tbuckley/cabot-search huggingface dataset:
Cue exposure therapy for the treatment of alcohol use disorders: A meta-analytic review
Authors: Angelina I. Mellentin, Lotte Skøt, Bent Nielsen, Gerard M. Schippers, Anette S. Nielsen, Elsebeth Stenager, Carsten Juhl
Journal: Clinical Psychology Review (2017)

Cue Exposure Therapy (CET) is a behavioristic psychological approach to treating substance use disorders (SUD). Prior systematic reviews have found CET to be ineffective when targeting SUDs. The effect of this approach on alcohol use disorders (AUD) seems more promising at trial level but has yet to be systematically reviewed and quantitatively analyzed. Therefore, we aimed to examine the effectiveness of CET targeting AUD compared to active control conditions in a meta-analytic review. Following a systematic search of the literature, a total of seven controlled trials were identified. CET showed no to small additional effects on drinking intensity and drinking frequency, a small additional effect on total drinking score and a moderate additional effect on latency to relapse. Stratification and analysis of a-priori defined trial covariates revealed that CET may have an increased effect in the longer term, and that CET combined with urge-specific coping skills may be the better option for treating AUD than conventional CET. Also, CET may prove less effective when comparing it to cognitive behaviour therapy as opposed to other active control conditions. The overall quality of evidence was graded low due to high risk of bias, inconsistency, imprecision and suspected publication bias. Sounder methodological trials are needed to derive a firm conclusion about the effectiveness of CET for treating AUD.
Abstract 1447: Identification of an oncogenic germline <i>KRAS</i> truncating mutation in hereditary cancers
Authors: Moloy T. Goswami, Daniel H. Hovelson, Anna Johnson, Scott A. Tomlins, Lucy Wang, Kimberly Zhulke, Bhavneet Singh, Sharath Kumar Anand, Andi Cani, Albert Liu, Steven Kamberov, Yi-Mi Wu, Dan Robinson, Arul Chinnaiyan, Kathleen A. Cooney
Journal: Cancer Research (2017)

Abstract Somatic strongly activating KRAS mutations play an oncogenic role across numerous human cancers, while less activating germline KRAS mutations are associated with developmental disorders. KRAS encodes two splice variant products—KRAS-4A and KRAS-4B—differing in their C-terminus through alternative fourth coding exons. Though KRAS-4A is homologous to the original transforming transcript identified in Kirsten rat sarcoma virus, its role in human cancer is less characterized compared to KRAS-4B. Here, through genetic analyses of three cohorts of patients with hereditary and/or aggressive cancers, we identified a rare KRAS-4A specific C-terminal truncating germline mutation (KRAS-4A C180X; rs373169526) in affected men of three families with hereditary prostate cancer and a patient with hereditary melanoma (minor allele frequency [MAF] of 0.0014 in these combined cancer cohorts assessed vs. 0.000056 in the ExAC population database, odds ratio 24.6 [95% confidence interval 5.1-103.5], two sided Fisher’s exact test p = 9.0E-5). The KRAS-4A C180X mutation truncates the C-terminus, removing the polybasic region and -CAAX motifs previously demonstrated to be necessary for Ras family member membrane association, MAP kinase signaling activation and transformation, suggesting a loss of function phenotype. However, in silico assessment of reported human variation demonstrates truncating germline variants only in KRAS-4A and not KRAS-4B, consistent with tolerance. Expression of KRAS-4A protein in NIH3T3 and MDCK leads to loss of exclusive membrane association and inhibits GTP loading, as expected, but paradoxically resulted in modest but significantly increased proliferation and soft agar colony growth compared to control or wildtype KRAS expressing cells. Pro-oncogenic phenotypes were not dependent on MAPK signaling, but showed sensitivity to AKT inhibition. In summary, we identified a germline truncating KRAS-4A mutation over-represented in hereditary cancers that defines a novel mechanism of KRAS activation not dependent on the C-terminal polybasic and -CAAX motifs. Citation Format: Moloy T. Goswami, Daniel H. Hovelson, Anna Johnson, Scott A. Tomlins, Lucy Wang, Kimberly Zhulke, Bhavneet Singh, Sharath Kumar Anand, Andi Cani, Albert Liu, Steven Kamberov, Yi-Mi Wu, Dan Robinson, Arul Chinnaiyan, Kathleen A. Cooney. Identification of an oncogenic germline KRAS truncating mutation in hereditary cancers [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 1447. doi:10.1158/1538-7445.AM2017-1447
Abstract 3157: Osimertinib (AZD9291) is effective against NSCLC cells harboring <i>EGFR</i> exon 20 insertion mutations
Authors: Yusoo Lee, Tae Min Kim, Dong-Wan Kim, Yong-Oon Ahn, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dae Seog Heo
Journal: Cancer Research (2017)

