tbuckley/cabot-search huggingface dataset:
Abstract 3080: Chronic exposure to arsenic induces malignant transformation in human kidney epithelial cells
Authors: Yu-Wei Chang, Kamaleshwar Singh
Journal: Cancer Research (2018)

Abstract Arsenic contamination is a significant environmental and public health issue worldwide including the United States. Accumulating evidence suggests that kidney is one of the target organ for arsenic-induced carcinogenesis and toxicological effects. However, the mechanism of arsenic-induced renal carcinogenesis is not well understood. Therefore, the objective of this study was to evaluate the carcinogenicity of chronic exposure to low dose arsenic on kidney epithelial cells, and identify the molecular mechanism underlying this process. HK-2 kidney epithelial cells derived from normal human kidney were treated with arsenic for acute, long-term and chronic durations and cellular response to arsenic exposure at these time points was determined by evaluating the changes in growth, morphology, and expression of genes. The results revealed a significant dose-dependent growth inhibition after acute exposure, whereas increased growth after long-term and chronic exposure to arsenic of HK-2 cells as compared to untreated control cells. The anchorage-independent growth assay for colony formation further confirmed malignant transformation of arsenic exposed cells. Additionally, the morphological changes of EMT and stemness were also observed in long-term arsenic exposed cells. These changes observed above were further confirmed by analysis of gene and protein expression. Our data suggest that cellular response of EMT and stemness act a driving factor and mechanistic basis for increased survival and malignant transformation in arsenic exposed cells. In summary, results of this study suggest that acute exposure to arsenic can cause loss of kidney epithelial cells with potential significance to acute kidney injury, whereas the chronic exposure to arsenic can increase the risk of kidney cancer through enhancing cell proliferation. Citation Format: Yu-Wei Chang, Kamaleshwar Singh. Chronic exposure to arsenic induces malignant transformation in human kidney epithelial 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 3080.
Breakthrough cell proliferation detection: Click chemistry based labeling of nucleic acid analogue
Authors: Scott Clarke, Jolene Bradford, Suzanne Buck, Kyle Gee, Brian Agnew, Adrian Salic
Journal: Cancer Research (2007)

5228   A rapid and simple flow cytometric based method for screening cell cycle blockers uses click based chemistry to detect proliferating cells. A novel method of measuring cell proliferation through the incorporation of the nucleic acid analog 5-ethynyl 2’deoxyuridine (EdU) into cellular DNA is demonstrated. In comparison to the antibody based BrdU cell proliferation assay, the EdU click reaction does not require harsh and cumbersome fixation and labeling protocols. The click reaction is shown to give rapid S-phase signal by flow cytometry and can be multiplexed with antibody based detection. It is compatible with both surface and intracellular antibody labeling protocols. The click reaction comprises of a copper catalyzed covalent coupling between the alkyne modified thymidine analog incorporated in the DNA and a dye azide conjugate. Jurkat cells, a human T-cell leukemia, treated with colchicine were pulsed with EdU for two hours. The cells were formaldehyde fixed, permeabilized, then labeled with an azide modified fluorophore conjugate and a cell cycle stain. Cells without colchicine addition were prepared with the same protocol. Bivariant plots were generated by flow cytometry showing EdU labeled DNA vs. cell cycle stain. Control cells showed a normal distribution of cells in S-phase while the treated cells showed a significant decrease in the S-phase distribution and an accompanying accumulation of cells in the G2M-phase. Because of the easy of use, this novel click based method has potential to replace the current BrdU antibody based method for determining cell proliferation.
Abstract 4811: Inhibition of PLK1 abrogates side population and increases radiation-induced DNA damage in human glioblastoma
Authors: Arvind Pandey, Junhua Mai, Satyendra C. Tripathi, Samir M. Hanash, Haifa Shen, Sankar Mitra
Journal: Cancer Research (2018)

