tbuckley/cabot-search huggingface dataset:
Reduced <i>NF1</i> Expression Confers Resistance to EGFR Inhibition in Lung Cancer
Authors: Elza C. de Bruin, Catherine Cowell, Patricia H. Warne, Ming Jiang, Rebecca E. Saunders, Mary Ann Melnick, Scott Gettinger, Zenta Walther, Anna Wurtz, Guus J. Heynen, Daniëlle A.M. Heideman, Javier Gómez-Román, Almudena García-Castaño, Yixuan Gong, Marc Ladanyi, Harold Varmus, René Bernards, Egbert F. Smit, Katerina Politi, Julian Downward
Journal: Cancer Discovery (2014)

Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.
Orthotopic transplantation of retinoblastoma cells into vitreous cavity of zebrafish for screening of anticancer drugs
Authors: Dong Hyun Jo, Dain Son, Yirang Na, Manyoung Jang, Jae-Hoon Choi, Jin Hyoung Kim, Young Suk Yu, Seung Hyeok Seok, Jeong Hun Kim
Journal: Molecular Cancer (2013)

Abstract Background With high throughput screening, novel therapeutic agents can be efficiently identified. Unfortunately, researchers only resort to in vitro cell viability assays for screening of anticancer drugs for retinoblastoma, the most common intraocular cancer in the childhood. Current available animal models of retinoblastoma require more than 2 weeks for tumour formation and the investigation of the efficacy of therapeutic agents. In this study, we established a novel orthotopic transplantation model of retinoblastoma in zebrafish as an in vivo animal model for screening of anticancer drugs. Methods We injected retinoblastoma cells into the vitreous cavity of zebrafish at 48 hours after fertilization. Eyeballs of zebrafish were scanned daily under the confocal laser microscope, and the tumor population was quantitatively analyzed by measuring the mean intensity of green fluorescent protein (GFP). Transplanted retinoblastoma cells were isolated to perform further analyses including Western blotting and reverse transcriptase-polymerase chain reaction to confirm that retinoblastoma cells maintained their characteristics as tumor cells even after transplantation and further isolation. To figure out the potential of this model for screening of anticancer drugs, zebrafish were cultured in Ringer’s solution containing carboplatin and melphalan after the injection of retinoblastoma cells. Results The degree of the tumor population was dependent on the number of retinoblastoma cells injected and maintained stably for at least 4 days. Transplanted retinoblastoma cells maintain their proliferative potential and characteristics as retinoblastoma cells after isolation. Interestingly, systemic application of carboplatin and melphalan demonstrated significant reduction in the tumor population, which could be quantitatively analyzed by the estimation of the mean intensity of GFP. Conclusions This orthotopic retinoblastoma model in zebrafish is expected to be utilized for the screening of anticancer drugs for the treatment of retinoblastoma.
Relationship between regional myocardial blood flow and thallium-201 distribution in the presence of coronary artery stenosis and dipyridamole-induced vasodilation.
Authors: A E Mays, F R Cobb
Journal: Journal of Clinical Investigation (1984)

This study assesses the relationship between the distribution of thallium-201 and myocardial blood flow during coronary vasodilation induced by intravenous dipyridamole in canine models of partial and complete coronary artery stenosis. 10 dogs were chronically instrumented with catheters in the left atrium and aorta and with a balloon occluder and electromagnetic flow probe on the proximal left circumflex coronary artery. Regional myocardial blood flow was measured during control conditions with radioisotope-labeled microspheres, and the phasic reactive hyperemic response to a 20-s transient occlusion was then recorded. Dipyridamole was then infused intravenously until phasic coronary blood flow increased to match peak hyperemic values. The left circumflex coronary artery was either partially occluded to reduce phasic blood flow to control values (group 1) or it was completely occluded (group 2), and thallium-201 and a second microsphere label were injected. 5 min later, the animals were sacrificed, the left ventricle was sectioned into 1-2-g samples, and thallium-201 activity and regional myocardial blood flow were measured. Curvilinear regression analyses between thallium-201 localization and myocardial blood flow during dipyridamole infusion demonstrated a slightly better fit to a second- as compared with a first-order model, indicating a slight roll-off of thallium activity as myocardial blood flow increases. During the dipyridamole infusion, the increases in phasic blood flow, the distributions of regional myocardial blood flow, and the relationships between thallium-201 localization and regional blood flow were comparable to values previously observed in exercising dogs with similar occlusions. These data provide basic validation that supports the use of intravenous dipyridamole and thallium-201 as an alternative to exercise stress and thallium-201 for evaluating the effects of coronary occlusive lesions on the distribution of regional myocardial blood flow.
Alloimmunization is associated with older age of transfused red blood cells in sickle cell disease
Authors: Payal C. Desai, Allison M. Deal, Emily R. Pfaff, Bahjat Qaqish, Leyna M. Hebden, Yara A. Park, Kenneth I. Ataga
Journal: American Journal of Hematology (2015)

