tbuckley/cabot-search huggingface dataset:
Abstract 863: Functions of FRAS1 as a driver gene of liver metastasis from gastric cancer analyzed by the genome editing technology
Authors: Shinichi Umeda, Mitsuro Kanda, Haruyoshi Tanaka, Fuminori Sonohara, Hideki Takami, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Cancer Research (2019)

Abstract Background: The prognosis of patients with liver metastasis from gastric cancer (GC) is dismal and it remains a serious problem in the management of GC. To elucidate complex molecular mechanisms underlying formation of liver metastasis is necessary for development of novel therapeutic modality. Methods: Transcriptome analysis of 57749 molecules with 4 groups (no recurrence, peritoneal recurrence, liver recurrence and nodal recurrence) was conducted to screen out the candidate molecules specific for liver metastasis. Subsequently, the stable knockout (KO) cells were established using the CRISPR/Cas9 system and cell functions, apoptosis, cell cycle, oxidative stress and cancer stemness were analyzed. PCR and antibody array analyses were conducted to identify the co-regulated molecules. Mouse subcutaneous xenograft models and liver metastasis models were generated to evaluate tumorigenicity of the KO cells in vivo. Tissue mRNA expression levels were determined by qRT-PCR in patients with stage II/III GC and correlated with recurrence patterns. Results: Fraser extracellular matrix complex subunit 1 (FRAS1) was identified as a candidate molecule overexpressed specifically in the liver metastasis group. Proliferation, adhesion, invasion and migration abilities were suppressed in FRAS1-KO cells compared to the control cells. Cell cycle alternation, increased proportions of apoptotic cells, increased oxidative stress and decreased cancer stemness were also observed in FRAS1-KO cells. PCR array analysis revealed that FRAS1 mRNA expression was positively correlated with TGFB1, MAP1B, AHNKA and negatively correlated with BMP2. Pathway analysis demonstrated that expression of MUC1, Survivin, Ki67 and Met proteins were decreased in FRAS1-KO cells. The tumorigenicity of FRAS1-KO cells was reduced in a mouse subcutaneous model and more clearly in liver metastasis models. Patients with high FRAS1 mRNA expression had a significantly higher incidence of liver recurrences after curative gastrectomy. Conclusion: Our results indicated that FRAS1 contributes to formation of liver metastasis from GC and is a potential therapeutic target. Citation Format: Shinichi Umeda, Mitsuro Kanda, Haruyoshi Tanaka, Fuminori Sonohara, Hideki Takami, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera. Functions of FRAS1 as a driver gene of liver metastasis from gastric cancer analyzed by the genome editing technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 863.
Abstract 1219: Generation of anti-OX40 antibody with different immunization strategies
Authors: Xiaojuan Chai, Wenfang Xin, Teddy Yang, Qing Duan, Louis Liu
Journal: Cancer Research (2019)

Abstract Variety of immunogen such as recombinant protein, DNA or cells has been used for animal immunization to develop hybridoma antibody. However, the effectiveness among different types of immunogen in generating functional antibodies especially antibody with agonistic activity has not been systematically investigated. OX40 (CD134) is a T cell costimulatory receptor that is found primarily on activated CD4+ and CD8+ T cells, regulatory T (Treg) cells and natural killer (NK) cells. Activation of OX40 by its natural ligand or an agonist antibody augments CD4 and CD8 T cell expansion, differentiation, and survival. Agonistic anti-OX40 antibody holds promise as therapeutics for cancer immunotherapy. In the present study, different immunization strategies (recombinant protein, cell and DNA) have been used to generate anti-OX40 antibody. Antigen specific immune response, number of binders, epitope bins and the functional activities obtained from different immunogens were analyzed and compared. Based on cross reactivity and cell based functional assay results, 25 clones from protein immunization, 22 from DNA immunization and 29 from cell based immunization were expanded and purified. Among the purified antibodies, antibodies obtained from DNA immunization showed stronger agonist activity in both Jurkat OX40-NFAT luciferase reporter activity and primary T cell activation assay. The antibodies obtained from DNA immunization also demonstrated in vivo efficacy and significantly inhibited tumor growth in MC38 syngeneic mouse model using human OX-40 knock-in mice. In summary, we have evaluated different immunization strategies using OX-40 as a case study and successfully generated high potency high affinity agonistic anti-OX40 antibody that support further development. Citation Format: Xiaojuan Chai, Wenfang Xin, Teddy Yang, Qing Duan, Louis Liu. Generation of anti-OX40 antibody with different immunization strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1219.
Abstract CT172: Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC)
Authors: Minish P Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul D. Brown
Journal: Cancer Research (2019)

