tbuckley/cabot-search huggingface dataset:
Abstract 413: Emerging principles in synthetic lethality in glioblastoma
Authors: Pia Hoellerbauer, Sonali Arora, Megan Kufeld, Lucas Carter, Emily J. Girard, Heather Feldman, Philip Corrin, James M. Olson, Patrick J. Paddison
Journal: Cancer Research (2018)

Abstract Synthetic lethality occurs when mutations in two otherwise nonessential genes are combined to cause lethality. Because cancer is a disease of genetic alteration, synthetic lethality has been heralded as a method to identity candidate therapeutic targets, e.g., where a target gene could be "synthetic lethal" with a cancer driver mutation. To define synthetic lethal relationships in glioblastoma (GBM), we have performed multiple focused-set and genome-wide CRISPR-Cas9 lethality screens in patient-derived GBM stem-like cells (GSCs) and nontransformed human neural progenitor cells. Because GSCs isolates likely represent a sub-clone of the original tumor and we can determine GSCs' genetic and epigenetic makeup, it is possible to address the concept of synthetic lethality for GBM. To this end, we recently performed comprehensive CRISPR-Cas9 retests of all scoring GBM lethal genes (&amp;gt;900) from screens in three patient isolates with different and overlapping genetic drivers. We then performed secondary retests of high-priority gene targets in 13 GSC harboring various alterations commonly found in GBMs, e.g., EGFRamp, NF1mut, PIK3CAmut, PTENloss/mut, TP53mut, etc. The results were surprising, first in what we did not find. We failed to find synthetic lethal targets for TP53loss/mut, RB1mut, or TERT expression, suggesting that synthetic lethal relationships for these alterations may not exist for GBM. Second, NF1mut interactors defined a broader class of synthetic lethal targets with general overactivity of the RTK/Ras pathway, which can arise from various activating lesions. Third, candidate synthetic lethal relationships can be observed, but, so far, only with EGFRamp, MYC/MYCNamp, and PTEN/PIK3CA alterations. Thus, in general our results suggest that the majority of synthetic lethal relationships in GBM arise from oncogenic activation of the RTK/Ras and PI-3 kinase pathway or amplification of MYC/MYCN. (Synthetic lethal targets will be revealed and discussed at the meeting.) Citation Format: Pia Hoellerbauer, Sonali Arora, Megan Kufeld, Lucas Carter, Emily J. Girard, Heather Feldman, Philip Corrin, James M. Olson, Patrick J. Paddison. Emerging principles in synthetic lethality in glioblastoma [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 413.
Cardiac Myosin Binding Protein C
Authors: SaulWinegrad
Journal: Circulation Research (1999)

Abstract—Myosin binding protein C (MyBP-C) is one of a group of myosin binding proteins that are present in the myofibrils of all striated muscle. The protein is found at 43-nm repeats along 7 to 9 transverse lines in a portion of the A band where crossbridges are found (C zone). MyBP-C contains myosin and titin binding sites at the C terminus of the molecule in all 3 of the isoforms (slow skeletal, fast skeletal, and cardiac). The cardiac isoform also includes a series of residues that contain 3 phosphorylatable sites and an additional immunoglobulin module at the N terminus that are not present in skeletal isoforms. The following 2 major functions of MyBP-C have been suggested: (1) a role in the formation of the sarcomeric myofibril as a result of binding to myosin and titin and (2) in the case of the cardiac isoform, regulation of contraction through phosphorylation. The first is supported by the demonstrated effect of MyBP-C on the packing of myosin in the thick filament, the coincidence of appearance...
Intermittent Parasystole—Mechanism of Protection
Authors: Howardcohen, Richardlangendorf, Alfredpick
Journal: Circulation (1973)

