tbuckley/cabot-search huggingface dataset:
Mutant TP53 in Duodenal Samples of Pancreatic Juice From Patients With Pancreatic Cancer or High-Grade Dysplasia
Authors: Mitsuro Kanda, Yoshihiko Sadakari, Michael Borges, Mark Topazian, James Farrell, Sapna Syngal, Jeffrey Lee, Ihab Kamel, Anne Marie Lennon, Spencer Knight, Sho Fujiwara, Ralph H. Hruban, Marcia Irene Canto, Michael Goggins
Journal: Clinical Gastroenterology and Hepatology (2012)
Kinetics of human hemopoietic cells after in vivo administration of granulocyte-macrophage colony-stimulating factor.
Authors: M Aglietta, W Piacibello, F Sanavio, A Stacchini, F Aprá, M Schena, C Mossetti, F Carnino, F Caligaris-Cappio, F Gavosto
Journal: Journal of Clinical Investigation (1989)

The kinetic changes induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) on hemopoietic cells were assessed in physiological conditions by administering GM-CSF (8 micrograms/kg per d) for 3 d to nine patients with solid tumors and normal bone marrow (BM), before chemotherapy. GM-CSF increased the number of circulating granulocytes and monocytes; platelets, erythrocytes, lymphocyte number, and subsets were unmodified. GM-CSF increased the percentage of BM S phase BFU-E (from 32 +/- 7 to 79 +/- 16%), day 14 colony-forming unit granulocyte-macrophage (CFU-GM) (from 43 +/- 20 to 82 +/- 11%) and day 7 CFU-GM (from 41 +/- 14 to 56 +/- 20%). The percentage of BM myeloblasts, promyelocytes, and myelocytes in S phase increased from 26 +/- 14 to 41 +/- 6%, and that of erythroblasts increased from 25 +/- 12 to 30 +/- 12%. This suggests that GM-CSF activates both erythroid and granulomonopoietic progenitors but that, among the morphologically recognizable BM precursors, only the granulomonopoietic lineage is a direct target of the molecule. GM-CSF increased the birth rate of cycling cells from 1.3 to 3.4 cells %/h and decreased the duration of the S phase from 14.3 to 9.1 h and the cell cycle time from 86 to 26 h. After treatment discontinuation, the number of circulating granulocytes and monocytes rapidly fell. The proportion of S phase BM cells dropped to values lower than pretreatment levels, suggesting a period of relative refractoriness to cell cycle-active antineoplastic agents.
Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis.
Authors: L S Lohmander, T Saxne, D K Heinegard
Journal: Annals of the Rheumatic Diseases (1994)

<b>Objective:</b> To review the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) specialties and neurologic subspecialties and discuss the implications of those trends for subspecialty viability. <b>Methods:</b> Data on numbers of residency and fellowship programs and graduates and ABPN certification candidates and diplomates were drawn from several sources, including ABPN records, Web sites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of the <i>Journal of the American Medical Association</i>. <b>Results:</b> About four-fifths of neurology graduates pursue fellowship training. While most recent neurology and child neurology graduates attempt to become certified by the ABPN, many clinical neurophysiologists elect not to do so. There appears to have been little interest in establishing fellowships in neurodevelopmental disabilities. The pass rate for fellowship graduates is equivalent to that for the "grandfathers" in clinical neurophysiology. Lower percentages of clinical neurophysiologists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high. <b>Conclusion:</b> The initial enthusiastic interest in training and certification in some of the ABPN neurologic subspecialties appears to have slowed, and the long-term viability of those subspecialties will depend upon the answers to a number of complicated social, economic, and political questions in the new health care era.
Phase III Trial Comparing Capecitabine Plus Cisplatin Versus Capecitabine Plus Cisplatin With Concurrent Capecitabine Radiotherapy in Completely Resected Gastric Cancer With D2 Lymph Node Dissection: The ARTIST Trial
Authors: Jeeyun Lee, Do Hoon Lim, Sung Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Min Gew Choi, Tae Sung Sohn, Jae Hyung Noh, Jae Moon Bae, Yong Chan Ahn, Insuk Sohn, Sin Ho Jung, Cheol Keun Park, Kyoung-Mee Kim, Won Ki Kang
Journal: Journal of Clinical Oncology (2011)

