tbuckley/cabot-search huggingface dataset:
Abstract 133: Aloe-emodin as a potential lead targets lung cancer stem cells
Authors: Pei-Jung Lee, Wan-Jiun Chen, Chao-Chi Ho, Pan-Chyr Yang, Huei-Wen Chen
Journal: Cancer Research (2017)

Abstract Cancer stem cells (CSCs) have been proposed to be responsible for tumor initiating, drug resistance, metastasis, and recurrence. Many novel therapeutic strategies have been designed to target and eliminate CSCs. According to our previous study, we have established a model of CSCs and cancer associated fibroblasts (CAFs) co-culture system for anti-CSCs drug screening. Here, we report one of the potential hits screened via this platform and the anti-CSCs activity was further investigated both in vitro and in vivo. Human lung CSCs and CAFs were primary cultured from patient with lung adenocarcinoma according to our previous study. Image-based high content screening system was used to analyze different parameters after drug treatment. Tumorogenicity and self-renew ability are examined by sphere forming ability. Aldehyde dehydrogenase (ALDH) activity was used to analyze stem cell population by flow cytometry. The expression level of stemness-related genes, Nanog, Oct3/4 and Sox2 were validated by real-time reverse transcriptase Q-PCR. The efficacy of the lead on tumor growth was examined by the xenograft model. Lung cancer stemness markers of the xenograft tumor tissues were also evaluated by immunohistochemistry. Using the image-based high content screening system to screen over one thousands of compounds, we have identified aloe-emodin (AE) shows higher potency targeting on lung cancer stem cells (under the concentration of 1 μM) and high specificity targeting on the cancer cell lines (IC50 &amp;lt; 20 μM); compared to normal human bronchial epithelium cells and human normal fibroblast represented by IC50 (26.77 μM v.s. 39.13 μM). The level of stemness markers, Nanog, Sox2 and Oct3/4 were significantly down regulated after AE treatment compared to cisplatin treatment. AE could suppress tumor initiating abilities and self-renew capacities represented by the ability to grow as tumors spheres in CL152 ALDH+ cells. Besides, AE could inhibit ALDH population in CL152 cells (40% reduced). Also, the AE can inhibit the cisplatin-induced ALDH population as well. Furthermore, we found that AE combine with cisplatin could inhibit tumor growth as comparing to cisplatin treatment in subcutaneous models in NOD/SCID mice, whereas, AE can inhibit the level of Nanog in mice tumor tissues. According to these results, AE is a potential lead targeting on lung cancer stem cells. To discover the pharmacological mechanism of AE on cancer stem cells will be helpful to develop new strategy for lung cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Pei-Jung Lee, Wan-Jiun Chen, Chao-Chi Ho, Pan-Chyr Yang, Huei-Wen Chen. Aloe-emodin as a potential lead targets lung cancer stem cells [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 133. doi:10.1158/1538-7445.AM2017-133
Abstract LB-142: Identification of STK33 as a cancer stemness kinase and regulator of Nanog function
Authors: Susan L. Tran, Yudai Furuta, Chen Zhu, Ao Yang, Xiangao Sun, Harry A. Rogoff, Chiang J. Li
Journal: Cancer Research (2017)

