tbuckley/cabot-search huggingface dataset:
Abstract 14999: Effect of a Machine Learning-Based Severe Sepsis Prediction Algorithm on Patient Survival and Hospital Length of Stay
Authors: Chris Barton, David Shimabukuro, Mitchell D Feldman, Samson Mataroso, Ritankar Das
Journal: Circulation (2017)

Introduction: Severe sepsis is a leading cause of death in the United States and costs health care systems up to $20 billion annually. Methods have been developed to electronically monitor patients for severe sepsis, but few have provided predictive capabilities to enable early intervention.Hypothesis: Patient length of stay (LOS) and in-hospital mortality rate decrease with the use of a machine learning-based severe sepsis prediction algorithm in the intensive care unit.Methods: A randomized clinical trial was conducted at two mixed medical-surgical intensive care units at UCSF from December 2016 to February 2017. This factorial, open label trial was designed to test whether InSight®, a machine learning-based severe sepsis prediction algorithm, was better than the current Electronic Health Record (EHR)-based severe sepsis detection system. All adult patients (18+) admitted to the participating units were eligible for study. Enrolled patients were automatically assigned to a trial arm according to a rando...
MNGI-32. LONG-TERM COGNITIVE OUTCOME OF MENINGIOMA AND THE EFFECTS OF TREATMENT (COMET) STUDY RESULTS
Authors: Xueying Zheng, Michael Hart, Sharon Erzinclioglu, Stefanie Enriquez-Geppert, Ramez Kirollos, John Duncan, John Pickard, Thomas Santarius
Journal: Neuro-Oncology (2018)

OBJECTIVES: Meningioma is the most common extra-axial tumour, however, little is known about the effect of the disease and its treatment on the brain, and patients functional and cognitive outcomes.We hypothesised that peri-operative factors can effect patients cognitive outcome.DESIGN: We aimed to identify clinical and radiological features associated with cognitive outcome in patients who had undergone resections of a supratentorial meningioma.Subjects: 28 active participants with both complete cognitive and radiological outcomes were identified in our database of focal brain injuries.The cognitive tests performed were the National Adult Reading Test (NART) and Cattell Culture Fair Test (CCFT).Methods: NART and CCFT scores were converted into intelligence quotient (IQ) scores, for use as markers of cognitive outcome.Independent t-tests and ANOVA statistics were utilised to identify features associated with lower IQ scores.RESULTS: There was a negative correlation between age and CCFT IQ scores (r=-0.632,P=0.007).Factors predisposing patients to poorer cognitive outcomes included: recurrent tumour (P<0.05);surgical complications, e.g.infection (P<0.10);additional neurosurgical intervention for complications, e.g.haematoma (P<0.05); and haemosiderin deposition on post-operative radiology (P<0.05).CONCLUSIONS: Peri-operative features can predict patients cognitive outcome.Cognitive dysfunction after meningioma surgery may be more common than currently appreciated. MNGI-33.
CMET-38. IMPACT ON THE CLINICAL COURSE OF EGFR MUTATION ON BRAIN METASTASES FROM NON-SMALL-CELL LUNG CANCER FROM VIEWPOINT OF NEURO-ONCOLOGISTS
Authors: Yuya Fujita, Manabu Kinoshita, Tomohiko Ozaki, Koji Takano, Kei Kunimasa, Madoka Kimura, Takako Inoue, Motohiro Tamiya, Kazumi Nishino, Toru Kumagai, Fumio Imamura
Journal: Neuro-Oncology (2018)

