tbuckley/cabot-search huggingface dataset:
Abstract 5372: The mutational landscape of primary cutaneous melanoma
Authors: Sofia Y. Chen, Rashid Mamunur, Jon Laye, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams
Journal: Cancer Research (2018)

Abstract Large-scale melanoma genome profiling studies to date have mainly focused on metastatic tumors. To better understand the link between genomic changes and outcome, primary tumors must be studied. We have designed a comprehensive targeted genomic panel to study genetic alterations in melanoma, and applied this to a large collection of 536 primary melanomas, part of the Leeds Melanoma Cohort. Patients were invited to participate 3 months after diagnosis of primary melanoma. 1% received targeted therapies or immunotherapy and thus, our analysis is reflective of the landscape of primary melanoma in the treatment naïve setting. The sequencing panel allowed us to study genetic alterations in over 500 genes, including more than 150 genes frequently mutated in melanoma and an additional 250 genes linked to other solid tumor types. Both tumor and germline DNA were analyzed for most samples. The average somatic mutation rates we observed was 15 mutations/MB (0 to 236 mutations/MB), while the nonsynonymous mutational load ranged from 0 to 57 mutations/MB (average 4 mutations/MB). We found that a high mutational burden (highest 20%, &amp;gt;45 nonsynonymous mutations/Mb) positively correlated with better survival (Cox proportional hazards model with age, sex and AJCC stage as additional covariates). Among the top recurrently mutated genes were well established melanoma driver genes such as BRAF (44%), NRAS (28%), NF1 (10%), CDKN2A (15%), TP53 (11%) and ARID2 (8%). We also found hotspot mutations in less well documented melanoma genes, including RQCD1 p.P131L (4.5%). Altogether, our preliminary data shows a strong correlation between survival and high mutational load in primary melanomas. Our data also suggests a similar landscape of driver mutations in primary and metastatic melanoma, with some variants/genes possibly reflecting the differences in disease stage. We will further investigate the mutational landscape in our cohort of primary melanomas, including analyses of gene co-occurrence and mutual exclusivity. Additionally, we will use extensive clinical parameters and transcriptomics to examine the possibility of predicting survival and other clinically relevant parameters in our cohort based on patient mutational profiles. Citation Format: Sofia Y. Chen, Rashid Mamunur, Jon Laye, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams. The mutational landscape of primary cutaneous melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5372.
Abstract 1988: The pivotal roles of adipocytes on regulation of cancer stemness and drug resistance in hepatocellular carcinoma
Authors: Shilpa Gurung, Terence Kin-Wah Lee
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is one of the deadliest cancers in the world with less than 10% 5-year survival rate. Liver cancer stem cells (CSCs) are sub-populations of the cancer cells that have been found to play a crucial role in tumor relapse and therapeutic resistance. Increasing reports showed the significant correlation between non-alcoholic fatty liver disease (NAFLD) and HCC development. Based on this evidence, we hypothesize adipocytes, one of the key cellular factors within the tumor microenvironment, play a crucial role in HCC development and progression via regulation of liver CSCs. To verify this, we have employed a co-culture system to dissect the potential cross-talk between fully differentiated adipocytes and HCC cells. Our pilot data showed that adipocytes enhanced the self-renewal ability of HCC cells through indirect paracrine secretion. Based on this finding, we examined the effect of the conditioned medium of adipocytes on regulation of liver CSC. Consistently, we found that HCC cells pre-incubated with conditioned medium of adipocytes showed enhanced in vivo tumorigenicity and chemo-resistance to doxorubicin and sorafenib. Furthermore, conditioned medium of adipocytes promoted the migration and invasion abilities of HCC cells. To delineate the molecular mechanism of how adipocytes, exert its CSC enhancing effect on HCC cells, we have collected the conditioned medium derived from adipocytes and analyzed their secretome profiles using Orbitrap Liquid Chromatography-Mass spectrometry. Upon analysis, we identified 209 proteins, among which we have focused on two proteins (CSF1 and FABP4) for further analysis as these are preferentially secreted from adipocytes. Respective inhibitors of the proteins are used to study the specificity of the protein in the medium and the downstream studied with the help of RNA sequencing which has been performed on conditioned medium treated HCC cells. Collectively, we demonstrated the pivotal role of adipocytes on regulation of liver CSCs through paracrine secretion. Thus, targeting adipocytes-derived signaling cascade may be a novel therapeutic strategy for treatment of fatty liver induced HCC. Citation Format: Shilpa Gurung, Terence Kin-Wah Lee. The pivotal roles of adipocytes on regulation of cancer stemness and drug resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1988.
Abstract 13750: Cardiac Resynchronization Therapy for Patients With Cardiac Sarcoidosis
Authors: Akinori Sairaku, Yukihiko Yoshida, Yukiko Nakano, Mayuho Maeda, Haruki Hashimoto, Haruo Hirayama, Yasuki Kihara
Journal: Circulation (2015)

