tbuckley/cabot-search huggingface dataset:
Anti-IL-6 receptor antibody (tocilizumab): a B cell targeting therapy
Authors: A. Snir, A. Kessel, T. Haj, I. Rosner, M. Rozenbaum, G. Slobodin, E. Toubi
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> B cells function as regulatory cells by producing inhibitory cytokines such as transforming growth factor β (TGF-β) and interleukin 10 (IL-10). Human CD25high B cells were shown to secrete higher levels of IL-10 versus CD25low B cells, suggesting this subset of cells to be immune-regulatory. Tocilizumab, a monoclonal antibody that acts as an IL-6R antagonist thus inhibiting IL-6 activity, and its autocrine growth activity on B cells is currently used for treatment of rheumatoid arthritis (RA). Following this treatment, one might expect a reduction in B cell activity status, and on the other hand increase of their regulatory properties. <h3>Methods</h3> Freshly purified B lymphocytes were isolated from 10 active RA patients, with inadequate response to methotrexate, at baseline and 3 months following add on tocilizumab. Clinical status was assessed by DAS 28 score and erythrocyte sedimentation rate (ESR). Using flow cytometry, B cells were stained for the expression of intracellular TGF-β, IL-10, membrane CD69, and MHC-II. These markers were assessed in primary (no-stimulated) CD25high B cells and expressed in MFI, with results given in mean ± SEM. <h3>Results</h3> Three months following initiation of tocilizumab, the expression of intracellular TGF-β in CD25high B cells was significantly increased (from 5.2 ± 2.3 at baseline to 8.1 ± 2.8; p &lt; 0.02); the expression of MHC-II on B cells was significantly reduced (from 9.1 ± 2.2 at baseline to 4.2 ± 0.4; p &lt; 0.04). In addition, the expression of CD69 also decreased (from 7.6 ± 2.4 at baseline to 2.7 ± 0.7; p &lt; 0.03). The expression of intracellular IL-10 was too low for comparison. These phenotypic B cell changes namely, the alteration in B cell activity and antigen presenting cell (APC) properties and the shift and/or expansion of the B cell subset with regulatory properties were found to occur in association with beneficial clinical outcome, namely DAS improvement from 6.8 ± 0.3 at baseline to 3.1 ± 0.4, p &lt; 0.002, and ESR decrease from 44.4 ± 8.6 at baseline to 7.4 ± 2.3, p &lt; 0.006. <h3>Conclusions</h3> Our unique finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-β expression and the alteration in their activation status and APC properties in CD25high B cells, suggests that the induction/expansion of B regulatory cells may be one of the mechanisms by which tocilizumab may possibly produce its beneficial clinical effects.
The NHLBI-Sponsored Consortium for preclinicAl assESsment of cARdioprotective Therapies (CAESAR)
Authors: Steven P. Jones, Xian-Liang Tang, Yiru Guo, Charles Steenbergen, David J. Lefer, Rakesh C. Kukreja, Maiying Kong, Qianhong Li, Shashi Bhushan, Xiaoping Zhu, Junjie Du, Yibing Nong, Heather L. Stowers, Kazuhisa Kondo, Gregory N. Hunt, Traci T. Goodchild, Adam Orr, Carlos C. Chang, Ramzi Ockaili, Fadi N. Salloum, Roberto Bolli
Journal: Circulation Research (2014)

