tbuckley/cabot-search huggingface dataset:
Anatomical site differences of SLS‐induced ICD
Authors: D. Leskur, J. Bukić, A. Petrić, L. Zekan, D. Rušić, A. Šešelja Perišin, I. Petrić, M. Stipić, N. Puizina‐Ivić, D. Modun
Journal: British Journal of Dermatology (2019)

Sodium lauryl sulphate (SLS) is a chemical used to induce skin irritation that mimics irritant contact dermatitis (ICD). ICD is a condition where direct contact with certain substances causes rash, redness, blistering, itching, dryness and cracking of the exposed skin. It is a common occupational disease and accounts for 4‐7% of all dermatological consultations in U.K. This SLS induced irritation is often used to test the effectiveness of different treatments that could be used to alleviate the ICD symptoms. Irritation is usually induced on the forearms but other locations such as upper back have been used. The extent of the irritation might be different between different anatomical locations. Those differences could affect the results of the treatment testing. That means that the beneficial effects achieved by the treatment on one location may not be achieved on the other. This study, from Croatia, aimed to investigate variations in skin response to irritation and its effects on treatment in an SLS induced ICD. The irritant was applied on the forearms and the upper back of the healthy volunteers. Emollient (moisturising) cream was chosen as a treatment. One forearm and one side of the back were treated with the emollient for nine days while others were left untreated. The skin parameters that indicate the extent of the irritation and the recovery were measured using skin probes. The authors found that the upper back had stronger reaction to the irritant and faster recovery of the skin than the forearms. Also, the tested emollient cream did not improve the skin recovery. In conclusion, the anatomical location is an important factor influencing the results of the studies testing treatment effectiveness. Future studies should always accurately report the testing location. The results of the studies using this irritation model, but on different anatomical locations, are not necessarily directly comparable.
Abstract 293: MicroRNA-125b-5p Protect the Mouse Heart from Ischemic Injury by Repressing Pro-apoptotic Bak1 And Klf13 in Cardiomyocytes
Authors: Zuzana Broskova, Kyoung-mi Park, Yongchao Wang, Il-man Kim
Journal: Circulation Research (2016)

Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), small non-coding RNAs that post-transcriptionally regulate target genes. For example, miR-125a is up-regulated in patients with heart failure (HF), while miR-125b is down-regulated in patients with end-stage dilated cardiomyopathy (DCM) and ischemic DCM. Circulating levels of these two miRs have been recently proposed as potential biomarkers of HF. We previously showed that β1-adrenergic receptor-mediated cardioprotective signaling through β-arrestin1 stimulates the processing of miR-125a and miR-125b in mouse heart (Figure A-C). Here, we hypothesize that these two miRs might confer cardioprotection against ischemic injury. Using cultured cardiomyocyte (CM) and in vivo approaches, we show that these miRs are ischemic stress-responsive protectors against CM apoptosis. CMs lacking miR-125a or miR-125b have an increased sensitivity to stress-induced apoptosis, while CMs overexpressing miR-125a or miR-125b have increased phospho-AKT pro-survival signaling. Moreover, we demonstrate that loss-of-function of miR-125b in mouse heart causes abnormalities in cardiac structure and function after myocardial infarction. The cardioprotective roles of the two miRs during ischemic injury are in part attributed to direct repression of the pro-apoptotic genes Bak1 and Klf13 in CMs (Figure D). In conclusion, these findings reveal pivotal roles for miR-125a and miR-125b as important regulators of CM survival during cardiac injury.
Abstract 6: Computationally assisted target screening of STING agonist for immunologic therapy
Authors: Grace A. Binder, Christine S. Gambino, Anna Kharitonova, Rainer S. Metcalf, Kenyon G. Daniel, Wayne C. Guida
Journal: Cancer Research (2019)

