tbuckley/cabot-search huggingface dataset:
Abstract 5254: Combined <i>in vitro</i> TTFields and paclitaxel reduce proliferation and clonogenicity in non-small cell lung cancer (NSCLC) cells from a patient previously treated with standard-of-care
Authors: Sharon K. Michelhaugh, Sandeep Mittal
Journal: Cancer Research (2020)

Abstract TTFields therapy in conjunction with chemotherapy has been FDA approved as a first line treatment regimen for patients with unresectable malignant pleural mesothelioma. Clinical trials are underway to test the efficacy of TTFields in patients with progressive NSCLC or NSCLC brain metastases following standard-of-care or radiosurgery, respectively. Our study utilized tumor cells extracted from a NSCLC metastatic brain tumor from a patient previously treated with standard-of-care chemoradiation prior to progression to brain metastasis. These patient-derived NSCLC cells were subjected to TTFields application with and without paclitaxel to determine if the combination of TTFields with paclitaxel would be more effective than either treatment alone. Written informed consent was obtained from the patient, who was 60 years-old and female. She received concurrent carboplatin/paclitaxel and radiotherapy to the upper lobe of her left lung prior to discovery and resection of a solitary brain lesion. Cells isolated from the metastatic brain tumor were cultured for 3 passages prior to plating on coverslips (4 × 104 each) in DMEM/F12 media with 10% fetal bovine serum. TTFields were applied at ~1.6 V/cm at 150 kHz. Paclitaxel was added to the media to a final concentration of 5 nM. Cells were treated for 14 days. At the end of the treatment period, some coverslips of cells were lysed and assayed for lactate dehydrogenase (LDH) to represent cell number (n=5) and another set of coverslips of cells were harvested and replated in triplicate for the clonogenic assay (n=3). Groups were compared with one-way ANOVA. Data shown in table are mean ± SD. For the LDH assay, ANOVA p&amp;lt;0.0001. For the clonogenic assay, ANOVA p=0.0003. Overall, the combination of TTFields with paclitaxel produced additive reductions in cell proliferation (75%) and reduced the clonogenic potential (95%) compared to untreated controls. The additive effects of TTFields and paclitaxel suggest that they target different cell populations within a heterogeneous tumor, and that lung cancer patients previously treated with standard-of-care may benefit from TTFields therapy. Proliferation and clonogenic assay results from combined TTFields and paclitaxelAssayControlPaclitaxel (5 nM)TTFieldsTTFields ± Paclitaxel (5 nM)Proliferation (LDH assay)1.83±0.090.81±0.041.34±0.150.46±0.21Clonogenicity (cell counts)26641±46258697±161717399±59981598±598 Citation Format: Sharon K. Michelhaugh, Sandeep Mittal. Combined in vitro TTFields and paclitaxel reduce proliferation and clonogenicity in non-small cell lung cancer (NSCLC) cells from a patient previously treated with standard-of-care [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5254.
