tbuckley/cabot-search huggingface dataset:
Do Imaging Biomarkers Relate to Outcome in Patients Treated with VEGF Inhibitors?
Authors: James P.B. O'Connor, Gordon C. Jayson
Journal: Clinical Cancer Research (2012)

The management of solid tumors has been transformed by the advent of VEGF pathway inhibitors. Early clinical evaluation of these drugs has used pharmacodynamic biomarkers derived from advanced imaging such as dynamic MRI, computed tomography (CT), and ultrasound to establish proof of principle. We have reviewed published studies that used these imaging techniques to determine whether the same biomarkers relate to survival in renal, hepatocellular, and brain tumors in patients treated with VEGF inhibitors. Data show that in renal cancer, pretreatment measurements of K(trans) and early pharmacodynamic reduction in tumor enhancement and density have prognostic significance in patients treated with VEGF inhibitors. A weaker, but significant, relationship is seen with subtle early size change (10% in one dimension) and survival. Data from high-grade glioma suggest that pretreatment fractional blood volume and K(trans) were prognostic of overall survival. However, lack of control data with other therapies prevents assessment of the predictive nature of these biomarkers, and such studies are urgently required.
Elevated high density lipoprotein cholesterol levels correlate with decreased apolipoprotein A-I and A-II fractional catabolic rate in women.
Authors: E A Brinton, S Eisenberg, J L Breslow
Journal: Journal of Clinical Investigation (1989)

High levels of HDL-cholesterol (HDL-C) protect against coronary heart disease susceptibility, but the metabolic mechanisms underlying elevated HDL-C levels are poorly understood. We now report the turnover of isologous radioiodinated HDL apolipoproteins, apo A-I and apo A-II, in 15 female subjects on a metabolic diet with HDL-C levels ranging from 51 to 122 mg/dl. The metabolic parameters, fractional catabolic rate (FCR) and absolute synthetic rate (SR), were determined for apo A-I and apo A-II in all subjects. There was an inverse correlation between plasma HDL-C and the FCR of apo A-I and apo A-II (r = -0.75, P less than 0.001, and r = -0.54, P = 0.036, respectively), but no correlation with the SR of either apo A-I or apo A-II (r = 0.09, and r = -0.16, respectively, both P = NS). Apo A-I levels correlated inversely with apo A-I FCR (r = -0.64, P = 0.01) but not with apo A-I SR (r = 0.30, P = NS). In contrast, plasma levels of apo A-II did not correlate with apo A-II FCR (r = -0.38, P = 0.16), but did correlate with apo A-II SR (r = 0.65, P = 0.009). Further analysis showed that apo A-I and apo A-II FCR were inversely correlated with the HDL-C/apo A-I + A-II ratio (r = -0.69 and -0.61, P = 0.005 and 0.015, respectively). These data suggest that: (a) low HDL apolipoprotein FCR is the predominant metabolic mechanism of elevated HDL-C levels; (b) apo A-I FCR is the primary factor in controlling plasma apo A-I levels, but apo A-II SR is the primary factor controlling plasma apo A-II levels; (c) low HDL apolipoprotein FCR is associated with a lipid-rich HDL fraction. These findings elucidate aspects of HDL metabolism which contribute to high HDL-C levels and which may constitute mechanisms for protection against coronary heart disease.
Absence of HIV Transmission From an Infected Orthopedic Surgeon
Authors: C. Fordham von Reyn
Journal: JAMA (1993)

