tbuckley/cabot-search huggingface dataset:
Abstract 3553: Mutant KRas-mediated AKT2 activation supports lung cancer growth by activating complex II-driven mitochondrial metabolism
Authors: Kwan-Hee Park, Ho-Young Lee
Journal: Cancer Research (2017)

Abstract Non-small cell lung cancer (NSCLC), the most common type of lung cancer (comprising 80-85 %), is a leading cause of cancer-related death worldwide. KRAS mutation is s major driver oncogene in NSCLC. Constitutive activation of K-Ras via oncogenic mutations plays a key role in development and progression of NSCLC, and is an important target for drug development. Indeed, drugs that target RAF-MAPK and PI3K, the well-established downstream pathways of K-Ras, are being evaluated in the clinic. However, to date, no effective treatments specifically targeting K-Ras have reached the clinic. A new direction for anti-Ras therapies targeting Ras-mediated altered cellular metabolism is implied by recent studies. Hence, as an attempt to investigate novel therapeutic targets to suppress KRAS-driven NSCLC, we assessed metabolic changes in NSCLC cell line and mouse model systems with oncogenic K-Ras mutations. We show that activation of Ras causes metabolic alterations, leading to aerobic glycolysis. Interestingly, despite the changes in the glycolytic pathway, NSCLC cell line and mouse models carrying K-Ras mutation revealed an elevated mitochondrial membrane potential, superoxide production as well as maximal oxygen consumption rate. Moreover, blockade of mitochondrial respiration effectively reduced mutant KRas-driven neoplastic phenotypes in NSCLC cell lines vitro and lung tumor formation in vivo. In contrast, blockade of glycolysis was not effective in the mutant KRas-driven tumorigenic activities. Mechanistically, mutant KRas-mediated activation of Akt2 led to increased expression of succinate dehydrogenase subunit A (SDHA) through increased protein stability by blocking proteasome-mediated degradation, resulting in mitochondrial complex II-dependent respiration. Our study suggests that induction of mitochondrial complex II-dependent respiration is an important mechanism by which oncogenic mutant KRas induces metabolic changes and ROS stress in NSCLC cells, contributing to lung carcinogenesis. Our findings elucidate potential metabolic targets that may provide novel therapeutic strategy for treating NSCLC with oncogenic KRAS mutations. Citation Format: Kwan-Hee Park, Ho-Young Lee. Mutant KRas-mediated AKT2 activation supports lung cancer growth by activating complex II-driven mitochondrial metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3553. doi:10.1158/1538-7445.AM2017-3553
Abstract 1585: Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress
Authors: Joo Hyoung Lee, Minsung Kang, Gurudatta Naik, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan
Journal: Cancer Research (2017)

Abstract Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to re-activation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa (CRPC). Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR), and downstream pro-oxidant signaling. This reversal following ES treatment significantly decreased PCa cell proliferation through downregulation of GR, and upregulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant upregulation of enzymes in major ROS scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented antioxidant system through upregulation of glucose influx, pentose phosphate pathway (PPP) and NAD salvaging pathway. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced CRPC phenotype upon AR antagonism, and dual targeting action of ES on AR and GR can be further translated to PCa therapy. Citation Format: Joo Hyoung Lee, Minsung Kang, Gurudatta Naik, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1585. doi:10.1158/1538-7445.AM2017-1585
Abstract 591: Efficacy of ALKS 4230, a novel immunotherapeutic agent, in murine syngeneic tumor models alone and in combination with immune checkpoint inhibitors
Authors: Heather C. Losey, Jared E. Lopes, Reginald L. Dean, Michael R. Huff, Rosemarie A. Moroso, Juan C. Alvarez
Journal: Cancer Research (2017)

