tbuckley/cabot-search huggingface dataset:
Determination of Iodothyronine Absorption and Conversion of L-Thyroxine (T4) to L-Triiodothyronine (T3) using Turnover Rate Techniques
Authors: Martin I. Surks, Alan R. Schadlow, Jerrold M. Stock, Jack H. Oppenheimer
Journal: Journal of Clinical Investigation (1973)

The absorption of L-thyroxine (T(4)) and L-triiodothyronine (T(3)) and the fractional rate of conversion of T(4) to T(3) were determined from the turnover rates of T(4) and T(3) in seven patients without endogenous thyroid function during separate treatment periods with these iodothyronines. Serum T(3) concentration was measured by a radioimmunoassay procedure in which the iodothyronines are separated from the plasma proteins before incubation with anti-T(3) antibody. Metabolic clearance rates were calculated by an integral (noncompartmental) approach since the use of single compartment kinetics led to a 40% overestimation of the metabolic clearance rate of T(3). Based on the amount of hormone ingested and the observed hormonal turnover rates, the absorption of T(4) and T(3) (iodothyronine turnover/iodothyronine ingested) in man could be estimated. Absorption of T(3) was complete in three subjects but decreased to 43% in a fourth who was suffering from mild congestive heart failure. Mean T(4) absorption was 48.0+/-2.6% (SEM) for seven subjects. The mean fractional rate of T(4) to T(3) conversion determined during T(4) replacement therapy (T(3) turnover/T(4) turnover) was 42.6% (range 30.7-50.8%). Thus, approximately one-half of the T(4) which was deiodinated was converted to T(3) suggesting that monodeiodination is an obligatory step in the peripheral metabolism of T(4). Calculations based on these results together with other available data suggest that under normal physiologic circumstances the major portion of the T(3) pool is derived from monodeiodination of T(4).
Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As First-Line Treatment for Advanced Breast Cancer: Results From the FIRST Study
Authors: John F.R. Robertson, Antonio Llombart-Cussac, Janusz Rolski, David Feltl, John Dewar, Euan Macpherson, Justin Lindemann, Matthew J. Ellis
Journal: Journal of Clinical Oncology (2009)

To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the approved dose) with the aromatase inhibitor anastrozole as first-line endocrine therapy for advanced hormone receptor-positive breast cancer in postmenopausal women.FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) is a phase II, randomized, open-label, multicenter study of a fulvestrant high-dose (HD) regimen (500 mg/mo plus 500 mg on day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable disease for > or = 24 weeks. The primary analysis was performed 6 months after the last patient was randomly assigned.CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103), 72.5% v 67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386). Objective response rate (ORR) was also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. Time to progression (TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for fulvestrant HD v 12.5 months for anastrozole; hazard ratio, 0.63; 95% CI, 0.39 to 1.00; P = .0496). Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well tolerated, with no significant differences in the incidence of prespecified adverse events.First-line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety profile similar to that of anastrozole.
Adenosine Inhibits Matrix Metalloproteinase-9 Secretion By Neutrophils
Authors: Isabelle Ernens, Didier Rouy, Emilie Velot, Yvan Devaux, Daniel R. Wagner
Journal: Circulation Research (2006)

Matrix metalloproteinases (MMPs), and in particular MMP-9 secreted by neutrophils, are capable of degrading the matrix components of the heart and are thought to be the driving force behind myocardial matrix remodeling after infarction. Adenosine, a naturally produced nucleoside, has been shown to have cardioprotective effects and to inhibit secretion of various cytokines. The aim of our study was to determine the effect of adenosine on the secretion of MMP-9 by neutrophils. Neutrophils were isolated from healthy volunteers through Ficoll and Dextran sedimentation. Neutrophils were activated by N -formylmethionyl-leucyl-phenylalanine (fMLP) in the presence or absence of adenosine or adenosine analogs. Zymography and enzyme linked immunosorbent assay were used to measure MMP-9 secretion. Adenosine (1 μmol/L) decreased the fMLP-induced MMP-9 secretion by 30±2% (n=8, P &lt;0.001). The effect was dose-dependent and was not specific to fMLP because adenosine also inhibited MMP-9 secretion by LPS- or H 2 O 2 -stimulated neutrophils. The effect of adenosine was mimicked by the adenosine A2a receptor agonist CGS21680 and was inhibited by both the A2a antagonist SCH5826 and A2a RNA silencing. The A3 agonist IB-MECA moderately decreased fMLP-induced MMP-9 secretion. Agonists and antagonists of the other types of adenosine receptors had no significant effect. Adenosine increased intracellular cAMP concentration and accelerated the return to baseline of the intracytoplasmic calcium peak. The inhibition of MMP-9 secretion by adenosine, as well as the calcium effect, was prevented by the protein kinase A inhibitor H-89. In conclusion, we show here that adenosine inhibits MMP-9 secretion by neutrophils. Our results suggest that this effect implies the A2a receptor and is mediated through the cAMP/PKA/Ca 2+ pathway. Therefore, adenosine may represent a new approach to prevent matrix degradation and remodeling after myocardial injury.
Postoperative intrapleural BCG in lung cancer: lack of efficacy and possible enhancement of tumour growth.
Authors: W Bakker, J M Nijhuis-Heddes, A M Wever, A Brutel de la Riviere, E A van der Velde, J H Dijkman
Journal: Thorax (1981)