Rationale: Despite 4 decades of intense effort and substantial financial investment, the cardioprotection field has failed to deliver a single drug that effectively reduces myocardial infarct size in patients. A major reason is insufficient rigor and reproducibility in preclinical studies. Objective: To develop a multicenter, randomized, controlled, clinical trial-like infrastructure to conduct rigorous and reproducible preclinical evaluation of cardioprotective therapies. Methods and Results: With support from the National Heart, Lung, and Blood Institute, we established the Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR), based on the principles of randomization, investigator blinding, a priori sample size determination and exclusion criteria, appropriate statistical analyses, and assessment of reproducibility. To validate CAESAR, we tested the ability of ischemic preconditioning to reduce infarct size in 3 species (at 2 sites/species): mice (n=22–25 per group), rabbits (n=11–12 per group), and pigs (n=13 per group). During this validation phase, (1) we established protocols that gave similar results between centers and confirmed that ischemic preconditioning significantly reduced infarct size in all species and (2) we successfully established a multicenter structure to support CAESAR’s operations, including 2 surgical centers for each species, a Pathology Core (to assess infarct size), a Biomarker Core (to measure plasma cardiac troponin levels), and a Data Coordinating Center—all with the oversight of an external Protocol Review and Monitoring Committee. Conclusions: CAESAR is operational, generates reproducible results, can detect cardioprotection, and provides a mechanism for assessing potential infarct-sparing therapies with a level of rigor analogous to multicenter, randomized, controlled clinical trials. This is a revolutionary new approach to cardioprotection. Importantly, we provide state-of-the-art, detailed protocols (“CAESAR protocols”) for measuring infarct size in mice, rabbits, and pigs in a manner that is rigorous, accurate, and reproducible.
New developments in the therapy of amoebiasis.
Authors: S J Powell
Journal: Gut (1970)

Progress reportNew developments in the therapy of amoebiasis Although frequently overlooked in practice, it has long been taught that for the adequate therapy of invasive amoebiasis treatment should be directed at all the sites where Entamoeba histolytica may be present.Hence the ideal amoebicide should be active within the bowel lumen, in the bowel wall, and systemically, particularly in the liver.Until quite recently all available amoebicides were selective in their sites of action.They consisted of a small number of reliable tissue amoebicides (chiefly emetine preparations and chloroquine), indirect-acting broad- spectrum antibiotics, and a great many predominantly luminal amoebicides.Inadequate assessment of the latter on inappropriate clinical material often led to misleading claims of their efficacy in invasive amoebiasis.However, almost all forms of amoebiasis could be treated effectively provided the correct combinations of drugs were used, although therapy was often a little complicated and prolonged, and occasionally associated with toxicity.In 1964 a preliminary report of the effect of niridazole in amoebic liver abscess led to the introduction of a new series of compounds in therapy'.It was found that niridazole alone was capable of curing both intestinal and hepatic amoebiasis but it was soon evident that this drug possessed an un- desirable degree of toxicity2.It was not, however, long before another nitroheterocyclic compound was shown to yield even better results.This was the nitro-imidazole derivative, metronidazole.At a dosage of 200 mg three times daily for seven days the drug had been widely and safely used since 1959 for the treatment of tri- chomoniasis, but this regimen in amoebic dysentery had been disappointing.It was only in 1966, after considerably higher dosage regimens were used, that successful clinical trials in amoebic dysentery and amoebic liver abscess were reported3.Further studies showed that extremely small amounts of the
Multiple lymphadenopathy as an initial sign of extramammary Paget disease
Authors: S. Hirakawa, A. Tanemura, H. Mori, I. Katayama, K. Hashimoto
Journal: British Journal of Dermatology (2010)

Extramammary Paget disease (EMPD) often develops in external genitalia. Paget cells can, however, adopt an invasive phenotype and metastasize to regional lymph nodes and beyond, leading to poor patient outcomes. Based on this clinical observation, multiple lymphadenopathy may represent an initial sign of EMPD. To address the potential significance of multiple lymph node swelling in EMPD, we report two patients with cutaneous primary EMPD who showed multiple lymphadenopathy as an initial sign during the clinical course of the disease as well as tumour metastasis. Significantly, marked lymphatic vessel growth was observed in regional lymph nodes that underwent massive tumour cell invasion. Therefore, nodal lymphangiogenesis may promote tumour cell invasion and metastasis to distant organs, including the lymph nodes, emphasizing the clinical relevance of multiple lymphadenopathy.
Calcimimetic Inhibits Late-Stage Cyst Growth in ADPKD
Authors: Vincent H. Gattone, Neal X. Chen, Rachel M. Sinders, Mark F. Seifert, Danxia Duan, David Martin, Charles Henley, Sharon M. Moe
Journal: Journal of the American Society of Nephrology (2009)

