tbuckley/cabot-search huggingface dataset:
Abstract 12908: Impact of Bystander Cardiopulmonary Resuscitation by Family Members on Return of Spontaneous Circulation and Neurological Prognosis in Patients With Out-of-Hospital Cardiac Arrests: A Nationwide, Population-Based Cohort Study
Authors: Yasunori Suematsu, Shin-ichiro Miura, Vaziri D Nosratola, Naohiro Yonemoto, Hiroshi Nonogi, Ken Nagao, Takeshi Kimura, Keijiro Saku
Journal: Circulation (2016)

Introduction: Out-of-hospital cardiac arrests (OHCAs) are critical events and bystander cardiopulmonary resuscitation (byCPR) affects the survival and prognosis of OHCAs. Most byCPR occur in a family setting in Japan. Although there are many reports on the effect of byCPR, there are few considerations about the person who operated byCPR in Japan. Hypothesis: We hypothesized that byCPR by a family member is more effective for return of spontaneous circulation (ROSC) and neurological prognosis against OHCAs of cardiac origin compared to non-family operators without emergency medical services (EMS ). Methods: In All-Japan Utstein Registry of the Fire and Disaster Management Agency, 1,176,363 patients who suffered from OHCAs were enrolled between 2005 and 2014. We selected 162,390 patients who were witnessed, those aged &gt; 18 years and had OHCAs of cardiac origin. We classified the patients by age, gender, initial rhythm, verbal instruction, witness-to-CPR time by EMS, airway management, drug administration in ambulance, and secondary lifesaving treatment by doctor in ambulance. Results: In this study cohort, the byCPR by citizen were included family members (n=137,147), friends (n=9,132), colleagues (n=7,956), and passersby (n=8,155). The incidence of ROSC was 11.6%, 18.8%, 24.7%, and 22.2% among family members, friends, colleagues, and passersby, respectively and was significantly higher in friends (OR: 1.25, 95%CI: 1.18-1.33, p&lt;0.000), colleagues (OR: 1.35, 95%CI: 1.28-1.44, p&lt;0.000), or passersby (OR: 1.46, 95%CI: 1.38-1.55, p&lt;0.000) than family members. In family members, the rates of defibrillation, first aid and chest compression were significantly lower than those in others. The time from witness to byCPR was significantly later in family members than in others. The incidence of ROSC after adjusting above-mentioned factors and the rates of defibrillation was also significantly lower in family members than in others. We also performed same investigation for neurological prognosis, and the results were similar. Conclusions: The incidence of ROSC and neurologically intact survival in byCPR by family members were lower than in others, regardless of the presence of defibrillation. Family members need to have education as bystanders.
Abstract 4226: TNFRSF14 is a cell surface marker of MITF expression in melanoma
Authors: Ken Dutton-Regester, Nicholas K. Hayward
Journal: Cancer Research (2019)

Abstract Background: Transcriptional ‘cell states’ (defined as the genes expressed in a cell in any given point in time) can determine response to targeted and immune-based therapies in late-stage melanoma treatment. MITF and AXL are common markers of drug-sensitive and drug-resistant ‘cell states’, respectively; and extensive heterogeneity of both cell populations have been observed in melanoma cell lines and tumors. Understanding the mechanisms controlling these ‘cell-states’ may lead to therapeutic strategies to overcome resistance and improve patient survival. Problem: To date, certain experiments assessing cell population heterogeneity dynamics in melanoma (such as live cell sorting applications) has been limited by the lack of surface markers defining the MITF ‘cell-state’. Furthermore, existing antibodies against MITF commonly detect multiple expressed isoforms which can limit the accuracy of downstream experimental assays, such as in-cell western blot detection. Methods and Results: To find a suitable cell surface marker defining the MITF ‘cell state’, we used the PARIS GenePattern module with data from the Cancer Cell Encyclopedia. TNFRSF14, our highest ranked gene, was highly correlated to MITF transcript expression in melanoma cell lines. We confirmed this at the protein level through western blot detection and flow cytometry. Using flow cytometry, we could accurately follow ‘cell-state’ population dynamics of AXL and MITF following shRNA knockdown of MITF and during acquired drug resistance in culture. Outcomes: We have identified TNFRSF14 as a robust cell surface marker of MITF in melanoma. Our TNFRSF14 and AXL live cell flow protocol will be useful for those exploring ‘cell-state’ population dynamics and heterogeneity in melanoma and could contribute to new mechanistic insights of drug resistance. Citation Format: Ken Dutton-Regester, Nicholas K. Hayward. TNFRSF14 is a cell surface marker of MITF expression in melanoma [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 4226.
Abstract CT054: Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal cancer patients
Authors: Alberto A. Gabizon, Esther Tahover, Ruth Perets, Talia Golan, Ravit Geva, Yasmine Amitay, Hilary Shmeeda, Patricia Ohana
Journal: Cancer Research (2019)