Abstract Background: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising low intensity alternating electric fields. TTFields has demonstrated efficacy in non-small cell lung cancer (NSCLC) in in vitro and in vivo models, and in a Phase I/II clinical study. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. This prospective, multicenter study [NCT02831959] investigated the efficacy, safety and neurocognitive outcomes of TTFields in NSCLC patients with brain metastases. Methods: NSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &amp;gt; 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays and allows normal daily activities. Patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Patients in the control arm are allowed to cross over to TTFields arm at the time of second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2-10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1-4 and 5-10 brain metastases; bi-monthly intracranial progression rate from 2-12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Citation Format: Minish P Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul D. Brown. Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT172.
Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21
Authors: Louise M. E. Müller, Matthew Holmes, Joanne L. Michael, Gina B. Scott, Emma J. West, Karen J. Scott, Christopher Parrish, Kathryn Hall, Sina Stäble, Victoria A. Jennings, Matthew Cullen, Stewart McConnell, Catherine Langton, Emma L. Tidswell, Darren Shafren, Adel Samson, Kevin J. Harrington, Hardev Pandha, Christy Ralph, Richard J. Kelly, Gordon Cook, Alan A. Melcher, Fiona Errington-Mais
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible. <h3>Methods</h3> This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment. <h3>Results</h3> An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response. <h3>Conclusion</h3> This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.
Abstract 3041: CD72 as a potential new therapeutic target in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL)
Authors: Erika Von Euw, Eileen Taschereau, Da Ming Ou, Monica Mead, Sarah Larson, Dennis Slamon
Journal: Cancer Research (2019)

Abstract Cluster of differentiation 72 (CD72) is a 45 kDa type II transmembrane glycoprotein expressed primarily on the surface of B cells. In a search for a novel lymphoma specific target, public datasets were leveraged to assess mRNA expression. We investigated CD72 mRNA expression in cell lines (data from CCLE), patients (data from TCGA) and normal tissues (data from GTEx). The absence of CD72 in normal tissue and the presence in B cells and non-Hodgkin lymphomas (B-NHL) made CD72 a potential target for the treatment of B-NHL, mainly DLBCL and MCL. CD72 expression on the cell surface was tested by FACS in 15 DLBCL and 5 MCL cell lines. Of these, 12 DLBCL and 4 MCL were positive for CD72, while 3 DLBCL and 1 MCL showed no CD72 expression. In all cell lines tested, the cell surface expression of CD72 correlated with mRNA expression. To evaluate the potential of CD72 as an ADC target, 4 cell lines were treated in vitro with three commercial monoclonal anti-CD72 primary antibodies (clones J4-117, 3F3 and BU40), and MMAF-conjugated secondary antibody. The cell lines used were RL (DLBCL, CD72+), SCC-3 (DLBCL, CD72-), Jeko-1 and Mino (both MCL, CD72+). The cell growth inhibition after 96 hrs of treatment for for all control conditions; anti-CD72 primary antibody, IgG isotype, MMAF secondary antibody alone or combined with IgG isotype; tested in all cell lines, CD72+ or CD72- ranged from -3 to +4%. Conversely, anti-CD72 primary antibodies plus MMAF secondary antibody had marked growth inhibition effect ranged from 24 to 80% on the three CD72+ cell lines and no effect on cell growth in CD72- cell line, suggesting internalization of CD72 and growth inhibition dependent on the presence of CD72 on the cell surface. This is the first study demonstrating a potential role for CD72 as a novel target for DLBCL and MCL. These data suggest that CD72 may be a candidate for an ADC approach in DLBCL and MCL. Cell line% growth inhibition anti-CD72 + MMAF 2°Anti-CD72 clone J4-117Anti-CD72 clone 3F3Anti-CD72 clone BU40SCC-3 (CD72-)-31-5RL (CD72+)503330Jeko-1 (CD72+)433024Mino (CD72+)778066 Citation Format: Erika Von Euw, Eileen Taschereau, Da Ming Ou, Monica Mead, Sarah Larson, Dennis Slamon. CD72 as a potential new therapeutic target in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3041.
Abstract 2060: Combination of CD20 targeted engineered toxin body, MT-3724, with chemotherapy or IMiDs for the treatment of non Hodgkin's lymphoma
Authors: Jack P. Higgins, Aimee Iberg, Caleigh Howard, Erin Willert
Journal: Cancer Research (2019)