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.
Candidate Drug Targets for Prevention or Modification of Epilepsy
Authors: Nicholas H. Varvel, Jianxiong Jiang, Raymond Dingledine
Journal: The Annual Review of Pharmacology and Toxicology (2014)

Epilepsy is a prevalent neurological disorder afflicting nearly 50 million people worldwide. The disorder is characterized clinically by recurrent spontaneous seizures attributed to abnormal synchrony of brain neurons. Despite advances in the treatment of epilepsy, nearly one-third of patients are resistant to current therapies, and the underlying mechanisms whereby a healthy brain becomes epileptic remain unresolved. Therefore, researchers have a major impetus to identify and exploit new drug targets. Here we distinguish between epileptic effectors, or proteins that set the seizure threshold, and epileptogenic mediators, which control the expression or functional state of the effector proteins. Under this framework, we then discuss attempts to regulate the mediators to control epilepsy. Further insights into the complex processes that render the brain susceptible to seizures and the identification of novel mediators of these processes will lead the way to the development of drugs to modify disease outcome and, potentially, to prevent epileptogenesis.
Carcinogenicity of the Drinking Water Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone in the Rat
Authors: H. Komulainen, S.-L. Vaittinen, T. Vartiainen, J. Tuomisto, V.-M. Kosma, E. Kaliste-Korhonen, S. Lotjonen, R. K. Tuominen
Journal: JNCI Journal of the National Cancer Institute (1997)

Several epidemiologic studies have suggested that the consumption of chlorinated drinking water may be associated with the development of certain cancers in humans. 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), a byproduct of the chemical reactions that occur in chlorinated drinking water, has been found to be mutagenic in bacteria and mammalian cells; however, its potential to cause tumors in animals has not been tested previously.The objective of this study was to evaluate the carcinogenicity of MX in rats given MX in their drinking water.MX was administered to male and female Wistar rats (50 rats per dose group) in drinking water for 104 weeks at concentrations yielding the average daily doses of MX of 0.4 mg/kg of animal weight (low dose), 1.3 mg/kg (mid dose), and 5.0 mg/kg (high dose) for males and 0.6 mg/kg, 1.9 mg/kg, and 6.6 mg/kg for females, respectively. Control rats received water from the same source used for preparation of the MX dose formulations (after its adjustment to the same pH range). Body weight, clinical signs, and food and water consumption were recorded regularly. At the end of the treatment period, the animals were killed and full histopathologic analysis was performed on 47 tissues and all lesions.Dose-dependent increases in tumor incidence were observed in rats given MX-containing drinking water; the same MX doses had no obvious toxic effects on animals. MX consumption increased most drastically the prevalence of follicular adenoma (up to 43% and 72% in high-dose males and females, a test [one-sided] for positive trend in all dose groups P = .0045 and P = .0000, respectively) and carcinoma (55% [P = .0000] and 44% [P = .0000], respectively) in thyroid glands and cholangioma in the liver (8% [P = .0009] and 66% [P = .0000] in the high-dose males and females, respectively). Among rats given the higher doses of MX in their drinking water, cortical adenomas of the adrenal glands were increased in both sexes, alveolar and bronchiolar adenomas of the lungs and Langerhans' cell adenomas of the pancreas were increased in males, and lymphomas, leukemias, and adenocarcinomas and fibroadenomas of the mammary glands were increased in females. Even the lowest MX dose studied was carcinogenic.MX is a potent carcinogen in both male and female rats, and it causes tumors at doses that are not overtly toxic to rats.Although these findings cannot be extrapolated to humans, MX should be studied as a candidate risk factor in the possible association between consumption of chlorinated drinking water and cancer in humans.
In Vivo Therapeutic Gas Delivery for Neuroprotection With Echogenic Liposomes
Authors: George L. Britton, Hyunggun Kim, Patrick H. Kee, Jaroslaw Aronowski, Christy K. Holland, David D. McPherson, Shao-Ling Huang
Journal: Circulation (2010)

