tbuckley/cabot-search huggingface dataset:
Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis
Authors: Sara I. Cunha, Evangelia Pardali, Midory Thorikay, Charlotte Anderberg, Lukas Hawinkels, Marie-José Goumans, Jasbir Seehra, Carl-Henrik Heldin, Peter ten Dijke, Kristian Pietras
Journal: The Journal of Experimental Medicine (2010)

Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-β and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-β family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.
Statistical power and validity of Ebola vaccine trials in Sierra Leone: a simulation study of trial design and analysis
Authors: Steven E Bellan, Juliet R C Pulliam, Carl A B Pearson, David Champredon, Spencer J Fox, Laura Skrip, Alison P Galvani, Manoj Gambhir, Ben A Lopman, Travis C Porco, Lauren Ancel Meyers, Jonathan Dushoff
Journal: The Lancet Infectious Diseases (2015)
Update on Erythropoietin Treatment
Authors: Ernesto Paoletti, Giuseppe Cannella
Journal: Journal of the American Society of Nephrology (2006)

The partial correction of ESRD anemia by recombinant human erythropoietin (EPO) has resulted both in generalized improvement in quality of life and physical activity and in reduced mortality and hospitalization rate. The question remains as to whether normalizing hemoglobin (Hgb) is desirable in patients with chronic kidney disease (CKD). This review provides an analysis and commentary on the available reports and, for the most part, randomized, controlled trials on the topic. In dialysis patients, normalization of Hgb is associated with improved quality of life and exercise capacity but not with reduced mortality and hospitalization rate. Moreover, no significant changes in the degree of left ventricular hypertrophy have been demonstrated. By contrast, an increased mortality rate has been reported for hemodialysis patients with overt cardiovascular disease (CVD) when randomly assigned to normal hematocrit by EPO. Data regarding patients who have CKD but are not yet on renal replacement therapy are scarce, and the effects of EPO on renal disease progression require further elucidation through controlled trials. The conclusion that can be drawn from the available studies is that Hgb >11 g/dl is the minimum required to achieve improved quality of life in patients with CKD, whereas values >12 g/dl are not recommended for patients with overt CVD. Finally, Hgb normalization might reasonably be restricted to a selected population of younger, employed, and active individuals, provided that they do not have CVD.
High Frequencies of Naive Melan-a/Mart-1–Specific Cd8+ T Cells in a Large Proportion of Human Histocompatibility Leukocyte Antigen (Hla)-A2 Individuals
Authors: Mikaël J. Pittet, Danila Valmori, P. Rod Dunbar, Daniel E. Speiser, Danielle Liénard, Ferdy Lejeune, Katharina Fleischhauer, Vincenzo Cerundolo, Jean-Charles Cerottini, Pedro Romero
Journal: The Journal of Experimental Medicine (1999)

Using fluorescent HLA-A*0201 tetramers containing the immunodominant Melan-A/MART-1 (Melan-A) tumor-associated antigen (Ag), we previously observed that metastatic lymph nodes of melanoma patients contain high numbers of Ag-experienced Melan-A-specific cytolytic T lymphocytes (CTLs). In this paper, we enumerated and characterized ex vivo Melan-A-specific cells in peripheral blood samples from both melanoma patients and healthy individuals. High frequencies (>/=1 in 2,500 CD8(+) T cells) of Melan-A-specific cells were found in 10 out of 13 patients, and, surprisingly, in 6 out of 10 healthy individuals. Virtually all Melan-A-specific cells from 6 out of 6 healthy individuals and from 7 out of 10 patients displayed a naive CD45RA(hi)/RO(-) phenotype, whereas variable proportions of Ag-experienced CD45RA(lo)/RO(+) Melan-A-specific cells were observed in the remaining 3 patients. In contrast, ex vivo influenza matrix-specific CTLs from all individuals exhibited a CD45RA(lo)/RO(+) memory phenotype as expected. Ag specificity of tetramer-sorted A2/Melan-A(+) cells from healthy individuals was confirmed after mitogen-driven expansion. Likewise, functional limiting dilution analysis and interferon gamma ELISPOT assays independently confirmed that most of the Melan-A-specific cells were not Ag experienced. Thus, it appears that high frequencies of naive Melan-A-specific CD8(+) T cells can be found in a large proportion of HLA-A*0201(+) individuals. Furthermore, as demonstrated for one patient followed over time, dramatic phenotype changes of circulating Melan-A-specific cells can occur in vivo.
A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A
Authors: Francesca Colombo, Felicia S Falvella, Antonella Galvan, Elisa Frullanti, Hideo Kunitoh, Toshikazu Ushijima, Tommaso A Dragani
Journal: Molecular Cancer (2011)