Objective: Little is known about the clinical features in patients with cardiac sarcoidosis who receive cardiac resynchronization therapy (CRT). We aimed to clarify the clinical response to CRT in patients with cardiac sarcoidosis. Methods: We compared the clinical data on CRT between heart failure patients with cardiac sarcoidosis and those with other etiologies at 3 cardiovascular centers. The primary endpoint was composite outcome of cardiovascular death or hospitalization from worsening heart failure within 5 years after the CRT. Results: The patients with cardiac sarcoidosis (N=18) were more likely than those without cardiac sarcoidosis (N=141) to be female (83.3% vs. 22.7%; P&lt;0.001), and undergo an upgrade from a pacemaker or implantable cardioverter defibrillator (72.2% vs. 18.4%; P&lt;0.001). The composite outcome occurred with a similar frequency (38.9% vs. 48.2%; P=0.37). The patients with cardiac sarcoidosis were more likely than those without to have sustained ventricular arrhythmias occurring before or after the CRT (66.7% vs. 29.1%; P=0.003). The reduction in the left ventricular end-systolic volume after the CRT was significantly smaller in the patients with cardiac sarcoidosis than in those without (mean±SD, -1.5±28.7 vs. -20.1±33.7%; P=0.03). Patients with an improved clinical composite score were seen with a similar proportion (55.6% vs. 61.7%; P=0.86). Conclusions: Outcomes after the CRT may be acceptable in patients with cardiac sarcoidosis. A poor left ventricular reverse remodeling and higher occurrence of ventricular arrhythmias may characterize them.
I Have Neutropenia—What Do I Need to Know?
Authors: Arjun Gupta, Heather R. Wolfe, Howard (Jack) West
Journal: JAMA Oncology (2018)

I Have Neutropenia-What Do I Need to Know?Neutropenia means having an abnormally low number of neutrophils, a type of white blood cell that fights infection, in the blood. What Is Neutropenia?Neutropenia increases the risk of developing infections, which can become very severe.About half of all patients receiving chemotherapy develop neutropenia. What Should I Do If I Have Neutropenia?It is important to prevent infection and recognize it early if it develops.Lifestyle and diet practices help lower the risk of infection. Recognize Possible Infection and Seek Urgent HelpPatients with neutropenia should notify their cancer care team immediately and go to the nearest emergency department if they develop any of the following: • Fever that is higher than 100.4°F or 38°C taken by mouth.• Chills, sweats, or shivering.• Sore throat or painful mouth sores or ulcers.• Neck pain or a stiff neck.• Confusion or "seeming different."• Cough or shortness of breath.• Pain or burning with urination.• Red, itchy, or painful skin, especially around intravenous catheters and the rectal area.• Abdominal pain, vomiting, diarrhea, or pain with bowel movements.• Pain in or discharge from genital areas or pain during intercourse.
Ortner Syndrome Associated With Aortic Pseudoaneurysm After Repair of Aortic Coarctation 30 Years Previously
Authors: NaotoFukunaga, TadaakiKoyama, YasunobuKonishi, TakashiMurashita, MitsuruYuzaki, YuShomura, HiroshiFujiwara, YukikatsuOkada
Journal: Circulation (2012)
Abstract 11100: Difference in Clinical Characteristics, Left Atrial Reverse Remodeling and Functional Outcomes After Mitral Valve Replacement in Patients With Low-Gradient Very Severe Mitral Stenosis
Authors: In-Jeong Cho, Geu-Ru Hong, Chi Young Shim, Hyuk-Jae Chang, Jong-Won Ha, Namsik Chung
Journal: Circulation (2015)

