tbuckley/cabot-search huggingface dataset:
Abstract 307: TRIB3 regulates cell cycle progression and programmed cell death in non-small cell lung cancer
Authors: Abeer Almiman, Daotai Nie, Jamila Adom
Journal: Cancer Research (2017)

Abstract Introduction: The pseudokinase Tribbles pseudokinase 3 (TRIB3) is known as a regulator in cellular responses to a variety of stresses such as glucose insufficiency and (ER) stress. TRIB3 has been described in some studies as a tumor suppressor due to its effect on inactivating PI3K/Akt pathway, but other studies suggest TRIB3 as a stimulator of tumor progression. In this study, we aimed to define the functions of TRIB3 in in non-small cell lung cancer. Methods: TRIB3 expression was altered using a lentiviral vector to overexpress TRIB3 in non-small cell lung cancer. A CRISPR-CAS9 construct with guiding sequence matching to TRIB3 gene was used to knock out its expression. Cell proliferation was evaluated using MTS and trypan blue assays. Boyden chamber assay was used to assess the cell migration while cell cycle phases were determined using flow cytometry. Heatmap analysis was performed to assess the changes in the expressions of genes in cell cycle progression and apoptosis. Results: TRIB3 overexpression led to reduced cell proliferation and migration. Moreover, it contributed to the increased of cell cycle arrest at G0/G1 phase. QPCR analyses of cell cycle related genes showed an upregulation of CDK inhibitors in (NCI-H358) TRIB3 overexpression cells, while depletion of TRIB3 led to the down-regulation of CDK inhibitors. TRIB3 overexpression led to downregulation of LC3B and other autophagy markers while increasing the expression of apoptotic genes. Conclusion: Increased TRIB3 expression in non-small cell lung cancer cells inhibited proliferation by blocking cell cycle progression through the upregulation of CDK inhibitors, led to activation of cell death through apoptosis. Our study reveals a significant role of TRIB3 in regulating cell cycle progression, apoptosis and autophagy. Citation Format: Abeer Almiman, Daotai Nie, Jamila Adom. TRIB3 regulates cell cycle progression and programmed cell death in non-small cell lung 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 307. doi:10.1158/1538-7445.AM2017-307
Dietary magnesium supplementation prevents and reverses vascular and soft tissue calcifications in uremic rats
Authors: Juan M. Diaz-Tocados, Alan Peralta-Ramirez, María E. Rodríguez-Ortiz, Ana I. Raya, Ignacio Lopez, Carmen Pineda, Carmen Herencia, Addy Montes de Oca, Noemi Vergara, Sonja Steppan, M. Victoria Pendon-Ruiz de Mier, Paula Buendía, Andrés Carmona, Julia Carracedo, Juan F. Alcalá-Díaz, Joao Frazao, Julio M. Martínez-Moreno, Antonio Canalejo, Arnold Felsenfeld, Mariano Rodriguez, Escolástico Aguilera-Tejero, Yolanda Almadén, Juan R. Muñoz-Castañeda
Journal: Kidney International (2017)
Abstract 1484: Genome wide study reveal microrna based methylation phenotype in oral cancer
Authors: Roshni Roy, Aniruddha Chatterjee, Navonil De Sarkar, Bidyut Roy
Journal: Cancer Research (2017)