Molecular and genetic alternations of non-small-cell lung cancer (NSCLC) now plays an important role in patient care of this neoplasm. The authors focused on the impact of EGFR mutation status on brain metastases (BM) from NSCLC to better understand the most desirable management of BM from NSCLC. This was a retrospective observational study analyzing 266 patients with BM from NSCLC diagnosed between January 2008 and December 2015 in our institute. EGFR mutation, overall survival (OS), durations from diagnosis to brain metastases, and related factors with OS were measured. Among 266 patients, 127 patients (47.7%) had EGFR mutations. EGFR-mutant (EGFR-mt), compared with EGFR wild-type (EGFR-wt), showed longer median OS from diagnosis (40 vs 21 months, P < 0.001) and after BM diagnosis (22 vs 11 months, P < 0.001) and higher frequency of BM, around 80% of which occurred within 2 years. Good prognostic factors for OS were positive EGFR mutation (Hazard Ratio (HR) 0.64), no BM at diagnosis (HR 0.56), and single brain metastasis (HR 0.65). Patients harboring EGFR-mt single brain metastasis showed longer OS and durations from 1st brain metastasis to 2nd brain metastases than patients with either multiple BM or EGFR-wt BM. For those without BM at diagnosis, EGFR mutation status did not have any impact on OS (40 for EGFR-mt vs 37 months for EGFR-wt). CONCLUSIONS: Our study is in agreement with other studies that EGFR mutation is associated with prognosis of patients with BM from NSCLC. Results of our study also suggest that careful observation or screening for BM is recommended especially with the first 2 years for NSCLC patients with EGFR mutation. Aggressive treatments for EGFR-mt NSCLC patients with single BM should be considered taking into account that these patients could show prolonged survival after BM.
A Combination CDK4/6 and IGF1R Inhibitor Strategy for Ewing Sarcoma
Authors: Lillian M. Guenther, Neekesh V. Dharia, Linda Ross, Amy Conway, Amanda L. Robichaud, Jerrel L. Catlett, Caroline S. Wechsler, Elizabeth S. Frank, Amy Goodale, Alanna J. Church, Yuen-Yi Tseng, Rajarshi Guha, Crystal G. McKnight, Katherine A. Janeway, Jesse S. Boehm, Jaume Mora, Mindy I. Davis, Gabriela Alexe, Federica Piccioni, Kimberly Stegmaier
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Novel targeted therapeutics have transformed the care of subsets of patients with cancer. In pediatric malignancies, however, with simple tumor genomes and infrequent targetable mutations, there have been few new FDA-approved targeted drugs. The cyclin-dependent kinase (CDK)4/6 pathway recently emerged as a dependency in Ewing sarcoma. Given the heightened efficacy of this class with targeted drug combinations in other cancers, as well as the propensity of resistance to emerge with single agents, we aimed to identify genes mediating resistance to CDK4/6 inhibitors and biologically relevant combinations for use with CDK4/6 inhibitors in Ewing. Experimental Design: We performed a genome-scale open reading frame (ORF) screen in 2 Ewing cell lines sensitive to CDK4/6 inhibitors to identify genes conferring resistance. Concurrently, we established resistance to a CDK4/6 inhibitor in a Ewing cell line. Results: The ORF screen revealed IGF1R as a gene whose overexpression promoted drug escape. We also found elevated levels of phospho-IGF1R in our resistant Ewing cell line, supporting the relevance of IGF1R signaling to acquired resistance. In a small-molecule screen, an IGF1R inhibitor scored as synergistic with CDK4/6 inhibitor treatment. The combination of CDK4/6 inhibitors and IGF1R inhibitors was synergistic in vitro and active in mouse models. Mechanistically, this combination more profoundly repressed cell cycle and PI3K/mTOR signaling than either single drug perturbation. Conclusions: Taken together, these results suggest that IGF1R inhibitors activation is an escape mechanism to CDK4/6 inhibitors in Ewing sarcoma and that dual targeting of CDK4/6 inhibitors and IGF1R inhibitors provides a candidate synergistic combination for clinical application in this disease.
Iron homeostasis in pregnancy and spontaneous abortion
Authors: Yifan Guo, Na Zhang, Daoqiang Zhang, Quanzhong Ren, Tomas Ganz, Sijin Liu, Elizabeta Nemeth
Journal: American Journal of Hematology (2018)

