tbuckley/cabot-search huggingface dataset:
Abstract 4421: A novel long non-coding RNA competes with endogenous RNA and mediates prostate cancer progression
Authors: Xiao-Lei Shi, Yu-Tian Xiao, Fei Liu, Yue Yang, Xin-Wen Nian, Ya-Sheng Zhu, Shancheng Ren, Yinghao Sun
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) remains the leading cancer among men worldwide. There is a critical need for new biomarkers to predict PCa progression and emerging mechanisms of resistance. Long non-coding RNAs(lncRNAs) play pivotal roles in a plethora of cellular processes. Understanding the molecular mechanisms of lncRNAs implicated in the progression of PCa could have an important impact on cancer detection, diagnosis and prognosis. We previously identified 17 lncRNAs that were found to be differentially expressed in oriental PCa patients. Here, We focused on one uncharacterized lncRNA, which is highly expressed in locally advanced or metastatic PCa, and named it lncAPP. Silencing of lncAPP in PCa inhibitied proliferation and tumour invasion both in vitro and in vivo, resulting in a less aggressive phenotype. In addition, we found that expression of lncAPP in PCa correlated with epithelial-to-mesenchymal-transition(EMT). Using miRDB and Target Scan prediction algorithm, we identified a list of putative lncAPP-binding miRNAs. Specifically, using RNA immunoprecipitation assay and luciferase reporter assay, we demonstrated that lncAPP functions as a molecular sponge for miR218 to facilitate expression of ZEB2 and CDH2. In conclusion, we discovered a novel lncRNA which is highly expressed in PCa patients of poor prognosis. The expression of lncAPP is associated with tumor progression. We conclude that lncAPP is an intriguing therapeutic target in PCa. Citation Format: Xiao-Lei Shi, Yu-Tian Xiao, Fei Liu, Yue Yang, Xin-Wen Nian, Ya-Sheng Zhu, Shancheng Ren, Yinghao Sun. A novel long non-coding RNA competes with endogenous RNA and mediates prostate cancer progression [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 4421.
Abstract 4384: The differential induction of apoptosis in MCF-7 and MDA-MB-231 breast cancer cells in response to RBBP6 silencing is associated with p53 expression
Authors: Pontsho Moela, Lesetja Raymond Motadi
Journal: Cancer Research (2018)

Abstract Breast cancer remains a female-related health problem on a global scale, accounting for over a million newly estimated cases that are still on the rise. More than 50% cases of breast tumorigenesis are due to mutations or inactivation of p53, a tumor suppressor gene involved in the regulation of cell cycle and apoptosis. In breast cancer, the frequency of TP53 mutations varies greatly between the heterogeneous subtypes, with basal-like breast cancers having the highest frequency whereas the luminal subtypes have been shown to generally express wt. p53. Active p53 is responsible for sensing any cellular stress signal with a potential to damage DNA, thus deciding the cell's fate depending on whether the damage is reversible or not. Therefore cellular p53 levels remain in check by the MDM2 regulatory protein, which promotes the degradation of unwanted p53 via a negative feedback loop mechanism using its E3 ligase activity. However, this interaction between MDM2 and wild-type p53 is cancer promoting in the same way that E6 oncoprotein is capable of leading to the degradation of wild-type p53 in cervical cancer. Negative regulators of p53, therefore, threaten cancer repression and play a role in drug resistance among cancer patients. Of particular interest in this study is RBBP6, another negative regulator of p53 that uses the E3 ligase activity as well in order to promote p53 degradation. Previous studies have shown that silencing RBBP6 in breast cancer restores p53 followed by apoptosis induction. However, it is unclear whether the observed apoptosis is linked to the recovered p53. To test this hypothesis, we aim to analyze the differential susceptibilities of MCF-7 and MDA-MB-231 cells expressing wt. p53 and mt. p53, respectively, to RBBP6 silencing. Real-time cell analysis revealed a clear distinction between the growth of the two cell lines, with MCF-7 showing a significantly reduced proliferation in comparison to MDA-MB-231. Apoptosis induction was also high in MCF-7 AND lower is MDA-MB-231, as was further confirmed by the differential expression of pro-apoptotic genes between the two cell lines. These findings suggest that difference in p53 statuses of the two cell lines play a role in apoptosis induced by RBBP6 silencing. These findings are necessary for reaching a better understanding of molecular mechanisms that impact patient response and resistance to candidate therapeutics and may be helpful in developing more effective treatment strategies for different subtypes of breast cancer. Citation Format: Pontsho Moela, Lesetja Raymond Motadi. The differential induction of apoptosis in MCF-7 and MDA-MB-231 breast cancer cells in response to RBBP6 silencing is associated with p53 expression [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 4384.