Abstract Introduction: Oral cancer is one of the leading causes of cancer burden in India. Studies over the years have enforced the role of deregulated microRNA expression in oral cancer development and progression. Incidentally not much is known about the cause of microRNA deregulation or to what extent can it be attributed to methylation. Established genome wide microarray platforms like 450K Illumina Bead Chip have probes for very limited number of microRNAs along with restriction on distance of the probes from microRNA transcription start site. We have used genome wide methylation sequencing approach RRBS to get deeper insight on microRNA methylation. Aim: Genome wide methylation profile of 15 paired oral cancer and adjacent normal tissue was compared to generate a detailed map of microRNA methylation in oral cancer. The methylation results were further correlated to microRNA expression data generated on a subset of these samples. Methodology: RRBS based global methylation sequencing of 15 pairs of samples was conducted on HiSeq 2500 with an average 10X depth. Analyses were done using DMAP software. Previously generated TLDA based microRNA expression data was used for correlation analysis. Result: Similar to protein coding genes, microRNAs also showed methylation based clustering. Interestingly majority of methylation hits were more than 2kb upstream of miRNA transcription start site which is generally not considered in known microarrays. Distribution of hypo and hyper methylation sites is different across the various CpG features like cores and shelves as well as across chromosomes. MicroRNAs like mir-181c, miR-99b, miR-23a among others showed significant negative correlation between methylation frequency and expression level. IPA based pathway analysis emphasized repression of apoptosis and cell death pathways along with activation of cell proliferation and colony formation. Conclusion: Understanding the role of methylation in microRNA deregulation could help us detect and possibly prevent a chain of events, which lead to disrupted pathways eventually leading to cancer, at the onset. Note: This abstract was not presented at the meeting. Citation Format: Roshni Roy, Aniruddha Chatterjee, Navonil De Sarkar, Bidyut Roy. Genome wide study reveal microrna based methylation phenotype in oral 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 1484. doi:10.1158/1538-7445.AM2017-1484
Abstract 2931: Targeting membrane-bound carbonic anhydrases in breast cancer to intervene in the metastatic phenotype
Authors: Mam Y. Mboge, Zhijuan Chen, Brian P. Mahon, Chingkkuang Tu, Alyssa S. Wolff, John V. Mathias, Fabrizio Carta, Claudiu T. Supuran, Rob McKenna, Susan C. Frost
Journal: Cancer Research (2017)

Abstract Breast cancer is the second leading cause of cancer related deaths among women in the United States. Despite the tremendous progress that has been made towards treating localized tumors, nearly 40,000 women die each year, predominantly from metastatic drug resistance. The tumor microenvironment plays a pivotal role in determining tumor growth, invasion, metastasis, and therapeutic success or failure. Therefore, a therapy targeting the tumor microenvironment is needed to sufficiently preserve the quality of life of cancer patients, by inhibiting metastasis. Elevated levels of Carbonic anhydrase IX (CAIX) expression in primary breast cancers is a marker for highly aggressive and metastatic tumors, especially of the triple negative subtype (TNBC). It is also associated with hypoxia, extracellular acidification, and poor prognosis. Low pH (values of ~6.5-6.8) is toxic to normal cells in the tumor microenvironment while enhancing cancer cell proliferation and tumor growth. Our goal was to compare the structure of a CAIX-mimic bound to ureidosulfonamide inhibitors with the biological activity of these inhibitors in triple negative and estrogen receptor positive (ER+) breast cancer cell lines. CAIX is a reversible enzyme and at low pH (high proton concentration), the enzyme will consume protons, raising pH. Our hypothesis is that CAIX inhibition, in the context of an acidic microenvironment, will dysregulate its ability to maintain the acidic pH preferred by cancer cells which favors their growth and migration. In this study, we have shown the interaction of sulfonamide-based inhibitors with a CAIX-mimic using X-ray crystallography. These structures show that the inhibitors make multiple contacts within the active site cavity. This is consistent with the inhibitor-induced decrease in CAIX activity and to some extent expression. We have also investigated the effect of CA inhibition on breast cancer cell growth, proliferation, activation of cell death pathways and migration. This reveals that, although CA inhibition with the sulfonamide-based compounds inhibits cell growth and migration, it does not activate apoptotic pathways. In total, these observations indicate that CAIX is a viable small molecular drug target for the treatment of metastatic breast cancer. Citation Format: Mam Y. Mboge, Zhijuan Chen, Brian P. Mahon, Chingkkuang Tu, Alyssa S. Wolff, John V. Mathias, Fabrizio Carta, Claudiu T. Supuran, Rob McKenna, Susan C. Frost. Targeting membrane-bound carbonic anhydrases in breast cancer to intervene in the metastatic phenotype [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 2931. doi:10.1158/1538-7445.AM2017-2931
Abstract 3389: Integrated genomic analyses reveal frequent <i>TERT</i> aberrations in acral melanoma
Authors: Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria Zismann, Valerie De Luca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent
Journal: Cancer Research (2017)

