tbuckley/cabot-search huggingface dataset:
Abstract 950: New strategy to sensitize pancreatic and bladder cancer to gemcitabine
Authors: Simon Bayle, Francesca Vena, Andrii Monastyrskyi, William Roush, Derek Duckett
Journal: Cancer Research (2018)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), the major histological subtype of pancreatic cancer displays few symptoms for early detection and the majority of PDAC patients are diagnosed with advanced or metastatic disease. PDAC patients with advanced disease lack durable responses to chemotherapy and have a dismal prognosis. Gemcitabine is the cornerstone of care for advanced and metastatic PDAC. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. Accordingly, strategies that lead to upregulation of signaling pathways and enzymes involved in generating the active metabolite may lead to improved outcome in PDAC. We have developed a potent, selective, small molecule inhibitor of casein kinase-1 delta (CK1δ) and demonstrated that inhibition of CK1δ activity specifically compromises the growth, survival and invasion of breast cancer cells that overexpress CK1δ. Notably, our lead compound, SR-3029 provokes pre-clinical tumor regression of triple negative breast cancer (TNBC), including lung metastatic TNBC and basal-like PDX breast cancer models. We observed that CK1δ is upregulated in other cancers including bladder cancer and demonstrated that SR-3029 acts in synergy with DNA damaging cytotoxic agents. Notably, the combination of gemcitabine with SR-3029 resulted in synergistic antiproliferative activity and impaired colony formation in both pancreatic and bladder cancer cells. Mechanistic studies demonstrate that silencing CK1δ or inhibition of CK1δ activity by SR-3029 induces a significant upregulation of deoxycytidine kinase (DCK; rate limiting enzyme for gemcitabine activation) both at the RNA and protein levels, which results in increased cellular DCK and its active gemcitabine metabolite. We evaluated the effect of SR-3029 alone and in combination with gemcitabine in an orthotopic pancreatic tumor mouse model and observed much improved tumor growth inhibition with combination treatment, concomitant with increased expression of DCK. In conclusion, our study suggests that CK1δ plays signaling roles in DNA metabolism and the combination of CK1δ inhibition with gemcitabine holds promise as a future therapeutic option for metastatic pancreatic cancer as well as other cancers. Citation Format: Simon Bayle, Francesca Vena, Andrii Monastyrskyi, William Roush, Derek Duckett. New strategy to sensitize pancreatic and bladder cancer to gemcitabine [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 950.
Abstract 4373: AR signaling in concert with PP2A/B regulates YAP1 expression in prostate cancer cells
Authors: Bekir Cinar, Carlos S. Moreno
Journal: Cancer Research (2018)

Abstract The transcriptional coactivator YAP1 is a key nuclear effector of the Hippo pathway. STK4/MST1 and LATS1/2 are the core kinase components of the Hippo pathway, which restricts organ size and prevents tumorigenesis by attenuating cell proliferation and inducing cell death. Previously, we have reported that STK4/Hippo-YAP1 signaling could play a critical role in prostate cancer progression and therapeutic relapse. Here, we investigated the effects of androgen hormone signaling on YAP1 expression and post-transcriptional modifications in prostate cancer cells. We demonstrated that androgen exposure reduced Ser127 phosphorylation on YAP1 in a time-dependent manner in the castration-sensitive prostate cancer cell line, LNCaP, but without altering the levels of YAP1-Ser127 phosphorylation in the C4-2 cell line, a castration-resistant subline of LNCaP cells. As demonstrated by imaging and cell fractionation methods, androgen exposure promoted the nuclear accumulation of YAP1 in LNCaP; however, regardless of androgen exposure, YAP1 was accumulated in the nucleus of C4-2 cells. In addition, we demonstrated that androgen exposure reduced YAP1-Ser127 phosphorylation that was induced by okadaic acid, a potent activator of Ser/Thr phosphatases PP1 and PP2A. Also, we demonstrated that androgen exposure increased PP2A/B protein expression. Moreover, reduction of phospho-Ser127-YAP1 was correlated with increases in total YAP1 protein, which coincided with androgen receptor (AR) nuclear accumulation by androgen. Consistent with these observation, the genetic (siRNA) or the pharmacologic (enzalutamide) inhibition of AR signaling attenuated the expression of YAP1 protein. Furthermore, our analysis of the publicly available TCGA (The Cancer Genome Atlas) set indicated that YAP1 and AR mRNA expressions were positively correlated in prostate clinical samples. These observations suggest that YAP1 is a direct target of androgen hormone signaling, implicating that the AR-PP2A/B-YAP1 axis is a viable cancer drug target. Citation Format: Bekir Cinar, Carlos S. Moreno. AR signaling in concert with PP2A/B regulates YAP1 expression in prostate cancer cells [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 4373.
Abstract LB-170: 9cis-retinoid UAB30 manifests potent chemopreventive effects in a murine model of UVB-induced basal cell and squamous cell carcinoma
Authors: Sandeep C. Chaudhary, Mahendra P. Kashyap, Gloria Nguyen, Craig A. Elmets, Mohammad Athar
Journal: Cancer Research (2018)