Purpose The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP). Patients and Methods The XP arm received six cycles of XP (capecitabine 2,000 mg/m 2 per day on days 1 to 14 and cisplatin 60 mg/m 2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m 2 per day for 5 weeks) and two cycles of XP. Results Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471). Conclusion The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node–positive gastric cancer is planned.
Imaging focal and interstitial fibrosis with cardiovascular magnetic resonance in athletes with left ventricular hypertrophy: implications for sporting participation
Authors: Deirdre F Waterhouse, Tevfik F Ismail, Sanjay K Prasad, Mathew G Wilson, Rory O'Hanlon
Journal: British Journal of Sports Medicine (2012)

Long-term high-intensity physical activity is associated with morphological changes, termed as the ‘athlete's heart’. The differentiation of physiological cardiac adaptive changes in response to high-level exercise from pathological changes consistent with an inherited cardiomyopathy is imperative. Cardiovascular magnetic resonance (CMR) imaging allows definition of abnormal processes occurring at the tissue level, including, importantly, myocardial fibrosis. It is therefore vital in accurately making this differentiation. In this review, we will review the role of CMR imaging of fibrosis, and detail CMR characterisation of myocardial fibrosis in various cardiomyopathies, and the implications of fibrosis. Additionally, we will outline advances in imaging fibrosis, in particular T1 mapping. Finally we will address the role of CMR in pre-participation screening.
Serum and BAL Clara cell 10 kDa protein (CC10) levels and CC10-positive bronchiolar cells are decreased in smokers
Authors: N Shijubo, Y Itoh, T Yamaguchi, Y Shibuya, Y Morita, M Hirasawa, R Okutani, T Kawai, S Abe
Journal: European Respiratory Journal (1997)

Cigarette smoking has diverse effects on the structure and function of the lung. Smoking appears to reduce the levels of Clara cell 10 kDa protein (CC10) in the alveolar lining fluid, but the influence of smoking serum on CC10 levels is still debated, and it has not been clear whether smoking reduces the number of CC10-producing lung cells. The aims of this study were to clarify the influence of smoking on CC10 levels in the alveolar lining fluid and bloodstream, and on the number of CC10-producing lung cells. CC10 concentrations were measured in sera and bronchoalveolar lavage (BAL) fluids, by means of enzyme-linked immunosorbent assay using monoclonal and polyclonal antibody, and the immunohistochemical expression of CC10 was examined in the lungs of nonsmokers and smokers using the monoclonal antibody, TY-5, against CC10/human urinary protein-1. CC10 concentrations in sera and in BAL fluids from healthy smokers were significantly lower than in healthy nonsmokers. Immunohistochemical expression of CC10 was found exclusively in nonciliated bronchiolar epithelial cells. As compared to that of nonsmokers, the mean percentage of CC10-positive bronchiolar epithelial cells was significantly decreased in lung tissue specimens obtained from smokers who had normal results in pulmonary function tests. It was concluded that smoking reduces the proportion of Clara cell 10 kDa protein-producing bronchiolar epithelial cells, resulting in decreased levels of Clara cell 10 kDa protein in the lower respiratory tract and in the bloodstream. The protein is a new blood biochemical and immunohistochemical marker, reflecting structural changes in peripheral airways induced by cigarette smoking.
Sympathetic Activity and Baroreflex Sensitivity in Young Women Taking Oral Contraceptives
Authors: Christopher T. Minson, John R. Halliwill, Tamica M. Young, Michael J. Joyner
Journal: Circulation (2000)