Abstract Background: Although EGFR exon 20 insertion mutation is the third most common among EGFR-mutant NSCLC, this mutant clones are resistant to the first-generation EGFR TKIs. In addition, the efficacy of the second or third-generation EGFR TKIs is unknown in NSCLC with EGFR exon 20 insertion mutation. Methods: Various EGFR exon 20 insertion mutations were introduced into Ba/F3 cells as follows: A763_Y764insFQEA in C-helix; and V769_D770insASV, D770_N771insNPG, D770_N771insSVD, P772_H773insPR, H773_V774insNPH, H773_V774insH, and H773_V774insAH in loop following C-helix. The patient-derived SNU-3173 cell line was developed in a patient with EGFRH773_V774insAH mutation. Ba/F3 cells transfected with EGFR exon 20 insertion mutations and SNU-3173 were exposed to the EGFR TKIs (the 1st-generation gefitinib and erlotinib; the 2nd-generation dacomitinib and afatinib; and the 3rd-generation rociletinib, olmutinib, nazartinib, and osimertinib) and cell viability assays were performed. In addition, immunoblotting was performed to evaluate the downstream signals of EGFR pathway. Results: Cell viability assay showed that EGFR exon 20 insertion mutants are resistant to the 1st-generation EGFR TKIs, except for EGFRA763_Y764insFQEA-mutant Ba/F3 cells. IC50 values of the 2nd-generation EGFR TKIs are five to hundred-folds lower than the 1st-generation EGFR TKIs. The 2nd-generation EGFR TKIs were effective against EGFR exon 20 inserted Ba/F3 cells and down-regulated EGFR downstream signals. The 3rd-generation EGFR mutation-selective inhibitors showed a moderate efficacy except osimertinib that was effective and down-regulated EGFR downstream signals. In addition, SNU-3173 cells were moderately toxic to afatinib (IC50 46.2±5.2nM) as well as osimertinib (IC50 403.2±3.0nM). IC50 values of EGFR exon 20 insertion mutation Ba/F3 cellsIC50 (nM)FQEAASVSVDNPGPRHAHNPHGefitinib32.7525.7752.71597.01363.02581.02259.01701.0Erlotinib22.3486.9338.3765.7798.21523.01438.0562.1Dacomitinib0.00243.55.715.0205.0608.4556.312.3Afatinib0.0082.344.911.494.7297.7204.425.4Rociletinib219.7367.191.5131.21093.93710.05085.4498.7Olmutinib76.082.195.664.5332.6952.41406.6337.1Osimertinib3.68.18.9128.2247.2128.2880.338.2Nazartinib28.322.336.657.6747.8872.11606.8118.0 Conclusions: Overall, osimertinib showed effectiveness against NSCLC cells with EGFR exon 20 insertion mutations. Our results warrant a clinical trial of osimertinib in NSCLC patients with EGFR exon 20 insertion mutations. Citation Format: Yusoo Lee, Tae Min Kim, Dong-Wan Kim, Yong-Oon Ahn, Soyeon Kim, Bhumsuk Keam, Miso Kim, Dae Seog Heo. Osimertinib (AZD9291) is effective against NSCLC cells harboring EGFR exon 20 insertion mutations [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 3157. doi:10.1158/1538-7445.AM2017-3157
Abstract 2507: Using 1H NMR metabolomics to study breast cancer and endothelial cell metabolic interactions
Authors: Suehelay Acevedo-Acevedo, Sean P. Palecek
Journal: Cancer Research (2017)