Abstract Stimulator of interferon genes (STING) is a receptor protein involved in the propagation of innate immune sensing of cytosolic DNA through the production of IFN-β. Mechanistic studies have shown IFN-β production within the tumor microenvironment can result in activation of tumor antigen-specific CD8+ T-cell immunity that can lead to tumor regression [1, 2]. STING activation by STING agonists should result in innate T-cell mediated anti-tumor immunity in the tumor microenvironment and have significant potential as a cancer therapeutic. Conversely, inhibition of STING would lead to a decreased production of IFN-β which could have implications in the treatment of autoimmune disease such as lupus erythematosus. MD equilibrated crystal structures for human HAQ, REF, and WT alleles were clustered to find optimal conformations for diverse chemical library screening. Novel consensus docking protocols utilizing rigid receptor, induced fit, and quantum polarized ligand docking were applied for quantifying and refining proposed binding mechanisms of STING isoforms. Models for STING agonists and antagonists were developed. From directed virtual screening, a novel low-molecular-weight organic molecule (GF3-002) that is not based on a cyclic dinucleotide was found as a potential STING activator and is currently under investigation. GF3-002 and analogs were synthesized and structures were confirmed with LCMS and proton NMR. Both the HAQ and WT alleles, representing 78.3% of the human population were tested against compounds and controls. 2,3-cGAMP and DMSO were used as positive and negative controls, respectively. Microscale thermophoresis and SPR confirmed binding of GF3-002 to WT STING CTD with a kD of 3.2 ± 1.7 μM. IFN-dependent luciferase expression was measured by luminescence in THP-1 monocytic leukemia cells and found an EC50 of 29 ± 1.6 μM, compared to the native ligand 2,3-cGAMP EC50 of 42 ± 4.1 μM. Finally, qPCR was used quantify production of IFN-β via treatment of dendritic cells with GF3-002. 1. Sali, Characterization of a Novel Human-Specific STING Agonist that Elicits Antiviral Activity Against Emerging Alphaviruses. 2017. 2. Corrales, L., et al., Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell reports, 2015. 11(7): p. 1018-1030. Citation Format: Grace A. Binder, Christine S. Gambino, Anna Kharitonova, Rainer S. Metcalf, Kenyon G. Daniel, Wayne C. Guida. Computationally assisted target screening of STING agonist for immunologic therapy [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 6.
Abstract 993: Chemotherapy enhances exosome secretion via upregulation of cholesterol metabolism in acute myeloid leukemia
Authors: Chang-Sook Hong, Emily J. Jeong, Beatrice Razzo, Michael Boyiadzis, Theresa L. Whiteside
Journal: Cancer Research (2019)

Abstract Therapies for Acute Myelogenous Leukemia (AML) have not been successful largely due to disease recurrence after chemotherapy. Recent studies showed that exosomes play a significant role in leukemia chemo-resistance. Levels of exosomes in patients’ plasma are elevated at AML diagnosis relative to those in normal donors’ plasma and remain elevated when patients reach complete remission (CR). These exosomes carry immunosuppressive molecules, interfere with anti-leukemia immunity and promote blast chemoresistance. We hypothesized that the development of methods for blocking exosome secretion could benefit AML patients. To understand the mechanisms of enhanced exosome secretion in AML blasts, we focused on cholesterol synthesis in blasts and its relationship to exosome secretion. Cholesterol metabolism in AML cell lines after treatment of chemotherapeutic agents (cytarabine and decitabine) was shown to enhance (p&amp;lt;0.005) intracellular level of cholesterol and the expression of HMGCR (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase), the rate-limiting enzyme in cholesterol synthesizing mevalonate pathway. Consequently, the production of exosomes in the cell culture supernatants increased (p&amp;lt;0.02). Treatment with an HMGCR inhibitor, simvastatin, or siRNAs targeting HMGCR blocked (p&amp;lt;0.02) the chemotherapy- induced enhancement of exosome production. Exosomes carry HMGCR and chemotherapy enhanced HMGCR levels on exosomes. Our results show that chemotherapy enhances exosome secretion by increasing cholesterol synthesis in leukemic blasts. A pharmacologic blockade of HMGCR with simvastatin emerges as a potential future therapeutic for exosomes in AML. Note: This abstract was not presented at the meeting. Citation Format: Chang-Sook Hong, Emily J. Jeong, Beatrice Razzo, Michael Boyiadzis, Theresa L. Whiteside. Chemotherapy enhances exosome secretion via upregulation of cholesterol metabolism in acute myeloid leukemia [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 993.
Abstract 5048: Determination of haptoglobin, hemoglobin genotypes and malaria incidence in Nigerian breast cancer patients
Authors: Titilope M. Dokunmu, Patience Obi, Oluwakemi A. Rotimi, Omolara A. Fatiregun, Sulaiman O. Agodirin, Solomon O. Rotimi
Journal: Cancer Research (2019)