Abstract Background The MFSD2A gene maps within a linkage disequilibrium block containing the MYCL1- EcoRI polymorphism associated with prognosis and survival in lung cancer patients. Survival discrepancies between Asians and Caucasians point to ethnic differences in allelic frequencies of the functional genetic variations. Results Analysis of three single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1- EcoRI polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site. Conclusion SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.
Prevalence of paroxysmal nocturnal hemoglobinuria (PNH) cells in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA), or other bone marrow failure (BMF) syndromes: Interim results from the EXPLORE trial
Authors: N. Galili, F. Ravandi, G. Palermo, J. Bubis, A. Illingworth, H. Castro-Malaspina, A. Raza
Journal: Journal of Clinical Oncology (2009)

7082 Background: In patients with PNH, lack of the glycophosphatidylinositol (GPI)-anchored terminal complement inhibitor CD59 on hematopoietic stem cells results in chronic intravascular hemolysis, kidney and pulmonary disorders, thrombosis, and shortened life span. Presence of even minor populations of PNH cells in AA or MDS patients is medically important as it may indicate a higher likelihood of response to immunosuppressive therapy. We conducted the first large multicenter, point-prevalence study (EXamination of PNH, by Level Of CD59 on REd and white blood cells [EXPLORE]) of PNH cells in patients with AA, MDS, or other BMF syndromes. Here we report an interim analysis. Methods: A central laboratory conducted high-sensitivity flow cytometry utilizing a combination of GPI-linked antibodies (CD59, CD24, and CD14) and fluorescent aerolysin (FLAER) to identify GPI anchor-deficient PNH cells in RBC and WBC resulting in 0.01% sensitivity. The primary endpoint was percentage of patients who had a PNH WBC clone ≥1%. Results: Among 5,212 patients screened, 4,500 (86.3%) were MDS patients, 413 (7.9%) were AA patients, and 356 (6.8%) had other BMF syndromes. Approximately 1/4 (24.5%) of patients with AA, 1.2% with MDS, and 4.6% with other BMF were newly found to have a significant PNH clone ≥ 1%. Many of the newly identified clones were of clinical significance as the median PNH clone size was 11.1% in AA patients, 16.3% in MDS patients, and 32.6% in patients with other BMF. Presence of PNH cells (≥ 0.01%) was common in all examined BMF types: 70% of AA patients, 55% of MDS patients and 55% of patients with other BMF. PNH cells were identified in all MDS subtypes represented in the trial. Conclusions: Interim analysis from this first large multicenter study demonstrates that PNH cells are present in a majority of patients with AA, MDS, and other BMF. A spectrum of PNH clone sizes was noted in patients with each form of BMF. Screening patients with BMF with high-sensitivity flow cytometry for PNH cells may guide treatment options for the underlying BMF and/or PNH. The EXPLORE trial continues to enroll patients with AA. (EXPLORE Clinical Study Abstract 1/6/2009) [Table: see text]
Nitric Oxide Confers Therapeutic Activity to Dendritic Cells in a Mouse Model of Melanoma
Authors: Cristiana Perrotta, Sestina Falcone, Annalisa Capobianco, Annalisa Camporeale, Clara Sciorati, Clara De Palma, Addolorata Pisconti, Patrizia Rovere-Querini, Matteo Bellone, Angelo A. Manfredi, Emilio Clementi
Journal: Cancer Research (2004)