Abstract Breast cancer is the second most commonly diagnosed cancer among women worldwide. Patient death is typically caused by metastasis development rather than the primary tumor. Metastasis in breast cancer has been shown to occur via blood and lymphatic vessels. Research shows that breast cancer cells ‘educate’ lymphatic and blood endothelial cells to support tumor growth by stimulating growth factor secretion; specifically VEGF, PDGF-BB and EGF secretion. In addition, cell metabolism is altered during malignant transformation. Cancer cells have increased energy and macromolecule biosynthesis requirements to sustain rapid proliferation. Increased angiogenesis observed in tumors points to a need for an increased nutrient supply. However, it remains unclear how tumor endothelial cell metabolism is altered and how metabolism regulates tumor angiogenesis. Therefore, this study aims to use 1H NMR metabolomics to identify breast cancer-endothelial cell metabolic interactions in a high-throughput manner. Firstly, we studied if in vitro co-culture with breast cancer altered endothelial cell metabolism. We identified distinct metabolic profiles for HUVECs grown in monoculture or co-culture with three different breast cancer cell lines. Metabolism of HUVECs co-cultured with MCF7 and SKBR3 breast cancer cell lines was significantly altered compared to mono-culture control. The most impacted metabolic pathways by co-culture were amino acid metabolism, energy metabolism and lipid biosynthesis pathways. Culturing HUVECs with MDA-MB-231 triple negative breast cancer cells did not have a significant impact on HUVEC metabolism, however. Together, these results indicate that culturing HUVECs with certain breast cancer lines causes significant changes in endothelial metabolism. Alterations in endothelial cell metabolism in response to breast cancer co-culture can further our understanding of tumor-vascular interactions and may lead to identification of metabolic biomarkers or therapeutic targets that can disrupt tumor angiogenesis. Citation Format: Suehelay Acevedo-Acevedo, Sean P. Palecek. Using 1H NMR metabolomics to study breast cancer and endothelial cell metabolic interactions [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 2507. doi:10.1158/1538-7445.AM2017-2507
Abstract 3344: AKT mediates transcriptional regulation of H3K4 demethylase in PTEN null prostate cancer
Authors: Mohammad Imran Khan, Suvasmita Rath, Qateeb Khan, Vaqar M. Adhami, Hasan Mukhtar
Journal: Cancer Research (2017)

Abstract One of the common contributors to the pre-disposition of most human cancers is inappropriate activation of AKT due to loss of its negative regulator PTEN. Activated AKT regulates changes in metabolic processes such as acetyl-CoA production that impacts chromatin. AKT phosphorylates a wide variety of histone modulating enzymes including acetyltransferases and methyltransferases resulting in their hyperactivation or inhibition. Therefore, understanding the impact of AKT inhibition on global histone modification would be ideal to identify novel histone modifiers regulated by AKT. We performed unbiased and comprehensive profiling of histone modifications in prostate specific PTEN knockout mice treated with an AKT inhibitor (Perifosine, 10mg/kg body weight daily for 4 weeks) and observed that AKT inhibition significantly induces di and tri methylation of H3K4, concomitant with reduction acetylation of H3K9. Changes in other histone modifications such as H3K36 and H3K79 methylation and acetylation were not observed. Mechanistically, we observed that AKT inihibiton reduces the expression of H3K4 methylation related histone demethylases KDM5 family, especially KDM5B expression at transcriptional level. Similar observations were noted at translational level also. To further understand the transcriptional regulation of KDM5B by AKT we focused on miR-137 and miR-138 as these have been shown to transcriptionally regulate H3K4 demethylases. We observed that AKT activation negatively regulated miR-137 but not miR-138 levels, which further transcriptionally represses KDM5B expression. Overexpression of miR-137 significantly reduced KDM5B and increased H3K4 di and tri methylation levels but failed to change AKT phosphorylation. Genetic knockdown of AKT or inhibition of AKT phosphorylation increased miR137 and reduced both KDM5B levels. Overall, we observed that AKT transcriptionally regulates KDM5B mainly via repression of miR137. Our data identify a mechanism by which PI3K/AKT signaling modulates the prostate cancer epigenome through regulating H3K4 methylation and KDM5B expression. Additional studies that assess the impact of AKT inhibiton on genome occupancy of H3K4 methylation will help in the identification of targets and devise novel strategies to enhance the therapeutic efficacy of PI3K/AKT inhibitors that are currently in clinical development. Citation Format: Mohammad Imran Khan, Suvasmita Rath, Qateeb Khan, Vaqar M. Adhami, Hasan Mukhtar. AKT mediates transcriptional regulation of H3K4 demethylase in PTEN null prostate cancer [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 3344. doi:10.1158/1538-7445.AM2017-3344
Abstract 4526: Attenuation of hypoxia in solid tumor with multifunctional upconversion nanoparticles to enhance photodynamic therapy
Authors: Yan Zhang, Jingqiu Li, Jun Hu, Xiangliang Yang
Journal: Cancer Research (2017)

