tbuckley/cabot-search huggingface dataset:
Targeting eNOS in Pancreatic Cancer
Authors: Benjamin L. Lampson, S. DiSean Kendall, Brooke B. Ancrile, Meghan M. Morrison, Michael J. Shealy, Katharine S. Barrientos, Matthew S. Crowe, David F. Kashatus, Rebekah R. White, Susan B. Gurley, Diana M. Cardona, Christopher M. Counter
Journal: Cancer Research (2012)

Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS, NOS3, or NOS III) has been implicated recently in the pathogenesis of PDACs. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDACs. Genetic deficiency in eNOS limited the development of preinvasive pancreatic lesions and trended toward an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor N(G)-nitro-L-arginine methyl ester (l-NAME). Similarly, other transgenic models of oncogenic KRas-driven tumors responded to l-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which l-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose l-NAME for clinical investigations in treatment of PDACs and possibly other KRas-driven human cancers.
Aurora Kinase Inhibition As an Anticancer Strategy
Authors: John F. Hilton, Geoffrey I. Shapiro
Journal: Journal of Clinical Oncology (2013)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2013.50.7988 Journal of Clinical Oncology - published online before print September 16, 2013 PMID: 24043748 Aurora Kinase Inhibition As an Anticancer Strategy John F. HiltonxJohn F. HiltonSearch for articles by this author , Geoffrey I. ShapiroxGeoffrey I. ShapiroSearch for articles by this author Show More Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA https://doi.org/10.1200/JCO.2013.50.7988 First Page Full Text PDF Figures and Tables © 2013 by American Society of Clinical Oncology
Screening for Carriers of Tay-Sachs Disease
Authors: Laird G. Jackson
Journal: JAMA (1974)

<h3>To the Editor.—</h3> Rosner has opposed screening for carriers of Tay-Sachs disease followed by amniocentesis (228:829, 1974) and selective termination of affected pregnancies on the basis of alleged rabbinical opposition to abortion (<i>Lancet</i>1:359, 1974). Evans and Ellis (<i>Lancet</i>1:575, 1974) quoted Rabbi Jakobovits as stating that "no general ruling can be given on the termination of pregnancies in cases where the generation of a diseased child is suspected or established. All such cases would have to be submitted to individual rabbinical decision." Rosner<sup>1</sup>himself has acknowledged the lack of rabbinical consensus on abortion in these cases, and has written that since many important legal and moral considerations which cannot be spelled out in the presentation of general principles may weigh upon the verdict in any given case, it seems advisable to submit every individual case to rabbinical judgment in the light of the prevailing medical and other circumstances.
Drug Transporters in Drug Efficacy and Toxicity
Authors: M.K. DeGorter, C.Q. Xia, J.J. Yang, R.B. Kim
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Drug transporters are now widely acknowledged as important determinants governing drug absorption, excretion, and, in many cases, extent of drug entry into target organs. There is also a greater appreciation that altered drug transporter function, whether due to genetic polymorphisms, drug-drug interactions, or environmental factors such as dietary constituents, can result in unexpected toxicity. Such effects are in part due to the interplay between various uptake and efflux transporters with overlapping functional capabilities that can manifest as marked interindividual variability in drug disposition in vivo. Here we review transporters of the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies considered to be of major importance in drug therapy and outline how understanding the expression, function, and genetic variation in such drug transporters will result in better strategies for optimal drug design and tissue targeting as well as reduce the risk for drug-drug interactions and adverse drug responses.
Enhancement of Alkylating Agent Activity by SR-4233 in the FSaIIC Muraine Fibrosarcoma
Authors: S. A. Holden, B. A. Teicher, G. Ara, T. S. Herman, C. N. Coleman
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Enhancement of Alkylating Agent Activity by SR-4233 in the FSaIIC Muraine Fibrosarcoma Get access Sylvia A. Holden, Sylvia A. Holden Dana-Farber Cancer InstituteBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Beverly A. Teicher, Beverly A. Teicher * Dana-Farber Cancer Institute and Joint Center for Radiation TherapyBoston, Mass * Correspondence to: Beverly A. Teicher, Ph.D., Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Search for other works by this author on: Oxford Academic PubMed Google Scholar Gulshan Ara, Gulshan Ara Dana-Farber Cancer InstituteBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar Terence S. Herman, Terence S. Herman Dana-Farber Cancer Institute and Joint Center for Radiation TherapyBoston, Mass Search for other works by this author on: Oxford Academic PubMed Google Scholar C. Norman Coleman C. Norman Coleman Joint Center for Radiation Therapy Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 3, 5 February 1992, Pages 187–193, https://doi.org/10.1093/jnci/84.3.187 Published: 05 February 1992 Article history Received: 13 May 1991 Revision received: 18 November 1991 Accepted: 19 November 1991 Published: 05 February 1992
Telomere shortening correlates with increasing aneuploidy of chromosome 8 in human hepatocellular carcinoma
Authors: Ruben R. Plentz, Brigitte Schlegelberger, Peer Flemming, Michael Gebel, Hans Kreipe, Michael P. Manns, Lenhard K. Rudolph, Ludwig Wilkens
Journal: Hepatology (2005)

