tbuckley/cabot-search huggingface dataset:
Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma
Authors: Sarah Deleu, Miguel Lemaire, Janine Arts, Eline Menu, Els Van Valckenborgh, Isabelle Vande Broek, Hendrik De Raeve, Les Coulton, Ben Van Camp, Peter Croucher, Karin Vanderkerken
Journal: Cancer Research (2009)

The proteasome inhibitor bortezomib (Velcade) is currently approved as second-line treatment of multiple myeloma (MM). MM-related bone disease is one of the most debilitating complications of MM. Besides supportive care with biphosphonates, which have proven efficacy in reducing and delaying skeletal-related events, there is no specific treatment of lytic bone lesions. The present study investigated the effect of bortezomib alone or in combination with a hydroxamate-based histone deacetylase inhibitor, JNJ-26481585 on tumor burden, and MM bone disease in the 5T2MM model. Injection of 5T2MM cells into C57Bl/KaLwRij mice resulted in MM bone disease, characterized by an increase in the percentage osteoclasts, a decrease in osteoblasts, trabecular bone volume, trabecular number, and the development of bone lesions. Treatment of 5T2MM-bearing mice with bortezomib significantly reduced tumor burden, angiogenesis, and MM bone disease. More importantly, the combination of bortezomib with JNJ-26481585 resulted in a more pronounced reduction of osteoclasts and increase of osteoblasts, trabecular bone volume, and trabecular number compared with bortezomib as single agent. These data suggest that bortezomib has bone remodeling properties that can be improved in combination with low dose JNJ-26481585. The study indicates that this combination therapy could be a useful strategy for the treatment of MM patients, especially in those patients with skeletal complications.
Decrease in serum level of matrix metalloproteinases is predictive of the disease-modifying effect of osteoarthritis drugs assessed by quantitative MRI in patients with knee osteoarthritis
Authors: J-P Pelletier, J-P Raynauld, J Caron, F Mineau, F Abram, M Dorais, B Haraoui, D Choquette, J Martel-Pelletier
Journal: Annals of the Rheumatic Diseases (2010)

To explore the impact of disease-modifying osteoarthritis drug (DMOAD) treatment on biomarker levels and their correlation with cartilage volume loss and disease symptoms in a 2-year phase III clinical trial in patients with knee OA.161 patients with knee OA (according-to-protocol population) were selected from a 2-year DMOAD trial studying the effect of licofelone (200 mg twice daily) versus naproxen (500 mg twice daily). Clinical evaluation of patients was carried out using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Biomarker measurements of matrix metalloproteinase (MMP)-1, MMP-3, interleukin (IL)-6, C reactive protein (CRP), cartilage oligomeric matrix protein (COMP) and type I collagen C-terminal telopeptide (CTX-I) in serum, type II collagen C-terminal telopeptide (CTX-II) in urine, and knee MRI were performed at baseline and 2 years.Over time an increase occurred in all biomarker levels with the exception of IL-6, CRP and CTX-II which decreased. The increase in MMP-1 and MMP-3 was significantly less (p = 0.05; p < 0.01, respectively) in the licofelone group. The baseline MMP-1 level was significantly but inversely predictive of cartilage volume loss for the medial compartment in both univariate (p = 0.04) and multivariate (p ≤ 0.04) regression analyses, and COMP, a predictor for the lateral compartment, in both univariate and multivariate models (p < 0.01). Baseline levels of IL-6 and CRP also showed a significant relationship with volume loss for the medial compartment (univariate analysis, p = 0.04 and p = 0.01, respectively; multivariate analysis, p = 0.03, p = 0.01). A significant association (univariate) was observed between the change in the levels of MMP-1 (p = 0.03) and MMP-3 (p = 0.02) and cartilage volume loss (lateral compartment) over 2 years. Baseline levels of CTX-I correlated (p = 0.02) with an increase in the size of the bone marrow lesion in the medial compartment. The baseline CRP levels correlated with worsening of symptoms: WOMAC total index (p < 0.01), pain (p < 0.01) and function (p < 0.01).Higher baseline values of IL-6, CRP and COMP are predictive of greater risk of cartilage loss in OA. However, over time a reduction in MMP-1 and MMP-3 levels correlated best with reduction in cartilage volume loss and the effect of drug treatment. Baseline CRP was found to be a good predictor of the symptomatic response to treatment.
C4d as a Diagnostic Tool in Proliferative GN
Authors: Sanjeev Sethi, Samih H Nasr, An S. De Vriese, Fernando C. Fervenza
Journal: Journal of the American Society of Nephrology (2015)

