tbuckley/cabot-search huggingface dataset:
Abstract 4813: In vivo modeling of high grade glioma for oncology drug development
Authors: Cecilia Krona, Soumi Kundu, Karl Holmberg-Olausson, Riasat Islam, Rashmi Ramachandra, Ludmila Elfineh, Sven Nelander
Journal: Cancer Research (2017)

Abstract In a multi-disciplinary project, patient derived glioblastoma stem-cell cultures (GSCs) have been established and characterized extensively with the goal of applying computational efforts to integrate results from high-throughput screens of drugs and RNAi with genomic and transcriptional profiling to predict the most successful therapy for individual glioma patients. The main goal of this study was to develop a platform for testing the tumor-initiating capacity of GSCs in mouse brain and to label the cells with GFP-luciferase to enable non-invasive quantification of tumor growth by in vivo bioluminescence imaging. Adherently grown GFP-luciferase labeled glioblastoma stem-cell cultures were dissociated and injected stereotactically into immunodeficient mice. Tumor growth was monitored by IVIS imaging for up to 40 weeks and brains were collected for histopathological and immunohistochemical stainings. Automatic quantification and growth pattern analysis of tumor cells in brain sections was set up based on human cell specific staining and a CellProfiler Analyst’s machine learning classifier with a manual observer correlation of 0.86. GSC xenograft tumors with a wide range of histopathological features and biological behaviors recapitulating high grade astrocytoma was confirmed in mice injected with 14 of the 29 glioblastoma cell cultures (48%). Glial lineage markers, such as Sox2, GFAP, and Olig2, were expressed both in patient tumors and patient derived xenografts. Individual glioblastoma cell cultures were either characterized by formation of condensed tumors (8/14, 57%) or diffuse infiltrative growth through the brain parenchyma (6/14, 43%). In summary, we present a valuable mouse model for preclinical studies of glioma. Integrative analysis of molecular profiles with growth pattern data has the potential to unravel genes that distinguish tumors with more infiltrative growth. Our biobank of luciferase labeled GSCs may be useful for longitudinal monitoring of tumor growth dynamics in the setting of therapies and provides a foundation for testing the effect of predicted drug vulnerabilites in orthotopic xenografts mouse models. Citation Format: Cecilia Krona, Soumi Kundu, Karl Holmberg-Olausson, Riasat Islam, Rashmi Ramachandra, Ludmila Elfineh, Sven Nelander. In vivo modeling of high grade glioma for oncology drug development [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 4813. doi:10.1158/1538-7445.AM2017-4813
Abstract 2060: Characterizing acquired resistance to palbociclib in breast cancer
Authors: Smruthi Vijayaraghavan, Iman Doostan, Jason P.W. Carey, Khandan Keyomarsi
Journal: Cancer Research (2017)

Abstract The CDK4/6 inhibitor palbociclib is currently being used in combination with endocrine therapy to treat advanced ER positive breast cancer patients. While this treatment has shown great promise in the clinic, about 25% of the patients do not respond, and almost all patients eventually acquire resistance to palbociclib treatment. Hence, understanding the mechanism(s) of acquired resistance to CDK4/6 inhibition is crucial to devise alternate treatment strategies. To interrogate this, we developed MCF7 and T47D resistant cells by treating them with increasing doses of palbociclib over a 6-month period. After confirming that these cells were resistant to palbociclib, we performed genome-wide expression analysis via RNA-seq, in comparison with the parental (sensitive) cells. RNA- seq analysis revealed 2888 differentially expressed genes (p&amp;lt;0.05) in the resistant cells when compared to parental. Further, gene set enrichment analysis (GSEA) revealed enrichment of immune pathways (interferon alpha and gamma response, immune response) and pathways known to regulate EMT and cancer stem cells (IL-6/Stat3, IL-2/STAT-5, Notch, Wnt) in the resistant cells. Additionally, GSEA analysis revealed downregulation of G2/M checkpoint, estrogen response and DNA repair pathways (double strand break repair). Thus, this data suggests that combined targeting of two or more pathways that are altered in the resistant cells can provide a novel therapeutic strategy to combat CDK4/6 inhibitor resistance. Citation Format: Smruthi Vijayaraghavan, Iman Doostan, Jason P.W. Carey, Khandan Keyomarsi. Characterizing acquired resistance to palbociclib in breast 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 2060. doi:10.1158/1538-7445.AM2017-2060
Abstract 863: Neuronal splicing regulatory factors are upregulated in models of epithelial-mesenchymal transition
Authors: Yevgenia L. Khodor, Julia Froese, Frank Gertler, Robert A. Weinberg, Christopher B. Burge
Journal: Cancer Research (2017)

