tbuckley/cabot-search huggingface dataset:
Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial
Authors: S. Stintzing, P. Wirapati, H.-J. Lenz, D. Neureiter, L. Fischer von Weikersthal, T. Decker, A. Kiani, F. Kaiser, S. Al-Batran, T. Heintges, C. Lerchenmüller, C. Kahl, G. Seipelt, F. Kullmann, M. Moehler, W. Scheithauer, S. Held, D.P. Modest, A. Jung, T. Kirchner, D. Aderka, S. Tejpar, V. Heinemann
Journal: Annals of Oncology (2019)

BackgroundFIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined.Patients and MethodsIn this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan–Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.ResultsCMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n-=-592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P-=-0.051), PFS (P-<-0.001), and OS (P-<-0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.ConclusionsCMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.
TMIC-62. FYN, AN EFFECTOR OF ONCOGENIC RECEPTOR TYROSINE KINASES SIGNALING IN GLIOBLASTOMA, INHIBITS ANTI-GLIOMA IMMUNE RESPONSES: IMPLICATIONS FOR IMMUNOTHERAPY
Authors: Andrea Comba, Patrick J Dunn, Anna E Argento, Padma Kadiyala, Maria Ventosa, Priti Patel, Daniel Zamler, Felipe Nunez, Lili Zhao, Maria Castro, Pedro Lowenstein
Journal: Neuro-Oncology (2019)

Abstract There is currently much excitement for the use of immunotherapies in cancer. In spite of positive results using checkpoint inhibitors in melanoma and CAR T cells in leukemias, these strategies have not yet achieved robust clinical responses in human gliomas. A powerful inhibitory microenvironment is thought to be the culprit. Mechanisms that determine the inhibitory microenvironment remain poorly understood. Herein we demonstrate that FYN, a downstream target of receptor tyrosine kinases signaling, inhibits the anti-glioma immune response. We utilized genetically engineered mouse models (GEMM) of glioma based on the Sleeping Beauty Transposon method. We examined the activities of FYN in NP (N-ras + shp53), NPA (NP + shATRX), and NPD (NP + PDGF overexpression) tumors. We also generated FYN knockdown glioma stem cells in vitro to induce gliomas in immune-competent and immune-deficient mice of varying genetic backgrounds (NSG, CD8-/-). Flow cytometry was used to characterize immune cells within the glioma microenvironment. Our results show that FYN knockdown in NP, NPA, or NPD GEMM of glioma reduced tumor progression and increased survival by 25–77%. GSEA analysis of differential expressed genes of WT vs. FYN knockdown gliomas revealed enrichments of gene ontologies related to immune functions. In NSG and CD8-/- immune-deficient mice, FYN knockdown failed to inhibits tumor growth and increase animal survival. These results suggest that FYN enhances tumor progression through changes in anti-glioma immune activation. Examination of tumor immune infiltrates by flow cytometry indicate a 50–70% reduction in powerful immune inhibitory myeloid derived cells (MDSCs) with no changes in the total level of CD8+ and CD4+ cells. Our results show for the first time that FYN reduces anti-glioma immune responses, likely through a reduction in inhibitory MDSCs. The specific inhibition of FYN exclusively within glioma cells, could improve the efficacy of anti-glioma immunotherapies.
Mash Screen: high-throughput sequence containment estimation for genome discovery
Authors: Brian D. Ondov, Gabriel J. Starrett, Anna Sappington, Aleksandra Kostic, Sergey Koren, Christopher B. Buck, Adam M. Phillippy
Journal: Genome biology (2019)

The MinHash algorithm has proven effective for rapidly estimating the resemblance of two genomes or metagenomes. However, this method cannot reliably estimate the containment of a genome within a metagenome. Here, we describe an online algorithm capable of measuring the containment of genomes and proteomes within either assembled or unassembled sequencing read sets. We describe several use cases, including contamination screening and retrospective analysis of metagenomes for novel genome discovery. Using this tool, we provide containment estimates for every NCBI RefSeq genome within every SRA metagenome and demonstrate the identification of a novel polyomavirus species from a public metagenome.
Abstract 13389: High-Sensitivity Cardiac Troponin at Any Detectable Concentration Identifies Higher Risk of Major Cardiovascular Events in Patients With Stable Ischemic Heart Disease
Authors: Nicholas A Marston, Marc P Bonaca, Petr Jarolim, Deepak L Bhatt, Philippe G Steg, Marc Cohen, Robert F Storey, Per Johanson, Erica Goodrich, Steve D Wiviott, Eugene Braunwald, Marc S Sabatine, David A Morrow
Journal: Circulation (2018)