<h3>Objective.</h3> —To determine the risk of human immunodeficiency virus (HIV) transmission from an HIV-infected orthopedic surgeon to patients undergoing invasive procedures. <h3>Design.</h3> —Retrospective epidemiologic follow-up study. <h3>Participants.</h3> —A total of 2317 former patients on whom the orthopedic surgeon performed invasive procedures between January 1, 1978, and June 30, 1992. <h3>Main Outcome Measures.</h3> —HIV infection or death from an acquired immunodeficiency syndrome (AIDS)—defining tumor or opportunistic infection. <h3>Results.</h3> —An orthopedic surgeon voluntarily withdrew from practice after testing positive for HIV. Testing for HIV was performed on 1174 former patients, representing 50.7% of patients on whom the orthopedic surgeon performed invasive procedures during the 13.5-year period. Patients were tested from each year and from each category of invasive procedure. All patients were HIV-negative by enzyme-linked immunosorbent assay. Two former patients reported known HIV infection prior to surgery. Review of AIDS case registries and vital records failed to detect cases of HIV infection among former surgical patients. The estimated cost of the initial patient notification and testing was $158500. The patient notification and testing were conducted while maintaining the confidentiality of the orthopedic surgeon who was an active participant in the planning and execution of the study. <h3>Conclusions.</h3> —The risk of HIV transmission from an HIV-infected surgeon who adheres to recommended infection control practices is extremely low. Notification and HIV testing of former patients in this setting is both disruptive and expensive and is not routinely recommended. (<i>JAMA</i>. 1993;269:1807-1811)
Non-tuberculous mycobacterial lung infection complicated by chronic necrotising pulmonary aspergillosis
Authors: I Hafeez
Journal: Thorax (2000)

We report four cases of pulmonary mycobacterial disease (three due to <i>Mycobacterium malmoense</i> and one to <i>Myco- bacterium avium intracellulare</i>) complicated by the development of chronic necrotising pulmonary aspergillosis. Difficulties with treatment and the potential benefits of steroids are discussed.
Expansion of human NOD/SCID-repopulating cells by stem cell factor, Flk2/Flt3 ligand, thrombopoietin, IL-6, and soluble IL-6 receptor
Authors: Takahiro Ueda, Kohichiro Tsuji, Hiroshi Yoshino, Yasuhiro Ebihara, Hiroshi Yagasaki, Hiroaki Hisakawa, Tetsuo Mitsui, Atsushi Manabe, Ryuhei Tanaka, Kimio Kobayashi, Mamoru Ito, Kiyoshi Yasukawa, Tatsutoshi Nakahata
Journal: Journal of Clinical Investigation (2000)

Here, we demonstrate a significant ex vivo expansion of human hematopoietic stem cells capable of repopulating in NOD/SCID mice. Using a combination of stem cell factor (SCF), Flk2/Flt3 ligand (FL), thrombopoietin (TPO), and a complex of IL-6 and soluble IL-6 receptor (IL-6/sIL-6R), we cultured cord blood CD34+ cells for 7 days and transplanted these cells into NOD/SCID mice. Bone marrow engraftment was judged successful when recipient animals contained measurable numbers of human CD45+ cells 10–12 weeks after transplantation. When cells were cultured with SCF+FL+TPO+IL-6/sIL-6R, 13 of 16 recipients were successfully engrafted, and CD45+ cells represented 11.5% of bone marrow cells in engrafted recipients. Cells cultured with a subset of these factors were less efficiently engrafted, both as measured by frequency of successful transplantations and prevalence of CD45+ cells. In animals receiving cells cultured with all 4 factors, human CD45+ cells represented various lineages, including a large number of CD34+ cells. The proportion of CD45+ cells in recipient marrow was 10 times higher in animals receiving these cultured cells than in those receiving comparable numbers of fresh CD34+ cells, and the expansion rate was estimated at 4.2-fold by a limiting dilution method. Addition of IL-3 to the cytokine combination abrogated the repopulating ability of the expanded cells. The present study may provide a novel culture method for the expansion of human transplantable hematopoietic stem cells suitable for clinical applications.
Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial
Authors: Sandeep T Patil, Lu Zhang, Ferenc Martenyi, Stephen L Lowe, Kimberley A Jackson, Boris V Andreev, Alla S Avedisova, Leonid M Bardenstein, Issak Y Gurovich, Margarita A Morozova, Sergey N Mosolov, Nikolai G Neznanov, Alexander M Reznik, Anatoly B Smulevich, Vladimir A Tochilov, Bryan G Johnson, James A Monn, Darryle D Schoepp
Journal: Nature Medicine (2007)
Mapping the Road Forward in Alzheimer’s Disease
Authors: David M. Holtzman, Alison Goate, Jeffrey Kelly, Reisa Sperling
Journal: Science Translational Medicine (2011)

