tbuckley/cabot-search huggingface dataset:
Imbalance of the interleukin 1 system in colonic mucosa—association with intestinal inflammation and interleukin 1 receptor agonist genotype 2
Authors: T Andus, R Daig, D Vogl, E Aschenbrenner, G Lock, S Hollerbach, M Köllinger, J Schölmerich, V Gross
Journal: Gut (1997)

Background— Interleukin 1 (IL-1) α and β are potent cytokines which play key roles in inflammation. They are controlled by IL-1 receptor antagonist (IL-1ra). Aims— To investigate the influence of mucosal inflammation and IL-1ra genotype on the IL-1ra:IL-1 balance. Patients and methods— IL-1α, IL-1β, and IL-1ra were measured by enzyme linked immunosorbent assay (ELISA) in biopsy specimens taken from inflamed and non-inflamed colon of 60 patients with Crohn’s disease (CD), 34 with ulcerative colitis (UC), 15 inflammatory controls, and 103 non-inflamed controls. IL-1ra genotype was determined by polymerase chain reaction and gel electrophoresis. Results— IL-1α and IL-1β were significantly increased in inflamed mucosa in inflammatory bowel disease (IBD) (CD: 53.5 (22.4) and 409.9 (118.7) pg/mg protein, respectively; UC: 18.9 (6.8) and 214.5 (78.2) pg/mg, respectively) and non-IBD patients (19.2 (7.4) and 281.4 (121.0) pg/mg, respectively; p&lt;0.0001) compared with normal controls (2.8 (0.6) and 30.6 (5.6) pg/mg, respectively). In CD IL-1α and β were also significantly increased in non-inflamed mucosa (6.1 (1.3) pg/mg and 88.7 (17.4) pg/mg, respectively; p&lt;0.0012). IL-1ra:(IL-1α+β) ratios were significantly decreased in inflamed mucosa of patients with CD (182 (45); p&lt;0.0001), UC (425 (136); p=0.0018) and without IBD (221 (76); p&lt;0.0001), and in non-inflamed mucosa in CD (369 (149); p&lt;0.0001) compared with normal controls (1307 (245); p&lt;0.0001). Patients with IL-1ra genotype 2 had slightly but significantly reduced mucosal IL-1ra concentrations (p=0.003). The greatest difference was seen in colonic biopsy specimens from patients with inflamed Crohn’s disease. Conclusion— Mucosal inflammation can modulate the balance of the IL-1:IL-1ra system in colonic mucosa.
Hypercholesterolaemia and its management
Authors: D. Bhatnagar, H. Soran, P. N Durrington
Journal: BMJ (2008)

Hypercholesterolaemia is one of the major causes of atherosclerosis. Although there are many causes, hypercholesterolaemia is the permissive factor that allows other risk factors to operate.1 The incidence of coronary heart disease is usually low where population plasma cholesterol concentrations are low.2 In Britain coronary heart disease is a major cause of mortality, and a recent Department of Health survey suggested that the average plasma cholesterol concentration in the United Kingdom was 5.9 mmol/l, much higher than the 4 mmol/l seen in rural China and Japan, where heart disease is uncommon.3 Many studies before and after the introduction of statins have indicated that reducing the prevalence of hypercholesterolaemia is an important means of decreasing coronary risk.

Cholesterol plays an important role as the precursor for steroid hormones and bile acids and it is essential for the structural integrity of cell membranes. It is transported in the body in lipoproteins. Figure 1⇓ shows the role of cholesterol in lipoprotein metabolism.



Fig 1 The role of cholesterol in the metabolism of lipoprotein. Adapted from Charlton-Menys4