Introduction: Use of high-sensitivity troponin (hsTn) in stable patients (pts) with established ischemic heart disease (SIHD) is an emerging application to identify heightened risk of major cardiov...
Outcome of Hematopoietic Stem Cell Transplantation in the Patients with Pediatric Acute Lymphoblastic Leukemia Enrolled in the Japan Association of Childhood Leukemia Study (JACLS) ALL-02
Authors: Mio Yano, Hisashi Ishida, Yoshiko Hashii, Asahito Hama, Yoshiyuki Kosaka, Tsukasa Hori, Junichi Hara, Hiroshi Kawaguchi, Etsuro Ito, Akiko M Saito, Atsushi Sato, Hiroki Hori, Keizo Horibe, Toshihiko Imamura
Journal: Blood (2019)
Antenatal Preparation for Labour
Authors: D. R. Firth
Journal: BMJ (1964)

ribs.This may be done by the examiner's placing his left hand underneath the patient's right lower ribs, the examiner's right hand being in front of the lower thorax, and then gently but suddenly compressing the liver area.An equally good method, which avoids any pressure near the gall-bladder area, is to compress the lower thorax from side to side, the examiner's hands being placed over the lower ribs on either side.In my experience this sign, dramatic when present, is always positive in early amoebic lesions of the liver, and a good response may confidently be expected from emetine in such cases.
Preclinical Evaluation of Human Placental-Derived Allogeneic CD19 CAR-T Cells Against B Cell Malignancies
Authors: Kathy Karasiewicz, Shuyang He, Mary Ng, Kristina Tess, Weifang Ling, Gunnar F. Kaufmann, Jerome B. Zeldis, Henry Ji, Robert Hariri, Xiaokui Zhang
Journal: Blood (2019)
IMMU-19. QUINOLINATE-INDUCED IMMUNE SUPPRESSION IN GLIOBLASTOMA
Authors: Pravin Kesarwani, Shiva Kant, Antony Prabhu, Prakash Chinnaiyan
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma continues to be an invariably fatal malignancy with limited treatment options. We performed integrative cross-platform analyses coupling global metabolomic profiling with genomics in patient-derived tumors to provide insight into metabolic programs that may be driving the aggressive phenotype of this malignancy. A persistent theme that emerged was the interplay between metabolic remodeling and immune response. Most notable was a 64-fold accumulation of quinolinate, which represents a downstream intermediary of tryptophan metabolism, in glioblastoma, when compared to low-grade astrocytoma. We discovered a dynamic interaction between cells within the tumor microenvironment that contributes to the generation of quinolinate. Specifically, neither tumor cells nor immune cells demonstrated the capacity to completely metabolize tryptophan. Tumor cells were required to metabolize tryptophan to kynurenine, while only cells of monocyte lineage, including M1/M2 macrophages and microglial cells, demonstrated the capacity to generate quinolinate from tumor-generated kynurenine. We next sought to determine if the observed accumulation of quinolinate in glioblastoma had immune consequences. We discovered a novel role quinolinate plays in increasing (~50%) immunosuppressive M2 macrophage (CD45+CD11b+F4/80+ and CD206+) polarization and promoting a suppressive molecular phenotype (IL4Rα +). These findings were functionally recapitulated, with quinolinate-induced M2 macrophages demonstrating potent inhibition of CD8+T-cell proliferation. Intriguingly, quinolinate also skewed M1 polarization towards an “M2-like” phenotype both molecularly (CD45+CD11b+F4/80+CD206+) and functionally, by inhibiting CD8+T-cell proliferation and decreasing phagocytosis efficiency. Targeting quinolinate’s upstream enzyme kynurenine-3-monooxygenase (KMO) inhibited M2 polarization in vitro and deceased M2 macrophage levels in vivo by 60%. This was unique to KMO, as targeting tryptophan metabolism by inhibiting the more established, upstream target IDO1 did not influence M2 macrophage levels. As emerging studies suggest M2 macrophages play a central role in contributing towards the potent immunosuppressive microenvironment in glioblastoma, therapeutic strategies designed to target quinolinate metabolism may serve as a novel immuno-metabolic checkpoint with direct clinical implications in this malignancy.
Melphalan Based Regimens for Treatment of Newly Diagnosed Amyloidosis, Lessons from Clinical Literature: A Systematic Review
Authors: Muhaddis Ejaz Ahmad, Muhammad Abdullah Yousaf, Abdul Rafae, Mustafa Nadeem Malik, Tariq Iqtidar Sadiq Syed, Syed Maaz Abdullah, Maimoona Khan, Asma Waheed, Fazeel Qamar, Ahmed Ibrahim, Faiz Anwer
Journal: Blood (2019)
A CASE OF OVARIAN PREGNANCY
Authors: W. C. Spackman
Journal: BMJ (1934)