Abstract Epithelial-mesenchymal transition (EMT) is an essential developmental program through which epithelial cells lose their polarity and junctions with neighboring cells and acquire migratory and invasive properties. Cancer cells hijack at least a portion of the EMT program to increase their invasive properties, acquire resistance to senescence, and metastasize. Major changes in cell signaling, transcriptional and post-transcriptional regulation occur during EMT. To study post-transcriptional changes we characterized gene expression and splicing across EMT in 3 cell culture models of EMT: the luminal epithelial MCF7ras breast cancer cell line with EMT induced by SLUG+SOX9 and in basal human mammary epithelial (HMLEras) cells, with EMT induced by either SNAIL or ZEB1. RNA-seq was performed at 2-day intervals across these transitions. We observed broad overlaps between these systems, with 821 genes that changed significantly in all three. In all three time courses, genes associated with cell cycle and growth decreased in expression, while genes associated with signaling, cell motion, adhesion, extracellular matrix organization, and differentiation increased. Intriguingly, genes associated with neurogenesis and angiogenesis were also induced in the MCF7 and HMLER-Snail time courses. Those include known axon guidance and angiogenic factors in the Robo and Slit families. We also found many alternative splicing events shared in all 3 systems, including 272 skipped exons. Sequence analysis of regions around these exons revealed binding motifs for canonical splicing regulators, including ESRP1 and ESRP2 and the RBFOX protein family, which are known to play a role in EMT. While most genes encoding RNA binding proteins decreased in expression in EMT, a small subset consistently increased in expression, including some that matched our motif analysis. Specifically, several splicing factors associated with nervous system development were upregulated, including factors of the QKI and NOVA families. We have validated the increased expression of QKI and NOVA1 proteins during EMT in vitro, and of QKI and NOVA2 in tumor sections. Further, we found that perturbation of QKI expression affects the motility of mesenchymal cancer cells in culture. Together, our results point to the existence of a program of alternative splicing shared between neuronal and mesenchymal cells. Citation Format: Yevgenia L. Khodor, Julia Froese, Frank Gertler, Robert A. Weinberg, Christopher B. Burge. Neuronal splicing regulatory factors are upregulated in models of epithelial-mesenchymal transition [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 863. doi:10.1158/1538-7445.AM2017-863
Abstract 1613: Genetically modified neuronal stem cells expressing IL-12 and TNFSF14 attenuate highly metastatic mammary tumors in a mouse model
Authors: Tej B. Shrestha, Dezhang Lu, Matthew T. Basel, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer
Journal: Cancer Research (2017)

Abstract Interleukin 12 (IL-12) is a heterodimeric cytokine encoded by two genes, p35 and p40. IL-12, also known as T cell-stimulating factor, induces proliferation of T-lymphocytes and natural killer (NK) cells, while also demonstrating an anti-angiogenic effect and inhibition of regulatory T cells. Similarly, LIGHT (TNFSF14) is a transmembrane protein which acts as a costimulatory factor for the activation lymphoid cells and stimulates the proliferation of T cells, leading to increased apoptosis of tumor cells. Expression of IL-12 and LIGHT specifically in the tumor region could activate T cells and stimulate the immune system to attenuate the tumor. Tumor homing neuronal stem cells C17.2 (NSC) were genetically engineered to express the mouse-LIGHT gene and IL-12 using a retrovirus. The expression of LIGHT and IL-12 genes in NSC was confirmed by PCR, ELISA and Western blot. To test the antitumor effects of the engineered cells, Balb/C mice bearing 4T1 mammary tumors were treated with NSC-LIGHT, NSC-IL-12 and NSC-LIGHT/IL-12 cells intratumorally (I.T.) at day nine. Repeated tumor measurement over time showed attenuation of mammary tumor growth in the both NSC/IL-12 and NSC/LIGHT groups in comparison with control groups PBS and NSC. Tumor growth was further reduced by treating the mice with NSC expressing both cytokines LIGHT and IL-12. Tumor metastasis was also evaluated by removing the primary tumor surgically and observing mice for any sign of metastatic burden. Treatment groups had less metastatic tumor burden and survived longer than the control group. Therefore, tumor homing NPC-LIGHT/IL-12 cells could be effective for the treatment of highly metastatic mammary tumors. Citation Format: Tej B. Shrestha, Dezhang Lu, Matthew T. Basel, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer. Genetically modified neuronal stem cells expressing IL-12 and TNFSF14 attenuate highly metastatic mammary tumors in a mouse model [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 1613. doi:10.1158/1538-7445.AM2017-1613
Abstract 2274: Extreme telomere length was associated with gastric adenocarcinoma risk: The Singapore Chinese Health Study
Authors: Zhensheng Wang, Woon-Puay Koh, Aizhen Jin, Renwei Wang, Jian-Min Yuan
Journal: Cancer Research (2017)