Proliferative GN is classified as immune complex-mediated or complement-mediated (C3 glomerulopathy). Immune complex-mediated GN results from glomerular deposition of immune-complexes/Ig and C3; the C3 is derived from activation of the classical and/or lectin pathways of complement. C3 glomerulopathy results from deposition of C3 and other complement fragments with minimal or no deposition of immune complexes/Ig; the C3 is derived from activation of the alternative pathway of complement. C4d is a byproduct of activation of the classic and lectin pathways. Although widely used as a marker for antibody-mediated rejection, the significance of C4d in C3 glomerulopathy is undetermined. We studied glomerular C4d staining in 18 biopsy specimens of immune-complex GN, 30 biopsy specimens of C3 GN, and 13 biopsy specimens of postinfectious GN. All specimens of immune complex-mediated GN, except two specimens of IgA nephropathy and one specimen of sclerosing membranoproliferative GN, showed bright (2-3+) C4d staining. The staining pattern of C4d mirrored the staining patterns of Ig and C3. Conversely, C4d staining was completely negative in 24 (80%) of 30 specimens of C3 glomerulopathy, and only trace/1+ C4d staining was detected in six (20%) specimens. With regard to postinfectious GN, C4d staining was negative in six (46%) of 13 specimens, suggesting an abnormality in the alternative pathway, and it was positive in seven (54%) specimens. To summarize, C4d serves as a positive marker for immune complex-mediated GN but is absent or minimally detected in C3 glomerulopathy.
Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial
Authors: Winette TA van der Graaf, Jean-Yves Blay, Sant P Chawla, Dong-Wan Kim, Binh Bui-Nguyen, Paolo G Casali, Patrick Schöffski, Massimo Aglietta, Arthur P Staddon, Yasuo Beppu, Axel Le Cesne, Hans Gelderblom, Ian R Judson, Nobuhito Araki, Monia Ouali, Sandrine Marreaud, Rachel Hodge, Mohammed R Dewji, Corneel Coens, George D Demetri, Christopher D Fletcher, Angelo Paolo Dei Tos, Peter Hohenberger
Journal: The Lancet (2012)
Work capacity and left ventricular function during rehabilitation after myocardial revascularization surgery.
Authors: C Foster, M L Pollock, J D Anholm, R W Squires, A Ward, D S Dymond, J L Rod, R P Saichek, D H Schmidt
Journal: Circulation (1984)