PREGNANCY rmE:DIAJORNAL 229 glycogen value for this liver was below what one might expect as normal, but normal control figures for the human do not seem to be readily available.All that can be said is that apparently this liver was poor in glycogen.But in the absence of further evidence, and remembering that the patient took or retained little food for twenty- four hours (apart from the intravenous glucose given about eleven hours before death), it would be rash on this score to attribute the chronic hypoglycaemia to a hepatic cause.To account for the chronic hypoglycaemia one is apparently driven, in the present state of knowledge of this complicated subject, for want of a better explanation, to consider absolute hyperinsulinism; but here again there is very little evidence to go upon.Finally, it is interesting to speculate as to whether the fulminant course of the bronchopneumonia may have been deter- mined to some degree by the chronic hypoglycaemia.NOTE.-Since the above was written we have come across a case of apparently true hyperinsulinism, or what certain authors might call dysinsulinism.This was a man, aged 28 years, who complained of slight mental confusion, slight dimness of vision, and weakness about three hours after the heavier meals.The fasting blood sugar was only 80 mg. per 100 c.cm.After ingesting 50 grams of glucose the blood sugar in half an hour was 90, in one hour 135, in two hours 97, in three hours 64, in four hours 66, and in five hours 78 mg. per 100 c.cm.His physical examination was normal in all respects, and we could find no evidence to implicate either the ductless glands or the liver.
NCOG-08. COGNITIVE DEFICITS AS A PREDICTOR OF THE COURSE OF TREATMENT IN DIFFUSE GLIOMA
Authors: Suzanne IJpelaar, Emma Van Kessel, Martine Van Zandvoort, Filip De Vos, Joost Verhoeff, Pierre Robe, Tom Snijders
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Over half of patients with a diffuse glioma suffer from cognitive deficits in one or more domains. Cognitive functioning, especially for the domains executive functioning (EF) and memory, is an independent prognostic factor for overall survival. A possible explanation for this prognostic effect is that patients with cognitive deficits receive less intensive treatment, or do not tolerate treatment as well as other patients. METHODS Retrospective cohort study of patients with a diffuse glioma (WHO grade 2–4) who underwent an awake craniotomy, with pre-operative neuropsychological testing, followed by adjuvant radio- and/or chemotherapy. Outcome measures were (a) choice of adjuvant treatment, compared to appropriate treatment according to contemporary guidelines; (b) intensity and compliance: number of received treatment cycles, and adherence to prescribed medication; and (c) complications. Cognitive deficits (in one or more domains, Z-score &lt; -2), as well as deficits in the domains EF and memory, were correlated to the outcome measures. RESULTS We included 187 consecutive patients. Cognitive deficits in one or more domains, EF or memory were neither associated to the choice of treatment (adherence to guidelines), nor to intensity or compliance of treatment. Having a cognitive deficit was associated with an increased risk of complications (P &lt; .001), including severe complications (CTCAE grade 3–5, p &lt; .05). A deficit in EF was also associated with more complications (p &lt; .005). This risk of complications was increased for the categories of infectious, cerebral, gastro-intestinal and hematological complications. CONCLUSION Of all patients with a diffuse glioma, patients with cognitive deficits have an increased risk of complications of postoperative antineoplastic therapy. Choice of, intensity of, and compliance to treatment did not differ from cognitively intact patients. The increased risk of complications may form an explanation for the poor prognosis of glioma patients with cognitive deficits.
Artesunate Inhibits Graft-Versus-Host Disease in Mice Via a Mechanism of Inducing Mitochondrial Calcium Overloading in Activated T Cells
Authors: Ying Wang, Shan He, Yongnian Liu, Robert Hooper, Hongshuang Yu, Yuanyuan Tian, Bui Tien, Bryant M Schultz, John W Elrod, Jonathan Soboloff, Yi Zhang
Journal: Blood (2019)
Outcome after different treatments for patients with HPV+ tonsillar cancer.
Authors: Per Attner
Journal: Journal of Clinical Oncology (2012)