Fifty-six patients out of a group of 99 with lung cancer received postoperative intrapleural BCG (Pasteur strain) in three different dosages (16 X 10(6) culturable particles (cp), 32 X 10(6) cp, and 64 X 10(6) cp). When comparing the whole group of 99 patients with a historical control group of 126 patients no statistically significant differences were found in survival and disease-free interval. The two groups were well matched in respect of age, sex, histology, stage of disease, and type of operation. Patients with epidermoid carcinoma stage I receiving BCG, however, did significantly worse than those who had not received BCG in terms of disease-free interval. This unfavourable trend was caused by earlier local recurrences rather than metastases. The possible phenomenon of enhanced tumour growth noted in or patients with epidermoid carcinoma stage I might be related to the dosages used in this study, but the different BCG strain used hinders comparison with other studies. We conclude that BCG has no beneficial effect on survival or on disease-free interval; possible enhancement of tumour growth in stage I epidermoid carcinoma was found.
Comment on “Effects of long-term angiotensin II AT-1 receptor blockade on survival, hemodynamics and cardiac remodeling in chronic heart failure in rats”
Authors: R Willenheimer
Journal: Cardiovascular Research (1999)

I read with great interest the paper by Richer et al. [1], regarding the long-term effects of the angiotensin II AT1 receptor blocker irbesartan on survival, hemodynamics and cardiac remodelling in rats with chronic heart failure. It was shown that irbesartan 50 mg/kg/day had a major impact on survival compared to placebo in rats with heart failure following coronary ligation. The authors state that irbesartan opposed cardiac hypertrophy without …
Socio-Economic and Geographical Disparities in Colorectal Adenomas and Colorectal Cancers Detection : a Population-Based Study
Authors: Isabelle Fournel, Abderrahmane Bourredjem, Erik André Sauleau, Vanessa Cottet, Anne Marie Bouvier, Olivier Dejardin, Guy Launoy, Claire Bonithon Kopp
Journal: Annals of Oncology (2013)
Transplantation milestones. Viewed with one- and two-way paradigms of tolerance
Authors: T E Starzl, A J Demetris
Journal: JAMA (1995)

TEN YEARS ago in this journal's Landmark Article series of reproduced historical publications, the remarkable impact was described<sup>1</sup>of the 1956 report in<i>JAMA</i>by Merrill et al<sup>2</sup>of an identical twin renal transplantation. The operation was performed in December 1954, by Joseph E. Murray (Nobel Laureate, 1990) and his associates at the Peter Bent Brigham Hospital, Boston, Mass. By avoiding problems with rejection, such cases symbolized what might someday be accomplished if the immunologic reaction could be controlled. Then, on January 24, 1959, the barrier posed by genetic nonidentity was breached for the kidneys with a successful fraternal twin transplantation<sup>3</sup>by the same team. Over the ensuing 35 years, the beachhead has been expanded by the successful allotransplantation of the liver,<sup>4</sup>heart,<sup>5</sup>lung,<sup>6</sup>pancreas,<sup>7</sup>intestine,<sup>8</sup>multiple abdominal viscera,<sup>9</sup>and bone marrow.<sup>10,11</sup>Such milestones are never eroded from the landscape, but
Evolutionary Insights into Premetazoan Functions of the Neuronal Protein Homer
Authors: Pawel Burkhardt, Mads Grønborg, Kent McDonald, Tara Sulur, Qi Wang, Nicole King
Journal: Molecular Biology and Evolution (2014)

