tbuckley/cabot-search huggingface dataset:
Abstract 387: Glutamine metabolism reprogramming in adipocyte-tumor microenvironment promotes triple-negative breast cancer growth
Authors: Yang Liu, Tingli Zhao, Zhengzheng Li, Lai Wang, Mei Yang, Shengtao Yuan, Li Sun
Journal: Cancer Research (2018)

Abstract OBJECTIVE Adipocytes are the most abundant stromal partners in breast tissue. However, the crosstalk between breast cancer cells and adipocytes has been given less attention compared to cancer-associated fibroblasts. We try to explain whether cancer associate adipocytes (CAAs) in microenvironment can lead to metabolic remodeling of triple-negative breast cancer, promoted cancer proliferation, migration and the potential mechanism. METHOD A Transwell co-culture model in vitro and orthotopic mouse model of human breast tumor formation in vivo were used to study the crosstalk between adipocytes and breast cancer cells, and then using clinical breast cancer sample analysis to study the mechanism of glutamine reprograming. RESULTS We find that while cocultivated adipocytes with breast cancer cells, it exhibited enhanced oxygen consumption rate (OCR) and ATP, accompanied by increasing glucose and glutamine uptake. Interestingly, the metabolic way is significantly different between phenotype-specific breast cancer cells. Compared with non-triple-negative breast cancer cells, triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468) are more dependent on glutamine. We show that cancer associate adipocytes (CAAs) promote growth of breast cancer cells through key enzymes such as GLUL/GLS/GDH and transporters such as SLC1A5/SLC38A1/SLC38A2 related to glutamine metabolism in vitro. Using cytokine antibody microarrays, IL-6/IL-8/ leptin/TIPM2 is secreted by CAAs and is required to enhance breast cancer cells malignancy in vitro. Consistently, the correlation of inflammatory cytokines and adipokines with prognosis is analyzed by the Kaplan-Meier plotter, the data suggest that inflammatory cytokines and adipokines is associated with glutamine metabolism in triple-negative breast cancer microenvironment. CONCLUSIONS These results suggest that adipocytes promote proliferation of triple-negative breast cancer via metabolism reprogramming potentially by inducing inflammatory cytokines and adipokines upregulation of cancer associate adipocytes (CAAs). Citation Format: Yang Liu, Tingli Zhao, Zhengzheng Li, Lai Wang, Mei Yang, Shengtao Yuan, Li Sun. Glutamine metabolism reprogramming in adipocyte-tumor microenvironment promotes triple-negative breast cancer growth [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 387.
Abstract 5308: Using RNA expression data for splicing variant assessment and confirmation
Authors: Jim Lund, Shannon Bailey, Sharvari Gujja, Jeffrey Gulcher
Journal: Cancer Research (2018)

Abstract Nine percent of disease-causing mutations classified in HGMD have the potential to impact RNA splicing. Splicing variants called from DNA sequence data, especially variants outside the canonical splice site, are difficult to evaluate clinically as they often have no effect on protein expression. A method to utilize RNA-Seq data for splice site variant classification was developed. RNA reads aligned to the region of a splice site variant are examined to determine if RNA read through is present which indicates normal splicing at the site is disrupted. Thousands of paired tumor and normal TCGA DNA and RNA samples were used to evaluate the algorithm and rule out alternate splicing in the tissue as explanation for RNA read through. Splicing variants can also alter exon usage and RNA isoform expression, and this can be identified by examining RNA isoform expression. An analysis of splicing variants in the TCGA project datasets has generated sets of confirmed functional and non-disruptive splicing varaints. This splicing dataset can be used to test and refine splicing defect prediction algorithms. Citation Format: Jim Lund, Shannon Bailey, Sharvari Gujja, Jeffrey Gulcher. Using RNA expression data for splicing variant assessment and confirmation [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 5308.
Involvement of Cytokines in the Mechanism of Whole-Body Hyperthermia-Induced Cardioprotection
Authors: NobushigeYamashita, ShiroHoshida, KinyaOtsu, NaoyukiTaniguchi, TsunehikoKuzuya, MasatsuguHori
Journal: Circulation (2000)