Alzheimer's disease (AD) is the most common cause of dementia and will lead to a worldwide public health crisis if it continues unchecked. Despite tremendous advances in our scientific understanding of AD, we still do not have effective ways to delay, prevent, or slow this disease. At the 2011 Abelson meeting, a diverse group of scientists discussed current challenges in the AD field and made recommendations in the areas of genetics, clinical trials, protein aggregation, and the cell biology of the nervous system. We hope these recommendations will boost research progress in AD and increase the likelihood of developing effective therapies in the near future.
Runx2 Transcriptional Activation of Indian Hedgehog and a Downstream Bone Metastatic Pathway in Breast Cancer Cells
Authors: Jitesh Pratap, John J. Wixted, Tripti Gaur, Sayyed K. Zaidi, Jason Dobson, Karthiga Devi Gokul, Sadiq Hussain, Andre J. van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian
Journal: Cancer Research (2008)

Runx2, required for bone formation, is ectopically expressed in breast cancer cells. To address the mechanism by which Runx2 contributes to the osteolytic disease induced by MDA-MB-231 cells, we investigated the effect of Runx2 on key components of the "vicious cycle" of transforming growth factor beta (TGFbeta)-mediated tumor growth and osteolysis. We find that Runx2 directly up-regulates Indian Hedgehog (IHH) and colocalizes with Gli2, a Hedgehog signaling molecule. These events further activate parathyroid hormone-related protein (PTHrP). Furthermore, Runx2 directly regulates the TGFbeta-induced PTHrP levels. A subnuclear targeting deficient mutant Runx2, which disrupts TGFbeta-induced Runx2-Smad interactions, failed to induce IHH and downstream events. In addition, Runx2 knockdown in MDA-MB-231 inhibited IHH and PTHrP expression in the presence of TGFbeta. In vivo blockade of the Runx2-IHH pathway in MDA-MB-231 cells by Runx2 short hairpin RNA inhibition prevented the osteolytic disease. Thus, our studies define a novel role of Runx2 in up-regulating the vicious cycle of metastatic bone disease, in addition to Runx2 regulation of genes related to progression of tumor metastasis.
Discovery of a Novel ERK Inhibitor with Activity in Models of Acquired Resistance to BRAF and MEK Inhibitors
Authors: Erick J. Morris, Sharda Jha, Clifford R. Restaino, Priya Dayananth, Hugh Zhu, Alan Cooper, Donna Carr, Yongi Deng, Weihong Jin, Stuart Black, Brian Long, Jenny Liu, Edward DiNunzio, William Windsor, Rumin Zhang, Shuxia Zhao, Minilik H. Angagaw, Elaine M. Pinheiro, Jagdish Desai, Li Xiao, Gerald Shipps, Alan Hruza, James Wang, Joe Kelly, Sunil Paliwal, Xiaolei Gao, Boga Sobhana Babu, Liang Zhu, Pierre Daublain, Ling Zhang, Bart A. Lutterbach, Marc R. Pelletier, Ulrike Philippar, Phieng Siliphaivanh, David Witter, Paul Kirschmeier, W. Robert Bishop, Daniel Hicklin, D. Gary Gilliland, Lata Jayaraman, Leigh Zawel, Stephen Fawell, Ahmed A. Samatar
Journal: Cancer Discovery (2013)

The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.
Particle size study of nine metered dose inhalers, and their deposition probabilities in the airways
Authors: A Bouchikhi, MH Becquemin, J Bignon, M Roy, A Teillac
Journal: European Respiratory Journal (1988)