Introduction: The discrepancy between planimetered mitral valve area (MVA) and mean diastolic pressure gradient (MDPG) has not been studied extensively in patients with mitral stenosis (MS). Hypothesis: The purpose of the current study was to investigate the difference in characteristics and outcomes after mitral valve replacement (MVR) between low and high MDPG groups in very severe MS patients. Methods: This study evaluated 140 patients who received isolated MVR due to very severe MS (planimetered MVA ≤ 1.0 cm2) and performed follow-up echocardiography at least 12 months after MVR. Patients were divided into two groups according to preoperative MDPG (Low-gradient, &lt; 10 mmHg; High-gradient, ≥ 10 mm Hg). Strain and strain rate analysis was performed using speckle tracking echocardiography before MVR in 56 patients. Results: There were 82 patients in low-gradient group and 58 patients in high-gradient group. The low-gradient group was older and demonstrated higher prevalence of female gender, diabetes mellitus, and atrial fibrillation (all p &lt;0.05). When comparing the low-gradient and high-gradient groups, the left atrial volume index was larger (LAVI, 105.1 ± 51.9 ml/m2 vs. 87.8 ± 42.9 ml/m2, p &lt; 0.001) and strain rate during isovolumic relaxation was lower (0.17 ± 0.08 s-1 vs. 0.29 ± 0.09 s-1, p &lt; 0.001) in low-gradient group. After MVR, the percentage in LAVI reduction after MVR was significantly smaller in low-gradient group (-29.9 ± 15.1% vs. -43.5 ± 16.4%, p &lt; 0.001). Persistent symptoms after MVR was more common in the low-gradient group compared to the high-gradient group (p = 0.004), even though preoperative functional class was similar between the groups. Conclusions: Low-gradient very severe MS was common in the population of high prevalence in diastolic dysfunction, such as the elderly, women, diabetes mellitus, and atrial fibrillation, was associated with impaired myocardial isovolumic relaxation, and demonstrated unfavorable left atrial reverse remodeling and a greater risk of persistent symptoms after MVR. These data might suggest the importance of concurrent management of diastolic dysfunction in low-gradient very severe MS.
Aprotinin Inhibits Plasmin-Induced Platelet Activation During Cardiopulmonary Bypass
Authors: OsamuShigeta, HiroshiKojima, TomoakiJikuya, YasushiTerada, NaotakaAtsumi, YuzuruSakakibara, ToshiroNagasawa, ToshioMitsui
Journal: Circulation (1997)

Background In the past few years, aprotinin has been used in cardiac surgery with impressive results of reducing blood loss, but several adverse effects of aprotinin also have been reported. One of the most likely mechanisms is the inhibition of plasmin by aprotinin, although this indirect effect has not been reproduced in all experimental studies. Methods and Results We evaluated the platelet function and fibrinolytic activity during human cardiac surgery, with or without aprotinin. During cardiopulmonary bypass (CPB) in humans without aprotinin (n=16), decrease of platelet aggregation induced by thrombin, increase of α-granule secretion of platelet and microparticle formation, and increase of plasmin/α2-antiplasmin complex (PIC) were observed. In contrast, low-dose aprotinin (1.0×106 KIU), which was administered only into the priming fluid of extracorporeal circuits (n=10), maintained platelet aggregation induced by thrombin and reduced α-granule secretion and microparticle formation of platelets during...
Expression and Intracellular Localization of an SCN5A Double Mutant R1232W/T1620M Implicated in Brugada Syndrome
Authors: GhayathBaroudi, SaidAcharfi, ChantalLarouche, MohamedChahine
Journal: Circulation Research (2002)