Background—Hyperthermia increases cardiac tolerance to ischemia/reperfusion injury and activates manganese superoxide dismutase (Mn-SOD), an intrinsic radical scavenger, in myocardium in a biphasic manner. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induced a biphasic cardioprotection that corresponded to the activation of Mn-SOD. However, a direct association between Mn-SOD activation in myocardium and the acquisition of tolerance to ischemia/reperfusion injury induced by hyperthermia and the involvement of the cytokines in the signal transduction pathway for the hyperthermia-induced cardioprotection have not yet been elucidated. Methods and Results—Hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. At 0.5 and 72 hours after hyperthermia, ischemia was induced by occlusion of the left coronary artery for 20 minutes, followed by reperfusion for 48 hours. Inhibition of the increases in Mn-SOD content and activity 72 hours after hyperthermia by t...
Some Pitfalls of Vectorcardiographic Diagnosis of Myocardial Infarction with Particular Respect to Emphysema
Authors: Kazuhikomurata, Satorumatsushita, Hiroshikurihara, Masujiseki
Journal: Circulation (1967)

Vectorcardiographic changes indicating old myocardial infarction were observed in eight of 288 patients who at autopsy did not show extensive myocardial disease. Of these eight patients four had been given a misdiagnosis of anteroseptal infarction, while four had been suspected of having anterolateral or anterior infarction on the basis of an abnormal configuration of the initial portion of the QRS loop. The possibility of overdiagnosis of myocardial infarction should be borne in mind in reading vectorcardiograms, especially in the absence of clear-cut history of the condition. A prominent Q wave simulating anteroseptal or anterior infarction was observed in lead V2 or V3, or in both in 12-lead electrocardiograms in all these eight cases. A high incidence of coronary sclerosis, scattered myocardial fibrosis and pulmonary emphysema was noted in these false positive cases at autopsy, but right ventricular hypertrophy, significant septal hypertrophy, or giant right atrium was not demonstrated.
Abstract 5812: Synergistic induction of urinary bladder cell death and reduction of drug resistance in vitro and effective control of xenograft tumor growth in vivo by a triple combination of gemcitabine, cisplatin, and romidepsin
Authors: Hwa-Chain R. Wang, Pawat Pattarawat
Journal: Cancer Research (2018)

Abstract Human urinary bladder cancer is the fifth most commonly diagnosed cancer in the United States. Long-term survival of patients is still suboptimal with current therapeutic regimens failing to impede drug resistance and recurrence. Thus, it is urgent to develop therapeutic regimens that effectively control tumor growth, drug resistance, and recurrence to reduce the morbidity and mortality of this disease. We investigated the efficacy of combination regimens to control various human urinary bladder cancer cells in vitro and cell-derived xenografts in vivo. Our studies revealed, for the first time, a combination of gemcitabine plus cisplatin and romidepsin effective in synergistically inducing cell death and reducing drug resistance in vitro. The enhanced Ras-ERK-Nox pathway played an essential role in mediating signals to elevate reactive oxygen species, leading to enhanced caspase activation, enhanced DNA damage and oxidation, and reduced glutathione, which synergistically increased cell death and reduced drug resistance in cells treated with combined gemcitabine, cisplatin, and romidepsin. The unfolded protein response also played a role in the modulation of cyto-protection and cell death through the combined regimen. In vivo studies verified the efficacy of gemcitabine plus cisplatin and romidepsin in control of xenograft tumor growth in immune-deficient mice. Hence, our results lead us to suggest that a combination of gemcitabine, cisplatin, and romidepsin should be seriously considered as an advanced regimen over the conventional gemcitabine plus cisplatin regimen for controlling the development and recurrence of human urinary bladder cancer. Citation Format: Hwa-Chain R. Wang, Pawat Pattarawat. Synergistic induction of urinary bladder cell death and reduction of drug resistance in vitro and effective control of xenograft tumor growth in vivo by a triple combination of gemcitabine, cisplatin, and romidepsin [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 5812.
Abstract 17073: Accumulation of P62 by Dysregulation of Autophagy Induces Rip1-dependent Necroptosis in Cardiomyocytes: a Novel Interplay Between Autophagy and Necroptosis
Authors: Makotoogasawara, Toshiyukiyano, Takayukimiki, Masayatanno, Atsushikuno, Hidemichikouzu, Hiromichimurase, Toshiyukitobisawa, Shingomuratsubaki, Keitaronishizawa, Masashimizuno, Satokoishikawa, Tetsujimiura
Journal: Circulation (2014)

