tbuckley/cabot-search huggingface dataset:
Synergistic Action of a RAF Inhibitor and a Dual PI3K/mTOR Inhibitor in Thyroid Cancer
Authors: Ning Jin, Tianyun Jiang, David M. Rosen, Barry D. Nelkin, Douglas W. Ball
Journal: Clinical Cancer Research (2011)

In thyroid cancer clinical trials, agents targeting VEGF receptors (VEGFR) and RET, among other kinases, have led to partial responses but few complete or durable responses. The RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways are frequently activated in differentiated and medullary thyroid cancer (DTC and MTC) and may provide therapeutic targets for these diseases. We tested a novel drug combination targeting RAF, phosphoinositide 3-kinase (PI3K), and mTOR, plus VEGFR2 and RET, in thyroid cancer preclinical models with defined genetic backgrounds.RAF265, an ATP-competitive pan-RAF inhibitor active against VEGFR2, and BEZ-235, a PI3K inhibitor also active against Torc1 and Torc2, were tested alone and in combination in a panel of thyroid cancer lines. We tested RAF265 and BEZ-235 for kinase inhibition, growth inhibition and cell-cycle alterations, and inhibition of signaling targets and tumor growth in xenograft models.Both drugs potently inhibited their kinase targets in the extracellular signal-regulated kinase (ERK) and PI3K pathways. In addition, RAF265 had significant RET inhibitory activity (IC₅₀ = 25-50 nmol/L for RET(C634W)). The combination strongly inhibited proliferation of DTC and MTC cell lines with mutations in RAS, BRAF, PTEN, and RET. Synergy was shown for B-CPAP (BRAF(V600E)) and TT cells (RET(C634W)). The combination of both drugs significantly inhibited growth of CAL62 (KRAS(G12R/G12R)) and TT xenografts, thoroughly inhibiting ERK and PI3K pathway signaling.Combined blockade of ERK and PI3K signaling potently inhibits growth in preclinical models representing the key genotypes seen in refractory thyroid cancer. These targets and therapies are promising for further development in both differentiated and medullary thyroid cancers.
Myocardial Protection by Brief Ischemia in Noncardiac Tissue
Authors: Ben C.G. Gho, Regien G. Schoemaker, Mirella A. van den Doel, Dirk J. Duncker, Pieter D. Verdouw
Journal: Circulation (1996)

Background Brief coronary artery occlusions (CAOs) protect both the artery's own perfusion territory (“myocardial preconditioning”) and adjacent “virgin” myocardium. Whether ischemia in remote organs protects myocardium is unknown. We examined whether brief occlusion of the anterior mesenteric artery (MAO) or left renal artery (RAO) protects against myocardial infarction. Methods and Results Area at risk (AR) and infarcted area (IA) were determined in anesthetized rats after 180 minutes of reperfusion following a 60-minute CAO. At normothermia (body temperature, 36.5°C to 37.5°C), IA/AR was 68±2% (mean±SEM, n=11) in control rats and 50±3% (n=9, P &lt;.001) in rats preconditioned by 15-minute CAO 10 minutes before 60-minute CAO. A 15-minute MAO was equally protective (IA/AR=50±3%, n=10, P &lt;.001), whereas 15-minute RAO failed to limit IA/AR (72±5%, n=8). Hypothermia (body temperature, 30°C to 31°C) did not affect IA/AR (67±3%, n=11) in control animals but enhanced protection by 15-minute CAO (IA/AR=22±3%, n=8), whereas protection by 15-minute MAO (IA/AR=44±5%, n=11, P &lt;.001) was minimally enhanced. Hypothermia unmasked protection by 15-minute RAO (IA/AR=46±6%, n=9, P &lt;.01). Hexamethonium (20 mg/kg IV) did not alter protection by 15-minute CAO, but it abolished protection by 15-minute MAO. When MAO was sustained throughout the study, cardioprotection was absent. Conclusions Brief ischemia in “remote” organs protects myocardium against infarction as effectively as myocardial preconditioning. The mechanism of protection by MAO differs from that of CAO, because ganglion blockade abolished protection by MAO but not by CAO. The neurogenic pathway is activated during reperfusion after 15-minute MAO, because sustained MAO failed to produce cardioprotection.
Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer
Authors: M.K. Boisen, J.S. Johansen, C. Dehlendorff, J.S. Larsen, K. Østerlind, J. Hansen, S.E. Nielsen, P. Pfeiffer, L.S. Tarpgaard, N.H. Holländer, N. Keldsen, T.F. Hansen, B.B. Jensen, B.V. Jensen
Journal: Annals of Oncology (2013)
The Network of Psychological Variables in Patients With Diabetes and Their Importance for Quality of Life and Metabolic Control
Authors: Matthias Rose, Herbert Fliege, Martin Hildebrandt, Thea Schirop, Burghard F. Klapp
Journal: Diabetes Care (2002)