Abstract ALKS 4230 is a novel immunotherapeutic agent being tested in an ongoing phase 1 study to evaluate safety and tolerability in the treatment of patients with refractory solid tumors. ALKS 4230 is a selective agonist of the intermediate-affinity interleukin 2 (IL-2) receptor that when administered to mice results in a significant increase in numbers of memory CD8+ T cells and NK cells with no expansion of CD4+ regulatory T cells (Tregs). The selectivity achieved by ALKS 4230 is due to the fact that the molecule is a fusion of circularly permuted IL-2 to the extracellular portion of the IL-2 receptor α, and the resulting fusion protein is sterically prevented from binding to the high-affinity IL-2 receptor expressed on Tregs. The efficacy of ALKS 4230 was compared to recombinant human IL-2 in a B16F10 lung tumor metastasis model. ALKS 4230 treatment resulted in dose-dependent reduction of lung tumor colonization, with 100% inhibition at the highest dose tested. In contrast, while IL-2 was able to reduce lung tumor colonization, the maximal level of inhibition achieved was 60-70% at multiple dose levels such that increasing doses did not result in greater inhibition. Thus, the activation and expansion of effector cells without expansion of Tregs in response to ALKS 4230 treatment correlates with its improved efficacy over IL-2, which non-selectively expands both effector cells and Tregs. The antitumor efficacy mediated by ALKS 4230 was further evaluated in several murine subcutaneous syngeneic tumor models, including B16F10, MC38 and EMT6. Treatment with ALKS 4230 or its murine ortholog resulted in inhibition of tumor growth and improved survival in multiple models. When dosed in combination with anti-CTLA-4 or anti-PD-1 antibodies, ALKS 4230 resulted in further improvement of tumor growth inhibition and survival. These results demonstrate the murine antitumor efficacy of ALKS 4230 alone and in combination with immune checkpoint inhibitors and support the ongoing clinical evaluation of ALKS 4230 as an immunotherapy for cancer. Citation Format: Heather C. Losey, Jared E. Lopes, Reginald L. Dean, Michael R. Huff, Rosemarie A. Moroso, Juan C. Alvarez. Efficacy of ALKS 4230, a novel immunotherapeutic agent, in murine syngeneic tumor models alone and in combination with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 591. doi:10.1158/1538-7445.AM2017-591
Abstract 215: Intralipid Protects The Heart In Late Pregnancy Against Ischemia Reperfusion Injury Via Stat3 Signaling Pathway
Authors: Jingyuan Li, Mansoureh Eghbali
Journal: Circulation Research (2013)

We have recently reported that the hearts of late pregnant (LP) mice are more prone to ischemia/reperfusion (I/R) injury compared to non pregnant mice. We also found that intralipid, a fat emulsion commonly used for parenteral nutrition, protects the male rodent heart against I/R injury if administrated during reperfusion. The activation of the survivor activating factor enhancement (SAFE) pathway, which includes the activation of the transcription factor signal transducer and activator of transcription-3 (STAT3), has recently been highlighted in cardioprotection. Here we explored the therapeutic potential of intralipid in the protection of LP mouse hearts against I/R injury as well as the involvement of STAT3 signaling pathway. Isolated LP mouse hearts were subjected to 20 min ischemia followed by reperfusion with i) Krebs Henseleit buffer (CTRL group), ii) 1% intralipid (ITLD group) or iii) ITLD+STAT3 inhibitor Stattic (20 µM, Stattic group). The duration of reperfusion was 40 min for heart functional measurements and infarct size assessment. Postischemic administration of intralipid significantly improved the cardiac function of LP mice after ischemia. The rate pressure product (RPP) at the end of reperfusion was improved from 1617±287mmHg*beats/min (n=6) in CTRL to 11556±784 mmHg*beats/min (n=5) in the ITLD group. The infarct size was also significantly reduced by postischemic administration of intralipid to 17±2% (n=5) from 59±5%(n=6) in CTRL (p&lt;0.01). A specific inhibitor of STAT3, Stattic, fully abolished, intralipid-induced cardioprotection, as the RPP at the end of reperfusion in the Stattic group (1345±559, n=3) was similar to CTRL group, and significantly lower compared with ITLD group. Furthermore, the infarct size in the Stattic group was markedly higher compared with ITLD group (48±99% (n=3) vs. 17±2%(n=5) in ITLD group, p&lt;0.01). In conclusion, intralipid protects the late pregnant heart against I/R injury via the STAT3 signaling pathway.
Association Analysis of the MHC in Lupus Nephritis
Authors: Ricong Xu, Qibin Li, Rongjun Liu, Juan Shen, Ming Li, Minghui Zhao, Meng Wang, Qijun Liao, Haiping Mao, Zhijian Li, Na Zhou, Peiran Yin, Yue Li, Xueqing Tang, Tian Wu, Zhong Zhong, Yan Wang, Zhen Ai, Ou Wang, Nan Chen, Xiaoqin Yang, Junbin Fang, Ping Fu, Jieruo Gu, Kun Ye, Jian Chen, Lie Dai, Huafeng Liu, Zhangsuo Liu, Yunhua Liao, Jianxin Wan, Guohua Ding, Jinghong Zhao, Hao Zhang, Shuxia Fu, Liangdan Sun, Xuejun Zhang, Huanming Yang, Jian Wang, Jun Wang, Jianjun Liu, Yingrui Li, Xueqing Yu
Journal: Journal of the American Society of Nephrology (2017)