Abstract 2960: Anti-cancer activity of NCTD: promotion of pro-apoptosis and anti-invasion in human oral cancer cells
Authors: Chi-Hyun Ahn, Kyoung-Ok Hong, Ji-Ae Shin, Seong Doo Hong, Sung-Dae Cho
Journal: Cancer Research (2020)

Abstract Norcantharidin (NCTD), a demethylated analog of cantharidin isolated from blister beetles, has been used as a promising anticancer agent; however, the anti-tumor potentials of NCTD against human oral cancer has not been fully understood. Here, this study was aimed to investigate the pro-apoptotic and anti-invasive effect and its molecular targets of NCTD in human oral cancer cell lines. Trypan blue exclusion assay, live/dead assay, western blotting, 4-6-Diamidino-2-Phenylindole staining, flow cytometric analysis, Terminal Deoxynucleotidyl Transferase dUTP Nick end Labeling (TUNEL) assay, immunohistochemistry and tumor xenograft mice models were performed to investigate the pro-apoptotic effect of NCTD. Clonogenic, wound healing, invasion, zymography, western blotting and immunocytochemistry assays were performed to investigate the anti-invasive effect of NCTD. NCTD significantly inhibited cell growth and increased the number of dead cells in oral cancer cell lines. It induced the following apoptotic phenomena: (1) the cleavages of poly (ADP-ribose) polymerase and casepase-3; (2) increase in apoptotic morphological changes (nuclear condensation and fragmentation); (3) increase in annexin V-positive cells or sub-G1 population of cells. NCTD significantly activated the p38 mitogen-activated protein kinase (MAPK) pathway. A p38 MAPK inhibitor (SB203580) partially attenuated NCTD-induced apoptosis in oral cancer cell lines. NCTD strongly suppressed tumor growth in the tumor xenograft bearing HSC-3 cells, and the number of TUNEL-positive cells increased in NCTD-treated tumor tissues. Also, NCTD markedly suppressed the colony formation, migration, and invasion of YD-15 cells as well as the activities of MMP-2 and MMP-9. It disrupted F-actin reorganization through suppressing the FAK/Paxillin axis. Moreover, NCTD exhibited a powerful anti-invasive effect compared with that of PF-562271. Collectively, these results suggest that NCTD has a potential pro-apoptotic and anti-invasive activity against oral cancer cell lines. Therefore, these results suggest that NCTD could be a potential anticancer drug candidate for the treatment of human oral cancer. This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and future Planning [2017R1D1A1B03029317, 2018R1D1A1B07043080, and 2019R1A2C1085896]. Citation Format: Chi-Hyun Ahn, Kyoung-Ok Hong, Ji-Ae Shin, Seong Doo Hong, Sung-Dae Cho. Anti-cancer activity of NCTD: promotion of pro-apoptosis and anti-invasion in human oral cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2960.
Characteristics and impacts of itch in children with inflammatory skin disorders*
Authors: M.M. Fang, C.J. Nowinski, J. Lai, S. Shaunfield, J.I. Silverberg, S.M. Rangel, D. Cella, A.S. Paller
Journal: British Journal of Dermatology (2020)

Background Itch is a cardinal feature of paediatric disorders and can impair quality of life. However, few studies have addressed symptoms and impacts of itch in paediatric patients. Objectives We focused on understanding the child's experience of itch and the impact of itch specifically on affected children, including comparison with the adult experience. Methods Semistructured interviews (nine parents, 15 children with itch) explored concerns related to paediatric itch experiences and effects. Themes were compared with those of previous adult interviews. Literature was reviewed to identify the need for a more comprehensive measure of paediatric itch. Results Itch quality, intensity, duration and environmental triggers (sweating, climate change, stress and certain fabrics) are important aspects of the child's itch experience. Skin disruption, physical function, concentration, emotional reactions, stigma and relationships/social effects are itch impact themes that emerged. No paediatric-specific scale comprehensively captures the paediatric patient itch experience. However, differences between child and adult reports of itch-related pain, functional limitations, fatigue and restlessness, emotional reactions to itch, and treatment effects emphasize the need for a paediatric-specific measurement tool. Conclusions Children and parents endorse the importance of capturing the paediatric-focused characteristics and impacts of itch in measuring disease severity and response to intervention.