Abstract Susceptibility of dendritic cells (DCs) to tumor-induced apoptosis reduces their efficacy in cancer therapy. Here we show that delivery within exponentially growing B16 melanomas of DCs treated ex vivo with nitric oxide (NO), released by the NO donor (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO), significantly reduced tumor growth, with cure of 37% of animals. DETA-NO-treated DCs became resistant to tumor-induced apoptosis because DETA-NO prevented tumor-induced changes in the expression of Bcl-2, Bax, and Bcl-xL; activation of caspase-9; and a reduction in the mitochondrial membrane potential. DETA-NO also increased DC cytotoxic activity against tumor cells and DC ability to trigger T-lymphocyte proliferation. All of the effects of DETA-NO were mediated through cGMP generation. NO and NO-generating drugs may therefore be used to increase the anticancer efficacy of DCs.
Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study
Authors: Victor Moreno, F Xavier Bosch, Nubia Muñoz, Chris JLM Meijer, Keerti V Shah, Jan MM Walboomers, Rolando Herrero, Silvia Franceschi
Journal: The Lancet (2002)
NY-ESO-1 Protein Formulated in ISCOMATRIX Adjuvant Is a Potent Anticancer Vaccine Inducing Both Humoral and CD8+ T-Cell-Mediated Immunity and Protection against NY-ESO-1+ Tumors
Authors: Eugene Maraskovsky, Sigrid Sjölander, Debbie P. Drane, Max Schnurr, Thuy T. T. Le, Luis Mateo, Thomas Luft, Kelly-Anne Masterman, Tsin-Yee Tai, Qiyuan Chen, Simon Green, Anders Sjölander, Martin J. Pearse, Francois A. Lemonnier, Weisan Chen, Jonathan Cebon, Andreas Suhrbier
Journal: Clinical Cancer Research (2004)

Abstract NY-ESO-1 is a 180 amino-acid human tumor antigen expressed by many different tumor types and belongs to the family of “cancer-testis” antigens. In humans, NY-ESO-1 is one of the most immunogenic tumor antigens and NY-ESO-1 peptides have been shown to induce NY-ESO-1-specific CD8+ CTLs capable of altering the natural course of NY-ESO-1-expressing tumors in cancer patients. Here we describe the preclinical immunogenicity and efficacy of NY-ESO-1 protein formulated with the ISCOMATRIX adjuvant (NY-ESO-1 vaccine). In vitro, the NY-ESO-1 vaccine was readily taken up by human monocyte-derived dendritic cells, and on maturation, these human monocyte-derived dendritic cells efficiently cross-presented HLA-A2-restricted epitopes to NY-ESO-1-specific CD8+ T cells. In addition, epitopes of NY-ESO-1 protein were also presented on MHC class II molecules to NY-ESO-1-specific CD4+ T cells. The NY-ESO-1 vaccine induced strong NY-ESO-1-specific IFN-γ and IgG2a responses in C57BL/6 mice. Furthermore, the NY-ESO-1 vaccine induced NY-ESO-1-specific CD8+ CTLs in HLA-A2 transgenic mice that were capable of lysing human HLA-A2+ NY-ESO-1+ tumor cells. Finally, C57BL/6 mice, immunized with the NY-ESO-1 vaccine, were protected against challenge with a B16 melanoma cell line expressing NY-ESO-1. These data illustrate that the NY-ESO-1 vaccine represents a potent therapeutic anticancer vaccine.
Detection of<i>EGFR</i>Gene Mutation in Lung Cancer by Mutant-Enriched Polymerase Chain Reaction Assay
Authors: Hiroaki Asano, Shinichi Toyooka, Masaki Tokumo, Kouichi Ichimura, Keisuke Aoe, Sachio Ito, Kazunori Tsukuda, Mamoru Ouchida, Motoi Aoe, Hideki Katayama, Akio Hiraki, Kazuro Sugi, Katsuyuki Kiura, Hiroshi Date, Nobuyoshi Shimizu
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Mutations in the epidermal growth factor receptor (EGFR) gene have been reported to be present in non–small cell lung cancer (NSCLC) and related to the responsiveness of tumors to EGFR tyrosine kinase inhibitors, suggesting its usefulness as a biomarker. Because clinical samples contain tumor and normal cells or genes, a highly sensitive assay for detecting mutation is critical for clinical applications. Experimental Design: The mutant-enriched PCR is a rapid and sensitive assay with selective restriction enzyme digestion. We developed the mutant-enriched PCR assay targeting exons 19 and 21 of EGFR and applied the developed assay to detect mutations in 108 cases of surgically resected specimens of NSCLCs, 18 samples of computed tomography (CT)–guided needle lung biopsies, and 20 samples of pleural fluid. In addition, results were then compared with those from direct sequencing and a nonenriched PCR assay. Results: The mutant-enriched PCR that was proved to enrich one mutant of 2 × 103 normal genes detected mutations in 37 cases of 108 resected tumors, seven samples of CT-guided lung biopsies, and seven samples of pleural fluid. Among mutant cases, four resected tumors, two CT-guided lung biopsies, and two pleural fluid were identified as additional mutant cases by the mutant-enriched PCR, which were considered normal based on nonenriched assays. Conclusions: Our results indicate that EGFR mutations are readily detectable by mutant-enriched PCR in various clinical samples. Thus, mutant-enriched PCR may provide a valuable method of potentially detecting a small fraction of mutant genes in heterogeneous specimens, indicating its possible use in clinical application for NSCLC.
The Inducible Costimulator (ICOS) Is Critical for the Development of Human T <sub>H</sub> 17 Cells
Authors: Chrystal M. Paulos, Carmine Carpenito, Gabriela Plesa, Megan M. Suhoski, Angel Varela-Rohena, Tatiana N. Golovina, Richard G. Carroll, James L. Riley, Carl H. June
Journal: Science Translational Medicine (2010)