Reconstructing the evolution and ancestral functions of synaptic proteins promises to shed light on how neurons first evolved. The postsynaptic density (PSD) protein Homer scaffolds membrane receptors and regulates Ca(2+) signaling in diverse metazoan cell types (including neurons and muscle cells), yet its ancestry and core functions are poorly understood. We find that the protein domain organization and essential biochemical properties of metazoan Homer proteins, including their ability to tetramerize, are conserved in the choanoflagellate Salpingoeca rosetta, one of the closest living relatives of metazoans. Unlike in neurons, Homer localizes to the nucleoplasm in S. rosetta and interacts directly with Flotillin, a protein more commonly associated with cell membranes. Surprisingly, we found that the Homer/Flotillin interaction and its localization to the nucleus are conserved in metazoan astrocytes. These findings suggest that Homer originally interacted with Flotillin in the nucleus of the last common ancestor of metazoans and choanoflagellates and was later co-opted to function as a membrane receptor scaffold in the PSD.
A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)
Authors: G.R. Blumenschein, E.F. Smit, D. Planchard, D.-W. Kim, J. Cadranel, T. De Pas, F. Dunphy, K. Udud, M.-J. Ahn, N.H. Hanna, J.-H. Kim, J. Mazieres, S.-W. Kim, P. Baas, E. Rappold, S. Redhu, A. Puski, F.S. Wu, P.A. Jänne
Journal: Annals of Oncology (2015)
Atypical mycobacterial infections
Authors: S V. Karthik, K. V Mulay
Journal: Journal of the Royal Society of Medicine (2003)

Ms Montague and her colleagues (March 2003 JRSM1) are unsure about the value of chemotherapy in atypical mycobacterial cervical adenitis. They refer to encouraging results with the macrolide clarithromycin, but both primary and secondary resistance to this agent are well recognized. There is evidence that combination therapy with rifabutin or rifampicin alongside clarithromycin has a synergistic effect, particularly against Mycobacterium avium-intracellulare complex.2 This not only ensures maximum antimycobacterial activity but also may protect against the development of secondary clarithromycin resistance. Multidrug regimens employing standard antimycobacterials (isoniazid, ethambutol and/or streptomycin) used with the above combination have proven effective in cases of disseminated atypical mycobacterial infections, particularly in patients with AIDS.3 With excision biopsy early diagnosis is feasible with tools such as the polymerase-chain-reaction linked ELISA with mycobacterial DNA probes. The antimicrobial susceptibility of atypical mycobacteria can be assessed rapidly in tissue specimens by use of mycobacteria growth indicator tubes, which also give an indication of minimum inhibitory concentrations.4 These tools for rapid diagnosis, not yet widely available, can be helpful in decisions about postoperative chemotherapy.
Age related macular degeneration: Smoking entails major risk of blindness
Authors: C S. P Kelly
Journal: BMJ (2003)

EDITOR—Chopdar et al's review of age related macular degeneration was timely,1 but they paid insufficient attention to the association between smoking and age related macular degeneration.

Pooled results from three large population based cross sectional studies found an odds ratio for all types of age related macular degeneration of 3.12 (95% confidence interval 2.10 to 4.64) for current smokers compared with never smokers.2 …
Successful treatment of refractory neuro-Behcet's disease with infliximab: a case report to show its efficacy by magnetic resonance imaging, transcranial magnetic stimulation and cytokine profile
Authors: K Fujikawa, K Aratake, A Kawakami, T Aramaki, N Iwanaga, Y Izumi, K Arima, M Kamachi, M Tamai, M Huang, H Nakamura, Y Nishiura, T Origuchi, H Ida, K Eguchi
Journal: Annals of the Rheumatic Diseases (2006)

imaging, transcranial magnetic stimulation and cytokine profile
Persisting unilateral lung hypoperfusion after resection of a subcarinal bronchogenic cyst
Authors: M Barker, G Kusenbach, E Muhler, E Kleinhans, G Alzen
Journal: European Respiratory Journal (1996)

As a rare malformation with a wide variety of clinical modes of presentation, the bronchogenic cyst remains a diagnostic challenge. We report a case with a subcarinal bronchogenic cyst and stenosis of the left main bronchus presenting as "unilateral hyperlucent lung". Hypoplasia of the ipsilateral pulmonary vascular system persisted after surgical restitution of ventilation and is most likely due to an associated vascular malformation. Alternatively, anatomical fixation of pulmonary reflex vasoconstriction can be discussed.
Inhibition of Experimental Hypercholesterolemia and Atherogenesis by 4-Amino Pteroylglutamic Acid (Aminopterin)
Authors: CARL MUSCHENHEIM, SEYMOUR ADVOCATE, DONALD W. HOSKINS
Journal: Circulation Research (1960)

