tbuckley/cabot-search huggingface dataset:
Is overall asthma control being achieved? A hypothesis-generating study
Authors: E.D. Bateman, J. Bousquet, G.L. Braunstein
Journal: European Respiratory Journal (2001)

The efficacy of asthma therapy is traditionally measured using single end-points. In contrast, the aim of therapy is to achieve overall control, defined by management guidelines as achieving a number of treatment goals. These goals reflect expert opinion, rather than being evidence based. The objective of this study was to determine whether guideline-defined asthma control is achievable. Eight studies of salmeterol/fluticasone propionate combination therapy were analysed using three asthma control measures of varying stringency, derived from the guideline goals. For each measure, only patients meeting all goals were classified as controlled. The analysis demonstrated that asthma control, as defined by management guidelines, can be achieved. For a given therapy, similar proportions of patients achieved control irrespective of disease severity, suggesting that outcome expectations should not be reduced for patients with more severe disease. Substantially more patients achieved the target values for individual goals than achieved overall control, indicating that reliance on individual end-points is likely to result in significant overestimation of true control. The findings of this hypothesis-generating study should be prospectively tested. Future research will include a randomized controlled study designed to assess the proportion of patients able to achieve overall control of asthma when treatment is titrated appropriately.
Toxoplasma Polymorphic Effectors Determine Macrophage Polarization and Intestinal Inflammation
Authors: Kirk D.C. Jensen, Yiding Wang, Elia D. Tait Wojno, Anjali J. Shastri, Kenneth Hu, Lara Cornel, Erwan Boedec, Yi-Ching Ong, Yueh-hsiu Chien, Christopher A. Hunter, John C. Boothroyd, Jeroen P.J. Saeij
Journal: Cell Host & Microbe (2011)
Thymic stromal lymphopoietin: master switch for allergic inflammation
Authors: Yong-Jun Liu
Journal: The Journal of Experimental Medicine (2006)

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL) 7-like cytokine that triggers dendritic cell-mediated T helper (Th)2 inflammatory responses. TSLP is highly expressed by keratinocytes in skin lesions of patients with atopic dermatitis and is associated with dendritic cell activation in situ, suggesting that TSLP might be a master switch for allergic inflammation at the epithelial cell-dendritic cell interface. New reports now establish a direct link between TSLP expression and the pathogenesis of atopic dermatitis and asthma in vivo, and begin to reveal the molecular mechanisms underlying TSLP-induced allergic inflammation.
Early Anterior/Posterior Patterning of the Midbrain and Cerebellum
Authors: Aimin Liu, Alexandra L Joyner
Journal: Annual Review of Neuroscience (2001)

Transplantation studies performed in chicken embryos indicated that early anterior/posterior patterning of the vertebrate midbrain and cerebellum might be regulated by an organizing center at the junction between the midbrain and hindbrain. More than a decade of molecular and genetic studies have shown that such an organizer is indeed central to development of the midbrain and anterior hindbrain. Furthermore, a complicated molecular network that includes multiple positive and negative feedback loops underlies the establishment and refinement of a mid/hindbrain organizer, as well as the subsequent function of the organizer. In this review, we first introduce the expression patterns of the genes known to be involved in this patterning process and the quail-chick transplantation experiments that have provided the foundation for understanding the genetic pathways regulating mid/hindbrain patterning. Subsequently, we discuss the molecular genetic studies that have revealed the roles for many genes in normal early patterning of this region. Finally, some of the remaining questions and future directions are discussed.
A novel form of integrin dysfunction involving β1, β2, and β3 integrins
Authors: Alison McDowall, David Inwald, Birgit Leitinger, Alison Jones, Ri Liesner, Nigel Klein, Nancy Hogg
Journal: Journal of Clinical Investigation (2003)