A prospective randomized trial was conducted to evaluate the effects of exercise-based cardiac rehabilitation after myocardial revascularization surgery (MRS) on work capacity (measured in mets) and left ventricular function as determined from ejection fraction (LVEF). Twenty-eight patients undergoing MRS were randomly assigned to experimental (aerobic exercise, n = 19) or control (muscle relaxation and low-level exercise, n = 9) groups. Patients were studied before surgery (T1) and 2 (T2), 8 (T3), and 24 (T4) weeks after surgery with first-pass radionuclide angiography both while they were at rest and during maximal upright cycle ergometric exercise. Subsets of patients were also studied at T2, T3, and T4 at a standard workload of 75 W, and during maximal exercise 1 year after surgery (T5). Work capacity improved in both groups although significantly more so in the experimental group (3.9, 3.8, 6.0, and 7.3 mets and 3.7, 3.7, 4.9, and 5.7 mets at T1, T2, T3, and T4 in the experimental and control groups, respectively). The differences between groups were significant by T3. Peak exercise LVEF increased significantly in both groups from T1 to T2 then decreased at T3 and remained unchanged through T5. Peak exercise LVEF at T3 to T5 remained significantly above that observed at T1. LVEF responses were not related to the exercise program. During a standard workload, heart rate decreased, blood pressure increased, and LVEF did not change in either group. After conclusion of the formal protocol (T4), work capacity and LVEF did not change for either group throughout an additional 6 months (T5).(ABSTRACT TRUNCATED AT 250 WORDS)
The<i>NOD2</i>insC polymorphism is associated with worse outcome following ileal pouch-anal anastomosis for ulcerative colitis
Authors: Andrea D Tyler, Raquel Milgrom, Joanne M Stempak, Wei Xu, John Hunter Brumell, Aleixo M Muise, Rishabh Sehgal, Zane Cohen, Walter Koltun, Bo Shen, Mark S Silverberg
Journal: Gut (2012)

<h3>Background</h3> Inflammatory complications after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis (UC) are common. <h3>Objective</h3> To investigate whether genetic factors are associated with adverse pouch outcomes such as chronic pouchitis (CP) and a Crohn9s disease-like (CDL) phenotype. <h3>Design</h3> 866 patients were recruited from three centres in North America: Mount Sinai Hospital (Toronto, Ontario, Canada), the Cleveland Clinic (Cleveland, Ohio, USA) and Penn State Milton S Hershey Medical Center (Hershey, Pennsylvania, USA). DNA and clinical and demographic information were collected. Subjects were classified into post-surgical outcome groups: no chronic pouchitis (NCP), CP and CDL phenotype. <h3>Results</h3> Clinical and genetic data were available on 714 individuals. 487 (68.2%) were classified as NCP, 118 (16.5%) CP and 109 (15.3%) CDL. The presence of arthritis or arthropathy (p=0.02), primary sclerosing cholangitis (p=0.009) and duration of time from ileostomy closure to recruitment (p=0.001) were significantly associated with outcome. The <i>NOD2</i>insC (rs2066847) risk variant was the single nucleotide polymorphism (SNP) most significantly associated with pouch outcome (p=7.4×10<sup>−5</sup>). Specifically, it was associated with both CP and CDL in comparison with NCP (OR=3.2 and 4.3, respectively). Additionally, SNPs in <i>NOX3</i> (rs6557421, rs12661812), <i>DAGLB</i> (rs836518) and <i>NCF4</i> (rs8137602) were shown to be associated with pouch outcome with slightly weaker effects. A multivariable risk model combining previously identified clinical (smoking status, family history of inflammatory bowel disease), serological (anti-<i>Saccharomyces cerevisiae</i> antibody IgG, perinuclear antineutrophil cytoplasmic antibody and anti-CBir1) and genetic markers was constructed and resulted in an OR of 2.72 (p=8.89×10<sup>−7</sup>) for NCP versus CP/CDL and 3.22 (p=4.11×10<sup>−8</sup>) for NCP versus CDL, respectively. <h3>Conclusion</h3> Genetic polymorphisms, in particular, the <i>NOD2</i>insC risk allele, are associated with chronic inflammatory pouch outcomes among patients with UC and IPAA.
The final pathogenetic steps in focal bone erosions in rheumatoid arthritis
Authors: S R Goldring
Journal: Annals of the Rheumatic Diseases (2000)