Conventionally the upper limit for laboratory reference ranges is based on the 95th or 90th centile for a healthy population. This does not apply to plasma cholesterol, however, as several studies show that the epidemiological relation between plasma cholesterol and risk of coronary heart disease extends to the lower end of the cholesterol distribution. Although the relation becomes progressively steeper, there is no obvious threshold below which it ceases to exist.5 Therefore, it is more rational to base a desirable or healthy concentration of plasma cholesterol on the value at which coronary risk is considered unacceptably high. Most patients developing coronary heart disease have plasma cholesterol concentrations that are likely to be between the 30th and 90th centile for their population …
Death, Cardiac Dysfunction, and Arrhythmias Are Increased by Calmodulin Kinase II in Calcineurin Cardiomyopathy
Authors: Michelle S.C. Khoo, Jingdong Li, Madhu V. Singh, Yingbo Yang, Prince Kannankeril, Yuejin Wu, Chad E. Grueter, Xiaoqun Guan, Carmine V. Oddis, Rong Zhang, Lisa Mendes, Gemin Ni, Ernest C. Madu, Jinying Yang, Martha Bass, Rey J. Gomez, Brian E. Wadzinski, Eric N. Olson, Roger J. Colbran, Mark E. Anderson
Journal: Circulation (2006)

Activation of cellular Ca2+ signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca2+-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death.We found that activity and expression of a second Ca2+-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy.CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.
Analysis of Biomarkers and PK Modeling of ABT-767 in Patients With BRCA1/BRCA2-Mutated Tumors or High Grade Serous Ovarian Cancer
Authors: M. de Jonge, C. van Herpen, J. Gietema, K. Timms, M. Dunbar, R. Hetman, C. Serpenti, H. Xiong, M. Zhu, R. Mittapalli, P. Ansell, S. Shepherd
Journal: Annals of Oncology (2015)
Human Pulmonary Chimerism after Hematopoietic Stem Cell Transplantation
Authors: Benjamin T. Suratt, Carlyne D. Cool, Amanda E. Serls, Lin Chen, Marileila Varella-Garcia, Elizabeth J. Shpall, Kevin K. Brown, G. Scott Worthen
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Many of the body's tissues once thought to be only locally regenerative may, in fact, be actively replaced by circulating stem cells after hematopoietic stem cell transplantation. Localization of donor-derived cells ("chimerism") has recently been shown to occur in the lungs of mice after either hematopoietic stem cell transplantation or infusion of cultured marrow. To determine whether tissues of the human lung might be similarly derived from extrapulmonary sources, we examined lung specimens from a retrospective cohort of female allogeneic hematopoietic stem cell transplant recipients who received stem cells from male donors. Tissue samples from three such patients who had undergone diagnostic lung biopsy or autopsy were examined. Slides were stained by immunohistochemistry for cytokeratin (epithelium) and platelet endothelial cell adhesion molecule, CD31 (PECAM) (endothelium) and were imaged and then examined by fluorescent in situ hybridization analysis to identify male cells. The resulting overlapping in situ hybridization and immunohistochemistry images were examined for the presence and, if present, cell type of donor cells in the lung. We found significant rates of epithelial (2.5-8.0%) and endothelial (37.5-42.3%) chimerism. These results suggest that significant chimerism of the human lung may follow hematopoietic stem cell transplantation and that adult human stem cells could potentially play a therapeutic role in treatment of the damaged lung.
The way to dusty death?
Authors: J N Townend
Journal: Thorax (2005)

“Environmental cardiology”—the relationship between air pollution, autonomic control, inflammation, and adverse cardiac events

As cardiologists know to their cost, the course of coronary artery disease is highly unpredictable. Although the disease accounts for about 20% of all deaths in developed countries and high levels of morbidity, in most cases the disease is clinically silent. Autopsy studies reveal that more than half of all people over the age of 60 and over a quarter of adults under this age have coronary artery disease. Even when this is manifest as angina, the annual event rate is only about 3%. When adverse events occur, however, they usually do so without apparent cause and without warning. About half of the deaths due to coronary artery disease are sudden and, of these, half are due to plaque rupture and intracoronary thrombosis.1 In the remainder, although severe coronary artery disease is often present, no evidence of thrombus is found at autopsy and the cause of death is believed to be arrhythmic. If most adult residents of the western world are walking around with coronary artery disease, what are the factors that determine whether, on any given day, the disease remains silent or presents with an acute coronary syndrome or sudden arrhythmic death? Could external environmental factors increase the chances of plaque rupture or arrhythmia? If so, what are the mechanisms?

