tbuckley/cabot-search huggingface dataset:
New and emerging HDAC inhibitors for cancer treatment
Authors: Alison C. West, Ricky W. Johnstone
Journal: Journal of Clinical Investigation (2014)

Epigenetic enzymes are often dysregulated in human tumors through mutation, altered expression, or inappropriate recruitment to certain loci. The identification of these enzymes and their partner proteins has driven the rapid development of small-molecule inhibitors that target the cancer epigenome. Herein, we discuss the influence of aberrantly regulated histone deacetylases (HDACs) in tumorigenesis. We examine HDAC inhibitors (HDACis) targeting class I, II, and IV HDACs that are currently under development for use as anticancer agents following the FDA approval of two HDACis, vorinostat and romidepsin.
Forget personalised medicine and focus on abating disease activity
Authors: Josef S Smolen, Daniel Aletaha
Journal: Annals of the Rheumatic Diseases (2012)

In this viewpoint, we summarise three different lines of evidence suggesting that current biological therapies directed at different molecules or cells have similar efficacy in rheumatoid arthritis and target similar populations of patients; therefore, distinct biological effects of targeted therapies may not account for differences in response. Moreover, currently available individual biomarkers or multiple biomarker sets do not provide information beyond that conveyed by clinical disease activity. Smart and novel research designs will have to be developed to find pertinent biomarkers. Until then, the focus of clinicians may have to solely rest on clinical disease activity assessment and targeting remission or low disease activity rapidly.
How is freedom distributed across the earth?
Authors: Jüri Allik, Anu Realo
Journal: Behavioral and Brain Sciences (2013)

Although Van de Vliert presented an entertaining story containing several original observations, an implicit assumption that climate affects human society identically through the history is not realistic. If almost everything is explained by cold winters or hot summers, then nothing is explained. Ignoring rival explanations does not make the proposed theory more convincing.
Leg bone pain syndrome in a kidney transplant patient treated with tacrolimus (FK506)
Authors: V. VILLAVERDE, M. CANTALEJO, A. BALSA, E. M. MOLA, A. SANZ
Journal: Annals of the Rheumatic Diseases (1999)

Cladribine in the treatment of systemic lupus erythematosus nephritisSystemic lupus erythematosus (SLE) nephritis often requires treatment with cyclophosphamide, which carries the risk of major side eVects including infection, ovarian failure and bladder malignancy.Therapeutic strategies that would specifically target lymphocytes are appealing.Following the first report of the use of the purine nucleoside analogue cladribine (2-chloro-2'deoxyadenosine), a selective lymphocyte depleting agent, in the treatment of lupus nephritis, 1 we report our experience in two patients with severe renal involvement.
Effects of the positive inotropic agent Org 30029 on developed force and aequorin light transients in intact canine ventricular myocardium.
Authors: Y Kawabata, M Endoh
Journal: Circulation Research (1993)

The action of a novel cardiotonic agent N-hydroxy-5,6-dimethoxy-benzo[b]thiophene-2-carboximide hydrochloride (Org 30029) on intracellular aequorin light transients and isometric contractions was investigated in isolated canine ventricular trabeculae. The positive inotropic effect of Org 30029 (30 microM-3 mM) was consistently associated with prolongation of the duration of contraction and an increase in the amplitude of the intracellular Ca2+ transients. The maximum inotropic response to Org 30029 was approximately 150% of the maximum response to isoproterenol, whereas the maximum increase in the amplitude of Ca2+ transients produced by Org 30029 was only 20% of the isoproterenol-induced maximum. The duration of isometric contractions was prolonged by Org 30029, with no change in the duration of the light transients. The concentration-response curve for the positive inotropic effect of Org 30029 was shifted by carbamylcholine chloride (carbachol, 3 microM) to the right and downward, but the maximum response to Org 30029 was greater than that to isoproterenol even in the presence of carbachol. Carbachol abolished the increase in light transients and cAMP accumulation induced by Org 30029 (1 mM), whereas it only partially attenuated the positive inotropic effect of Org 30029. In the presence of carbachol (3 microM), Org 30029 increased the force of contraction in a concentration-dependent manner without augmenting the aequorin light transients. These results are compatible with the hypothesis that Org 30029 increases cardiac contractility by increasing myofilament Ca2+ responsiveness.
Phase II study of doxifluridine in advanced colorectal adenocarcinoma.
Authors: R Abele, P Alberto, S Kaplan, P Siegenthaler, V Hofmann, H J Ryssel, D Hartmann, E E Holdener, F Cavalli
Journal: Journal of Clinical Oncology (1983)

Doxifluridine, a new fluoropyrimidine derivative, was tested in a cooperative phase II trial by the Swiss Group for Clinical Cancer Research in advanced measurable colorectal cancer. The drug was given in a five consecutive day schedule by a bolus intravenous injection at a dose of 4 g/m2 per day and repeated every three to four weeks. Of 42 eligible patients, 40 had no previous chemotherapy. Response was defined in 27 patients having received two or more courses of doxifluridine. Seven responses (26%) were observed. Responses were seen only in sigmoid and rectum primary tumors. Toxicity consisted mainly of leukopenia (53% of the evaluable patients), nausea and vomiting (38%). Other toxicities such as dermatitis, myocardial injury, and hair loss were also observed. Doxifluridine has therapeutic activity, albeit limited, in advanced rectosigmoid adenocarcinoma.
Radiologic Features, Staging, and Operability of Primary Lung Cancer in the Western Cape, South Africa: A 1-Year Retrospective Study
Authors: Aldoph B. Nanguzgambo, Kushroo Aubeelack, Florian von Groote-Bidlingmaier, Susanna M. Hattingh, Mercia Louw, Coenraad F.N. Koegelenberg, Chris T. Bolliger
Journal: Journal of Thoracic Oncology (2010)
Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function
Authors: Bernhard Lehnertz, Jeffrey P. Northrop, Frann Antignano, Kyle Burrows, Sima Hadidi, Sarah C. Mullaly, Fabio M.V. Rossi, Colby Zaph
Journal: The Journal of Experimental Medicine (2010)

Accumulating evidence suggests that the regulation of gene expression by histone lysine methylation is crucial for several biological processes. The histone lysine methyltransferase G9a is responsible for the majority of dimethylation of histone H3 at lysine 9 (H3K9me2) and is required for the efficient repression of developmentally regulated genes during embryonic stem cell differentiation. However, whether G9a plays a similar role in adult cells is still unclear. We identify a critical role for G9a in CD4(+) T helper (Th) cell differentiation and function. G9a-deficient Th cells are specifically impaired in their induction of Th2 lineage-specific cytokines IL-4, IL-5, and IL-13 and fail to protect against infection with the intestinal helminth Trichuris muris. Furthermore, G9a-deficient Th cells are characterised by the increased expression of IL-17A, which is associated with a loss of H3K9me2 at the Il17a locus. Collectively, our results establish unpredicted and complex roles for G9a in regulating gene expression during lineage commitment in adult CD4(+) T cells.
Type IIc Sodium–Dependent Phosphate Transporter Regulates Calcium Metabolism
Authors: Hiroko Segawa, Akemi Onitsuka, Masashi Kuwahata, Etsuyo Hanabusa, Junya Furutani, Ichiro Kaneko, Yuka Tomoe, Fumito Aranami, Natsuki Matsumoto, Mikiko Ito, Mitsuru Matsumoto, Minqi Li, Norio Amizuka, Ken-ichi Miyamoto
Journal: Journal of the American Society of Nephrology (2008)

Primary renal inorganic phosphate (Pi) wasting leads to hypophosphatemia, which is associated with skeletal mineralization defects. In humans, mutations in the gene encoding the type IIc sodium–dependent phosphate transporter lead to hereditary hypophophatemic rickets with hypercalciuria, but whether Pi wasting directly causes the bone disorder is unknown. Here, we generated Npt2c-null mice to define the contribution of Npt2c to Pi homeostasis and to bone abnormalities. Homozygous mutants (Npt2c−/−) exhibited hypercalcemia, hypercalciuria, and elevated plasma 1,25-dihydroxyvitamin D3 levels, but they did not develop hypophosphatemia, hyperphosphaturia, renal calcification, rickets, or osteomalacia. The increased levels of 1,25-dihydroxyvitamin D3 in Npt2c−/− mice compared with age-matched Npt2c+/+ mice may be the result of reduced catabolism, because we observed significantly reduced expression of renal 25-hydroxyvitamin D–24-hydroxylase mRNA but no change in 1α-hydroxylase mRNA levels. Enhanced intestinal absorption of calcium (Ca) contributed to the hypercalcemia and increased urinary Ca excretion. Furthermore, plasma levels of the phosphaturic protein fibroblast growth factor 23 were significantly decreased in Npt2c−/− mice. Sodium-dependent Pi co-transport at the renal brush border membrane, however, was not different among Npt2c+/+, Npt2c+/−, and Npt2c−/− mice. In summary, these data suggest that Npt2c maintains normal Ca metabolism, in part by modulating the vitamin D/fibroblast growth factor 23 axis.
Use of Oligonucleotide Aptamer Ligands to Modulate the Function of Immune Receptors
Authors: Eli Gilboa, James McNamara, Fernando Pastor
Journal: Clinical Cancer Research (2013)

Abstract The paucity of costimulation at the tumor site compromises the ability of tumor-specific T cells to eliminate the tumor. The recent U.S. Food and Drug Administration approval of ipilumimab, an antibody that blocks the inhibitory action of CTLA-4, and clinical trials targeting 4-1BB and PD-1 or PD-L1, have underscored the therapeutic potential of using immunomodulatory antibodies to stimulate protective immunity in human patients. Nonetheless, systemic administration of immunomodulatory antibodies has been associated with dose-limiting autoimmune pathologies, conceivably reflecting also the activation of resident autoreactive T cells. Arguably, targeting immunomodulatory ligands to the disseminated tumor lesions of the patient would reduce such drug-associated toxicities. We have recently developed a new class of inhibitory (CTLA-4) and agonistic (4-1BB and OX-40) ligands composed of short oligonucleotide (ODN) aptamers that exhibited bioactivities comparable or superior to that of antibodies. To reduce toxicity, the immunomodulatory aptamers were targeted to the tumor by conjugation to a second aptamer that bound to a product expressed on the surface of the tumor cell, the targeting aptamer, generating a bispecific aptamer conjugate analogous to bispecific antibodies. In a proof-of-concept study in mice, we have shown that an agonistic 4-1BB–binding aptamer conjugated to a prostate-specific membrane antigen (PSMA)–binding aptamer led to the inhibition of PSMA-expressing tumors, was more effective than, and synergized with, vaccination, and exhibited a superior therapeutic index compared with nontargeted costimulation with 4-1BB antibodies or 4-1BB aptamers. The cell-free chemically synthesized ODN aptamers offer significant advantages over antibodies in terms of synthesis, cost, as well as conjugation chemistry needed to generate bispecific ligand fusions. Clin Cancer Res; 19(5); 1054–62. ©2012 AACR.
Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome
Authors: Aleksander Krag, Sφren Mφller, Jens H. Henriksen, Niels-Henrik Holstein-Rathlou, Fin Stolze Larsen, Flemming Bendtsen
Journal: Hepatology (2007)

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty-three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n = 11) or a placebo (P group, n = 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance ( C Na), lithium clearance ( C Li), osmolal clearance ( C Osm), and urine sodium concentration ( U Na) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 ± 19 versus 92 ± 25 mL/min, P &lt; 0.005) and in the R group (31 ± 19 versus 41 ± 31 mL/min, P &lt; 0.05) after terlipressin. In the N group, terlipressin induced an increase in C Na (0.89 ± 0.21 versus 1.52 ± 1.45 mL/min, P &lt; 0.05), C Li (17.3 ± 8.9 versus 21.5 ± 11.6 mL/min, P &lt; 0.05), and C Osm (2.10 ± 0.81 versus 3.06 ± 2.0 mL/min, P &lt; 0.05). In the R group, terlipressin induced an increase in C Na (0.11 ± 0.18 versus 0.35 ± 0.40 mL/min, P &lt; 0.05) and C Li (5.5 ± 4.2 versus 9.5 ± 8.55 mL/min, P &lt; 0.05). U Na increased in both groups after terlipressin ( P &lt; 0.005). Plasma norepinephrine ( P &lt; 0.05) and renin ( P &lt; 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. Conclusion: The vasopressin 1 receptor agonist terlipressin improves renal function and induces natriuresis in patients with cirrhosis and ascites without HRS. Vasoconstrictors may represent a novel future treatment modality for these patients. (Hepatology 2007.)
Expression Profiling of Serous Low Malignant Potential, Low-Grade, and High-Grade Tumors of the Ovary
Authors: Tomas Bonome, Ji-Young Lee, Dong-Choon Park, Mike Radonovich, Cindy Pise-Masison, John Brady, Ginger J. Gardner, Ke Hao, Wing H. Wong, J. Carl Barrett, Karen H. Lu, Anil K. Sood, David M. Gershenson, Samuel C. Mok, Michael J. Birrer
Journal: Cancer Research (2005)

Abstract Papillary serous low malignant potential (LMP) tumors are characterized by malignant features and metastatic potential yet display a benign clinical course. The role of LMP tumors in the development of invasive epithelial cancer of the ovary is not clearly defined. The aim of this study is to determine the relationships among LMP tumors and invasive ovarian cancers and identify genes contributing to their phenotypes. Affymetrix U133 Plus 2.0 microarrays (Santa Clara, CA) were used to interrogate 80 microdissected serous LMP tumors and invasive ovarian malignancies along with 10 ovarian surface epithelium (OSE) brushings. Gene expression profiles for each tumor class were used to complete unsupervised hierarchical clustering analyses and identify differentially expressed genes contributing to these associations. Unsupervised hierarchical clustering analysis revealed a distinct separation between clusters containing borderline and high-grade lesions. The majority of low-grade tumors clustered with LMP tumors. Comparing OSE with high-grade and LMP expression profiles revealed enhanced expression of genes linked to cell proliferation, chromosomal instability, and epigenetic silencing in high-grade cancers, whereas LMP tumors displayed activated p53 signaling. The expression profiles of LMP, low-grade, and high-grade papillary serous ovarian carcinomas suggest that LMP tumors are distinct from high-grade cancers; however, they are remarkably similar to low-grade cancers. Prominent expression of p53 pathway members may play an important role in the LMP tumor phenotype.
Unresponsiveness to a self-peptide of mouse lysozyme owing to hindrance of T cell receptor-major histocompatibility complex/peptide interaction caused by flanking epitopic residues.
Authors: K D Moudgil, I S Grewal, P E Jensen, E E Sercarz
Journal: The Journal of Experimental Medicine (1996)

A self-peptide containing amino acid residues 46-61 (NRGDQSTDYGIFQINSR) of mouse lysozyme (ML) (p46-61, which binds strongly to the A(k) molecule but does not bind to the E(k) molecule), can induce a strong proliferative T cell response in CBA/J mice (A[k], E[k]) but no response at all in B10.A(4R) and CBA/J mice. The critical residues within p46-59 are immunogenic in both B10.A(4R) and CBA/J mice. The critical residues within p46-61 reside between amino acid positions 51 and 59. T cells of B10.A(4R) mice primed with the truncated peptides in vivo cannot be restimulated by p46-61 in vitro. This suggests that T cell receptor (TCR) contact (epitopic) residue(s) flanking the minimal 51-59 determinant within p46-61 hinder the interaction of the p46-61/A(k) complex with the appropriate TCR(S), thereby causing a lack of proliferative T cell response in this mouse strain. Unlike B10.A(4R) mice, [B10.A(4R) x CBA/J]F1 mice responded vigorously to p46-61, suggesting that thymic APC of B10.A(4R) mice do not present a self ligand to T cells resulting in a p46-61-specific hole in the T cell repertoire in B10.A(4R) or the F1 mice. Moreover, APC from B10.A(4R) mice are capable of efficiently presenting p46-61 to peptide-specific T cell lines from CBA/J mice. The proliferative unresponsiveness of B10.A(4R) mice to p46-61 is not due to non-major histocompatibility complex genes because B10.A mice (A[k], E[k]) respond well to p46-61. Interestingly, B10.A(4R) mice can raise a good proliferative response to p46-61 (R61A) (in which the arginine residue at position 61 (R61L/F/N/K), indicating that R61 was indeed responsible for hindering the interaction of p46-61 with the appropriate TCR. Finally, chimeric mice [B10.A(4R)--&amp;gt;B10.A] responded vigorously to p46-61, suggesting that thymic antigen presentation environment of the B10.A mouse was critical for development of a p46-61-reactive T cell repertoire. Thus, we provide experimental demonstration of a novel mechanism for unresponsiveness to a self peptide, p46-61, in the B10.A(4R) mouse owing to hindrance: in this system it is the interaction between the available TCR and the A(k)/p46-61 complex, which is hindered by epitopic residue(s) within p46-61. We argue that besides possessing T cells that are hindered by R61 of p46-61, CBA/J and B10.A mice have developed an additional subset of T cells bearing TCRs which are not hinderable by R61, presumably through positive selection with peptides derived from class II E(k), or class I D(k)/D(d) molecules. These results have important implications in self tolerance, shaping of the T cell repertoire, and in defining susceptibility to autoimmunity.
Reply from chairman of BMA's medical ethics committee
Authors: J S. Horner
Journal: BMJ (1996)

EDITOR,—The issue on which the BMA has focused in the recent controversy is the principle of informed and considered consent. We looked beyond the case in hand to its potential impact on one of the cornerstones of medical practice, being profoundly aware that the final result may set precedents regarding the extraction and use of genetic material from dying or dead people. A letter was sent to the Human Fertilisation and Embryology Authority because aspects of …
Auditing audits: the method of Oxfordshire Medical Audit Advisory Group.
Authors: J Derry, M Lawrence, K Griew, J Anderson, J Humphreys, K S Pandher
Journal: BMJ (1991)

OBJECTIVES--To develop a systematic method for both summative and formative audit of practice audits, and to use the method to review Oxfordshire practice audits and to plan improvement. DESIGN--Development of a coding system for the audit cycle subsequently used prospectively to assess audits reported to medical audit advisory group coordinators on practice visits. SETTING--All 85 general practices in Oxfordshire, of which 80 were visited by Oxfordshire Medical Audit Advisory Group coordinators. MAIN OUTCOME MEASURES--Satisfaction of criteria for different levels of audit (full, partial, potential, planning or no audit) according to coding scores for practice audits. RESULTS--46 (58%) practices were classified as doing audit, the remainder doing no audit or only collecting data for family health services authority returns. Of audits being undertaken, 55/102 (54%) included planning care or the setting of targets. CONCLUSIONS--The coding system offers the prospect of formative assessment for practices to help them improve their audits, and summative assessment for the family health services authority to satisfy the needs for professional accountability. Its use in Oxfordshire disclosed considerable deficiencies in the process of practice audit. IMPLICATIONS AND ACTION--Practices in Oxfordshire should improve their audits. The advisory groups target to March 1992 is for 50% of practices to be doing full or partial and 25% potential audit and half of the remainder planning audit. Practices are encouraged to include in their audit implementing change, planning care, and agreeing criteria for further assessment.
588 ANGIOTENSIN-CONVERTING ENZYME I/D POLYMORPHISM IS ASSOCIATED WITH SIGNIFICANTLY DIFFERENT VALUES OF HEPATIC VENOUS PRESSURE GRADIENT IN PATIENTS WITH LIVER CIRRHOSIS
Authors: B.E. Annicchiarico, C. Santonocito, C. Di Stasi, C. Zuppi, M. Siciliano, M.E. Riccioni, E. Capoluongo
Journal: Journal of Hepatology (2011)
Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia
Authors: David W. Bilheimer, Joseph L. Goldstein, Scott M. Grundy, Thomas E. Starzl, Michael S. Brown
Journal: New England Journal of Medicine (1984)

Original Article from The New England Journal of Medicine — Liver Transplantation to Provide Low-Density-Lipoprotein Receptors and Lower Plasma Cholesterol in a Child with Homozygous Familial Hypercholesterolemia
Formation of the Venous Pole of the Heart From an <i>Nkx2–5</i> –Negative Precursor Population Requires <i>Tbx18</i>
Authors: Vincent M. Christoffels, Mathilda T.M. Mommersteeg, Mark-Oliver Trowe, Owen W.J. Prall, Corrie de Gier-de Vries, Alexandre T. Soufan, Markus Bussen, Karin Schuster-Gossler, Richard P. Harvey, Antoon F.M. Moorman, Andreas Kispert
Journal: Circulation Research (2006)

The venous pole of the mammalian heart is a structurally and electrically complex region, yet the lineage and molecular mechanisms underlying its formation have remained largely unexplored. In contrast to classical studies that attribute the origin of the myocardial sinus horns to the embryonic venous pole, we find that the sinus horns form only after heart looping by differentiation of mesenchymal cells of the septum transversum region into myocardium. The myocardial sinus horns and their mesenchymal precursor cells never express Nkx2–5 , a transcription factor critical for heart development. In addition, lineage studies show that the sinus horns do not derive from cells previously positive for Nkx2–5 . In contrast, the sinus horns express the T-box transcription factor gene Tbx18 . Mice deficient for Tbx18 fail to form sinus horns from the pericardial mesenchyme and have defective caval veins, whereas the pulmonary vein and atrial structures are unaffected. Our studies define a novel heart precursor population that contributes exclusively to the myocardium surrounding the sinus horns or systemic venous tributaries of the developing heart, which are a source of congenital malformation and cardiac arrhythmias.