The adhesion receptors known as integrins perform key functions for hematopoietic cells. The platelet integrin alphaIIbbeta3 is critical in hemostasis, and the beta1 and beta2 integrins on leukocytes have many roles in cell-mediated immunity. Mutations in the beta2 subunit lead to integrin nonexpression and to an immune deficiency, leukocyte adhesion deficiency-1. Mutations in either the alpha or beta subunit of alphaIIbbeta3 usually lead to integrin nonexpression and a bleeding tendency termed Glanzmann thrombasthenia. Here we describe a unique patient with clinical features of both Glanzmann thrombasthenia and leukocyte adhesion deficiency-1. The patient has normal expression of beta1, beta2, and beta3 integrins, but all are dysfunctional. The key findings are that "inside-out" signaling pathways leading to integrin activation are defective and that this is associated with abnormal integrin clustering. The integrins themselves are intact and capable of function following extracellular stimulation. T cell motility is normal, as are the expression levels and electrophoretic characteristics of all cytoskeletal and signaling proteins tested, except PKC-alpha, which has enhanced expression in the patient's cells. To our knowledge, this is the first description of a dysfunction affecting three classes of integrins. We propose that it is caused by a lesion in an intracellular factor or signaling pathway essential for integrin activation in hematopoietic cells and results in lack of regulation of clustering, an essential component of integrin-mediated adhesion.
Double-blind, Placebo-controlled Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis
Authors: Arata Azuma, Toshihiro Nukiwa, Eiyasu Tsuboi, Moritaka Suga, Shosaku Abe, Koichiro Nakata, Yoshio Taguchi, Sonoko Nagai, Harumi Itoh, Motoharu Ohi, Atsuhiko Sato, Shoji Kudoh
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without an effective therapy to date. In a double-blind, randomized, placebo-controlled trial, 107 patients were prospectively evaluated for efficacy of a novel compound, pirfenidone. The difference in the change in the lowest oxygen saturation by pulse oximetry (SpO2) during a 6-minute exercise test, the primary endpoint, from baseline to 6 months was not significant between the two groups (p = 0.0722). In a prespecified subset of patients who maintained a SpO2 greater than 80% during a 6-minute exercise test at baseline, the lowest SpO2 improved during a 6-minute exercise test in the pirfenidone group at 6 and 9 months (p = 0.0069 and 0.0305, respectively). Positive treatment effect was demonstrated in secondary endpoints: (1) change in VC measurements at 9 months (p = 0.0366) and (2) episodes of acute exacerbation of IPF occurring exclusively in the placebo group during the 9 months (p = 0.0031). Significant adverse events were associated with pirfenidone; however, adherence to treatment regimen was similar between pirfenidone and placebo groups. In conclusion, treatment with pirfenidone improved VC and prevented acute exacerbation of IPF during the 9 months of follow-up. Future long-term studies are needed to clarify the overall safety and efficacy of pirfenidone in IPF.
Sympathetic Nerve Sprouting, Electrical Remodeling, and Increased Vulnerability to Ventricular Fibrillation in Hypercholesterolemic Rabbits
Authors: Yen-Bin Liu, Chau-Chung Wu, Long-Sheng Lu, Ming-Jai Su, Chii-Wann Lin, Shien-Fong Lin, Lan S. Chen, Michael C. Fishbein, Peng-Sheng Chen, Yuan-Teh Lee
Journal: Circulation Research (2003)

Whether hypercholesterolemia (HC) can induce proarrhythmic neural and electrophysiological remodeling is unclear. We fed rabbits with either high cholesterol (HC, n=10) or standard (S, n=10) chows for 12 weeks (protocol 1), and with HC (n=12) or S (n=10) chows for 8 weeks (protocol 2). In protocol 3, 10 rabbits were fed with various protocols to observe the effects of different serum cholesterol levels. Results showed that the serum cholesterol levels were 2097+/-288 mg/dL in HC group and 59+/-9 mg/dL in S group for protocol 1 and were 1889+/-577 mg/dL in HC group and 50+/-21 mg/dL in S group for protocol 2. Density of growth-associated protein 43- (GAP43) and tyrosine hydroxylase- (TH) positive nerves in the heart was significantly higher in HC than S in protocol 1. Compared with S, HC rabbits had longer QTc intervals, more QTc dispersion, longer action potential duration, increased heterogeneity of repolarization and higher peak calcium current (ICa) density (14.0+/-3.1 versus 9.1+/-3.4 pA/pF; P<0.01) in protocol 1 and 2. Ventricular fibrillation was either induced or occurred spontaneously in 9/12 of hearts of HC group and 2/10 of hearts in S group in protocol 2. Protocol 3 showed a strong correlation between serum cholesterol level and nerve density for GAP43 (R2=0.94; P<0.001) and TH (R2=0.91; P<0.001). We conclude that HC resulted in nerve sprouting, sympathetic hyperinnervation, and increased ICa. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.
Regulating research, regulating professionals
Authors: Mary Dixon-Woods
Journal: Journal of the Royal Society of Medicine (2010)