Abstract Vitamin A derivatives such as retinoids are known to inhibit cell proliferation and induce cellular differentiation/apoptosis in various tumor cells. Although many retinoids have been limited due to their severe adverse effects, but 9cUAB30, a highly selective novel retinoid X receptors (RXR)-agonist has been shown an effective anti-carcinogenic activity. Here, we demonstrated the chemopreventive and chemotherapeutic efficacy of 9cUAB30 in UVB-induced photocarcinogenesis in Ptch+/-/SKH-1 murine model, which develops both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Both topical and systemic application to 9cUAB30 significantly reduced UVB-induced skin photocarcinogenesis in terms of tumor number and tumor volume. 9cUAB30 reduced UVB-induced skin hyperplasia, proliferation, and enhanced differentiation of suprabasal epidermal keratinocytes. Induction of apoptosis was also noted in these neoplastic lesions treated with this retinoid. 9cUAB30 was almost equally potent in the inhibition of either UVB-induced skin BCCs or SCCs in Ptch+/-/SKH-1 mice. 9cUAB30-treated residual tumors were manifesting reduced epithelial-mesenchymal transition (EMT) progression with a less aggressive tumor phenotype, which was associated with the enhanced expression of E-cadherin and reduced expression of N-cadherin, Fibronectin, Snail and Twist. 9cUAB30-mediated therapeutic intervention against these tumors was also involved induction of extensive DNA double strand breaks (DSBs) characterized by the enhanced phosphorylation of H2AX. This DNA damage response was unique to 9cUAB30 compare to other known RXR inhibitors such as Bexarotene. It was also independent of reactive oxygen species (ROS) production as ROS scavenger namely, N-acetyl cysteine did not effectively block it. However, 9cUAB30 provoked DNA damage response signaling was associated with the enhanced phosphorylation and activation of ATM, Rad50, ATR, Chk1, and Chk2. In summary, these data demonstrate that 9cUAB30 is a novel cancer chemopreventive agent for UVB-induced skin neoplasm and acts by invoking extensive DDSBs similar to those caused by chemotherapeutic drug like cisplatin. Citation Format: Sandeep C. Chaudhary, Mahendra P. Kashyap, Gloria Nguyen, Craig A. Elmets, Mohammad Athar. 9cis-retinoid UAB30 manifests potent chemopreventive effects in a murine model of UVB-induced basal cell and squamous cell 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 LB-170.
Measles Virus Nucleoprotein Induces a Regulatory Immune Response and Reduces Atherosclerosis in Mice
Authors: HafidAit-Oufella, BrankaHorvat, YannKerdiles, OlivierHerbin, PierreGourdy, JamilaKhallou-Laschet, RégineMerval, BrunoEsposito, AlainTedgui, ZiadMallat
Journal: Circulation (2007)

Background— Recent studies clearly suggest that regulatory T cells play a critical role in the control of the immunoinflammatory response in atherosclerosis and substantially limit lesion development. Measles virus infection or vaccination is associated with immune depression, in part through the induction of an antiinflammatory response by measles virus nucleoprotein. We hypothesized that the antiinflammatory properties of measles virus nucleoprotein may limit the development atherosclerosis. Methods and Results— Here, we show for the first time that repetitive administration of measles virus nucleoprotein to apolipoprotein E–deficient mice promotes an antiinflammatory T-regulatory-cell type 1–like response and inhibits macrophage and T-cell accumulation within the lesions. Treatment with measles virus nucleoprotein significantly reduces the development of new atherosclerotic plaques and markedly inhibits the progression of established lesions. The antiatherosclerotic potential of nucleoprotein is retain...
Abstract 12348: Different Outcomes by First Documented Rhythm After Witnessed Out-of-Hospital Cardiac Arrest in Children
Authors: Masahiko Hara, Kenichi Hayashi, Tetsuhisa Kitamura
Journal: Circulation (2015)

