tbuckley/cabot-search huggingface dataset:
Abstract 3973: Dabrafenib suppresses the growth of <i>BRAF-WT</i> cancers through inhibition of novel targets Nek9 and Cdk16
Authors: Manali S. Phadke, Lily Rix, Inna Smalley, Annamarie Bryant, Harshani Lawrence, Braydon Schaible, Ann Chen, Uwe Rix, Keiran Smalley
Journal: Cancer Research (2018)

Abstract Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS and KRAS-mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho-CHK1, decreased CDK4 expression and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS and KRAS-mutant cancer cells by dabrafenib but not vemurafenib. Combined silencing of NEK9 and CDK16 were associated with enhanced inhibition of melanoma cell proliferation and a greater induction of cell cycle arrest. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations. Citation Format: Manali S. Phadke, Lily Rix, Inna Smalley, Annamarie Bryant, Harshani Lawrence, Braydon Schaible, Ann Chen, Uwe Rix, Keiran Smalley. Dabrafenib suppresses the growth of BRAF-WT cancers through inhibition of novel targets Nek9 and Cdk16 [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 3973.
Abstract 4708: Imprime (beta-1,3/1,6 glucan) synergizes with a CD40 agonist to stimulate T cell-dependent antitumor activity in a poorly immunogenic model of pancreatic carcinoma
Authors: Mingen Liu, Kathleen Graham, Anissa S. Chan, Nadine R. Ottoson, Nandita Bose, Gregory L. Beatty
Journal: Cancer Research (2018)

Abstract Introduction: While some solid tumors show remarkable sensitivity to immunotherapy, pancreatic ductal adenocarcinoma (PDAC) has demonstrated impressive resistance. This poor responsiveness to immunotherapy may reflect multiple mechanisms necessary for generating productive T-cell immunosurveillance, including ineffective tumor antigen presentation by myeloid cells. Here, we hypothesized that combining two immune agonists capable of “licensing” myeloid cells with enhanced T-cell stimulatory properties would synergize to reverse the poorly immunogenic state of pancreatic cancer and, in doing so, drive productive T cell-dependent antitumor immunity. Methods: C57BL/6 mice were challenged subcutaneously with a syngeneic PDAC cell line (7940B.PDA) derived from a tumor arising spontaneously in the KrasG12D/+; Trp53R172H/+; Pdx-1 Cre (KPC) mouse model. Mice with tumors measuring approximately 5 mm3 in diameter were treated with defined combinations of gemcitabine chemotherapy, a CD40 agonist (FGK45), and Imprime (a yeast β-1,3/1,6 glucan that coordinately activates innate and adaptive immune responses through pattern recognition receptors). CD4 and CD8 T cells were depleted in vivo using GK1.5 and 2.43 antibodies, respectively. Tumor growth curves and overall survival were determined. Results: Monotherapy with Imprime or a CD40 agonist only modestly delayed tumor outgrowth compared to chemotherapy alone. Delivering chemotherapy 48 hours prior to Imprime administration produced a two-fold increase in the median overall survival, but responses were not durable and all mice relapsed. In contrast, concurrent single administration of Imprime and a CD40 agonist induced complete and durable regressions in 60% of mice. Tumor-free mice resisted tumor rechallenge and therapeutic efficacy was completely abrogated with CD4/CD8 cell depletion. Conclusions: The combination of two myeloid-directed immune agonists (Imprime and a CD40 agonist) shows promising activity for stimulating T cell-dependent antitumor immunity against PDAC, a poorly immunogenic cancer. Citation Format: Mingen Liu, Kathleen Graham, Anissa S. Chan, Nadine R. Ottoson, Nandita Bose, Gregory L. Beatty. Imprime (beta-1,3/1,6 glucan) synergizes with a CD40 agonist to stimulate T cell-dependent antitumor activity in a poorly immunogenic model of pancreatic 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 4708.
Early start of the West Nile fever transmission season 2018 in Europe
Authors: Joana M. Haussig, Johanna J. Young, Céline M. Gossner, Eszter Mezei, Antonino Bella, Anca Sirbu, Danai Pervanidou, Mitra B. Drakulovic, Bertrand Sudre
Journal: Eurosurveillance (2018)