This study deals with the particle size measurement of nine aerosol metered dose inhalers. Calibration was made possible by the use of a laser particle velocimeter (aerodynamic Particle Sizer from TSI). The count median aerodynamic diameters (CMAD) show little variation, from 0.63 to 0.73 micron, with standard deviations (sigma g) between 1.2 and 1.8. Aerodynamic diameter aerosol diagram analysis showed multimodal mass distribution for all the tested dose inhalers. Calculations for the airway deposition probabilities (extrathoracic, tracheobronchial and alveolar) refer to the studies made by W. Stahlhofen and co-workers. As most aerosol metered dose inhalers have a predominantly bronchial therapeutic destination, the deposition at the bronchial level could be enhanced with the following parameters: inspired volume of 1500 ml, inspiratory time of 2 sec, aerosol mass median aerodynamic diameter (MMAD) of 7.5 microns, with a monodispersed distribution. The respective influences of the excipients and propellents used for the aerosolization of these dose metered inhalers are also discussed.
Circulating Tumor Cell Detection Predicts Early Metastatic Relapse After Neoadjuvant Chemotherapy in Large Operable and Locally Advanced Breast Cancer in a Phase II Randomized Trial
Authors: Jean-Yves Pierga, François-Clément Bidard, Claire Mathiot, Etienne Brain, Suzette Delaloge, Sylvie Giachetti, Patricia de Cremoux, Rémy Salmon, Anne Vincent-Salomon, Michel Marty
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Circulating tumor cells in blood from metastatic breast cancer patients have been reported as a surrogate marker for tumor response and shorter survival. The aim of this study was to determine whether circulating tumor cells are present in the blood of patients with large operable or locally advanced breast cancer before neoadjuvant chemotherapy and after neoadjuvant chemotherapy before surgery. Experimental Design: Blood samples of 7.5 mL were obtained on CellSave tubes from patients included in a phase II trial (REMAGUS 02). Circulating tumor cells were immunomagnetically separated and fluorescently stained by the CellSearch system. Blood from 20 metastatic breast cancer patients was used as a positive control. Results: From October 2004 to July 2006, preneoadjuvant chemotherapy and/or postneoadjuvant chemotherapy blood samples were obtained from 118 patients. At least 1 circulating tumor cell was detected in 22 of 97 patients with preneoadjuvant chemotherapy samples (23%; 95% confidence interval, 15-31%; median, 2 cells; range, 1-17 cells). Circulating tumor cell positivity rates were 17% in 86 postneoadjuvant chemotherapy samples and 27% in all 118 patients. Persistence of circulating tumor cells at the end of neoadjuvant chemotherapy was not correlated with treatment response. After a short median follow-up of 18 months, the presence of circulating tumor cells (P = 0.017), hormone receptor negativity, and large tumor size were independent prognostic factors for shorter distant metastasis–free survival. Conclusion: Circulating tumor cells can be detected by the CellSearch system at a low cutoff of 1 cell in 27% of patients receiving neoadjuvant chemotherapy. Circulating tumor cell detection was not correlated to the primary tumor response but is an independent prognostic factor for early relapse.
NHS needs outside expertise for workforce planning
Authors: Adrian O'Dowd
Journal: BMJ (2007)

Outside expertise in workforce planning should be brought into the NHS to help improve its record on matching staff numbers to patients' needs, MPs have been told. 

Independent health economists could help the NHS make its workforce planning more accurate, the parliamentary health select committee was told last week in the latest evidence session of its inquiry into workforce planning. 

Susan Hodgetts, chief executive of the Institute of Healthcare Management, the professional body for health service managers, said health economists would give workforce planning a “reality check.” 

In prepared written evidence, she said, “There is a case for workforce …
The impact of stress on tumor growth: peripheral CRF mediates tumor-promoting effects of stress
Authors: Alicia Arranz, Maria Venihaki, Berber Mol, Ariadne Androulidaki, Erini Dermitzaki, Olga Rassouli, Jorge Ripoll, Efstathios N Stathopoulos, Rosa P Gomariz, Andrew N Margioris, Christos Tsatsanis
Journal: Molecular Cancer (2010)

Abstract Introduction Stress has been shown to be a tumor promoting factor. Both clinical and laboratory studies have shown that chronic stress is associated with tumor growth in several types of cancer. Corticotropin Releasing Factor (CRF) is the major hypothalamic mediator of stress, but is also expressed in peripheral tissues. Earlier studies have shown that peripheral CRF affects breast cancer cell proliferation and motility. The aim of the present study was to assess the significance of peripheral CRF on tumor growth as a mediator of the response to stress in vivo. Methods For this purpose we used the 4T1 breast cancer cell line in cell culture and in vivo. Cells were treated with CRF in culture and gene specific arrays were performed to identify genes directly affected by CRF and involved in breast cancer cell growth. To assess the impact of peripheral CRF as a stress mediator in tumor growth, Balb/c mice were orthotopically injected with 4T1 cells in the mammary fat pad to induce breast tumors. Mice were subjected to repetitive immobilization stress as a model of chronic stress. To inhibit the action of CRF, the CRF antagonist antalarmin was injected intraperitoneally. Breast tissue samples were histologically analyzed and assessed for neoangiogenesis. Results Array analysis revealed among other genes that CRF induced the expression of SMAD2 and β-catenin, genes involved in breast cancer cell proliferation and cytoskeletal changes associated with metastasis. Cell transfection and luciferase assays confirmed the role of CRF in WNT- β-catenin signaling. CRF induced 4T1 cell proliferation and augmented the TGF-β action on proliferation confirming its impact on TGFβ/SMAD2 signaling. In addition, CRF promoted actin reorganization and cell migration, suggesting a direct tumor-promoting action. Chronic stress augmented tumor growth in 4T1 breast tumor bearing mice and peripheral administration of the CRF antagonist antalarmin suppressed this effect. Moreover, antalarmin suppressed neoangiogenesis in 4T1 tumors in vivo. Conclusion This is the first report demonstrating that peripheral CRF, at least in part, mediates the tumor-promoting effects of stress and implicates CRF in SMAD2 and β-catenin expression.
Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B
Authors: S G Lim
Journal: Gut (2002)