Abstract In recent years evidence has accumulated in support of the cancer stem cell (CSC) model in cancer chemotherapy resistance, highlighting the urgency and necessity of identifying CSC targets for developing novel cancer therapeutics. A number of studies have suggested that Nanog is a crucial factor that can confer stemness properties to a portion of the heterogeneous cancer cell population. Although latent in normal somatic cells, aberrant expression of Nanog has been reported in many types of human cancers. Importantly, the expression levels of Nanog are often positively correlated with treatment resistance and poor survival of cancer patients. Various studies have shown that upregulation of Nanog expression enhances the tumorigenicity both in vivo and in vitro whereas repression or ablation of Nanog inhibits tumor initiation. Thus, expression of the stemness factor Nanog is linked to tumor progression, therapeutic resistance, relapse and metastasis. However, Nanog is considered a non-druggable target. Here we provide data to support a role for STK33 (Serine Threonine Kinase 33) as a novel regulator of Nanog and as a potential therapeutic target. Ectopic STK33 expression promotes stemness phenotypes of cancer cells and increases expression levels of CSC drivers including Nanog, KLF4, and SOX2. On the other hand, knockdown of STK33 inhibits expression of Nanog and results in a reduction of the stemness phenotype. STK33 directly interacts with Nanog and appears to promote its stabilization through phosphorylation, resulting in increased Nanog transcriptional activity. Moreover, BBI-503 (Amcasertib), a first-in-class cancer stemness inhibitor, potently inhibits STK33, which led to inhibition of phosphorylation of Nanog. Collectively, our data demonstrate STK33 is a critical element in the signaling network that governs the stemness of cancer cells, and as a promising therapeutic target for cancer. Citation Format: Susan L. Tran, Yudai Furuta, Chen Zhu, Ao Yang, Xiangao Sun, Harry A. Rogoff, Chiang J. Li. Identification of STK33 as a cancer stemness kinase and regulator of Nanog function [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-142. doi:10.1158/1538-7445.AM2017-LB-142
Abstract 5726: A novel tumor-promoting role for miR-4516 in glioblastoma
Authors: Tiantian Cui, Ashley Gray, Ziyan Liu, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti
Journal: Cancer Research (2017)

Abstract Background: Glioblastomas are the most aggressive high-grade brain tumors, which are often life-threatening due to their location and rapid growth. Although survival rates differ depending on a variety of genetic and environmental factors, the average survival rate for a glioblastoma (GBM) patient is less than 15 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. Here we demonstrate a novel role for miR-4516 in promoting growth and migration of GBM and establish the molecular mechanisms mediating these functions. Methods: Formalin-fixed, paraffin-embedded tissue blocks (n=268) were collected for all patients and total RNA was isolated. miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle,WA). Functional characterization studies were conducted in vitro and in vivo. The effect of miR-4516 on GBM cell growth and motility were evaluated by cell proliferation assay, migration and invasion assay, and Annexin-V assay. Realtime PCR, immunoblotting, and 3’ untranslated region luciferase assays were used to analyze miR-4516 targets and signaling pathways. Intracranial injection will be performed to investigate the role of miR-4516 in tumor growth in vivo. Results: Univariate analysis showed that miR-4516 expression in GBM patients was inversely correlated with overall survival (FDR=0.002, p=1.02E-05). Knockdown of miR-4516 blocked tumor growth and induced cell apoptosis. Tumor cell growth, migration and invasion were induced in both transient miR-4516 overexpressed GBM cells (LN229, LN18, and U87) and stable miR-4516 overexpressed GBM cells (U87-EGFRvIII). These miR-4516 tumor-promoting effects were mediated in part via direct targeting PTPN14 and CDKN1A. Investigation of the other miR-4516 targets and in vivo functional study are in process. Conclusion: Taken together, these results suggest that miR-4516 acts as a prognostic biomarker for GBM patients. Funding Information: 1R01CA169368 (PI: Houghton; Co-I:Chakravarti); 1R01CA11522358 Multiple-PI R01: Chakravarti (PI); Xia (PI); 1R01CA1145128 Baroukhim (PI); Chakravarti (Co-PI) 7/2015-6/2020; R01CA108633 (PI:Chakravarti); 1RC2CA148190 (Scientific PI: Chakravarti) Citation Format: Tiantian Cui, Ashley Gray, Ziyan Liu, Marjolein Geurts, Pierre Robe, Joseph McElroy, Erica Hlavin Bell, Arnab Chakravarti. A novel tumor-promoting role for miR-4516 in glioblastoma [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 5726. doi:10.1158/1538-7445.AM2017-5726
Abstract 257: Bone Marrow Cells Form New Cardiomyocytes in the Infarcted Myocardium
Authors: Fumihiro Sanada, Junghyung Kim, Anna Czarna, Sergio Signore, Andrea Sorrentino, Chiara Mangiaracina, Ramaswamy Kannappan, Kazuya Isobe, Polina Goichberg, Marcello Rota, Toru Hosoda, Jan Kajstura, Piero Anversa, Annarosa Leri
Journal: Circulation Research (2013)