Abstract Glioblastoma multiforme (GBM), a highly malignant form of brain tumor has limited treatment modalities with poor patient survival. Expression of CD133, a marker of cancer stem cells (CSCs), has been linked to GBM recurrence, metastasis and radiation/drug resistance. The GBM CSCs exhibit high level of ABC transporters, DNA repair enzymes and anti-apoptotic proteins. The side population (SP) phenotype of CSCs with high levels of ABC transporters is associated with chemo-resistance. Overexpression of Polo-like kinase-1 (PLK1), a key cell cycle regulator, has been linked to poor prognosis of various cancers. However, the role of PLK1 in radio/chemo-resistance of GBM is poorly understood. In this study, we explored the use of PLK1 inhibitor Volasertib in combination with temozolomide (TMZ) followed by radiation to overcome resistance in GBM, both in vitro and in vivo. Our results revealed that Volasertib and TMZ act synergistically at a sub-lethal dose to inhibit cell proliferation and induce apoptosis. Both Volasertib and TMZ strongly induce reactive oxygen species (ROS) which may cause cell death by reducing repair capacity. Combined treatment with TMZ and Volasertib followed by radiation showed persistent DNA damage after removal of drugs for 24 hrs. In contrast to earlier reports, significant decrease in the side population was also observed, even after radiation treatment. We also observed that Volasertib alone or in combination with TMZ activated STAT1 pathways and inhibited MAPK/AKT activation. As the latter pathway promotes apoptosis, our results suggest higher tumor growth inhibitory effect of combinatorial treatment compared to single agents in xenograft mouse model. In summary, while Volasertib can be used alone or in the combination with radiation, Volasertib combined with TMZ may be useful to inhibit recurrence of GBM after radiation therapy. Furthermore, increased STAT1 expression may modulate the tumor-microenvironment and improve immunotherapy by MHC class 1 upregulation. Citation Format: Arvind Pandey, Junhua Mai, Satyendra C. Tripathi, Samir M. Hanash, Haifa Shen, Sankar Mitra. Inhibition of PLK1 abrogates side population and increases radiation-induced DNA damage in human glioblastoma [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 4811.
Abstract 4559: KY-B602, a humanized anti-human OX40 antibody, enhances CD4+T cell activation and inhibits tumor growth in a syngeneic model
Authors: feng hao, feng he, mingxuan ning, zhaoshuai bai, jinying ning
Journal: Cancer Research (2018)

Abstract OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is mainly expressed on activated T cells. As a secondary costimulatory molecule, activated OX40 can increase effector T-cell survival, proliferation, and memory. Anti-OX40 monoclonal antibodies have shown anti-tumor efficacy. Recent preclinical studies further support the potential synergistic effects of agonist OX40 immunotherapy in combination with cancer vaccination or in sequential co-administration with PD1 antibody to revert PD1 resistance. Several anti-OX40 agonistic monoclonal antibodies are currently tested in early phase cancer clinical trials either in monotherapy or in combination with other immune modulators. KY-B602 is a novel humanized IgG1 anti-OX40 antibody under pre-clinical development. It was generated from hybridoma and humanized by CDR grafting and structure simulation. KY-B602 specifically binds to the extracellular domain of human OX40 with high affinity (KD = 5.1 nM, determined by Biacore). FACS study showed KY-B602 also binds to both human and cynomolgus monkey OX40 over-expressed on 293T cells (EC50 =4.6nM, EC50=6.1nM, respectively). Another, in HT1080 cell reporter assay, KY-B602 significantly increased IL-8 secretion through OX40 pathway. In addition, KY-B602 dose-dependently augmented IL-2 and IFN-gamma secretion from CD4+T cells, that were pre-stimulated with IL-2 and PHA. However, in FACS competition assay, KY-B602 did not affect OX40L binding to OX40, suggesting that KY-B602 binds to a different epitope with that of OX40L. Moreover, KY-B602 inhibits in vivo tumor growth in MC38 syngeneic model. In summary, the current data of KY-B602 support its potency for cancer therapy. Citation Format: feng hao, feng he, mingxuan ning, zhaoshuai bai, jinying ning. KY-B602, a humanized anti-human OX40 antibody, enhances CD4+T cell activation and inhibits tumor growth in a syngeneic model [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 4559.
Abstract P134: One Year Follow-up of the mActive Randomized Clinical mHealth Trial of Physical Activity
Authors: Bruno Urrea, David I Feldman, Janelle W Coughlin, Roger S Blumenthal, Michael J Blaha, Seth S Martin
Journal: Circulation (2016)