Abstract 19104: Troponin Elevation is Strongly Associated With Death in Dengue Patients With Cardiac Involvement
Authors: Ariane Macedo, Carlos E Ornelas, Henrique P Pena, Simone Ramalho, Yolanda M Ornellas
Journal: Circulation (2017)

Introduction: Dengue is currently one of the most important emerging infectious diseases in the world , and complications involving organ systems are seen with varying incidence. Cardiac involvemen...
Abstract 1138: LBH, a novel WNT effector in promoting basal-like breast cancer
Authors: Kilan C. Ashad-Bishop, Karoline J. Briegel
Journal: Cancer Research (2018)

Abstract BACKGROUND: Clinically aggressive basal-like breast cancers (BLBC) disproportionally contribute to cancer deaths, but lack effective treatment options due to absence of expression of key therapeutic targets (ER, PR, HER2). New evidence suggests BLBC may originate from luminal breast epithelial cells through luminal-to-basal cell lineage conversion and dedifferentiation. However, the factors that reprogram cell fate and differentiation states during BLBC development remain poorly understood. Our laboratory has identified a novel WNT/β-Catenin target transcriptional regulator, Limb-Bud-and-Heart (LBH), which is majorly overexpressed in aggressive BLBC harboring WNT hyperactivation. We previously showed in a conditional LBH knockout mouse model in vivo that LBH is a key stem cell and basal lineage regulator in normal mammary gland development. However, it's role in breast cancer remains elusive. Here, we crossed conditional LBH knockout (KO) mice with a mouse model for WNT-driven breast cancer (MMTV-Wnt1) to test if LBH is a critical effector of WNT-driven basaloid breast cancer, and whether its inhibition may affect BLBC tumorigenesis. RESULTS: In our in vivo mouse model, epithelial-specific LBH inactivation using a Keratin 14/K14-Cre significantly attenuated Wnt1-induced mammary gland hyperplasia and delayed tumor onset. Yet, tumor volumes and burden were not changed, indicating that LBH is not essential for WNT-induced tumorigenesis. However, LBH-deficient MMTV-Wnt1-transgenic tumors exhibited pronounced histopathological differences compared to LBH WT MMTV-Wnt1-transgenic tumors. Whereas Wnt1+;K14CreLbh WT tumors were highly vascularized, disorganized, with mixed basal and luminal cell identity; tumors from Wnt1+;K14CreLbh KO mice were more organized, differentiated, and predominantly luminal Keratin 8 positive. We are currently investigating if the attenuated hyperplasia and tumor onset caused by LBH loss may be due to a deficiency in cancer stem cells in this breast cancer model. CONCLUSION: Our data indicate that LBH is an essential cell fate regulator downstream of WNT signaling that maintains basal lineage identity and the undifferentiated nature of BLBC. Thus, LBH inhibition may be a novel strategy to reduce the high mortality of BLBC patients through differentiation therapy. Citation Format: Kilan C. Ashad-Bishop, Karoline J. Briegel. LBH, a novel WNT effector in promoting basal-like breast cancer [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 1138.