Analysis of ten cases of intermittent ventricular parasystole suggested temporary loss of protection of the parasystolic focus resulting in discharge and resetting of the parasystole by sinus or other supraventricular beats. Parasystolic centers appear to be protected from supraventricular and other ventricular ectopic impulses early in their cycle by their refractory periods, and late in the cycle by diastolic depolarization. Between these two areas of protection is a period of susceptibility during which supraventricular beats can discharge the parasystolic focus. This phenomenon accounted for fixed coupling of the first parasystolic beat of a series to a preceding sinus beat. Under certain conditions all parasystolic beats may have such fixed coupling, a new and previously unconsidered mechanism for parasystole with fixed coupling. In one case of intermittent ventricular parasystole, the parasystole was shown to originate in the posterior fascicle of the left bundle branch on the basis of the shape...
Temporal Trends in Survival to Adulthood Among Patients Born With Congenital Heart Disease From 1970 to 1992 in Belgium
Authors: PhilipMoons, LoreBovijn, WernerBudts, AnnBelmans, MarcGewillig
Journal: Circulation (2010)

Background—Over the past decades, the life expectancy of individuals with congenital heart disease (CHD) has increased significantly. However, precise estimates for survival to adulthood are scarce for patients with CHD. We investigated the proportion of CHD patients born between 1990 and 1992 who survived into adulthood. We also compared their survival with that of CHD patients born in earlier eras and evaluated survival as a function of the type of heart defect. Methods and Results—We reviewed the CHD program administrative and clinical database at the University Hospitals Leuven (Leuven, Belgium) and analyzed the records of 7497 CHD patients born from 1970 to 1992. Survival to 18 years of age in patients born between 1990 and 1992 was 88.6% (95% confidence interval [CI], 86.3% to 90.5%), which was significantly greater than that of patients born in previous decades (P<0.0001). For patients born between 1990 and 1992, survival into adulthood for those with mild heart defects was 98.0% (95% CI, 95.8% to ...
Abstract 2837: Single-cell heterogeneity with transcriptional memory confers resistance to cancer therapy
Authors: Sydney Shaffer, Benjamin Emert, Arjun Raj
Journal: Cancer Research (2018)

Abstract Targeted therapies for cancer are a promising class of drugs that inhibit the specific molecular alterations that underlie the uncontrolled proliferation seen in cancer. The primary shortcoming of targeted therapy is disease relapse, which is driven by a subpopulation of cells that are resistant to these drugs. This phenomenon is generally thought to be genetic in origin; however, our recent work on melanoma shows that nongenetic cellular plasticity may provide a mechanism of resistance to these therapies. Furthermore, we showed that through the addition of the drug itself, cells transition from this transient plasticity into a new, stably resistant cell state via cellular reprogramming, suggesting that the time an individual cell exists in a state is important for producing the divergent resistance phenotype. However, there are currently no methods available to quantify the timescale of these fluctuations for the whole transcriptome. Thus, broadly generalizing this concept of timescales for cellular plasticity, we developed a novel method for genome-wide quantification of the timescales of gene expression memory based on a modern version of the ingenious Luria-Delbrück fluctuation analysis. Specifically, we isolated individual cells, allowed them to expand, and then performed RNA sequencing on each of the samples. For genes with uniform expression, all the samples should have similar RNA sequencing counts; however, for genes that occasionally turn on in a subset of cells, the RNA sequencing counts across all samples should show high variance. In melanoma, this method revealed the gene expression state of rare cells resistant to targeted therapy. In a completely new model, triple-negative breast cancer, this method revealed a novel rare subpopulation of cells exhibiting resistance to chemotherapy. More generally, this method has the potential to reveal other new phenotypes associated with rare cell biology, including metastasis and the early stages of stem cell differentiation. Citation Format: Sydney Shaffer, Benjamin Emert, Arjun Raj. Single-cell heterogeneity with transcriptional memory confers resistance to cancer therapy [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 2837.
Abstract 120: Local immune cytolytic activity stratifies clinical outcome and is linked to the immune microenvironment in breast cancer
Authors: Tstutomu Kawaguchi, Qianya Qi, Xuan Peng, Kerry-Ann McDonald, Sumana Narayanan, Jessica Young, Song Liu, Li Yan, Kazuaki Takabe
Journal: Cancer Research (2018)