In Europe, surveillance indicates that the 2018 West Nile fever transmission season started earlier than in previous years and with a steeper increase of locally-acquired human infections. Between 2014 and 2017, European Union/European Economic Area (EU/EEA) and EU enlargement countries notified five to 25 cases in weeks 25 to 31 compared with 168 cases in 2018. Clinicians and public health authorities should be alerted to ensure timely implementation of prevention measures including blood safety measures.
Oppression of Left Main Trunk Due to Pseudoaneurysm With Graft Detachment in Patients With Behcet Disease Previously Treated by Bentall Procedure
Authors: YuKataoka, TakeshiTsutsumi, KouheiIshibashi, MasahiroHigashi, IsaoMorii, AtsushiKawamura, HatsueIshibashi-Ueda, KenjiMinatoya, HitoshiOgino, YoritakaOtsuka
Journal: Circulation (2009)
Molecular Genetics and New Medication Strategies for Opioid Addiction
Authors: Yasmin L. Hurd, Charles P. O’Brien
Journal: American Journal of Psychiatry (2018)

The opioid epidemic is at the epicenter of the drug crisis, resulting in an inconceivable number of overdose deaths and exorbitant associated medical costs that have crippled many communities across the socioeconomic spectrum in the United States. Classic medications for the treatment of opioid use disorder predominantly target the opioid system and thus have been underutilized, in part due to their own potential for abuse and heavy regulatory burden for patients and clinicians. Opioid antagonists are now evolving in their use, not only to prevent acute overdoses but as extended-use treatment options. Strategies that target specific genetic and epigenetic factors, along with novel nonopioid medications, hold promise as future therapeutic interventions for opioid abuse. Success in increasing the treatment options in the clinical toolbox will, hopefully, help to end the historical pattern of recurring opioid epidemics. [AJP at 175: Remembering Our Past As We Envision Our Future Drug Addiction in Relation to Problems of Adolescence Zimmering and colleagues wrote in the midst of an opiate epidemic among young people that "only the human being, or rather certain types of human beings, will return to the enslaving, self-destructive habit." (Am J Psychiatry 1952; 109:272-278 )].
Abstract 2230: Low frequency variant detection in cell free DNA by applying molecular identifiers to targeted NGS
Authors: Ashley Wood, Sukhinder Sandhu, Mida Pezeshkian, Vanessa Kelchner, Jordan RoseFigura, Justin Lenhart, Laurie Kurihara, Vladimir Makarov
Journal: Cancer Research (2018)

Abstract The growing use of liquid biopsy for early detection and monitoring of disease necessitates accurate variant detection at &amp;lt;1% allele frequencies due to a low population of disease DNA within circulating, cell-free DNA (cfDNA). Reliable, low-frequency variant detection by next-generation sequencing (NGS) is challenging due to background noise from PCR and sequencing errors. We employed molecular identifiers (MIDs) to uniquely label individual DNA molecules prior to amplification, facilitating the distinction of true variants from PCR and sequencing errors. We incorporated MIDs in both our amplicon library prep that uses multiplex PCR for targeted NGS and our whole genome library prep followed by targeting with hybridization capture using an 800kb pan-cancer panel. We performed low frequency spike-in experiments at &amp;lt;1% allele frequencies. We prepared MID libraries with various amplicon panels including a 17 amplicon EGFR pathway panel and a 104 amplicon SNP panel. Deep sequencing to &amp;gt;30,000x was done to maximize MID family size (number of PCR duplicates) and optimize generation of a consensus sequence. This analysis identified all known variants present at 1%, 0.5%, and 0.25% allele frequencies. Next, the hybridization capture libraries were prepared with low-frequency spike-in samples, sequenced to &amp;gt;8000x, and all known variants at 1% and 0.5% allele frequencies were maintained in the consensus data. In both cases, the number of false positives was reduced, resulting in improved specificity. Further, EGFR amplicon libraries and hybridization capture libraries were prepared using cfDNA samples from lung, ovarian, liver, stomach, and colon cancers. Variant calling based on MID generated consensus sequences identified mutations in cfDNA samples as well as corresponding tumor and normal samples when available. This study highlights the ability of MID technology to enable low frequency variant detection, critical to track known variants and identify novel pathogenic mutations in cfDNA samples. Citation Format: Ashley Wood, Sukhinder Sandhu, Mida Pezeshkian, Vanessa Kelchner, Jordan RoseFigura, Justin Lenhart, Laurie Kurihara, Vladimir Makarov. Low frequency variant detection in cell free DNA by applying molecular identifiers to targeted NGS [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 2230.
Impairment of Endothelium-Dependent Arterial Relaxation By High-Fat Feeding in ApoE-Deficient Mice
Authors: ValérieDeckert, GérardLizard, NicolasDuverger, AnneAthias, VivianePalleau, FlorenceEmmanuel, MaryvonneMoisant, PhilippeGambert, ChristianLallemant, LaurentLagrost
Journal: Circulation (1999)