Abstract 84: E2F8 tumor suppressive role in Non-Alcoholic Steatohepatitis
Authors: Shaaron L. Ochoa-Rios, Lindsey N. Kent, Gustavo Leone
Journal: Cancer Research (2020)

Abstract Non-Alcoholic Steatohepatitis (NASH) is the aggressive form of Non-Alcoholic Fatty Liver Disease (NAFLD). NAFLD is the accumulation of extra fat in liver cells, most commonly known as fatty liver. Some of the main conditions that distinguish NAFLD from NASH are severe liver inflammation, increased lipid accumulation and fibrosis. NASH is caused by an excess of fat in the liver which is linked to obesity and diet. Diets high in fats and sugars, typical of a Western diet, have been shown to induce NASH. Approximately 25% of NASH cases progress to Hepatocellular Carcinoma (HCC). Currently, there is no approved therapy for NASH and complications due to NASH is estimated to be the main reason for liver transplant. E2F8, a member of a family of transcription factors that are well known for regulating the cell cycle, has been shown to promote hepatic steatosis in a zebrafish model. Previous research from our lab has demonstrated that E2F8 has a tumor-suppressive role and loss of E2F8 leads to HCC in a carcinogen-induced model. Here, we use a mouse model to conditionally delete E2f8 in hepatocytes to sensitize to liver cancer and evaluate the effects of E2F8 on NASH development. Mice were fed with a low-fat diet (LFD), high-fat diet (HFD), choline-deficient high-fat diet (CDHFD) or Western diet (WD). Our results show that control mice in a LFD maintained a normal liver and E2F8 had a tumor-suppressive role for all diets including LF. However, a HFD induced NAFLD while a CDHFD and WD caused NASH by inflammation and fibrosis, respectively. We demonstrate that E2f8 ablation influences collagen deposition, lipid accumulation, and E-cadherin expression. Additionally, experimental mice fed a HFD had an incidence of less than 40% of spontaneous HCC, while experimental mice fed a WD had an incidence of more than 50% of spontaneous HCC; demonstrating that E2F8 tumor-suppressive role is essential to prevent progression to HCC in a NASH model. We hypothesize, that E2F8 has a role in the regulation of liver metabolism. Collectively, our study demonstrates that a WD and E2F8 hepatocyte deletion leads to an increase in lipid and collagen accumulation and HCC occurrence. Citation Format: Shaaron L. Ochoa-Rios, Lindsey N. Kent, Gustavo Leone. E2F8 tumor suppressive role in Non-Alcoholic Steatohepatitis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 84.
Abstract 5828: Effect of Roscovitine and mifepristone in luminal breast cancer cells
Authors: Lucía Vottero, Claudia Lanari, Victoria T. Fabris
Journal: Cancer Research (2020)

Abstract The cyclin dependent kinase (CDK)4/6 inhibitors have been recently approved in combination with endocrine therapy for luminal breast cancer treatment. On the other hand, the use of CDK2 inhibitors, such as Roscovitine, appears as a therapeutic alternative to overcome the acquisition of resistance to CDK4/6 inhibitors. However, there are few clinical trials using CDK2 inhibitors for breast cancer treatment. Most of the reports on the effects of Roscovitine were performed in MCF-7 or MDA-MB-231 cells. The aim of this work was to evaluate the effect of Roscovitine on cell proliferation in T47D human breast cancer cells which express both progesterone receptor (PR) isoforms PRA and PRB, and in the T47D-YA and T47D-YB cell lines expressing only PRA or PRB, respectively. We have previously demonstrated that cells overexpressing PRB showed higher levels of cyclin A as compared with those overexpressing PRA, thus we hypothesized that they would be more sensitive to CDK2 inhibitors. Roscovitine inhibited cell proliferation in a dose dependent manner similarly in both MCF-7 cells (used as positive control) and in T47D cells, with IC50 of 11.99 µM and 11.93 µM respectively. In addition, Roscovitine inhibited cell proliferation induced by estrogen treatment in both cell lines (p&amp;lt;0.01); however the percentage of inhibition was higher in MCF-7 compared with T47D cells (70% versus 50%, respectively; p&amp;lt;0.05). Roscovitine also inhibited cell proliferation induced by the fibroblast growth factor FGF2 in T47D cells (Roscovitine 2 µM p&amp;lt;0.001 and 5 µM p&amp;lt;0.05). Whereas both T47D-YA and -YB cells were similarly inhibited by Roscovitine, only in T47D-YA cells the combination of the antiprogestin mifepristone (MFP; 10 nM) and Roscovitine 1 µM in the presence of FGF2 induced a higher inhibitory effect than MFP or Roscovitine single treatments (p&amp;lt;0.01). We conclude that CDK2 inhibitors may be an option for luminal breast cancer treatment independent of the levels of cyclin A, and that they might be used in combination with antiprogestins only in breast cancer cells overexpressing PRA isoform. Citation Format: Lucía Vottero, Claudia Lanari, Victoria T. Fabris. Effect of Roscovitine and mifepristone in luminal breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5828.