Abstract MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1 (SLTA) ribosome inactivating protein. Engineered Toxin Bodies (ETBs) are unique as they can induce internalization after binding to non- or poorly-internalizing receptors with subsequent enzymatic and permanent ribosome destruction through SLTA, representing a novel mechanism of direct cell-kill in oncology. MT-3724 has demonstrated single agent anti-tumor activity in heavily pre-treated relapsed/refractory (R/R) Non-Hodgkin’s lymphoma NHL patients in a Phase I clinical study. Specifically, in R/R diffuse large B cell lymphoma (DLBCL) patients who had low pre-existing serum levels of rituximab, an objective response rate (ORR) of 30% (3 of 10) and disease control rate of 70% (7 of 10) has been observed thus far (NCT02361346). Given the unique ribosomal inhibition mechanism of action for MT-3724, we hypothesized that combination of MT-3724 with agents possessing a differentiated mechanism of action could result in additive or synergistic cellular cytotoxicity in CD20 positive NHL cell lines. Preclinical studies were conducted to assess MT-3724 in combination with cytotoxic chemotherapeutic agents (doxorubicin, gemcitabine, bendamustine, and vincristine) or an immunomodulatory (IMiD) agent (lenalidomide) on selected NHL cell lines. The combination of MT-3724 with all agents demonstrated additive or synergistic cytotoxicity of NHL cell lines. The single agent clinical activity of MT-3724 in heavily pre-treated R/R NHL patients along with this preclinical combinatorial effect of MT-3724 with chemotherapy and IMiDs used in the treatment of R/R NHL have lead the opening of a Phase 2a study of MT-3724 in combination with Gemcitabine and oxaliplatin (GEMOX, NCT03488251) and another planned Phase 2a study of MT-3724 in combination with lenalidomide (NCT03645395). MT-3724 has demonstrated good tolerability and early signs of clinical activity as monotherapy in patients with R/R NHL along with additive and/or synergistic effects in combination with chemotherapy and IMiDs preclinically. Additional clinical studies to evaluate MT-3724 as single agent and in combination with GEMOX or lenalidomide are underway. Citation Format: Jack P. Higgins, Aimee Iberg, Caleigh Howard, Erin Willert. Combination of CD20 targeted engineered toxin body, MT-3724, with chemotherapy or IMiDs for the treatment of non Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2060.
Reflections on Randomized Trials and Observational Studies
Authors: Sir Rory Collins, John D. Rutherford
Journal: Circulation (2019)

Rory Collins is the Head, Nuffield Department of Population Health, University of Oxford, Principal Investigator and Chief Executive, UK Biobank, and the British Heart Foundation Professor of Medicine and Epidemiology at the University of Oxford. He was born in Hong Kong and received his medical degree from St Thomas's Hospital Medical School, University of London. He was Knighted for Services to Science in 2011 and became a Fellow of the Royal Society in 2015. He has delivered the Paul Dudley White International Lecture of the American Heart Association and the Royal Society of Medicine William Harvey Lecture, and he has received both the European Society of Cardiology Gold Medal and the British Cardiovascular Society MacKenzie Medal.
Physicians’ Responsibilities in Shared Decision-making for Lung Cancer Screening
Authors: Gabrielle De Allie, Parris Tanksley, Eric Y. Chang
Journal: JAMA Internal Medicine (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Abstract 1519: The impact of ICOS+ Tregs on prognosis of gastric cancer patients
Authors: Shinya Urakawa, Hisashi Wada, Masaki Mori, Yuichiro Doki
Journal: Cancer Research (2019)