The inducible costimulator ICOS is critical for the differentiation and expansion of human T H 17 cells and promotes the antitumor capacity of these cells.
Cell Surface Proteomic Map of HIV Infection Reveals Antagonism of Amino Acid Metabolism by Vpu and Nef
Authors: Nicholas J. Matheson, Jonathan Sumner, Kim Wals, Radu Rapiteanu, Michael P. Weekes, Raphael Vigan, Julia Weinelt, Michael Schindler, Robin Antrobus, Ana S.H. Costa, Christian Frezza, Clary B. Clish, Stuart J.D. Neil, Paul J. Lehner
Journal: Cell Host & Microbe (2015)

Critical cell surface immunoreceptors downregulated during HIV infection have previously been identified using non-systematic, candidate approaches. To gain a comprehensive, unbiased overview of how HIV infection remodels the T cell surface, we took a distinct, systems-level, quantitative proteomic approach. >100 plasma membrane proteins, many without characterized immune functions, were downregulated during HIV infection. Host factors targeted by the viral accessory proteins Vpu or Nef included the amino acid transporter SNAT1 and the serine carriers SERINC3/5. We focused on SNAT1, a β-TrCP-dependent Vpu substrate. SNAT1 antagonism was acquired by Vpu variants from the lineage of SIVcpz/HIV-1 viruses responsible for pandemic AIDS. We found marked SNAT1 induction in activated primary human CD4+ T cells, and used Consumption and Release (CoRe) metabolomics to identify alanine as an endogenous SNAT1 substrate required for T cell mitogenesis. Downregulation of SNAT1 therefore defines a unique paradigm of HIV interference with immunometabolism.
Suppression of growth, migration and invasion of highly-metastatic human breast cancer cells by berbamine and its molecular mechanisms of action
Authors: Shan Wang, Qian Liu, Ying Zhang, Ke Liu, Pengfei Yu, Kun Liu, Jinling Luan, Huiying Duan, Zhaoqiao Lu, Fengfei Wang, Erxi Wu, Kazumi Yagasaki, Guoying Zhang
Journal: Molecular Cancer (2009)