Brugada syndrome is an inherited cardiac disorder caused by mutations in the cardiac sodium channel gene, SCN5A, that leads to ventricular fibrillation and sudden death. This study reports the changes in functional expression and cellular localization of an SCN5A double mutant (R1232W/T1620M) recently discovered in patients with Brugada syndrome. Mutant and wild-type (WT) human heart sodium channels (hNav1.5) were expressed in tsA201 cells in the presence of the β1-auxiliary subunit. Patch-clamp experiments in whole-cell configuration were conducted to assess functional expression. Immunohistochemistry and confocal microscopy were used to determine the spatial distribution of either WT or mutant cardiac sodium channels. The results show an abolition of functional sodium channel expression of the hNav1.5/R1232W/T1620M mutant in the tsA201 cells. A conservative positively charged mutant, hNav1.5/R1232K/T1620M, produced functional channels. Immunofluorescent staining showed that the FLAG-tagged hNav1.5/WT tr...
Abstract 16483: Prognostic Value of Neurological Exam in Cardiac Arrest Patients Treated With Therapeutic Hypothermia in the Absence of Withdrawal of Life-sustaining Therapy
Authors: Elizabeth Matthews, Jessica Magid-Bernstein, Angela Velazquez, Cristina Falo, Soojin Park, Jan Claassen, Sachin Agarwal
Journal: Circulation (2015)

Objectives: Withdrawal of life-sustaining therapy (WLST) is the most common cause of death following cardiac arrest (CA). A well-described “self-fulfilling prophecy” exists, in which a poor exam often prompts WLST. The prognostic value of the neurological exam at various time points, in the absence of WLST, remains unknown. Methods: All patients (N=291) treated at Columbia University with therapeutic hypothermia (TH) following CA between May 2007 and February 2015 were identified. Neurological exams were documented at admission, 72 hours, five days and seven days after arrest. Glasgow coma motor scores (GCS-motor) no better than extensor posturing, bilaterally absent pupillary light response and bilaterally absent corneal reflexes were considered poor exams. Patients were excluded if the cause of death was WLST (n=125) or they died despite full support prior to 7 days (n=70). A cerebral performance score (CPC) at hospital discharge of 3-5 was considered a bad outcome. False positive rates (FPRs) in percentages were calculated. Results: A total of 96 patients were analyzed (average age 59±17 years, 40% female, 91% with pre-hospitalization CPC 1-2, bystander CPR in 69%, initial rhythm of VT/FT in 41%, mean ROSC 19±15 minutes). Sixty-one percent of patients had a poor outcome. GCS-motor was associated with a poor outcome, with FPRs of 36.3% (21-63.6), 29.4% (15.7-47.7), 11.8% (3.8-28.4) and 10.8% (3.5-26.4) at admission, 72 hours, five days and seven days respectively. Bilaterally absent corneal reflexes had FPRs of 29.2% (13.4-51.3), 26.3% (10.1-51.4), 5.3% (0.3-28.1) and 0% (0-18.5). Bilaterally absent pupillary response had the lowest FPRs at 8.3% (2.2-23.6), 0% (0-13.3), 0% (0-14.1), and 0% (0-13.7). Conclusion: A poor neurological exam remains a significant predictor of poor outcome following cardiac arrest. In the setting of TH, the pupillary exam reaches 100% specificity at 72 hours, while the GCS-motor and corneal reflex have unacceptably high rates of good outcomes despite poor exams. They become more specific over time, suggesting that patients may benefit from delaying prognostication until at least five days after arrest.
Abstract 1221: Chronic lymphocytic leukemia risk variants are associated with alteration of epigenetic states in regulatory regions
Authors: Huihuang Yan, Shulan Tian, Geffen Kleinstern, Susan Slager
Journal: Cancer Research (2018)