Background: Necroptosis, a recently recognized form of cell death, has been implicated in various pathological conditions including myocardial infarction. Activation of receptor-interacting protein kinase (RIP) 1, leading to RIP1-RIP3 complex formation, is a trigger event of necroptosis, but the mechanism for RIP1 activation has not been characterized fully. Objective: We examined the relationship between RIP1-dependent necroptosis and autophagy in cardiomyocytes. Methods: In H9c2 cardiomyoblasts, the necroptotic pathway was activated using TNF-α (TNF, 50 ng/ml) alone or co-incubation of TNF-α with 20 μM z-VAD-fmk, a pan-caspase inhibitor (TNF/zVAD). As an index of necrosis, the amount of LDH released into the culture medium 24 h after serum withdrawal was expressed as a percentage of total LDH. Necrostatin-1 (Nec-1, 20 μM) and cyclosporine A (CsA, 1 μM) were used for inhibiting RIP1-dependent necroptosis and mitochondrial permeability transition pore opening, respectively. Results: Treatment with TNF ind...
Silence is golden: gene silencing of <i>V. cholerae</i> during intestinal colonization delivers new aspects to the acid tolerance response
Authors: Fatih Cakar, Franz G. Zingl, Stefan Schild
Journal: Gut Microbes (2018)

Bacterial pathogens of the gastrointestinal tract alter their expression profile upon ingestion by the host and activate a variety of factors enhancing colonization and virulence. However, gene silencing during infection might be as important as gene activation to achieve full colonization fitness. Thus, we developed and successfully applied a reporter technology to identify 101 in vivo repressed (ivr) genes of the bacterial pathogen Vibrio cholerae. In depth analysis of the in vivo repressed H+/Cl− transporter ClcA revealed an inverse requirement along gastrointestinal colonization. ClcA could be linked to acid tolerance response required during stomach passage, but ClcA expression is detrimental during subsequent colonization of the lower intestinal tract as it exploits the proton-motive force in alkaline environments. The study summarized in this addendum demonstrates that constitutive expression of ivr genes can reduce intestinal colonization fitness of V. cholerae, highlighting the necessity to downregulate these genes in vivo.
Abstract 4740: CLEVER-1 as a marker to identify breast cancer patients under immunosuppression
Authors: Reetta E. Virtakoivu, Pia Boström, Riitta Aaltonen, Ilkka Koskivuo, Sirpa Jalkanen, Maija Hollmén
Journal: Cancer Research (2018)

Abstract TAMs are the main innate immune cells regulating tumor growth and metastasis. In tumors, TAMs exhibit an immunosuppressive M2 phenotype attenuating anti-tumor immune responses. CLEVER-1 is a multifunctional scavenger receptor specifically expressed on a subset of M2 macrophages and human monocytes. Interestingly, a subset of CLEVER-1+ monocytes and TAMs are increased in conditions where immunosuppressive functions prevail, like pregnancy and cancer. In addition, high CLEVER-1 mRNA levels associates with poorer overall survival of breast cancer patients. Therefore, we want to investigate can CLEVER-1 be used as a surrogate marker for identifying cancer patients under immunosuppression. Since we detected CLEVER-1+ TAMs in 40% of breast cancer patients, we will characterize whether the amount of CLEVER-1+ TAMs in tumor biopsy samples correlates with the number of CLEVER-1+ monocytes in breast cancer patient blood. We will collect blood, plasma, healthy breast tissue and tumor tissue from 200 newly diagnosed treatment naive breast cancer patients. The tissue samples and the blood from each patient are characterized by flow cytometry to identify the activation status of monocyte and macrophage populations in relation to CD4/CD8, Th1, Th2, Th17 and Treg populations. By now, we have received 25 patient samples from which 12 have been initially analyzed for CLEVER-1 expression in the peripheral blood together with other immune cell populations. Our preliminary data show that CLEVER-1 expression on peripheral blood monocytes is increased in breast cancer patients who have higher levels of Tregs. Additionally, the amount of CD4+ effector T cells (Th1 and Th17) was decreased among patients, whereas the amount of Th2 CD4+ cells was increased when comparing to the blood of healthy volunteers. The abnormal Th1/Th2 ratio is linked to cancer progression. The expected outcome is that CLEVER-1 could be used as a surrogate marker to identify patients under immune suppression. These patients could benefit from anti-CLEVER-1 therapy or other clinically available immunomodulatory drugs (e.g. anti-CTLA-4; ipilimumab, anti-PD1; nivolumab). Citation Format: Reetta E. Virtakoivu, Pia Boström, Riitta Aaltonen, Ilkka Koskivuo, Sirpa Jalkanen, Maija Hollmén. CLEVER-1 as a marker to identify breast cancer patients under immunosuppression [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 4740.
Abstract 5412: miR155 and miR9 expression in human prostate cancer cell lines and prostate cancer tissue
Authors: Ines Benedetti, Juan Rebollo, Niradiz Reyes
Journal: Cancer Research (2018)

