tbuckley/cabot-search huggingface dataset:
Cathepsin B Inhibition Limits Bone Metastasis in Breast Cancer
Authors: Nimali P. Withana, Galia Blum, Mansoureh Sameni, Clare Slaney, Arulselvi Anbalagan, Mary B. Olive, Bradley N. Bidwell, Laura Edgington, Ling Wang, Kamiar Moin, Bonnie F. Sloane, Robin L. Anderson, Matthew S. Bogyo, Belinda S. Parker
Journal: Cancer Research (2012)

Abstract Metastasis to bone is a major cause of morbidity in breast cancer patients, emphasizing the importance of identifying molecular drivers of bone metastasis for new therapeutic targets. The endogenous cysteine cathepsin inhibitor stefin A is a suppressor of breast cancer metastasis to bone that is coexpressed with cathepsin B in bone metastases. In this study, we used the immunocompetent 4T1.2 model of breast cancer which exhibits spontaneous bone metastasis to evaluate the function and therapeutic targeting potential of cathepsin B in this setting of advanced disease. Cathepsin B abundancy in the model mimicked human disease, both at the level of primary tumors and matched spinal metastases. RNA interference–mediated knockdown of cathepsin B in tumor cells reduced collagen I degradation in vitro and bone metastasis in vivo. Similarly, intraperitoneal administration of the highly selective cathepsin B inhibitor CA-074 reduced metastasis in tumor-bearing animals, a reduction that was not reproduced by the broad spectrum cysteine cathepsin inhibitor JPM-OEt. Notably, metastasis suppression by CA-074 was maintained in a late treatment setting, pointing to a role in metastatic outgrowth. Together, our findings established a prometastatic role for cathepsin B in distant metastasis and illustrated the therapeutic benefits of its selective inhibition in vivo. Cancer Res; 72(5); 1199–209. ©2012 AACR.
Endothelial Progenitor Thrombospondin-1 Mediates Diabetes-Induced Delay in Reendothelialization Following Arterial Injury
Authors: Masaaki Ii, Hideya Takenaka, Jun Asai, Kayoko Ibusuki, Yusuke Mizukami, Kazuichi Maruyama, Young-sup Yoon, Andrea Wecker, Corinne Luedemann, Elizabeth Eaton, Marcy Silver, Tina Thorne, Douglas W. Losordo
Journal: Circulation Research (2006)

Delayed reendothelialization contributes to restenosis after angioplasty and stenting in diabetes. Prior data have shown that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to endothelial recovery after arterial injury. We investigated the hypothesis that the EPC contribution to reendothelialization may be impaired in diabetes, resulting in delayed reendothelialization. Reendothelialization was significantly reduced in diabetic mice compared with nondiabetic mice in a wire-induced carotid denudation model. The EPC contribution to neoendothelium was significantly reduced in Tie2/LacZ BM-transplanted diabetic versus nondiabetic mice. BM from diabetic and nondiabetic mice was transplanted into nondiabetic mice, revealing that reendothelialization was impaired in the recipients of diabetic BM. To examine the relative roles of denuded artery versus EPCs in diabetes, we injected diabetic and nondiabetic EPCs intravenously after arterial injury in diabetic and nondiabetic mice. Diabetic EPCs recruitment to the neoendothelium was significantly reduced, regardless of the diabetic status of the recipient mice. In vitro, diabetic EPCs exhibited decreased migration and adhesion activities. Vascular endothelial growth factor and endothelial NO synthase expressions were also significantly reduced in diabetic EPCs. Notably, thrombospondin-1 mRNA expression was significantly upregulated in diabetic EPCs, associating with the decreased EPC adhesion activity in vitro and in vivo. Reendothelialization is impaired by malfunctioning EPCs in diabetes. Diabetic EPCs have phenotypic differences involving thrombospondin-1 expression compared with nondiabetic EPCs, revealing potential novel mechanistic insights and therapeutic targets to improve reendothelialization and reduce restenosis in diabetes.
Effects of long and short acting β2-agonists on respiratory muscles during hypercapnia
Authors: Masanori Yokoba, Tsuyoshi Ichikawa, Naohito Ishii, Akira Takakura, Masahiko Kimura, Atsuhiko Matsunaga, Tadashi Abe, Noriyuki Masuda, Paul Easton, Masato Katagiri
Journal: European Respiratory Journal (2012)

Both short acting Salbutamol (Salb) and long acting Sameterol (Salm) β2-agonists are widely used bronchodilators. Both significantly increase sniff nasal inspiratory pressure and inspiratory muscle EMG in humans (ERJ P2965,2003, P358s,2005). Do these β2-agonists exert similar effects on expiratory muscles as on inspiratory muscles, during breathing?

