tbuckley/cabot-search huggingface dataset:
Observations on the microenvironmental nature of cartilage degradation in rheumatoid arthritis
Authors: D. E Woolley, L. C Tetlow
Journal: Annals of the Rheumatic Diseases (1997)

Over the past 40 years rheumatoid arthritis (RA) has been the subject of extensive immunological and histological investigations. Rheumatoid synovial tissues, obtained from synovectomy, joint arthroplasty or biopsy have been examined by various pathologists and researchers using a range of ever more sophisticated techniques. From conventional histology using haematoxylin and eosin, to immunolocalisation, in situ hybridisation, and more recently to the use of extracted RNA for specific gene analysis. From early studies describing synovial A and B cells as the major components of rheumatoid synovium, we now have a better understanding of T cell subsets, monocyte-macrophage populations, and the expression of disease related genes such as cytokines and proteinases. This knowledge undoubtedly provides a better understanding of the inflammatory processes that operate in rheumatoid synovial tissue; but the cardinal feature of RA is cartilage and bone degradation. Far fewer studies have been reported on these sites of cartilage erosion or bone loss, yet it is here that the catabolic processes responsible for joint destruction are manifest.

Our interest in the ‘rheumatoid lesion’, a term used to describe the cartilage-pannus junction or sites of cartilage erosion, started in 1976 with the finding of the enzyme collagenase at sites of cartilage loss.1 2 Since then we have examined numerous cartilage-pannus specimens derived from more than 150 different cases of knee joint surgery, using a variety of immunological and histochemical techniques to identify specific cell types and different matrix degrading enzymes. During these studies we have become aware of the broad range of histological findings and the variations in proteinase expression.3 4 As knowledge of the mechanisms responsible for joint destruction is essential for the development of preventative pharmacological treatments, this overview presents our observations on the complex cellular and enzymic processes involved in cartilage degradation and subchondral bone remodelling of …
Role of Cardiac Myosin Binding Protein C in Sustaining Left Ventricular Systolic Stiffening
Authors: Bradley M. Palmer, Dimitrios Georgakopoulos, Paul M. Janssen, Yuan Wang, Norman R. Alpert, Diego F. Belardi, Samantha P. Harris, Richard L. Moss, Patrick G. Burgon, Christine E. Seidman, J.G. Seidman, David W. Maughan, David A. Kass
Journal: Circulation Research (2004)

Despite advances in the molecular biology of cardiac myosin binding protein-C (cMyBP-C), little is understood about its precise role in muscle contraction, particularly in the intact heart. We tested the hypothesis that cMyBP-C is central to the time course and magnitude of left ventricular systolic elastance (chamber stiffening), and assessed mechanisms for this influence in intact hearts, trabeculae, and skinned fibers from wild-type (+/+) and homozygous truncated cMyBP-C (t/t) male mice. cMyBP-C protein was not detected by gel electrophoresis or Western blot in t/t myocardium. cMyBP-C t/t ventricles displayed reduced peak elastance, but more strikingly a marked abbreviation of the systolic elastance time course, which peaked earlier (27.6±2.1 ms) than in +/+ controls (47.8±1.6 ms). Control hearts reached only 42±4% of maximum elastance at the onset of ejection, with substantial further stiffening during ejection. This contrasted to t/t mutants, which reached 77±3% of peak elastance before ejection of peak. These unusual findings were not observed in alternative models involving severe cardiomyopathy, but were recapitulated in a cMyBP-C null mouse. The abbreviated elastance time course and lower peak were consistent with earlier time-to-peak trabecular tension, increased unloaded shortening velocity in t/t skinned muscle strips, and dramatically reduced myofilament stiffness at diastolic calcium concentrations. These results provide novel insights into the role of cMyBP-C in myocardial systolic mechanics. Abnormal sarcomere shortening velocity and abbreviated muscle stiffening may underlie development of cardiac dysfunction associated with deficient incorporation of cMyBP-C.
Combination Therapy Enhances the Inhibition of Tumor Growth with the Fully Human Anti–Type 1 Insulin-Like Growth Factor Receptor Monoclonal Antibody CP-751,871
Authors: Bruce D. Cohen, Deborah A. Baker, Catherine Soderstrom, George Tkalcevic, Ann Marie Rossi, Penny E. Miller, Mark W. Tengowski, Faye Wang, Antonio Gualberto, Jean S. Beebe, James D. Moyer
Journal: Clinical Cancer Research (2005)