Background—Atherogenic lipoproteins can impair the endothelium-dependent arterial relaxation, and circumstantial evidence suggests a beneficial role of plasma high density lipoproteins and apolipoprotein (apo) A-I in counteracting the endothelium dysfunction. In the present study, vascular reactivity was determined in control, apoE-deficient mice (apoE-KO mice), and apoE-deficient mice expressing human apoA-I (apoE-KO/HuAITg mice). Methods and Results—In the first part of the study, control and apoE-KO mice were fed a low-fat or a high-fat diet for 23 weeks, and the vasoactive responses of isolated thoracic aortic segments to norepinephrine, sodium nitroprusside, and acetylcholine (ACh) were determined. Whereas norepinephrine, sodium nitroprusside, and ACh evoked similar vascular responses in control and apoE-KO mice fed the low-fat diet, high-fat feeding in apoE-KO mice produced a significant 3-fold increase in the mean concentration required to produce a half-maximal relaxing effect (EC50) of ACh as com...
Abstract 194: Prognostic implication of stromal hyaluronic acid protein expression in resected oropharynx and oral cavity cancer
Authors: Yoon Ho Ko, Hye Sung Won, Der Sheng Sun, Soon Auck Hong, Ji Hyung Hong
Journal: Cancer Research (2018)

Abstract Background: Hyaluronic acid (HA) is a well-characterized component of extracellular matrix (ECM), which plays a critical role in a variety of cellular processes and regulates cell adhesion, migration, and proliferation associated with prognosis of various tumor types. However, the clinical prognostic significance in resected head and neck squamous cell carcinoma (HNSCC) is not well identified. Methods: The resected tissues from oropharynx or oral cavity cancer patients undergoing surgery were made for tissue microarray (TMA) divided into stroma and cancer panels. Including HA protein expression, HA synthases (HAS) and hyaluronidases (HYAL1) was also assessed by immunohistochemistry. Results: A total of 160 resected oropharynx or oral cavity cancer tissues between 1994 and 2012 were analyzed in this study. Stromal HA expression, positive in 31 (19.4%) of patients, showed a trend favoring for HPV negative tumor. Other clinicopathological characteristics did not differ according to stromal HA protein expression. However, the HA expression in stroma were statistically associated with clinical outcomes. In the multivariate analysis for clinical outcomes, stromal HA expression was found to be an independent indicator for disease recurrence. (HR, 2.716; 95 % CI, 1.323 - 5.575, P = 0.007), and the combined analysis of tumoral and stromal expression of HA showed that patients with a cancer and stroma-positive HA expression showed a significantly worse outcome than those with other combinations (RFS, P = 0.023, OS, P = 0.082). In addition, when using stratification of HPV stastus, the stromal HA expression remained an independent indicator for disease recurrence and survival(HR, 2.712; 95% CI, 1.323 - 5.56; P = 0.006). Conclusions: The HA expression in stroma could be related with poor prognosis independently in surgically resected HNSCC. Thus, the finding suggested that HA in stroma may serve not only as a prognostic marker but also as a supposed target for HNSCC treatment. Citation Format: Yoon Ho Ko, Hye Sung Won, Der Sheng Sun, Soon Auck Hong, Ji Hyung Hong. Prognostic implication of stromal hyaluronic acid protein expression in resected oropharynx and oral cavity cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 194.
Abstract 4135: <i>c-MYC</i> drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification
Authors: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Xu Beisi, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look
Journal: Cancer Research (2018)

Abstract The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that c-MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high risk childhood neuroblastomas. Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Xu Beisi, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. c-MYC drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [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 4135.
Tailoring Chemotherapy for the African-Centric S47 Variant of TP53
Authors: Thibaut Barnoud, Anna Budina-Kolomets, Subhasree Basu, Julia I.-Ju Leu, Madeline Good, Che-Pei Kung, Jingjing Liu, Qin Liu, Jessie Villanueva, Rugang Zhang, Donna L. George, Maureen E. Murphy
Journal: Cancer Research (2018)