Abstract Background: Evidence regarding extreme telomere length and increased gastric cancer risk has been limited in retrospective case-control study setting which was potentially subjected to selection bias and reverse causality. We conducted a prospective analysis in an Eastern Asian population to examine the hypothesis that extreme telomere length is associated with increased risk of gastric adenocarcinoma. Methods: Among 63,257 participants of the Singapore Chinese Health Study, a population-based prospective cohort of Chinese men and women aged 45-74 years recruited between 1993 and 1998, 28,219 provided baseline blood samples. We used quantitative polymerase chain reaction (PCR) method to quantify relative telomere length determined by the ratio of telomere repeat copy number (T) to single-copy gene for albumin (S) (i.e., TSR) on all subjects. The present analysis included 24,846 subjects with valid TSR values after excluding samples with insufficient DNA (n = 1,908) and/or patients with prevalent cancer at baseline blood draw (n = 1,465). As of December 31, 2014, 191 study participants who were free of cancer developed gastric adenocarcinoma. The information on demographic and lifestyle characteristics was collected using structured questionnaires at baseline and two follow-up interviews. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and the corresponding 95% confidence interval (CI) of developing gastric adenocarcinoma for different levels of decile TSR. Restricted cubic spline (RCS) analysis was applied to examine the nonlinear relationship between TSR level and gastric adenocarcinoma risk. Results: The RCS analysis revealed a U-shaped relationship between TSR and gastric adenocarcinoma risk (p-value for non-linear association=0.009). Compared with the 4th decile, HR (95% CI) for the lowest and highest deciles of TSR 2.27 (1.17-4.40) and 1.98 (0.95-4.13), respectively after adjusting for age, sex, education, interview year, dialect group and smoking status. Conclusions: This was the first prospective analysis of TSR and risk of developing gastric adenocarcinoma in a general population. The study demonstrates both extreme short and long telomere length to be associated with significantly increased risk of gastric adenocarcinoma. These results suggest a complex relationship between telomere length and gastric cancer risk. Citation Format: Zhensheng Wang, Woon-Puay Koh, Aizhen Jin, Renwei Wang, Jian-Min Yuan. Extreme telomere length was associated with gastric adenocarcinoma risk: The Singapore Chinese Health Study [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 2274. doi:10.1158/1538-7445.AM2017-2274
Abstract 3828: The role of CK2 for overcoming paclitaxel resistance in gastric cancer
Authors: Minkyu Jung
Journal: Cancer Research (2017)