Abstract Background: A phase 1A/1B study was conducted to investigate the safety of Promitil, a liposomal formulation of a lipidic prodrug of mitomycin-c (MLP) within an open, dose-escalating, phase (1A, n=27) followed by an expanded phase (1B, n=61) restricted to metastatic colorectal cancer (mCRC) patients after failure to two or more lines of therapy. We report here on the correlation between pharmacokinetic (PK) parameters and clinical observations in patients with mCRC. Methods: PK analysis of plasma MLP levels was obtained in 53 mCRC patients (F=26, M=27), who received Promitil every 4 weeks either as single agent (n=28), in combination with capecitabine (Cap) (n=12), or in combination with Cap and bevacizumab (Bev) (n=13). The MLP dose range was 0.5-3.5 mg/kg with most patients (N=29) receiving 2.0-2.5 mg/kg. Out of 53 patients analyzed, 39 patients completed the 3rd cycle (study week 12) and were efficacy-evaluable by CT scan and Recist criteria. PK of plasma MLP levels was analyzed by noncompartmental methods. For statistical analysis and correlations of T½ and Clearance (CL) with age, sex, BMI, baseline neutrophil/lymphocyte ratio (NLR), CEA, and survival, we used t test and Pearson or Spearman coefficients. Results: The PK of MLP was stealth-like with long T½ (~1 day), slow CL, and small Volume of distribution. Stable Disease (SD) was reported in 14 patients (36%), and Progressive Disease (PD) in 25 patients. Median survival of all 39 patients (SD+PD) was 8.3 months. SD patients had significantly longer median survival than PD patients (14.3 vs 6.5 months, p=0.0002). SD patients had significantly longer T½ and slower CL than non-SD patients. A longer T½ and slower CL were significantly correlated with longer survival. A high NLR and high CEA were correlated with shorter T½ and/or faster CL. Dose of MLP, addition of Cap and/or Bev, age and BMI did not have any apparent effect on response or survival. Conclusions: SD was indicative of extended survival. The longer circulation time of the liposomal prodrug in SD patients and its correlation with longer survival are consistent with the well-known correlation between liposome circulation time and localization in tumors. A high NLR may signal inflammatory macrophage activation resulting in shorter liposomal circulation half-life and reducing the chances of disease control. Citation Format: Alberto A. Gabizon, Esther Tahover, Ruth Perets, Talia Golan, Ravit Geva, Yasmine Amitay, Hilary Shmeeda, Patricia Ohana. Clinical and pharmacokinetic study with a lipidic prodrug of mitomycin-c entrapped in liposomes in metastatic colorectal 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 CT054.
Abstract 2457: Prediction of selective genetic vulnerabilities from large-scale functional screens in cancer cells
Authors: Benedikt Rauscher
Journal: Cancer Research (2019)