OBJECTIVE—The primary goals in treating patients with diabetes are maintaining blood glucose levels as close to normal as possible and making a relatively normal quality of life achievable. Both of these goals are influenced by a multitude of somatic and psychological factors that should be seen as building a complex network. We examined whether a mathematical model can be construed that can depict the relative significance of each factor for achieving these treatment goals. RESEARCH DESIGN AND METHODS—A total of 625 patients from 32 different treatment facilities were examined (224 type 1 and 401 type 2 diabetic patients) using HbA1c values (high-performance liquid chromatography), number of secondary illnesses, and standardized questionnaires with respect to health-related quality of life (World Health Organization Quality of Life questionnaire), coping behavior (Freiburger Illness-Coping Strategies questionnaire), diabetes-specific knowledge (Test of Diabetes-Specific Knowledge), doctor-patient relationship (Medical Interview Satisfaction Scale), and personality characteristics (Giessen Test and Assessment of Beliefs in Self-Efficacy and Optimism). The analyses were carried out by means of a structural equation model. RESULTS—The model proved to be valid (χ2 = 88.5, df = 76, P = 0.16), showing a sound fit (adjusted goodness of fit [AGFI] = 0.94). It explained 62% of the variance of the quality of life and 5% of the HbA1c values. Subjects characterized by strong beliefs in their self-efficacy and an optimistic outlook on life were more likely to be satisfied with their doctor-patient relationships. They demonstrated more active coping behavior and proved to have a higher quality of life. Active coping behavior was the only psychological variable significant for the HbA1c values. CONCLUSIONS—It was possible to illustrate the various factors involved and their mutual dependency and significance for the treatment goals. Belief in self-efficacy and active coping behavior appear to have the greatest relevance for achieving the primary treatment goals.
<i>Mycoplasma pneumoniae</i>and<i>Chlamydia pneumoniae</i>infections in children with pneumonia
Authors: S. Esposito, F. Blasi, F. Bellini, L. Allegra, N. Principi
Journal: European Respiratory Journal (2001)

The most common clinical signs, host responses and radiographic patterns were studied in 203 Italian children hospitalized for community-acquired pneumonia in order to clarify the role of clinical and radiological characteristics in the diagnosis of Mycoplasma pneumoniae and/or Chlamydia pneumoniae infections. Antibody measurements in paired sera and polymerase chain reaction on nasopharyngeal aspirates were used to establish the diagnoses of acute M. pneumoniae and C. pneumoniae infection, and the aetiologic data were correlated with the clinical, laboratory and radiographic data obtained on admission. No significant association was observed between evidence of M. pneumoniae and/or C. pneumoniae infection and periods of episode during the year, mean age of the study subjects, individual symptoms, physical findings or laboratory test results. Furthermore, no significant correlation was observed in relation to the radiological findings and M. pneumoniae and/or C. pneumoniae infection. This study shows that neither clinical findings nor laboratory parameters distinguished Mycoplasma pneumoniae and/or Chlamydia pneumoniae infection in children with pneumonia. Radiological findings also have a limited capacity to differentiate aetiologic agents. The priorities for future research include the development of rapid, easily accessible and cost-effective diagnostic tests useful for each episode of pneumonia in children.
THE RENAL CLEARANCES OF SUBSTITUTED HIPPURIC ACID DERIVATIVES AND OTHER AROMATIC ACIDS IN DOG AND MAN 1
Authors: Homer W. Smith, Norma Finkelstein, Lucy Aliminosa, Betty Crawford, Martha Graber
Journal: Journal of Clinical Investigation (1945)