This paper was published as Journal of the Royal Society of Medicine, 2010, 103 (4), pp. 125-126.  It is available from http://jrsm.rsmjournals.com/cgi/content/citation/103/4/125.  DOI: 10.1258/jrsm.2010.10k013
TNF/TNFR FAMILY MEMBERS IN COSTIMULATION OF T CELL RESPONSES
Authors: Tania H. Watts
Journal: Annual Review of Immunology (2004)

Several members of the tumor necrosis factor receptor (TNFR) family function after initial T cell activation to sustain T cell responses. This review focuses on CD27, 4-1BB (CD137), OX40 (CD134), HVEM, CD30, and GITR, all of which can have costimulatory effects on T cells. The effects of these costimulatory TNFR family members can often be functionally, temporally, or spatially segregated from those of CD28 and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival. Depending on the disease condition, stimulation via costimulatory TNF family members can exacerbate or ameliorate disease. Despite these complexities, stimulation or blockade of TNFR family costimulators shows promise for several therapeutic applications, including cancer, infectious disease, transplantation, and autoimmunity.
Renal and systemic hemodynamic effects of synthetic atrial natriuretic peptide in the anesthetized rat.
Authors: B R Dunn, I Ichikawa, J M Pfeffer, J L Troy, B M Brenner
Journal: Circulation Research (1986)

To characterize the hemodynamic events responsible for alterations in renal function during administration of atrial natriuretic peptide, we studied the systemic, renal, and glomerular circulatory effects of intravenous rANP[126-149], administered as a 4 micrograms/kg prime and 0.5 microgram/kg per minute continuous infusion in anesthetized, euvolemic rats. With this protocol, a small decline in mean systemic arterial blood pressure occurred in the context of markedly enhanced urinary sodium excretion, hemoconcentration, and reduced left ventricular end-diastolic pressure and +dP/dt. However, despite a significant decrement in renal vascular resistance, total peripheral resistance remained constant, thereby denoting a preferential renal vasodilatory effect of this peptide in vivo. Whole kidney and single nephron GFR increased by approximately 20%, while effective renal and glomerular plasma flow rates remained stable, resulting in a substantial rise in filtration fraction. Of all the parameters potentially capable of augmenting single nephron GFR, only glomerular capillary hydraulic pressure increased significantly and therefore accounted entirely for the hyperfiltration observed during ANP infusion. This rise in glomerular capillary pressure, in turn, resulted from afferent arteriolar vasodilatation and concurrent efferent arteriolar vasoconstriction, findings that proved independent of both endogenous angiotensin II activity and ANP-induced reductions in renal perfusion pressure. These renal hemodynamic effects are unique when compared with actions of previously studied renal vasodilatory agents.
PERIVASCULAR REACTIONS IN LUNG AND LIVER FOLLOWING INTRAVENOUS INJECTION OF STREPTOCOCCI INTO PREVIOUSLY SENSITIZED ANIMALS
Authors: Charles H. Hitchcock, Anthony R. Camero, Homer F. Swift
Journal: The Journal of Experimental Medicine (1934)

Intravenous inoculation of small doses of non-hemolytic streptococci into previously sensitized rabbits is usually followed by the appearance of perivascular cellular aggregates in lung and liver. The characteristic cell in these aggregates is moderately large, with vesicular nucleus, prominent nucleoli, clumped chromatin, and basophilic cytoplasm. In addition, the lesions contain small lymphocytes and granulocytes. This lesion is easily differentiated by architecture and cell content from normally occurring lymphoid aggregates, and from spontaneous rabbit hepatic cirrhosis. This mononuclear response does not occur when the intravenous dose is large enough to cause death of the animal within 24 hours. In spleen and lymph nodes the characteristic basophilic cells, which normally occur in these organs, are present in increased numbers. Following intravenous treatment alone, or sensitization without intravenous treatment, the lesions occur much less frequently, and when present are smaller and more sparsely found. Inasmuch as in the present series of experiments this lesion was not found in normal animals, and infrequently in those treated by the intravenous route alone, it is suggested that the preliminary sensitization serves to enhance the animal's reactivity to the antigen. In this way a small dose of bacteria is capable of eliciting the cellular phenomenon, which in unsensitized animals appears only when larger doses of antigen are administered over longer periods of time. Too large a dose of antigen, however, results in shock and cell death rather than proliferation.
Phase I Trial of Combined-Modality Therapy for Localized Esophageal Cancer: Escalating Doses of Continuous-Infusion Paclitaxel With Cisplatin and Concurrent Radiation Therapy
Authors: Baruch Brenner, David H. Ilson, Bruce D. Minsky, Manjit S. Bains, William Tong, Mithat Gonen, David P. Kelsen
Journal: Journal of Clinical Oncology (2003)