Abstract As a non-invasive therapeutic technique, photodynamic therapy (PDT) requires sufficient oxygen in order to generate adequate singlet oxygen upon the excitation of photosensitizer using an appropriate light wavelength. It has limited efficacy in preexisting hypoxia in tumor and PDT-induced hypoxia, owing to the limit oxygen level in the tissue and the consumption of the oxygen during the PDT treatment. Herein, taking advantage of hyperbaric oxygen (HBO), multifunctional upconversion nanovehicle is constructed to overcome the above-mentioned problems. HBO provides timely oxygen supply during the treatment, which greatly enhances the photodynamic effect of the loaded nanoparticles, as demonstrated by the accelerated generation of 1O2 and elevated cytotoxicity. Tumor growth is greatly regressed in the HBO-PDT treated mice. Our finding provides new insights into the modulation of unfavourable tumor microenvironment with the perfect marriage between HBO and NIR-light sensitized upconversion nanoparticles to overcome the current limitation of cancer photodynamic therapies. Note: This abstract was not presented at the meeting. Citation Format: Yan Zhang, Jingqiu Li, Jun Hu, Xiangliang Yang. Attenuation of hypoxia in solid tumor with multifunctional upconversion nanoparticles to enhance photodynamic therapy [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 4526. doi:10.1158/1538-7445.AM2017-4526
Abstract 1939: Loss of MST/Hippo signaling promotes tumorigenesis in a genetically engineered mouse model of fusion-positive alveolar rhabdomyosarcoma
Authors: Kristianne Oristian, Lisa E. Crose, Rex Bentley, Nina Kuprasertkul, David G. Kirsch, Corinne Linardic
Journal: Cancer Research (2017)

Abstract While improvement in survival for pediatric cancer patients over the last 40 years has been encouraging, certain cancer types evade cure. One such example is fusion-positive alveolar rhabdomyosarcoma (aRMS), a pediatric soft tissue sarcoma of mesenchymal origin with skeletal muscle features and a 5-year survival rate of &amp;lt;50%. A hallmark of this aggressive malignancy is the t{2;13} translocation fusion gene PAX3-FOXO1 (PF). Primary cell-based modeling experiments in our laboratory and others have shown that PF is necessary but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously we showed that PF-positive aRMS tumorigenesis relies on alterations in Hippo pathway signaling, including upregulation of the YAP transcriptional co-activator, and downregulation of the MST/Hippo kinase, which occurs when the scaffold protein RASSF4 (itself a PF transcriptional target) binds and inhibits MST1/Hippo. We hypothesized that ablating MST/Hippo signaling in an existing genetically engineered mouse model (GEMM) of aRMS would accelerate tumorigenesis and provide insight into the role of this pathway in aRMS. To assess the role of MST/Hippo signaling in aRMS, MST1/2-floxed (Stk3F/F;Stk4F/F) mice were crossed with an established MSTWT aRMS GEMM driven by conditional expression of Pax3-Foxo1 from the endogenous Pax3 locus and conditional loss of Cdkn2a in Myf6-expressing cells. Statistical analysis revealed that compared to MSTWT aRMS control animals, MSTNull have significantly accelerated tumorigenesis (median survival 112 vs. 224 days, p&amp;lt; 0.0001) and increased tumor penetrance (76% vs. 27%). MSTNull animals developed tumors disproportionately in the head and neck as compared to control, and incurred multiple tumors per animal. Tumors were analyzed via immunohistochemistry for MyoD and myogenin, markers of RMS, as well as Myf5, an early marker of myogenesis. Tumors in both cohorts were for positive for aRMS markers. Tumor-derived cell lines were used for in vitro cell-based assays and molecular interrogation. We have identified the MST/Hippo signaling axis as an important tumor suppressor mechanism in aRMS. The rapid onset and increased penetrance of tumorigenesis in this GEMM provides a powerful tool for interrogating aRMS biology and screening novel therapeutics. Citation Format: Kristianne Oristian, Lisa E. Crose, Rex Bentley, Nina Kuprasertkul, David G. Kirsch, Corinne Linardic. Loss of MST/Hippo signaling promotes tumorigenesis in a genetically engineered mouse model of fusion-positive alveolar rhabdomyosarcoma [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 1939. doi:10.1158/1538-7445.AM2017-1939
Abstract 5326: EZH2 regulation through lysine 63 linked ubiquitination in prostate cancer
Authors: Wenfu Lu, Shenji Lu, Bo Li, Yingqiu Xie, Michael G. Izban, Billy R. Ballard, Sandeep A. Sathyanarayana, Samuel E. Adunyah, Robert J. Matusik, Zhenbang Chen
Journal: Cancer Research (2017)