Abstract Despite advances in cancer treatment, gastric cancer is still one of the most fatal cancers. This is because paclitaxel, the most widely used treatment for gastric cancer, has limited clinical utility by the development of resistance. Casein kinase 2 (CK2) activation has been reported to be involved in proliferation in various tumors and resistance form chemotherapy. Therefore, we investigated the association between paclitaxel resistance and CK2 activation. CK2 expression was evaluated by immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded tumors from 59 AGC patients who were treated with paclitaxel as second line therapy. Patients with high expression of CK2 (29/59, 39%) showed lower disease control rate (DCR) (47.7 % vs. 72.3 %, p=0.017) and shorter progression free survival (PFS) (2.8 months vs. 4.8 months, p=0.009) compared to those who with low expression. Cell proliferation assay were carried out by MTT assay after drug treatment with paclitaxel, CX-4945 (CK2 inhibitor) in 49 gastric cancer cell lines. CK2 protein expression was shown to be associated with paclitaxel sensitivity. Of the gastric cancer cell lines, SNU-1 was selected for paclitaxel resistance, high expression of CK2, and high sensitivity to CX-4945. Combination therapy CX-4945 and paclitaxel showed synergistic antitumor effect in SNU-1 by MTT assay and showed inhibition of down signaling of PI3K/AKT pathway on western blot. In conclusion, CK2 activation was shown to be related to paclitaxel resistance. CX-4945 in combination with paclitaxel could be treatment of choice in gastric cancer with paclitaxel resistance. Citation Format: Minkyu Jung. The role of CK2 for overcoming paclitaxel resistance in gastric 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 3828. doi:10.1158/1538-7445.AM2017-3828
Margaret McCartney: Alarm overload makes a difficult job harder
Authors: Margaret McCartney
Journal: BMJ (2017)

“Just ask . . . could it be sepsis?” The Sepsis Trust has issued posters instructing parents to ask this, as “it’s a simple question but could save a life.” It’s also produced a list of what to look out for. Any child who is breathing quickly, has a fit or is unconscious, looks mottled, blue, or pale, has a non-blanching rash, is very lethargic or difficult to wake, or is abnormally cold to touch “might have sepsis”; and anyone whose child under 5 is not feeding, is vomiting repeatedly, or has not passed urine in 12 hours is urged to seek advice.1

General practice …
Abstract 3514: Assessing the role of CREB in fibrolamellar hepatocellular carcinoma with PRKACA-DNAJB1 fusion protein
Authors: Anju Karki, Michael J. LaQuaglia, Amanda M. Dios, Ghazaleh Sadri-Vakili, Khashayar Vakili
Journal: Cancer Research (2017)

Abstract Introduction: Fibrolamellar Hepatocellular Carcinoma (FLHCC) is a rare form of liver cancer that occurs predominantly in adolescents or young adults. Curing or prolonging the lives of patients with FLHCC is extremely challenging. Despite aggressive surgical resections of primary tumors as well as metastatic lesions, outcomes tend to be poor due to lack of effective chemotherapy. Previous studies have demonstrated the presence of PRKACA-DNAJB1 fusion protein in the majority of FLHCC patients. DNAJB1 is a heat shock protein and PKA is a kinase that phosphorylates numerous substrates including cAMP-regulatory element-binding protein (CREB), a proto-oncogenic transcription factor. Therefore, we sought to examine whether the presence of the fusion protein in FLHCC is associated with increased CREB phosphorylation. Methods: We analyzed tumor and matched non-neoplastic liver tissue from 7 pediatric patients with a pathologic diagnosis of FLHCC. We assessed the presence of the PRKACA-DNAJB1 fusion protein using PKA antibody, as well as total CREB and phosphorylated (p-CREB) using immunoblot analyses with specific antibodies. Results: Immunoblot analysis using anti-PKA antibody confirmed the occurrence of PRKACA-DNAJB1 fusion transcripts in 6/7 (86%) FLHCC tumor samples. Immunoblot analyses of the 6 patients with the fusion protein revealed a trend towards a decrease in p-CREB expression in tumor samples compared to non-neoplastic tissue controls (p=0.15). Conclusions: The pattern of p-CREB in FLHCC with PRKACA-DNAJB1 fusion protein suggests that the fusion protein does not exert its proto-oncogenic effects through the transcriptional activity of CREB. Citation Format: Anju Karki, Michael J. LaQuaglia, Amanda M. Dios, Ghazaleh Sadri-Vakili, Khashayar Vakili. Assessing the role of CREB in fibrolamellar hepatocellular carcinoma with PRKACA-DNAJB1 fusion protein [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 3514. doi:10.1158/1538-7445.AM2017-3514
Abstract 3235: Development of potent and selective inhibitors for ATR: An adjuvant for DNA damage based chemotherapeutics
Authors: Sivapriya Kirubakaran, Vijay Thiruvenkatam Thiruvenkatam, Althaf Shaik
Journal: Cancer Research (2017)