Abstract 1758: Discovery of novel potent and selective inhibitors of PRMT5 with anti-tumor activity in hepatocellular carcinoma and lung pre-clinical models
Authors: Francois Gonzalvez, Koen Vandyck, Yannick Debing, Kusum Gupta, Dinah Misner, Qingling Zhang, Jyanwei Liu, Antitsa Stoycheva, Sarah Stevens, Julian Symons, Leonid Beigelman, Pierre Raboisson, Jerome Deval
Journal: Cancer Research (2020)

Abstract Protein arginine methyltransferase-5 (PRMT5) regulates many essential biological processes by catalyzing the symmetric di-methylation of arginine (sDMA) on a variety of histones and non-histone proteins. PRMT5 activity is dysregulated across many hematological and solid tumor and its overexpression is associated with poor patient prognosis. PRMT5 is also often overexpressed in cancer cells. Genetic and pharmacological inactivation have confirmed the importance of PRMT5 activity to the survival of many cancer cells, including hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC). Thus, inhibiting PRTMT5 activity has emerged as an attractive therapeutic strategy in oncology. We used structure-based drug design to identify novel small molecule inhibitors of PRMT5. ALG-070005, ALG-070043 and ALG-070017 inhibited PRMT5 enzymatic activity in biochemical assays with half-maximal inhibitory concentrations (IC50s) values between 50-150 pM and showed high selectivity against a panel of six other PRMTs. In HepG2 cells (HCC), ALG-070005, ALG-070043 and ALG-070017 potently decreased sDMA levels and inhibited cell proliferation with IC50 values of 1, 3, and 0.2 nM, respectively. These compounds also exhibited similar antiproliferative activity in A549 NSCLC cells. The three novel PRMT5 inhibitors demonstrated favorable ADME/PK profiles with exposure levels in target organs well above IC50 values, even 24 hours after dosing. When dosed orally in mice, these Aligos compounds inhibited tumor growth in HCC and NSCLC xenograft models, with concomitant inhibition of sDMA in the tumor. In conclusion, we identified and characterized novel potent and selective inhibitors of PRMT5 with antiproliferative effects in various preclinical models of HCC and lung cancers. These drug candidates also have a broad therapeutic potential in oncology beyond HCC and lung cancer. Citation Format: Francois Gonzalvez, Koen Vandyck, Yannick Debing, Kusum Gupta, Dinah Misner, Qingling Zhang, Jyanwei Liu, Antitsa Stoycheva, Sarah Stevens, Julian Symons, Leonid Beigelman, Pierre Raboisson, Jerome Deval. Discovery of novel potent and selective inhibitors of PRMT5 with anti-tumor activity in hepatocellular carcinoma and lung pre-clinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1758.