Rabbits pretreated with Aminopterin (4-amino pteroylglutamic acid) for 4 weeks were fed an atherogenic diet for 8 weeks, during which Aminopterin injections also were continued. The atherogenic diet consisted of a stock diet with 3/4 per cent cholesterol added. As a result of some manipulation of the Aminopterin dosage during the period before cholesterol feeding was begun, some of the Aminopterin-treated animals lost weight from overdosage, and 7 of the original 20 died. The surviving animals upon reduction of dosage made good weight gains, comparable to the controls, during the cholesterol feeding period. When sacrificed after 8 weeks of cholesterol feeding, the control animals, 21 in number, all had grossly demonstrable 1+ to 4+ atheromatosis of the aorta. Of the 13 surviving Aminopterin-treated animals, 9 had no atheromatosis or doubtful deposits of minimal extent. Only 4 had definite atheromatosis comparable in extent to the controls. Serum cholesterol levels were 30 to 50 per cent lower in the treated animals than in the controls.
Conditioning Effect of Blood Flow on Resistance Artery Smooth Muscle Myosin Phosphatase
Authors: Haiying Zhang, Steven A. Fisher
Journal: Circulation Research (2007)

Myosin phosphatase is the primary effector of smooth muscle relaxation and a target of signaling pathways that regulate vascular tone. The mesenteric small resistance artery and large vessel smooth muscle express distinct isoforms of the myosin phosphatase targeting subunit (MYPT1), and the isoforms in the small resistance artery switch in a disease model of altered blood flow. We thus hypothesized that small resistance artery smooth muscle phenotype is responsive to altered blood flow. To test this hypothesis alternating pairs of rat second order mesenteric arteries were ligated so that the upstream first order mesenteric artery (MA1) is under chronic low flow and the adjacent first order mesenteric artery under chronic high flow. The initial response was similar in high flow and low flow MA1, and included rapid reduction in MYPT1 and switch to the 3' alternative exon skipped/leucine zipper positive MYPT1 isoform. Between 14 to 28 days, MYPT1 abundance was restored along with reversion to the MYPT1 leucine zipper(-) isoform under chronic high flow. In contrast, under continued low flow, there was further switching to the MYPT1 leucine zipper(+) isoform. As would be predicted based on the switch to the MYPT1 leucine zipper(+) isoform, the sensitivity for relaxation to the NO donor SIN-1 and to cGMP was increased in the Day28 low flow first order mesenteric artery. We conclude that pulsatile blood flow conditions the phasic program of gene expression in the small resistance artery smooth muscle. The loss of this conditioning effect significantly increases the sensitivity to vasodilator signals in the setting of chronically reduced blood flow.
Evidence that Chlamydia trachomatis causes seronegative arthritis in women.
Authors: D Taylor-Robinson, B J Thomas, J Dixey, M F Osborn, P M Furr, A C Keat
Journal: Annals of the Rheumatic Diseases (1988)

Chlamydia trachomatis elementary bodies (EBs) were found in synovial membranes or synovial fluid cell deposits from five of 15 women with seronegative mono- or oligoarthritis by means of a fluorescein conjugated anti-chlamydial monoclonal antibody (Micro Trak; Syva). Genital tract specimens were taken from only five of the patients, one of whom had intra-articular EBs, but none was chlamydia positive. Six of 10 patients tested were HLA-B27 positive, and chlamydial IgG antibody, measured by microimmunofluorescence, was present at a titre of 1/greater than or equal to 64 in the sera of five of the 15 patients, three of the five having EBs in their joints. In contrast, chlamydial EBs were not detected in the joints of a control group of 10 other women, most of whom had rheumatoid arthritis. None of them was HLA-B27 positive, and only one had a chlamydial antibody titre of 1/greater than or equal to 64. Neither Mycoplasma hominis nor ureaplasmas were isolated from the synovial fluids of seven patients and five controls who were tested. Antibody to M genitalium, however, was detected in five of the 10 patients but in none of the controls. This evidence apart, there was no other suggest that mycoplasmas or ureaplasmas might be responsible for arthritis which could not be attributed to chlamydiae.
Role of Microparticles as Messengers Enhancing Stem Cell Activity After Genetic Engineering
Authors: Elisa A. Liehn, Octavian Bucur, Christian Weber
Journal: Circulation Research (2012)