Abstract Breast cancer is the second leading cause of cancer morbidity and mortality globally. Cancer chemotherapy commonly result in hemolysis, which impacts patient overall health. There is a need to determine genetic factors associated with hemolysis in breast cancer patients. Haptoglobin (Hp), a polymorphic protein plays important role in hemoglobin clearance and disease predisposition, but has been reported to have no prognostic factor in breast cancer. However, understanding selection pressure that drives certain gene mutations in specific populations and how it confers protection or susceptibility to diseases is crucial. In Nigeria, breast cancer, malaria infection and sickle cell disease are prevalent and associated with hemolysis, but little is known of their association in breast cancer patients. This study aims to determine relationship between haptoglobin, hemoglobin genotypes and submicroscopic malaria co-morbidity in clinically diagnosed breast cancer and healthy Nigerian women. DNA was extracted from blood using standard methods. Haptoglobin 2 and hemoglobin genotypes were detected by RFLP-PCR, while Plasmodium falciparum infection was detected by primer specific amplification of plasmodium cytochrome oxidase III gene (cox III) in 75 clinically diagnosed breast cancer (BC) and 287 healthy women (control; HC). Proportions were determined and compared in the two groups and test of association was carried out with significance level set at P &amp;lt;0.05. In BC groups, 3 (4.1%) of 72 Hp 2-2 phenotypes was detected compared to a significantly higher occurrence of 48 (16.7%) of 287 in HC group (p &amp;lt;0.05). Conversely, malaria infection was detected in 68 (94.4%) BC versus 255 (88.9%) in HC group. A similar proportion had Hp deletions (2 in BC and 8 in HC group). There was a low prevalence of hemoglobin S genotype in the entire population and relative risk for Hp 2-2 polymorphism in hemoglobin genotypes was not significantly different. In conclusion, this study reports in breast cancer and healthy women an inverse correlation of haptoglobin (Hp2-2) genotype with malaria incidence in southwest Nigeria. The results imply a possible protection against hemolysis and can play significant role in determining choice of cancer therapy for good patient treatment outcomes. Citation Format: Titilope M. Dokunmu, Patience Obi, Oluwakemi A. Rotimi, Omolara A. Fatiregun, Sulaiman O. Agodirin, Solomon O. Rotimi. Determination of haptoglobin, hemoglobin genotypes and malaria incidence in Nigerian breast 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 5048.
Abortion: AMA sues over North Dakota law, saying it forces physicians to lie
Authors: Owen Dyer
Journal: BMJ (2019)

The American Medical Association, normally known for steering clear of politics, has waded into the abortion debate with a lawsuit challenging North Dakota’s abortion law, arguing that it “unconstitutionally forces physicians to act as the mouthpiece of the state.”

The suit targets one new law and one older one. The new law requires doctors to tell pregnant patients that medication abortions, using a combination of mifepristone and misoprostol, can be reversed. That is “a patently false and unproven claim unsupported by scientific evidence,” the AMA alleges in its legal complaint.1

The existing North Dakota law requires …
Abstract 15292: Quantitative Waveform Measures Predict Survival From Out-of-hospital Cardiac Arrest Independent of Prior Cardiovascular Disease
Authors: Michiel Hulleman, Marieke T Blom, David D Salcido
Journal: Circulation (2015)

Introduction: Quantitative waveform measures (QWM) of ventricular fibrillation (VF) can predict survival from out-of-hospital cardiac arrest (OHCA). However, cardiovascular disease (CVD) can change QWM as well as outcome from OHCA. We assessed the hypothesis that risk factors for and the presence of CVD were associated with changes in VF amplitude spectrum area (AMSA) and survival from OHCA. Methods: Data from ARREST, a registry of all OHCAs in North-Holland, the Netherlands, were used. Medical history was collected from the general practitioner using a questionnaire. AMSA was calculated for the first artifact free VF segment (mean segment duration 4.8 sec, sample frequency 125 Hz) and prior to every shock. Linear regression was used to assess the association between AMSA, risk factors and CVD, adjusting for resuscitation characteristics. Logistic regression was used to associate AMSA, resuscitation characteristics, risk factors and CVD with survival to hospital discharge. Results: We included 693 patients with an OHCA between 2006 and 2010, available medical history and VF on ECG recording with AED (n=163) or manual defibrillator (n=530), receiving a total of 2675, median 3 defibrillation shocks. Time from EMS call to first rhythm recording was median (IQR) 8.8 min (5.7-11.6), and 295 patients survived to hospital discharge (43%). Mean AMSA for the first analyzable segment was 12.7 (±16.0) mV-Hz, significantly lower for cardiomyopathy and obesity, and higher for known familial sudden cardiac death (SCD) (Table 1). Higher AMSA per mV-Hz increase (adjusted for resuscitation characteristics, risk factors and CVD) was significantly associated with higher survival to discharge (OR 1.04; 95% CI 1.02-1.06; P&lt;0.001). Conclusions: Changes in AMSA due to reported CVD and risk factors are of small magnitude. AMSA remains an independent predictor of survival to hospital discharge, even when adjusting for resuscitation characteristics, risk factors and CVD.
Use of direct cholangiopancreatoscopy to identify pancreaticobiliary fistula
Authors: Nathaniel Avila, Paul Tarnasky, Prashant Kedia
Journal: Endoscopy (2019)