Abstract Background: Differential expression of miRNAs between malignant, precancerous lesions, and nonmalignant prostate tissues may indicate that these molecules play a role in cancer biology. Several miRNAs have been commonly reported to be differentially expressed in prostate cancer, compared to benign prostate tissue, but some results have been contradictory. Expression patterns of specific miRNAs across prostate cancer, precancerous lesions, and benign tissue have not been determined. Design: The expression patterns of 20 miRNAs were determined in the metastatic prostate cancer cells lines LNCaP and PC3, using the nontumorigenic prostate cell line PWR-1E as reference. Differentially expressed miR-9 and miR-155 were subsequently evaluated in epithelial cells obtained by laser capture microdissection from cancerous lesions, high-grade prostatic intraepithelial neoplasia, proliferative inflammatory atrophy, and benign tissue from radical prostatectomy and transurethral prostatectomy tissue specimens, from patients diagnosed with prostate cancer. Total RNA was extracted from the cell lines and microdissected epithelial cells and expression of miR-9 and miR-155 was evaluated by qPCR; miRNA levels in individual samples were normalized to corresponding RNU62 levels. Fold-change values were calculated, and p value &amp;lt; 0.05 was considered statistically significant. The Ethical Review Board of the academic institution approved this study. Results: Differential expression of several miRNAs was found between cell lines. Four miRNAs showed a similar expression profile in the cancer cell lines, two were overexpressed in metastatic cell lines LNCaP and PC3 compared to the nontumorigenic PWR-1E cells (hsa-miR-195, hsa-miR-9), and two were underexpressed (hsa-miR-143, hsa-miR-155). Evaluation of miRNA expression in laser capture microdissected epithelial cells showed a trend towards higher expression of miR-9, and lower expression of miR-155 in microdissected epithelial cells derived from prostate tissue with cancer and proliferative inflammatory atrophy compared to epithelial cells from benign tissue. Conclusions: Our results are in agreement with the description of miR-9 as oncomiRNA. miR-155 was underexpressed in LNCaP and PC3 cells in relation to nontumorigenic PWR-1E cells. Also, this miRNA showed a trend towards underexpression in epithelial cells microdissected from prostate tissue with cancer and proliferative inflammatory atrophy compared to epithelial cells from benign tissue. Further studies of these deregulated miRNAs will help clarify their role in prostate tumorigenesis. Citation Format: Ines Benedetti, Juan Rebollo, Niradiz Reyes. miR155 and miR9 expression in human prostate cancer cell lines and prostate cancer tissue [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 5412.
Abstract 1170: NCI-H1975 L858R/T790M/C797S isogenic cell line for next-generation EGFR inhibitor screening
Authors: Feng Hao, Feng He, Wenna Zhang, Zhaoshuai Bai, Jinying Ning
Journal: Cancer Research (2018)

Abstract Non-small-cell lung cancer (NSCLC) is the most common cause of cancer death. Over-activation of EGFR occurs in 13%~23% of NSCLC. The identification of EGFR as a cancer driver gene had led to rapid development of NSCLC targeted therapy, but the mutation of EGFR during treatment can cause drug resistance and cancer relapse. For example, T790M mutation causes resistance to the first generation of EGFR inhibitor Erlotinib and C797S mutation contributes to the resistance to the 3rd EGFR inhibitor AZD9291. There are several human cell lines for T790M mutation research, but there is not yet any primary human cancer cell line with C797S mutation. In the current study, a human isogenic EGFR C797S mutation cell line was generated through introducing nucleotide mutation into the EGFR gene in NCI-H1975 cell line using CRISRP technology, which originally bears L858R and T790M mutations of EGFR. First, the sgRNA sequence around the exon-20 of EGFR gene was screened using CRIPSR plasmid. Second, the donor plasmid with the homology arm containing exon-20 of EGFR and selecting marker was constructed and co-transfected into the parental cell line. Then, the NCI-H1975 C797S isogenic cell line was obtained and confirmed after screening over 100 single clones using the PCR method. The NCI-H1975 C797S isogenic cell line was resistant to AZD9291 but sensitive with EAI045 (the potential 4th generation EGFR inhibitor) combined with cetuximab. These data indicate that our NCI-H1975 L858R/T790M/C797S isogenic line is a useful model for next generation EGFR inhibitor study. Citation Format: Feng Hao, Feng He, Wenna Zhang, Zhaoshuai Bai, Jinying Ning. NCI-H1975 L858R/T790M/C797S isogenic cell line for next-generation EGFR inhibitor screening [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 1170.
Age of Data at the Time of Publication of Contemporary Clinical Trials
Authors: John Welsh, Yuan Lu, Sanket S. Dhruva, Behnood Bikdeli, Nihar R. Desai, Liliya Benchetrit, Chloe O. Zimmerman, Lin Mu, Joseph S. Ross, Harlan M. Krumholz
Journal: JAMA Network Open (2018)

