tbuckley/cabot-search huggingface dataset:
Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.
Authors: M Croft, D D Duncan, S L Swain
Journal: The Journal of Experimental Medicine (1992)

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.
Comparison of interferon γ release assays and conventional screening tests before tumour necrosis factor α blockade in patients with inflammatory arthritis
Authors: J Martin, C Walsh, A Gibbs, T McDonnell, U Fearon, J Keane, M B Codd, J Dodd, D Veale, O FitzGerald, B Bresnihan
Journal: Annals of the Rheumatic Diseases (2009)

To compare the performance of two interferon gamma release assays (IGRAs) and conventional screening tests in patients with inflammatory arthritis undergoing screening for latent tuberculosis infection (LTBI) before treatment with anti-tumour necrosis factor alpha (anti-TNFalpha) compounds.Successive patients were subjected to conventional LTBI screening, including a tuberculin skin test (TST). The T-SPOT.TB test was performed on all patients and the QuantiFERON-TB Gold test was performed on a large subset. The results of the IGRAs were compared with the results of conventional screening tests.A total 150 patients were evaluated. The majority (57.9%) had rheumatoid arthritis. Previous vaccination with Bacille Calmette-Guerin was confirmed in 82% of patients. No patient had received prior anti-TB treatment. A total of 57 patients (38.0%) had at least one positive conventional risk factor. In contrast, an unequivocally positive T-SPOT.TB test was seen in only 14/143 (9.8%). There was 98.2% agreement between the two IGRAs. Statistically significant associations were found between each of the IGRAs and both TST and risk history, but not chest x-ray (CXR). A positive IGRA result was significantly associated with increased age. TB was not reactivated in any patient during the follow-up period.This study suggests that IGRAs may be useful when screening for LTBI before anti-TNFalpha therapy in patients with immune-mediated inflammatory diseases. The observations reported here also highlight the inadequate performance of CXR as a marker of LTBI.
Connective Tissue Growth Factor Expressed in Tubular Epithelium Plays a Pivotal Role in Renal Fibrogenesis
Authors: Hirokazu Okada, Tomohiro Kikuta, Tatsuya Kobayashi, Tsutomu Inoue, Yoshihiko Kanno, Masaharu Takigawa, Takeshi Sugaya, Jeffrey B. Kopp, Hiromichi Suzuki
Journal: Journal of the American Society of Nephrology (2004)

Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-β. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-β1-induced CTGF. In these co-cultures, TGF-β1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-β1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-β1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-β1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-β1-dependent interstitial fibrosis.
Tissue Damage–Associated “Danger Signals” Influence T-cell Responses That Promote the Progression of Preneoplasia to Cancer
Authors: Ying He, Jikun Zha, Yamin Wang, Wenhua Liu, Xuanming Yang, Ping Yu
Journal: Cancer Research (2012)

T-cell responses may be shaped by sterile "danger signals" that are constituted by damage-associated molecular patterns (DAMP). However, whether and what type of adaptive immune responses are triggered in vivo by DAMPs induced by tumor progression are not well characterized. In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxinα(1)β(2) (LT) on their surface. Intriguingly, these tumor-activated T cells recruited macrophages to the lesion and were essential to promote the preneoplasia to invasive carcinoma in an LTβ receptor (LTβR)-dependent manner. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy.
Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia
Authors: Charuhas V. Thakar, Kamyar Zahedi, Monica P. Revelo, Zhaohui Wang, Charles E. Burnham, Sharon Barone, Shannon Bevans, Alex B. Lentsch, Hamid Rabb, Manoocher Soleimani
Journal: Journal of Clinical Investigation (2005)

Thrombospondin 1 (TSP-1) is a matricellular protein that inhibits angiogenesis and causes apoptosis in vivo and in vitro in several cancerous cells and tissues. Here we identify TSP-1 as the molecule with the highest induction level at 3 hours of IR injury in rat and mouse kidneys subjected to ischemia/reperfusion (IR) injury using the DNA microarray approach. Northern hybridizations demonstrated that TSP-1 expression was undetectable at baseline, induced at 3 and 12 hours, and returned to baseline levels at 48 hours of reperfusion. Immunocytochemical staining identified the injured proximal tubules as the predominant sites of expression of TSP-1 in IR injury and showed colocalization of TSP-1 with activated caspase-3. Addition of purified TSP-1 to normal kidney proximal tubule cells or cells subjected to ATP depletion in vitro induced injury as demonstrated by cytochrome c immunocytochemical staining and caspase-3 activity. The deleterious role of TSP-1 in ischemic kidney injury was demonstrated directly in TSP-1 null mice, which showed significant protection against IR injury–induced renal failure and tubular damage. We propose that TSP-1 is a novel regulator of ischemic damage in the kidney and may play an important role in the pathophysiology of ischemic kidney failure.
Hepatitis B virus genotypes: Do they play a role in the outcome of HBV infection?
Authors: Scott K. Fung, Anna S. F. Lok
Journal: Hepatology (2004)