Abstract Chronic lymphocytic leukemia risk variants are associated with alteration of epigenetic state in regulatory regions The vast majority of disease-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWASs) reside in noncoding genomic regions. Functional impact of noncoding casual variants on target gene expression often involves regulatory mechanisms, typically through altering local chromatin accessibility, histone modifications, transcription factor (TF) binding affinity and chromatin interactions. In chronic lymphocytic leukemia (CLL), we and others have identified 41 GWAS risk variants, whose mechanism of action in CLL etiology remains largely unknown. In this study, we aim to decipher the regulatory potential of these variants and to better understand the mechanisms contributing to dysregulation of genes implicated in CLL pathogenesis. We performed ChIP-seq for H3K4me3, H3K4me1, H3K27ac and H3K27me3 in CLL. In addition, we also analyzed over 250 public ChIP-seq, ATAC-seq, DNase-seq, FAIRE-seq, and chromatin interaction data in CLL, B cells and/or lymphoblastoid cell lines. Comparing the 41 index SNPs and the nearby SNPs they associated with in linkage disequilibrium (R2 at least 0.5 in the EUR ethnic group in 1000 Genomes Project) to the above epigenetic data sets revealed overlaps with regulatory regions in 38 of the risk loci, with 28 of the loci overlapping super-enhancers. We used two approaches to elucidate the mechanisms of potential SNP causality. First, we used GATK UnifiedGenotyper to infer genotype for the SNPs that overlapped open chromatin regions and ChIP-seq peaks, by which evidence of imbalance between reference and alternative allele was identified at heterozygous sites. Second, for SNPs located within open chromatin regions or ChIP-seq peaks, we used FIMO program to scan the 100bp sequences centered on the SNPs for significant matches (p=1e-05) to the position weight matrices in five TF binding motif databases; SNPs that had TF motifs altered by the alternative alleles were retained. Together, these two approaches revealed evidence for allele imbalance or TF binding motif alterations at 36 of the 38 CLL risk loci, suggesting the generality of epigenetic regulation in CLL pathogenesis. Further analysis of chromatin interaction, gene expression and expression quantitative trait loci data will likely link the casual SNPs to their target genes. Citation Format: Huihuang Yan, Shulan Tian, Geffen Kleinstern, Susan Slager. Chronic lymphocytic leukemia risk variants are associated with alteration of epigenetic states in regulatory regions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1221.
Abstract 2363: Novel CDH1 mutations in breast invasive lobular carcinoma
Authors: Garrett M. Frampton, Ryan Hartmaier, Ethan Sokol, Anika Gupta, Joel Greenbowe, Steven Roels, Laurie Gay, Philip J. Stephens
Journal: Cancer Research (2018)

Abstract Breast invasive lobular carcinoma (ILC) is the second most common type of breast cancer, making up approximately 10% of all invasive breast cancers. Breast ILC is characterized by loss of e-cadherin protein expression (CDH1), which is usually caused by loss of function mutations in the CDH1 gene. A subset of breast ILC cases have no identifiable CDH1 mutation, but presumably inactivate CDH1 through currently unknown mechanisms. Tumors from more than 150,000 unique patients including more than 15,000 breast cancers were examined by comprehensive genomic profiling to detect base substitutions, indels, copy number alterations, and genomic rearrangements in the full coding regions of up to 465 genes. Statistical significance of the disease distributions was calculated using Fisher's exact test with false discovery rate multiple hypothesis testing correction. Of 760 breast ILC cases, 583 (76.7%) had a known loss-of-function mutation in the CDH1 gene. To identify previously unknown mutations that result in or substitute for CDH1 loss-of-function we performed statistical analysis on all mutations, in any gene, occurring more than once in the 177 ILC cases without an identifiable CDH1 mutation. The most statistically significant mutation was very near to a splice site of CDH1 (chr16:68863554 c.2296-3A&amp;gt;G), occurring in 7 CDH1 negative ILC cases as well as 9 other cases in cancer types that frequently harbor CDH1 mutations (7 breast, 2 gastroesophageal junction) and 1 colorectal cancer. Based on tumor-only test based zygosity modeling, this mutation is only observed as somatic and usually homozygous in the tumor. Four other positions near to splice sites of CDH1 (chr16:68844247 c.832+3A&amp;gt;G, chr16:68849667 c.1565+5G&amp;gt;A, chr16:68856133 c.1936+5G&amp;gt;A, chr16:68857532 c.2164+3A&amp;gt;C), mutated in 13 CDH1 negative ILC cases, were also statically significant, somatic, and usually homozygous. No statistically significant mutations were found in genes other than CDH1. Previously unappreciated somatic, non-canonical splice site mutations in CDH1 occur in ~10% (20/177) of breast ILC cases with no known CDH1 mutation. These mutations occur almost exclusively in tumor types known to harbor frequent CDH1 mutations and are usually homozygous in the tumor, strongly indicating that they are CDH1 loss-of-function mutations. Citation Format: Garrett M. Frampton, Ryan Hartmaier, Ethan Sokol, Anika Gupta, Joel Greenbowe, Steven Roels, Laurie Gay, Philip J. Stephens. Novel CDH1 mutations in breast invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2363.