tbuckley/cabot-search huggingface dataset:
Functional Variants of the <i>NEIL1</i> and <i>NEIL2</i> Genes and Risk and Progression of Squamous Cell Carcinoma of the Oral Cavity and Oropharynx
Authors: Xiaodong Zhai, Hui Zhao, Zhensheng Liu, Li-E Wang, Adel K. El-Naggar, Erich M. Sturgis, Qingyi Wei
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Human DNA glycosylases NEIL1 and NEIL2 participate in oxidized base excision repair and protect cells from DNA damage. NEIL1 (MIM:608844) and NEIL2 (MIM:608933) variants may affect their protein functions, leading to altered cell death and carcinogenesis. To date, only one reported study has investigated the association between NEIL1 and NEIL2 polymorphisms and cancer risk. Experimental Design: Genotype and haplotypes of the NEIL1 NT_010194.16:g.46434077G&amp;gt;T (rs7182283) and g.46438282C&amp;gt;G (rs4462560) and NEIL2 NT_077531.3:g.4102971C&amp;gt;G (rs804270) polymorphisms were determined for 872 patients with newly diagnosed squamous cell carcinomas of the oral cavity and oropharynx (SCCOOP) and 1,044 cancer-free non–Hispanic white control subjects frequency-matched by age and sex. Crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using multivariate logistic regression, and false-positive report probabilities were also calculated. Results: We found no overall differences in the frequencies of alleles, genotypes, and haplotypes of NEIL1 g.46434077G&amp;gt;T and NEIL1 g.46438282C&amp;gt;G polymorphisms between cases and controls. However, the NEIL2 g.4102971CC genotype was associated with a significantly increased risk of SCCOOP (adjusted OR, 1.30; 95% CI, 1.02-1.65); this increase in risk was the highest among current alcohol drinkers (adjusted OR, 1.87; 95% CI, 1.28-2.72), particularly in patients with oropharyngeal cancer (adjusted OR, 1.35; 95% CI, 1.04-1.76). The NEIL2 g.4102971CC genotype was also significantly associated with SCCOOP of advanced stages. Conclusions: Polymorphisms of the NEIL2 gene may be markers for risk and progression of SCCOOP, particularly in patients with oropharyngeal cancer. Larger studies are needed to confirm our findings.
Immune responses to colophony, an agent causing occupational asthma.
Authors: R T Cullen, B Cherrie, C A Soutar
Journal: Thorax (1992)

BACKGROUND: Inhalation of fumes from heated colophony (pine resin) is a recognised cause of occupational asthma, although the mechanisms by which colophony produces symptoms are unclear and specific immune responses to colophony have not been reported in sensitised workers. A study was carried out to determine whether colophony is antigenic. METHODS: The immune responses to colophony were studied in C57BL/6 mice and Dunkin Hartley guinea pigs after intraperitoneal injection of colophony conjugated to bovine serum albumin (BSA) or human IgG by a mixed anhydride procedure. Colophony and dinitrofluorobenzene were also compared in an assay of dermal sensitisation. RESULTS: Mice immunised with the colophony conjugates produced antibodies which recognised conjugates of both BSA and human IgG irrespective of which had been used as the immunogen. Solutions of unconjugated colophony inhibited the binding of antibodies to the BSA-colophony and BSA-abietic acid conjugates, confirming that the antibodies recognised one or more components in the colophony. Portuguese colophony also abrogated the antigen binding of serum from guinea pigs immunised with the BSA-colophony conjugate. Spleen cells from immunised mice proliferated in the presence of the conjugates. Although there was some cross reactivity in these responses, it was not as marked as in the antibody assays. Unconjugated colophony failed to induce an immune response when injected intraperitoneally with adjuvant. Skin sensitisation could not be induced in mice by topical application, or by subcutaneous or intradermal injection of unconjugated colophony. CONCLUSIONS: Colophony components have the potential to act as haptens and an immune component could be involved in the pathogenesis of occupational asthma in workers exposed to colophony. Colophony is not readily immunogenic unless conjugated ex vivo to proteins.
Hypertension in relation to musculoskeletal disorders.
Authors: J S Lawrence
Journal: Annals of the Rheumatic Diseases (1975)