Direct cholangiopancreatoscopy for the diagnosis of a pancreaticobiliary fistula is infrequently reported [1] [2]. We report the case of a 70-year-old man who presented with cholangitis. A magnetic resonance cholangiopancreatography revealed a complex 6.6 cm cystic mass in the pancreatic head and neck, inseparable from the dilated main pancreatic duct (PD), and a possible fistulous connection between the common bile duct (CBD) and main PD ([Fig. 1], [Video 1]).
Horizontal Transfer of Bacterial Cytolethal Distending Toxin B Genes to Insects
Authors: Kirsten I Verster, Jennifer H Wisecaver, Marianthi Karageorgi, Rebecca P Duncan, Andrew D Gloss, Ellie E Armstrong, Donald K Price, Aruna R Menon, Zainab M Ali, Noah K Whiteman
Journal: Molecular Biology and Evolution (2019)

Abstract Horizontal gene transfer events have played a major role in the evolution of microbial species, but their importance in animals is less clear. Here, we report horizontal gene transfer of cytolethal distending toxin B (cdtB), prokaryotic genes encoding eukaryote-targeting DNase I toxins, into the genomes of vinegar flies (Diptera: Drosophilidae) and aphids (Hemiptera: Aphididae). We found insect-encoded cdtB genes are most closely related to orthologs from bacteriophage that infect Candidatus Hamiltonella defensa, a bacterial mutualistic symbiont of aphids that confers resistance to parasitoid wasps. In drosophilids, cdtB orthologs are highly expressed during the parasitoid-prone larval stage and encode a protein with ancestral DNase activity. We show that cdtB has been domesticated by diverse insects and hypothesize that it functions in defense against their natural enemies.
Endoscopic submucosal dissection of a laterally spreading tumor in the right colon with a gastroscope after shortening the colon using a new double-balloon platform
Authors: Jérémie Jacques, Jérémie Albouys, Anne Guyot, Sophie Geyl, Romain Legros, Ulriikka Chaput, Mathieu Pioche
Journal: Endoscopy (2019)

Endoscopic submucosal dissection (ESD) allows en bloc resection of large superficial lesions in the gastrointestinal tract. Although ESD is frequently used in the rectum, esophagus, and stomach, it is only performed in the colon by high-volume experts, owing to the difficulty resecting lesions in this location [1]. This location is technically challenging due to bowel movements, poor scope maneuverability due to loops, and thinness of the submucosal space and the muscular layer. Poor scope maneuverability is one of the most important risk factors for failure of colonic ESD and colon perforation.
Abstract 39: Microvessel-on-a-chip for investigating glioma-vascular interactions
Authors: Magda Gerigk, Harry J. Bulstrode, Yan Yan Shery Huang
Journal: Cancer Research (2019)

Abstract Introduction: Gliomas, which are heterogeneous tumors made up of malignant glial and stromal cells, can often grow and progress without angiogenesis and thus escape anti-angiogenic therapies. One of the alternative mechanisms of tumor blood supply is vessel co-option, where cancer cells migrate along the pre-existing vessel of the host organ, preserving the blood-brain barrier (BBB). However, studying this phenomenon is currently limited mainly to animal models. With the push to reduce in vivo approaches, developing an experimental, organ-on-a-chip model to encompass one or more tractable microenvironmental factors, will enable us to better understand their mechanistic roles in brain tumor progression. Methods and Results: An extracellular matrix-integrated PDMS-based microfluidic chip with a rounded microvessel, mimicking the BBB, was generated using a human microvascular cell line (hCMEC/D3), in the presence of flow. In the chip, a vessel of ~100µm diameter was interfaced with a 3D brain cancer cell culture (either U87, glioma neural stem or normal neural stem cell, embedded in a collagen-based ECM). The system was coupled with live-cell imaging and image analysis, which enabled tracking of cell-cell and cell-microenvironment interactions. Changes in gene expression and protein distribution in endothelial cells were successfully quantified, thus enabling the characterization of the influence of cancer cells population on the microvessel. Conclusions: Development and optimization of the novel device has given us the opportunity to study the influence of glioma cells on normal brain endothelium, when agiogenesis does not occur. Crucially, this can be done in controlled, user-defined environment (i.e. choice of ECM components and stiffness, microvessel size and flow rate) unlike in animal models. Note: This abstract was not presented at the meeting. Citation Format: Magda Gerigk, Harry J. Bulstrode, Yan Yan Shery Huang. Microvessel-on-a-chip for investigating glioma-vascular interactions [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 39.
Abstract 16409: Potential Role for βArrestins in Cardiac Regeneration
Authors: Anna M Gumpert, Mai Chen, Henriette Brinks, Karsten Peppel, Erhe Gao, Walter J Koch
Journal: Circulation (2012)

Development of chronic heart failure (HF) syndrome following myocardial injury (MI) is characterized by an extensive loss of myocytes due to considerable apoptosis and necrosis. As bone marrow deri...
Wide Interest in a Vitamin C Drug Cocktail for Sepsis Despite Lagging Evidence
Authors: Rita Rubin
Journal: JAMA (2019)

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