Red blood cell (RBC) alloimmunization is a significant clinical complication of sickle cell disease (SCD). It can lead to difficulty with cross‐matching for future transfusions and may sometimes trigger life‐threatening delayed hemolytic transfusion reactions. We conducted a retrospective study to explore the association of clinical complications and age of RBC with alloimmunization in patients with SCD followed at a single institution from 2005 to 2012. One hundred and sixty six patients with a total of 488 RBC transfusions were evaluated. Nineteen patients (11%) developed new alloantibodies following blood transfusions during the period of review. The median age of RBC units was 20 days (interquartile range: 14–27 days). RBC antibody formation was significantly associated with the age of RBC units ( P = 0.002), with a hazard ratio of 3.5 (95% CI: 1.71–7.11) for a RBC unit that was 7 days old and 9.8 (95% CI: 2.66–35.97) for a unit that was 35 days old, 28 days after the blood transfusion. No association was observed between RBC alloimmunization and acute vaso‐occlusive complications. Although increased echocardiography‐derived tricuspid regurgitant jet velocity (TRV) was associated with the presence of RBC alloantibodies ( P = 0.02), TRV was not significantly associated with alloimmunization when adjusted for patient age and number of transfused RBC units. Our study suggests that RBC antibody formation is significantly associated with older age of RBCs at the time of transfusion. Prospective studies in patients with SCD are required to confirm this finding. Am. J. Hematol. 90:691–695, 2015. © 2015 Wiley Periodicals, Inc.
Targeted Resequencing Identified Damaging Rare Variants in IFNGR1 Associated with Atopic Dermatitis Complicated By Eczema Herpeticum
Authors: Li Gao, Ryan Heiser, Nicholas M. Rafaels, Lili Huang, Joseph Potee, Rasika A. Mathias, Lisa A. Beck, Kathleen C. Barnes, Donald Y.M. Leung
Journal: Journal of Allergy and Clinical Immunology (2014)
Genome-Wide Mutational Signatures of Aristolochic Acid and Its Application as a Screening Tool
Authors: Song Ling Poon, See-Tong Pang, John R. McPherson, Willie Yu, Kie Kyon Huang, Peiyong Guan, Wen-Hui Weng, Ee Yan Siew, Yujing Liu, Hong Lee Heng, Soo Ching Chong, Anna Gan, Su Ting Tay, Weng Khong Lim, Ioana Cutcutache, Dachuan Huang, Lian Dee Ler, Maarja-Liisa Nairismägi, Ming Hui Lee, Ying-Hsu Chang, Kai-Jie Yu, Waraporn Chan-on, Bin-Kui Li, Yun-Fei Yuan, Chao-Nan Qian, Kwai-Fong Ng, Ching-Fang Wu, Cheng-Lung Hsu, Ralph M. Bunte, Michael R. Stratton, P. Andrew Futreal, Wing-Kin Sung, Cheng-Keng Chuang, Choon Kiat Ong, Steven G. Rozen, Patrick Tan, Bin Tean Teh
Journal: Science Translational Medicine (2013)

Genome-wide mutational signatures of the group 1 carcinogen aristolochic acid are observed in urothelial cancers and liver cancers from Asia.
Expression of the pro-angiogenic factors vascular endothelial growth factor and interleukin-8/CXCL8 by human breast carcinomas is responsive to nutrient deprivation and endoplasmic reticulum stress.
Authors: Philip L Marjon, Ekaterina V Bobrovnikova-Marjon, Steve F Abcouwer
Journal: Molecular Cancer (2004)