Abstract Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create new vulnerabilities for potential therapeutic exploitation. To identify genotype-dependent vulnerabilities, a large number of forward genetic screens in different genetic backgrounds have been conducted. To aggregate and mine functional data from published screens in a standardized format, we recently developed GenomeCRISPR, a curated database for high-throughput CRISPR-Cas9 experiments. We then devised MINGLE, a computational framework that integrates genetic screens in large panels of cancer cell lines to predict genetic interactions between variant and knockout alleles. We showed that our method identifies specific known and previously unknown genetic relationships. For example, we identified a synthetic lethal dependency between RNF43 and members of the Glucosidase II complex. Additional experiments confirmed that the Glucosidase II complex acts as a regulator of Wnt/beta-catenin signalling. In our first study we analyzed a dataset consisting of screens performed in sixty cell lines. Since then the amount of data available for this analysis has increased several fold. We are continuously integrating the new data that become available as we work towards the next iteration of a genetic interaction map in cancer cells. We are specifically interested in using the increased resolution of this new map to understand how genetic networks differ between individual cancer types. Citation Format: Benedikt Rauscher. Prediction of selective genetic vulnerabilities from large-scale functional screens in 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 2457.
Abstract 20: Pharmacology and metabolism of GLL398, an oral selective estrogen receptor degrader for endocrine therapy of breast cancer
Authors: Shanchun Guo, Changde Zhang, Madhu Mottamal, Ahamed Hossain, Jiawang Liu, Jiawang Liu, Guangdi Wang
Journal: Cancer Research (2019)

Abstract Selective estrogen receptor degrader (SERD) has proven clinically effective in treating advanced or metastatic breast cancer since the approval of fulvestrant by FDA in 2002. Recent expansion of indications as a first line monotherapy and as combination therapy with CDK4/6 inhibitors further demonstrates its clinical utility as an efficacious breast cancer endocrine regimen. However, the poor pharmacokinetic properties of fulvestrant and its injection-only administration route has driven continued efforts to develop orally bioavailability SERD that could potentially improve clinical response to SERD treatment. GLL398, a boron-modified GW5638 analog, showed superior oral bioavailability while retaining both antiestrogenic activity and ER degrading efficacy at a potency level comparable to the more active metabolite of GW5638, GW7604. Here we report further studies on the pharmacology, pharmacokinetics, and metabolism of GLL398. Consistent with GLL398’s robust activities in breast cancer cells that are tamoxifen resistant or express constitutively active, mutant ESR1 (Y537S), it was found to bind the mutant ERY537S at a high affinity. Molecular modeling of the binding mode of GLL398 to ER also found its molecular interactions consistent with the experimentally determined high binding affinity towards WT ER and ERY537S. To test if the superior oral bioavailability can be translated to potent efficacy in vivo, mice bearing MCF-7 derived xenograft breast tumors and patient derived xenograft (PDX) tumors harboring ERY537S were treated with GLL398 which potently inhibited tumor growth in mice. Finally the metabolism of GLL398 was also investigated to elucidate the biotransformation of the drug and its potential contribution to the superior oral bioavailability over GW7604. Citation Format: Shanchun Guo, Changde Zhang, Madhu Mottamal, Ahamed Hossain, Jiawang Liu, Jiawang Liu, Guangdi Wang. Pharmacology and metabolism of GLL398, an oral selective estrogen receptor degrader for endocrine therapy of breast 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 20.
Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines
Authors: Nicholas Hernandez, Giorgia Bucciol, Leen Moens, Jérémie Le Pen, Mohammad Shahrooei, Ekaterini Goudouris, Afshin Shirkani, Majid Changi-Ashtiani, Hassan Rokni-Zadeh, Esra Hazar Sayar, Ismail Reisli, Alain Lefevre-Utile, Dick Zijlmans, Andrea Jurado, Ruben Pholien, Scott Drutman, Serkan Belkaya, Aurelie Cobat, Robbert Boudewijns, Dirk Jochmans, Johan Neyts, Yoann Seeleuthner, Lazaro Lorenzo-Diaz, Chibuzo Enemchukwu, Ian Tietjen, Hans-Heinrich Hoffmann, Mana Momenilandi, Laura Pöyhönen, Marilda M. Siqueira, Sheila M. Barbosa de Lima, Denise C. de Souza Matos, Akira Homma, Maria de Lourdes S. Maia, Tamiris Azamor da Costa Barros, Patricia Mouta Nunes de Oliveira, Emersom Ciclini Mesquita, Rik Gijsbers, Shen-Ying Zhang, Stephen J. Seligman, Laurent Abel, Paul Hertzog, Nico Marr, Reinaldo de Menezes Martins, Isabelle Meyts, Qian Zhang, Margaret R. MacDonald, Charles M. Rice, Jean-Laurent Casanova, Emmanuelle Jouanguy, Xavier Bossuyt
Journal: The Journal of Experimental Medicine (2019)