The tumor suppressor TP53 is the most frequently mutated gene in human cancer and serves to restrict tumor initiation and progression. Single-nucleotide polymorphisms (SNP) in TP53 and p53 pathway genes can have a marked impact on p53 tumor suppressor function, and some have been associated with increased cancer risk and impaired response to therapy. Approximately 6% of Africans and 1% of African Americans express a p53 allele with a serine instead of proline at position 47 (Pro47Ser). This SNP impairs p53-mediated apoptosis in response to radiation and genotoxic agents and is associated with increased cancer risk in humans and in a mouse model. In this study, we compared the ability of wild-type (WT) and S47 p53 to suppress tumor development and respond to therapy. Our goal was to find therapeutic compounds that are more, not less, efficacious in S47 tumors. We identified the superior efficacy of two agents, cisplatin and BET inhibitors, on S47 tumors compared with WT. Cisplatin caused dramatic decreases in the progression of S47 tumors by activating the p53/PIN1 axis to drive the mitochondrial cell death program. These findings serve as important proof of principle that chemotherapy can be tailored to p53 genotype.Significance: A rare African-derived radioresistant p53 SNP provides proof of principle that chemotherapy can be tailored to TP53 genotype. Cancer Res; 78(19); 5694-705. ©2018 AACR.
Abstract 1567: Ku70, Ku80 and Rab5C as biomarkers for radiotherapy resistance in rectal tumors during neoadjuvant therapy
Authors: Vilma Regina Martins, Antuani Rafael Baptistella, Petrus Paulo Silva, Edson Kuatelela Cassinela, Fabio Marchi, Adriana Fp Leme, Maria Dirlei Begnami, Samuel Aguiar
Journal: Cancer Research (2018)

Abstract Rectal cancer is the second most common cancer in the large intestine, corresponding to one-third of the total cases of colorectal cancer. The neoadjuvant chemoradiation in rectal cancer treatment reduces the risk of local recurrence, but pathologic complete response is achieved only in 10-40% of patients. The response to neoadjuvant treatment is poorly understated in rectal tumors as well as the mechanisms associated with chemoradiation resistance. In order to identify the players involved with the therapy resistance, we performed proteomic analysis of biopsies from stage II and III rectal adenocarcinoma patients before neoadjuvant treatment and compared with residual tumor tissue removed by surgery after neoadjuvant therapy. Ku70, Ku80 and Rab5C showed a significant increased expression after the chemoradiation treatment. To better understand the mechanism associated with therapy resistance, we generated an ionizing radiation-resistant rectal adenocarcinoma cell line. These cells and also their secreted exosomes exhibit overexpression of the same three proteins identified in tissue samples from patients submitted to chemoradiation. Using this in vitro model, we identified that Rab5C modulates EGFR internalization promoted by irradiation, which was also essential to regulate the expression of the DNA repair proteins Ku70 and Ku80, and cell resistance to ionizing radiation. Taken together, these findings indicate that EGFR and Rab5C are potential targets to sensitize rectal cancer cells to neoadjuvant treatment. In addition, the presence of Ku70, Ku80 and Rab5C in circulating exosomes can be explored as biomarkers to follow resistance to radiotherapy in patients under neoadjunat therapy for rectal tumors. Citation Format: Vilma Regina Martins, Antuani Rafael Baptistella, Petrus Paulo Silva, Edson Kuatelela Cassinela, Fabio Marchi, Adriana Fp Leme, Maria Dirlei Begnami, Samuel Aguiar. Ku70, Ku80 and Rab5C as biomarkers for radiotherapy resistance in rectal tumors during neoadjuvant therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1567.
<i>In Vivo</i> Estimation of Oncolytic Virus Populations within Tumors
Authors: Mi-Yeon Jung, Chetan P. Offord, Matthew K. Ennis, Iris Kemler, Claudia Neuhauser, David Dingli
Journal: Cancer Research (2018)

The use of replication-competent viruses as oncolytic agents is rapidly expanding, with several oncolytic viruses approved for cancer therapy. As responses to therapy are highly variable, understanding the dynamics of therapy is critical for optimal application of virotherapy in practice. Although mathematical models have been developed to understand the dynamics of tumor virotherapy, a scarcity of in vivo data has made difficult parametrization of these models. To tackle this problem, we studied the in vitro and in vivo spread of two oncolytic measles viruses that induce expression of the sodium iodide symporter (NIS) in cells. NIS expression enabled infected cells to concentrate radioactive isotopes that could be reproducibly and quantitatively imaged using SPECT/CT. We observed a strong linear relationship in vitro between infectious virus particles, viral N and NIS gene expression, and radioactive isotope uptake. In vivo radioisotope uptake was highly correlated with viral N and NIS gene expression. Similar expression patterns between viral N and NIS gene expression in vitro and in vivo implied that the oncolytic virus behaved similarly in both scenarios. Significant titers of viable virus were consistently isolated from tumors explanted from mice that had been injected with oncolytic measle viruses. We observed a weaker but positive in vivo relationship between radioisotope uptake and the viable virus titer recovered from tumors; this was likely due to anisotropies in the viral distribution in vivo These data suggest that methods that enable quantitation of in vivo anisotropies are required for continuing development of oncolytic virotherapy.Significance: These findings address a fundamental gap in our knowledge of oncolytic virotherapy by presenting technology that gives insight into the behavior of oncolytic viruses in vivoCancer Res; 78(20); 5992-6000. ©2018 AACR.