The ability of c-kit-positive bone marrow cells (c-kit-BMCs) to form cardiomyocytes following delivery to the acutely infarcted myocardium is a matter of debate. In an attempt to resolve the controversy, we raised the possibility that c-kit-BMCs represent a functionally heterogeneous pool, containing cells with distinct transdifferentiation potential. To test this hypothesis, c-kit-BMCs were infected with EGFP-lentiviruses and injected in infarcted hearts. At 1 and 2 weeks, the regenerated myocardium was enzymatically digested and EGFP-labeled myocytes, endothelial cells (ECs), fibroblasts, and c-kit-cells were sorted. By employing a PCR-based method of detection of viral integrants, we searched for unique sites of viral insertion in the infected c-kit-BMCs and their progeny. Common insertion sites were found in the DNA of all cell populations, documenting that single c-kit-BMCs transdifferentiated into multiple cell lineages. However, the 31 detected clones shared 9 distinct sites of integration, suggesting that myocytes in different animals were generated by specific subsets of c-kit-BMCs, which retained the ability to transdifferentiate. To strengthen the observation that myocardial regeneration is oligoclonal in nature, freshly isolated FACS-sorted c-kit-BMCs were simultaneously transduced with 3 lentiviruses, each encoding red, green or blue (RGB) fluorescent proteins. Different combinations of inserted vectors resulted in the formation of numerous c-kit-BMC clones of mixed colors. RGB-infected HSCs were injected in infarcted rats; at 4 days, engrafted c-kit-BMCs showed a polyclonal pattern characterized by the presence of cells labeled by most of the color combinations seen in vitro. However, at 2 weeks, only a few of the homogeneously colored colonies seen at 4 days persisted and formed large patches of cells composed of myocytes, ECs, and smooth muscle cells. Our findings document that c-kit-BMCs are functionally heterogeneous and have different ability to survive, engraft, and transdifferentiate in the ischemic heart. At present, clonal c-kit-BMCs are being analyzed by RNA-sequencing for the identification of the unique phenotypical properties of c-kit-BMCs with high transdifferentiation potential.
Overcoming Acquired Resistance to AZD9291, A Third-Generation EGFR Inhibitor, through Modulation of MEK/ERK-Dependent Bim and Mcl-1 Degradation
Authors: Puyu Shi, You-Take Oh, Liang Deng, Guojing Zhang, Guoqing Qian, Shuo Zhang, Hui Ren, Grant Wu, Benjamin Legendre, Emily Anderson, Suresh S. Ramalingam, Taofeek K. Owonikoko, Mingwei Chen, Shi-Yong Sun
Journal: Clinical Cancer Research (2017)