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.
Abstract 3340: Lung cancer stigma: A ten year look at public attitudes about lung cancer
Authors: Maureen Rigney, Eleni Rapsomaniki, Jennifer C. King
Journal: Cancer Research (2019)

Abstract Background: Lung cancer is the leading cause of cancer death in the United States in both men and women (ACS Facts and Figures, 2018). The presence of lung cancer stigma is well documented (Chapple et al, 2004; Chambers et al, 2012; Marlow et al, 2015) and has been shown to impact the care and treatment of lung cancer survivors (Tod et al. 2008; Carter-Harris et al 2014). In 2008, a large survey of over 1000 members of the general population revealed that most participants felt lung cancer was principally caused by external factors, that it was preventable, and that lung cancer patients were at least partly to blame for their illness (Weiss et al. 2014; 2017). We replicated the survey to understand whether perceptions have changed over the last decade. Methods: 1001 members of the general public were surveyed with the identical survey instrument from 2008 survey along with three additional questions at the end. The survey was carried out by phone and online between June 6 and July 26, 2018. Statistical analysis was performed comparing 2008 and 2018 datasets using paired t-tests if normally distributed or Mann-Whitney U tests for continuous data and Chi-squared or Fisher’s exact test for categorical data. Results: General awareness about lung cancer has significantly improved over the last decade with 94% of the public reporting familiarity with lung cancer (p&amp;lt;.001). Sixty five percent of respondents reported increased visibility of lung cancer in the media. Despite the increased visibility of the disease, stigma remains a critical problem. There were no statistically significant changes in the proportion that felt that patients are at least partly to blame for their illness (56% in 2018). Sixty-eight percent of respondents felt that patients experience the same or more stigma than 10 years ago. In addition, despite the increased awareness there was no increase in the proportion of people who donate or volunteer time to lung cancer organizations and no increase in those selecting lung cancer as the type of cancer they believe should receive more research support. Conclusions: After a decade of research progress in lung cancer, these data show that lung cancer awareness has been considerably elevated. Unfortunately, they also indicate that the stigma surrounding the disease remains pervasive. This work underscores the need to address stigma with proactive multilevel approaches (Hamann, 2018). Citation Format: Maureen Rigney, Eleni Rapsomaniki, Jennifer C. King. Lung cancer stigma: A ten year look at public attitudes about lung 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 3340.
Abstract 12201: High-Density Lipoprotein Cholesterol Levels and Cardiovascular Outcomes in Japanese Patients After Percutaneous Coronary Intervention: A Report From the CREDO-Kyoto Registry Cohort-2
Authors: Masayasu Izuhara, Koh Ono, Hiroki Shiomi, Takeshi Morimoto, Yutaka Furukawa, Yoshihisa Nakagawa, Satoshi Shizuta, Tomohisa Tada, Junichi Tazaki, Takehiro Horie, Yasuhide Kuwabara, Osamu Baba, Tomohiro Nishino, Toru Kita, Takeshi Kimura
Journal: Circulation (2015)