e16048 Background: In the last few years, oncological treatment for tonsillar cancer has intensified with accelerated radiotherapy and chemotherapy, which has resulted in more side effects. Patients with HPV-positive tonsillar cancer have better prognosis than those with HPV-negative tumors, and it is possible that patients with HPV-positive tonsillar cancer may benefit from a reduced, less-toxic treatment without compromising survival. Methods: To evaluate the possible difference in survival after different oncological treatments of patients with HPV-positive tonsillar cancer, we evaluated all 211 patients diagnosed with tonsillar cancer between 2000-2007, in Stockholm, Sweden. Included patients were those with available pretreatment biopsies, and treated with intent to cure. A total of 172 patients had HPV-positive tumors and of those, 98 were treated with conventional radiotherapy, 44 were treated with accelerated radiotherapy and 30 were treated with chemoradiotherapy. Results: No significant differences in overall and disease-free survival were seen between the three treatment groups, but there was a trend, where chemoradiotherapy was better than radiotherapy; and accelerated radiotherapy was better than conventional radiotherapy. This trend needs to be followed further. Conclusions: In this study, patients with HPV-positive tonsillar cancer treated with conventional radiotherapy, accelerated radiotherapy or chemoradiotherapy had similar survival rates. However, there is a trend for better survival and less metastasis after intensified treatment underlining the need for prospective studies, where less intense treatment is compared to more intense treatment.
PRMT5 Is a Key Epigenetic Regulator That Promotes Transcriptional Activation in Mantle Cell Lymphoma By Regulating the Lysine Methyltransferase SETD7 and MLL1 Activity
Authors: JI Hyun Chung, Shelby Sloan, Peggy Scherle, Kris Vaddi, Said Sif, Rosa Lapalombella, Robert A Baiocchi
Journal: Blood (2019)
RARE-38. CNS LYMPHOMA INVOLVING HYPOTHALAMIC-PITUITARY AXIS
Authors: Dong-Won Shin, Hee Jun Yoo, Jeong Hoon Kim
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND It is rare for CNS lymphoma which involves the hypothalamic-pituitary axis. It could result in misdiagnoses such as pituitary adenoma, craniopharyngioma, or glioma. We report clinical findings of eight cases of either primary or secondary lymphoma involving the hypothalamic-pituitary axis(H-P axis). METHODS We retrospectively reviewed 488 patients who were diagnosed as CNS lymphoma from 2000 to 2017 in our institute. There were eight patients (8/488, 1.6%) who had H-P axis involvement in radiographic findings while six patients received chemotherapy. We analyzed patient characteristics, pathologies, clinical features, laboratory findings, imaging, and treatment outcome. RESULTS The mean age was 48-year-old (range 18~80) and male to female ratio was 5:3. We performed endonasal TSA for four patients, endoscopic biopsy for two patients, and stereotactic biopsy for two patients. There were six patients of diffuse large B-cell lymphoma and two patients of MALT lymphoma. Seven patients were PCNSL and one patient was metastasized lymphoma. All patients had hormone imbalance whereas three patients had visual disturbance and one patient had diabetes insipidus. Initial serum LDH was 337±167IU/L(range 169~567 except one patient). MRI finding was different from the usual pattern which was low SI in T1 and high SI with perilesional edema in T2, on the other hands, our patients group revealed that five patients(62.5%) had iso SI in both T1 and T2, and only two patients(25%) showed perilesional edema in T2. Median OS and PFS of six patients who received chemotherapy were 34.8 months(range 0.9~93.7) and 33.0 months(range 0.9~93.4), respectively. Two patients(25%) died in 26 days and 51 days after diagnosis because of pneumonia and cardiac arrest, respectively. And one patient lost to follow up after diagnosis. CONCLUSION CNS lymphoma involving H-P axis is rare, however, we need to understand its unique characteristic.
Development of an Allogeneic Anti-Bcma T Cell Therapy Utilizing a Novel Dimeric Antigen Receptor (DAR) Structure
Authors: Bei Bei Ding, John Dixon Gray, Nan Zhang, Yanliang Zhang, Xia Cao, Irina Krapf, Qingdong Mark Deng, Angel Wei, Jerome B. Zeldis, Robert D. Knight, Gunnar F. Kaufmann, Henry Ji, Wenzhong Guo
Journal: Blood (2019)
Therapeutic Targeting of RUNX-NFATC2 Axis for Acute Promyelocytic Leukemia and T Cell Immunity
Authors: Hirohito Kubota, Kana Furuichi, Tatsuya Masuda, Toshiya Tatsuta, Hidefumi Hiramatsu, Junko Takita, Sugiyama Hiroshi, Souichi Adachi, Yasuhiko Kamikubo
Journal: Blood (2019)
Transcriptional Landscape of the Microenvironment in Bone Marrow Fibrosis at Single Cell Level
Authors: Nils B. Leimkühler, Ronghui Li, Helene Gleitz, Inge Snoeren, Stijn Fuchs, Martina Crysandt, Steffen Koschmieder, Christoph Kuppe, Guntram Buesche, Hans H Kreipe, Ivan Costa, Rafael Kramann, Rebekka K. Schneider
Journal: Blood (2019)
Glucocorticoids paradoxically facilitate steroid resistance in T cell acute lymphoblastic leukemias and thymocytes
Authors: Lauren K. Meyer, Benjamin J. Huang, Cristina Delgado-Martin, Ritu P. Roy, Aaron Hechmer, Anica M. Wandler, Tiffaney L. Vincent, Paolo Fortina, Adam B. Olshen, Brent L. Wood, Terzah M. Horton, Kevin M. Shannon, David T. Teachey, Michelle L. Hermiston
Journal: Journal of Clinical Investigation (2019)