Background: Preventing the tragedy of pediatric out-of-hospital cardiac arrest (OHCA) is an important public health problem, and further accumulation of evidence is needed to improve the outcomes after pediatric OHCA. However, little evidence is available about the prognostic differences by first documented rhythm. Methods and Results: We enrolled 3968 young (&lt; 18 years old) witnessed OHCA patients between 2005 and 2012 from a prospective nationwide population-based cohort database in Japan. We assessed and compared the neurologically favorable one-month survival defined as Glasgow-Pittsburg cerebral performance category 1 or 2 by first documented rhythm (pulseless ventricular tachycardia/ventricular fibrillation [pVT/VF], pulseless electrical activity [PEA], and asystole). The number of OHCA patients with pVT/VF, PEA, and asystole were 556, 1249, and 2163, respectively. The proportion of overall neurologically favorable one-month survival in patients with pVT/VF, PEA and asystole were 36.5%, 5.0%, and 1.8%, respectively in all study population and 73.8%, 27.7%, and 13.8%, respectively in patients who achieved prehospital ROSC. Figure shows the relationship between time from collapse to first cardiopulmonary resuscitation (CPR) and the endpoint in total population with estimated probabilities of the endpoint (line) and the respective 95% confidence intervals (bands). The proportion of asystole increased as the time from collapse to CPR delayed whereas those of pVT/VF and PEA decreased (Trend p&lt;0.001). Earlier initiation of CPR after pediatric OHCA resulted in higher achievement rate of prehospital ROSC (adjusted odds ratio 0.97, 95% confidence interval 0.95-1.00, p=0.025) which showed much better prognoses than those in total study population. Conclusions: The pediatric OHCA outcome differed by the type first documented rhythm. Shortening of time to first CPR is crucial for improving outcomes after pediatric OHCA.
Abstract 3074: CD95/Fas increases type I interferon expression through NF-κB activation
Authors: Abdul Qadir Syed, Marcus Peter
Journal: Cancer Research (2018)

Abstract CD95/Fas, an apoptosis-inducing death receptor, has also been shown to be required for the proliferation and survival of cancer cells. Chronic stimulation through CD95 enhanced formation of cancer stem cell enriched spheres and it increased expression of cancer stem cell markers and a set of genes consistent with a Type I Interferon (IFN) signature. We reported that CD95 stimulation induces upregulation of Type I IFNs that bind to both Type I receptors IFNAR1 and IFNAR2, resulting in activation of JAK kinases, activation of STAT1, and induction of a number of STAT1-regulated genes. However, the mechanism through which CD95 induces Type I IFNs and STAT1 activation is unknown. In this study we have investigated the mechanism of CD95 stimulation of Type I IFN production in the context of breast cancer. We show that knockout of CD95, FADD or Caspase-8 in MCF7 cells using the CRIPSR/Cas9 gene editing system resulted in a loss of the ability of CD95 to increase IFNα, IFNβ, STAT1, STAT2 expression and the phosphorylation of STAT1 and STAT3. The caspase-8 selective inhibitor zIETD-fmk blocked phosphorylation of STAT1 and STAT3 and blocked Type I IFN expression following CD95 stimulation. This identifies caspase-8 as a critical mediator of the Type I IFN-inducing activity of CD95. On other hand, we also showed that CD95 stimulation induced an antiviral program through RIG-I signaling, which is known to induce NF-κB and IFN signaling. RIG-1, MDA5, IRF7 expression and phosphorylation of IRF3 were increased with prolonged CD95 stimulation. Knocking down IRF3 using a siIRF3 smart pool partially reduced the phosphorylation of STAT1 and STAT3 in response to CD95 stimulation. Finally, we show that NF-κB activation is a key regulator of CD95-mediated Type I IFN expression. A NF-κB inhibitor completely blocked STAT1, STAT2 expression and phosphorylation of STAT1 and STAT3 following CD95 stimulation. Knocking out CD95, FADD or Caspase-8 or knocking down IRF3 also reduced NF-κB activation in response to CD95 stimulation. We conclude that CD95 stimulation induces Type I IFN expression through activation of caspase-8 and NF-κB and identify RIG-1 as a possible mediator of NF-κB activation during CD95 stimulation. Citation Format: Abdul Qadir Syed, Marcus Peter. CD95/Fas increases type I interferon expression through NF-κB activation [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 3074.
Abstract 9603: Extreme Hypercholesterolemia Exacerbated by Breast Feeding: Infantile Cases of Sitosterolemia With Novel Mutations in ABCG5 Gene
Authors: HayatoTada, Masa-akiKawashiri, TetsuoKonno, KenshiHayashi, AtsushiNohara, AkihiroInazu, HiroshiMabuchi, MasakazuYamagishi
Journal: Circulation (2014)

