tbuckley/cabot-search huggingface dataset:
Shared Epitope–Antagonistic Ligands: A New Therapeutic Strategy in Mice With Erosive Arthritis
Authors: Song Ling, Ying Liu, Jiaqi Fu, Alessandro Colletta, Chaim Gilon, Joseph Holoshitz
Journal: Arthritis & Rheumatology (2015)

Objective The mechanisms underlying bone damage in rheumatoid arthritis (RA) are incompletely understood. We recently identified the shared epitope (SE), an HLA–DRB1–coded 5–amino acid sequence motif carried by the majority of RA patients as a signal transduction ligand that interacts with cell surface calreticulin and accelerates osteoclast (OC)–mediated bone damage in collagen‐induced arthritis (CIA). Given the role of the SE/calreticulin pathway in arthritis‐associated bone damage, we sought to determine the therapeutic targetability of calreticulin. Methods A library of backbone‐cyclized peptidomimetic compounds, all carrying an identical core DKCLA sequence, was synthesized. The ability of these compounds to inhibit SE‐activated signaling and OC differentiation was tested in vitro. The effect on disease severity and OC‐mediated bone damage was studied by weekly intraperitoneal administration of the compounds to DBA/1 mice with CIA. Results Two members of the peptidomimetics library were found to have SE‐antagonistic effects and antiosteoclast differentiation effects at picomolar concentrations in vitro. The lead mimetic compound, designated HS(4‐4)c Trp, potently ameliorated arthritis and bone damage in vivo when administered in picogram doses to mice with CIA. Another mimetic analog, designated HS(3‐4)c Trp, was found to lack activity, both in vitro and in vivo. The differential activity of the 2 analogs depended on minor differences in their respective ring sizes and correlated with distinctive geometry when computationally docked to the SE binding site on calreticulin. Conclusion These findings identify calreticulin as a novel therapeutic target in erosive arthritis and provide sound rationale and early structure/activity relationships for future drug design.
Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60)
Authors: Michael Pfreundschuh, Joerg Schubert, Marita Ziepert, Rudolf Schmits, Martin Mohren, Eva Lengfelder, Marcel Reiser, Christina Nickenig, Michael Clemens, Norma Peter, Carsten Bokemeyer, Hartmut Eimermacher, Anthony Ho, Martin Hoffmann, Roland Mertelsmann, Lorenz Trümper, Leopold Balleisen, Ruediger Liersch, Bernd Metzner, Frank Hartmann, Bertram Glass, Viola Poeschel, Norbert Schmitz, Christian Ruebe, Alfred C Feller, Markus Loeffler
Journal: The Lancet Oncology (2008)
Angiotensin II receptor antagonist TCV-116 induces regression of hypertensive left ventricular hypertrophy in vivo and inhibits the intracellular signaling pathway of stretch-mediated cardiomyocyte hypertrophy in vitro.
Authors: M Kojima, I Shiojima, T Yamazaki, I Komuro, Z Zou, Y Wang, T Mizuno, K Ueki, K Tobe, T Kadowaki
Journal: Circulation (1994)