Abstract Genomic analyses of cutaneous melanoma (CM) have yielded biological and therapeutic insights, but understanding of non-ultraviolet (UV)-derived CMs remains limited. Deeper analysis of acral lentiginous melanoma (ALM), a rare sun-shielded melanoma subtype associated with worse survival than CM, is needed to delineate non-UV oncogenic mechanisms. We thus performed comprehensive genomic and transcriptomic analysis of 34 ALM patients. Unlike CM, somatic alterations were dominated by structural variation and absence of UV-derived mutation signatures. Only 38% of patients demonstrated driver BRAF/NRAS/NF1 mutations. Contrasting with CM, we observed PAK1 copy gains in 15% of patients, and somatic TERT translocations, copy gains, and missense and promoter mutations, or germline events, in 41% of patients. We further show that in vitro TERT inhibition has cytotoxic effects on primary ALM cells. These findings provide insight into the role of TERT in ALM tumorigenesis, and reveal preliminary evidence that TERT inhibition represents a potential therapeutic strategy in ALM. Citation Format: Winnie S. Liang, William Hendricks, Jeffrey Kiefer, Jessica Schmidt, Shobana Sekar, John Carpten, David W. Craig, Jonathan Adkins, Lori Cuyugan, Zarko Manojlovic, Rebecca F. Halperin, Adrienne Helland, Sara Nasser, Christophe Legendre, Laurence H. Hurley, Karthigayini Sivaprakasam, Douglas B. Johnson, Holly Crandall, Klaus J. Busam, Victoria Zismann, Valerie De Luca, Jeeyun Lee, Aleksandar Sekulic, Charlotte E. Ariyan, Jeffrey Sosman, Jeffrey Trent. Integrated genomic analyses reveal frequent TERT aberrations in acral melanoma [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 3389. doi:10.1158/1538-7445.AM2017-3389
Abstract LB-003: Racial differences of intron retention and DNA methylation in breast cancer
Authors: Dongwook Kim, Manu Shivakumar, Youngji Lee, Olufunmilayo Olopade, Dokyoon Kim, Younghee Lee
Journal: Cancer Research (2017)

Abstract Regulation of gene expression by DNA methylation in gene promoter regions is well-studied; however, the effects of methylation in the gene body (i.e., exons and introns) on gene expression are comparatively understudied. Recently, hyper-methylation has been implicated in the inclusion of alternatively spliced exons; moreover, exon recognition can be enhanced by recruiting the methyl-CpG-binding protein (MeCP2) to hyper-methylated sites. In this study, we examined whether or not the level of methylation of an intron is correlated with how frequently that intron is retained during splicing using DNA methylation and RNA sequencing data from breast cancer tissue samples in The Cancer Genome Atlas (TCGA). We found that hypo-methylation of introns is correlated with higher levels of intron expression in mRNA and that most novel cancer-specific mRNA isoforms are due to intron retention. The methylation level of an intron is inversely correlated with its retention in mRNA transcripts from the gene in which it is located. Furthermore, we observed significant racial differences in the methylation level of retained introns: In samples from African-American donors, retained introns were not only less methylated compared to Caucasian donors, but also were more highly expressed. This underscores the need for Understanding racial epigenetic differences and their correlation with breast cancer is an important step toward achieving personalized cancer care. Citation Format: Dongwook Kim, Manu Shivakumar, Youngji Lee, Olufunmilayo Olopade, Dokyoon Kim, Younghee Lee. Racial differences of intron retention and DNA methylation 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 LB-003. doi:10.1158/1538-7445.AM2017-LB-003
Abstract 5156: A synthesized RNA aptamer targeting and inhibiting non-small cell lung cancer
Authors: Hanlu Wang, Meng Qin, Zhihua Ren, Irvin S.Y. Chen, Yongping Jiang
Journal: Cancer Research (2017)