Of the environmental factors examined, air pollution has become a prime suspect. While modern levels of particulate and gaseous pollutants are far lower than those of the 1950s, they continue to be related to daily total and cardiovascular mortality rates.2 A large number of papers from independent researchers in geographically and climatically distinct regions of the world have shown a consistent association between daily levels of pollution and cardiovascular mortality and morbidity including strokes, …
Pirfenidone for Diabetic Nephropathy
Authors: Kumar Sharma, Joachim H. Ix, Anna V. Mathew, Monique Cho, Axel Pflueger, Stephen R. Dunn, Barbara Francos, Shoba Sharma, Bonita Falkner, Tracy A. McGowan, Michael Donohue, Satish RamachandraRao, Ronghui Xu, Fernando C. Fervenza, Jeffrey B. Kopp
Journal: Journal of the American Society of Nephrology (2011)

Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.
Turning T cells on: epigenetically enhanced expression of effector T-cell costimulatory molecules on irradiated human tumor cells
Authors: Anita Kumari, Ercan Cacan, Susanna F Greer, Charlie Garnett-Benson
Journal: Journal for ImmunoTherapy of Cancer (2013)

<h3>Background</h3> Sub-lethal doses of radiation can alter the phenotype of target tissue by modulating gene expression and making tumor cells more susceptible to T-cell-mediated immune attack. We have previously shown that sub-lethal tumor cell irradiation enhances killing of colorectal carcinoma cells by tumor-specific cytotoxic T cells by unknown mechanisms. Recent data from our lab indicates that irradiation of tumor cells results in the upregulation of OX40L and 41BBL, and that T cells incubated with irradiated tumor cells displayed improved CTL survival, activation and effector activity. The objective of this current study was to determine the mechanism of enhanced OX40L and 41BBL expression in human colorectal tumor cells. <h3>Methods</h3> Two colorectal carcinoma cell lines, HCT116 and SW620, were examined for changes in the expression of 41BBL and OX40L in response to inhibition of histone deacetylases (using TSA) and DNA methyltransferases (using 5-Aza-2′-deoxycytidine) to evaluate if epigenetic mechanisms of gene expression can modulate these genes. Tumor cells were treated with radiation, TSA, or 5-Aza-dC, and subsequently evaluated for changes in gene expression using RT-qPCR and flow cytometry. Moreover, we assessed levels of histone acetylation at the 41BBL promoter using chromatin immunoprecipitation assays in irradiated HCT116 cells. <h3>Results</h3> Our data indicate that expression of 41BBL and OX40L can indeed be epigenetically regulated, as inhibition of histone deacetylases and of DNA methyltransferases results in increased OX40L and 41BBL mRNA and protein expression. Treatment of tumor cells with TSA enhanced the expression of these genes more than treatment with 5-Aza-dC, and co-incubation of T cells with TSA-treated tumor cells enhanced T-cell survival and activation, similar to radiation. Furthermore, chromatin immunoprecipitation experiments revealed significantly increased histone H3 acetylation of 41BBL promoters specifically following irradiation. <h3>Conclusions</h3> Full understanding of specific mechanisms of immunogenic modulation (altered expression of immune relevant genes) of irradiated tumor cells will be required to determine how to best utilize radiation as a tool to enhance cancer immunotherapy approaches. Overall, our results suggest that radiation can be used to make human tumors more immunogenic through epigenetic modulation of genes stimulatory to effector T-cells.
Estrous Cycle Modulates Ovarian Carcinoma Growth
Authors: Guillermo N. Armaiz-Pena, Lingegowda S. Mangala, Whitney A. Spannuth, Yvonne G. Lin, Nicholas B. Jennings, Alpa M. Nick, Robert R. Langley, Rosemarie Schmandt, Susan K. Lutgendorf, Steven W. Cole, Anil K. Sood
Journal: Clinical Cancer Research (2009)