Outcome ofSee Article on Page 865 H epatitis B virus (HBV) has been classified into 8 genotypes (A-H) based on an intergroup divergence of 8% or more in the complete nucleotide sequence.'JFigure 1 illustrates the geographic distribution of HBV genotypes, but existing information is incomplete, as data in many parts of the world are not available or are based on very small numbers of patients studied.Additionally, the distribution of HBV genotypes may vary with time and with population migration, as demonstrated in a recent study in the United States.3Furthermore, subtypes have now been identified within some genotypes.In the 2.5 years since our last editorial,' there has been an explosion of knowledge in the literature on the epidemiology of HBV genotypes, and their association with hepatitis B e antigen (HBeAg) seroconversion, activity of liver disease, and treatment response. HBV Genotypes, HBeAg Seroconversion and Outcome of Chronic HBV InfectionMost of the information on the clinical significance of HBV genotypes has been based on studies of patients with chronic HBV infection in Asia.Because of the preponderance of genotypes B and C in Asian countries, the studies are restricted to comparisons of patients with these two genotypes.Nevertheless, such comparisons provide very important information on the relation between HBV genotype B and C and the rate of progression of liver disease, since the age at the onset of infection is presumed to be the same (perinatal period) in the vast majority of patients.These studies clearly showed that compared to genotype C, HBV genotype B is associated with spontaneous HBeAg seroconversion at a younger age, less active liver disease, and a slower rate of progression to cirrhosis-3 Some studies also found that genotype B patients are less likely to have hepatitis flares and more likely to remain in remission after HBeAg seroc~nversion.~Most studies, in-
Treating asthma means treating airway smooth muscle cells
Authors: S. Zuyderduyn, M. B. Sukkar, A. Fust, S. Dhaliwal, J. K. Burgess
Journal: European Respiratory Journal (2008)

Asthma is characterised by airway hyperresponsiveness, airway inflammation and airway remodelling. Airway smooth muscle cells are known to be the main effector cells of airway narrowing. In the present paper, studies will be discussed that have led to a novel view of the role of airway smooth muscle in the pathogenesis of asthma in which airway hyperresponsiveness, remodelling and inflammation are, at least in part, attributable to airway smooth muscle. Furthermore, how this new view may lead to a change in the phenotyping and treatment of patients with asthma will be discussed.
Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment
Authors: A. Heintz, M. Damm, M. Brand, T. Koch, A. Deussen
Journal: Cardiovascular Research (2007)

AimsThis study addressed the hypotheses that the hypercapnic flow response in wild-type (WT) mouse heart is mainly mediated by nitric oxide (NO) and, thus, severely blunted in endothelial nitric oxide synthase knockout (eNOS-KO) mice and in WT mice after continuous pharmacological block (2 weeks) of NOS enzymes (WT-LN).
ERYTHROMYCIN IN LOCAL TREATMENT OF CUTANEOUS BACTERIAL INFECTIONS
Authors: Clarence S. Livingood
Journal: JAMA (1953)

Erythromycin, discovered by McGuire and his associates1in 1952, is a new antibiotic produced by a micro-organism (identified as a strain of Streptomyces erythreus that was isolated from a soil sample collected on the Island of Panay, Philippine Islands. This antibiotic is white, crystalline, soluble in water to the extent of about 2 mg. per milliliter, and highly soluble in some organic solvents, such as alcohol and acetone. It is a basic compound with an empiric formula that is thought to approximate C39H73NO13; there is no benzene ring structure in the formula. Stability data indicate that the dry crystalline compound is stable at room temperature for at least a year, but solutions of the antibiotic are comparatively unstable. The best stability is achieved with low temperature and neutral pH. At room temperature with a pH of 7, 86% activity remained after a storage period
Outcomes of Medical Management of Acute Type B Aortic Dissection
Authors: Anthony L. Estrera, Charles C. Miller, Hazim J. Safi, Jennifer S. Goodrick, Arash Keyhani, Eyal E. Porat, Paul E. Achouh, Riad Meada, Ali Azizzadeh, Jayesh Dhareshwar, Adnan Allaham
Journal: Circulation (2006)