The presence of peri-articular osteoporosis and focal bone erosions at the joint margins and within the subchondral bone adjacent to inflamed joints has been considered the radiographic hallmark of rheumatoid arthritis (RA).1-4 In addition, in recent years there has been an increased awareness that RA also produces adverse effects on systemic bone remodelling at sites not directly involved with joint inflammation. Numerous reports have documented that people with RA have reduced axial and appendicular bone mass and that this bone loss is associated with an increased risk of fracture.5-11 Thus, it is possible to identify three distinct patterns of bone loss in RA. These include systemic osteoporosis, juxta-articular osteopenia adjacent to inflamed joints and focal marginal and subchondral bone erosions that are associated directly with inflamed synovial tissues. Each of these disorders represents an example of disturbed skeletal tissue remodelling in which there is a net loss of bone, although the precise mechanisms responsible for the bone loss in each of these conditions may involve differential cellular and regulatory processes. This review will focus on the mechanisms involved in the pathogenesis of focal bone erosions that are directly associated with the inflammatory synovial lesion.

Insights into the processes underlying the development of focal bone erosions in RA have been derived principally from histopathological evaluation of joint tissues from patients with RA and from animal models of inflammatory arthritis. Early studies by Bromley and Woolley demonstrated the presence of multinucleated cells with phenotypic features of osteoclasts in resorption lacunae at the pannus-bone interface.12-14 More recently, in our own studies,15 we have used in situ hybridisation to demonstrate that multinucleate and some mononuclear cells in resorption lacunae at the bone-pannus interface exhibit the entire repertoire of phenotypic markers that are associated with the fully differentiated osteoclast. This includes …
Plasma Levels of Cholesteryl Ester Transfer Protein and the Risk of Future Coronary Artery Disease in Apparently Healthy Men and Women
Authors: S. Matthijs Boekholdt, Jan-Albert Kuivenhoven, Nicholas J. Wareham, Ron J.G. Peters, J. Wouter Jukema, Robert Luben, Sheila A. Bingham, Nicholas E. Day, John J.P. Kastelein, Kay-Tee Khaw
Journal: Circulation (2004)

Low plasma levels of cholesteryl ester transfer protein (CETP) are associated with elevated levels of HDL cholesterol (HDL-C), but it remains unclear whether this translates into a concomitant reduction in the risk of coronary artery disease (CAD). Evidence exists that the effect of CETP depends on metabolic context, in particular on triglyceride levels.A nested case-control study was performed in the prospective EPIC-Norfolk cohort study. Cases were apparently healthy men and women aged 45 to 79 years who developed fatal or nonfatal CAD during follow-up. Control subjects were matched by age, sex, and enrollment time. CETP levels were not significantly different between cases and controls (4.0+/-2.2 versus 3.8+/-2.1 mg/L, P=0.07). CETP levels were significantly related to plasma levels of total cholesterol, LDL cholesterol, and HDL-C. The risk of CAD increased with increasing CETP quintiles (P for linearity=0.02), such that subjects in the highest quintile had an adjusted OR of 1.43 (95% CI 1.03 to 1.99, P=0.03) versus those in the lowest. Among individuals with triglyceride levels below the median (1.7 mmol/L), no relationship between CETP levels and CAD risk was observed (P for linearity=0.5), but this relationship was strong among those with high triglyceride levels (P for linearity=0.02), such that those in the highest CETP quintile had an OR of 1.87 (95% CI 1.06 to 3.30, P=0.02).Elevated CETP levels are associated with an increasing risk of future CAD in apparently healthy individuals, but only in those with high triglyceride levels.
Differential Effects of Gefitinib and Cetuximab on Non–small-cell Lung Cancers Bearing Epidermal Growth Factor Receptor Mutations
Authors: Toru Mukohara, Jeffrey A. Engelman, Nasser H. Hanna, Beow Y. Yeap, Susumu Kobayashi, Neal Lindeman, Balázs Halmos, Joseph Pearlberg, Zenta Tsuchihashi, Lewis C. Cantley, Daniel G. Tenen, Bruce E. Johnson, Pasi A. Jänne
Journal: JNCI Journal of the National Cancer Institute (2005)