Background: Novel mobile health (mHealth) technologies have transformed behavioral change research. Leveraging digital activity tracking technology, the mActive randomized clinical mHealth trial of cardiology patients showed that automated text message coaching increased short-term physical activity by 25%. In this one-year follow-up study, we aimed to understand the post-trial behavior of participants and examine their long-term perspectives. Methods: After trial completion, participants retained their digital activity tracking device (Fitbug) and their ongoing behavior was no longer directed by the research team. At one year, 34 of 48 participants answered a Google survey with questions about ongoing activity tracking usage and preferences regarding activity tracking devices and text messages. A proportion for each response was calculated. During focus groups (n=18), open questions were asked to promote discussion with themes assessed in a qualitative analysis. Results: On the survey (Table), 50% (17 of 34) reported still having the mActive pedometer and 27% continued activity tracking after the trial. Among those no longer tracking activity, 71% reported wanting to resume doing so; there was not a strong preference towards any particular activity tracking device. Preferences regarding text feedback were varied with most preferring 1-2 messages per day with a mix of positive and negative messages. During focus groups, participants emphasized a desire for feedback through personalized real-time text messages, and also expressed interest in having activity data synchronize with their electronic medical record to review it with their physician. Conclusions: After the trial, 1/3 of mActive participants continued to track activity. Integration of activity data with the electronic medical record and long-term delivery of real-time feedback could increase the desirability of long-term activity tracking. Future studies may address whether these capabilities aid in long-term engagement and behavioral change.
Abstract 4792: Preclinical evaluation of GST-HG161, a potent and highly selective c-MET inhibitor
Authors: Xiongbin Xu, Gang Li, Lihong Hu, Junguo Hao, Charles Z. Ding, Shuhui Chen
Journal: Cancer Research (2018)

Abstract Objective: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Studies indicate that aberrant activation of mesenchymal-epithelial transition factor (c-MET) is associated with HCC development. Blocking c-MET signaling shows antitumor efficacy in patients with HCC. Thus, c-MET has been an attractive therapeutic target for HCC. We disclose here for the first time a potent and selective c-MET inhibitor GST-HG161 and show the antitumor efficacy data in preclinical models of HCC. Method: MHCC97H HCC cell line with c-MET overexpression was used to evaluate the anti-proliferative activity of GST-HG161 in a 120-hour viability assay. Selectivity was evaluated with a panel of cell lines without overexpression of c-MET. Daily oral administration of GST-HG161 doses of 1, 3, 10 and 30mg/kg was used to evaluate its in vivo antitumor efficacy in two animal models of HCC with c-MET overexpression, MHCC97H xenograft (CDX) model and LI-03-0317 xenograft (PDX) model. The c-MET protein levels and gene copy number in LI-03-0317 PDX were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. High c-MET expression in LI-03-0317 PDX was determined by the presence of tumor cells with membrane staining of 3+ intensity. Effect of GST-HG161 on c-MET signaling inhibition was assessed by western blot analysis of downstream effector proteins including p-MET, p-AKT and p-ERK. Result: GST-HG161 displayed potent anti-proliferative activity in MHCC97H HCC cell line (IC50 = 5 nM) while showed little activity in the cell lines without c-MET overexpression. It significantly inhibited tumor growth at tested doses (3, 10 and 30mg/kg) (P&amp;lt;0.05) in both MHCC97H CDX model and LI-03-0317 PDX model. In MHCC97H CDX model, western blot analysis showed that GST-HG161 potently inhibited p-MET and downstream effector proteins p-AKT and p-ERK in the tumor tissue, indicating that the tumor growth inhibition in this model was mediated through inhibition of c-MET. Conclusion: GST-HG161 is a potent and highly selective c-MET inhibitor. Its excellent antitumor efficacy as shown in the HCC mouse models provide us with confidence that GST-HG161 has high potential in the clinic for treating patients of HCC with high c-MET activity. Citation Format: Xiongbin Xu, Gang Li, Lihong Hu, Junguo Hao, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of GST-HG161, a potent and highly selective c-MET inhibitor [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 4792.
Implementation of a nurse communication strategy to improve perception of nurse-patient communication at the bedside on an inpatient oncology unit.
Authors: Lyn Cain Zehner, Rachel Watson, Kimberley George-Shields, Carrie Lynn Friedman, Sandy Danquah, Yeruti Silva, Eunice Esunge
Journal: Journal of Clinical Oncology (2016)