Generalized osteoarthrosis was found to be significantly more common in older males with high than with low diastolic blood pressure. The excess of osteoarthrosis in those with hypertension was mainly in the hips, knees, carpometacarpal and metacarpophalangeal joints, and was independent of obesity in the hypertensive group. It was not associated with a higher cholesterol or uric acid level in the serum. Radiological evidence of avascular necrosis was present in 36% of males with osteoarthrosis of the hips and diastolic blood pressure above 100 mmHg, in 20% with a diastolic pressure of 81-100 mmHg, but was found in none of those with osteoarthrosis and blood pressure of 80 mmHg or below. Only those with osteoarthrosis and a diastolic pressure above 100 mmHg had significantly more avascular necrosis that expected. Osteoarthrosis of the knee in female was more frequent in the hypertensive groups independent of obesity. It is concluded that vascular disorders are involved in this form of generalized osteoarthrosis.
The Role of Clock Genes in Pharmacology
Authors: Georgios K. Paschos, Julie E. Baggs, John B. Hogenesch, Garret A. FitzGerald
Journal: The Annual Review of Pharmacology and Toxicology (2010)

The physiology of a wide variety of organisms is organized according to periodic environmental changes imposed by the earth's rotation. This way, a large number of physiological processes present diurnal rhythms regulated by an internal timing system called the circadian clock. As part of the rhythmicity in physiology, drug efficacy and toxicity can vary with time. Studies over the past four decades present diurnal oscillations in drug absorption, distribution, metabolism, and excretion. On the other hand, diurnal variations in the availability and sensitivity of drug targets have been correlated with time-dependent changes in drug effectiveness. In this review, we provide evidence supporting the regulation of drug kinetics and dynamics by the circadian clock. We also use the examples of hypertension and cancer to show current achievements and challenges in chronopharmacology.
Diabetes and Coronary Artery Bypass Surgery
Authors: Finlay A. McAlister, Jeremy Man, Lana Bistritz, Hani Amad, Puneeta Tandon
Journal: Diabetes Care (2003)

To determine the adequacy of perioperative glycemic control in diabetic patients undergoing coronary artery bypass grafting (CABG) and to explore the association between glycemic control and in-hospital morbidity/mortality.Retrospective cohort study of consecutive patients with diabetes undergoing CABG between April 2000 and March 2001 who survived at least 24 h postoperatively.Of the 291 patients in this study, 95% had type 2 diabetes and 40% had retinopathy, nephropathy, or neuropathy at baseline. During hospitalization (median 7 days), 78 (27%) of these patients suffered a nonfatal stroke or myocardial infarction, septic complication, or died ("adverse outcomes"). Glycemic control was suboptimal (average glucose on first postoperative day was 11.4 [11.2-11.6] mmol/l) and was significantly associated with adverse outcomes post-CABG (P = 0.03). Patients whose average glucose level was in the highest quartile on postoperative day 1 had higher risk of adverse outcomes after the first postoperative day than those with glucose in the lowest quartile (odds ratio 2.5 [1.1-5.3]). Even after adjustment for other clinical and operative factors, average blood glucose level on the first postoperative day remained significantly associated with subsequent adverse outcomes: for each 1-mmol/l increase above 6.1 mmol/l, risk increased by 17%.Perioperative glycemic control in our cohort of diabetic patients undergoing CABG in a tertiary care facility was suboptimal. We believe closure of this care gap is imperative, because hyperglycemia in the first postoperative day was associated with subsequent adverse outcomes in our study patients.
Non-HDL Cholesterol as a Predictor of Cardiovascular Disease in Type 2 Diabetes
Authors: Weiquan Lu, Helaine E. Resnick, Kathleen A. Jablonski, Kristina L. Jones, Arvind K. Jain, Wm. James Howard, David C. Robbins, Barbara V. Howard
Journal: Diabetes Care (2003)

OBJECTIVE—To determine whether non-HDL cholesterol, a measure of total cholesterol minus HDL cholesterol, is a predictor of CVD in patients with diabetes. RESEARCH DESIGN AND METHODS—The Strong Heart Study, a population-based study of CVD and its risk factors in 13 American Indian communities in three geographic areas in the U.S. The baseline examination, conducted between July 1989 and January 1992, consisted of a personal interview, a physical examination, and laboratory tests. Of the 4,549 women and men aged 45−74 years participating in the study, 2,108 had diabetes but no CVD at baseline. Data on fatal and nonfatal CVD were collected during the follow-up period through 31 December 1998 (average 9 years). RESULTS—Multivariable analyses indicated that non-HDL cholesterol is a strong predictor of CVD in men and women with diabetes and is particularly indicative of coronary events. Hazard ratios for the highest tertile of non-HDL cholesterol in men and women with diabetes (2.23 and 1.80, respectively) were higher than those for either LDL cholesterol or triglycerides alone in both men and women and were higher than the ratio of total/HDL cholesterol in women. The utility of non-HDL cholesterol in predicting CVD extended over a wide range of triglyceride concentrations. CONCLUSIONS—This study suggests that non-HDL cholesterol index may be particularly useful in predicting CVD risk in patients with diabetes.
Proapoptotic Activation of Death Receptor 5 on Tumor Endothelial Cells Disrupts the Vasculature and Reduces Tumor Growth
Authors: Nicholas S. Wilson, Annie Yang, Becky Yang, Suzana Couto, Howard Stern, Alvin Gogineni, Robert Pitti, Scot Marsters, Robby M. Weimer, Mallika Singh, Avi Ashkenazi
Journal: Cancer Cell (2012)
Effect of Thyroidectomy in Rheumatoid Arthritis
Authors: V. A. I. Laine, K. J. Vainio, T. E. Holopainen
Journal: Annals of the Rheumatic Diseases (1954)