Abstract 3533: Elevated expression of heme related proteins in viable tumor cells treated with vascular disrupting agent, combretastatin A-4 phosphate in xenograft models of NSCLC
Authors: Sanchareeka Dey, Sharda Kumari, Sarada Preeta Kalainayakan, Poorva Ghosh, Li Zhang, Li Liu
Journal: Cancer Research (2018)

Abstract Tumors cannot grow without a supply of oxygen and nutrients. Hence, targeting tumor vasculature with Vascular Disrupting Agents (VDAs) represents a promising therapeutic strategy, especially for the treatment of solid tumors. However, VDAs cause central necrosis, leaving a rim of viable tumor cells that often eventually lead to tumor recurrence and development of resistance. Here, we aim to better understand the underlying molecular mechanisms leading to the acquisition of VDA-resistance and its correlation with the extent of hypoxia and respiratory functions. A well-known VDA, Combretastatin A-4 phosphate (CA4P), was used for the study. First, a NSCLC cell line expressing luciferase was implanted into the right flanks of female SCID mice. Next, CA4P was administered intraperitoneally. The effect was monitored 3 and 24 hours post injection of CA4P through BLI (Perkin Elmer's IVIS Lumina III) after subcutaneous injection of luciferin. After sacrificing the mice, the tumors were harvested, formalin-fixed, and paraffin-embedded for Immunohistochemistry (IHC). Our BLI data indicated significant decrease in radiance 3 hour post treatment (total flux in photons per second) which remained so at 24 hours, when luciferin was re-administered. Our IHC data indicated enhanced levels of enzymes involved in heme biosynthesis, uptake and degradation, and hemoproteins involved in oxidative phosphorylation. Furthermore, we examined the effect of a mitochondrial targeting agent (MTA) that undermined the expression of these proteins, on the progression of subcutaneous tumor xenografts. Citation Format: Sanchareeka Dey, Sharda Kumari, Sarada Preeta Kalainayakan, Poorva Ghosh, Li Zhang, Li Liu. Elevated expression of heme related proteins in viable tumor cells treated with vascular disrupting agent, combretastatin A-4 phosphate in xenograft models of NSCLC [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 3533.
Abstract 1549: LAPTM5 in clear cell renal cell carcinoma
Authors: Hyewon Ryu, Solbi Kim, Nayoung Kim, Jin-Man Kim, Hyo Jin Lee
Journal: Cancer Research (2018)

Abstract Lysosomal-associated multispanning membrane protein 5 (LAPTM5) is membrane protein that mostly expressed in immune cells and hematopoietic cells. Recently, it has been demonstrated that LAPTM5 expression levels are decreased in several cancer cells by inducing regression of Hela cells and neuroblastomas. However, its exact role in cancer has yet to be defined. Furthermore, the clinical effect of LAPTM5 expression in cancer has not been reported so far. Thus, we investigated the association between LAPTM5 expression and its clinicopathological characteristics in 112 cases of clear cell renal cell carcinoma using tissue microarrays by immunohistochemical staining. Tumors were classified into four grades based on the staining intensity: 0 = no staining, +1 = weak, +2 = intermediate, and +3 = strong. The staining intensity was classified into LAPTM5-negative group or LAPTM5-positive groups. (0; negative, +1 ~ +3; positive). Of all 112 cases, 9 cases showed LAPTM5-negative, while 93 cases showed LAPTM5-positive: +1 (35 cases), +2 (28 cases), and +3 (30 cases). LAPTM5-positivity was significantly associated with decreased tumor recurrence. In addition, recurrence-free survival (RFS) (p = 0.010), cancer-specific survival (CSS) (p = 0.022), and overall survival (OS) (p = 0.022) were significantly decreased in the LAPTM5-negative group. Univariate analysis indicated that tumor size (HR = 3.44; 95% CI, 1.000-11.836), Fuhrman nuclear grade (HR = 1.863; 95% CI, 1.169-2.971), and negative LAPTM5 expression (HR = 3.173; 95% CI, 1.249-8.064) significantly affected the RFS of clear cell renal cell carcinoma patients. Moreover, CSS and OS were significantly affected by Fuhrman nuclear grade (HR = 2.177; 95% CI, 1.261-3.757 and HR = 1.673, 95% CI, 1.062-2.635, respectively) and negative LAPTM5 expression (HR = 3.398; 95% CI, 1.110-10.405 and HR = 2.826; 95% CI, 1.136-7.031, respectively). Multivariate analysis showed that a high Fuhrman nuclear grade and negative LAPTM5 expression were significant independent risk factors. Based on these results, loss of LAPTM5 was associated with poor oncological outcomes; this suggests that LAPTM5 might be a useful prognostic marker in patients with clear cell renal cell carcinoma. Citation Format: Hyewon Ryu, Solbi Kim, Nayoung Kim, Jin-Man Kim, Hyo Jin Lee. LAPTM5 in clear cell renal cell carcinoma [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 1549.