Background: Low levels of HDL-C is associated with increased coronary risks in patients without known coronary artery disease (CAD) and high risks of cardiovascular events in patients with stable CAD. But it is still controversial whether low HDL-C influences cardiovascular outcomes, especially in patients with known CAD receiving current optimized treatments. Objective: We determined whether low HDL-C is a risk factor for adverse cardiovascular events in patients with known CAD who underwent percutaneous coronary intervention (PCI). Methods: We evaluated 10,391 patients who underwent PCI from January 2005 to December 2007. In total, 3,838 (36.9%) patients had low HDL-C (HDL-C &lt;40 mg/dL in males and &lt;50 mg/dL in females) and 6,553 (63.1%) patients had normal HDL-C based on measurements on admission. Results: The unadjusted 5-year incidence of major adverse cardiac events (MACE: composite of cardiovascular death, myocardial infarction or stroke) was significantly higher in the low HDL-C group than in the normal HDL-C group (17.6% vs. 14.0%, P&lt;0.0001). However, after adjusting for confounders, low HDL-C was not associated with a higher risk of MACE (adjusted hazard ratio [HR] 1.07, 95% confidence interval (CI) 0.97-1.19; P=0.19). There was no significant interaction between the effect of low HDL-C on MACE and several subgroup factors including age, sex, clinical presentation of CAD, statins use, serum low-density lipoprotein cholesterol level, and serum triglycerides level. Conclusions: Low HDL-C, as compared with normal HDL-C, was not associated with higher 5-year risk of MACE in patients who underwent PCI.
Trends in Diverting Loop Ileostomy vs Total Abdominal Colectomy as Surgical Management for<i>Clostridium difficile</i>Colitis
Authors: Yen-Yi Juo, Yas Sanaiha, Ziyad Jabaji, Peyman Benharash
Journal: JAMA Surgery (2019)

<h3>Importance</h3> Diverting loop ileostomy and colonic lavage has generated much interest since it was first reported as a potential alternative to total abdominal colectomy for treating<i>Clostridium difficile</i>colitis in 2011. To our knowledge, few studies have validated the benefit reported in the initial description, and the association of this new approach with practice patterns has not been described. <h3>Objective</h3> To examine the national adoption pattern and outcomes of diverting loop ileostomy vs total abdominal colectomy as treatment for fulminant<i>C difficile</i>colitis. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used data from hospitals participating in the National Inpatient Sample database across the United States from January 2011 to September 2015 and included 3021 adult patients who underwent surgery for<i>C difficile</i>colitis during the study period, comprising 2408 subtotal colectomies and 613 loop ileostomies. The data were analyzed between November 2018 and April 2019. <h3>Exposures</h3> Loop ileostomy as surgery of choice. <h3>Main Outcomes and Measures</h3> In-hospital mortality. <h3>Results</h3> Of 2408 participants, 1416 (58.8%) were women, 1781 (78.4%) were white, and 627 (21.6%) were individuals of color and the mean (SD) age was 68.2 (14.8) years. During the overall study period, 613 patients (20.28%) underwent diverting loop ileostomy without total abdominal colectomy. The annual proportion of patients undergoing only diversion increased from 11.16% in 2011 to 25.30% in 2015. Significantly more loop ileostomies were performed within the first day of hospitalization, in contrast to subtotal colectomies (23.31% vs 12.21%;<i>P</i> &lt; .01). There was no significant difference in in-hospital mortality rates between the 2 groups (25.98% vs 31.18%;<i>P</i> = .28). <h3>Conclusions and Relevance</h3> This study demonstrates the adoption of diverting loop ileostomy to treat<i>C difficile</i>colitis across the United States. While fulminant<i>C difficile</i>colitis remains a condition with high mortality rates, no significant difference in this outcome was observed between loop ileostomy and total abdominal colectomy. Loop ileostomy may represent a viable surgical alternative to total abdominal colectomy, although the grounds for selection of treatment need to be clarified.
O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy
Authors: Boris Görg, Ayşe Karababa, Elina Schütz, Martha Paluschinski, Alina Schrimpf, Aygul Shafigullina, Mirco Castoldi, Hans J. Bidmon, Dieter Häussinger
Journal: Journal of Hepatology (2019)