BACKGROUND Previous studies have demonstrated that angiotensin II (Ang II) acts as a growth-promoting factor directly on cardiac myocytes and that angiotensin-converting enzyme inhibitor induces regression of hypertrophied hearts both in experimental animals and in humans. These results suggest that the renin-angiotensin system (RAS) is involved in the formation of left ventricular hypertrophy (LVH). To elucidate the role of RAS in the progression of cardiac hypertrophy, we evaluated the effect of an Ang II receptor antagonist on LVH in spontaneously hypertensive rats (SHRs) and investigated the molecular mechanisms by which antagonizing Ang II receptors reduces cell hypertrophy of myocytes using the in vitro model of mechanical stretch. METHODS AND RESULTS In the in vivo study, we treated SHRs with the nonpeptide Ang II receptor antagonist TCV-116 (0.1, 1, or 10 mg/kg per day) or hydralazine (10 mg/kg per day). Blood pressure was measured by the tail-cuff method, and wall thickness of left ventricle was serially monitored using M-mode echocardiography. Rats were killed at the age of 13, 17, 21, or 25 weeks, and left ventricular (LV) weight, transverse diameter of cardiomyocytes, relative amount of V3 myosin heavy chain (MHC), and degree of interstitial collagen accumulation were examined. Untreated SHRs progressively developed severe hypertension, but treatment with TCV-116 or hydralazine inhibited the increase in blood pressure. Treatment with TCV-116 reduced LV weight, LV wall thickness, transverse diameter of myocytes, relative amount of V3 MHC, and interstitial fibrosis, whereas treatment with hydralazine slightly prevented an increase in LV wall thickness but did not exert significant reduction in other parameters. In the in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes and mechanically stretched with or without pretreatment of CV-11974 (an active metabolite of TCV-116), and [3H]phenylalanine incorporation, activity of mitogen-activated protein (MAP) kinase, and c-fos mRNA expression were analyzed. Pretreatment of cultured cardiomyocytes with 10(-7) mol/L CV-11974 inhibited an increase in [3H]phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by stretch of cardiomyocytes. CONCLUSIONS The Ang II receptor antagonist TCV-116 induced regression of cardiac hypertrophy and had cardioprotective effects on hypertrophied myocardium in vivo, and antagonizing Ang II receptors inhibited intracellular signaling of stretch-mediated cardiomyocyte hypertrophy in vitro. These results suggest a crucial role of the cardiac RAS in the development of LVH produced by pressure overload.
Microenvironmental Regulation of Epithelial–Mesenchymal Transitions in Cancer
Authors: Dingcheng Gao, Linda T. Vahdat, Stephen Wong, Jenny C. Chang, Vivek Mittal
Journal: Cancer Research (2012)

The evolution of the cancer cell into a metastatic entity is the major cause of death in patients with cancer. Activation of the epithelial-to-mesenchymal transition (EMT) endows invasive and metastatic properties upon cancer cells that favor successful colonization of distal target organs. The observation that in many cancers distant metastases resemble the epithelial phenotype of primary tumors has led to speculation that the disseminated tumor cells recruited to the target organs undergo mesenchymal-to-epithelial transition (MET). However, the MET cascade has not been recapitulated in vivo, and the cellular and molecular regulators that promote MET remain unknown. In a recent report, using a model of spontaneous breast cancer, we have shown that bone marrow-derived myeloid progenitor cells in the premetastatic lung secrete the proteoglycan versican, which induces MET of metastatic tumor cells and accelerates metastases. This review summarizes recent progress in MET research, outlines a unique paracrine cross-talk between the microenvironment and the cancer cells, which promotes tumor outgrowth in the metastatic organ, and discusses opportunities for novel antimetastatic approaches for cancer therapy.
Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction
Authors: Jing Zhang, Liang Ding, Yannan Zhao, Wenjie Sun, Bing Chen, Hang Lin, Xia Wang, Lujie Zhang, Biao Xu, Jianwu Dai
Journal: Circulation (2009)

