tbuckley/cabot-search huggingface dataset:
The pleiotropic role of proteoglycans in extracellular vesicle mediated communication in the tumor microenvironment
Authors: M. Cerezo-Magaña, A. Bång-Rudenstam, M. Belting
Journal: Seminars in Cancer Biology (2019)

Compartmental exchange between cells through extracellular vesicles (EVs), including exosomes and microvesicles, has emerged as a central mechanism that coordinates the complex communication between malignant and stromal cells during tumor initiation and evolution. Some of the most critical processes of EV-mediated communication, including EV biogenesis and EV uptake, can be mediated by heparan sulfate proteoglycans (HSPGs) that reside on the surface of producer and recipient cells as well as on EVs. With interestingly similar, HSPG-dependent, pathways as the ones exploited by some viruses, EVs may, in an evolutionary perspective, be viewed as endogenous counterparts of viral particles. Cancer cell-derived EVs exert their protumorigenic effects by direct interactions of biologically active surface molecules, by transfer of proteins and nucleic acids into recipient cells or by transfer of metabolites that can be utilized as an energy source by the recipient cell. Here, we discuss the pleiotropic role of the HSPG family in these different contexts of EV communication with a specific focus on tumor development. We propose EV-associated PGs as dynamic reservoirs and chaperones of signaling molecules with potential implications in ligand exchange between EVs and tumor target cells. The protumorigenic consequences of EV mediated communication through HSPG should motivate the development of therapeutic approaches targeting EV-HSPG interactions as a novel strategy in cancer treatment.
Results from an Ongoing Phase 1 Study Indicate ACDT-301 (Camidanlumab Tesirine) Is Well-Tolerated in Patients with Relapsed or Refractory CD25-Positive Acute Leukemia
Authors: Aaron D Goldberg, Martin S. Tallman, Melhem M Solh, David Ungar, David A. Rizzieri, Roland B. Walter, Alexander I Spira, Ki-Young Chung, Wendy Stock, Shui He, Joseph Boni, Ehab Atallah
Journal: Blood (2017)
Abstract 191: Extracellular signaling linked to PI3K/AKT triggers the formation of vasculogenic mimcry in ovarian cancer
Authors: Andres Valdivia, Gabriel Mingo, Varina Aldana, Alejandra Sandoval, Alejandro Corvalan, Francisco Nualart, Gareth I. Owen
Journal: Cancer Research (2019)

Abstract Introduction: The presence of an endothelial cell-free perfusion pathway, known as Vasculogenic Mimicry (VM), strongly correlates with reduced patient survival, however the mechanisms by which a tumor can create a self-generated irrigation system remain unknown. Currently there is no mechanism of VM formation reported in fluid conducting tubular structures. Herein, using a standardized in vitro model, we sought to understand the pathways required for VM formation. Methods: We utilized confocal microscopy and Imaris reconstruction to demonstrate that cancer cells can create an internal tubular network in cultured cancer cell lines, cancer spheres and primary cancer cultures of ovarian cancer. Matrigel and 3D matrices containing specific protein components allowed the deciphering of the extracellular matrix proteins involved in VM formation. Intercellular pathways were resolved using chemical inhibitors. Results: VM only occurs when cells are grown in 3D culture and only 30% of primary cancer cultures undergo this process. The presence of laminin 1 is sufficient to trigger the formation of tubular structures and this may involve the alpha2beta1 integrin and metalloproteases. Downstream FAK and PI3K/AKT intercellular pathways are required to form functional tubular networks. Microarray data elucidated the presence of the mRNA transcripts that were increased in cells that undergo VM. Discussion: We demonstrate that Laminin 1, a component of the extracellular matrix (ECM), can promote the process of VM, which further involves the downstream signaling of the potentially druggable targets of the PI3K pathway. As VM is associated with reduced patient survival, elucidation of the mechanisms of formation may deliver new cancer therapies. Funding: FONDECYT 1180241, CONICYT FONDAP 15130011, IMII P09/016F Citation Format: Andres Valdivia, Gabriel Mingo, Varina Aldana, Alejandra Sandoval, Alejandro Corvalan, Francisco Nualart, Gareth I. Owen. Extracellular signaling linked to PI3K/AKT triggers the formation of vasculogenic mimcry in ovarian cancer [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 191.
The association between birthmarks and childhood cancer in the collaborative perinatal project.
Authors: Kimberly J. Johnson, Logan G. Spector, Julie A. Ross, Mark A. Klebanoff
Journal: Cancer Research (2006)