10059 Background:Patients spend more time with nurses when in the hospital than with any other health care professional. Patient experience scores have been used as a measure of quality patient outcomes. The Hospital Consumer Assessment of Healthcare Providers and Systems Survey (HCAHPS) score Communication with Nurses, correlates with improvements in 4 other dimensions Pain, Communication about Medications, Responsiveness of Staff and Overall Rating. As patient experience scores are tied to Medicare reimbursement, nurses have an impact on reimbursement. The Nurse Communication scores on the inpatient 29 bed oncology unit reflected an opportunity for improvement. The purpose of this project was to develop a communication strategy that staff would implement at the bedside. The goal was to achieve an improvement in the HCAHPS Communication with Nurses question.Methods:The John Hopkins Nursing Evidence Based Practice model the team selected specific strategies for improving communication and incorporated ideas from patient advisors. The interventions consisted of sitting at the bedside, expressing active listening, and attention to eye contact when using equipment and documenting in the electronic medical record. Staff received interactive training and then role played to assist in implementing the strategies without changing work flow. Sitting at the bedside was to occur once each 12 hour shift. A survey was developed to elicit feedback from staff regarding the strategies. Data on staff sitting at the bedside was collected over 3 months by the nurse manager.Results:The nurse communication HCAHPS score improved from an average of 64% for the first 5 months of 2015 to an average of 87% for the following 8 months. Other associated scores also improved. The Overall Rating for the unit moved from an average of 50% to 69%. The top 3 reported barriers to sitting included too many visitors, chair unavailable, patient in isolation. A majority of staff reported patient load impacted ability to sit at the bedside.Conclusions:Implementation of the new strategy has contributed to improved patient outcomes. Staff related sitting at the bedside enhanced communication with patients.
Abstract 4787: SKLB188 inhibits the growth of head and neck cancer cell growth by suppressing EGFR signaling
Authors: Shile Huang, Mansoureh Barzegar, Shuang Ma, Shengyong Yang
Journal: Cancer Research (2018)

Abstract Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. So far, only Cetuximab, an anti-EGFR monoclonal antibody, has been approved for EGFR-target therapy in HNSCC. Here we show that SKLB188, a newly synthesized small molecule compound, inhibited cell proliferation and induced apoptosis of HNSCC cells in vitro and in vivo, by targeting EGFR signaling. SKLB188 induced cell cycle arrest in G1 phase, by downregulating the expression of Cdc25A, cyclins D1/A and cyclin dependent kinases (CDK2/4), and upregulating the expression of CDK inhibitors (p21Cip1 and p27Kip1), leading to decreased phosphorylation of Rb. SKLB188 also downregulated the expression of Mcl-1 and survivin, inducing caspase-dependent apoptosis. Molecular docking predicted that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay revealed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC50 = 5 nM). Western blot analysis showed that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose-dependently inhibited FaDu xenograft growth in nude mice, and concurrently inhibited the phosphorylation of Erk1/2 and Akt in the tumors. Taken together, our results support that SKLB188 inhibits the growth of HNSCC cells in vitro and in vivo by targeting EGFR signaling. Citation Format: Shile Huang, Mansoureh Barzegar, Shuang Ma, Shengyong Yang. SKLB188 inhibits the growth of head and neck cancer cell growth by suppressing EGFR signaling [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 4787.
Abstract 706: In vivo tumor-associated mutation screen identifies PI3K activation as a mechanism of resistance to PD-1 blockade
Authors: Natalie B. Collins, Brian C. Miller, Kevin Bi, Rose Al Abosy, Kathleen Yates, Yashaswi Shrestha, John Doench, Jesse Boehm, W Nicholas Haining
Journal: Cancer Research (2018)