Background— Vascular endothelial growth factor (VEGF) is an important active protein for the induction of angiogenesis and improvement in cardiac function after myocardial ischemia; however, the lack of a delivery system targeted to the injured myocardium reduces the local therapeutic efficacy of VEGF and increases its possible adverse effects. Methods and Results— We produced a fusion protein (CBD-VEGF) consisting of VEGF and a collagen-binding domain (CBD). The fusion protein specifically bound to type I collagen in vitro. In addition, CBD-VEGF promoted human umbilical vein endothelial cell proliferation after binding to collagen, which indicates that it retained both growth factor activity and collagen-binding ability. When implanted subcutaneously in rats, collagen membranes loaded with CBD-VEGF were significantly vascularized. After it was injected into rats with acute myocardial infarction, CBD-VEGF was largely retained in the cardiac extracellular matrix, in which collagen I was rich. Four weeks after VEGF or CBD-VEGF was injected into the infarct border zone, cardiac function detected by echocardiography and hemodynamics was preserved in the CBD-VEGF group. Administration of CBD-VEGF also induced reduction of scar size, whereas native VEGF did not have these effects. In addition, a significant increase in the number of capillary vessels in infarcted hearts was found in the CBD-VEGF group. Conclusions— The injection of CBD-VEGF improved cardiac function in rats with induced acute myocardial infarction. This could potentially provide a new treatment option for myocardial infarction.
A Pilot Surrogate End Point Biomarker Trial of Perillyl Alcohol in Breast Neoplasia
Authors: Vered Stearns, Andrew Coop, Baljit Singh, Ann Gallagher, Hideko Yamauchi, Ronald Lieberman, Marie Pennanen, Bruce Trock, Daniel F. Hayes, Matthew J. Ellis
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Efficient strategies to screen promising agents in early phase development are essential for rapid progress in breast cancer chemoprevention. We report our experience with the natural compound perillyl alcohol (POH) administered in a short-term surrogate end point biomarker (SEB) protocol, using the “window” between diagnostic and definitive surgery. Experimental Design: Eligible patients included those with a diagnosis of atypical ductal hyperplasia, ductal carcinoma in situ, lobular carcinoma in situ, or invasive carcinoma (&amp;lt;3 cm in size) that required further surgery. Thirty-seven of 267 women screened were enrolled in the study (14%). Five women received single-dose POH (1.5 g/m2) 2 days before surgery, 16 received escalating doses of POH (1.2 g/m2 to 4.8 g/m2/day) for 2 days before surgery, and 16 served as untreated controls. Exploratory SEB analysis [estrogen receptor, progesterone receptor, proliferation, apoptosis, M6P/insulin-like growth factor (IGF)-2R, IGF1, IGF2 and transforming growth factor β] was conducted before and after POH. Results: Only a small portion of the population screened entered the study. Reasons for nonparticipation included protocol ineligibility, conflict of timing of surgery, miscellaneous logistical reasons, or patient’s choice. POH administration was well tolerated and did not interfere with surgical management. The power to observe changes in candidate SEB was diminished by a 44% incidence of cases in which the index lesion was not present in the definitive surgical specimen. Conclusions: Preoperative POH exposure was safe and suitable for a more definitive phase II SEB study. Further investigations must overcome logistical obstacles to accrual, and they must focus on approaches to maximize tissue collection and to incorporate genomic analysis of target lesions.
Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering
Authors: Changsoo Kang, Sheikh Riazuddin, Jennifer Mundorff, Donna Krasnewich, Penelope Friedman, James C. Mullikin, Dennis Drayna
Journal: New England Journal of Medicine (2010)

Stuttering is a disorder of unknown cause characterized by repetitions, prolongations, and interruptions in the flow of speech. Genetic factors have been implicated in this disorder, and previous studies of stuttering have identified linkage to markers on chromosome 12.We analyzed the chromosome 12q23.3 genomic region in consanguineous Pakistani families, some members of which had nonsyndromic stuttering and in unrelated case and control subjects from Pakistan and North America.We identified a missense mutation in the N-acetylglucosamine-1-phosphate transferase gene (GNPTAB), which encodes the alpha and beta catalytic subunits of GlcNAc-phosphotransferase (GNPT [EC 2.7.8.15]), that was associated with stuttering in a large, consanguineous Pakistani family. This mutation occurred in the affected members of approximately 10% of Pakistani families studied, but it occurred only once in 192 chromosomes from unaffected, unrelated Pakistani control subjects and was not observed in 552 chromosomes from unaffected, unrelated North American control subjects. This and three other mutations in GNPTAB occurred in unrelated subjects with stuttering but not in control subjects. We also identified three mutations in the GNPTG gene, which encodes the gamma subunit of GNPT, in affected subjects of Asian and European descent but not in control subjects. Furthermore, we identified three mutations in the NAGPA gene, which encodes the so-called uncovering enzyme, in other affected subjects but not in control subjects. These genes encode enzymes that generate the mannose-6-phosphate signal, which directs a diverse group of hydrolases to the lysosome. Deficits in this system are associated with the mucolipidoses, rare lysosomal storage disorders that are most commonly associated with bone, connective tissue, and neurologic symptoms.Susceptibility to nonsyndromic stuttering is associated with variations in genes governing lysosomal metabolism.
HLA-DRB1 typing in rheumatoid arthritis: predicting response to specific treatments
Authors: J. R O'Dell, B. S Nepom, C. Haire, V. H Gersuk, L. Gaur, G. F Moore, W. Drymalski, W. Palmer, P J. Eckhoff, L. W Klassen, S. Wees, G. Thiele, G. T Nepom
Journal: Annals of the Rheumatic Diseases (1998)