Background: Sitosterolemia is an extremely rare inherited disease characterized by increased levels of plant sterols such as sitosterol, the cause of which is ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene mutations. It has been described that infantile sitosterolemic cases exhibit clinical manifestations resembling homozygous FH, including severe hypercholesterolemia, the mechanism of which still remains unclear. In the present study, we tried to determine the molecular diagnosis for 6 Japanese infantile cases with severe hypercholesterolemia and systemic xanthomas without any mutations in LDL receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL receptor adaptor protein 1 (LDLRAP1) genes, then evaluated their clinical features, especially the responsiveness to variety of therapies, including statins, ezetimibe, colestimide, and weaning from breast feeding. Methods and Results: We performed genetic analysis for ABCG5, and ABCG8 genes for those...
Abstract 5490: Targeting mitochondrial function in lung tumor growth and progression
Authors: Sarada Preeta Kalainayakan, Poorva Ghosh, Sancharika Dey, Li Liu, Li Zhang
Journal: Cancer Research (2018)

Abstract Contrary to Warburg's hypothesis, mitochondrial oxidative phosphorylation contributes significantly to fuel cancer cells. Besides oxidative phosphorylation, mitochondria are also involved in heme synthesis. Heme serves as a prosthetic group for several proteins that constitute the complexes of mitochondrial electron transport chain. Therefore, heme plays a pivotal role in mitochondrial oxidative phosphorylation. Recently, our lab demonstrated that non-small cell lung cancer (NSCLC) cells exhibit intensified mitochondrial respiration. Targeting increased mitochondrial respiration with therapeutic agents effectively hampers proliferation of NSCLC cells in vitro. Previous results from our lab also demonstrated that NSCLC cell lines exhibited elevated heme synthesis, heme uptake, and expression of hemoproteins. These results suggest that increased mitochondrial respiration is facilitated by excess intracellular heme that is incorporated into hemoproteins. Our study aims to assess whether targeting mitochondrial function and heme synthesis affects NSCLC tumor growth and progression in vivo. To this end, luciferase-expressing NSCLC cells were implanted in NOD/SCID mice to generate lung orthotopic xenografts. The mice bearing orthotopically implanted NSCLC tumors were treated with various agents that target mitochondrial function alone (MTA1 or MTA2) and in combination with heme synthesis inhibitor. Tumor growth was monitored by noninvasive bioluminescence imaging (BLI). Our BLI data demonstrated that there was a significant reduction in radiance in mice that received the mitochondria-targeting agent alone (MTA1) and a combination of mitochondrial-targeting agents (MTA1 and MTA2). BLI data also demonstrated that there was a considerable reduction in radiance in mice that received combination of MTA and heme synthesis inhibitor. Treatments with combination of MTAs and heme inhibitor are under way. Our Immunohistochemistry data indicate that there was a reduction in expression of proteins involved in heme transport as well as hemoproteins involved in mitochondrial respiration in mice treated with the mitochondria-targeting agent. Our results suggest that targeting mitochondria significantly inhibits lung tumor growth by affecting proteins involved in heme synthesis and degradation, and consequently decreasing mitochondrial respiration. Citation Format: Sarada Preeta Kalainayakan, Poorva Ghosh, Sancharika Dey, Li Liu, Li Zhang. Targeting mitochondrial function in lung tumor growth and progression [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 5490.
Abstract 2331: Antioxidant enzymes mediate the survival of ECM-detached ovarian cancer cells
Authors: Calli A. Versagli, Cassandra Libbing
Journal: Cancer Research (2018)