<h3>Introduction</h3> The current Baveno VI criteria dictate that cirrhotic patients with a liver stiffness (LF) of less than 20kPa and a platelet count of &gt;150x10^9 are low risk of developing oesophageal varices (OV). Patients with compensated cirrhosis criteria are surveyed every 2–3 years if there is no evidence of OV, or every year if there is evidence of OV. Our aim was to establish whether a tertiary liver unit was appropriately referring patients for an OGD. <h3>Method</h3> We collected the following data from patients with a diagnosis of compensated liver cirrhosis: LF, platelet count, aeitology of liver disease, and results of an index OGD. Data was obtained from 300 patients. The aeitology of liver cirrhosis was as follows: ARLD (49%), NAFLD (19%), ASH+NASH (5%), viral hepatitis (15%), autoimmune (6%), cryptogenic (3%), and unknown/other (3%). <h3>Results</h3> 204 patients (68%) were referred for a fibroscan. Of those, 113 (55%) had a LF of more than 20 kPA, and 86 patients (76%) were referred for an OGD. The findings of the endoscopy are shown in figure 1. 60% of patients had evidence of OV on their index scope. 182 of 300 patients (60%) had platelets &lt;150x10^9, and 149 (82%) were referred for an OGD. The findings of the OGD are shown in figure 2. 60% had evidence of OV on their index scope. 53 patients (18%) had both normal LF and platelet count. Despite this, 25 (47%) were referred for an index OGD for OV surveillance. 22 patients (88%) had a normal examination, and 12% had evidence of OV (see figure 3). 76 patients (25%) had both abnormal LF and platelet count, and 58 (76%) were referred for an index scope. Varices were present in 55% of these cases. There were no risks identified in those not referred for an OGD, when it was clinically indicated. <h3>Discussion</h3> We found that patients with abnormalities in LF and/or platelet count were referred for an index OGD in more than 70% of cases. The presence of OV was identified in 55–60% of cases. 24% of patients with abnormalities in both LF and platelet count were not referred for an OGD. Conversely, despite not meeting Baveno criteria, 18% of patients were referred for an OGD, which was normal in 88%. With current unavoidable delays with surveillance endoscopy, applying the Baveno criteria can avoid unnecessary invasive procedures.
Chronic antioxidant supplementation attenuates nuclear factor-κB activation and preserves endothelial function in hypercholesterolemic pigs
Authors: Martin Rodriguez-Porcel, Lilach O Lerman, David R Holmes, Darcy Richardson, Claudio Napoli, Amir Lerman
Journal: Cardiovascular Research (2002)

Objective: Hypercholesterolemia (HC), a pro-oxidant condition, activates nuclear factor-kappa beta (NF-κB) and is associated with coronary endothelial dysfunction. The physiological significance of in vivo chronic antioxidant intervention on HC-induced NF-κB activation and coronary endothelial function remains unclear. Methods: Four groups of pigs were studied after 12 weeks of normal diet, normal diet with concomitant antioxidant intervention (100 IU/kg of vitamin E and 1 g of vitamin C daily), 2% HC diet, or HC diet+antioxidant supplementation. NF-κB activation and the nitric oxide (NO) pathway were investigated by Western blotting and immunohistochemistry, while oxidative stress was evaluated by coronary artery tissue radical scavenger activity and levels of vitamin E and C. Endothelial function was studied in vitro by coronary vasoreactivity to bradykinin and substance P. Results: HC animals had increased activation of NF-κB, decreased endothelial NO synthase expression, and decreased radical scavenger system activity, associated with impaired coronary endothelial function. Antioxidant supplementation in HC normalized NF-κB activation and NO bioactivity, and preserves coronary endothelial function. Conclusions: This study demonstrates for the first time that in vivo chronic interruption of the endogenous oxidative stress cascade reduces HC-induced NF-κB activation and normalizes NO bioactivity in association with preservation of coronary endothelial function. This study suggests a role for increased oxidative stress and NFκB activation in early atherosclerosis.
THE INFLUENCE OF THE CELLULAR INFILTRATE ON THE EVOLUTION AND INTENSITY OF DELAYED HYPERSENSITIVITY REACTIONS
Authors: William C. Hill
Journal: The Journal of Experimental Medicine (1969)