Abstract During pregnancy, iron requirements are increased to support maternal erythropoietic expansion and fetal growth and development. To meet these requirements, dietary iron absorption increases, and available iron stores are mobilized. These adjustments are thought to be in large part mediated by the iron‐regulatory hormone hepcidin, which controls the concentrations of ferroportin, the sole exporter of iron into the extracellular fluid and blood plasma. Hepcidin regulation of iron availability during healthy and abnormal pregnancies is not well understood. In our cross‐sectional study, we compared hepcidin, iron and hematological parameters between nonpregnant control women, healthy pregnant women in the first and second trimester, and women with spontaneous abortion in the first trimester. We found that in healthy pregnancy, hepcidin increased in the first trimester compared with nonpregnant women, but then decreased during the second trimester. The second trimester hepcidin levels decreased despite stable serum iron concentrations, suggesting active suppression of hepcidin, presumably to enhance iron availability as iron demand increases. In women with spontaneous abortion during the first trimester, hepcidin, serum iron, and ferritin concentrations were all increased compared with the first trimester healthy pregnancy. Although the specific mechanisms remain to be determined, our findings demonstrate that maternal hepcidin is regulated by signals related to the progression of pregnancy, and that pregnancy loss is associated with profound changes in maternal iron metabolism. These observations highlight the existence of fetoplacental signals that modulate maternal iron homeostasis.
Lipid encapsulation promotes co-localization of methylated CpG ODN and TLR9 in late endosomes: A new model for the immunostimulatory activity of CpG DNA
Authors: Ying Tam, Susan de Jong, Genc Basha, Kaley Wilson, Mikameh Kazem, Pieter Cullis
Journal: Cancer Research (2008)

3802  Over the past several years, there has been significant interest in the development of immunostimulatory CpG oligonucleotides (CpG ODN) as a cancer immunotherapeutic. Toll-like receptor 9 (TLR9) recognizes CpG motifs present in pathogenic DNA and CpG ODN, triggering potent innate and adaptive immune responses. We have previously shown that encapsulation in lipid nanoparticles (LN) effectively protects the CpG ODN payload and enhances delivery and uptake by target immune cells, resulting in dramatically enhanced immunostimulatory activity and anti-tumor efficacy a number of animal models. Based on these data, Tekmira Pharmaceuticals is developing INX-0167, a phosphodiester CpG ODN encapsulated in a LN as an oncology therapeutic.  It is generally accepted that TLR9 distinguishes immunogenic, pathogenic DNA from non-stimulatory vertebrate DNA based, in part, on its methylation status, where TLR9 specifically binds and is activated by unmethylated but not methylated CpG (mCpG) motifs and consistent with this premise, numerous studies have shown that CpG methylation effectively abrogates immunostimulatory activity. However, we have shown that mCpG is capable of inducing TLR9-mediated immune responses when delivered in LN that are equal or greater than those induced by the equivalent unmethylated CpG ODN, thus implicating an alternate mechanism by which the relative immunostimulatory activity of CpG and mCpG DNA is regulated.  We show here that methylation status, rather than impacting binding affinity, determines the ability of “free” CpG DNA to co-localize with TLR9 in the late endosomal compartment of antigen-presenting cells. While free methylated and unmethylated CpG ODN are taken up and traffic to the endosome similarly, only unmethylated ODN promotes effective trafficking of TLR9 to the late endosomal compartment allowing for co-localization and interaction with its CpG ligand. However, when delivered in LN form, CpG DNA mobilizes and co-localizes with TLR9 regardless of methylation status, a property that is even shared with empty LN. We demonstrate that colocalization following exposure to either free unmethylated CpG or LN CpG or mCpG ODN is mediated by a src-family kinase (SFK) signaling pathway, inhibition of which effectively abrogates immunostimulatory activity. It is therefore proposed that immune cells distinguish unmethylated, pathogenic DNA from methylated, mammalian DNA based on the ability of TLR9 to co-localize with its ligand rather than a differential affinity of TLR9 for CpG and mCpG DNA. Therefore, the lack of immunological activity of free mCpG ODN is due to a failure to localize with TLR9 in the late endosomal compartment. Ultimately, we confirm this hypothesis by studies in which pre-dosing with empty LN to induce TLR9 mobilization to the endosomal compartment endows free mCpG ODN with immunostimulatory activity.
Zebularine, a cytidine deaminase and DNA methylation inhibitor, has in vitro growth inhibitory effects on human leukemia cells in association with demethylation and re-expression of p15INK4B
Authors: Stuart A. Scott, Wei-Feng Dong, Naoto Takahashi, Ryo Ichinohasama, David P. Sheridan, C. R. Geyer, John F. Decoteau
Journal: Cancer Research (2005)