Lupus nephritis (LN) is one of the most prevalent and serious complications of SLE, with significant effects on patient and renal survival. Although a large number of genetic variants associated with SLE have been identified, biomarkers that correlate with LN are extremely limited. In this study, we performed a comprehensive sequencing analysis of the whole MHC region in 1331 patients with LN and 1296 healthy controls and validated the independent associations in another 950 patients with LN and 1000 controls. We discovered five independent risk variants for LN within the MHC region, including HLA-DRβ1 amino acid 11 (Pomnibus<0.001), HLA-DQβ1 amino acid 45 (P<0.001; odds ratio, 0.58; 95% confidence interval, 0.52 to 0.65), HLA-A amino acid 156 (Pomnibus<0.001), HLA-DPβ1 amino acid 76 (Pomnibus<0.001), and a missense variant in PRRC2A (rs114580964; P<0.001; odds ratio, 0.38; 95% confidence interval, 0.30 to 0.49) at genome-wide significance. These data implicate aberrant peptide presentation by MHC classes 1 and 2 molecules and sex hormone modulation in the development of LN.
Abstract 498: Attenuation of polycyclic aromatic hydrocarbon (PAH)-mediated pulmonary carcinogenesis in mice by omega-3-fatty acids
Authors: Bhagavatula Moorthy, Weiwu Jiang, Lihua Wang, Sudha R. Kondraganti, Guodong Zhou
Journal: Cancer Research (2017)

Abstract 3-Methylcholanthrene (MC) and benzo[a]pyrene (BP) are potent polycyclic aromatic hydrocarbons (PAHs) carcinogens. PAHs are present in cigarette smoke, diesel exhausts, and charcoal broiled meats, etc. Cytochrome P450 (CYP) 1A/1B1 enzymes play key roles in the activation of PAHs to carcinogenic metabolites, which initiate carcinogenesis by binding covalently to DNA, and the adducts, if not repaired, could lead to tumorigenesis. In this study we tested the hypothesis that pre-treatment of mice with omega-3-fatty acids, i.e. [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) will lead to attenuation of PAH-mediated pulmonary DNA adduct formation and pulmonary tumorigenesis. Twelve week old male and female A/J mice received EPA (60 mg/kg) and DHA (40 mg/kg) from day 1 to day 24. Control mice were treated with vehicle corn oil. On day 3, mice were treated with BP (40 µmol/kg) or 3-methylcholanthrene (MC, 40 µmol/kg) by i.p. In the short-term experiment (DNA adduct studies), 3-5 mice from each group were terminated at day 10 (7 days after BP or MC treatment). EPA/DHA significantly suppressed formation of BP-DNA and MC-DNA adducts in lung and liver of both male and female mice. In the long-term experiment (tumor studies), 8 mice for each group continued to receive EPA/DHA twice per week till end of experiment (16 weeks). Pulmonary tumor incidence and multiplicity was significantly suppressed in mice given EPA+DHA, compared to those given the PAHs, BP or MC alone. These studies suggest that the omega 3-fatty acids could be developed as novel candidates for the prevention of PAH-mediated lung cancers in humans. Citation Format: Bhagavatula Moorthy, Weiwu Jiang, Lihua Wang, Sudha R. Kondraganti, Guodong Zhou. Attenuation of polycyclic aromatic hydrocarbon (PAH)-mediated pulmonary carcinogenesis in mice by omega-3-fatty acids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 498. doi:10.1158/1538-7445.AM2017-498
Contemporary Legal Updates to the Definition of Brain Death in Nevada
Authors: Ariane Lewis
Journal: JAMA Neurology (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Abstract 2161: Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in <i>MYC+/BCL2+</i> double hit lymphoma
Authors: Anna Esteve-Arenys, Juan Garcia-Valero, David Gonzalez, Aránzazu Chamorro-Jorganes, Vanina Rodriguez, Ivan Dlouhy, Itziar Salaverria, Elias Campo, Dolors Colomer, Antonio Martinez, Grzegorz Rymkiewicz, Patricia Pérez-Galán, Armando Lopez-Guillermo, Gaël Roué
Journal: Cancer Research (2017)

Abstract Double-hit lymphoma (DHL) is a rare subtype of B-cell lymphoma characterized by MYC and either BCL2 or BCL6 chromosomal rearrangements. DHL cases may have different morphology and are included in the updated 2016 WHO classification as a new category of high grade B-cell lymphoma with rearrangements. DHL patients usually undergo a rapidly progressing clinical course and are poorly responsive to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival of approximately one year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of some lymphoid malignancies. In this study, we demonstrate that single-agent ABT-199 efficiently displaces pro-apoptotic BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+ DHL cell lines and primary cultures, as well as in a xenograft mouse model of DHL. We further identify the accumulation of the BCL2-like protein, BFL-1, to be a major mechanism involved in acquired resistance to ABT-199. We show this phenomenon to be manageable by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1 as one of the top apoptosis-related gene modulated by the compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 at both mRNA and protein levels further overcomes resistance to ABT-199 both in vitro and in vivo, allowing DHL cultures and tumor xenografts to undergo synergistic caspase-mediated apoptosis. Together, these findings highlight the relevance of BFL-1 in DHL-associated drug resistance and support the combined use of BCL-2 antagonist and BET inhibitor as a promising therapeutic strategy in patients with aggressive DHL. Citation Format: Anna Esteve-Arenys, Juan Garcia-Valero, David Gonzalez, Aránzazu Chamorro-Jorganes, Vanina Rodriguez, Ivan Dlouhy, Itziar Salaverria, Elias Campo, Dolors Colomer, Antonio Martinez, Grzegorz Rymkiewicz, Patricia Pérez-Galán, Armando Lopez-Guillermo, Gaël Roué. Pharmacological downregulation of BFL-1 by the BET bromodomain inhibitor CPI203 overcomes ABT-199 resistance in MYC+/BCL2+ double hit lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2161. doi:10.1158/1538-7445.AM2017-2161
The Scientific Basis of Guideline Recommendations on Sugar Intake
Authors: Stephen Strum
Journal: Annals of Internal Medicine (2017)