When a delayed-type hypersensitivity (DTH) reaction is elicted in a sensitive animal at a skin site in which an accumulation of mononuclear cells has been induced by a prior injection of a nonspecific stimulus, those properties characteristic of a DTH reaction, i.e. erythema, edema, and induration, become evident much more rapidly and intensely than a reaction in an unprepared skin site. This rapid, intense reaction has the histology of a classical delayed reaction and persists as long or longer than a classical DTH reaction in the same animal. Two facts are evident from these observations. Firstly, early in the development of a delayed reaction, the slow accumulation of mononuclear cells may be completely independent of the presence of specific antigen. Secondly, there is a reaction between specific antigen and an antibody-like substance which may or may not be attached to cells. The reaction develops so rapidly at a prepared site that the pharmacological mediators which are responsible for edema must be presumed to be released abruptly. A classical delayed reaction is attributable to the time needed for the accumulation of cells in sufficient numbers. It follows that the rate-limiting step in a classical delayed reaction is the process of cell accumulation. The present observations indicate that this process is independent of the presence of specific antigen.
Effects of diacetyl monoxime on the electrical properties of sheep and guinea pig ventricular muscle
Authors: Y. Liu, C. Cabo, R. Salomonsz, M. Delmar, J. Davidenko, J. Jalife
Journal: Cardiovascular Research (1993)

Objective: Diacetyl monoxime (DAM), a nucleophilic agent with "phosphatase-like" activity, has been found to effectively and reversibly block cardiac muscle contraction, while the cells remain capable of generating transmembrane action potentials. The aim of this study was to characterise the effects of DAM on the electrical properties of cardiac muscle. Methods: Sheep epicardial muscle, guinea pig papillary muscle, and guinea pig ventricular myocytes were studied using conventional microelectrode techniques as well as single electrode current and voltage clamp techniques. Results: DAM (5-20 mM) decreased action potential duration at 50% and 90% repolarisation levels (APD50, APD90) and refractory period in a dose dependent manner without causing significant changes in action potential amplitude, maximum upstroke velocity, or resting membrane potential. DAM induced a slight decrease in action potential conduction velocity in both the longitudinal and transverse directions, but on average the conduction velocity recorded in the presence of the drug was not significantly different from control. The time course of the APD restitution curve was not significantly changed but the frequency dependent APD variations were reduced. The ionic bases for these changes were studied in guinea pig ventricular myocytes. As with the results obtained in tissue preparations, DAM 15 mM decreased APD50and APD90 by 35% and 29%, respectively. Under voltage clamp conditions, DAM led to a 35% reduction of ICa. The delayed rectifier IK current and the inward rectifier background current were also partially depressed by DAM but to a lesser extent. All of these effects were reversible upon washout. Conclusions: Aside from its well known effect as an electromechanical uncoupler, DAM causes a small, reversible, and non-selective reduction of several membrane conductances. Provided such effects are taken into consideration, DAM is a valuable tool in electrophysiological studies. Cardiovascular Research 1993;27:1991-1997
Frontal brain lobe impairment in obstructive sleep apnoea: a proton MR spectroscopy study
Authors: M. Alchanatis, N. Deligiorgis, N. Zias, A. Amfilochiou, E. Gotsis, A. Karakatsani, A. Papadimitriou
Journal: European Respiratory Journal (2004)