Currently, the optimal treatment of acute type B aortic dissection remains controversial. The purpose of this study was to report early clinical outcomes of medical management for acute type B aortic dissection.Between January 2001 and March 2005, 129 consecutive patients with the confirmed diagnosis of acute type B aortic dissection were studied. Mean age was 61 years (range, 29 to 94), with 33.3% (43/129) female. Acute type B aortic dissection protocol was instituted with the intent to manage all patients medically. Indications for surgical intervention included rupture, aortic expansion, malperfusion, and intractable pain. All patients were followed-up after discharge. Hospital mortality was 10.1% (13/129), 19% (4/21) when vascular intervention was required, and 8.3% (9/108) when medical management was maintained. Early intervention was required in 21 cases (16.2%), 19 (14.7%) open vascular/aortic cases and 2 cases (1.6%) of percutaneous aortic interventions. Morbidity included rupture (4.7%), stroke (4.7%), paraplegia (8.5%), bowel ischemia (7%), acute renal failure (21%), dialysis requirement (13%), and peripheral ischemia (4.7%). Late vascular-related procedures were performed in 5.2% (6/116) of cases. Univariate risk factors for early mortality were rupture (P<0.0001), need for laparotomy (P<0.008), acute renal failure (P<0.0001), need for dialysis (P<0.0001), and lower extremity ischemia (P<0.0004). The only independent risk factors for hospital mortality by multiple logistic regression was rupture (P<0.0009), and independent risk factors for midterm death were history of chronic obstructive pulmonary disease (P<0.002) and low glomerular filtration rate (<57 mL/min; P<0.0001).Medical management for acute type B aortic dissection is associated acceptable outcomes. Outcomes of other management strategies, eg, endovascular stenting, for acute type B aortic dissection need to be compared with these results.
Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated
Authors: Shao H. Yang, Douglas A. Andres, H. Peter Spielmann, Stephen G. Young, Loren G. Fong
Journal: Journal of Clinical Investigation (2008)

Hutchinson-Gilford progeria syndrome (HGPS), a rare disease that results in what appears to be premature aging, is caused by the production of a mutant form of prelamin A known as progerin. Progerin retains a farnesyl lipid anchor at its carboxyl terminus, a modification that is thought to be important in disease pathogenesis. Inhibition of protein farnesylation improves the hallmark nuclear shape abnormalities in HGPS cells and ameliorates disease phenotypes in mice harboring a knockin HGPS mutation (LmnaHG/+). The amelioration of disease, however, is incomplete, leading us to hypothesize that nonfarnesylated progerin also might be capable of eliciting disease. To test this hypothesis, we created knockin mice expressing nonfarnesylated progerin (LmnanHG/+). LmnanHG/+ mice developed the same disease phenotypes observed in LmnaHG/+ mice, although the phenotypes were milder, and mouse embryonic fibroblasts (MEFs) derived from these mice contained fewer misshapen nuclei. The steady-state levels of progerin in LmnanHG/+ MEFs and tissues were lower, suggesting a possible explanation for the milder phenotypes. These data support the concept that inhibition of protein farnesylation in progeria could be therapeutically useful but also suggest that this approach may be limited, as progerin elicits disease phenotypes whether or not it is farnesylated.
Hypercalcemia and metastatic calcification
Authors: D.N.S Kerr
Journal: Cardiovascular Research (1997)

Time for primary review 27 days.

I grew up in Edinburgh, at the same latitude as Copenhagen, and then covered by a pall of coal smoke which gave it the sobriquet ‘auld reekie’. Many bandy-legged and dwarfed citizens carried the legacy of rickets contracted before the discovery of vitamin D, the fortification of food and the Clean Air Acts. However vitamin D, good in the right dose, is dangerous in overdose and there is no doubt that Gorm's Vikings miscalculated the dose–response curve of cod liver oil; a teaspoon would have been a better implement than their ladle or Mrs. T's tablespoon. In view of their formidable achievements, it is likely that the Vikings escaped the worst effects of vitamin D intoxication by irregular dosage and non-compliance. Their cavalier approach was repeated with more disastrous results after 1924 when high doses of tasteless ergocalciferol (vitamin D2) from irradiated ergosterol became available and were indiscriminately prescribed for rheumatoid arthritis, tuberculosis, Paget's disease and chilblains, in none of which it has been shown to produce benefit, and osteoporosis.