Ischemia-related neurological injury is a primary cause of stroke disability. Studies have demonstrated that xenon (Xe) may have potential as an effective and nontoxic neuroprotectant. Xe delivery is, however, hampered by lack of suitable administration methods. We have developed a pressurization-freeze method to encapsulate Xe into echogenic liposomes (Xe-ELIP) and have modulated local gas release with transvascular ultrasound exposure.Fifteen microliters of Xe were encapsulated into each 1 mg of liposomes (70% Xe and 30% argon). Xe delivery from Xe-ELIP into cells and consequent neuroprotective effects were evaluated with oxygen/glucose-deprived and control neuronal cells in vitro. Xe-ELIP were administered into Sprague-Dawley rats intravenously or intra-arterially after right middle cerebral artery occlusion. One-megahertz low-amplitude (0.18 MPa) continuous wave ultrasound directed onto the internal carotid artery triggered Xe release from circulating Xe-ELIP. Effects of Xe delivery on ischemia-induced neurological injury and disability were evaluated. Xe-ELIP delivery to oxygen/glucose-deprived neuronal cells improved cell viability in vitro and resulted in a 48% infarct volume decrease in vivo. Intravenous Xe-ELIP administration in combination with the ultrasound directed onto the carotid artery enhanced local Xe release from circulating Xe-ELIP and demonstrated 75% infarct volume reduction. This was comparable to the effect after intra-arterial administration. Behavioral tests on limb placement and grid and beam walking correlated with infarct reduction.This novel methodology may provide a noninvasive strategy for ultrasound-enhanced local therapeutic gas delivery for cerebral ischemia-related injury while minimizing systemic side effects.
Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000
Authors: Suresh H. Moolgavkar, Theodore R. Holford, David T. Levy, Chung Yin Kong, Millenia Foy, Lauren Clarke, Jihyoun Jeon, William D. Hazelton, Rafael Meza, Frank Schultz, William McCarthy, Robert Boer, Olga Gorlova, G. Scott Gazelle, Marek Kimmel, Pamela M. McMahon, Harry J. de Koning, Eric J. Feuer
Journal: JNCI Journal of the National Cancer Institute (2012)

BackgroundConsiderable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000.
MicroRNA-223 Antagonizes Angiogenesis by Targeting β1 Integrin and Preventing Growth Factor Signaling in Endothelial Cells
Authors: Lei Shi, Beate Fisslthaler, Nina Zippel, Timo Frömel, Jiong Hu, Amro Elgheznawy, Heinrich Heide, Rüdiger Popp, Ingrid Fleming
Journal: Circulation Research (2013)