Patients with obstructive sleep apnoea syndrome frequently have cognitive deficits, especially related to executive functions, which cannot be fully explained by daytime sleepiness and are partial irreversible after nasal continuous positive airway pressure treatment. The causal mechanism of these cognitive deficits is not yet known, but it has been proposed that they are associated with chemical and structural brain cell injury. The aim of this study was to investigate brain metabolism in patients with sleep apnoea syndrome. Twenty-two patients with severe sleep apnoea and 10 healthy volunteers of comparable age were studied using single voxel proton magnetic resonance spectroscopy. Magnetic resonance spectra were obtained from prefrontal cortex, parieto-occipital and frontal periventricular white matter. N -acetylaspartate-to-creatine and choline-to-creatine ratios were significantly lower in the frontal white matter of obstructive sleep apnoea patients when compared to controls. Absolute concentrations of N -acetylaspartate and choline were also significantly reduced in the frontal white matter of patients with sleep apnoea. Frontal lobe white matter lesions are known to be associated with cognitive executive dysfunction. The findings of this study may offer an explanation for the sometimes irreversible cognitive deficits associated with sleep apnoea.
Discovery and Characterization of a Fully Human Monoclonal Antibody Inhibitor of Plasma Kallikrein for the Treatment of Plasma Kallikrein-Mediated Edema
Authors: Daniel Sexton, Ryan Faucette, Malini Viswanathan, Niksa Kastrapeli, Kris Kopacz, Greg Conley, Allison Lindberg, Janja Cosic, Stephen Comeau, Shauna Mason, Jon Kenniston, Mike DiLeo, Jie Chen, Robert Ladner, Andrew Nixon, Christopher TenHoor
Journal: Journal of Allergy and Clinical Immunology (2013)
Enhanced Expression of Receptor for Advanced Glycation End Products in Chronic Kidney Disease
Authors: Fan Fan Hou, Hao Ren, William F. Owen, Zhi Jian Guo, Ping Yan Chen, Ann Marie Schmidt, Toshio Miyata, Xun Zhang
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Inappropriate chronic inflammation associated with progressive, chronic kidney disease (CKD) reflects sustained activation of immunocompetent cells, like monocytes/macrophages. Advanced glycation end products (AGE) accumulate in CKD, but it is unclear if they stimulate monocytes by binding with the receptor for AGE (RAGE). Posited was the notion that RAGE plays a contributory role to monocyte-mediated systemic inflammation of progressive CKD. Peripheral blood monocytes were isolated from 102 patients without diabetes with varying severity of CKD. RAGE expression on peripheral blood monocytes increased with worsening CKD (r2 = 0.73) and was strongly correlated with plasma levels of pentosidine, a marker for AGE (r = 0.71). Strongly positive statistical correlations were observed in patients with CKD between monocyte RAGE and plasma levels of tumor necrosis factor alpha (TNF-α) (r = 0.61), the monocyte activation marker, neopterin (r = 0.65), and the systemic acute phase reactant, C-reactive protein (r = 0.44). Monocytes obtained from patients with CKD showed a monotonic increase in the number and affinity of specific AGE binding sites and increased production of TNF-α under stimulation of AGE. All these upregulatory responses in uremic monocytes could be largely blocked by an anti-RAGE antibody. It was concluded that RAGE expression was upregulated on monocytes from patients with CKD. Enhanced RAGE may amplify AGE-induced monocytes perturbation and contribute to monocyte-mediated systemic inflammation in progressive CKD.
Antitumor Activity of Novel Indirubin Derivatives in Rat Tumor Model
Authors: Soo-A Kim, Yong-Chul Kim, Si-Wouk Kim, Sang-Ho Lee, Jung-Joon Min, Sang-Gun Ahn, Jung-Hoon Yoon
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The novel indirubin derivatives 5′-nitro-indirubinoxime, 5′-fluoro-indirubinoxime, and 5′-trimethylacetamino-indirubinoxime were designed and tested for antitumor activity both in vitro and in vivo using rat tumor model. Experimental Design: Three-week-old male Sprague-Dawley rats were inoculated s.c. on the left flank with 107 RK3E-ras rat kidney epithelial cells harboring k-ras gene. Alternatively, 5 × 106 RK3E-ras cells were injected into the oral mucosa. Indirubin derivative treatment began on the 3rd or 6th day after oral or s.c. cell injection, respectively. Indirubin derivatives were directly injected into the tumor every other day for a total of five times. Animals were monitored daily and tumor volume was measured by caliper. Results: Indirubin derivatives showed potent antiproliferative activity on various human cancer cells and oncogenic RK3E-ras rat kidney cells, with IC50 ranging from 1 to 12 μmol/L. Treatment with indirubin derivatives induced the activation of caspase-7 followed by apoptosis in RK3E-ras cells. Indirubin derivatives showed strong antitumor activity in rat solid and oral tumor models. Direct injection of indirubin derivatives every other day for 10 days induced significant inhibition of tumor growth in Sprague-Dawley rats bearing RK3E-ras-induced tumors. Histologically, treatment with indirubin derivatives caused significant inhibition of tumor formation with increased apoptosis and decreased tumor cell proliferation. Conclusions: Our data showed that novel indirubin derivatives 5′-nitro-indirubinoxime, 5′-fluoro-indirubinoxime, and 5′-trimethylacetamino-indirubinoxime effectively arrested the tumor growth by inhibiting cell proliferation and inducing apoptosis. These findings provide the potential value of indirubin derivatives as novel candidates for antitumor agents.