Abstract P315: Three-year Progression of Sleep-disordered Breathing is Associated with Cardiovascular Disease Risk Factors in Young Adults
Authors: Christopher E Kline, Thomas B Rice, Patrick J Strollo, Emma Barinas-Mitchell
Journal: Circulation (2016)

Introduction: Sleep-disordered breathing (SDB) is a common sleep disorder that is significantly associated with cardiovascular disease (CVD) risk. Less is known about the short-term cardiovascular implications of mild-severity SDB progression, as mild SDB is less commonly associated with CVD but often develops into more severe SDB over time if left untreated. Hypothesis: We hypothesized that worsening of SDB severity over 3 years would be associated with greater changes in common CVD risk factors (body weight, heart rate [HR], blood pressure [BP], insulin resistance, and C-reactive protein [CRP]). Methods: A sample of 32 adults (38.6±6.4 y; 31.9±4.0 kg/m2; 72% female) who previously had participated in a 1-year lifestyle intervention were followed from 1-year post-intervention (2Y) for an additional 3 years (5Y). At 2Y and 5Y, SDB was assessed with an ambulatory monitor (ResMed ApneaLink); the oxygen desaturation index (ODI; the number of times per hour of recording that the blood oxygen saturation [SaO2] level was reduced by ≥4%) and mean SaO2 served as the primary indices of SDB severity. At 2Y and 5Y, body weight and resting BP and HR were assessed using standard procedures and fasting blood samples were obtained and measured for glucose, insulin, and CRP. Insulin resistance was measured via the Homeostatic Model Assessment method. Multiple linear regression and analysis of covariance were used to examine the associations between changes in SDB severity and changes in CVD risk factors, adjusting for 2Y values of CVD risk factors. Results: ODI at 2Y was 5.3±6.6. At 5Y, ODI had changed (i.e., improved) by -0.2±4.9, with ODI worsening by ≥2 in 7 adults and improving by ≥2 in 11 adults. Mean SaO2 at 2Y was 95.5±1.6% and changed (i.e., improved) by +0.1±1.1% at 5Y; mean SaO2 worsened in 10 adults and improved in 12 adults. Three-year change in ODI, but not SaO2, was significantly associated with weight change (β=.42, P=.02). Compared to those whose ODI worsened or did not change, improved ODI was associated with more favorable changes in CRP (-1.8 vs. +0.8 mg/L; P=.04) and heart rate (-5.0 vs. +0.2 beats/min; P=.05); however, these associations were weakened after further adjustment for weight change (P=.16 and P=.07, respectively). Compared to those whose SaO2 remained unchanged or improved, worsened SaO2 was associated with increased insulin resistance (+1.1 vs. -0.4; P&lt;.01); results were unchanged following adjustment for weight change (P=.01). Changes in ODI and SaO2 were not related to changes in BP. Conclusions: Even marginal worsening of SDB severity over 3 years is associated with elevation in some CVD risk markers. Treatment of mild SDB in young- to middle-aged adults may reduce risk for CVD.