<b>Background:</b> Nucleoside analogues such as lamivudine for chronic hepatitis B have an excellent safety profile while patients are on therapy but reactivation flares occur in 19–50% of patients after stopping therapy, some of whom develop liver decompensation. <b>Aims:</b> To describe and report three cases who developed fatal hepatitis B reactivation after stopping nucleoside analogue therapy. <b>Subjects and results:</b> Three patients are described who developed hepatitis B reactivation and liver decompensation after stopping therapy. One of the three patients was participating in a famciclovir trial and the other two were receiving lamivudine therapy for active hepatitis B infection. All three patients had documented hepatitis B flares, and all had hepatitis B virus DNA detected at that time. All patients developed decompensated liver disease despite one patient having had a prior liver biopsy showing absence of cirrhosis. Reintroduction of lamivudine therapy failed to halt progression of liver decompensation even after hepatitis B virus DNA had been demonstrated to be absent. Sequencing for lamivudine resistant mutants in two cases where serum was available failed to show evidence of mutations associated with lamivudine resistance. <b>Conclusion:</b> Hepatitis B virus reactivation, leading to decompensation and death, are possible complications of treatment withdrawal and patients should be monitored closely if therapy is ceased.
Unmelanized Plumage Patterns in Old World Leaf Warblers Do Not Correspond to Sequence Variation at the Melanocortin-1 Receptor Locus (MC1R)
Authors: E. A. MacDougall-Shackleton
Journal: Molecular Biology and Evolution (2003)

Evolutionary changes in patterns and coloration of plumage are likely to represent a major mechanism for speciation among birds, yet the molecular basis for such changes remains poorly understood. Recently much attention has focused on the melanocortin-1 receptor (MC1R) as a candidate locus for determining the level and extent of epidermal melanin deposition. We tested the hypothesis that MC1R sequence variation is associated with interspecific variation in unmelanized plumage pattern elements in Old World leaf warblers (genus Phylloscopus). This genus is characterized by a variety of plumage patterns that nonetheless vary along similar lines. Species vary in the presence or absence of pale (unmelanized) pattern elements against a dark background, and these patterns are used in species recognition and courtship. We sequenced most of the MC1R coding region for eight Phylloscopus species, representing the full range of plumage patterns found in this genus. Although MC1R sequence varied among species, this variation was not related to melanin-based plumage variation. Rather, evolution of this locus in these birds appears to be conservative. Ratios of nonsynonymous to synonymous substitutions (dN/dS) were consistently low, suggesting that strong purifying selection has operated at this locus, and likelihood ratio testing revealed no evidence of variable selective pressures among lineages or across codons. Adaptive evolution at MC1R may be constrained by the adaptive importance of plumage pattern elements in this genus.
Corticosteroids and corticotrophin in the treatment of Crohn's disease.
Authors: J H Jones, J E Lennard-Jones
Journal: Gut (1966)

EDITORIAL SYNOPSIS This paper presents results in the treatment of 105 patients suffering from Crohn's disease retrospectively analysed after 10 years, of whom 30 were treated with corticosteroids.The treatment was most useful in patients with extensive small bowel disease and those with recurrent disease after resection.Immediate improvement was seen in 22 out of the 30 patients, but the long- term results of treatment were only moderately encouraging: seven patients needed continued treatment; eight subsequently required operation; four died; and only three were able to give up the treatment altogether.