The insulin-like growth factor (IGF) signaling pathway is implicated in cellular mitogenesis, angiogenesis, tumor cell survival, and tumorigenesis. Inhibition of this pathway results in decreased cell growth, inhibition of tumor formation in animal models, and increased apoptosis in cells treated with cytotoxic chemotherapy. We generated and characterized a human monoclonal antibody that targeted the IGF receptor.By use of XenoMouse technology, we generated CP-751,871, a fully human IgG2 antibody with high affinity (K(d) = 1.5 nmol/L) for human IGF-1R and evaluated its biological, pharmacologic, and antitumor properties.This antibody blocks binding of IGF-1 to its receptor (IC(50) 1.8 nmol/L), IGF-1-induced receptor autophosphorylation (IC(50) 0.42 nmol/L) and induced the down-regulation of IGF-1R in vitro and in tumor xenografts. The extent of IGF-1R down-regulation in vivo was proportional to CP-751,871 concentrations in the serum of tumor-bearing mice. Pharmacokinetic profiles in cynomolgus monkeys indicated a close to linear increase of exposure following i.v. dosing of antibody in the range of 3 to 100 mg/kg. CP-751,871 showed significant antitumor activity both as a single agent and in combination with Adriamycin, 5-fluorouracil, or tamoxifen in multiple tumor models. A biomarker assay was developed to establish the relationship between circulating antibody concentrations and down-regulation of IGF-1R in peripheral blood cells. The concentration of CP-751,871 required to down-regulate 50% of IGF-1R on peripheral blood cells was 0.3 nmol/L.These data suggest that inhibition of the IGF cascade by use of this monoclonal antibody may be of clinical benefit in the treatment of human cancers.
Giant cell arteritis associated with demyelinating polyradiculoneuropathy
Authors: M G. GASALLA
Journal: Annals of the Rheumatic Diseases (2001)

Auditory neurons are selective for temporal sound information that is important for rhythm, pitch, and timbre perception. Traditional models assume that periodicity information is represented either by the discharge rate of tuned modulation filters or synchrony in the discharge pattern. Compelling evidence for an invariant rate or synchrony code, however, is lacking and neither of these models account for how the sound envelope shape is encoded. We examined the neuronal representation for envelope shape and periodicity in the cat central nucleus of the inferior colliculus (CNIC) with modulated broadband noise that lacks spectral cues and produces a periodicity pitch percept solely based on timing information. The modulation transfer functions of CNIC neurons differed dramatically across stimulus conditions with identical periodicity but different envelope shapes implying that shape contributed significantly to the neuronal response. We therefore devised a shuffled correlation procedure to quantify how periodicity and envelope shape contribute to the temporal discharge pattern. Sustained responses faithfully encode envelope shape at low modulation rates but deteriorate and fail to account for timing and envelope information at high rates. Surprisingly, onset responses accurately entrained to the stimulus and provided a means of encoding repetition information at high rates. Finally, we demonstrate that envelope shape information is accurately reflected in the population discharge pattern such that shape is readily discriminated for repetition frequencies up to ∼100 Hz. These results argue against conventional rate- or synchrony-based codes and provide two complementary temporal mechanisms by which CNIC neurons can encode envelope shape and repetition information in natural sounds.
The rituals of explanation
Authors: Jeffrey Foss
Journal: Behavioral and Brain Sciences (2006)

Boyer &amp; Lienard's (B&amp;L's) explanation of ritualized behavior is plausible because it fits so well with elementary facts about evolution of plasticity in our behavioral repertoire. Its scope, however, may be broader than its authors explicitly admit. Science itself may be illuminated as ritual behavior. Science, like other rituals, can sustain both healthy and pathological forms.
Issues at the interface between primary and secondary care in the management of common respiratory disease bullet 1: The challenge of improving the delivery of lung cancer care
Authors: M. F Muers, W. F Holmes, C. Littlewood
Journal: Thorax (1999)