In 8 normal subjects, we inserted electrodes into parasternal intercostals (PARA) and transversus abdominis (TA) muscles using ultrasound.

After baseline measurement, 20µg/min of Salb was administrated continuously in Salb group (n=4):, or 100µg of Salm was inhaled Salm group (n=4). Then, ventilation, as well as PARA and TA EMG were measured during resting and CO2 stimulated breathing in both groups.

Data was analyzed with and without β2-agonist in four conditions (room air, Etco2=50 Torr (CO2Mild), 55 Torr (CO2Mod) and 60 Torr (CO2Hi)). Tidal EMG was expressed as percent maximum tidal EMG (%EMGmax).

Compared to baseline,

A) with Salb, 1) VT increased significantly in all conditions, and VI and f increased significantly in CO2Mod and CO2Hi. 2) PARA EMG increased significantly in CO2Mod and CO2Hi, 3) TA EMG decreased significantly in CO2Hi.

B) with Salm, 1) f and VI increased significantly in CO2Hi, but VT did not increase in all conditions, 2) PARA EMG increased significantly in all conditions, 3) TA EMG did not change in all conditions.

We conclude that during resting and CO2 stimulated breathing β2-agonists do affect both t inspiratory and expiratory muscles, but there is a different effect on breathing pattern and muscle activation for short versus long acting β2-agonists.

This study was approved by Kitasato university human ethics committee.
The Nazi Hypothermia Experiments and Unethical Research Today
Authors: Marcia Angell
Journal: New England Journal of Medicine (1990)

For nearly 50 years there has been debate about whether anyone should use information gained from Nazi experimentation on concentration camp victims. Those opposed to making any use of such data believe that it would tend to blunt the horror of what happened and thus in a sense dishonor those who died and offend the sensibilities of those who survived. According to this view, nothing should be seen as offsetting, even in the smallest way, the evil of the Nazi experiments. Of more practical importance, using information from the death camps might be seen as sanctioning the use of results . . .
Increased gastric Pco <sub>2</sub> during exercise is indicative of gastric ischaemia: a tonometric study
Authors: J J Kolkman, A B J Groeneveld, F G van der Berg, J A Rauwerda, S G M Meuwissen
Journal: Gut (1999)

Background Diagnosis of gastric ischaemia is difficult and angiography is an invasive procedure. Angiographic findings may not correlate with clinical importance. Aims To investigate whether tonometric measurement of intragastric P co 2 during exercise can be used to detect clinically important gastric ischaemia. Methods Fourteen patients with unexplained abdominal pain or weight loss were studied. Splanchnic angiography served as the gold standard. Three patients were studied again after a revascularisation procedure. Gastric P co 2 was measured from a nasogastric tonometer, with 10 minute dwell times, and after acid suppression. Gastric and capillary P co 2 were measured before, during, and after submaximal exercise of 10 minutes duration. Results Seven patients had normal angiograms; seven had more than 50% stenosis in the coeliac (n=7) or superior mesenteric artery (n=4). Normal subjects showed no changes in tonometry. In patients with stenoses, the median intragastric P co 2 (Pi co 2 ) at rest was 5.2 kPa (range 4.8–11.2) and rose to 6.4 kPa (range 5.7–15.7) at peak exercise; the median intragastric blood P co 2 gradient increased from 0.0 kPa (range −0.8 to 5.9) to 1.7 kPa (range 0.9 to 10.3; p&lt;0.01). Only two subjects had abnormal tonometry at rest; all had supernormal values at peak exercise. The P co 2 gradient correlated with clinical and gastroscopic severity; in patients reexamined after revascularisation (n=3), exercise tonometry returned to normal. Conclusion Gastric tonometry during exercise is a promising non-invasive tool for diagnosing and grading gastrointestinal ischaemia and evaluating the results of revascularisation surgery for symptomatic gastric ischaemia.
Safety and tolerability of chikungunya virus-like particle vaccine in healthy adults: a phase 1 dose-escalation trial
Authors: Lee-Jah Chang, Kimberly A Dowd, Floreliz H Mendoza, Jamie G Saunders, Sandra Sitar, Sarah H Plummer, Galina Yamshchikov, Uzma N Sarwar, Zonghui Hu, Mary E Enama, Robert T Bailer, Richard A Koup, Richard M Schwartz, Wataru Akahata, Gary J Nabel, John R Mascola, Theodore C Pierson, Barney S Graham, Julie E Ledgerwood
Journal: The Lancet (2014)
The impact of airway infection on cardiovascular risk during COPD exacerbations
Authors: Anant R.C. Patel, Gavin C. Donaldson, Beverly S. Kowlessar, Alex J. Mackay, Davinder Garcha, Siobhan George, Jadwiga A. Wedzicha, John R. Hurst
Journal: European Respiratory Journal (2012)