Abstract Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer and is one of the leading causes of cancer death in women. It has been speculated that the high death rate associated with EOC is due to the fact that approximately 70% of all cases are diagnosed after the disease has already metastasized, thus making the illness more difficult to treat. In order to successfully survive the process of metastasis, EOC cells must be able to survive without anchorage to the extracellular matrix (ECM); however, the molecular mechanisms behind how EOC cells accomplish this feat has yet to be unveiled. Here, we present data that suggest antioxidant enzymes, namely Catalase, Peroxiredoxin 1, and Peroxiredoxin 2 all play a unique role in the survival and proliferation of ECM-detached SKOV3 cells. SKOV3 cells were genetically engineered to be deficient in Catalase, Peroxiredoxin 1, or Peroxiredoxin 2, and all three engineered cell types show abrogated anchorage-independent survival in soft agar. Furthermore, Catalase elimination in ECM-detached SKOV3 cells results in increased cell death at 48 hours, whereas elimination of Peroxiredoxin 1 or Peroxiredoxin 2 in ECM-detached SKOV3 cells results in decreased proliferation at 72 hours. Our current research is working to understand the molecular mechanisms behind the changes in survival and proliferation seen in antioxidant enzyme deficient SKOV3 cells. In aggregate, our data reveal that antioxidant enzymes may serve as attractive targets for the development of chemotherapeutics to eliminate metastatic ovarian cancer. Citation Format: Calli A. Versagli, Cassandra Libbing. Antioxidant enzymes mediate the survival of ECM-detached ovarian cancer cells [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 2331.
Abstract 4099: Novel patient-derived 3D (PD3D) cell models and matched patient-derived xenografts (PDX) from peritoneal metastasis of colorectal cancer for drug testing and biomarker analysis
Authors: Christian RA Regenbrecht, Guido Gambara, Eva Pachmayr, Alessandra Silvestri, Mathias Dahlmann, Bernadette Brzezicha, Britta Buettner, Beate Rau, Ulrich Keilholz, Urike Stein, Wolfgang Walther
Journal: Cancer Research (2018)

Abstract For patients with colorectal cancer (CRC) peritoneal metastases (PM) represent a terminal tumor stage with limited therapeutic options. To increase therapeutic efficacy and overall survival, availability of appropriate patient-derived 3D cell culture (PD3D) and patient-derived xenografts (PDX) models of PM could help improving the predictability of drug response for a specific tumor, but also foster the identification of novel biomarkers and therapeutic targets for CRC-PM patients. In this context, we generated the first scaffold-based PD3D and matching PDX models of CRC-PM as platform to test for chemotherapy response and to identify novel biomarkers. For model establishment, surgical specimens were processed either for PD3D cell culture or transplanted subcutaneously (s.c.) onto immunocompromized NOD scid gamma (NSG) mice. For 3D cell culture models, tissue was dissected, digested and filtered before embedding into a scaffold matrix. For PDX models engrafted tumors were transferred to NMRI nu/nu mice for further passaging. They were characterized by histopathology, immunohistochemistry and gene expression analyses using real-time RT-PCR. Chemosensitivity of both sibling models was evaluated on a panel of conventional chemotherapeutic and of targeted drugs. The same panel of drugs was used in 15 matched PD3D/PDX models and revealed individual response patterns both in PD3D and PDX. Most interestingly, different drug response pattern was observed in models derived from tumor tissue of the omentum vs. tissue from the peritoneum of the same patient. Our results demonstrate, that matched models maintain basic characteristics such as the morphology of the patient tumor in early passages, reflect heterogeneous response rates, and can be used as preclinical platform for translational studies of potential clinical use. Citation Format: Christian RA Regenbrecht, Guido Gambara, Eva Pachmayr, Alessandra Silvestri, Mathias Dahlmann, Bernadette Brzezicha, Britta Buettner, Beate Rau, Ulrich Keilholz, Urike Stein, Wolfgang Walther. Novel patient-derived 3D (PD3D) cell models and matched patient-derived xenografts (PDX) from peritoneal metastasis of colorectal cancer for drug testing and biomarker analysis [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 4099.