Abstract Chromosomal instability (CIN) leads to an increase in aneuploidy and chromosomal aberrations in human hepatocellular carcinoma (HCC). Telomere shortening appears as one mechanism fostering the development of CIN. Whether telomere shortening correlates to specific genetic changes that characterize a certain type of cancer has yet to be established. In our recent study, we combined on a cellular level the analysis of hepatocellular telomere fluorescent intensity (TFI) and copy number of chromosome 8—one of the hallmark chromosomal alterations in hepatocellular carcinoma (HCC). We investigated 15 cytological fine-needle biopsies of aneuploid HCC and 5 touch prints of cadaver livers without cancer. Hepatocyte-specific TFI and the measurement of centromere-specific probe for chromosome 8 were both performed by quantitative fluorescence in situ hybridization (qFISH) or FISH. Combined analysis of both methods (coFISH) allowed measurement of telomere length and chromosome 8 copy number on a single cell level. We observed that telomere shortening correlates significantly with increasing copy number of chromosome 8 in HCC on the cellular level. Above the level of 5 copies of chromosome 8 per nucleus, no further shortening of telomeres was found, indicating that telomeres had reached a critically short length at this stage of aneuploidy. In conclusion , our study gives direct evidence that telomere shortening is linked to a specific genetic alteration characteristic for human HCC. (Hepatology 2005;42:522–526.)
Hunt summons royal colleges for talks on preparing for industrial action
Authors: Z. Kmietowicz
Journal: BMJ (2015)

The health secretary for England has been holding discussions with royal colleges to prepare the NHS for any industrial action after the ballot by junior doctors over changes to their contract ends on 18 November.

A spokesman for the Royal College of Anaesthetists told The BMJ that there was overwhelming support for industrial action among junior doctors “across the board, not just among anaesthetists.”

The college president met Jeremy Hunt on Friday 6 November along with representatives of several other colleges, including the Royal College of Surgeons and the Royal College of Physicians, to assess …
Increased Risk of End-Stage Renal Disease in Familial IgA Nephropathy
Authors: Francesco Paolo Schena, Giuseppina Cerullo, Michele Rossini, Salvatore Giovanni Lanzilotta, Christian D’Altri, Carlo Manno
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Primary IgA nephropathy (IgAN) is characterized by recurrent episodes of macroscopic hematuria accompanied by upper respiratory tract infections or persistent asymptomatic microscopic hematuria with or without proteinuria. IgAN may involve one or more members of a family. Three generations of a cohort of 110 patients with biopsy-proven IgAN, living in Southern Italy, were checked for urinalysis, and the relative risk (RR) of developing the disease was evaluated. A total of 19 unrelated familial, 37 suspected, and 54 sporadic cases of IgAN were identified. Renal survival was estimated by the Kaplan-Meier method for censored data and compared by use of the log-rank test. More than 50% of the patients with IgAN clustered in kindred with more than two probably affected relatives. In 19 unrelated IgAN families, 8 had single-generation (SG) and 11 multigenerational (MG) involvement showing a prevalent vertical transmission of the trait. The RR was 16 times higher in first-degree relatives (odds ratio [OR], 16.4; 95% confidence interval [CI], 5.7 to 47.8; P < 0.0001) and >2 times higher, even if NS, in second-degree relatives (OR, 2.4; 95 % CI, 0.7 to 7.9; P = 0.145). The clinical and histologic picture of familial and sporadic IgAN appeared to be similar. The 20-yr renal survival rate from the apparent onset of the disease was significantly poorer in patients with familial (41%) than in patients with sporadic (94%) IgAN (P = 0.003). Furthermore, 15-yr renal survival from the time of renal biopsy was significantly worse in familial IgAN (P = 0.02); end-stage renal disease was present in 64% of familial and only in 8% of patients with sporadic IgAN. Finally, renal survival was significantly worse in patients belonging to families with SG rather than with MG involvement (P = 0.03). These data show, for the first time, that familial IgAN may be considered a nonbenign disease that occurs frequently in first-degree relatives. Familial IgAN has a poorer outcome than sporadic IgAN. Therefore, an accurate family history and urinalysis in all family members is urgently recommended in clinical practice. This procedure might avoid late referral of subjects with persistent and underestimated urinary abnormalities and late diagnosis of the disease.
Fat Distribution and Glucose Intolerance Among Greenland Inuit
Authors: Marit Eika Jørgensen, Knut Borch-Johnsen, Ronald Stolk, Peter Bjerregaard
Journal: Diabetes Care (2013)