Abstract Purpose: The mechanisms accounting for anticancer activity of AZD9291 (osimertinib or TAGRISSO), an approved third-generation EGFR inhibitor, in EGFR-mutant non–small cell lung cancer (NSCLC) cells and particularly for the subsequent development of acquired resistance are unclear and thus are the focus of this study. Experimental Design: AZD9219-resistant cell lines were established by exposing sensitive cell lines to AZD9291. Protein alterations were detected with Western blotting. Apoptosis was measured with annexin V/flow cytometry. Growth-inhibitory effects of tested drugs were evaluated in vitro with cell number estimation and colony formation assay and in vivo with mouse xenograft models. Protein degradation was determined by comparing protein half-lives and inhibiting proteasome. Gene knockdown were achieved with siRNA or shRNA. Results: AZD9291 potently induced apoptosis in EGFR-mutant NSCLC cell lines, in which ERK phosphorylation was suppressed accompanied with Bim elevation and Mcl-1 reduction likely due to enhanced Mcl-1 degradation and increased Bim stability. Blocking Bim elevation by gene knockdown or enforcing Mcl-1 expression attenuated or abolished AZD9291-induced apoptosis. Moreover, AZD9291 lost its ability to modulate Bim and Mcl-1 levels in AZD9291-resistant cell lines. The combination of a MEK inhibitor with AZD9291 restores the sensitivity of AZD9291-resistant cells including those with C797S mutation to undergo apoptosis and growth regression in vitro and in vivo. Conclusions: Modulation of MEK/ERK-dependent Bim and Mcl-1 degradation critically mediates sensitivity and resistance of EGFR-mutant NSCLC cells to AZD9291 and hence is an effective strategy to overcome acquired resistance to AZD9291. Clin Cancer Res; 23(21); 6567–79. ©2017 AACR.
Abstract 690: Identifying the genetic basis of stage 4S neuroblastoma
Authors: Zalman Vaksman, Lee D. McDaniel, Maura Diamond, John M. Maris, Sharon J. Diskin
Journal: Cancer Research (2017)

Abstract Introduction: The 5 year mortality rate for stage 4 metastatic neuroblastoma (NBL) is ~50%; however, the stage 4S subset of NBL is typically classified as low-risk with tumors exhibiting spontaneous regression. To date, the underlying genetic mechanisms influencing this distinct phenotype remain unknown. Method: To identify genetic determinants specific to the 4S phenotype, we performed genome-wide association study (GWAS) analyses. Blood DNA samples from 6,195 NBL patients and 11,384 non-NBL controls were genotyped using Illumina SNP arrays. European ancestry subjects were selected for inclusion in a discovery [stage 4S (n=148), stage 4 (n=996), non-NBL controls (n=9,923)] or replication cohort [stage 4S (n=76), stage 4 (n=608), non-NBL controls (n=1,461)]. Following imputation using 1KG Phase 3, we conducted case:case comparisons including stage 4S vs. 4 and stage 4S vs. 1, followed by comparisons of NBL cases in each group to matched non-NBL controls. Variants uniquely associated with 4S NBL were defined as those meeting the following criteria: (1) stage 4S vs. 4 meta P &amp;lt; 5.0 x 10-5 and P &amp;lt; 0.005 in the discovery cohort (2) 4S vs. non-NBL control P &amp;lt; 0.05 and (3) either not significant (P &amp;gt; 0.05) or odds ratio in the opposite direction in 4 vs. non-NBL controls. Results: 4S-specific variants that met our criteria spanned multiple regions with several harboring genes important to neuronal function including 9q34 (SARDH/DBH; rs2502746), 1p32.2 (KCNH1; rs12122529), 1p34 (KCNQ4; chr 1:41317634), 7q34 (CNTNAP2; rs79403134) and 2q24.1 (KCNJ3; rs78829625). At the 9q34 locus, rs2502746 showed further evidence as an expression quantitative trait locus (eQTL) for Dopamine Beta-Hydroxylase Antisense RNA1( DBH-AS1 P = 1.9 x 10-5 sun-exposed skin) and Sarcosine Dehydrogenase SARDH expression (P = 2.5 x 10-6 whole blood). Other 4S-specific loci observed include 3q27.3 (rs113207181), 8p21.3 (rs12548388), and 15q12 (rs62189512). Notably, none of the previously identified NBL susceptibility loci were found to be associated with 4S NBL in the 4S vs. non-NBL control comparison, suggesting a unique genetic basis for this enigmatic subset. Discussion: Although a unifying mechanism underlying 4S NBL has yet to be identified, our results suggest a potential role for ion-channel and neuronal function genes. Ongoing efforts include investigating the role these genes and associated pathways play in NBL, including an integrative genomic, epigenomic and transcriptome analysis of stage 4 and 4S NBL. Citation Format: Zalman Vaksman, Lee D. McDaniel, Maura Diamond, John M. Maris, Sharon J. Diskin. Identifying the genetic basis of stage 4S neuroblastoma [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 690. doi:10.1158/1538-7445.AM2017-690
Abstract 5558: Deconstruction of a human tumor microenvironment
Authors: Frances R. Balkwill, Oliver M. Pearce, Robin Delaine-Smith, Eleni Maniati, Sam Nichols, Jun Wang, Conrad Bessant, Martin Knight
Journal: Cancer Research (2017)