The effects of overdosage were described within four years of high dose ergocalciferol being released for sale; the condition was reviewed in a cluster of papers in the early 1950's [1–3]. Diagnosis was often delayed because the commonest symptoms were the non-specific ones of hypercalcemia — nausea, vomiting, weight loss, colic, constipation, thirst, polyuria, headache, weakness, apathy and depression roughly in that order [1]. Once suspected, the diagnosis was confirmed by the presence of hypercalcemia and renal impairment. Although vitamin D stimulates phosphate absorption, serum phosphate was often normal, as in Mrs. T, unless the renal damage was severe. Reduction of serum calcium by administration of cortisol distinguished this cause of hypercalcemia from hyperparathyroidism; one action of cortisol is to inhibit … 

* Corresponding author.
P2-298: Report on three consecutive randomized phase II trials using single-agent docetaxel and gemcitabine in diferent doses and schedules for patients in advanced non-small cell lung cancer (NSCLC)
Authors: Lothar R. Pilz, Nicholas Thatcher, Cornelius Kortsik, Gabriele Koschel, Jörg Mezger, Kathrin Schott von Römer, Christian Manegold
Journal: Journal of Thoracic Oncology (2007)
What about phonological facilitation, response-set membership, and phonological coactivation?
Authors: Peter A. Starreveld, Wido La Heij
Journal: Behavioral and Brain Sciences (1999)

We discuss two inconsistencies between Levelt et al.'s model and existing theory about, and data from, picture-word experiments. These inconsistencies show that the empirical support for weaver++ is much weaker than Levelt et al. suggest. We close with a discussion of the proposed explanation for phonological coactivation of near synonyms of a target word.
I<scp>NFERENCE AND</scp>C<scp>OMPUTATION WITH</scp>P<scp>OPULATION</scp>C<scp>ODES</scp>
Authors: Alexandre Pouget, Peter Dayan, Richard S. Zemel
Journal: Annual Review of Neuroscience (2003)

▪ Abstract In the vertebrate nervous system, sensory stimuli are typically encoded through the concerted activity of large populations of neurons. Classically, these patterns of activity have been treated as encoding the value of the stimulus (e.g., the orientation of a contour), and computation has been formalized in terms of function approximation. More recently, there have been several suggestions that neural computation is akin to a Bayesian inference process, with population activity patterns representing uncertainty about stimuli in the form of probability distributions (e.g., the probability density function over the orientation of a contour). This paper reviews both approaches, with a particular emphasis on the latter, which we see as a very promising framework for future modeling and experimental work.
Allosteric ligands for G protein-coupled receptors: A novel strategy with attractive therapeutic opportunities
Authors: Marco De Amici, Clelia Dallanoce, Ulrike Holzgrabe, Christian Tränkle, Klaus Mohr
Journal: Medicinal Research Reviews (2009)

Allosteric receptor ligands bind to a recognition site that is distinct from the binding site of the endogenous messenger molecule. As a consequence, allosteric agents may attach to receptors that are already transmitter-bound. Ternary complex formation opens an avenue to qualitatively new drug actions at G protein-coupled receptors (GPCRs), in particular receptor subtype selective potentiation of endogenous transmitter action. Consequently, suitable exploitation of allosteric recognition sites as alternative molecular targets could pave the way to a drug discovery paradigm different from those aimed at mimicking or blocking the effects of endogenous (orthosteric) receptor activators. The number of allosteric ligands reported to modulate GPCR function is steadily increasing and some have already reached routine clinical use. This review aims at introducing into this fascinating field of drug discovery and at providing an overview about the achievements that have already been made. Various case examples will be discussed in the framework of GPCR classification (family A, B, and C receptors). In addition, the behavior at muscarinic receptors of hybrid derivatives incorporating both an allosteric and an orthosteric fragment in a common molecular skeleton will be illustrated. © 2009 Wiley Periodicals, Inc. Med Res Rev, 30, No. 3, 463–549, 2010
Risk Prediction for Late-Stage Ovarian Cancer by Meta-analysis of 1525 Patient Samples
Authors: Markus Riester, Wei Wei, Levi Waldron, Aedin C. Culhane, Lorenzo Trippa, Esther Oliva, Sung-hoon Kim, Franziska Michor, Curtis Huttenhower, Giovanni Parmigiani, Michael J. Birrer
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundOvarian cancer causes more than 15000 deaths per year in the United States. The survival of patients is quite heterogeneous, and accurate prognostic tools would help with the clinical management of these patients.