A high amount of subcutaneous fat is suggested to explain the observation of lower obesity-associated metabolic risk among Inuit than among Europeans. We examined the association between measures of obesity (visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], BMI, waist circumference [WC], and percentage of body fat) and the indices of glucose metabolism (fasting and 2-h glucose levels, insulin resistance per homeostasis model assessment [HOMA-IR], and the insulin sensitivity index [ISI0,120]) among Greenland Inuit.A total of 3,108 adult Inuit participated in a population-based study. The examination included a 75-g oral glucose tolerance test and anthropometric measurements. VAT and SAT were measured by ultrasound according to a validated protocol. Information on sociodemographic characteristics and health behaviors was obtained by interview.Mean SATs were 1.8 and 3.5 cm in men and women, respectively. Mean VATs were 7.0 and 6.3 cm in men and women, respectively. The total prevalence of type 2 diabetes was 9%. Percentage of body fat generally was most strongly associated with all outcomes. Both SAT and VAT were significantly associated with glucose intolerance, fasting and 2-h plasma glucose levels, HOMA-IR, and ISI0,120. VAT was more strongly associated with all outcomes than was SAT. After further adjustment for BMI or WC, VAT was associated with glucose intolerance and insulin resistance, whereas there was a trend toward a negative or no association with SAT.High mean values of SAT may to a large extent explain the high WC in Inuit populations, and this is suggested to contribute to the lower observed metabolic risk for a given level of obesity.
The neural basis of predicate-argument structure
Authors: James R. Hurford
Journal: Behavioral and Brain Sciences (2003)

Neural correlates exist for a basic component of logical formulae, PREDICATE(x). Vision and audition research in primates and humans shows two independent neural pathways; one locates objects in body-centered space, the other attributes properties, such as colour, to objects. In vision these are the dorsal and ventral pathways. In audition, similarly separable "where" and "what" pathways exist. PREDICATE(x) is a schematic representation of the brain's integration of the two processes of delivery by the senses of the location of an arbitrary referent object, mapped in parietal cortex, and analysis of the properties of the referent by perceptual subsystems. The brain computes actions using a few "deictic" variables pointing to objects. Parallels exist between such nonlinguistic variables and linguistic deictic devices. Indexicality and reference have linguistic and nonlinguistic (e.g., visual) versions, sharing the concept of attention. The individual variables of logical formulae are interpreted as corresponding to these mental variables. In computing action, the deictic variables are linked with "semantic" information about the objects, corresponding to logical predicates. Mental scene descriptions are necessary for practical tasks of primates, and preexist language phylogenetically. The type of scene descriptions used by nonhuman primates would be reused for more complex cognitive, ultimately linguistic, purposes. The provision by the brain's sensory/perceptual systems of about four variables for temporary assignment to objects, and the separate processes of perceptual categorization of the objects so identified, constitute a pre-adaptive platform on which an early system for the linguistic description of scenes developed.
<i>NOS1AP</i> Is a Genetic Modifier of the Long-QT Syndrome
Authors: Lia Crotti, Maria Cristina Monti, Roberto Insolia, Anna Peljto, Althea Goosen, Paul A. Brink, David A. Greenberg, Peter J. Schwartz, Alfred L. George
Journal: Circulation (2009)

Background— In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population. Methods and Results— We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P =0.019; rs16847548, P =0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P =0.028; rs16847548, P =0.014), and with greater likelihood of having a QT interval in the top 40% of values among all mutation carriers (rs4657139, P =0.03; rs16847548, P =0.03). Conclusions— These findings indicate that NOS1AP , a gene first identified as affecting the QTc interval in a general population, also influences sudden death risk in subjects with LQTS. The association of NOS1AP genetic variants with risk for life-threatening arrhythmias suggests that this gene is a genetic modifier of LQTS, and this knowledge may be clinically useful for risk stratification for patients with this disease, after validation in other LQTS populations.
Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation
Authors: Xiaoling Xu, Kay-Uwe Wagner, Denise Larson, Zoë Weaver, Cuiling Li, Thomas Ried, Lothar Hennighausen, Anthony Wynshaw-Boris, Chu-Xia Deng
Journal: Nature Genetics (1999)
The effect of haemodynamic changes on maximum blood flow acceleration at the aortic root in the anaesthetized, open-chest dog
Authors: D. C. W. CHUNG, J. H. CHAMBERLAIN, R. G. F. L. SEED
Journal: Cardiovascular Research (1974)