Abstract A specific RNA aptamer (RA16) targeting non-small cell lung cancer (NCI-H460 cells) was previously reported by in vivo SELEX. The aptamer RA16 was identified specifically targeting and inhibiting human NCI-H460 cell proliferation in vitro, as well as xenograft tumor tissues in vivo. In this study, we synthesized RNA aptamer (syn-RA16) and make comparison studies with transcribed RNA aptamer (trans-RA16) in vitro in respect of the specific targeting and direct inhibitory activity towards NCI-H460 cells.To characterize the targeting specificity in vitro, biotin-labeled syn-RA16 and trans-RA16 were incubated with NCI-H460 cells, other tumor cell lines or normal control cells. Specific fluorescent binding was observed only for NCI-H460 cells, but not for HEK293T, Hela, and Jurkat cells or buffer control. Moreover, binding affinity of Kd values to the NCI-H460 cells for syn-RA16 and trans-RA16 were determined at 24.75±2.28 nM and 12.14±1.46 nM(n=3), respectively, by flow cytometry using streptavidin-PE labelling, indicating that the specific targeting binding affinity for syn-RA16 was highly retained, as trans-RA16. On the other hand, syn-RA16 aptamer, like trans-RA16 aptamer, was also capable of inhibiting non-small cell lung cancer cell (H460) proliferation in a dose-dependent manner. At 300 nM, syn-RA16 aptamer suppressed cell proliferation by 84.5%, comparing by 86.8% with trans-RA16. The IC50 for syn-RA16 was determined at 118.4±1.1 nM, while trans-RA16 was at 105.7±1.2 nM (n=4). Intestinally, both syn-RA16 and trans-RA16 exhibited no any inhibitory effect on HeLa and Jurkat cell lines even at concentration of 600 nM. In conclusion, a specific entire RA16 RNA aptamer was synthesized. The synthesized RA16, like transcribed RA16 aptamer, demonstrated the specific targeting ability and inhibitory activity to human NCI-H460 cells. The syn-RA16 could be potential to develop a diagnostic kit or treatment for NCI-H460 cell-related non-small cell lung cancer in the clinic. Citation Format: Hanlu Wang, Meng Qin, Zhihua Ren, Irvin S.Y. Chen, Yongping Jiang. A synthesized RNA aptamer targeting and inhibiting non-small cell lung 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 5156. doi:10.1158/1538-7445.AM2017-5156
Abstract 2976: Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy
Authors: Chiu-Min Lin, Chi-Shiun Chiang
Journal: Cancer Research (2017)

Abstract Many reports have shown that hypoxia and gliosis could promote tumor cells by shielding from the immune response and relapsing, but their roles on brain tumor therapies are still unclear. Using an invasive murine astrocytoma tumor model, ALTS1C1, we found that tumor invasion front is associated with a specific hypoxia region, naming tumor peripheral hypoxia, contributes to brain tumor therapy resistant and may be responsible for tumor recurrence after the therapy. Using this tumor model, we found that the overgrowing tumor caused the shortage of vessels and resulted in the hypoxia in the early stage of tumor progression, which is conventionally called chronic hypoxia or avascular hypoxia. When tumor continues to grow, a rim of hypoxia area was formed at tumor edge and subsequently activated nearby astrocytes. At the same time, the outward reactive astrocytes enhanced tumor invasion into normal parenchyma tissues. As a result, a specific hypoxia was produced in tumor peripheral, which has relative high microvascular density (MVD) and is associated with highly reactive astrocytosis. We explored the role of this region on the response to therapies. By quantitative counting the apoptotic tumor cells across the tumor cross-section following radiation- or chemo-therapy, we found that cells at the active astrocytic region (the peripheral region) are more resistant than cells in tumor core. These results indicate that the peripheral hypoxia, not the chronic hypoxia, is the main cause of the failure of brain tumor therapy. Most importantly, we found that the formation of tumor peripheral hypoxia might be associated with the activation of astrocytes. Therefore, tactics that can suppress astrocytosis and prevent the formation of peripheral hypoxia may be alternative approaches for complementing the shortage of traditional brain tumor therapy. Citation Format: Chiu-Min Lin, Chi-Shiun Chiang. Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2976. doi:10.1158/1538-7445.AM2017-2976
Abstract 4183: A novel selective DNA-PK inhibitor, M3814, as a potential combination partner of Etoposide and Cisplatin in the therapy of lung cancer
Authors: Christian Sirrenberg, Astrid Zimmermann, Thomas Grombacher, Lyubomir T. Vassilev, Lars Damstrup, Frank T. Zenke, Andree Blaukat
Journal: Cancer Research (2017)