Abstract Known genomic correlates of response to immunotherapy do not perfectly predict clinical outcome, supporting the existence of unknown mechanisms of resistance to tumor immunity. We hypothesize that somatic, cancer-associated mutations account for heterogeneity in spontaneous response to tumors and response to immunotherapy. We have undertaken a systematic in vivo screen to identify mechanisms of resistance to tumor immunity in order to define a comprehensive set of therapeutic targets and provide biomarkers of sensitivity to immunotherapy. Mouse tumor cell lines (MC38 colon carcinoma or B16 melanoma) were engineered to express a library of barcoded open reading frames (ORFs) mutagenized to encode known cancer-associated somatic mutations. Tumor-bearing animals were treated with anti-PD-1. A mutation in Phospho-Inositol 3 Kinase (PI3K), PIK3CA c.3140A&amp;gt;G, increased in representation in anti-PD-1 treated tumors but not in immunodeficient animals, suggesting that activity of the mutant allele conferred selective growth advantage in the setting of tumor immunity. This mutation encodes a constitutively active mutant catalytic domain, PIK3CA H1047R. MC38 tumors homogeneously expressing H1047R and implanted into wild-type mice failed to respond to anti-PD-1 therapy, while tumors expressing a control gene regressed. Pharmacologic PI3K inhibition resensitized tumors to treatment with anti-PD-1. PD-1-treated PIK3CA H1047R tumors had fewer infiltrating CD8+ T cells as measured by immunohistochemistry and flow cytometry. Single-cell RNA-seq of tumor-infiltrating immune cells revealed a population of myeloid cells expressing known immune inhibitory proteins that differentially enriched in PIK3CA H1047R-expressing tumors. Our data suggest that PI3K has, in addition to its well-described oncogenic role, a role in tumor immune evasion mediated by establishment of an inhibitory myeloid microenvironment. As such, activating mutations in PI3K may be useful as a biomarker of poor response to immunotherapy, and these studies provide a rationale for therapeutic combination trials of PI3K inhibition with checkpoint blockade and other myeloid-targeting immunotherapies. Citation Format: Natalie B. Collins, Brian C. Miller, Kevin Bi, Rose Al Abosy, Kathleen Yates, Yashaswi Shrestha, John Doench, Jesse Boehm, W Nicholas Haining. In vivo tumor-associated mutation screen identifies PI3K activation as a mechanism of resistance to PD-1 blockade [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 706.
Abstract 2134: IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis
Authors: Ryan D. Roberts, Hakan Cam, Laura Brandolini, John M. Hinckley, Amy C. Gross
Journal: Cancer Research (2018)

Abstract Osteosarcoma (OS) kills patients through aggressive metastatic spread, primarily to lung tissues. Our lab has sought to understand the tumor-host interactions that facilitate growth of OS cells specifically within the lung. We previously identified two intercellular signaling molecules, IL6 and CXCL8, which exhibit enhanced expression when primary tumors become lung metastases. Here, we show that epigenetic changes drive aberrant expression of ΔNp63, endowing OS cells with the capacity to colonize lung tissue. IL6 and CXCL8 serve as downstream mediators induced directly by ΔNp63 and necessary for survival and proliferation within the lung. Inhibition of IL6 and CXCL8 signaling has no direct effect on the proliferation of OS cells, but IL6 inhibition has a profound effect on their ability to form colonies in soft agar. In preclinical mouse models of OS, inhibitors of IL6 and CXCL8 signaling profoundly impair the ability of OS cells to colonize lung tissue, completely preventing metastasis in some models. Co-culture studies suggest that strong paracrine interactions with bronchial epithelial and smooth muscle cells, but not macrophages or lung fibroblasts, drive increased expression of IL6 and CXCL8. These data suggest a mechanism where aberrant ΔNp63 expression within developing OS tumors generates subsets of tumor cells endowed with increased IL6 and CXCL8 expression. This triggers feed-forward paracrine loops with bronchial epithelial and smooth muscle cells that facilitate growth and survival within the lung, leading to metastasis. Citation Format: Ryan D. Roberts, Hakan Cam, Laura Brandolini, John M. Hinckley, Amy C. Gross. IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis [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 2134.