Abstract Purpose: Although a recent genomic landscape study identified molecular and genetic signatures of immune cytolytic activity (CYT) related to immune-mediated cancer elimination, less is known about the clinical relevance of CYT in the tumors linked to immune microenvironment in breast cancer. The aim of our study was to assess whether intratumor CYT associates with genetic alterations and tumor immune microenvironment, which impacts survival in breast cancer patients. Experimental Design: We utilized genomic data from primary samples of 1,090 breast cancer patients with clinicopathologic information from The Cancer Genome Atlas (TCGA). We developed an immunogenomics pipeline that correlates CYT with clinical outcome and intratumor immune microenvironment, including infiltrating immune cell composition. Results: Breast cancer displays a range of intratumor CYT. Patients with high CYT showed significantly better prognostic outcome, independent of age, hormonal status, and stage. CYT also has a strongly positive association with the expression of immune checkpoint genes such as PD1, PD-L1, and CTLA4, as well as regulatory T-cell (Treg) markers such as FOXP3 and CCR4. Enrichment of immune-response gene sets was observed in the high-CYT tumors. CYT was associated with higher composition of immune-elimination cells such as CD8+ T-cell, CD4+ T-cell, gamma delta T-cell, and M1 macrophage, as opposed to negatively associated with immunosuppressive cells, such as Treg and M2 macrophage. High CYT was also associated with improved survival in tumor-infiltrating lymphocyte (TIL)-positive breast cancer. Conclusions: Patients with high CYT breast cancers show improved survival, likely due to high intratumor immunogenicity. CYT could also be used as a potential biomarker for immunologic response within tumors. Citation Format: Tstutomu Kawaguchi, Qianya Qi, Xuan Peng, Kerry-Ann McDonald, Sumana Narayanan, Jessica Young, Song Liu, Li Yan, Kazuaki Takabe. Local immune cytolytic activity stratifies clinical outcome and is linked to the immune microenvironment in breast cancer [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 120.
Nitric Oxide Enhances Angiogenesis via the Synthesis of Vascular Endothelial Growth Factor and cGMP After Stroke in the Rat
Authors: RuilanZhang, LeiWang, LiZhang, JieliChen, ZhenpingZhu, ZhenggangZhang, MichaelChopp
Journal: Circulation Research (2003)

We investigated the effects of NO on angiogenesis and the synthesis of vascular endothelial growth factor (VEGF) in a model of focal embolic cerebral ischemia in the rat. Compared with control rats, systemic administration of an NO donor, DETANONOate, to rats 24 hours after stroke significantly enlarged vascular perimeters and increased the number of proliferated cerebral endothelial cells and the numbers of newly generated vessels in the ischemic boundary regions, as evaluated by 3-dimensional laser scanning confocal microscopy. Treatment with DETANONOate significantly increased VEGF levels in the ischemic boundary regions as measured by ELISA. A capillary-like tube formation assay was used to investigate whether DETANONOate increases angiogenesis in ischemic brain via activation of soluble guanylate cyclase. DETANONOate-induced capillary-like tube formation was completely inhibited by a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). Blocking VEGF activity by a n...
Trends over time in Escherichia coli bloodstream infections, urinary tract infections, and antibiotic susceptibilities in Oxfordshire, UK, 1998–2016: a study of electronic health records
Authors: Karina-Doris Vihta, Nicole Stoesser, Martin J Llewelyn, T Phuong Quan, Tim Davies, Nicola J Fawcett, Laura Dunn, Katie Jeffery, Chris C Butler, Gail Hayward, Monique Andersson, Marcus Morgan, Sarah Oakley, Amy Mason, Susan Hopkins, David H Wyllie, Derrick W Crook, Mark H Wilcox, Alan P Johnson, Tim E A Peto, A Sarah Walker
Journal: The Lancet Infectious Diseases (2018)
Traumatic Brain Injury and Risk of Suicide
Authors: Lee Goldstein, Ramon Diaz-Arrastia
Journal: JAMA (2018)

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Abstract 1599: Capture of tumor cells in blood with "Universal CTC-chip"
Authors: Kazue Yoneda, Taiji Kuwata, Fumihiro Tanaka
Journal: Cancer Research (2018)