Background —We tested sympathetic and cardiovagal baroreflex sensitivity during the placebo or “low-hormone” phase (LH) and 2 to 3 weeks later during the “high-hormone” phase (HH) of oral contraceptive (OC) use in 9 women. Methods and Results —Sympathetic baroreflex sensitivity was assessed by intravenous doses of sodium nitroprusside and phenylephrine and defined as the slope relating muscle sympathetic nerve activity (by microneurography) and diastolic blood pressure. Cardiovagal baroreflex sensitivity was defined as the slope relating R-R interval and systolic blood pressure. No difference was observed for resting muscle sympathetic nerve activity or plasma norepinephrine levels. However, sympathetic baroreflex sensitivity was greater and mean arterial pressure was higher during the LH than in the HH phase. Similarly, cardiovagal baroreflex sensitivity was greater in the LH than in the HH phase. Conclusions —Sympathetic and cardiovagal baroreflex sensitivities change during the 28-day course of OC use. Furthermore, changes in baroreflex sensitivity with OC differ from changes in baroreflex sensitivity during the normal menstrual cycle.
Hypothesis: Ill health associated with low concentrations of nitrogen dioxide--an effect of ultrafine particles?
Authors: A Seaton
Journal: Thorax (2003)

The epidemiological associations between illness and nitrogen dioxide may be the consequence of confounding by particle numbers

In 1996 the Expert Panel on Air Quality Standards (EPAQS) recommended an ambient air standard for nitrogen dioxide (NO2) in the UK of 150 ppb measured hourly.1 This recommendation, like those for carbon monoxide (CO) and sulphur dioxide (SO2) that had preceded it, was based on human toxicology rather than on epidemiology. The EPAQS was unable to find evidence that these gases were likely to be toxic to humans at the recommended concentrations. However, at the time of the NO2 recommendation there was already epidemiological evidence that effects on populations rather than individuals might be associated with much lower concentrations and the EPAQS recommended that steps be taken to reduce annual average concentrations, although without proposing a long term standard. The UK government has subsequently adopted, as targets to be achieved by 2005, World Health Organization NO2 guideline standards of 105 ppb (200 μg/m3) over 1 hour and 21 ppb (40 μg/m3) as an annual average, the latter having been based on possible relationships between exposure to the gas and respiratory illness in children.2 Achievement of a long term standard does, of course, have the desirable consequence of reducing peaks and therefore short term exccedences. However, compliance with a very low average concentration of NO2 implies a substantial reduction in the concentration of the primary pollutant released from vehicle exhausts—that is, nitric oxide (NO). Since NO reacts with ozone to form NO2, lower concentrations will result in raised urban ozone concentrations, a gas that also has known toxic effects on the lungs and that, until now, has been seen primarily as a rural pollutant in the UK.

Progressive reductions in pollution are …
First-in-Humans Trial of an RNA Interference Therapeutic Targeting VEGF and KSP in Cancer Patients with Liver Involvement
Authors: Josep Tabernero, Geoffrey I. Shapiro, Patricia M. LoRusso, Andres Cervantes, Gary K. Schwartz, Glen J. Weiss, Luis Paz-Ares, Daniel C. Cho, Jeffrey R. Infante, Maria Alsina, Mrinal M. Gounder, Rick Falzone, Jamie Harrop, Amy C. Seila White, Iva Toudjarska, David Bumcrot, Rachel E. Meyers, Gregory Hinkle, Nenad Svrzikapa, Renta M. Hutabarat, Valerie A. Clausen, Jeffrey Cehelsky, Saraswathy V. Nochur, Christina Gamba-Vitalo, Akshay K. Vaishnaw, Dinah W.Y. Sah, Jared A. Gollob, Howard A. Burris
Journal: Cancer Discovery (2013)