Abstract Enhancer of zeste homolog 2 (EZH2) plays crucial roles on the development of cells and tissues as well as the progression of prostate cancer (PCa) and castration resistant prostate cancer (CRPC). EZH2 can upregulate and activate progenitor genes including androgen receptor (AR) and the target genes. However, the mechanisms by which EZH2 is regulated in PCa remain elusive. Literature reports that tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6) is essential for both normal tissue development and regulation of oncogenic signaling pathways in cancers. In this study, we reported that EZH2 is regulated by PTEN and SKP2 network in PCa. Specifically, we showed that the aberrant upregulation of EZH2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) in vitro and prostate tumors of Pten null mice in vivo, as compared to the controls. EZH2 levels were negatively correlated with TRAF6 in human PCa cells upon SKP2 dysregulation. Immunofluorescence (IF) staining results showed a co-localization of EZH2 and TRAF6 in nucleus of PC3 cells, and co-immunoprecipitation (co-IP) analysis further confirmed a physical binding of EZH2 and TRAF6 in PC3 cells. Ectopic expression of TRAF6 promoted the K63-linked polyubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. Conversely, TRAF6 knockdown resulted in a reduction of EZH2 polyubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of human EZH2 in vivo in 293T cells and in vitro in the recombinant human EZH2 protein, as compared with TRAF6 WT. Together, we report for the first time a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2-H3K27me3 in PCa cells. Our findings provide valuable clues on the mechanism and efficiency of targeting EZH2 in PCa and CRPC . Note: This abstract was not presented at the meeting. Citation Format: Wenfu Lu, Shenji Lu, Bo Li, Yingqiu Xie, Michael G. Izban, Billy R. Ballard, Sandeep A. Sathyanarayana, Samuel E. Adunyah, Robert J. Matusik, Zhenbang Chen. EZH2 regulation through lysine 63 linked ubiquitination in prostate cancer [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 5326. doi:10.1158/1538-7445.AM2017-5326
Abstract 4315: PTBP1 modulation of MCL1 mRNA regulates sensitivity to antitubulin chemotherapeutics
Authors: William J. Placzek, Jia Cui
Journal: Cancer Research (2017)

Abstract Background: Myeloid Cell Leukemia 1 (MCL1), an anti-apoptotic Bcl-2 family protein, is a key regulator of intrinsic apoptosis. Normal cells require strict control over MCL1 expression and aberrant MCL1 expression has been shown linked to the emergence of various diseases and chemoresistance. Previous studies have detailed how MCL1 expression is regulated by multiple mechanisms both transcriptionally and translationally. However, characterization of the post-transcriptional regulators of MCL1 mRNA is limited. Polypyrimidine tract binding protein 1 (PTBP1) is a known regulator of post-transcriptional gene expression that can control mRNA splicing, translation, stability, and localization. In the described study we characterize the impact that PTBP1 has on MCL1 expression, its molecular mechanisms, and its roles on cellular apoptosis. Methods: Cross-linking Immunoprecipitation (CLIP)-seq data analysis and RNA immunoprecipitation (RIP) were performed to analyze protein interactions with RNA and map the RNA binding sites on the genes of interests. RNA half-life was measured by treating cells with Actinomycin D and extracting total RNA at different time point. Cell viability was measured by the MTS assay and apoptosis was assessed by Annexin V/Propidium Iodide (PI) staining followed by flow cytometry analysis. Results: Our studies demonstrate that PTBP1 binds to MCL1 mRNA and that knockdown of PTBP1 up-regulates MCL1 expression in cancer. Mechanistically, PTBP1 silencing stabilizes MCL1 mRNA and increases MCL1 mRNA accumulation in cytoplasm. We further identify that this post-transcriptional regulation is mediated by microRNAs and Argonaute2 (Ago2). Moreover, we show that PTBP1 down-regulation is anti-apoptotic to antitubulin chemotherapeutics in a MCL1-dependent manner. Conclusions: Our findings suggest that PTBP1 is a novel post-transcriptional regulator of MCL1 mRNA by which it controls apoptotic response to antitubulin chemotherapeutics. Note: This abstract was not presented at the meeting. Citation Format: William J. Placzek, Jia Cui. PTBP1 modulation of MCL1 mRNA regulates sensitivity to antitubulin chemotherapeutics [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 4315. doi:10.1158/1538-7445.AM2017-4315