Many patients with non-small-cell lung cancer (NSCLC) who achieve radiographic responses to treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib have somatic mutations in the EGFR tyrosine kinase domain. However, little is known about the efficacy of cetuximab, an antibody against the EGFR extracellular domain, in EGFR mutant NSCLC.NSCLC cell lines carrying wild-type EGFR (A549, H441, and H1666) or mutant EGFR (H3255, DFCILU-011, PC-9, and HCC827) were treated with various dilutions of gefitinib or cetuximab relative to maximal achievable serum concentration. Cell growth was analyzed by the MTS assay, with differences between dose-response curves analyzed nonparametrically. Apoptosis was analyzed by propidium iodide staining and immunoblotting for PARP. Phosphorylation of EGFR and the downstream signaling components ERK1/2 and Akt were analyzed by immunoblotting. Statistical tests were two-sided.Growth of NSCLC lines with wild-type EGFR was slightly (A549 and H441) or moderately (H1666) inhibited by gefitinib and cetuximab, and the effects of the two agents were similar. Both agents also induced no (H441) or moderate (H1666) apoptosis in NSCLC cells with wild-type EGFR. By contrast, gefitinib was statistically significantly more effective than cetuximab at inhibiting growth of EGFR mutant cells (H3255: P = .003, DFCILU-011: P = .011, and PC-9: P = .003), and gefitinib-treated EGFR mutant cells had higher levels of apoptosis than cetuximab-treated cells (mean fold increase in apoptosis by 1 microM of gefitinib and 10 microg/mL of cetuximab relative to control, H3255: 8.3 [95% confidence interval {CI} = 4.8 to 11.8] and 2.1 [95% CI = 2.0 to 2.2], respectively, P = .025; DFCILU-011: 5.7 [95% CI = 5.1 to 6.3] and. 0.9 [95% CI = 0.3 to 1.5], respectively, P < .001). Gefitinib treatment decreased EGFR, ERK1/2, and Akt phosphorylation in EGFR mutant cell lines whereas cetuximab had relatively little effect. Both gefitinib and cetuximab inhibited the growth of HCC827 cells, but gefitinib inhibited growth to a greater extent (P = .003).EGFR mutations in NSCLC cells are associated with sensitivity to gefitinib but not to cetuximab.
Cyclic Changes in Arterial Pulse during Respiratory Support Revisited by Doppler Echocardiography
Authors: Antoine Vieillard-Baron, Karim Chergui, Roch Augarde, Sebastien Prin, Bernard Page, Alain Beauchet, François Jardin
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

It has long been known that there are cyclic changes in arterial pressure during mechanical ventilation. They are caused by cyclic changes in both the right and left ventricular stroke output, occurring in opposite phases. As a result, arterial pulse pressure is increased during inspiration and decreased during expiration. A cyclic improvement in left ventricular systolic function could thus be expected during mechanical lung inflation. We tested this hypothesis in 31 septic patients who were mechanically ventilated in controlled mode by combining left ventricular measurements by transesophageal echocardiography with invasive arterial pressure recordings and Doppler analysis of pulmonary venous flow and right and left ventricular stroke volume. Lung inflation by tidal ventilation significantly improved left ventricular stroke volume (26 +/- 0.4 cm3/m2 [mean +/- SEM] vs. 22.3 +/- 0.4 cm3/m2 at end deflation). Beat-to-beat analysis of pulmonary venous flow velocity illustrated the boosting effect of lung inflation on pulmonary venous return. The beneficial effect of inspiration thus appeared directly related to a significant increase in left ventricular diastolic volume (60.3 +/- 1.5 cm3/m2 vs. 53.3 +/- 1.4 cm3/m2 at end-expiration) and to a lesser extent to an improved left ventricular ejection fraction. We concluded that the transient beneficial hemodynamic effect of tidal ventilation on the left ventricular pump is essentially mediated by an improved left ventricular filling.
Efficacy and applicability of mass B. C.G. vaccination in tuberculosis control.
Authors: P. D. Hart
Journal: BMJ (1967)