Endothelial cells in situ are largely quiescent, and their isolation and culture are associated with the switch to a proliferative phenotype.To identify antiangiogenic microRNAs expressed by native endothelial cells that are altered after isolation and culture, as well as the protein targets that regulate responses to growth factors.Profiling studies revealed that miR-223 was highly expressed in freshly isolated human, murine, and porcine endothelial cells, but those levels decreased in culture. In primary cultures of endothelial cells, vascular endothelial cell growth factor and basic fibroblast growth factor further decreased miR-223 expression. The overexpression of precursor-miR-223 did not affect basal endothelial cell proliferation but abrogated vascular endothelial cell growth factor-induced and basic fibroblast growth factor-induced proliferation, as well as migration and sprouting. Inhibition of miR-223 in vivo using specific antagomirs potentiated postnatal retinal angiogenesis in wild-type mice, whereas recovery of perfusion after femoral artery ligation and endothelial sprouting from aortic rings from adult miR-223(-/y) animals were enhanced. MiR-223 overexpression had no effect on the growth factor-induced activation of ERK1/2 but inhibited the vascular endothelial cell growth factor-induced and basic fibroblast growth factor-induced phosphorylation of their receptors and activation of Akt. β1 integrin was identified as a target of miR-223 and its downregulation reproduced the defects in growth factor receptor phosphorylation and Akt signaling seen after miR-223 overexpression. Reintroduction of β1 integrin into miR-223-ovexpressing cells was sufficient to rescue growth factor signaling and angiogenesis.These results indicate that miR-223 is an antiangiogenic microRNA that prevents endothelial cell proliferation at least partly by targeting β1 integrin.
Premetastatic Lung “Niche”: Is Vascular Endothelial Growth Factor Receptor 1 Activation Required?
Authors: Dan G. Duda, Rakesh K. Jain
Journal: Cancer Research (2010)

Inflammatory pathways may mediate preparation of the "metastatic soil" in the lungs. Some of these pathways--activation and/or the recruitment of certain inflammatory cells--might depend on vascular endothelial growth factor receptor 1 (VEGFR1) activity. Thus, blocking the activity of VEGFR1 (or the interaction with its ligands) has emerged as a potential antimetastasis strategy to target not only angiogenesis and cancer cell survival and migration, but also the recruitment of tumor growth-promoting bone marrow-derived cells (BMDC). However, inhibition of VEGFR1 activity by blocking antibodies or by genetic deletion of the tyrosine kinase domain neither prevented nor changed the rate of spontaneous metastasis formation after surgical removal of primary tumors. Thus, development of VEGFR1-targeted agents should be pursued in selected tumors (e.g., by identifying cancers that depend on VEGFR1 signaling for survival) or in specific combination therapies. Preventing metastasis will likely require identification and blockade of additional or alternative proinflammatory pathways that mediate the priming of the metastatic soil and the growth of micrometastases.
Procedural Volume as a Marker of Quality for CABG Surgery
Authors: Eric D. Peterson
Journal: JAMA (2004)

ContextThere have been recent calls for using hospital procedural volume as a quality indicator for coronary artery bypass graft (CABG) surgery, but further research into analysis and policy implication is needed before hospital procedural volume is accepted as a standard quality metric.Objective To examine the contemporary association between hospital CABG procedure volume and outcome in a large national clinical database.Design, Setting, and Participants Observational analysis of 267089 isolated CABG procedures performed at 439 US hospitals participating in the Society of Thoracic Surgeons National Cardiac Database between January 1, 2000, and December 31, 2001.Main Outcome Measure Association between hospital CABG procedural volume and all-cause operative mortality (in-hospital or 30-day, whichever was longer). ResultsThe median (interquartile range) annual hospital-isolated CABG volume was 253 (165-417) procedures, with 82% of centers performing fewer than 500 procedures per year.The overall operative mortality was 2.66%.After adjusting for patient risk and clustering effects, rates of operative mortality decreased with increasing hospital CABG volume (0.07% for every 100 additional CABG procedures; adjusted odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-0.99;P=.004).While the association between volume and outcome was statistically significant overall, this association was not observed in patients younger than 65 years or in those at low operative risk and was confounded by surgeon volume.The ability of hospital volume to discriminate those centers with significantly better or worse mortality was limited due to the wide variability in risk-adjusted mortality among hospitals with similar volume.Closure of up to 100 of the lowest-volume centers (ie, those performing Յ150 CABG procedures/year) was estimated to avert fewer than 50 of 7110 (Ͻ1% of total) CABGrelated deaths. ConclusionIn contemporary practice, hospital procedural volume is only modestly associated with CABG outcomes and therefore may not be an adequate quality metric for CABG surgery.