6 4 0.1 to 0.3 5 xlo 0.3 to 1.97 8 4 0.13 to 0.26 63 0 to 0.31 m-Aminohippuric acid 5 2 0 to 0.06 2 ' 0 to 0.02 4 2 0 2 3 0 to 0.01 p-Amitohippuric acid 11i6 0 6 6 O to 0.18 9 c O to 0.10 8 6 O to 0.4 p-Aminohippuric acid 5 2 0 5 2 0 2 3 0 p-Acetylaminohippuric acid 28 0.08toO.1136 0 16 0 p-Acetylaminohippuric acid 2 2 0 1 ' 0 p-Aminomandelic acid 4 2 0 to 0.08 4 2 0 to 0.05 1 3 0.17 p-Aminophenylsuccinic acid 12 0.02 1 0.02 p-Aminophenaceturic acid 3 2 O to 0.01 Diodrast 9 2 0 1 ' 0.24 3 ' 0.24 to 0.35 p-Aminobenzoic acid 2 2 01 Precipitated with tungstate 1-5.2 Precipitated with cadmium sulfate 1-15.3 Diluted 1-2.5 with distilled water; precipitated with cadmium sulfate 1-5. 4 Precipitated with cadmium sulfate 1-5. 5 Precipitated with trichloroacetic acid 1-10.6 Diluted 1-2.5 with distilled water; precipitated with trichloroacetic acid 1-10. 7Diluted 1-2.5 with distilled water; precipitated with tungstate 1-5. 8Precipitated with trichloroacetic acid 1-5. 9Analyzed by fusion method.10 Direct rather than additive determination.
Diagnosis and Treatment of Syphilis
Authors: P. Frederick Sparling
Journal: New England Journal of Medicine (1971)

IN spite of excellent methods for diagnosing and treating syphilis, the disease is still widespread. There was a marked upsurge in the reported cases of infectious (primary and secondary) syphilis in the United States in the late 1950's and early 1960's, which reached a peak in 1965, when over 25,000 cases were reported.1 A gradual decrease in reported cases of infectious syphilis occurred after 1965, but in the first seven months of 1970 a steady, 10 to 12 per cent, increase in cases is again being reported.2 Moreover, the true incidence is undoubtedly much higher. Fleming et al. recently mailed . . .
INHIBITION OF THEILER'S ENCEPHALOMYELITIS VIRUS (GDVII STRAIN) OF MICE BY AN INTESTINAL MUCOPOLYSACCHARIDE
Authors: Benjamin Mandel, Efraim Racker
Journal: The Journal of Experimental Medicine (1953)

A mucopolysaccharide inhibitor of Theiler's GDVII virus has been purified from intestinal tissue of adult mice. The purified material has been shown to consist chiefly of carbohydrate. Following acid hydrolysis of the inhibitor, several amino adds were found to be present. The carbohydrate components shown to be present thus far are galactose, hexosamine, N-acetylhexosamine, methylpentose, hexurornic acid; an indication has been obtained that sedoheptulose is also present. The available evidence strongly suggests that this mucopolysaccharide, and not some other substance present in minute amounts, is the inhibitor of the GDVII virus.
Effect of slow-release theophylline on nasal antigen challenge in subjects with allergic rhinitis
Authors: M Aubier, C Neukirch, M Maachi, D Boucara, R Engelstatter, V Steinijans, R Samoyeau, M Dehoux
Journal: European Respiratory Journal (1998)

It has been recognized recently that theophylline possesses anti-inflammatory effects that could be of clinical interest in patients with airway inflammatory diseases such as asthma and allergic rhinitis (AR). The aim of the present study was to explore the effect of theophylline on the nasal eosinophilic inflammatory response following allergen challenge in patients with AR. Fourteen subjects suffering from seasonal rhinitis with an early reaction after nasal allergen provocation were challenged outside the pollen season after pretreatment for 3 weeks with placebo or slow-release theophylline (Euphylong in a randomized double-blind, cross-over study. Nasal blocking index (NBI), nasal airway resistance and symptoms were recorded before, and 1 and 5 h after challenge; additionally, nasal lavage fluid was collected before, as well as 1 and 5 h after challenge. Eosinophil cationic protein (ECP) was measured in the lavage as well as the number of eosinophils before, and 1 h and 5 h after allergen challenge. After 3 weeks of treatment, baseline concentrations of ECP in nasal lavage amounted to 826+/-329 ng x L(-1) (placebo) and 936+/-351 ng x L(-1) (theophylline). The ECP levels did not increase during the early phase response. Five hours after challenge, ECP in the placebo group increased markedly (p&lt;0.01), whereas no significant increase was observed during theophylline treatment. In parallel, the number of eosinophils in the nasal lavage fluid was lower during theophylline treatment. Additionally, theophylline therapy also significantly reduced the nasal symptoms and had some protective effect against nasal obstruction following allergen challenge. These results confirm the anti-inflammatory effects of theophylline and suggest that these effects may be of clinical benefit in patients with allergic rhinitis.
Drink! Drink! Drink!
Authors: Liam Farrell
Journal: BMJ (2006)

In Ireland we love our funerals. George Best's could not live up to the media hype, but it was still pretty big, the biggest since that of the hunger striker and MP Bobby Sands. Both were wasted, self destructive lives; one drank himself to death, the other starved himself to death, though I don't think either man would enjoy the comparison. 