Abstract Background: Circulating tumor cells (CTCs) are not only a surrogate of distant metastasis, but also useful for material of liquid biopsy. "Universal" CTC-chip is a polymeric microfluidic device that can capture CTCs according to their surface marker from whole blood. We have examined the capture efficiency of lung cancer and mesothelioma cells in the blood with CTC-chip coated with antibodies against various surface marker. Methods: Lung cancer cell lines (PC-9) or mesothelioma cell lines (ACC-MESO-4, MSTO-211H) were used in this study. Cells were CFSE-labeled and added in the blood of healthy donor. A polymeric CTC-chip was coated with two steps: base- and capture-antibody. As capture antibody, we used anti-EpCAM, podoplanin, and EGFR antibody. After flowing these samples, capture efficiency was calculated (number of captured cells/number of flowed cells). Results: Capture efficiency of PC-9, MESO-4, and METO-211H was 100.0%, 9.5% and 9.1% (EpCAM-chip; anti-EpCAM antibody clone HEA125); 5.8%, 85.9% and 9.0 % (podoplanin-chip; anti-podoplanin antibody clone E1); 38.6, 112.5%, 11.7% (podoplanin-chip; anti-podoplanin antibody clone NZ-1); 30.2%, 21.8%, 38.5% (EGFR-chip; anti-EGFR antibody clone 528), respectively. Conclusion: Using "Universal CTC-chip" with various antibodies, it was possible to capture nonepithelial tumor cells such as mesothelioma cells. Citation Format: Kazue Yoneda, Taiji Kuwata, Fumihiro Tanaka. Capture of tumor cells in blood with "Universal CTC-chip" [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 1599.
Abstract 13333: Restrictive Lung Function is Related to Sympathetic Hyperactivity in Patients With Chronic Heart Failure
Authors: Shuji Joho, Ryuichi Ushijima, Takashi Akabane, Tadakazu Hirai, Hiroshi Inoue
Journal: Circulation (2015)

Introduction: Sympathoexcitation and impaired lung function are common characteristics of patients with severe heart failure (HF). However, whether impaired lung function is associated with sympathoexcitation independently of HF severity remains unknown. Hypothesis: We postulated that impaired lung function itself is associated with sympathetic overactivation independently of HF severity. Methods: Muscle sympathetic nerve activity and clinical variables were determined in 83 HF patients with left ventricular ejection fraction (LVEF) &lt; 0.45. Abnormal spirometric findings with restrictive and obstructive changes were defined as reduced forced vital capacity (%FVC) &lt; 80% and a ratio of forced expiratory volume in the first second to FVC (FEV1.0%) &lt; 70%, respectively. Results: Restrictive and obstructive changes were identified in 17 and 21 patients, respectively. Muscle sympathetic nerve activity was higher in patients with, than without restrictive changes (p&lt;0.01), but comparable in those with or without obstructive changes. Univariate analyses showed that %FVC, glomerular filtration rate, specific activity scale, brain natriuretic peptide level, LVEF, age and use of aldosterone receptor blockers were significant predictors of burst incidence. Multivariate analysis revealed that %FVC, LVEF and glomerular filtration rate were common independent factors of increased burst rate and burst incidence. Changes in %FVC during follow-up negatively correlated with changes in burst rate (n=11, p&lt;0.01). Conclusions: Restrictive lung function is associated with increased sympathetic nerve activity independently of HF severity.
Abstract 1447: Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma
Authors: Edwin J. Ostrin, Johannes F. Fahrmann, Ichidai Tanaka, Muge Celiktas, Clemente Aguilar, Mitzi Aguilar, Jennifer B. Dennison, Eunice Murage, Satyendra C. Tripathi, Oliver Delgado, Hong Wang, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio I. Wistuba, Ayumu Taguchi, Samir M. Hanash
Journal: Cancer Research (2018)