The expression of pro-angiogenic cytokines, such as vascular endothelial growth factor (VEGF) and interleukin-8/CXCL8 (IL-8), plays an important role in tumor growth and metastasis. Low oxygen tension within poorly-vascularized tumors is thought to be the prime stimulus causing the secretion of VEGF. The expression of IL-8 by solid tumors is thought to be primarily due to intrinsic influences, such as constitutive activation of nuclear factor kappa B (NF-κB). However, VEGF expression is responsive to glucose deprivation, suggesting that low concentrations of nutrients other than oxygen may play a role in triggering the pro-angiogenic phenotype. Glucose deprivation causes endoplasmic reticulum (ER) stress and alters gene expression through the unfolded protein response (UPR) signaling pathway. A branch of the UPR, known as the ER overload response (EOR), can cause NF-κB activation. Thus, we hypothesized that treatments that cause ER stress and deprivation of other nutrients, such as amino acids, would trigger the expression of angiogenic cytokines by breast cancer cell lines. We found that glutamine deprivation and treatment with a chemical inducer of ER stress (tunicamycin) caused a marked induction of the secretion of both VEGF and IL-8 protein by a human breast adenocarcinoma cell line (TSE cells). Glutamine deprivation, glucose deprivation and several chemical inducers of ER stress increased VEGF and IL-8 mRNA expression in TSE and other breast cancer cell lines cultured under both normoxic and hypoxic conditions, though hypoxia generally diminished the effects of glucose deprivation. Of all amino acids tested, ambient glutamine availability had the largest effect on VEGF and IL-8 mRNA expression. The induction of VEGF mRNA expression, but not IL-8, was sustained and closely corresponded with the upregulated expression of the ER stress-responsive genes glucose-regulated protein 78 (GRP78) and growth arrest and DNA damage inducible gene 153 (GADD153). These results suggest that nutrient deprivation within the solid tumor microenvironment might contribute to the activation of a pro-angiogenic phenotype. The angiogenic switch may act to increase blood supply in response to nutrient deprivation as well as hypoxia.
Intracoronary and Intravenous Adenosine 5′-Triphosphate, Adenosine, Papaverine, and Contrast Medium to Assess Fractional Flow Reserve in Humans
Authors: Bernard De Bruyne, Nico H.J. Pijls, Emanuele Barbato, Jozef Bartunek, Jan-Willem Bech, William Wijns, Guy R. Heyndrickx
Journal: Circulation (2003)

Background— Inducing both maximal and steady-state coronary hyperemia is of clinical importance to take full advantage of fractional flow reserve measurements. The present study compares different dosages and routes of administration of adenosine 5′-triphosphate (ATP), adenosine, contrast medium, and papaverine regarding their potential to achieve both maximal and steady-state hyperemia. Methods and Results— In 21 patients with an isolated coronary stenosis, coronary vasodilation was induced successively by papaverine (20 mg intracoronary), adenosine (20 and 40 μg intracoronary), ATP (20 and 40 μg intracoronary), iohexol (6 mL intracoronary), adenosine or ATP through an antecubital vein (140 and 180 μg · kg − 1 · min − 1 ), or adenosine or ATP through a femoral vein (140 and 180 μg · kg − 1 · min − 1 ). Because vessel dimensions did not change, the ratio of distal coronary pressure (P d ) to aortic pressure (P a ) was used as an index of myocardial resistance. P d /P a was 0.77±0.21 at rest and decreased to 0.61±0.21 after papaverine. P d /P a decreased to a similar level with all other vasodilators, except with contrast medium (0.68±0.21; P &lt;0.01 versus papaverine). Steady-state hyperemia could only be obtained by intracoronary papaverine and by intravenous ATP or adenosine. In another 23 patients, an intravenous infusion of ATP was varied from 0 to 280 μg · kg − 1 · min − 1 . At doses &gt;140 μg · kg − 1 · min − 1 , there was neither a further decrease in P d /P a ratio nor a further increase in coronary flow velocities. Conclusion— Provided sufficient dosages are used, ATP, adenosine, and papaverine (but not contrast medium) induce maximal hyperemia and are therefore suitable to assess fractional flow reserve. Only intracoronary papaverine and intravenous ATP or adenosine induce steady-state hyperemia enabling a pressure pullback maneuver that is useful in assessing diffuse coronary atherosclerosis.
The Challenge of Viral Reservoirs in HIV-1 Infection
Authors: Joel N. Blankson, Deborah Persaud, Robert F. Siliciano
Journal: Annual Review of Medicine (2002)