and me, and arising from this a committee was formed, with myself as chairman, to conduct a trial on the efficacy of B.C.G. in Britain.Daniels was its first secretary, and was co-ordinator of the trial during its intake and for the first year of its follow-up until his death in 1953.Marc Daniels's interests in epidemiology and in the applica- tion of statistics in tuberculosis research were far-reaching.As a contributor to the conception, design, and development of this vaccines study he was able to bring his talents to bear with great effect.He would have been fascinated by the results and their implications, and would, we may be sure, have helped to improve the quality and depth of work in this field.The subject of this lecture is highly appropriate as a tribute
Glucagon-like peptide-1 analogues for type 2 diabetes
Authors: John P H Wilding, Kevin Hardy
Journal: BMJ (2011)

#### Case scenario

A 58 year old woman attends a diabetes clinic with type 2 diabetes of seven years’ duration and no history of macrovascular disease. She is obese (body mass index 37), but says she eats a healthy diet and describes this. Her blood pressure is 134/78 mm Hg, and she has microalbuminuria, but normal renal function and a lipid profile within target levels ranges. She is taking simvastatin 40 mg daily and perindopril 4 mg daily. Glycated haemoglobin (HbA1c) is 8.3% despite treatment with metformin 850 mg three times a day and gliclazide 160 mg twice a day. How would you best manage her hyperglycaemia? (The table⇓ shows the drug treatment options.) 

After discussion with the patient of the benefits and risks of the available treatment options (including the “do nothing” option, risks of hypoglycaemia, and effects on body weight), you agree on a glucagon-like peptide-1 (GLP-1) analogue (exenatide or liraglutide).

View this table:

Drug treatment options 



Glucagon-like peptide-1 (GLP-1) is a naturally occurring peptide hormone, released from the gut after eating. GLP-1 stimulates insulin release (the incretin effect), suppresses glucagon release (thus reducing hepatic gluconeogenesis), delays gastric emptying, and promotes satiety. Natural GLP-1 has a short half life of a few minutes as a result of breakdown by endopeptidases such as dipeptidyl peptidase-4. GLP-1 analogues, also known as incretin mimetics (exenatide and liraglutide), are modified GLP-1-like peptides that are resistant to degradation by dipeptidyl peptidase-4, with elimination half lives of 2.4 hours and 13 hours respectively. GLP-1 analogues are indicated as an adjunct to other treatments in the management of type 2 diabetes and are given once daily (liraglutide) or twice daily (exenatide) by subcutaneous injection.

### Exenatide

Exenatide has been studied in several randomised controlled trials in which either exenatide or placebo was added for up to six months to existing treatment …
5-Hydroxymethylcytosine is associated with enhancers and gene bodies in human embryonic stem cells
Authors: Hume Stroud, Suhua Feng, Shannon Morey Kinney, Sriharsa Pradhan, Steven E Jacobsen
Journal: Genome biology (2011)

Abstract Background 5-Hydroxymethylcytosine (5hmC) was recently found to be abundantly present in certain cell types, including embryonic stem cells. There is growing evidence that TET proteins, which convert 5-methylcytosine (5mC) to 5hmC, play important biological roles. To further understand the function of 5hmC, an analysis of the genome-wide localization of this mark is required. Results Here, we have generated a genome-wide map of 5hmC in human embryonic stem cells by hmeDIP-seq, in which hydroxymethyl-DNA immunoprecipitation is followed by massively parallel sequencing. We found that 5hmC is enriched in enhancers as well as in gene bodies, suggesting a potential role for 5hmC in gene regulation. Consistent with localization of 5hmC at enhancers, 5hmC was significantly enriched in histone modifications associated with enhancers, such as H3K4me1 and H3K27ac. 5hmC was also enriched in other protein-DNA interaction sites, such as OCT4 and NANOG binding sites. Furthermore, we found that 5hmC regions tend to have an excess of G over C on one strand of DNA. Conclusions Our findings suggest that 5hmC may be targeted to certain genomic regions based both on gene expression and sequence composition.