5355  With the exception of certain predisposing syndromes and in utero exposure to X-rays, there are few confirmed risk factors for childhood cancer. A few studies have found an excess of minor congenital malformations in children with cancer. It has been suggested that these “mild errors of morphogenesis” (MEM), which can be detected at birth, represent general genetic instability that could increase the risk of malignancy. One study noted a positive association between birthmarks, considered to be MEMs, and acute lymphoblastic leukemia (ALL) in children who were not documented as having neurofibromatosis type I, a genetic disease characterized by cafe au lait spots and an increased risk for ALL. We examined whether the frequency of birthmarks is increased in children with cancer using data from the Collaborative Perinatal Project (CPP), a prospective cohort study comprised of 54,795 U.S. children born between 1959 and 1968. The CPP systematically collected data related to all aspects of the overall health of its participants at multiple time points, including detailed information on the pregnancy, delivery, and growth and development of the child up to the age of 7 or 8 years. In addition, extensive information was collected on social and demographic characteristics of the child’s family. There were 51 incident cases of childhood cancer identified over 7-8 years of follow-up including: 17 leukemias, 8 central nervous system tumors, 6 neuroblastomas, 7 Wilms’ tumors, 5 lymphomas, 3 retinoblastomas, and 5 other cancers. Birthmarks were documented during the first year through history or medical exams that occurred at birth, 4 months and 1 year and included: hemangiomas (port-wine, strawberry, or cavernous), pigmented nevi, lymphangiomas, and cafe au lait spots. In the CPP, 2505 (4.6%) of subjects had a documented birthmark, including 7 (14%) children with cancer and 2498 (4.6%) children without cancer. In a Cox proportional hazards regression model, birthmarks were associated with a significant increase in the risk of cancer (hazard ratio (HR) = 3.0; 95% confidence interval (CI)=1.35-6.68). Adjusting for gender, race, socioeconomic status, gestational age, or birth weight did not materially change the risk estimate. There was a slight attenuation of the risk estimate when cases diagnosed in the first year of life were excluded (HR=2.6; 95%CI=1.02-6.61). No specific childhood malignancies were notably affected by birthmarks, nor did any particular type of birthmark occur more frequently in children with cancer. In conclusion, although this study was based on a small number of cases, we found birthmarks to be in excess in children who were diagnosed with cancer. These findings provide additional support for the possibility of a shared etiology of MEMs and childhood cancer. This work was supported by the University of Minnesota Children’s Cancer Research Fund.
ARIH2 Is a Vif-Dependent Regulator of CUL5-Mediated APOBEC3G Degradation in HIV Infection
Authors: Ruth Hüttenhain, Jiewei Xu, Lily A. Burton, David E. Gordon, Judd F. Hultquist, Jeffrey R. Johnson, Laura Satkamp, Joseph Hiatt, David Y. Rhee, Kheewoong Baek, David C. Crosby, Alan D. Frankel, Alexander Marson, J. Wade Harper, Arno F. Alpi, Brenda A. Schulman, John D. Gross, Nevan J. Krogan
Journal: Cell Host & Microbe (2019)
Abstract 12887: Radiofrequency Catheter Ablation to Ventricular Tachycardia with Tetoralogy of Fallot [[Unable to Display Character: ―]]Usefulness of Ablation to Narrow Channel of Macroreentrant Circuit Around Ventricular Septal Patch[[Unable to Display Character: ―]]
Authors: Hiroshi Furushima, Masaomi Chinushi, Hiroshi Watanabe, Daisuke Izumi, Akinori Sato, Kenichi Iijima
Journal: Circulation (2012)