A viral reservoir is a cell type or anatomical site in association with which a replication-competent form of the virus accumulates and persists with more stable kinetic properties than the main pool of actively replicating virus. This article reviews several cell types and anatomical sites proposed as potential reservoirs for HIV-1. It is now clear that HIV-1 persists in a small reservoir of latently infected resting memory CD4(+) T cells, which shows minimal decay even in patients on highly active antiretroviral therapy (HAART). The persistence of virus in this reservoir is consistent with the biology of these cells and the long-term persistence of immunologic memory. The viral replication that continues in patients on suppressive HAART may also contribute to the stability of this reservoir. There may be other reservoirs, but the latent reservoir in resting CD4(+) T cells appears to be sufficient to guarantee lifetime persistence of HIV-1 in the majority of patients on current HAART regimens, and unless new approaches are developed, eradication will not be possible. The clinical implications of this and other HIV-1 reservoirs are discussed.
Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation
Authors: Mohamed A. Saleh, William G. McMaster, Jing Wu, Allison E. Norlander, Samuel A. Funt, Salim R. Thabet, Annet Kirabo, Liang Xiao, Wei Chen, Hana A. Itani, Danielle Michell, Tianxiao Huan, Yahua Zhang, Satoshi Takaki, Jens Titze, Daniel Levy, David G. Harrison, Meena S. Madhur
Journal: Journal of Clinical Investigation (2015)

The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II–induced (Ang II–induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk–/– mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk–/– mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-γ–producing CD8+ T cells in the spleen and kidneys of Lnk–/– mice compared with WT mice. Moreover, IFN-γ deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.
Pilot, proof-of-concept studies for determining the feasibility of the use of FLT-PET in patients with pancreatic adenocarcinoma.
Authors: Angela Lamarca, Prakash Manoharan, Marie-Claude Asselin, Ioannis Trigonis, Pamela Hindmarsh, Sarah Wood, Ray McMahon, Madhu Rao, Richard Hubner, Tamal Mahbubunnabi, Derek O'Reilly, Rahul Deshpande, Juan W. Valle, Azeem Saleem
Journal: Journal of Clinical Oncology (2013)

TPS4146 Background: Pancreatic cancer (PC) has one of the lowest 5-year survival rates. Gemcitabine (G)-based chemotherapy is standard-of-care first-line systemic therapy. Fluorine-18 radiolabelled 3-deoxy-3-fluorothymidine (FLT), a thymidine analogue, is a substrate for thymidine kinase 1 (TK1), which is highly expressed in proliferating cells in late G1/S phase. FLT uptake (imaged and quantified by positron emission tomography (PET)) correlates with pathology-based proliferation markers and with decreases with therapy in a number of cancers. G, a nucleoside analogue, decreases proliferation by inhibiting DNA synthesis, primarily acting on S and G1/S phase thus decreasing tumour FLT uptake. Human equilibrative nucleoside transporter (hENT1) transports G and FLT into cells, making hENT1 activity a key determinant of both FLT uptake and G efficacy. Methods: Two parallel proof-of-concept studies are designed to explore the feasibility of assessing proliferation, nucleoside transport, magnitude of treatment-related FLT uptake changes and understanding the pathophysiological basis of FLT-PET imaging in patients (pts) with (1) localized or (2) advanced PC. Up to 24 PC pts with ECOG PS 0-2, able to undergo imaging and with at least one potentially evaluable lesion larger than 2cm on CT/MRI are eligible. Pts with localized disease (study 1) will have dynamic FLT-PET pre-operatively preceded by a radiolabelled H 2 O PET scan to assess tumour perfusion. These pts will also undergo 2-deoxy-2-fluoro-D-glucose (FDG)-PET and diffusion-weighted MR scans. For pts with metastatic disease (study 2), dynamic FLT-PET will be performed before and after G-based chemotherapy. FLT uptake expressed as a standardized uptake value (SUV), will be determined. Tumour pathological markers from the surgical samples and imaging parameters will be correlated; hENT1 status will be assessed (by immunohistochemistry) after surgery (study 1) and before treatment (study 2). Reproducibility FLT-PET studies will be performed in a cohort of subjects to assess the variability in uptake quantification.
Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma
Authors: M.M. Mita, E. Poplin, C.D. Britten, W.D. Tap, E.H. Rubin, B.B. Scott, L. Berk, V.M. Rivera, J.W. Loewy, P. Dodion, F. Haluska, J. Sarantopoulos, A. Mita, A. Tolcher
Journal: Annals of Oncology (2012)
Sequencing of Type I Insulin-Like Growth Factor Receptor Inhibition Affects Chemotherapy Response <i>In vitro</i> and <i>In vivo</i>
Authors: Xianke Zeng, Deepali Sachdev, Hua Zhang, Martine Gaillard-Kelly, Douglas Yee
Journal: Clinical Cancer Research (2009)