The effect of load changes on various indices of myocardial function was investigated in anaesthetized open-chest dogs. Alterations of left ventricular end diastolic volume were associated with changes of maximum acceleration, peak flow, and maximum dP/dt, as were sudden changes in afterload (aortic impedance). (Max dP/dt)/IP was not affected by these manoeuvres.
Sodium Excretion in Response to Vasopressin and Selective Vasopressin Receptor Antagonists
Authors: Julie Perucca, Daniel G. Bichet, Pascale Bardoux, Nadine Bouby, Lise Bankir
Journal: Journal of the American Society of Nephrology (2008)

The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However, for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 μg/kg but increased it at doses >5 μg/kg, an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma, renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.
Investigation of <i>In Vivo</i> Targeting Kinetics of α<sub>v</sub>β<sub>3</sub>-Specific Superparamagnetic Nanoprobes by Time-Resolved MRI
Authors: Chase W. Kessinger, Osamu Togao, Chalermchai Khemtong, Gang Huang, Masaya Takahashi, Jinming Gao
Journal: Theranostics (2011)

Nanoparticulate imaging probes have become an increasingly important arsenal in the visualization of molecular markers for early diagnosis and post-therapy assessment of diseases. Surface functionalization of these nanoparticles has led to the development of a variety of targeted nanoprobes for various imaging modalities (e.g. PET, MRI, optical). Despite these advances, detailed understanding of the nanoparticle targeting kinetics, particularly at the early time points immediately after injection, is still lacking. In this study, we report the combination of a T(2)*-weighted time-resolved-MRI (TR-MRI) method with ultra-sensitive superparamagnetic polymeric micelle (SPPM) nanoprobes to quantify the targeting kinetics of cyclic (RGDfK) (cRGD)-encoded SPPM to angiogenic endothelium in subcutaneous human tumor xenograft models in mice. TR-MRI analyses of the α(v)β(3)-targeted and non-targeted SPPMs allowed for the subtraction of blood volume and extravascular signal components from the cRGD-SPPM data, resulting in a specific measurement of the accumulation kinetics of nanoprobes in lung, breast and brain cancer preclinical models. In all three models, α(v)β(3)-specific accumulation of SPPM nanoprobes was observed in the first 5 mins after intravenous injection (first order rate constants were in the range of 0.22-0.24 min(-1)). Similar α(v)β(3)-targeting kinetics was observed for cRGD-SPPM nanoprobes in different tumor xenograft models, consistent with the targeting of mouse angiogenic endothelium despite tumor inoculation from different human cancer cell lines. Results from this study offer new opportunities in the quantitative characterization of the targeting kinetics of cancer-specific nanoparticles to their intended biological targets in an intact animal, which provides fundamental insights on molecular recognition processes in vivo for further development of these nanoprobes.
Antibiotic treatment and long term prognosis of reactive arthritis
Authors: K Laasila
Journal: Annals of the Rheumatic Diseases (2003)

To evaluate whether a three month course of lymecycline has an effect on the long term prognosis of reactive arthritis (ReA).In 1987-88 a double-blind controlled study with three month course of lymecycline/placebo was conducted. 17 of 23 patients treated at the outpatient department of Helsinki University Central Hospital volunteered to take part in a follow up study, where a physical examination were performed, and erythrocyte sedimentation rate, C reactive protein, rheumatoid factor, and radiographs of the lumbosacral spine and sacroiliac joints and of symptomatic peripheral joints were examined.16/17 (94%) patients reported some kind of back pain and 10/17 (59%) peripheral joint symptoms during the follow up. Two patients had unilateral grade 1 sacroiliitis, one patient grade 4 sacroiliitis, and one patient bilateral grade 2 sacroiliitis. In one patient the disease had progressed to ankylosing spondylitis (AS), and in another to chronic spondyloarthropathy. In addition, two patients had small erosions in radiocarpal joints. No statistically significant differences were found between placebo and lymecycline groups in the development of chronic arthritis, sacroiliitis, or AS.The results of the initial study showed that long term treatment with lymecycline in patients with acute ReA decreased the duration of arthritis in those with Chlamydia trachomatis triggered ReA, but not in other patients with ReA. Ten years after the acute arthritis one patient had developed AS, and three had radiological sacroiliitis, three patients had radiological changes at peripheral joints. Long term lymecycline treatment did not change the natural history of the disease.