[Background] Cather ablation (CA) of ventricular tachycardia (VT) after repair of tetralogy of Fallot (TOF) can be difficult because of complex anatomy and/or hypertrophied myocardium. In such pati...
Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML).
Authors: Courtney Denton Dinardo, Anthony Selwyn Stein, Eytan M. Stein, Amir Tahmasb Fathi, Olga Frankfurt, Andre C. Schuh, Giovanni Martinelli, Prapti Arvind Patel, Emmanuel Raffoux, Peter Tan, Amer Methqal Zeidan, Stéphane de Botton, Hagop M. Kantarjian, Richard M. Stone, Du Hung Lam, Jing Gong, Vickie Zhang, Thomas Winkler, Bin Wu, Paresh Vyas
Journal: Journal of Clinical Oncology (2019)

7011 Background: IVO, a mutant IDH1 (mIDH1) inhibitor, is approved for the treatment of relapsed/refractory mIDH1 AML. We report results from an ongoing phase 1b study of patients (pts) with mIDH1 ND AML ineligible for intensive treatment who received combination IVO+AZA (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m 2 on D1–7 in 28-d cycles. ORR comprised CR + CRi/CRp + PR+ MLFS. CR with partial hematologic recovery (CRh) was defined as CR with ANC &gt; 0.5×10 9 /L and platelets &gt; 50×10 9 /L. Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of 9Oct2018, 23 pts received IVO+AZA (11 male; median age 76 yrs [range 61–88]). Median duration of exposure was 11 mo (0.3–25.3); 12 pts remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% pts were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% pts were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18): CR 57%, CRi/CRp 13%, and MLFS 9%. CR+CRh rate was 70% (n = 16). Median time to response was 1.8 mo (0.7–3.8) and to CR 3.5 mo (0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10/16 pts (63%) with CR/CRh, including 9/13 (69%) with CR. Conclusions: IVO+AZA was well tolerated with a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other non-intensive therapies. CR and ORR rates exceeded those of AZA alone (Dombret et al., Blood 2015) and most responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO +AZA (AGILE, NCT03173248) is actively enrolling pts. Clinical trial information: NCT02677922.
Abstract 15503: Impact of Real-World Adherence to QD versus BID Non-Vitamin K Antagonist Oral Anticoagulant Agents on Stroke and Major Bleeding Events Among Non-Valvular Atrial Fibrillation Patients
Authors: Colleen A McHorney, Eric D Peterson, Veronica Ashton, François Laliberté, Concetta Crivera, Guillaume Germain, Naveed Sheikh, Jeff Schein, Patrick Lefebvre
Journal: Circulation (2017)

Introduction: The efficacy of NOACs to prevent stroke in NVAF patients is well recognized although they are also associated with an increased risk of bleeding. Objective: To estimate the real-world...
Abstract 2776: Mitochondrial calcium uniporter in pancreatic cancer metastasis and metabolic stress resistance
Authors: Xiuchao Wang, Shengchen Lin, Jianwei Sun, Jiaxin Kang, Jihui Hao, Shengyu Yang
Journal: Cancer Research (2019)

Abstract Despite recent advances in cancer diagnosis and therapeutic modalities, the prognosis for pancreatic ductal carcinoma (PDAC) remains very poor. Most PDAC patients succumb to local and distant metastasis soon after the initial diagnosis. Therefore understanding molecular mechanisms underlying PDAC metastasis is crucial to the development of more effective PDAC therapies. Here we examined the role of mitochondrial calcium uniporter (MCU), a mitochondrial inner membrane calcium channel responsible for mitochondrial Ca2+ uptake, in pancreatic cancer metastasis and progression. We discovered that MCU is overexpressed in PDAC when compared to adjacent pancreatic tissues. MCU overexpression in PDAC patients is significantly associated with PDAC lymph node metastasis, histologic grade and pTNM stage. We also found that higher levels of MCU in PDAC patients was associated with worse overall survival (OS, P&amp;lt;0.01) and relapse-free survival (RFS, P&amp;lt;0.05) after surgical resection of tumors. MCU knockdown inhibits the PDAC cell motility, invasiveness, metabolic stress resistance and chemoresistance in cell culture models and PDAC metastasis in an orthotopic xenograft mouse model. Mechanistically, MCU controls the activation of the Keap1-Nrf2 signaling pathway through promoting mitochondrial ROS production and the oxidation of mitochondrion-recruited Keap1. Our data support that MCU regulates cancer cell metabolic stress resistance and oxidative stress response to drive PDAC metastasis and progression. Inhibiting MCU expression or blocking mitochondrial calcium influx may be an attractive approach for treating metastatic PDAC. Citation Format: Xiuchao Wang, Shengchen Lin, Jianwei Sun, Jiaxin Kang, Jihui Hao, Shengyu Yang. Mitochondrial calcium uniporter in pancreatic cancer metastasis and metabolic stress resistance [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 2776.
ERS statement on chest imaging in acute respiratory failure
Authors: Davide Chiumello, Giuseppe Francesco Sferrazza Papa, Antonio Artigas, Belaid Bouhemad, Aleksandar Grgic, Leo Heunks, Klaus Markstaller, Giulia M. Pellegrino, Lara Pisani, David Rigau, Marcus J. Schultz, Giovanni Sotgiu, Peter Spieth, Maurizio Zompatori, Paolo Navalesi
Journal: European Respiratory Journal (2019)