Letters1 August 2017The Scientific Basis of Guideline Recommendations on Sugar IntakeStephen Strum, MDStephen Strum, MDFrom Community Practice of Medical Oncology & Internal Medicine, Jacksonville, Oregon.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L17-0254 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Reading Erickson and colleagues' review (1) was certainly frustrating if the goal in reading any article is to apply the findings to clinical practice. That the population in the United States and increasingly abroad is growing in girth is obvious. Persons with a body mass index of 25 kg/m2 or less have become rarities. We are amidst an epidemic of overconsumption of calories, with excessive consumption of high–glycemic index carbohydrates coupled with more sedentary lifestyles a major part of this problem.Taking a dietary history of my patients who are overweight or obese routinely indicates that, for ...Reference1. Erickson J, Sadeghirad B, Lytvyn L, Slavin J, Johnston BC. The scientific basis of guideline recommendations on sugar intake. A systematic review. Ann Intern Med. 2017;166:257-67. [PMID: 27992898]. doi:10.7326/M16-2020 LinkGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Community Practice of Medical Oncology & Internal Medicine, Jacksonville, Oregon.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L17-0254. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoThe Scientific Basis of Guideline Recommendations on Sugar Intake Jennifer Erickson , Behnam Sadeghirad , Lyubov Lytvyn , Joanne Slavin , and Bradley C. Johnston The Scientific Basis of Guideline Recommendations on Sugar Intake Behnam Sadeghirad and Bradley C. Johnston The Scientific Basis of Guideline Recommendations on Sugar Intake C. Albert Yeung Metrics 1 August 2017Volume 167, Issue 3Page: 218KeywordsCarbohydratesConflicts of interestDisclosureEatingFoodGlucoseIngestionLipidsOverweightProteins ePublished: 1 August 2017 Issue Published: 1 August 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
FRI0426 No demonstrable effect of IL-23 receptor variants on clinical measures and IL23/ IL-17 levels in ankylosing spondylitis
Authors: J Nossent, S Johnsen, G Bakland
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> IL23 binding to IL23 receptor (IL23R) is necessary for the maturation of Th17 cells and generation of proinflammatory IL17 and TNF in AS. IL23R variants have considerable impact on AS susceptibility in genome-wide association studies. <h3>Objectives</h3> To describe the effect of genotypic IL23R variants on proinflammatory cytokines and disease measures in AS. <h3>Methods</h3> Cross sectional cohort study of patients with established AS (n=334, 90% B27 +, mean age at study 45 years) included in a disease registry. IL23R genotyping for nonsynonymous SNP9s (rs11209026 (protective allele A) and rs11209032 (risk allele A) was done by Taqman RT-PCR, while IL23, IL17, IL6 and TNF levels determined by sandwich ELISA and compared with age and gender matched healthy controls (n=72). Genotypic associations with clinical and serological features were analyzed with nonparametric methods. <h3>Results</h3> There was no significant difference between in AS patients and controls regarding IL23 (276 vs 262 pg/ml, p&gt;0.4) and IL17 levels (184 vs 233 pg/ml, p&gt;0.2). Only 22 (6.6%) AS patients carried the protective rs11209026 A allele, while 206 (61.7%) carried the rs11209032 A risk allele (p=0.03). There was no demonstrable influence of individual genotypes (A vs G, AA vs AG vs GG) or haplotypic combinations on BASFI, spinal function tests, CRP, ESR, IL-23 or IL-17 levels (all p&gt;0.3) <h3>Conclusions</h3> While there is a high prevalence of the IL-23R rs11209032 A risk allele in Caucasian AS patients, this has no demonstrable bearing on clinical disease measures or serum IL-23 and IL-17 levels. <h3>Acknowledgements</h3> The authors wish to acknowledge the technical assistance by mrs K Nilsen and the financial support of the North Norwegian Health Authority Research Fund <h3>Disclosure of Interest</h3> None declared