Abstract Low tryptophan levels promote tumor immune evasion by suppressing immune function. Elucidation of the immunomodulatory effects of altered tryptophan catabolism has relevance to cancer immunotherapy. Previous studies have largely focused on the role of the rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan depletion in the microenvironment. However, IDO1 levels are highly heterogeneous in different cancers, and numerous other downstream tryptophan catabolites have also been shown to have immunomodulatory activity. We surveyed the proteomes of 123 cancer cell lines for regulators of tryptophan metabolism which revealed overexpression of kynureninase (KYNU) in KEAP1 mutant lung adenocarcinomas. Functional analysis indicated that KYNU expression is regulated through nuclear factor, erythroid 2-like (Nrf2) activation. KYNU-high cell lines exhibited increased secretion of KYNU-derived anthranilate/3-hydroxyanthranilate. Ex-vivo studies using isolated PBMCs demonstrated that 3-hydroxyanthranilate reduced CD8+ T-cell viability. KYNU mRNA expression in three independent datasets of lung adenocarcinomas and additionally KYNU protein expression in lung adenocarcinoma tissue microarrays revealed that high KYNU expression predicts poor survival and disease recurrence. Our findings indicate that KYNU promotes immune suppression and is an independent prognostic marker for lung adenocarcinoma. Citation Format: Edwin J. Ostrin, Johannes F. Fahrmann, Ichidai Tanaka, Muge Celiktas, Clemente Aguilar, Mitzi Aguilar, Jennifer B. Dennison, Eunice Murage, Satyendra C. Tripathi, Oliver Delgado, Hong Wang, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio I. Wistuba, Ayumu Taguchi, Samir M. Hanash. Aberrant tryptophan catabolism marked by high kynureninase expression contributes to immunosuppression and poor outcome in lung adenocarcinoma [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 1447.
Intramolecular Interaction of SUR2 Subtypes for Intracellular ADP-Induced Differential Control of KATP Channels
Authors: KenjiMatsushita, KengoKinoshita, TetsuroMatsuoka, AkikazuFujita, TakashiFujikado, YasuoTano, HarukiNakamura, YoshihisaKurachi
Journal: Circulation Research (2002)

ATP-sensitive K+ (KATP) channels are composed of sulfonylurea receptors (SURs) and inwardly rectifying Kir6.2-channels. The C-terminal 42 amino acid residues (C42) of SURs are responsible for ADP-induced differential activation of KATP channels in SUR-subtypes. By examining ADP-effect on KATP channels containing various chimeras of SUR2A and SUR2B, we identified a segment of 7 residues at central portion of C42 critical for this phenomenon. A 3-D structure model of the region containing the second nucleotide-binding domain (NBD2) of SUR and C42 was developed based on the structure of HisP, a nucleotide-binding protein forming the bacterial Histidine transporter complex. In the model, the polar and charged residues in the critical segment located within a distance that allows their electrostatic interaction with Arg1344 at the Walker-A loop of NBD2. Therefore, the interaction might be involved in the control of ADP-induced differential activation of SUR2-subtype KATP channels.
Gene Therapy for Attenuating Cardiac Allograft Arteriopathy Using Ex Vivo E2F Decoy Transfection by HVJ-AVE–Liposome Method in Mice and Nonhuman Primates
Authors: MotohiroKawauchi, Jun-ichiSuzuki, RyuichiMorishita, YukoWada, AtsushiIzawa, NaruyaTomita, JunAmano, YasufumiKaneda, ToshioOgihara, ShinichiTakamoto, MitsuakiIsobe
Journal: Circulation Research (2000)

Abstract—Cardiac allograft arteriopathy, which limits the long-term survival of recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. The transcription factor E2F plays a pivotal role in the coordinated transcription of cell-cycle regulatory genes. To test the hypothesis that double-stranded DNA with specific affinity for E2F (E2F decoy) is effective in preventing intimal hyperplasia, we performed ex vivo single intraluminal delivery of E2F decoy into cardiac allografts of mice and Japanese monkeys using the hemagglutinating virus of Japan (HVJ) artificial viral envelope–liposome method. In murine models, antisense cyclin-dependent kinase 2 (cdk2) kinase oligodeoxynucleotide (ODN) and no transfers were performed to compare the effects. Severe intimal thickening was observed, and multiple cell-cycle regulatory genes were enhanced in untreated allografts. E2F decoy prevented neointimal formation and suppressed these genes for up to 8 weeks, whereas antisen...