Abstract Purpose: The effects of reproductive hormones on ovarian cancer growth are not well understood. Here, we examined the effects of estrous cycle variation and specific reproductive hormones on ovarian cancer growth. Experimental Design: We investigated the role of reproductive hormones in ovarian cancer growth using both in vivo and in vitro models of tumor growth. Results: In vivo experiments using the HeyA8 and SKOV3ip1 ovarian cancer models showed that tumor cell inoculation during proestrus significantly increased tumor burden (251-273%) compared with injection during the estrus phase. Treatment of ovariectomized mice with 17β-estradiol resulted in a 404% to 483% increase in tumor growth compared with controls. Progestins had no significant effect, but did block estrogen-stimulated tumor growth. Tumors collected from mice sacrificed during proestrus showed increased levels of vascular endothelial growth factor (VEGF) and microvessel density compared with mice injected during estrus. HeyA8, SKOV3ip1, and mouse endothelial (MOEC) cells expressed estrogen receptor α and β and progesterone receptor at the protein and mRNA levels, whereas 2774 ovarian cancer cells were estrogen receptor–negative. In vitro assays showed that 17β-estradiol significantly increased ovarian cancer cell adhesion to collagen in estrogen receptor–positive, but not in estrogen receptor–negative cells. Additionally, 17β-estradiol increased the migratory potential of MOEC cells, which was abrogated by the mitogen-activated protein kinase (MAPK) inhibitor, PD 09859. Treatment with 17β-estradiol activated MAPK in MOEC cells, but not in HeyA8 or SKOV3ip1 cells. Conclusion: Our data suggest that estrogen may promote in vivo ovarian cancer growth, both directly and indirectly, by making the tumor microenvironment more conducive for cancer growth.
Forskolin potentiates the coronary vasoactivity of adenosine in the open-chest dog.
Authors: S Kusachi, W J Bugni, R A Olsson
Journal: Circulation Research (1984)

Forskolin, a plant diterpene, directly stimulates adenylate cyclase and also potentiates receptor-mediated stimulation of this enzyme by many stimulatory--but not inhibitory--agonists. We exploited the potentiating effect of forskolin to test the hypothesis that adenosine initiates coronary relaxation through activation of adenylate cyclase. In six open-chest dogs, intracoronary forskolin infusions which produced plasma concentrations between 0.15 and 0.48 microM barely changed coronary flow and had no effect on cardiac performance or oxygen metabolism, and did not cause hypotension. Under these conditions, the EC50 of adenosine, 0.66 microM (range 1.3-2.4), P less than 0.05. In five of the six dogs, higher doses of forskolin, 0.6-6.3 microM, produced the previously described positive inotropic, chronotropic, and systemic hypotensive effects of this drug. These larger doses of the drug increased coronary flow and MVO2 but decreased oxygen extraction, reflecting a combination of direct and metabolic vasodilation. The potentiation of the vasoactivity of adenosine by forskolin supports the hypothesis that the coronary receptor is an adenylate cyclase stimulatory (Ra or A2) receptor.
Heparanase Is Involved in Angiogenesis in Esophageal Cancer through Induction of Cyclooxygenase-2
Authors: Takaomi Okawa, Yoshio Naomoto, Tetsuji Nobuhisa, Munenori Takaoka, Takayuki Motoki, Yasuhiro Shirakawa, Tomoki Yamatsuji, Hiroyasu Inoue, Mamoru Ouchida, Mehmet Gunduz, Motowo Nakajima, Noriaki Tanaka
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Both heparanase and cyclooxygenase-2 (COX-2) are thought to play critical roles for tumor malignancy, including angiogenesis, although it is unknown about their relationship with each other in cancer progression. We hypothesized that they may link to each other on tumor angiogenesis. Experimental Design: The expressions of heparanase and COX-2 in 77 primary human esophageal cancer tissues were assessed by immunohistochemistry to do statistical analysis for the correlation between their clinicopathologic features, microvessel density, and survival of those clinical cases. Human esophageal cancer cells were transduced with heparanase cDNA and used for reverse transcription-PCR and Western blot to determine the expression of heparanase and COX-2. COX-2 promoter vector and its deletion/mutation constructs were also used along with transduction of heparanase cDNA for luciferase assay. Results: Heparanase and COX-2 protein expression exhibited a similar pattern in esophageal tumor tissues, and their expression correlated with tumor malignancy and poor survival. Their expression also revealed a significant correlation with high intratumoral microvessel density. Up-regulation of COX-2 mRNA and protein was observed in esophageal cancer cells transfected with heparanase cDNA. COX-2 promoter was activated after heparanase cDNA was transduced and the deletion/mutation of three transcription factor (cyclic AMP response element, nuclear factor-κB, and nuclear factor-interleukin-6) binding elements in COX-2 promoter strongly suppressed its activity. Conclusion: Our results suggest that heparanase may play a novel role for COX-2-mediated tumor angiogenesis.
Role of airway receptors in the breathing pattern of patients with chronic obstructive lung disease.
Authors: A J Winning, R D Hamilton, A Guz
Journal: Thorax (1985)