To define the maximum-tolerated dose (MTD) of paclitaxel when given as a weekly 96-hour infusion with cisplatin and radiotherapy for patients with esophageal cancer.Thirty-four patients with locally advanced esophageal cancer and three patients with local recurrence or positive resection margins were treated. Weekly paclitaxel doses of 10, 20, 30, 40, 60, and 80 mg/m(2), given as a continuous 96-hour infusion, were administered with weekly cisplatin, 30 mg/m(2) on day 1, weeks 1 to 6, and concurrent radiation (50.4 Gy). Plasma paclitaxel steady-state levels were measured.Dose-limiting toxicity, defined as a treatment break longer than 2 weeks for toxicity, occurred in one patient in the 80-mg/m(2)/wk dose level. Major causes for any (including < or = 2 weeks) treatment breaks were mediport complications and neutropenic fever, which occurred mostly at that dose level. At a paclitaxel dose of 60 mg/m(2)/wk, myelosuppression, mostly neutropenia, was relatively mild and transient; stomatitis, esophagitis, diarrhea. and peripheral neuropathy were uncommon and usually of grade 2 or less. Therefore, the MTD was established at 60 mg/m(2)/wk. The mean steady-state concentration of paclitaxel at the MTD was 17.2 nmol/L. Complete (R0) resection was possible in 16 (73%) of 22 patients who underwent subsequent surgery, and the pathologic complete response rate was 24%.Weekly, 96-hour infusion of paclitaxel 60 mg/m(2)/wk, given with concurrent cisplatin and radiotherapy, is a safe and tolerable regimen for patients with localized esophageal cancer. Preliminary efficacy data are encouraging. This regimen is the basis of ongoing Radiation Therapy Oncology Group phase II randomized trials in esophageal and gastric cancers.
Malfunctioning Mitral Valve-in-Valve Bioprosthesis Assessment by 3-Dimensional Transesophageal Echocardiography
Authors: Carmen Olmos, Pedro Marcos-Alberca, Fabián Islas, Dafne Viliani, Carlos Almería, Enrique Rodríguez, Carlos Macaya, Leopoldo Pérez de Isla
Journal: Circulation (2013)
Platelet-Derived Growth Factor Receptor Regulates Myeloid and Monocytic Differentiation of HL-60 Cells
Authors: Gudrun Reiterer, Andrew Yen
Journal: Cancer Research (2007)

Here, we show that the platelet-derived growth factor receptor (PDGFR) regulates myeloid and monocytic differentiation of HL-60 myeloblastic leukemia cells in response to retinoic acid (RA) and vitamin D3 (D3), respectively. Both RA and D3 decreased the expression of PDGFR-alpha and PDGFR-beta throughout differentiation. When cells were treated with the PDGFR inhibitor AG1296 in addition to RA or D3, signs of terminal differentiation such as inducible oxidative metabolism and cell substrate adhesion were enhanced. These changes were accompanied by an increased extracellular signal-regulated kinase 1/2 activation. AG1296 also resulted in elevated expression of differentiation markers CD11b and CD66c when administered with RA or D3. Interestingly, other markers did not follow the same pattern. Cells receiving AG1296 in addition to RA or D3 showed decreased G1-G0 arrest and CD14, CD38, and CD89 expression. We thus provide evidence that certain sets of differentiation markers can be enhanced, whereas others can be inhibited by the PDGFR pathway. In addition, we found calcium levels to be decreased by RA and D3 but increased when AG1296 was given in addition to RA or D3, suggesting that calcium levels decrease during myeloid or monocytic differentiation, and elevated calcium levels can disturb the expression of certain differentiation markers.
Differential Gene Expression in Metastasizing Cells Shed from Kidney Tumors
Authors: Maximilian Bockhorn, Sylvie Roberge, Cristina Sousa, Rakesh K. Jain, Lance L. Munn
Journal: Cancer Research (2004)