The purpose of this study was to determine if there is an association between maternal herpes simplex virus (HSV) infection and pre-eclampsia/eclampsia or gestational hypertension. The US Nationwide Inpatient Sample database was searched for women aged 15–44 years who delivered in a hospital between 2005 and 2014. The patients were categorized into those with and without HSV and pre-eclampsia/eclampsia and gestational hypertension were compared between the groups. The analytic sample size (n=8 264 076) was equivalent to a population-based sample size of 40 653 030 patients. After adjusting for significant variables including age, race, income, insurance status, diabetes mellitus (DM), gestational DM, obesity, and multiple gestations, multivariate regression analysis indicated that HSV was associated with a higher OR for gestational hypertension (adjusted OR 1.038; 95% CI 1.004 to 1.072). However, HSV was not associated with pre-eclampsia/eclampsia (OR 1.001; 95% CI 0.968 to 1.035) in univariate regression analysis. The results of the current study suggest that HSV infection is associated with gestational hypertension but not pre-eclampsia. Given the prevalence of HSV infection and its potential association with hypertensive disorders of pregnancy, further study of HSV and hypertension in pregnancy is warranted.
Malignant mesothelioma due to environmental exposure to erionite: follow-up of a Turkish emigrant cohort
Authors: M Metintas, G Hillerdal, S Metintas
Journal: European Respiratory Journal (1999)

The incidence of malignant mesothelioma is extremely high in some Turkish villages where there is a low-level environmental exposure to erionite, a fibrous zeolite. The best known example is the village of Karain. However, since epidemiological studies are difficult to perform in Turkey, the incidence and the dose-response curve have not been thoroughly examined. A small cohort of immigrants from Karain who have lived in Sweden for many years were studied. Exposure data, i.e. the time residing in Karain, and hospital records including pathological diagnosis, were recorded. The cohort consisted of 162 people. During the observation time, 18 deaths occurred, 14 (78%) of which were due to malignant pleural mesothelioma. In addition, there were five patients with mesothelioma who were still alive, one of whom had a peritoneal mesothelioma. Thus, the risk of mesothelioma is 135-times and 1,336-times greater in males and females, respectively, than for the same sex and age groups in Sweden. The risk increased with duration of residence.
FANCD2 Is a Potential Therapeutic Target and Biomarker in Alveolar Rhabdomyosarcoma Harboring the PAX3–FOXO1 Fusion Gene
Authors: Mamata Singh, Justin M. Leasure, Christopher Chronowski, Brian Geier, Kathryn Bondra, Wenrui Duan, Lauren A. Hensley, Miguel Villalona-Calero, Ning Li, Anthony M. Vergis, Raushan T. Kurmasheva, Changxian Shen, Gary Woods, Nikhil Sebastian, Denise Fabian, Rita Kaplon, Sue Hammond, Kamalakannan Palanichamy, Arnab Chakravarti, Peter J. Houghton
Journal: Clinical Cancer Research (2014)

Alveolar rhabdomyosarcoma that harbors the PAX3-FOXO1 fusion gene (t-ARMS) is a common and lethal subtype of this childhood malignancy. Improvement in clinical outcomes in this disease is predicated upon the identification of novel therapeutic targets.Robust mouse models were used for in vivo analysis, and molecular studies were performed on xenografts treated in parallel. Two independent patient sets (n = 101 and 124) of clinically annotated tumor specimens were used for analysis of FANCD2 levels and its association with clinical and molecular characteristics and outcomes.Our xenograft studies reveal a selective suppression of FANCD2 by m-TOR kinase inhibition and radiosensitization of the t-ARMS line only. In the initial patient set, we show that FANCD2 transcript levels are prognostic in univariate analysis, and are significantly associated with metastatic disease and that the copresence of the translocation and high expression of FANCD2 is independently prognostic. We also demonstrate a significant and nonrandom enrichment of mTOR-associated genes that correlate with FANCD2 gene expression within the t-ARMS samples, but not within other cases. In the second patient set, we show that on a protein level, FANCD2 expression correlates with PAX3-FOXO1 fusion gene and is strongly associated with phospho-P70S6K expression in cases with the fusion gene.Our data demonstrate that FANCD2 may have a significant role in the radiation resistance and virulence of t-ARMS. Indirectly targeting this DNA repair protein, through mTOR inhibition, may represent a novel and selective treatment strategy.
Controversies and issues in developmental theories of mind: Some constructive remarks
Authors: Steven R. Quartz, T. J. Sejnowski
Journal: Behavioral and Brain Sciences (1997)