Abstract Background and Aim: Foxp3+ CD4+ regulatory T cells (Tregs) have a suppressive role in antitumor immunity. Among Foxp3+ CD4+ population, effector Tregs (eTregs) with highly suppressive functions are located in a subpopulation of Tregs. We have reported that ICOS has the potential as a novel marker for eTregs in gastric cancer (GC) and ICOS+ Tregs were abundant in H. pylori (HP) Ab-positive GC patients. In the present study, we investigate whether HP induce ICOS+ Tregs in GC. Materials and Methods: Tumor-infiltrating lymphocytes (TILs), normal mucosa-infiltrating lymphocytes (NILs) and peripheral blood mononuclear cells (PBMCs) were obtained from 117 gastric cancer patients. Tregs, ICOS+ Tregs, linage- CD11c- CD123+ HLA-DR+ plasmacytoid dendritic cells (pDCs), TLR9+pDCs, ICOS-L+ pDCs were analyzed by flow cytometry and multicolor immunohistochemistry. HP Ab was analyzed by ELISA. For induction assay of ICOS+ Tregs, naïve CD4 T cells were cultured with pDCs under stimulation with TGF-β, CD3/CD28 mAbs and frozen-and-thawed HP (NCTC11637). Results: In GC tissues, %ICOS-L in pDCs was positively correlated with %ICOS in Tregs (r2=0.52, p&amp;lt;0.001). %TLR9 in pDCs and %ICOS-L in pDCs were significantly higher in HP Ab-positive patients than others (p=0.001 and p=0.042, respectively). %ICOS+ in Tregs was significantly higher in HP-Ab positive patients than others (p=0.020). By multicolor immunohistochemistry, a large number of ICOS/Foxp3 double positive cells were observed. In induction assay, addition of HP (NCTC11637) increased the expression of ICOS-L in pDC and induction of ICOS+ Tregs, which were suppressed by TLR9 antagonist. %ICOS+ in Tregs were significantly lower in HP-eradicated patients than others (p&amp;lt;0.001). Interestingly, %ICOS+ in Tregs were also significantly lower in patients eradicated within four weeks before their surgical treatments (p&amp;lt;0.001). Conclusion: Our results indicate the induction pathway from HP to ICOS+ Tregs mediated by TLR9 and ICOS-L in pDCs. Preoperative eradication for HP may have a potential as an indirect immune therapy for gastric cancer patients. Citation Format: Shinya Urakawa, Hisashi Wada, Masaki Mori, Yuichiro Doki. The impact of ICOS+ Tregs on prognosis of gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1519.
A Unique Genome-wide Association Study of a Psychiatric Disorder From India
Authors: Vishwajit L. Nimgaonkar, Joel Wood, Smita Deshpande
Journal: JAMA Psychiatry (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Psychiatry journal
Response to: ‘Neutrophil extracellular traps and low-density granulocytes are associated with the interferon signature in systemic lupus erythematosus, but not in antiphospholipid syndrome’ by van den Hoogen <i>et al</i>
Authors: Mariana J Kaplan, Kerry A Casey
Journal: Annals of the Rheumatic Diseases (2019)

We very much appreciate the interest of van den Hoogen et al 1 in our study.2 Their independent confirmation of the linkage between the type I interferon (IFN) axis, disease activity, hypocomplementaemia and elevated low-density granulocyte (LDG) numbers in patients with systemic lupus erythematosus (SLE) is highly encouraging for the field considering the demographic differences between the Utrecht and National Institutes …