Arterial stiffness, a validated measure of cardiovascular risk, increases from stable COPD to exacerbation (Patel et al, ERS 2011). We hypothesised this increased cardiovascular risk was mediated by airway infection.  We measured aortic pulse wave velocity (aPWV) in the stable state, at exacerbation and during recovery at 3,7,14 and 35days thereafter. Infective exacerbations were defined by a potentially pathogenic microbe (PPM) in exacerbation sputum by culture or positive PCR for  H. influenzae, S. pneumoniae, M. catarrhalis , or human rhinovirus. Differences in the area under the curve (AUC) adjusted for stable aPWV level between groups were compared by unpaired t-test.  55 COPD patients (32 male, 11 current smokers) had a mean±SD FEV 1  of 1.14±0.41L (46.7±18.5%predicted) and FEV 1 /FVC ratio 0.46±0.14. Two-thirds of them (36/55, 65%) produced a sputum sample at exacerbation. Two-thirds of these events (24/36, 67%) had an identifiable PPM. Patients with an infective exacerbation had a greater rise in arterial stiffness from stable state to exacerbation (1.4±1.7ms-1 vs 0.4±1.0ms-1, p=0.050). Arterial stiffness was also higher during the recovery period in those with an infective exacerbation (AUC 37.4±55.2ms-1days vs 11.4±44.3ms-1days, p=0.036).  The increase in arterial stiffness during COPD exacerbations appears to be driven by airway infection and may explain the association between these infective events and increased cardiovascular risk.
Decreased Expression of Gene Cluster at Chromosome 1q21 Defines Molecular Subgroups of Chemoradiotherapy Response in Esophageal Cancers
Authors: Madan G. Luthra, Jaffer A. Ajani, Julie Izzo, Joe Ensor, Tsung-Teh Wu, Asif Rashid, Li Zhang, Alexandria Phan, Norio Fukami, Rajyalakshmi Luthra
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Resistance to preoperative chemoradiotherapy (CTXRT) in 75% of patients with esophageal adenocarcinoma (EAC) underscores the need for identification of biomarkers of CTXRT response. We previously noted an association between decreased expression of epidermal differentiation complex (EDC) genes S100A2 and SPRR3 at chromosome 1q21 and CTXRT resistance. In the current study, we did an in-depth investigation of the expression of 1q21-1q25 region genes to uncover the role of the EDC and its flanking genes in CTXRT response. Experimental Design: We compared 19 pretreatment EAC specimens with normal squamous mucosa for the expression of 517 genes at chromosome 1q21-1q25 and selected target genes based on their differential expression. Using the pathologic complete-response (pathCR) status of the resected specimens as a representation of CTXRT sensitivity, we assessed the association between the expression of target genes and CTXRT response and clinical outcomes. Results: On the basis of the expression levels of IVL, CRNN, NICE-1, S100A2, and SPPR3, genes within and in close proximity to the EDC, cancers were segregated into high (subgroup I) or low (subgroup II) expressers. Four of the five pathCRs were high expressers. Thus, low expressers, with one exception, were all nonresponders. Patients in subgroup I also had longer survival than those in subgroup II, although this result was not statistically significant owing to the small study number. Conclusions: The expression levels of genes mapping within and close to the EDC define CTXRT response subgroups in EACs.
Accessing and distributing EMBL data using CORBA (common object request broker architecture)
Authors: Lichun Wang, Patricia Rodriguez-Tomé, Nicole Redaschi, Phil McNeil, Alan Robinson, Philip Lijnzaad
Journal: Genome biology (2000)