Chest imaging in patients with acute respiratory failure plays an important role in diagnosing, monitoring and assessing the underlying disease. The available modalities range from plain chest X-ray to computed tomography, lung ultrasound, electrical impedance tomography and positron emission tomography. Surprisingly, there are presently no clear-cut recommendations for critical care physicians regarding indications for and limitations of these different techniques. The purpose of the present European Respiratory Society (ERS) statement is to provide physicians with a comprehensive clinical review of chest imaging techniques for the assessment of patients with acute respiratory failure, based on the scientific evidence as identified by systematic searches. For each of these imaging techniques, the panel evaluated the following items: possible indications, technical aspects, qualitative and quantitative analysis of lung morphology and the potential interplay with mechanical ventilation. A systematic search of the literature was performed from inception to September 2018. A first search provided 1833 references. After evaluating the full text and discussion among the committee, 135 references were used to prepare the current statement. These chest imaging techniques allow a better assessment and understanding of the pathogenesis and pathophysiology of patients with acute respiratory failure, but have different indications and can provide additional information to each other.
Abstract 3914: mTOR pathway components dictate cell response to Src inhibitors in prostate cancer cells
Authors: Yao Dai, Dietmar W. Siemann
Journal: Cancer Research (2019)

Abstract Src inhibitors have been actively evaluated in the clinic for the treatment of advanced prostate cancer however the effects are modest. One interpretation is that oncogenic signaling pathways are redundant and blocking one pathway is not sufficient to yield considerable efficacies. mTOR pathway is commonly hyperactivated in prostate cancer. However, the functional role of mTOR in Src inhibitor-mediated response remains largely unknown. In the current study, we combined mTOR inhibitor rapamycin and Src inhibitor dasatinib to detect functional behaviors in prostate cancer cells. Cell proliferation and clonogenic survival were detected by MTT and colony formation assay, respectively. Wound-healing” scratch assay was conducted to monitor cell migration, and Matrigel-based transwell assay was applied to assess cell invasion. Protein expression was detected by Western blotting. Gene silencing was detected by siRNA transfection. We found that two agents combined together showed greater inhibition on proliferation and clonogenic survival than either agent alone. Such combination effects were additive or synergistic depending on the cell types, as reflected by combination index calculation. In addition, cell migration and invasion were inhibited in a greater extent by rapamycin plus dasatinib, compared to either treatment alone. At the molecular level, co-targeting mTOR and Src lead to clear inhibition of Src and its downstream pathway focal adhesion kinase (FAK), Akt and mTOR downstream components S6RP and 4E-BP1. Interestingly, knockdown 4EBP1, but not S6RP, attenuated dasatinib-mediated functional inhibition. These data indicate that adding mTOR inhibitors to Src-based intervention may achieve better treatment outcomes. Such combination could be evaluated as a novel treatment strategy for prostate cancer patients who are less responsive to Src inhibitors. In addition, 4EBP1 may be used as a candidate predictive biomarker for monitoring clinical effectiveness of Src inhibitors in prostate cancer. Citation Format: Yao Dai, Dietmar W. Siemann. mTOR pathway components dictate cell response to Src inhibitors in prostate cancer cells [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 3914.
Abstract 5160: Extracellular vesicles from scirrhous gastric cancer cells induce premetastatic niche formation for peritoneal metastasis
Authors: Tomohisa Okuno, Masakazu Yashiro, Shuhei Kushiyama, Sadaaki Nishimura, Shingo Togano, Kenji Kuroda, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2019)