<h3>OBJECTIVE</h3> To determine the predictive value of shared epitope alleles for response to treatment in patients with rheumatoid arthritis. <h3>METHODS</h3> Patients from our previously published triple DMARD study were tested for the presence of shared epitope alleles (DRB1 *0401,0404/0408, 0405,0101, 1001,and 1402). Patients who were shared epitope positive were then compared with those who were negative to see if there was a differential effect on therapeutic response. <h3>RESULTS</h3> Shared epitope positive patients were much more likely to achieve a 50% response if treated with methotrexate-sulphasalazine-hydroxychloroquine compared with methotrexate alone (94% responders versus 32%, p&lt;0.0001). In contrast shared epitope negative patients did equally well regardless of treatment (88% responders for methotrexate-sulphasalazine-hydroxychloroquine versus 83% for methotrexate). Additionally, a trend toward an inverse relation of the gene dose was seen for response to methotrexate treatment (p=0.05). <h3>CONCLUSIONS</h3> These data suggest that determining shared epitope status may provide clinical information useful in selecting among treatment options.
On alternatives to selection-induced mutation in the Bgl operon of Escherichia coli.
Authors: B G Hall
Journal: Molecular Biology and Evolution (1994)

Selection-induced mutations are nonrandom mutations that occur as specific and direct responses to environmental challenge. Examples of selection-induced mutations have been reported both in bacteria and in yeast. I previously showed (Hall 1988) that excisions of the mobile genetic element IS150 from within bglF are selection induced and argued that they occurred because they were potentially advantageous under the selective conditions employed. Mittler and Lenski (Mittler and Lenski 1992) have argued that such excisions are not selection induced but that they occur randomly in nondividing cells. Here I provide further evidence that IS150 excisions are induced by selection and that the excisions are immediately, rather than only potentially, advantageous to the cell. I also provide evidence that excisions, which Mittler and Lenski claim occur randomly in saturated broth cultures, actually occur after samples from those cultures are plated onto selective medium.
A patient with acute pancreatitis and unusual vermiform stools
Authors: W L Hazen, D P Hayes, H J M Pullens
Journal: Gut (2013)

A 66-year-old woman was admitted with severe pancreatitis of unknown aetiology. Medical history disclosed insulin-dependent diabetes. She was treated conservatively with fluid and electrolyte correction. The patient was haemodynamically stable throughout the disease course. On day 4 she developed a paralytic ileus. Parenteral nutrition was initiated. Gradually, the ileus resolved. Enteral feeding was resumed on day 13 via a nasojejunal feeding tube. Over the following days, the patient developed watery diarrhoea. PCR and cultures failed to demonstrate a microbial cause. Suddenly, at day 21, the patient excreted per …
Toxicities of ethylene glycol and ethylene glycol monoethyl ether in Fischer 344/N rats and B6C3F1 mice.
Authors: R L Melnick
Journal: Environmental Health Perspectives (1984)

The toxicities of ethylene glycol (EG) and ethylene glycol monoethyl ether (EGEE) were studied in Fischer 344/N rats and B6C3F1 mice. In a 13-week study, EG was administered in feed to groups of 10 rats and 10 mice of both sexes at dose levels of 0 (control), 0.32, 0.63, 1.25, 2.5 and 5.0%. Kidney/body weight ratios were elevated in the 2.5 and 5.0% dose groups of male and female rats relative to controls, while serum urea nitrogen and serum creatinine levels were elevated in the two highest dose groups of male rats. Toxic nephrosis and crystal deposits in renal tubules were observed in the 2.5 and 5.0% dose groups of male rats. Crystals were also observed in brains of male rats in the 5.0% dose group. Nephrosis was the only lesion observed in female rats (5.0% dose group). Mild, compound-related lesions were seen in kidneys (nephrosis) and livers (centrilobular degeneration) of male mice in the 2.5 and 5.0% dose groups. There were no adverse effects observed in female mice. Groups of 50 rats and 50 mice of both sexes were administered EGEE by gavage in a 2-year study at dose levels of 0 (control), 0.5, 1.0 and 2.0 g/kg body weight. Testicular atrophy was observed in male rats that died early in this study and in the medium- and high-dose male mouse groups.(ABSTRACT TRUNCATED AT 250 WORDS)
A simulation system for biomarker evolution in neurodegenerative disease
Authors: Alexandra L. Young, Neil P. Oxtoby, Sebastien Ourselin, Jonathan M. Schott, Daniel C. Alexander
Journal: Medical Image Analysis (2015)