D espite significant therapeutic advances over several decades, myocardial infarction remains the most common cause of death worldwide.In this context, cell-based therapy was considered a promising novel strategy for regeneration of healthy, functionally integrated, myocardial tissue.Unfortunately, the clinical trials using cell-based therapy did not always confirm the preclinical experimental results. 1,2herefore, in the last decade, the efforts were focused on studying the complex molecular and cellular mechanisms contributing to improved myocardial remodeling and function after stem cell transplantation.
MiR‐199a‐5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer
Authors: Weijie Guo, Zhaoping Qiu, Zhichao Wang, Qifeng Wang, Ning Tan, Taoyang Chen, Zhiao Chen, Shenglin Huang, Jianren Gu, Jinjun Li, Ming Yao, Yingjun Zhao, Xianghuo He
Journal: Hepatology (2015)

Cancer cells possess a unique metabolic phenotype that allows them to preferentially utilize glucose through aerobic glycolysis. This phenomenon is referred to as the “Warburg effect.” Accumulating evidence suggests that microRNAs (miRNAs), a class of small noncoding regulatory RNAs, interact with oncogenes/tumor suppressors and induce such metabolic reprograming in cancer cells. To systematically study the metabolic roles of miRNAs in cancer cells, we developed a gain‐of‐function miRNA screen in HeLa cells. Subsequent investigation of the characterized miRNAs indicated that miR‐199a‐5p acts as a suppressor for glucose metabolism. Furthermore, miR‐199a‐5p is often down‐regulated in human liver cancer, and its low expression level was correlated with a low survival rate, large tumor size, poor tumor differentiation status, high tumor‐node‐metastasis stage and the presence of tumor thrombus of patients. MicroRNA‐199a‐5p directly targets the 3′‐untranslated region of hexokinase 2 (HK2), an enzyme that catalyzes the irreversible first step of glycolysis, thereby suppressing glucose consumption, lactate production, cellular glucose‐6‐phosphate and adenosine triphosphate levels, cell proliferation, and tumorigenesis of liver cancer cells. Moreover, HK2 is frequently up‐regulated in liver cancer tissues and associated with poor patient outcomes. The up‐regulation of hypoxia‐inducible factor‐1α under hypoxic conditions suppresses the expression of miR‐199a‐5p and promotes glycolysis, whereas reintroduction of miR‐199a‐5p interferes with the expression of HK2, abrogating hypoxia‐enhanced glycolysis. Conclusion : miR‐199a‐5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients. (H epatology 2015;62:1132‐1144)
NO and cardiac diastolic function
Authors: W Paulus
Journal: Cardiovascular Research (1999)

Time for primary review 34 days. 

Since the first report of a role for nitric oxide (NO) in modulating myocardial contractile function in 1991 [1], an enormous number of studies have been published in this field (recently reviewed in Refs. [2–4]). It is now recognised that, under physiological conditions, the major sources of NO that are important for contractile regulation are (1) endothelial-type nitric oxide synthase (eNOS) expressed in cardiac endothelial cells, and (2) eNOS expressed in cardiac myocytes themselves. In a variety of pathological situations, contractile function may also be influenced by inducible NOS (iNOS) expressed in several cell types, including infiltrating inflammatory cells, coronary microvascular and endocardial endothelial cells, coronary vascular smooth muscle, and cardiac myocytes. In contrast to the relatively well-defined, essentially species-independent primary action of NO in the vasculature (i.e., mediation of endothelium-dependent vasodilatation), in the heart multiple and sometimes contradictory actions of NO have been reported (Table 1). Some of these actions may be species-specific while others have not always been reproduced by independent laboratories despite the use of apparently similar experimental preparations and protocols. Apart from species and methodological differences, additional relevant factors that are likely to influence the response to NO include: the cellular source of NO, the amount released (or experimentally studied), prevailing redox balance and antioxidant status, the target tissue (e.g., atrial or ventricular tissue), interactions with neurohumoral and other stimuli, the presence of immune activation or disease, and the activation of distinct cGMP-dependent and -independent subcellular signal transduction pathways.

View this table:

Table 1 
Reported actions of NO on the heart. Due to constraints of space, only a limited number of original references have been cited. Many other original references may be found in the bibliography of Refs. [2–4]



Most studies that have investigated the effects of NO on contractile function have focused on … 

* Corresponding author. Tel.: +32-53-724-433