Abstract Background Breast cancer is the second leading cause of cancer related deaths among females worldwide. Berbamine (BER), a kind of bis-benzylisoquinoline alkaloid, has been used to treat clinical patients with inflammation and cancer for many years in China. The purpose of this study is to investigate the activity of BER against highly-metastatic human breast cancer and its molecular mechanisms of action. Results In our study, we found that BER inhibits growth of highly-metastatic human breast cancer cell lines MDA-MB-231 and MDA-MB-435S cells dose-dependently and time-dependently. The sera from BER-treated rats suppress the growth of MDA-MB-231 cells. BER shows synergistic effects with some existing anticancer agents such as trichostatin A (TSA, the histone deacetylase inhibitor), celecoxib (the inhibitor of COX-2), and carmofur against the growth of MDA-MB-231 cells. BER also displays the strong activity of inducing apoptosis in both estrogen receptor-negative MDA-MB-231 cells and estrogen receptor-alpha-positive MCF-7 breast cancer cells, but not in normal human mammary epithelial cell line MCF10A. BER down-regulates anti-apoptotic protein Bcl-2 levels and up-regulates pro-apoptotic protein Bax expressions in MDA-MB-231 and MDA-MB-435S cells. BER also has synergistic effects with anticancer agents trichostatin A, celecoxib and/or carmofur on reducing Bcl-2/Bax ratios and VEGF secretions in MDA-MB-231 cells. In addition, BER significantly suppresses cell migration and invasion, as well as decreases pro-MMP-9/pro-MMP-2 activation in breast cancer cells. Furthermore, BER suppresses Akt and nuclear factor κ B signaling by reducing the phosphorylation of c-Met and Akt, and inhibiting their downstream targets such as nuclear factor κ B p-65, Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2 on protein and/or mRNA levels in breast cancer cells. Conclusion Our findings have showed that BER suppresses the growth, migration and invasion in highly-metastatic human breast cancer cells by possibly inhibiting Akt and NF- κ B signaling with their upstream target c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9 and MMP-2. BER has synergistic effects with anticancer agents trichostatin A, celecoxib and carmofur on inhibiting the growth of MDA-MB-231 cells and reducing the ratio of Bcl-2/Bax and/or VEGF expressions in the cancer cells. These findings suggest that BER may have the wide therapeutic and/or adjuvant therapeutic application in the treatment of human breast cancer and other cancers.
NUP98–PHF23 Is a Chromatin-Modifying Oncoprotein That Causes a Wide Array of Leukemias Sensitive to Inhibition of PHD Histone Reader Function
Authors: Sheryl M. Gough, Fan Lee, Fan Yang, Robert L. Walker, Yeulin J. Zhu, Marbin Pineda, Masahiro Onozawa, Yang Jo Chung, Sven Bilke, Elise K. Wagner, John M. Denu, Yi Ning, Bowen Xu, Gang Greg Wang, Paul S. Meltzer, Peter D. Aplan
Journal: Cancer Discovery (2014)

In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and preleukemic tissues display a stem cell-like expression signature, including Hoxa, Hoxb, and Meis1 genes. The PHF23 plant homeodomain (PHD) motif is known to bind to H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein binds to chromatin at a specific subset of H3K4me3 sites, including at Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD motifs to H3K4me3, rapidly and selectively killed NP23-expressing myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98-JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.
The current status of robotic oncologic surgery
Authors: Hua‐yin Yu, David F. Friedlander, Sunil Patel, Jim C. Hu
Journal: CA A Cancer Journal for Clinicians (2012)

Abstract Answer questions and earn CME/CNE The use of robotic assistance facilitates minimally invasive surgery and has been widely adopted across multiple specialties. This article reviews the published literature on use of this technology for treatment of oncologic conditions. PubMed searches were performed for articles published between 2000 and 2012 using the keywords “robotic” or “robotic surgery” in conjunction with “oncology” or “cancer.” Although the most common use for robotics was to treat urologic oncologic conditions, it has also been widely adopted for gynecologic, general, thoracic, and head and neck surgeries. For several procedures, there is evidence that robotics offers short‐term benefits such as shorter lengths of stay and lower intraoperative blood loss, with safety profiles and oncologic outcomes comparable to open or conventional laparoscopic approaches. However, long‐term oncologic outcomes are generally lacking, and robotic surgeries are more costly than open or laparoscopic surgeries. Robotic technology is widely used in oncologic surgery with demonstrated short‐term advantages. However, whether the benefits of robotics justify the higher costs warrant large comparative effectiveness studies with long‐term outcomes. CA Cancer J Clin 2013. © 2012 American Cancer Society.
A Most Unfortunate Needlestick Injury: Why the doctor paid a taxi for the nurse
Authors: M. A Van Agtmael
Journal: BMJ (1997)

A few months ago when I was inserting an intravenous catheter into the cubital vein of a patient with malaria I accidentally stung the assisting nurse in the back of her hand with the needle that was withdrawn from the catheter. As the nurse had an adequate hepatitis B vaccination titre I advised her to contact me only if she developed fever. Eighteen days later she called and said that she had flu. I asked her to come to the …