The EMBL Nucleotide Sequence Database is a comprehensive database of DNA and RNA sequences and related information traditionally made available in flat-file format. Queries through tools such as SRS (Sequence Retrieval System) also return data in flat-file format. Flat files have a number of shortcomings, however, and the resources therefore currently lack a flexible environment to meet individual researchers' needs. The Object Management Group's common object request broker architecture (CORBA) is an industry standard that provides platform-independent programming interfaces and models for portable distributed object-oriented computing applications. Its independence from programming languages, computing platforms and network protocols makes it attractive for developing new applications for querying and distributing biological data.A CORBA infrastructure developed by EMBL-EBI provides an efficient means of accessing and distributing EMBL data. The EMBL object model is defined such that it provides a basis for specifying interfaces in interface definition language (IDL) and thus for developing the CORBA servers. The mapping from the object model to the relational schema in the underlying Oracle database uses the facilities provided by PersistenceTM, an object/relational tool. The techniques of developing loaders and 'live object caching' with persistent objects achieve a smart live object cache where objects are created on demand. The objects are managed by an evictor pattern mechanism.The CORBA interfaces to the EMBL database address some of the problems of traditional flat-file formats and provide an efficient means for accessing and distributing EMBL data. CORBA also provides a flexible environment for users to develop their applications by building clients to our CORBA servers, which can be integrated into existing systems.
Interpreting radiographic data in rheumatoid arthritis
Authors: P A Ory
Journal: Annals of the Rheumatic Diseases (2003)

Plain film radiography is the preferred method for evaluating disease progression in rheumatoid arthritis and for establishing the efficacy of new disease modifying antirheumatic agents. However, the relative efficacy of these agents cannot be determined by comparing radiographic data from different studies, and a standardised system is needed.
Vascular Calcification
Authors: Cecilia M. Giachelli
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Uremic patients are prone to widespread ectopic extraskeletal calcification resulting from an imbalance of systemic inorganic phosphate (Pi). There can be serious consequences of this process, particularly when it results in the calcification of the vasculature. A recent study examined the response of cultured human aortic smooth muscle cells to varying levels of extracellular Pi. Cells that were exposed to Pi levels similar to those seen in uremic patients (&gt;1.4 mmol/L) showed dose-dependent increases in cell culture calcium deposition. The results of this study also defined the role of elevated phosphate in transforming the vascular phenotype of these cells to an osteogenic phenotype, such that a predisposition for calcification was created. Pi-induced changes included increased expression of the osteogenic markers osteocalcin and core-binding factor-1 genes, the latter of which is considered a "master gene" critical for osteoblast differentiation. These changes occur early after exposure to high phosphate levels and seem to be mediated by a sodium-dependent phosphate co-transporter, Pit-1 (Glvr-1). Calcification of vascular cells also seems to occur in the absence of a mineral imbalance but in the presence of platelet-derived growth factor, a potent atherogenic factor. Taken together, these data suggest that calcification of vascular cells can occur early in a phosphate-rich environment similar to that seen in patients with renal failure and in a platelet-derived growth factor–rich atherosclerotic region under normal phosphorus conditions. From a clinical viewpoint, it seems that early control or prevention of hyperphosphatemia may reduce coronary calcification and its associated morbidity and mortality for patients on dialysis. E-mail: ceci@u.washington.edu
Feasibility and safety of cCD20 RNA CAR-bearing T cell therapy for the treatment of canine B cell malignancies
Authors: Jenessa B Smith, M Kazim Panjwani, Keith Schutsky, Josephine Gnanandarajah, Sondra Calhoun, Laurence Cooper, Nicola Mason, Daniel J Powell
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts CD19 chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating human hematological malignancies. However, the full potential of CAR technology has not been reached in solid malignancies and limitations exist in utilizing genetically identical murine models
Cytarabine Dose for Acute Myeloid Leukemia
Authors: Bob Löwenberg, Thomas Pabst, Edo Vellenga, Wim van Putten, Harry C. Schouten, Carlos Graux, Augustin Ferrant, Pieter Sonneveld, Bart J. Biemond, Alois Gratwohl, Georgine E. de Greef, Leo F. Verdonck, Martijn R. Schaafsma, Michael Gregor, Matthias Theobald, Urs Schanz, Johan Maertens, Gert J. Ossenkoppele
Journal: New England Journal of Medicine (2011)

Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated.We compared two induction regimens in patients 18 to 60 years of age (median, 49) who had newly diagnosed AML. The intermediate-dose group, totaling 431 patients, received cytarabine at a dose of 200 mg per square meter given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg per square meter by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group, totaling 429 patients, received a dose-escalated regimen of 1000 mg of cytarabine per square meter every 12 hours in cycle 1 and 2000 mg per square meter twice daily in cycle 2. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem-cell transplantation. Complete remission rates, survival rates, and toxic effects were assessed for each treatment group.At a median follow-up of 5 years, no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. The high-dose treatment resulted in higher incidences of grade 3 and grade 4 toxic effects (in cycle 1), prolonged hospitalization, and delayed neutrophil recovery (in cycle 2) and platelet recovery (in cycles 2 and 3).Induction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship above this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit. (Netherlands Trial Register number, NTR230.).
Targeted Gene Disruption Reveals an Adhesin Indispensable for Pathogenicity of <i>Blastomyces dermatitidis </i>
Authors: T. Tristan Brandhorst, Marcel Wüthrich, Thomas Warner, Bruce Klein
Journal: The Journal of Experimental Medicine (1999)

Systemic fungal infections are becoming more common and difficult to treat, yet the pathogenesis of these infectious diseases remains poorly understood. In many cases, pathogenicity can be attributed to the ability of the fungi to adhere to target tissues, but the lack of tractable genetic systems has limited progress in understanding and interfering with the offending fungal products. In Blastomyces dermatitidis, the agent of blastomycosis, a respiratory and disseminated mycosis of people and animals worldwide, expression of the putative adhesin encoded by the WI-1 gene was investigated as a possible virulence factor. DNA-mediated gene transfer was used to disrupt the WI-1 locus by allelic replacement, resulting in impaired binding and entry of yeasts into macrophages, loss of adherence to lung tissue, and abolishment of virulence in mice; each of these properties was fully restored after reconstitution of WI-1 by means of gene transfer. These findings establish the pivotal role of WI-1 in adherence and virulence of B. dermatitidis yeasts. To our knowledge, they offer the first example of a genetically proven virulence determinant among systemic dimorphic fungi, and underscore the value of reverse genetics for studies of pathogenesis in these organisms.
Effect of montelukast added to inhaled corticosteroids on fractional exhaled nitric oxide in asthmatic children
Authors: L. Ghiro, S. Zanconato, O. Rampon, V. Piovan, M.F. Pasquale, E. Baraldi
Journal: European Respiratory Journal (2002)

The aim of this prospective, self-controlled, single-blind study was to assess the effect of montelukast added to maintenance therapy with inhaled corticosteroids (ICS) on fractional exhaled nitric oxide (FE NO ) in asthmatic children. Thirty-five children (age 11.2±0.4 yrs (mean±sem)) with mild-to-moderate persistent asthma treated with low to medium doses of ICS and FE NO &gt;20 parts per billion (ppb) were included. The patients were randomly assigned to two groups: 17 patients continued ICS (group C) and 18 had montelukast added to ICS for 3 weeks (group M). FE NO measurements were performed in both groups at baseline (T 1 ) and after 3 weeks (T 2 ), and in group M also after 2 weeks of washout. FE NO was measured by a chemiluminescence analyser using an on-line method (50 mL·s −1 ) with nitric oxide-free air. The overall mean daily dose of ICS was equivalent to 530±58 µg·day −1 of beclomethasone in group M and to 564±55 µg·day −1 of beclomethasone in group C. There were no significant differences in baseline FE NO and forced expiratory volume in one second (FEV 1 ) between the two groups. After 3 weeks there was a significant reduction of FE NO values in patients of group M (T 1 52.2±7.8 ppb, T 2 36.1±4.6 ppb) but no significant changes in group C (T 1 43.5±6.0 ppb, T 2 47.8±9.4 ppb). In group M after 2 weeks of montelukast withdrawal, FE NO rose to baseline values (55.6±8.7 ppb). In conclusion, after montelukast treatment there is a fractional exhaled nitric oxide reduction in asthmatic children receiving maintenance therapy with inhaled corticosteroids. This suggests an anti-inflammatory effect of montelukast additive to that of inhaled corticosteroids.