Abstract 2344: Composite score of healthy lifestyle factors and risk of hepatocellular carcinoma: Findings from a prospective cohort study
Authors: Hung N. Luu, Renwei Wang, Jaideep Behari, Jennifer Adams-Haduch, Andrew O. Odegaard, George Goh Bee, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan
Journal: Cancer Research (2020)

Abstract Background. While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) were examined substantially, their combined impact on HCC risk has not been evaluated. Methods. The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean Diet (aMED), and sleep duration, with the risk of developing HCC was examined in the Singapore Chinese Health Study (SCHS), an on-going prospective cohort of 63,257 Chinese men and women aged 45-74 at enrollment in 1993-1998 with up to 25 years of follow-up. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with the composite score after adjustment for multiple potential confounders. The unconditional logistic regression method was used to confirm the association between the composite lifestyle score and HCC risk among hepatitis B surface antigen (HBsAg) negative individuals to eliminate its potential confounding effect. Results. After a mean follow-up of 17.7 years, 561 participants of the SCHS developed HCC. Individuals with higher composite scores, which represented for healthier lifestyles, were at significantly lower risk of HCC. Compared with the lowest composite score (i.e., 0-4), the HRs (95% CIs) for 5, 6, 7 and 8 were 0.48 (0.36-0.64), 0.44 (0.34-0.67), 0.37 (0.28-0.48), and 0.26 (0.17-0.39), respectively (Ptrend&amp;lt;0.001). A similar inverse association was observed in participants with negative HBsAg serology; HR was 0.12 (95% CI: 0.04-0.38) for the highest versus the lowest category of the composite scores (Ptrend=0.01). Conclusion. Healthy lifestyles are protective against the development of HCC, especially for individuals without viral infection. This finding highlights the importance of a comprehensive lifestyle modification strategy for primary prevention of HCC. Funding: The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01 CA144034 and UM1 CA182876). Citation Format: Hung N. Luu, Renwei Wang, Jaideep Behari, Jennifer Adams-Haduch, Andrew O. Odegaard, George Goh Bee, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan. Composite score of healthy lifestyle factors and risk of hepatocellular carcinoma: Findings from a prospective cohort study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2344.
Abstract LB-055: Novel therapeutic option targeting the tumor cell lysosomes
Authors: Vadim Le Joncour, Pauliina Filppu, Minna Holopainen, Maija Hyvönen, S. Pauliina Turunen, Harri Sihto, Isabel Burghardt, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Reijo Käkela, Pirjo Laakkonen
Journal: Cancer Research (2020)

Abstract Malignant brain tumors represent a surgical and therapeutic challenge. Despite major breakthrough in the precision neurosurgery and the personalized medicine, it remains impossible to circumvent the tumor relapse. This is due to the highly infiltrative nature of the glioma cells, with single tumor-initiating cells invading far distances in the brain. However, we recently identified a major flaw in the invasive tumor cell biology: a high sensitivity to the lysosomal membrane permeabilization (LMP). We first identified the fatty acid binding-protein 3 (FABP3) specifically expressed by invasive gliomas cells. Expression of FABP3 is indispensable to the transportation of poly-unsaturated fatty acids (PUFAs), which cannot be otherwise synthetized by the cells, from the extracellular space to biological membranes. Silencing of FABP3 stopped the supply of PUFAs that are essential to the lysosomal membrane maintenance. Induction of the LMP activated a cascade of events including the release of the lysosomal cathepsins in the cytosol, leading to the tumor cell death. Interestingly, the specific killing of invasive glioma cells through the LMP can be achieved by using lysosomotropic drugs, such as anti-histamines. These cationic amphiphilic molecules accumulate in the lysosome and induce the phospholipidosis of the lysosomal membrane. We therefore tested the ability of the blood-brain-barrier permeable clemastine, an anti-histamine, to reduce the tumorigenicity several patient-derived gliomas implanted in nude mice. Although clemastine treatment did not modify the primary tumor mass growth, it completely eradicated the invasive population. These promising results obtained by therapeutic activation of the LMP could also be beneficial for other aggressive cancers models, such as brain metastases of breast cancer or metastatic pancreatic cancer. Citation Format: Vadim Le Joncour, Pauliina Filppu, Minna Holopainen, Maija Hyvönen, S. Pauliina Turunen, Harri Sihto, Isabel Burghardt, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Reijo Käkela, Pirjo Laakkonen. Novel therapeutic option targeting the tumor cell lysosomes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-055.