As the commentaries reveal, cognitive neuroscience's first steps toward a theory of development are marked by vigorous debate, ranging from basic points of definition to the fine details of mechanism. In this Response, we present the neural constructivist position on this broad spectrum of issues, from basic questions such as what sets constructivism apart from other theories (particularly selectionism) to its relation to behavioral theories and to its underlying mechanisms. We conclude that the real value of global theories at this stage of cognitive neuroscience is not just their answers but the new set of research questions they pose.
Magnetic resonance assessment of diffuse lung injury in rats
Authors: Miwa Morikawa, Yukihiro Umeda, Masaki Anzai, Yoshiki Demura, Chisato Honjo, Maiko Kadowaki, Yasuyuki Sumida, Shingo Ameshima, Takeshi Ishizaki, Hidemasa Uematsu, Hirohiko Kimura, Hidehiko Okazawa, Tamotsu Ishizuka
Journal: European Respiratory Journal (2013)

Background; Recent studies have reported the effectiveness of magnetic resonance imaging (MRI) for diagnosing pulmonary nodules. However, its utility for cases of diffuse lung injury remains unknown.  Purpose; We evaluated the effectiveness of MRI for detecting diffuse lung injury in experimental animals.  Methods; Studies were performed with 18 healthy male rats, which were divided into 3 groups; no experimental intervention (control group, n=6), pulmonary edema induced by ligation of the inferior vena cava and intravenous injection of 20% body-weight Ringer’s solution after anaesthesia (ED group, n=6), and interstitial pneumonitis induced by bleomycin (IP group, n=6). After euthanasia, the lungs were inflated by use of a tracheotomy to a pressure of 20 cm H 2 O then excised en bloc. Each specimen was placed in a plastic tube then examined by MRI, with T1 and T2 values acquired by analyzing the obtained images.  Results; There was clear visualization provided by the MR images of the lung vascular system, bronchi, and parenchyma in all groups. In the ED and IP groups, increases in diffuse signals from the lung parenchyma were noted, while no such findings were observed in the control group. T1 and T2 values in the ED and IP groups were significantly increased as compared with the control (P
Regulation of granulocyte apoptosis and implications for anti-inflammatory therapy
Authors: E R CHILVERS, A G ROSSI, J MURRAY, C HASLETT
Journal: Thorax (1998)

The elimination of unwanted cells is now regarded as an essential component of many normal biological programmes. These include embryonic remodelling, the removal of autoreactive thymic T cells, and the disposal of senescent enterocytes at the villus tip. Hence cell death, in particular apoptosis or “programmed cell death”, appears to be a prerequisite for life.1 In the particular example of inflammation many of the unique features of apoptosis, such as the retention of plasma membrane integrity, the loss of the cytotoxic and secretory capacity of the cell, and the ability of apoptotic cells to be recognised and phagocytically removed, suggest that this remarkable process may play a key role in limiting tissue injury and facilitating the successful resolution of inflammation.2-5 Furthermore, the ingestion of apoptotic cells by macrophages, unlike the uptake of other biological and non-biological material, fails to induce a secretory or pro-inflammatory response.6 7 Although a number of different cells within the lung have the capacity to undergo apoptosis (including the bronchial epithelial cell and type II pneumocyte8 9), the central role of the granulocyte as the primary effector cell in most forms of lung and airway wall inflammation, coupled with the huge potential for these cells to induce tissue injury if not cleared, marks the apoptotic capacity of these cells as being of particular importance in lung inflammation.

Despite the considerable interest generated by the discovery that neutrophils and eosinophils undergo constitutive apoptosis when aged in vitro,2 10 a process that results in their ingestion by either …
Immunochemical evidence for an additional H-2 region closely linked to H-2D.
Authors: T H Hansen, S E Cullen, D H Sachs
Journal: The Journal of Experimental Medicine (1977)

Anti-H-2 reagents have been tested on solubilized spleen cell preparations in combinations expected to be specific for D region products. Two different types of molecules were detected. One showed the expected reactivity with both antisera to private and antisera to public specificities. However, an additional molecule was detected which reacted only with antisera to public specificities. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis migration patterns indicated that both products have a similar molecular size of approximately 45,000 daltons. The data therefore present chemical evidence for the existence of a third H-2-associated gene product of 45,000 mol wt in addition to the classical H-2K and H-2D antigens.
Accuracy of oxygen delivery by liquid oxygen canisters
Authors: MJ Kampelmacher, PB Cornelisse, GP Alsbach, RG van Kesteren, CF Melissant, JM Douze, JW Lammers
Journal: European Respiratory Journal (1998)