While starving yourself to death for your country remains relatively uncommon, drinking yourself to death is epidemic in Ireland. We have made the devil's bargain: …
Double-Blind, Placebo-Controlled, Randomized Phase III Trial of Darbepoetin Alfa in Lung Cancer Patients Receiving Chemotherapy
Authors: J. Vansteenkiste
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Patients receiving chemotherapy often develop anemia. Darbepoetin alfa (Aranesp™) is an erythropoiesis-stimulating glycoprotein that has been shown, in dose-finding studies, to be safe and clinically active when administered to patients with cancer every 1, 2, or 3 weeks. This phase III study compared the safety and efficacy of darbepoetin alfa with placebo in patients with lung cancer receiving chemotherapy. Methods: In this multicenter, double-blind, placebo-controlled study, 320 anemic patients (hemoglobin ≤11.0 g/dL) were randomly assigned to receive darbepoetin alfa or placebo injections weekly for 12 weeks. The 297 patients who completed at least the first 28 days of study were assessed for red blood cell transfusions, the primary endpoint. Patients were also assessed for hemoglobin concentration (i.e., hematopoietic response), adverse events, antibody formation to darbepoetin alfa, hospitalizations, Functional Assessment of Cancer Therapy (FACT)–Fatigue score, and disease outcome. Efficacy endpoints were assessed using Kaplan–Meier analyses, Cox proportional hazards analyses, and chi-square tests where appropriate. All statistical tests were two-sided. Results: Patients receiving darbepoetin alfa required fewer transfusions (27% versus 52%; mean difference = 25%; 95% confidence interval [CI] = 14% to 36%; P<.001), required fewer units of blood (0.67 versus 1.92; mean difference = 1.25, 95% CI = 0.65 to 1.84; P<.001), had more hematopoietic responses (66% versus 24%; mean difference = 42%; 95% CI = 31% to 53%; P<.001), and had better improvement in FACT–Fatigue scores (56% versus 44% overall improvement; 32% versus 19% with ≥25% improvement; mean difference = 13%; 95% CI = 2% to 23%, P = .019) than patients receiving placebo. Patients receiving darbepoetin alfa did not appear to have any untoward effect in disease outcome and did not develop antibodies to the drug. Adverse events were similar between the groups. Conclusions: Patients with chemotherapy-associated anemia can safely and effectively be treated with weekly darbepoetin alfa therapy. Darbepoetin alfa decreased blood transfusion requirements, increased hemoglobin concentration, and decreased fatigue. Although no conclusions can be drawn about survival from this study, the potential salutary effect on disease outcome warrants further investigation in a prospectively designed study.
Changes in CREB Phosphorylation and BDNF Plasma Levels during Psychotherapy of Depression
Authors: Jakob M. Koch, Dunja Hinze-Selch, Karoline Stingele, Christian Huchzermeier, Robert Göder, Mareen Seeck-Hirschner, Josef B. Aldenhoff
Journal: Psychotherapy and Psychosomatics (2009)

&lt;i&gt;Background:&lt;/i&gt; The cyclic adenosine monophosphate response element-binding proteins (CREB) and their interaction with brain-derived neurotrophic factor (BDNF) are essential elements in signal transduction pathways important for cellular resilience and neuroplasticity. They play a decisive role in the concept of altered neuroplasticity in major depression. We have previously demonstrated that the increase in phosphorylated CREB (pCREB) in T lymphocytes is significantly associated with clinical improvement in patients treated with antidepressants. In the present study, we focused on patients treated only with psychotherapy to exclude direct pharmacological actions. In addition to pCREB, we also measured the BDNF plasma levels. &lt;i&gt;Methods:&lt;/i&gt; pCREB in T lymphocytes was determined by Western blot; the BDNF plasma levels with solid-phase ELISA. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Thirty patients meeting DSM-IV criteria for major depressive episodes (MDE) were recruited into this 6-week study. They received interpersonal psychotherapy (IPT) twice weekly. &lt;i&gt;Results:&lt;/i&gt; After 6 weeks of IPT, 17 patients responded (reduction of ≥50% of baseline HAMD); after 1 week of treatment pCREB increased significantly compared to the nonresponder group. Measurement of the BDNF plasma levels revealed no differences between the responder and nonresponder groups. Furthermore, the correlations between BDNF plasma levels and pCREB were not significant. &lt;i&gt;Conclusions:&lt;/i&gt; The early increase in pCREB is related to treatment response and does not depend on pharmacological interventions or BDNF plasma levels. For the first time, cellular biological markers could be associated with response to psychotherapy.
Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B
Authors: Yi-Cheng Chen, Chia-Ming Chu, Yun-Fan Liaw
Journal: Hepatology (2009)

Hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus infection confers a favorable prognosis, but untoward outcomes may develop in some patients. The impact of the age of HBeAg seroconversion on prognosis is not clearly known. HBeAg-positive patients with biopsy-proven chronic hepatitis B were followed up long-term. Follow-up studies included liver biochemistry, alpha-fetoprotein, and ultrasonography every 3 to 6 months or more frequently if clinically indicated. Of the patients who underwent spontaneous HBeAg seroconversion, the incidences of HBeAg-negative hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen seroclearance were compared between patient groups with different ages at the time of HBeAg seroconversion using Kaplan–Meier survival analysis and Poisson regression model. Spontaneous HBeAg seroconversion was documented in 508 patients. Of the 483 patients who had no evidence of cirrhosis or HCC at the time of HBeAg seroconversion, HBeAg seroconversion occurred before age 30 in 218 patients (group A), between age 31 and 40 in 199 patients (group B), and after age 40 in 66 patients (group C). The 15-year cumulative incidences of HBeAg-negative hepatitis, cirrhosis, and HCC increased with increasing age of HBeAg seroconversion, the lowest being in group A (31.2%, 3.7%, and 2.1%, respectively) and highest being in group C (66.7% [ P &lt; 0.0001], 42.9% [ P &lt;0.0001], and 7.7% [ P = 0.29], respectively). The hazard ratio of HBeAg-negative hepatitis, cirrhosis, and HCC was 2.95, 17.6, and 5.22, respectively, in group C compared with group A. Conclusion: Patients with HBeAg seroconversion before age 30 have excellent prognosis, whereas patients with delayed HBeAg seroconversion after age 40 have significantly higher incidences of HBeAg-negative hepatitis, cirrhosis, and HCC. (Hepatology 2010.)
Fast-Food and Full-Service Restaurant Consumption Among Children and Adolescents
Authors: Lisa M. Powell, Binh T. Nguyen
Journal: JAMA Pediatrics (2012)

Objective: To examine the effect of fast-food and fullservice restaurant consumption on total energy intake, dietary indicators, and beverage consumption.Design: Individual-level fixed-effects estimation based on 2 nonconsecutive 24-hour dietary recalls.
Differential expression of multiple transglutaminases in human colon: impaired keratinocyte transglutaminase expression in ulcerative colitis
Authors: G D'Argenio
Journal: Gut (2005)

<b>Background and aims:</b> Ulcerative colitis (UC) is characterised by refractory inflammatory ulceration and damage to the colon. The mechanisms underlying impaired healing have yet to be defined. As transglutaminase expression resulting in matrix protein cross linking is associated with increased wound healing in a rat model of colitis, we hypothesised that different types of transglutaminase might also play a role in UC. <b>Patients and methods:</b> Endoscopic and histological indices were studied in 26 patients with UC (10 active and 16 inactive) and in 20 normal controls undergoing colonoscopy. Transglutaminase activity was evaluated in plasma (factor XIIIa) by a radioenzymatic method. Factor XIIIa, tissue and keratinocyte transglutaminase protein content, and mRNA expression in the colon were evaluated by western blot analysis and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. Colonic location of transglutaminases and their reaction products, the ε-(γ-glutamyl)lysine bonds, was evaluated by immunohistochemistry using specific monoclonal antibodies. <b>Results:</b> Transglutaminase activity was significantly lower in the plasma of patients with active UC (4.2 (2.4) mU/ml; p&lt;0.05 <i>v</i> controls) than in those with inactive UC and controls (10.6 (2.2) and 12.1 (1.7) mU/ml). As shown by western blot, protein levels of tissue transglutaminase and factor XIIIa were unchanged in active UC compared with inactive disease and controls, while the keratinocyte form was reduced in active UC. Tissue transglutaminase and factor XIIIa immunostaining was strongly present in damaged areas colocalising with isopeptide bonds. In contrast, the keratinocyte form was almost absent in active UC and localised in the upper part of the crypts in normal subjects. RT-PCR showed upregulation of tissue transglutaminase mRNA in active UC (320% compared with controls) while keratinocyte transglutaminase gene expression was downregulated in active UC. <b>Conclusions:</b> The results of the present study support the concept that, in the damaged colon, transglutaminases are needed in response to chronic injury and underline the key role of these enzymes in mucosal healing.