<h3>Importance</h3> As medical knowledge and clinical practice rapidly evolve over time, there is an imperative to publish results of clinical trials in a timely way and reduce unnecessary delays. <h3>Objectives</h3> To characterize the age of clinical trial data at the time of publication in journals with a high impact factor and highlight the time from final data collection to publication. <h3>Design and Setting</h3> A cross-sectional analysis was conducted of all randomized clinical trials published from January 1 through December 31, 2015, in the<i>Annals of Internal Medicine, BMJ, JAMA, JAMA Internal Medicine, Lancet,</i>and<i>New England Journal of Medicine</i>. Multivariable linear regression analyses were conducted to assess whether data age (adjusted for follow-up duration) and publication time were associated with trial characteristics. <h3>Main Outcomes and Measures</h3> The outcome measures were the midpoint of data collection until publication (data age), the time from first participant enrollment to last participant enrollment (enrollment time), and the time from final data collection to publication (publication time). <h3>Results</h3> There were 341 clinical trials published in 2015 by the 6 journals. For assessment of the primary end point, 37 trials (10.9%) had a follow-up period of less than 1 month, 172 trials (50.4%) had a follow-up period of 1 month to 1 year, and 132 trials (38.7%) had a follow-up period of more than 1 year. For all trials, the median data age at publication was 33.9 months (interquartile range, 23.5-46.3 months). Among trials with a follow-up period of 1 month or less, the median data age was 30.6 months (interquartile range, 18.6-39.0 months). A total of 68 trials (19.9%) required more than 4 years to complete enrollment. The median time from the completion of data collection to publication was 14.8 months (interquartile range, 7.4-22.2 months); publication time was 2 or more years in 63 trials (18.5%). In multivariable regression analyses adjusted for follow-up time, inconclusive or unfavorable trial results were significantly associated with older data age (&gt;235 days). Compared with trials funded only by private industry, trials funded by government were associated with a significantly longer time to publication (&gt;180 days). <h3>Conclusions and Relevance</h3> Clinical trials in journals with a high impact factor were published with a median data age of nearly 3 years. For a substantial proportion of studies, time for enrollment and time from completion of data collection to publication were quite long, indicating marked opportunities for improvement in clinical trials to reduce data age.
Abstract 15513: miR-210 HypoxamiR Stimulates Neoangiogenesis in Response to Peripheral Ischemia
Authors: Biagina Maimone, Germana Zaccagnini, Christine Voellenkle, Fabio Martelli
Journal: Circulation (2016)

Background: MicroRNA-210 (miR-210) is induced by hypoxia in endothelial cells. The analysis of miR-210-loaded RISC complexes by transcriptomics identified many miR-210 targets involved in cell migration and angiogenesis. Accordingly, miR-210 expression increased endothelial tubulogenesis and VEGF-driven migration in vitro. Here, we investigated the regulation of angiogenesis by miR-210 in peripheral ischemia. Methods and Results: Transcriptomic analysis by RNA seq of hypoxic endothelial cells showed that MIR210 Host Gene was the most induced long noncoding RNAs (27±1 fold, adj p<1 E-76). Accordingly, its product miR-210 was also increased (35±5 fold; p<0.00001). In keeping with in vitro data, miR-210 was induced 2.9±0.6 fold (p<0.04) in ischemic muscles of a mouse model of hindlimb ischemia induced by femoral artery dissection. miR-210 role was investigated by the administration of miR-210 complementary LNA oligos (anti-210) and in doxycycline-inducible miR-210 transgenic mice (Tg-210). MiR-210 stimulated...