Glucocorticoids (GCs) are a central component of therapy for patients with T cell acute lymphoblastic leukemia (T-ALL), and although resistance to GCs is a strong negative prognostic indicator in T-ALL, the mechanisms of GC resistance remain poorly understood. Using diagnostic samples from patients enrolled in the frontline Children's Oncology Group (COG) T-ALL clinical trial AALL1231, we demonstrated that one-third of primary T-ALLs were resistant to GCs when cells were cultured in the presence of IL-7, a cytokine that is critical for normal T cell function and that plays a well-established role in leukemogenesis. We demonstrated that in these T-ALLs and in distinct populations of normal developing thymocytes, GCs paradoxically induced their own resistance by promoting upregulation of IL-7 receptor (IL-7R) expression. In the presence of IL-7, this augmented downstream signal transduction, resulting in increased STAT5 transcriptional output and upregulation of the prosurvival protein BCL-2. Taken together, we showed that IL-7 mediates an intrinsic and physiologic mechanism of GC resistance in normal thymocyte development that is retained during leukemogenesis in a subset of T-ALLs and is reversible with targeted inhibition of the IL-7R/JAK/STAT5/BCL-2 axis.
Annals Story Slam - Applesauce
Authors: Amanda Hempel
Journal: Annals of Internal Medicine (2019)

Web Exclusives5 November 2019Annals Story Slam - ApplesauceFREEAmanda Hempel, MDAmanda Hempel, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W19-0020 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Applesauce "Applesauce," by Amanda Hempel, MD (Duration 5:46)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 5 November 2019Volume 171, Issue 9Page: SS1 ePublished: 5 November 2019 Issue Published: 5 November 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.Loading ...
FT596: Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR-NK Cell with Engineered Persistence for the Treatment of B Cell Malignancies
Authors: Jode P Goodridge, Sajid Mahmood, Huang Zhu, Svetlana Gaidarova, Robert Blum, Ryan Bjordahl, Frank Cichocki, Hui-yi Chu, Greg Bonello, Tom Lee, Brian Groff, Miguel Meza, Bruce Walcheck, Karl-Johan Malmberg, Jeffrey S. Miller, Dan S Kaufman, Bahram Valamehr
Journal: Blood (2019)
Fostamatinib, a Spleen Tyrosine Kinase (SYK) Inhibitor, for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia (wAIHA): Final Results of the Phase 2, Multicenter, Open-Label Study
Authors: Kerry A. Rogers, Michael A. Boxer, Michael Y. Choi, Richy Agajanian, Donald M. Arnold, Catherine M. Broome, Joshua J. Field, Irina Murakhovskaya, Donna Chow, Robert P. Numerof, Hanzhe Zheng, Sandy Tong, David J. Kuter
Journal: Blood (2019)