody, also induced IFN-γ in vivo but required IL-12, not CD70. Isolated CD205+ DCs expressed cell surface CD70 when presenting antigen to T cell receptor transgenic T cells, and this distinction was independent of maturation stimuli. CD70 was also essential for CD205+ DC function in vivo. Detection of the IL-12–independent IFN-γ pathway was obscured with nontargeted LACK, which was presented by both DC subsets. This in situ analysis points to CD70 as a decision maker for Th1 differentiation by CD205+ DCs, even in Th2-prone BALB/c animals and potentially in vaccine design. The results indicate that two DC subsets have innate propensities to differentially affect the Th1/Th2 balance in vivo and by distinct mechanisms.
Medical students' knowledge of smoking
Authors: M B ALLEN
Journal: Thorax (1999)

Smoking has a huge impact on health care provision, an estimated additional £1.4 billion being spent annually on smoking related diseases in Britain.1 This will continue to rise with the suggested improvements in lung cancer care2 and the estimated increased morbidity due to COPD.3 Helping people to stop smoking will clearly reduce the impact of these and other smoking related diseases, but how is this best achieved? Evidence suggests that advice and support from the primary care doctor to individuals who are contemplating stopping is the simplest and most cost effective method,2 4 5 though the newly published smoking cessation guidelines6 also describe …
MicroRNA expressions associated with progression of prostate cancer cells to antiandrogen therapy resistance
Authors: Richard Ottman, Camha Nguyen, Robert Lorch, Ratna Chakrabarti
Journal: Molecular Cancer (2014)

Development of resistance to androgen deprivation therapy (ADT) is a major obstacle for the management of advanced prostate cancer. Therapies with androgen receptor (AR) antagonists and androgen withdrawal initially regress tumors but development of compensatory mechanisms including AR bypass signaling leads to re-growth of tumors. MicroRNAs (miRNAs) are small regulatory RNAs that are involved in maintenance of cell homeostasis but are often altered in tumor cells.In this study, we determined the association of genome wide miRNA expression (1113 unique miRNAs) with development of resistance to ADT. We used androgen sensitive prostate cancer cells that progressed to ADT and AR antagonist Casodex (CDX) resistance upon androgen withdrawal and treatment with CDX. Validation of expression of a subset of 100 miRNAs led to identification of 43 miRNAs that are significantly altered during progression of cells to treatment resistance. We also show a correlation of altered expression of 10 proteins targeted by some of these miRNAs in these cells.We conclude that dynamic alterations in miRNA expression occur early on during androgen deprivation therapy, and androgen receptor blockade. The cumulative effect of these altered miRNA expression profiles is the temporal modulation of multiple signaling pathways promoting survival and acquisition of resistance. These early events are driving the transition to castration resistance and cannot be studied in already developed CRPC cell lines or tissues. Furthermore our results can be used a prognostic marker of cancers with a potential to be resistant to ADT.
Amino-Biphosphonate–Mediated MMP-9 Inhibition Breaks the Tumor-Bone Marrow Axis Responsible for Myeloid-Derived Suppressor Cell Expansion and Macrophage Infiltration in Tumor Stroma
Authors: Cecilia Melani, Sabina Sangaletti, Francesca M. Barazzetta, Zena Werb, Mario P. Colombo
Journal: Cancer Research (2007)

Abstract BALB-neuT mice expressing an activated rat c-erbB-2/neu transgene under the mouse mammary tumor virus long terminal repeat show enhanced hematopoiesis with hyperproduction of myeloid-derived suppressor cells (MDSC) because of vascular endothelial growth factor (VEGF) secreted by the tumor. Here, we show that both tumor and stromal cells express matrix metalloproteinase-9 (MMP-9), thereby increasing the levels of pro–MMP-9 in the sera of tumor-bearing mice. Treatment with amino-biphosphonates impaired tumor growth, significantly decreased MMP-9 expression and the number of macrophages in tumor stroma, and reduced MDSC expansion both in bone marrow and peripheral blood by dropping serum pro–MMP-9 and VEGF. We dissected the role of tumor-derived MMP-9 from that secreted by stromal leukocytes by transplanting bone marrow from MMP-9 knockout mice into BALB-neuT mice. Although bone marrow progenitor–derived MMP-9 had a major role in driving MDSC expansion, amino-biphosphonate treatment of bone marrow chimeras further reduced both myelopoiesis and the supportive tumor stroma, thus enhancing tumor necrosis. Moreover, by reducing MDSC, amino-biphosphonates overcome the tumor-induced immune suppression and improved the generation and maintenance of antitumor immune response induced by immunization against the p185/HER-2. Our data reveal that suppression of MMP-9 activity breaks the vicious loop linking tumor growth and myeloid cell expansion, thus reducing immunosuppression. Amino-biphosphonates disclose a specific MMP-9 inhibitory activity that may broaden their application above their current usage. [Cancer Res 2007;67(23):11438–46]