RNA interference (RNAi) is a potent and specific mechanism for regulating gene expression. Harnessing RNAi to silence genes involved in disease holds promise for the development of a new class of therapeutics. Delivery is key to realizing the potential of RNAi, and lipid nanoparticles (LNP) have proved effective in delivery of siRNAs to the liver and to tumors in animals. To examine the activity and safety of LNP-formulated siRNAs in humans, we initiated a trial of ALN-VSP, an LNP formulation of siRNAs targeting VEGF and kinesin spindle protein (KSP), in patients with cancer. Here, we show detection of drug in tumor biopsies, siRNA-mediated mRNA cleavage in the liver, pharmacodynamics suggestive of target downregulation, and antitumor activity, including complete regression of liver metastases in endometrial cancer. In addition, we show that biweekly intravenous administration of ALN-VSP was safe and well tolerated. These data provide proof-of-concept for RNAi therapeutics in humans and form the basis for further development in cancer.The fi ndings in this report show safety, pharmacokinetics, RNAi mechanism of action, and clinical activity with a novel fi rst-in-class LNP-formulated RNAi therapeutic in patients with cancer. The ability to harness RNAi to facilitate specifi c multitargeting, as well as increase the number of druggable targets, has important implications for future drug development in oncology.
Resistance to Insulin Therapy Among Patients and Providers
Authors: Mark Peyrot, Richard R. Rubin, Torsten Lauritzen, Soren E. Skovlund, Frank J. Snoek, David R. Matthews, Rüdiger Landgraf, Line Kleinebreil
Journal: Diabetes Care (2005)

OBJECTIVE—To examine the correlates of patient and provider attitudes toward insulin therapy. RESEARCH DESIGN AND METHODS—Data are from surveys of patients with type 2 diabetes not taking insulin (n = 2,061) and diabetes care providers (nurses = 1,109; physicians = 2,681) in 13 countries in Asia, Australia, Europe, and North America. Multiple regression analysis is used to identify correlates of attitudes toward insulin therapy among patients, physicians, and nurses. RESULTS—Patient and provider attitudes differ significantly across countries, controlling for individual characteristics. Patients rate the clinical efficacy of insulin as low and would blame themselves if they had to start insulin therapy. Self-blame is significantly lower among those who have better diet and exercise adherence and less diabetes-related distress. Patients who are not managing their diabetes well (poor perceived control, more complications, and diabetes-related distress) are significantly more likely to see insulin therapy as potentially beneficial. Most nurses and general practitioners (50–55%) delay insulin therapy until absolutely necessary, but specialists and opinion leaders are less likely to do so. Delay of insulin therapy is significantly less likely when physicians and nurses see their patients as more adherent to medication or appointment regimens, view insulin as more efficacious, and when they are less likely to delay oral diabetes medications. CONCLUSIONS—Patient and provider resistance to insulin therapy is substantial, and for providers it is part of a larger pattern of reluctance to prescribe blood glucose–lowering medication. Interventions to facilitate timely initiation of insulin therapy will need to address factors associated with this resistance.
Regulation of Estrogenic Effects by Beclin 1 in Breast Cancer Cells
Authors: Shali John, Irina Nayvelt, Hui-Chen Hsu, PingAr Yang, Wensheng Liu, Gokul M. Das, Thresia Thomas, T.J. Thomas
Journal: Cancer Research (2008)

Abstract Beclin 1 is an essential mediator of autophagy and a regulator of cell growth and cell death. We examined the effect of Beclin 1 overexpression on the action of estradiol (E2) and two antiestrogens, raloxifene and 4-hydroxytamoxifen, in estrogen receptor α (ERα)-positive MCF-7 breast cancer cells. [3H]-thymidine incorporation studies showed that Beclin 1–overexpressing cells (MCF-7.beclin) had a lower proliferative response to E2 compared with cells transfected with vector control (MCF-7.control). There was only a 35% increase in [3H]-thymidine incorporation, after 24 hours of E2 treatment of MCF-7.beclin cells compared with untreated cells, whereas this increase was 2-fold for MCF-7.control cells. E2-induced changes in the expression of early-response genes were examined by real-time quantitiative PCR. There were significant differences in the pattern of expression of E2-induced genes c-myc, c-fos, Erg-1, and Nur77 between MCF-7.beclin and MCF-7.control cells two hours after treatment. Although E2-induced growth of MCF-7.control cells was completely inhibited by 500 nmol/L raloxifene or 500 nmol/L 4-hydroxytamoxifen, these concentrations of antiestrogens had no significant effect on the growth of MCF-7.beclin cells. Confocal microscopic and coimmunoprecipitation studies showed evidence for colocalization and association of Beclin 1 and ERα. In addition, E2 caused a decrease in Akt phosphorylation in MCF-7.beclin cells, compared with a 3-fold increase in MCF-7 cells, five minutes after treatment. These results indicate that Beclin 1 can down-regulate estrogenic signaling and growth response, and contribute to the development of antiestrogen resistance. This observation might be useful to define and overcome antiestrogen resistance of breast cancer. [Cancer Res 2008;68(19):7855–63]
Oxidized low-density lipoprotein increases superoxide production by endothelial nitric oxide synthase by inhibiting PKC?
Authors: I FLEMING, A MOHAMED, J GALLE, L TURCHANOWA, R BRANDES, B FISSLTHALER, R BUSSE
Journal: Cardiovascular Research (2004)