1818  Promoter methylation is a major mechanism of transcriptional silencing in cancer cells that can be reversed by pharmacological treatment with known inhibitors of DNA methylation, such as 5-azacytidine (5-Aza) and its deoxy analog, 5-aza-2’-deoxycytidine (5-Aza-dC). Unfortunately, the clinical use of these drugs has been complicated by their toxicity profile and instability in aqueous solution. Recently, the cytidine analog zebularine has been proposed as an effective, stable and minimally toxic inhibitor of DNA methylation. Zebularine inhibits p16INK4A promoter methylation in T24 human bladder cancer cells in vitro and oral administration of zebularine shows in vivo antitumor effects on EJ6 human bladder cancer cells grown in mice. As promoter methylation and transcriptional silencing of the neighboring p15INK4B tumor suppressor gene occurs at a high frequency in human acute myeloid leukemia (AML), we analyzed the demethylation and anti-proliferative effects of zebularine on the human AML cell line AML193, a cell line with a methylated p15INK4B gene. Treatment of AML193 cells with zebularine resulted in a dose dependent increase in detectable p15INK4B mRNA in association with demethylation of the p15INK4B promoter CpG island. Zebularine mediated induction of p15INK4B mRNA was also associated with an increase in local acetylation of histones H3 and H4 as determined by chromatin immunoprecipitation. Interestingly, zebularine induced upregulation of p15INK4B mRNA was further augmented by co-treatment with 5-Aza-dC, a known inhibitor of DNA methylation, and the histone deacetylase inhibitor trichostatin A, with the greatest p15INK4B mRNA induction observed after treatment with all three agents. Using dosages that effectively demethylated the p15INK4B promoter, zebularine was tested for its effects on AML cell growth and was found to greatly inhibit cell viability and proliferation. Furthermore, zebularine treatment increased the percentage of cells arrested in G2/M of the cell cycle and dramatically induced apoptosis as determined by propidium iodide staining and increases in global phosphorylation of histone H3 at serine-10, histone H2A.X at serine-139, and histone H2B at serine-14. Taken together, our findings indicate that zebularine is an effective inhibitor of p15INK4B promoter methylation and cell growth in human AML in vitro. By expanding the spectrum of zebularine antitumor effects to include hematological malignancies, our study also provides further support for the clinical potential of this agent as a cancer therapy, alone, or in combination with other drugs such as 5-Aza-dC and histone deacetylase inhibitors.
Abstract 9816: Placenta Characteristics in Women With Heart Disease and Possible Impact on Fetal Outcomes
Authors: Fabio V Lima, Paraskevi Koutrolou-Sotiropoulou, Puja B Parikh, Charles Miller, Cecilia Avila, Javed Butler, Kathleen Stergiopoulos
Journal: Circulation (2015)