Abstract We developed a novel orthotopic mouse tumor model of renal cell carcinoma to collect and characterize cells spontaneously shed from SN12C (renal cell carcinoma) and SN12L1 (high metastatic variant of SN12C) tumors grown in kidneys of severe combined immunodeficient mice. Viability of the shed cell population was greater for SN12L1 tumors (25%) compared with SN12C tumors (11%, P &amp;lt; 0.05). Gene array analysis of 23 genes involved in metastasis showed that CD44, α3 integrin, and caveolin were down-regulated in the shed tumor cells compared with their primary counterparts, and blocking α3 integrin or CD44 function inhibited attachment and migration of both cell lines. These results suggest that cohesion of the cells within the primary tumor mediated by CD44 and α3 integrins hinders metastasis and that shedding is a passive process not necessarily mediated by cell migration in these tumors. Furthermore, resistance to apoptosis may enhance metastasis in the higher metastatic tumor.
Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura.
Authors: Benjamin P Berman, Barret D Pfeiffer, Todd R Laverty, Steven L Salzberg, Gerald M Rubin, Michael B Eisen, Susan E Celniker
Journal: Genome biology (2004)

The identification of sequences that control transcription in metazoans is a major goal of genome analysis. In a previous study, we demonstrated that searching for clusters of predicted transcription factor binding sites could discover active regulatory sequences, and identified 37 regions of the Drosophila melanogaster genome with high densities of predicted binding sites for five transcription factors involved in anterior-posterior embryonic patterning. Nine of these clusters overlapped known enhancers. Here, we report the results of in vivo functional analysis of 27 remaining clusters. We generated transgenic flies carrying each cluster attached to a basal promoter and reporter gene, and assayed embryos for reporter gene expression. Six clusters are enhancers of adjacent genes: giant, fushi tarazu, odd-skipped, nubbin, squeeze and pdm2; three drive expression in patterns unrelated to those of neighboring genes; the remaining 18 do not appear to have enhancer activity. We used the Drosophila pseudoobscura genome to compare patterns of evolution in and around the 15 positive and 18 false-positive predictions. Although conservation of primary sequence cannot distinguish true from false positives, conservation of binding-site clustering accurately discriminates functional binding-site clusters from those with no function. We incorporated conservation of binding-site clustering into a new genome-wide enhancer screen, and predict several hundred new regulatory sequences, including 85 adjacent to genes with embryonic patterns. Measuring conservation of sequence features closely linked to function - such as binding-site clustering - makes better use of comparative sequence data than commonly used methods that examine only sequence identity.
Podocyte-Specific Loss of Functional MicroRNAs Leads to Rapid Glomerular and Tubular Injury
Authors: Jacqueline Ho, Kar Hui Ng, Seymour Rosen, Ales Dostal, Richard I. Gregory, Jordan A. Kreidberg
Journal: Journal of the American Society of Nephrology (2008)

MicroRNAs (miRNAs) are in a class of endogenous, small, noncoding RNAs that exert their effects through posttranscriptional repression of specific target mRNAs. Although miRNAs have been implicated in the regulation of diverse biologic processes, little is known about miRNA function in the kidney. Here, mice lacking functional miRNAs in the developing podocyte were generated through podocyte-specific knockout of Dicer, an enzyme required for the production of mature miRNAs (Nphs2-Cre; Dicer(flx/flx)). Podocyte-specific loss of miRNAs resulted in significant proteinuria by 2 wk after birth, rapid progression of marked glomerular and tubular injury beginning at 3 wk, and death by 4 wk. Expression of the slit diaphragm proteins nephrin and podocin was decreased, and expression of the transcription factor WT1 was relatively unaffected. To identify miRNA-mRNA interactions that contribute to this phenotype, we profiled the glomerular expression of miRNAs; three miRNAs expressed in glomeruli were identified: mmu-miR-23b, mmu-miR-24, and mmu-miR-26a. These results suggest that miRNA function is dispensable for the initial development of glomeruli but is critical to maintain the glomerular filtration barrier.