The oxygen flow rate delivered by liquid oxygen canisters may be less than intended, owing to inaccuracies of the set flow rates and/or as a result of the outflow resistance caused by the humidifier, oxygen tubing, delivery or conserving device. The aim of this study was to investigate the accuracy of oxygen delivery by liquid oxygen canisters at different flow rates and levels of outflow resistance. Four stationary and 18 portable liquid oxygen canisters from three manufacturers were tested. All flows were measured using a Timemeter RT 200 Calibration Analyser. An adjustable obstruction was used to calculate the effect of the outflow resistance on the delivered flow rate. The measured and set flow rates of both stationary and portable canisters were strongly correlated. Expressed as a percentage of the set flow rate, the measured flow rate of the canisters varied from 36-128%, with the lowest values at flow rates &lt;1 L x min(-1). Sixty-two (26%) of the measured flow rates differed &gt; or =10% from the set flow rate. A difference of 0.5-1.0 L x min(-1) occurred in 16 (7%) of the measurements, but only at set flow rates &gt;2 L x min(-1). Irrespective of the set flow rate, the measured flow rate was hardly affected by the outflow resistance. We conclude that the accuracy of oxygen delivery by liquid oxygen canisters depends on the inaccuracy of the set flow rates rather than on the outflow resistance, even at high flow rates. Although the differences between the measured and set flow rates were mostly small, they may have clinical significance, particularly in patients with chronic obstructive pulmonary disease. To prevent inaccuracy, monthly checks of the canisters by the oxygen provider at the patient's home are more important than yearly maintenance.
Effectiveness of an interactive platform, and the ESC/HFA heartfailurematters.org website in patients with heart failure: design of the multicentre randomized e‐Vita heart failure trial
Authors: Kim P. Wagenaar, Berna D.L. Broekhuizen, Kenneth Dickstein, Tiny Jaarsma, Arno W. Hoes, Frans H. Rutten
Journal: European Journal of Heart Failure (2015)
Phase I and Pharmacokinetic Study of DE-310 in Patients with Advanced Solid Tumors
Authors: Otto Soepenberg, Maja J. A. de Jonge, Alex Sparreboom, Peter de Bruin, Ferry A. L. M. Eskens, Gerda de Heus, Jantien Wanders, Peter Cheverton, Murray P. Ducharme, Jaap Verweij
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To assess the maximum-tolerated dose, toxicity, and pharmacokinetics of DE-310, a macromolecular prodrug of the topoisomerase I inhibitor exatecan (DX-8951f). in patients with advanced solid tumors. Experimental Design: Patients received DE-310 as a 3-hour infusion once every 2 weeks (dose, 1.0-2.0 mg/m2) or once every 6 weeks (dose, 6.0-9.0 mg/m2). Because pharmacokinetics revealed a drug terminal half-life exceeding the 2 weeks administration interval, the protocol was amended to a 6-week interval between administrations also based on available information from a parallel trial using an every 4 weeks schedule. Conjugated DX-8951 (the carrier-linked molecule), and the metabolites DX-8951 and glycyl-DX-8951 were assayed in various matrices up to 35 days post first and second dose. Results: Twenty-seven patients were enrolled into the study and received a total of 86 administrations. Neutropenia and grade 3 thrombocytopenia, and grade 3 hepatotoxicity with veno-occlusive disease, were dose-limiting toxicities. Other hematologic and nonhematologic toxicities were mild to moderate and reversible. The apparent half-life of conjugated DX-8951, glycyl-DX-8951, and DX-8951 was 13 days. The area under the curve ratio for conjugated DX-8951 to DX-8951 was 600. No drug concentration was detectable in erythrocytes, skin, and saliva, although low levels of glycyl-DX-8951 and DX-8951 were detectable in tumor biopsies. One patient with metastatic adenocarcinoma of unknown primary achieved a histologically proven complete remission. One confirmed partial remission was observed in a patient with metastatic pancreatic cancer and disease stabilization was noted in 14 additional patients. Conclusions: The recommended phase II dose of DE-310 is 7.5 mg/m2 given once every 6 weeks. The active moiety DX-8951 is released slowly from DE-310 and over an extended period, achieving the desired prolonged exposure to this topoisomerase I inhibitor.