Background: Pregnant women with cardiomyopathy (CM) have higher rates of major adverse cardiovascular events (MACE) and fetal adverse clinical events (FACE) than those with other heart disease (HD) (congenital, valvular, or arrhythmia) and no HD, per a prior cohort. 1 Fetuses of mothers with CM are at higher risk for death, premature delivery, underweight, respiratory distress, and lower APGAR scores compared to those with HD. We sought to identify whether pregnant women with known CM or HD demonstrate a pattern of placental changes. Hypothesis: We anticipate pregnant women with a history of CM will have higher rates of abnormal placental characteristics compared with those with HD. Methods and results: We studied 86 pregnancies in women with CM or HD. Of these, 52 (60%) had HD and 34 (40%) had CM. Pathologic analyses were performed on 53 HD and 37 CM placentas. Gestational age in the HD and CM groups were different (38.6 vs 35.5, p &lt; 0.001), as was the incidence of gestational hypertension (21 vs 50%, p 0.003). Among the maternal HD group, 44% had history of congenital heart disease, 33% prior corrective cardiac surgery and 31% had history of arrhythmia. Placental and fetal weight were lower among CM patients compared to those with HD (396 vs. 478 grams, p 0.007; and 2443 versus 3181 grams, p&lt;0.001, respectively). Placentas of those patients with CM compared to those with HD were also more likely to have ischemic changes (65% vs. 34%, p 0.005) and be immature (60% vs. 9%, p&lt;0.001). Pathological villous vascular congestion, fetal membrane abnormalities, fetal surface coloration abnormalities, umbilical cord abnormalities and extent of subchorionic fibrin and placenta calcification were not significantly different between the two groups. Conclusion: Abnormal placental pathologic characteristics such as low weight, ischemic changes and immaturity may contribute to fetal adverse events in pregnant women with CM. 1 Koutrolou-Sotiropoulou P, Parikh PB, Miller C, Lima FV, Butler J, Stergiopoulos K. Impact of Heart Disease on Maternal and Fetal Outcomes in Pregnant Women. Am J Cardiol In Press 2015.
Abstract 15355: Dysnatremia is Associated With Adverse Outcomes in Pediatric Patients After Surgery Under Cardiopulmonary Bypass for Congenital Heart Disease
Authors: Andrea Ontaneda, Javier Lasa, Ayse Akcan-Arikan, Jorge Coss-Bu, Lara Shekerdemian
Journal: Circulation (2016)

Background: Sodium imbalances are one of the most common electrolyte disorders in ICU and have been associated with adverse outcomes in many patient groups. Few studies have investigated associatio...
Abstract 12292: Hypokalemia in Patients Undergoing Targeted Temperature Management Following Cardiac Arrest: Temporal Pattern and Prognostic Significance
Authors: Arash Nayeri, Hannah Gluck, Eric Farber-Eger, Srikanth Krishnan, Kamran Shamsa, Michael Lee, Quinn Wells, John McPherson
Journal: Circulation (2017)

Introduction: Hypokalemia has been consistently reported as a common occurrence during targeted temperature management (TTM) in comatose survivors of cardiac arrest. Hypothesis: Serum potassium lik...
ANGI-10. WSD1227: A BRAIN PENETRABLE VEGFR2 INHIBITOR FOR THE TREATMENT OF PRIMARY AND METASTATIC BRAIN TUMORS
Authors: Jinqiang Zhang, Wei Zhong, Zhihua Mu, Claire Sun
Journal: Neuro-Oncology (2018)