We present a framework for simulating cross-sectional or longitudinal biomarker data sets from neurodegenerative disease cohorts that reflect the temporal evolution of the disease and population diversity. The simulation system provides a mechanism for evaluating the performance of data-driven models of disease progression, which bring together biomarker measurements from large cross-sectional (or short term longitudinal) cohorts to recover the average population-wide dynamics. We demonstrate the use of the simulation framework in two different ways. First, to evaluate the performance of the Event Based Model (EBM) for recovering biomarker abnormality orderings from cross-sectional datasets. Second, to evaluate the performance of a differential equation model (DEM) for recovering biomarker abnormality trajectories from short-term longitudinal datasets. Results highlight several important considerations when applying data-driven models to sporadic disease datasets as well as key areas for future work. The system reveals several important insights into the behaviour of each model. For example, the EBM is robust to noise on the underlying biomarker trajectory parameters, under-sampling of the underlying disease time course and outliers who follow alternative event sequences. However, the EBM is sensitive to accurate estimation of the distribution of normal and abnormal biomarker measurements. In contrast, we find that the DEM is sensitive to noise on the biomarker trajectory parameters, resulting in an over estimation of the time taken for biomarker trajectories to go from normal to abnormal. This over estimate is approximately twice as long as the actual transition time of the trajectory for the expected noise level in neurodegenerative disease datasets. This simulation framework is equally applicable to a range of other models and longitudinal analysis techniques.
Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS–ADRDA criteria
Authors: Bruno Dubois, Howard H Feldman, Claudia Jacova, Steven T DeKosky, Pascale Barberger-Gateau, Jeffrey Cummings, André Delacourte, Douglas Galasko, Serge Gauthier, Gregory Jicha, Kenichi Meguro, John O'Brien, Florence Pasquier, Philippe Robert, Martin Rossor, Steven Salloway, Yaakov Stern, Pieter J Visser, Philip Scheltens
Journal: The Lancet Neurology (2007)
Resolvins: Anti-Inflammatory and Proresolving Mediators Derived from Omega-3 Polyunsaturated Fatty Acids
Authors: Michael J. Zhang, Matthew Spite
Journal: Annual Review of Nutrition (2012)

Omega-3 polyunsaturated fatty acids (PUFAs) are essential to health, and deficiencies in these PUFAs are linked to chronic disease. Although important insights into the diverse biological roles of PUFAs have been made, the mechanistic basis underlying their protective actions is still emerging. Studies over the past decade have elucidated that omega-3 PUFAs are enzymatically converted into bioactive autacoids that have inflammation-resolving properties. Among these, resolvins have emerged as an important family that has potent and stereospecific immunomodulatory roles, elucidation of which has contributed to a growing body of literature demonstrating that resolution of acute inflammation is an active process. In addition to their direct interactions with immune cells, resolvins have effects on nonimmune cells as well, suggesting a much broader role in biological systems than originally appreciated. In this review, we describe the endogenous biosynthesis and immunomodulatory actions of resolvins and highlight their emerging roles in health and disease.
Synergistic Antitumor Activity of Histamine Plus Melphalan in Isolated Limb Perfusion: Preclinical Studies
Authors: F. Brunstein, S. Hoving, A. L. B. Seynhaeve, S. T. van Tiel, G. Guetens, E. A. de Bruijn, A. M. M. Eggermont, T. L. M. ten Hagen
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-α) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-α. Methods: We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan. Results: The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H 1 and H 2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs. Conclusions: Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion.