tbuckley/cabot-search huggingface dataset:
Continuous Glucose Monitoring and the Reality of Metabolic Control in Preschool Children With Type 1 Diabetes
Authors: George S. Jeha, Lefkothea P. Karaviti, Barbara Anderson, E. O’Brian Smith, Susan Donaldson, Toniean S. McGirk, Morey W. Haymond
Journal: Diabetes Care (2004)

OBJECTIVE—To determine using the MiniMed continuous glucose monitoring system (CGMS) 1) whether twice-daily insulin injection therapy achieves adequate control in preschool children with type 1 diabetes and 2) whether the CGMS is more informative than self-monitoring of blood glucose (SMBG) regarding glucose control and well tolerated by preschool children and their families. RESEARCH DESIGN AND METHODS—Ten children &amp;lt;6 years of age with type 1 diabetes were monitored twice using the CGMS. The distribution of glucose values was analyzed, particularly the frequency, duration, and distribution of hypoglycemia. We analyzed the accuracy of the CGMS in detecting hypoglycemia as well as the clinical relevance of the difference between CGMS and SMBG values. RESULTS—Although hypoglycemia was more frequent during the night (0.8 nighttime episodes · subject–1 · 24 h–1 vs. 0.3 daytime episodes · subject–1 · 24 h–1), the difference did not reach statistical significance (P = 0.07). However, nighttime episodes lasted longer than daytime episodes (1.2 vs. 0.2 h · subject–1 · 24 h–1, P = 0.006). Hypoglycemia accounted for 7% and normoglycemia for 24%, while hyperglycemia occurred 64% of the time, with postprandial hyperglycemia being an almost universal feature (94 ± 7% of all postmeal values). The CGMS correlated well with SMBG without significant clinical discrepancy. The CGMS sensitivity to detect hypoglycemia was 70% with a specificity of 99%; however, the CGMS detected twice as many total episodes as SMBG (82 vs. 40). CONCLUSIONS—Twice-daily insulin injection rarely achieves control in preschool children with type 1 diabetes. The CGMS is well tolerated by patients and has the advantage of revealing daily glucose trends missed by SMBG.
Antitumor Activity of a Kinesin Inhibitor
Authors: Roman Sakowicz, Jeffrey T. Finer, Christophe Beraud, Anne Crompton, Evan Lewis, Alex Fritsch, Yan Lee, John Mak, Robert Moody, Rebecca Turincio, John C. Chabala, Paul Gonzales, Stephanie Roth, Steve Weitman, Kenneth W. Wood
Journal: Cancer Research (2004)

Abstract Several members of the kinesin family of microtubule motor proteins play essential roles in mitotic spindle function and are potential targets for the discovery of novel antimitotic cancer therapies. KSP, also known as HsEg5, is a kinesin that plays an essential role in formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. We identified a potent inhibitor of KSP, CK0106023, which causes mitotic arrest and growth inhibition in several human tumor cell lines. Here we show that CK0106023 is an allosteric inhibitor of KSP motor domain ATPase with a Ki of 12 nm. Among five kinesins tested, CK0106023 was specific for KSP. In tumor-bearing mice, CK0106023 exhibited antitumor activity comparable to or exceeding that of paclitaxel and caused the formation of monopolar mitotic figures identical to those produced in cultured cells. KSP was most abundant in proliferating human tissues and was absent from cultured postmitotic neurons. These findings are the first to demonstrate the feasibility of targeting mitotic kinesins for the treatment of cancer.
KETOCONAZOLE VERSUS NYSTATIN PLUS AMPHOTERICIN B FOR FUNGAL PROPHYLAXIS IN SEVERELY IMMUNOCOMPROMISED PATIENTS
Authors: I.M. Hann, R. Corringham, M. Keaney, P. Noone, J. Fox, M. Szawatkowski, H.G. Prentice, H.A. Blacklock, M. Shannon, E. Gascoigne, E. Boesen, A.V. Hoffbrand
Journal: The Lancet (1982)
Maintenance Treatment with Immunomodulator MGN1703 Following Induction with Standard 1ST Line Therapy Prolongs Progression-Free Survival in Patients with Metastatic Colorectal (MCRC): Results of the Phase II/III Impact Trial
Authors: D. Arnold, H.J. Schmoll, J. Riera-Knorrenschild, F. Mayer, H. Kroening, W. Scheithauer, D. Nitsche, M. Tschaika, M. Schmidt, B. Wittig
Journal: Annals of Oncology (2012)
Growth of monosodium urate monohydrate crystals: effect of cartilage and synovial fluid components on in vitro growth rates.
Authors: H M Burt, Y C Dutt
Journal: Annals of the Rheumatic Diseases (1986)

The effects of cartilage and synovial fluid components such as proteoglycans, chondroitin sulphate, hyaluronic acid, phospholipids, and albumin on the growth kinetics of monosodium urate monohydrate (MSUM) crystals were investigated. MSUM seed crystals were added to supersaturated sodium urate solutions, and the rate of decrease in the concentration of growth medium was used as a measure of the growth rate. A second order dependence of growth rate on supersaturation was found, and growth rate constants were determined with an integrated form of the growth equation. The additives, hyaluronic acid, proteoglycan monomer and aggregate, and phosphatidylserine, had no significant effect on the growth rate constant. Chondroitin sulphate and phosphatidylcholine increased the growth rate constant, possibly by promoting further nucleation in the growth medium. Albumin significantly inhibited MSUM crystallisation. The possible implications of these findings on in vivo MSUM crystallisation are discussed.
Androgen and Vitamin D Receptor Gene Polymorphisms: the Long and Short of Prostate Cancer Risk
Authors: D. Feldman
Journal: JNCI Journal of the National Cancer Institute (1997)

In this issue of the Journal, in a study of candidate genes and prostate cancer susceptibility, Ingles et al. ( 1) report on the association of polymorphisms in the genes encoding the androgen receptor (AR) and the vitamin D receptor (VDR) with the risk of prostate cancer. The polymorphisms, discussed in detail below, both result from variations in length of nucleotide repeats; the AR polymorphism is due to an expansion of CAG codons, whereas the VDR polymorphism is due to an increased number of adenosines in a poly-A tract. The short AR alleles (with <20 CAG repeats) were associated with an adjusted odds ratio of 2.1-fold greater risk of prostate cancer, and the long VDR alleles (with poly-A of o18) were associated with a 4.6-fold greater risk. In both cases, the at-risk genotypes were more strongly associated with advanced disease than with localized disease limited to the prostate. These polymorphisms are among the strongest genetic risk factors found yet for prostate cancer and are therefore of great potential significance. It should be emphasized, however, that the variant alleles under study are distributed among the normal population and that a polymorphism does not necessarily cause the cancer but is merely associated with increased risk of having the cancer. Given the importance of androgens for prostate growth, one might expect that a modification in the AR could cause a genetic effect on prostate cancer risk; the VDR, however, is another story, and the relationship of vitamin D to the prostate and prostate cancer has been recognized only recently (2-6). However, the AR and VDR have many similarities. Both are members of the steroid‐thyroid‐retinoid receptor superfamily of hormone-dependent nuclear transcription factors. The AR gene has been localized to the proximal long arm of the X chromosome and the VDR to chromosome 12q14. The hormonal ligands for both receptors circulate as prehormones, testosterone and 25hydroxyvitamin D, respectively. Both prehormones have low hormonal activity but can be converted to the highly active form by specific enzymes, 5a-reductase to produce 5a-dihydrotestosterone (DHT) and 1a-hydroxylase to produce 1a,25-dihydroxyvitamin D3 (calcitriol), respectively. In both cases, the nuclear receptor is essential for hormone action, and inactivating mutations in the receptors can cause hormone-resistant syndromes, androgen insensitivity syndrome, and hereditary vitamin D-resistant rickets. Both hormones act via their cognate receptors to regulate cell proliferation; DHT stimulates and calcitriol inhibits prostate cell growth. Also, both hormones stimulate secretion of prostate-specific antigen ( 5). The study by
Longitudinal Waves in the Walls of Fluid-Filled Elastic Tubes
Authors: ROBERT L. VAN CITTERS
Journal: Circulation Research (1960)

Experiments with a rubber tube model of the aorta have demonstrated the presence of longitudinal waves in the wall of the tubing. This mode of vibration was predicted by Lamb from the theoretical considerations, but has not previously been described. The characteristics of "impact waves" in arteries and of the longitudinal mural waves in the model appear to be similar. Longitudinal waves undoubtedly influence the arterial pulse contour. Theoretically, the damping coefficient for them is the same as that for radial waves.
Proton Pump Inhibitors Reduce the Risk of Neoplastic Progression in Patients With Barrett's Esophagus
Authors: Florine Kastelein, Manon C.W. Spaander, Ewout W. Steyerberg, Katharina Biermann, Vera E. Valkhoff, Ernst J. Kuipers, Marco J. Bruno
Journal: Clinical Gastroenterology and Hepatology (2012)
Government drops plans for minimum alcohol pricing in England and Wales
Authors: A. O'Dowd
Journal: BMJ (2013)

The government has abandoned plans to introduce a minimum price for a unit of alcohol in England and Wales, despite numerous recommendations to do so and Scotland’s decision to adopt such a policy.

The Home Office announced on 17 July that it was not introducing a minimum unit price because there was insufficient “concrete evidence” that such a move would work, but said that the idea would remain under consideration.

The announcement was condemned by academics, clinicians, and campaigning groups who said that the government had caved in to the alcohol industry’s arguments.

Jeremy Browne, crime prevention minister, speaking while the Home Office published its official response1 to its alcohol strategy consultation2 …
Modulation of allergen-specific T-lymphocyte function by virus-like particles decorated with HLA class II molecules
Authors: Victoria M. Leb, Beatrice Jahn-Schmid, Hans J. Kueng, Klaus G. Schmetterer, Daniela Haiderer, Alina Neunkirchner, Gottfried F. Fischer, Arnulf Hartl, Josef Thalhamer, Peter Steinberger, Barbara Bohle, Brian Seed, Winfried F. Pickl
Journal: Journal of Allergy and Clinical Immunology (2009)
Structural Analysis Identifies Imidazo[1,2-<i>b</i>]Pyridazines as PIM Kinase Inhibitors with <i>In vitro</i> Antileukemic Activity
Authors: Vanda Pogacic, Alex N. Bullock, Oleg Fedorov, Panagis Filippakopoulos, Christelle Gasser, Andrea Biondi, Sandrine Meyer-Monard, Stefan Knapp, Juerg Schwaller
Journal: Cancer Research (2007)

Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact with the NH(2)-terminal lobe helix alphaC rather than with the kinase hinge region. Thus, the identified inhibitors are ATP competitive but not ATP mimetic compounds, explaining their enhanced selectivity with respect to conventional type I kinase inhibitors. One of the identified imidazo[1,2-b]pyridazines (K00135) was further tested in several hematopoietic cellular systems. First, K00135 dose-dependently impaired survival of murine Ba/F3 cells that have been rendered cytokine independent by overexpression of human PIMs. Second, K00135 impaired survival and clonogenic growth of a panel of human acute leukemia cells. Third, exposure of K00135 significantly suppressed in vitro growth of leukemic blasts from five acute myelogenous leukemia patients but not of normal umbilical cord blood mononuclear cells. In vitro kinase assays and immunoblotting using lysates from human MV4;11 leukemic cells showed inhibition of phosphorylation of known PIM downstream targets, such as BAD and eukaryotic translation initiation factor 4E-binding protein 1, by K00135. Taken together, we report a family of small molecules that selectively interact and block PIM kinases and could serve as a lead to develop new targeted antileukemic therapeutics.
Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis
Authors: Anne Joutel, Pascal Favrole, Pierre Labauge, Hugues Chabriat, Christelle Lescoat, Frédéric Andreux, Valérie Domenga, Michaelle Cécillon, Katayoun Vahedi, Anne Ducros, Florence Cave-Riant, Marie Germaine Bousser, Elisabeth Tournier-Lasserve
Journal: The Lancet (2001)
Hypoxia in Models of Lung Cancer: Implications for Targeted Therapeutics
Authors: Edward E. Graves, Marta Vilalta, Ivana K. Cecic, Janine T. Erler, Phuoc T. Tran, Dean Felsher, Leanne Sayles, Alejandro Sweet-Cordero, Quynh-Thu Le, Amato J. Giaccia
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. Experimental Design: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of γH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. Results: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types. Conclusions: These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies. Clin Cancer Res; 16(19); 4843–52. ©2010 AACR.
Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC)
Authors: E. Van Cutsem, Y. Kang, H. Chung, A. Sawaki, F. Lordick, J. Hill, M. Lehle, A. Feyereislova, Y. Bang
Journal: Journal of Clinical Oncology (2009)

LBA4509 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]
Increased nitric oxide production by neutrophils in bronchial asthma
Authors: G. Ramesh, S.K. Jindal, N.K. Ganguly, V. Dhawan
Journal: European Respiratory Journal (2001)

This study was designed to assess the production of nitric oxide (NO) by neutrophils in bronchial asthma. Thirty asthmatic patients (ten each of mild, moderate and severe asthma) and ten healthy controls were included in the study. Neutrophils from peripheral venous blood were stimulated with latex, and production of nitrite (an NO metabolise) and l-citrulline (a co-product of NO) was studied. It was postulated that peripheral blood neutrophils, being in a primed or activated state in asthma, would reflect the changes occurring in bronchial tree neutrophils. Nitrite and l-citrulline production by neutrophils was significantly higher in asthmatics (p&lt;0.001) and increased with disease severity. A strong negative correlation was observed between peak expiratory flow and both nitrite (r=−0.87, p&lt;0.001) and l-citrulline (r=−0.88, p&lt;0.001) production. It is concluded that nitric oxide production by neutrophils is increased in bronchial asthma and can possibly contribute to airway narrowing and disease severity.
Autoantibodies produced spontaneously by young 1pr mice carry transforming growth factor beta and suppress cytotoxic T lymphocyte responses.
Authors: D A Rowley, E T Becken, R M Stach
Journal: The Journal of Experimental Medicine (1995)

Young MRL/MPJ-lpr (lpr) mice 8-12 wk old challenged with alloantigen had significantly lower specific cytolytic T lymphocyte (CTL) responses than control MRL/MPJ +/+ mice. Serum from lpr mice compared with serum from ++ or normal C3H mice powerfully suppressed CTL responses in mixed lymphocyte cultures (MLC); absorbing lpr serum on protein G, adding antibody against transforming growth factor beta (TGF-beta) to cultures or dissociating immunoglobulin G (IgG) and TGF-beta before additions to cultures prevented suppression. Apparently autoantibody, similar to IgG produced by normal mice in response to immunization, carries TGF-beta which suppresses CTL responses in vivo and in vitro.
ceRNA Cross-Talk in Cancer: When ce-bling Rivalries Go Awry
Authors: Florian A. Karreth, Pier Paolo Pandolfi
Journal: Cancer Discovery (2013)

Abstract The cancer transcriptome is characterized by aberrant expression of both protein-coding and noncoding transcripts. Similar to mRNAs, a significant portion of the noncoding transcriptome, including long noncoding RNAs and pseudogenes, harbors microRNA (miRNA)-response elements (MRE). The recent discovery of competitive endogenous RNAs (ceRNA), natural decoys that compete for a common pool of miRNAs, provides a framework to systematically functionalize MRE-harboring noncoding RNAs and integrate them with the protein-coding RNA dimension in complex ceRNA networks. Functional interactions in ceRNA networks aid in coordinating a number of biologic processes and, when perturbed, contribute to disease pathogenesis. In this review, we discuss recent discoveries that implicate natural miRNA decoys in the development of cancer. Significance: Cross-talk between ceRNAs through shared miRNAs represents a novel layer of gene regulation that plays important roles in the physiology and development of diseases such as cancer. As cross-talk can be predicted on the basis of the overlap of miRNA-binding sites, we are now one step closer to a complete functionalization of the human transcriptome, especially the noncoding space. Cancer Discov; 3(10); 1113–21. ©2013 AACR.
Gestational Diabetes Mellitus: Primum Non Nocere
Authors: Shivani Misra, Anne Dornhorst
Journal: Diabetes Care (2012)

Maturity-onset diabetes of the young (MODY) encompasses a collection of distinct forms of diabetes, which are inherited in an autosomal-dominant mode from the maternal or paternal side of the family or occasionally occur as a de novo mutation. All the genes involved affect either β-cell sensing or insulin secretion (1). The clinical presentations of MODY are heterogeneous, reflecting the different gene mutations involved, and the glucose dysregulation observed ranges from a relatively innocent rise in the fasting glucose to frank diabetes with neurological involvement (2,3).

An exact MODY prevalence within the general diabetes population has proven difficult to assess because of underrecognition and lack of routinely available and affordable diagnostic tools. A further confounder is that the reported regional prevalence of specific MODY mutations varies considerably (4). Conservative estimates suggest that between 0.14–1.8% of all cases of diabetes could be attributable to MODY (4). It is to be expected that among women screened for gestational diabetes mellitus (GDM) the prevalence of MODY will be higher, reflecting both the proportionately lower prevalence of type 2 diabetes in women of this age group and the probability that those with undiagnosed MODY will screen positive (5). From the few population studies reported, mutations in the hepatocyte nuclear factor 1 α ( HNF1a ) gene (MODY 3) and glucokinase ( GCK ) gene (MODY 2) account for the majority of cases (6).

MODY 2 is characterized by its high penetrance, early onset, and lifelong fasting hyperglycemia. It is due to mutations in the pancreatic GCK gene, which acts as the β-cell glucose sensor, setting the glucose threshold at which amplification of insulin …
Site and Mechanism of Uptake of <sup>3</sup> H-/-Norepinephrine by Isolated Perfused Rat Lungs
Authors: TERENCE E. NICHOLAS, JUDY M. STRUM, LYNNE S. ANGELO, ALAIN F. JUNOD
Journal: Circulation Research (1974)

The uptake of 3 H- l -norepinephrine was examined in isolated perfused rat lungs, and the mechanism of uptake was compared with that previously found for 5-hydroxytryptamine. Most of the norepinephrine taken up by the lungs was rapidly deaminated and O-methylated, and the metabolic products were subsequently returned to the perfusate. The presence of iproniazid and tropolone markedly inhibited this metabolism; because the metabolites were released from the lungs more rapidly than was norepinephrine itself, these inhibitors appeared to increase the rate of uptake of the amine. The uptake of norepinephrine was a saturable, temperature-dependent process with a K m of 1.11 x 10 -6 M and a V max measured during metabolic inhibition of 2.78 x 10 -9 moles/g min -1 . Uptake was inhibited by cocaine, imipramine, ouabain, and potassium-free medium as well as by decreasing the sodium concentration or increasing the potassium concentration of the medium. Although normetanephrine reduced the uptake of norepinephrine, metaraminol had no effect. Autoradiography indicated that norepinephrine was taken up into endothelial and smooth muscle cells, but the mechanism of the uptake appeared to combine features characteristic of both extraneuronal and neuronal uptake. The mechanism of uptake of norepinephrine by the lungs is compatible with a sodium-dependent, carrier-mediated transport, but several differences appear to exist between the transport and the site of uptake of norepinephrine and 5-hydroxytryptamine.
Points from Letters: Seasonal Charges?
Authors: B. Hill
Journal: BMJ (1964)

DRIISH N 779 of men in a free society would have tolerated; the position is changing rapidly with fewer doctors prepared to enter general practice and an expanding population.I hope that my fellow practitioners will grasp the opportunity provided by present events to express themselves individually and collec- tively as forcefully as possible, so that our representatives, our politicians, and the public at large shall be left in no doubt as to the feelings and desires of the active prac- titioner of the 1960's if he is to continue to work in a National Health Service.-Iam, etc., Sheffield 11.