Abstract Inhibition of DNA damage checkpoint and repair function has been a challenging as well a promising approach in cancer therapy. ATR kinase is one of the key mediator of DNA damage response which induces cell cycle arrest and DNA repair via its downstream proteins. Blocking ATR has proved to prevent the Chk1 pathway from stalled replication fork and enhances the replication stress and premature mitotic entry. In addition inhibition of ATR can selectively sensitize the cancer cell to radio and chemotherapy, due to defective DNA damage signaling through the loss of ATM or p53 mutation in cancer cell. Due to its inherent role in DDR, ATR has been explored as a potential target in enhancing the effect of radiation and chemo-therapy in addition enables highly selective targeting the cancer cell through synthetic lethality. Despite the attractiveness of ATR inhibition in the cancer therapy, specific ATR inhibitors have remained indefinable. Further, there is a limited proof of concept data for ATR inhibition. Considering these facts and challenges we will be presenting some preliminary results with respect to In-silico design, synthesis and evolution of potential and selective inhibitors for ATR. References Llona-Minguez, S., Hoglund, A., Jacques, S. A., Koolmeister, T. &amp; Helleday, T. Chemical strategies for development of ATR inhibitors. Expert Rev Mol Med 9, 10 (2014). Wagner, J. M. &amp; Kaufmann, S. H. Prospects for the Use of ATR Inhibitors to Treat Cancer. Pharmaceuticals 3, 1311-1334 (2010). Liu, Q. et al. Characterization of Torin2, an ATP-competitive inhibitor of mTOR, ATM, and ATR. Cancer Res 73, 2574-2586 (2013). Citation Format: Sivapriya Kirubakaran, Vijay Thiruvenkatam Thiruvenkatam, Althaf Shaik. Development of potent and selective inhibitors for ATR: An adjuvant for DNA damage based 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 3235. doi:10.1158/1538-7445.AM2017-3235
Global drive to increase breast feeding is unveiled
Authors: Adrian O’Dowd
Journal: BMJ (2017)

All countries must do better at increasing the level of breast feeding in mothers to help improve infant health and boost economies, experts have warned.

No country in the world currently meets the recommended standards for breast feeding, said a joint report published on 1 August by the World Health Organization and the children’s charity Unicef.1

The report, produced in collaboration with the Global Breastfeeding Collective—a partnership led by WHO and Unicef to rally political, legal, financial, and public support for breast feeding—details a global scorecard, which evaluated 194 nations.

The scorecard compiles data from countries all over the world on the status of seven priorities set by the collective to increase rates of breast feeding. It shows that only 40% of …
Abstract 3205: A nanomolar potency small-molecule compound against castration-resistant and bone metastatic prostate cancer
Authors: Kenza Mamouni, Lajos Gera, Xin Li, Daqing Wu
Journal: Cancer Research (2017)

Abstract A standard treatment for prostate cancer (PCa) is androgen deprivation therapy (ADT) that suppresses androgen receptor (AR) signaling axis. Although initially responsive, most patients receiving ADT eventually develop metastatic castration-resistant prostate cancer (CRPC), with more than 90% of them exhibiting bone metastases. A mechanism by which CRPC cells evade ADT is the expression of constitutively active AR variants (AR-Vs), such as the well-characterized AR-V7. Recently we developed GH501, a flurbiprofen-modified small-molecule compound, and investigated its anti-cancer activity and mechanism of action in pre-clinical models of CRPC. At nanomolar range, GH501 effectively induces cell cycle arrest and apoptosis in CRPC cells regardless of their resistance status to enzalutamide treatment. RNA-seq analysis of GH501 combined with Western blotting analysis identified key targets implicated in CRPC progression, including the full-length AR, AR-V7 variant, and other important genes implicated in CRPC progression. Importantly, low doses of GH501 effectively inhibit the skeletal growth of CRPC in a xenograft model without obvious in vivo toxicities. These preclinical results indicate that GH501 is a promising small-molecule compound that can be further developed for the treatment of lethal prostate cancer. Citation Format: Kenza Mamouni, Lajos Gera, Xin Li, Daqing Wu. A nanomolar potency small-molecule compound against castration-resistant and bone metastatic 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 3205. doi:10.1158/1538-7445.AM2017-3205