The VEGF pathway has emerged as an important target for cancer therapy by blocking the development of malignant neovasculature, thus to reduce oxygen availability to the tumor and decrease its growth. Anti-VEGF agents have been approved for several malignancies, such as GBM, NSCLC, mBC, CRC, OC, etc with satisfactory performance to extracranial lesions, but not in intracranial lesions. Insufficient penetration across BBB is one of factors limiting intracranial anti-tumor activity for those anti-VEGF agents, due to either large molecule weight or being substrate of BBB efflux transporters. The incidence of BM is increasing, and surgery/radiotherapy are the most common options for the management of BM. Patients with BM have a very poor prognosis and short survival. To address the role of anti-angiogenesis in the treatment of BM, a BBB penetrable, selective and potent VEGFR2 inhibitor WSD1227 is discovered with IC50 against VEGFR1/2/3 at 0.69/0.35/0.41nM versus against other targets such as PDGFRα IC50 22.9nM, PDGFRβ IC50 19.4nM, cKit IC50 383nM, FLT3 IC50 555 nM and CSF1R IC50 1062nM. In-vitro MDCKII transfected cell assays demonstrated WSD1227 is not a substrate of P-gp or BCRP, two main efflux transporters on human BBB. Preclinical CNS PK studies confirmed brain penetration of WSD1227 with Kp,uu,brain close to unity, thus not exacerbating VEGF related systemic toxicities. WSD1227 possessed superior PK profile with sufficient free PK exposure to achieve target engagement in mice. Treatment of tumor bearing mice in GBM, NSCLC, CRC and OC xenograft models with WSD1227 resulted in significant tumor growth inhibition. Predicted human PK properties are very promising to offer sufficient target engagement in clinic. Taken together, our data provide a good rationale for WSD1227 to be developed toward clinic to investigate anti-angiogenetic therapies for management of patients with primary or metastatic brain tumors.
ATIM-36. DOSE ESCALATION TRIAL OF D2C7 IMMUNOTOXIN (D2C7-IT) ADMINISTERED INTRATUMORALLY VIA CONVECTION-ENHANCED DELIVERY (CED) FOR RECURRENT MALIGNANT GLIOMA (MG)
Authors: Annick Desjardins, Dina Randazzo, Vidya Chandramohan, Katherine Peters, Margaret Johnson, Leslie Thomas, Stevie Threatt, Chevelle Bullock, James Herndon, Susan Boulton, Patrick Healy, Eric Lipp, John Sampson, Allan Friedman, Henry Friedman, David Ashley, Darell Bigner
Journal: Neuro-Oncology (2018)

BACKGROUNDD2C7-IT is a recombinant immunotoxin comprised of a dual-specific antibody fragment targeting EGFRwt and EGFRvIII and a genetically engineered form of the Pseudomonas exotoxin, PE38-KDEL. We report results of a phase 1 trial evaluating D2C7-IT delivered intratumorally by CED.
PATH-10. COPY NUMBER (CN)/SINGLE NUCLEOTIDE POLYMORPHISM (SNP) MICROARRAY ANALYSIS OF THE EGFR LOCUS IN GLIOSARCOMA
Authors: Lindsey Lowder, Ashley Woods, Stewart Neill, Jennifer Hauenstein, Saxe Debra, Brent Weinberg, Jeffrey Olson, Hui-Kuo Shu, Bree Eaton, Soma Sengupta
Journal: Neuro-Oncology (2018)

Epidermal growth factor receptor (EGFR) is overexpressed or mutated in a variety of malignancies, most notably non-small cell lung cancer, colorectal cancer and glioblastoma (GBM). Glioblastoma is an aggressive primary brain tumor and 35–50% of glioblastomas show amplification of the EGFR locus (7p11.2). Interestingly, gliosarcoma, a histologic variant of GBM, has a lower frequency of EGFR alterations (4–8%). We characterized EGFR alterations in gliosarcoma using a DNA copy number/single nucleotide polymorphism cytogenomic microarray using formalin fixed paraffin embedded tissue. A retrospective search for “gliosarcoma” from our database yielded 19 cases on which microarray analysis was performed. Of these cases, 2 showed an amplification at the EGFR locus (13%), 5 cases showed a gain of the entire chromosome 7 (26.3%), 3 cases showed gains at loci other than EGFR (15.8%) and the remaining 9 cases were negative for chromosome 7 alterations (47.4%). Our preliminary data show that amplification of the EGFR locus are infrequent (13%) in gliosarcomas. These preliminary findings demonstrate antithetical results regarding EGFR amplifications in conventional glioblastoma compared to gliosarcoma and suggests there may be an alternate driver in gliosarcoma genesis.