Abstract M3814 is a potent and selective inhibitor of DNA-PK, one of the key cellular regulators of DNA damage induced by ionizing radiation or certain cytostatics used in the treatment malignant disease. One of these drugs, Etoposide, induces double strand breaks (DSB) in cellular DNA. DSBs are most difficult to repair and, if left unrepaired, can lead to induction of cell cycle arrest and/or apoptosis and ultimately cell death. DNA-PK plays a critical role in the repair of DSB via the non-homologous end-joining pathway. M3814 was tested for activity in combination with Etoposide in a panel of 98 cancer cell lines derived from lung cancer. A broad potentiation effect of DNA-PK inhibitor was observed in most cancer cell lines. As a rule, cell lines sensitive to Etoposide demonstrated increased sensitivity to the combination. M3814 did not show significant effect on cancer cell growth/viability in combination with Cisplatin compared to Cisplatin alone at concentrations that effectively inhibit DNA-PK activity. At the same time, M3814 did not negatively affect the antitumor activity of Cisplatin. The therapeutic effect of M3814 in combination with the standard of care (SoC) regimen of Etoposide and Cisplatin was tested in the human small cell lung cancer xenograft model, NCI-H520. Triple combination of M3814, Etoposide and Cisplatin resulted in increased efficacy compared to SoC treatment arm. Since myeloid and lymphoid suppression is one of the dose limiting toxicities of the SoC regimen in patients, the effect of the triple combination on myeloid and lymphoid blood cells was investigated in immunocompetent mice. Whereas the SoC treatment showed reduction of the myeloid and lymphoid compartments, the addition of M3814 did not additionally reduce these cells neither in the treatment nor the recovery phase. Our results warrant further investigations to explore the potential of the combination in the clinical setting. Citation Format: Christian Sirrenberg, Astrid Zimmermann, Thomas Grombacher, Lyubomir T. Vassilev, Lars Damstrup, Frank T. Zenke, Andree Blaukat. A novel selective DNA-PK inhibitor, M3814, as a potential combination partner of Etoposide and Cisplatin in the therapy of lung 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 4183. doi:10.1158/1538-7445.AM2017-4183
A growth reference for mid upper arm circumference for age among school age children and adolescents, and validation for mortality: growth curve construction and longitudinal cohort study
Authors: Lazarus Mramba, Moses Ngari, Martha Mwangome, Lilian Muchai, Evasius Bauni, A Sarah Walker, Diana M Gibb, Gregory Fegan, James A Berkley
Journal: BMJ (2017)

Objectives To construct growth curves for mid-upper-arm circumference (MUAC)-for-age z score for 5-19 year olds that accord with the World Health Organization growth standards, and to evaluate their discriminatory performance for subsequent mortality.Design Growth curve construction and longitudinal cohort study.Setting United States and international growth data, and cohorts in Kenya, Uganda, and Zimbabwe.Participants The Health Examination Survey (HES)/National Health and Nutrition Examination Survey (NHANES) US population datasets (age 5-25 years), which were used to construct the 2007 WHO growth reference for body mass index in this age group, were merged with an imputed dataset matching the distribution of the WHO 2006 growth standards age 2-6 years. Validation data were from 685 HIV infected children aged 5-17 years participating in the Antiretroviral Research for Watoto (ARROW) trial in Uganda and Zimbabwe; and 1741 children aged 5-13 years discharged from a rural Kenyan hospital (3.8% HIV infected). Both cohorts were followed-up for survival during one year.Main outcome measures Concordance with WHO 2006 growth standards at age 60 months and survival during one year according to MUAC-for-age and body mass index-for-age z scores.Results The new growth curves transitioned smoothly with WHO growth standards at age 5 years. MUAC-for-age z scores of -2 to -3 and less than-3, compared with -2 or more, was associated with hazard ratios for death within one year of 3.63 (95% confidence interval 0.90 to 14.7; P=0.07) and 11.1 (3.40 to 36.0; P<0.001), respectively, among ARROW trial participants; and 2.22 (1.01 to 4.9; P=0.04) and 5.15 (2.49 to 10.7; P<0.001), respectively, among Kenyan children after discharge from hospital. The AUCs for MUAC-for-age and body mass index-for-age z scores for discriminating subsequent mortality were 0.81 (95% confidence interval 0.70 to 0.92) and 0.75 (0.63 to 0.86) in the ARROW trial (absolute difference 0.06, 95% confidence interval -0.032 to 0.16; P=0.2) and 0.73 (0.65 to 0.80) and 0.58 (0.49 to 0.67), respectively, in Kenya (absolute difference in AUC 0.15, 0.07 to 0.23; P=0.0002).Conclusions The MUAC-for-age z score is at least as effective as the body mass index-for-age z score for assessing mortality risks associated with undernutrition among African school aged children and adolescents. MUAC can provide simplified screening and diagnosis within nutrition and HIV programmes, and in research.