Abstract 14868: Incidence and Outcomes of Cardiopulmonary Resuscitation in Pediatric Intensive Care Units
Authors: Robert Berg, Amy Clark, Vinay M Nadkarni, Frank Moler, Robert M Sutton, David L Wessel, John T Berger, Kathleen Meert, J M Dean, Murray Pollack
Journal: Circulation (2015)

Introduction: Although registry and administrative data suggest that &gt;6000 children have in-hospital cardiac arrests each year, most occur in pediatric intensive care units (PICUs), and 39% survive to hospital discharge, prospective research quality data on the incidence and outcomes of PICU CPR are not currently available. Objectives: To determine the incidence and outcomes CPR provided in PICUs. Methods: Multi-center prospective observational study of children &lt;18 years old randomly selected and intensively followed from PICU admission to hospital discharge in the NICHD-funded Collaborative Pediatric Critical Care Research Network from December 2011 to April 2013. Results: Among 10,078 children enrolled, 139 (1.4%) received CPR for ≥1 minute and/or defibrillation. Of these children, 78% attained return of circulation, 45% survived to hospital discharge, and 89% of survivors had favorable neurological outcomes. The relative incidence of CPR events was higher for cardiac patients compared with non-cardiac patients (3.4% versus 0.8%, p&lt;0.001), but survival rate to hospital discharge with favorable neurological outcome was not statistically different (41% versus 39%, respectively). Shorter duration of CPR was associated with higher survival rates: 66% [29/44] survived to hospital discharge after 1-3 minutes of CPR versus 28% [9/32] after &gt;30 minutes, p&lt;0.001. Among survivors, 26/29 (90%) had a favorable neurological outcome after 1-3 minutes versus 8/9 (89%) after &gt;30 minutes of CPR. Conclusions: These data establish that contemporary PICU CPR, including long durations of CPR, results in high rates of survival to hospital discharge (45%) and favorable neurologic outcomes among survivors (89%). Rates of survival with favorable neurologic outcomes were similar among cardiac and non-cardiac patients. The rigorous prospective, observational study design avoided the limitations of missing data and potential selection biases inherent in registry and administrative data.
Abstract 4810: Targeting androgen receptor in combination with cisplatin: Effective treatment strategy for muscle invasive bladder cancer
Authors: Ashish Tyagi, Balaji Chandersekaran, Samarpit Rai, Houda Alatassi, Ahmed Q. Haddad, Murali K. Ankem, Chendil Damodaran
Journal: Cancer Research (2018)

Abstract Background: Bladder cancer is one of the major causes of cancer death in US and worldwide. Cisplatin is a key component of chemotherapeutic regimens employed in the treatment of advanced bladder cancer. The role of androgen and androgen receptor (AR) signaling in bladder cancer remains uncharacterized. Aim: The aim of the study is to delineate the role of AR in bladder cancer and to determine whether combination of AR inhibitor, enzalutamide (Enz) and cisplatin-based therapies effectively inhibit the growth of muscle invasive bladder cancer (MIBC). Methods: AR expression was determined in 75 human bladder cancer specimens and in a panel of bladder cancer cell lines. Cells grown in charcoal stripped media supplemented with dihydrotestosterone (DHT) were treated with cisplatin, enzalutamide (AR inhibitor), or a combination of both. Cellular/phenotypic analysis including MTT assay, apoptotic assay, migration as well as invasion assays and molecular analysis including western blotting, real time PCR analysis were performed. Isobologram analysis for the combination was performed and analyzed with CompuSyn. Experiments were repeated in triplicates and analyzed with unpaired Student's t-test and one way ANOVA *p≤0.05, **p≤0.01, ***p≤0.001. Results: AR expression was seen in around 40% of bladder cancer patients. Inhibition of AR signaling by enzalutamide effectively inhibited the growth of AR+ MIBC cells. Interestingly, enzalutamide in combination with cisplatin (Enz + Cis) synergistically inhibited the proliferation of MIBC cells, TCCSUP (CI: 0.42, 1.25 + 5 μM) and J82 (CI: 0.79, 2.5 + 5 μM) at low concentrations of enzalutamide and cisplatin resp.. The molecular studies revealed the induction of DNA damage markers (pATM, pATR, pChk1, pHis) and enhanced expression of the pro-apoptotic genes (Bax, caspases-3 and PARP) in Enz+Cis treated AR+ MIBC cells. In addition, we demonstrated abrogation of invasive and migratory potential with Enz+Cis treatment, by downregulation of the mesenchymal markers (N-cadherin, slug, β-catenin, and vimentin) in both cell lines. Our studies suggest combination of Enz + Cis may be effective in patients with AR+ MIBC. Conclusion: Combination of cisplatin and AR inhibition effectively inhibit bladder tumor growth and migration, and hold promise as synergetic therapies for AR+ bladder cancer patients. Citation Format: Ashish Tyagi, Balaji Chandersekaran, Samarpit Rai, Houda Alatassi, Ahmed Q. Haddad, Murali K. Ankem, Chendil Damodaran. Targeting androgen receptor in combination with cisplatin: Effective treatment strategy for muscle invasive bladder cancer [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 4810.