Oxidized low-density lipoprotein (ox-LDL) increases superoxide anion (O(2)(-)) production by the endothelial nitric oxide (NO) synthase (eNOS). We assessed whether the uncoupling of eNOS was associated with alterations in eNOS phosphorylation and/or the assembly of the eNOS signaling complex.In unstimulated human endothelial cells, eNOS Thr(495) was constitutively phosphorylated. ox-LDL, but not native LDL, enhanced the production of O(2)(-) by endothelial cells, an effect that was partially sensitive to NOS inhibition. ox-LDL, but not native LDL, induced a time- and concentration-dependent decrease in the phosphorylation of eNOS on Thr(495). Protein kinase C (PKC) has been reported to phosphorylate this residue, and the increase in the phosphorylation of Thr(495) induced by phorbol 12-myristate 13-acetate was attenuated in cells pretreated with ox-LDL. Moreover, the phosphorylation and activity of PKCalpha was attenuated by ox-LDL and paralleled the changes in eNOS phosphorylation. ox-LDL also induced the dissociation of eNOS from the plasma and Golgi membranes. In COS-7 cells, a T495A eNOS mutant generated significantly more O(2)(-) than a T495D mutant did, indicating that the dephosphorylation of Thr(495) alone can increase O(2)(-) production by eNOS. However, although the dephosphorylation of Thr(495) in histamine-stimulated endothelial cells enhanced the binding of calmodulin to eNOS, calmodulin no longer bound to eNOS from ox-LDL-treated endothelial cells.These results indicate that a decrease in the activity of PKCalpha in ox-LDL-treated endothelial cells is associated with the dephosphorylation of eNOS, dissociation of the eNOS signaling complex, and the enhanced production of eNOS-derived O(2)(-).
Lung Cancer and Hormone Replacement Therapy: Association in the Vitamins and Lifestyle Study
Authors: Christopher G. Slatore, Jason W. Chien, David H. Au, Jessie A. Satia, Emily White
Journal: Journal of Clinical Oncology (2010)

Lung cancer is the leading cause of cancer-related mortality among women. The role of hormone replacement therapy (HRT) in lung cancer development is unclear.We evaluated a prospective cohort of 36,588 peri- and postmenopausal women aged 50 to 76 years from Washington State recruited in 2000 to 2002 (Vitamins and Lifestyle [VITAL] Study). Lung cancer cases (n = 344) were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry during 6 years of follow-up. Hazard ratios (HRs) associated with use and duration of specific HRT formulations were calculated for total incident lung cancer, specific morphologies, and cancer by stage at diagnosis.After adjusting for smoking, age, and other potential confounders, there was an increased risk of incident lung cancer associated with increasing duration of estrogen plus progestin (E+P) use (HR = 1.27 for E+P use 1 to 9 years, 95% CI, 0.91 to 1.78; and HR = 1.48 for E+P use > or = 10 years, 95% CI, 1.03 to 2.12; P for trend = .03). There was no association with duration of unopposed estrogen use. Duration of E+P use was associated with an advanced stage at diagnosis (P for trend = .03).Use of E+P increased the risk of incident lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer. These findings may be helpful for informing women of their risk of developing lung cancer and delineating important pathways involved in hormone metabolism and lung cancer.