Abstract The purpose of this study was to understand the relationships between the molecular mechanisms of disease progression and higher-order features such as tissue stiffness, extent of disease and cellularity in the tumor microenvironment, TME. Using samples of human high-grade serous ovarian cancer metastases, ranging from normal to heavily diseased, we identified molecular components of the TME using transcriptomic and proteomic analysis. We integrated these data against higher-order features of the tissue, namely the biomechanics, cellularity, and disease score. We then used bioinformatics and multivariate statistics to identifying components of the TME that best model the higher-order features. For the first time, we revealed the complexity of extracellular matrix remodeling during metastases development, defining patterns of extracellular-matrix associated genes and proteins that predicted both extent of disease and tissue modulus. This allowed us to identify a core group of twenty-two matrix-associated molecules that modeled the dynamic process of tissue remodeling during tumor progression. We used these data to generate a ‘matrix index’, a quantitative measure of the gene expression of the twenty-two molecules. In cancer transcriptomic databases, this matrix index had prognostic significance in thirteen solid cancers including high-grade serous ovarian cancer, even after multivariate analysis. We conclude that there may be a common host matrix response to human solid cancers. Citation Format: Frances R. Balkwill, Oliver M. Pearce, Robin Delaine-Smith, Eleni Maniati, Sam Nichols, Jun Wang, Conrad Bessant, Martin Knight. Deconstruction of a human tumor microenvironment [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 5558. doi:10.1158/1538-7445.AM2017-5558
Cost-effectiveness of early identification of HIV infection
Authors: Brooke E Nichols, Gesine Meyer-Rath
Journal: The Lancet HIV (2017)

Early treatment of HIV-infected individuals with antiretroviral therapy (ART) is widely recognised not only to improve long-term outcomes for patients, 1 Group ISS Lundgren JD Babiker AG et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015; 373: 795-807 Crossref PubMed Scopus (2) Google Scholar but also to prevent HIV transmission. 2 Cohen MS Chen YQ McCauley M et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011; 365: 493-505 Crossref PubMed Scopus (5387) Google Scholar Consequently, immediate treatment is now recommended by WHO. 3 WHOConsolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Recommendations for a public health approach. 2nd edn. World Health Organization, Geneva2016 Google Scholar Although treatment is available, a large proportion of individuals present late into care (CD4 count <350 cells per μL). Even in the UK, which has good health-care access, about 40% of people infected with HIV present late for care, stymieing the potential preventive effect of treatment. 4 Skingsley A Kirwan P Yin Z et al. HIV new diagnoses, treatment and care in the UK: 2015 Report. Public Health England, London2015 Google Scholar Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysisScreening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted. Full-Text PDF Open Access
A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN.
Authors: Takefumi Komiya, Gideon Michael Blumenthal, Marc S. Ballas, Roopa Dechowdhury, Michell Manu, Suzanne Fioravanti, Thomas J Hornyak, Stephen Wank, Douglas Weinstein, Jennifer Morris, Stephen M. Hewitt, Regan Memmott, Phillip A. Dennis, Betsy Morrow
Journal: Journal of Clinical Oncology (2013)

2532 Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n=4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n=9, p=0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p=0.0026, 0.0391, respectively). The most common AEs (all grades &gt;25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.