Role of automatic staplers in the aetiology of broncho- pleural fistula SIR,-In their article in January 1985 (40:27-31) Mr M Hakim and Mr BB Milstein reported on the incidence of bronchopleural fistula following pneumonectomy.They suggest that the use of the TA-55 Premium instrument contributes to a significantly higher rate of bronchopleural fistula following pneumonectomy than the original style and indicate that the differences are related to differences in design and function of the two staplers.
Defective beta adrenergic response of cystic fibrosis sweat glands in vivo and in vitro.
Authors: K Sato, F Sato
Journal: Journal of Clinical Investigation (1984)

Abnormal ductal NaCl absorption has been known as the only defect in cystic fibrosis (CF) sweat glands. We have fortuitously found that the secretory portion of CF sweat glands is also abnormal in that it failed to show a sweating response to beta adrenergic stimulation (isoproterenol, [ISO]) both in vivo and in vitro. For the in vitro sweat test, eccrine sweat glands were isolated from skin biopsy specimens of the forearm, cannulated, and stimulated to secrete sweat. All 14 isolated CF sweat glands failed to respond to ISO + theophylline (TH, as aminophylline), but 17 of 18 control glands responded with a mean rate (SR) of 1.1 nl/min per gland. Cholinergic responsiveness of isolated CF sweat glands was comparable with that of control glands. The in vivo sweat test was performed by intradermal injection in the forearm of 0.2 ml of 2.4 or 8 X 10(-5) M ISO with or without 10(-2) M TH (and 1.4 X 10(-4) M atropine as a necessary anticholinergic agent). The beads of sweat secreted into the oil-filled sweat collection ring glued to the skin were then collected with a glass capillary under a stereomicroscope. Of 28 CF patients, 26 failed to show a secretory response to intradermal injection of ISO + TH, and 2 CF patients gave SR of less than 0.007 nl/min per gland in the first test but no response in the repeat test performed later. In contrast, all 35 age- and sex-matched control subjects responded with the mean SR of 0.72 nl/min per gland. Response of CF patients to epinephrine and phenylephrine was comparable with control, indicating that the alpha adrenergic responsiveness of CF sweat glands is not defective. A preliminary attempt was made to determine tissue cyclic AMP accumulation by radioimmunoassay in isolated sweat glands. No significant difference was observed between CF and control glands in their maximal accumulation of tissue cAMP in response to ISO or ISO + TH, except that the rise time of ISO + TH-induced cAMP accumulation in CF glands was significantly slower during the first 5 min of incubation. The data suggest that beta adrenergic regulation is abnormal in CF sweat glands and justifies further investigations into the mechanism of beta adrenergic regulation of the eccrine sweat gland in both normal and CF subjects.
In Mls-1a mice, fetal-type beta-gene rearrangements are frequent among self-anergic V beta 6 T cells.
Authors: R Rajasekar, A Sirr, M McCarty, G K Sim, A Augustin
Journal: The Journal of Experimental Medicine (1993)

T lymphocytes generated in the fetal and neonatal period are characterized by T cell receptor (TCR) gene rearrangements that lack N region nucleotides (fetal-type TCR). Using fetal-type TCR as a lineage marker, we show that such T cells are long-lived and persist in the periphery of adult mice. Moreover, in both neonatal and adult environments, upon encounter with self-antigens, they are less likely to be deleted. Inefficient clonal deletion could be due to the intrinsic properties of the T cells generated during this period, or to yet unknown properties of the perinatal thymus. Such anergic T cells constitute a subset that can further expand in vivo in an antigen-independent fashion, leaving open the possibility for self-aggression under the appropriate triggering conditions.