Abstract Background: Human scirrhous gastric carcinoma (SGC) is also known as diffusely infiltrating carcinoma, type 4 on Borrmann’s criteria, and linitis plastica-type carcinoma. SGC is characterized by frequent peritoneal metastasis, high proliferation and infiltration activity with extensive fibrosis in the tumor stroma. We previously reported that a soluble factor(s) from SGC cells changed the peritoneum to pre-metastatic niche such as round shape of mesothelial cells and peritoneal fibrosis, which is a favorable environment for cancer cells to metastasize. Extracellular vesicles (EVs; Exosomes) might be one of soluble factor(s) which might change the peritoneal component to pre-metastatic niche. In this study, we investigated the effect of EVs from SGC cells on the pre-metastatic niche formation of the peritoneum. Methods: Four SGC cell lines, OCUM-2M, OCUM-2MD3, OCUM-12, KATO-III, 2 non-SGC cell lines, MKN74, MKN45, and peritoneal mesothelial cells (PM cells) were used. The effect of EVs from gastric cancer cells on the peritoneum was examined in vitro and in vivo, as follows. PKH26-labeled EVs from OCUM-2MD3 cells were intravenously injected into nude mice for 3 weeks, then we examined the distribution of PKH26-labeled EVs by a fluorescence microscope. Next, we injected EVs intraperitoneally into nude mice, and investigated the morphology of peritoneum. Effect of EVs on the gene expression of PM cells was examined by RT-PCR. Clinical significance of EVs markers, CD9 and CD63, was evaluated by immunohistochemistry using 63 human gastric cancer specimens. Results: PKH26-labeled EVs frequently distributed to peritoneum and the liver. The morphology of PM cells changed from round shape to spindle shape by EVs addiction in vitro and in vivo. mRNA expression level of ZEB and N-cadherin of PM cells was significantly increased following the addiction of EVs. The high expression of EVs markers, CD9 and CD63, was significantly correlated with frequent peritoneal metastasis. Conclusion: EVs from SGC cells might frequently distribute to mesothelial cells of peritoneum. EVs from SGC cells might play an important role for the formation of a pre-metastatic niche on peritoneum by the morphologic change of peritoneal mesothelial cells. Citation Format: Tomohisa Okuno, Masakazu Yashiro, Shuhei Kushiyama, Sadaaki Nishimura, Shingo Togano, Kenji Kuroda, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Extracellular vesicles from scirrhous gastric cancer cells induce premetastatic niche formation for peritoneal metastasis [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 5160.
Abstract 16967: A Clinical Assessment in Diastolic Heart Failure: The Correlation Between a Combination of Clinical Findings and Indices with Echocardiography in Hemodialysis Outpatients
Authors: Kazunari Ozaki, Hirofumi Makino, Motokuni Aoki, Tatsuya Shudo, Mitsuru Kageyama, Shin'ichi Morikiyo, Nobukazu Horie, Takashi Nishimoto, Keisuke Hagihara, Ryuichi Morishita
Journal: Circulation (2012)

Purpose: Ideal design of non-invasive assessments for diastolic heart failure (DHF) remains limited due to the lack of modest clinical criteria to describe the patients. Numerical scoring systems t...
A retrospective multicenter study evaluating the efficacy and safety of irinotecan in patients with advanced gastric cancer: analysis of Glasgow prognostic score (GPS)
Authors: K. Harada, S. Nakano, S. Yuki, K. Sawada, T. Muranaka, Y. Kawamoto, H. Nakatsumi, H. Yoshita, T. Ando, Y. Kobayashi, T. Miyagishima, K. Hatanaka, A. Tanimoto, A. Ishiguro, T. Honda, M. Dazai, T. Sasaki, Y. Komatsu
Journal: Annals of Oncology (2019)