The aim of this study was to determine the optimal sequence of combining anti-type I insulin-like growth factor receptor (IGF1R) antibodies with chemotherapeutic drugs in cancer cells in vitro and in vivo.MCF-7 and LCC6 cells were treated with subcytotoxic concentrations of doxorubicin with or without anti-IGF1R antibodies (scFv-Fc or EM164 and its humanized version AVE1642). Treatments were given simultaneously, doxorubicin followed by anti-IGF1R antibody, or anti-IGF1R antibody followed by doxorubicin, with measurement of in vitro proliferation, apoptosis, and anchorage-independent growth. The effects of sequencing on LCC6 xenograft growth and metastasis were studied.Doxorubicin followed by anti-IGF1R antibody (scFv-Fc or EM164) was the most effective combination strategy to inhibit cell monolayer growth and anchorage-independent growth. This sequential combination triggered increased poly (ADP-ribose) polymerase cleavage compared with other treatment sequences. The reverse sequence, antibody followed by doxorubicin treatment, protected cells from chemotherapy by decreasing apoptosis, arresting cells in S phase, and inhibiting the level and activity of topoisomerase IIalpha. Finally, our in vivo data show that recovery of IGF1R prior to doxorubicin therapy resulted in the best therapeutic responses. Low doses of AVE1642 that allowed IGF1R expression to recover at one week were more effective in combination with doxorubicin than higher antibody doses.The timing of IGF1R inhibition affects responses to chemotherapy. The optimal sequence was doxorubicin followed by anti-IGF1R antibody, whereas the opposite sequence inhibited doxorubicin effects. Thus, the dose and sequencing of anti-IGF1R therapies should be considered in the design of future clinical trials.
Increased prevalence of symptomatic macrovascular disease in systemic sclerosis.
Authors: D J Veale, T A Collidge, J J Belch
Journal: Annals of the Rheumatic Diseases (1995)

To determine the prevalence of symptomatic macrovascular disease, as defined by the World Health Organisation questionnaire for intermittent claudication, in patients with systemic sclerosis (SSc), and to compare the prevalence in this population with a cross sectional population study group reported in the Edinburgh Artery Study (EAS).A group of 53 patients with a diagnosis of limited or diffuse systemic sclerosis were identified from our register. They were asked to complete the WHO questionnaire to establish the presence or absence of intermittent claudication. In addition, each patient's case notes were reviewed to establish the existence of definite peripheral vascular disease and to determine their risk factor profile.Forty six patients responded to the questionnaire, giving a response rate of 87%. Intermittent claudication was found in 10 SSc patients (21.7%) according to the questionnaire (two with diffuse and eight with limited SSc), compared with a prevalence rate of 4.6% for claudication in the EAS. Three SSc patients experienced clinical events attributable to occlusion of a major artery proven on angiography. Four patients had hypertension, there were three current and four ex-smokers, and two had increased total cholesterol. None of these patients had diabetes.This study demonstrated a greater prevalence of macrovascular disease in patients with SSc than had been found in a neighbouring population.