tbuckley/cabot-search huggingface dataset:
Abstract 4474: An intricate role of p53 and p21 in cellular alterations and drug penetration in spheroids of colorectal cancer cells
Authors: Viswanath Das, Narendran Annadurai, Marián Hajdúch
Journal: Cancer Research (2018)

Abstract The tumor protein p53 and cyclin-dependent kinase inhibitor p21Waf1/Cip1 (p21) are two proteins with an intriguing and a paradoxical role in cancer. Through p53-dependent signals, p21 negatively controls cell cycle progression to protect cells against deleterious effects of DNA damage. Although p53 is a tumor suppressor protein, recent evidence shows that some patients with wild-type (wt) p53 develop aggressive and drug-resistant cancers. Similarly, recent studies also suggest the oncogenic role of p21. In a p53 deficient background, p21 results in the development of a subset of highly proliferative and resistant population of cancer cells. In this study, we examined the role of p53 and p21 in inducing cellular alterations using a panel of colorectal carcinoma cell lines with different p53 and p21 background and spheroid and spheroid-derived cell cultures. First, our data show that despite the presence of proliferating cells, spheroid-derived cultures of HCT116/p53wt cells continue to display an elevated p21 level even after 6 days of culture as a monolayer. These p21-overexpressing proliferating cells show increased resistance to doxorubicin and paclitaxel in comparison to their parental monolayer counterpart. In contrast to HCT116/p53wt cells, DLD-1/p53mut cells did not show elevated p21 levels following reversal from spheroid to monolayer. The increased p21 level in spheroids and spheroid-derived cultures of HCT116/p53wt cells led us to examine the role of p53 and p21 in drug penetration. Spheroids of HCT116/p53wt cells were less permeable to doxorubicin and showed increased expression of intracellular junctional (IJ) proteins (adherens and tight junctions). Knocking-out p21 in HCT116/p53wt cells decreased the level of IJ proteins, resulting in an increased doxorubicin penetration. Re-expression of p21 in p21-knocked-out HCT116/p53wt cells restored IJ protein levels, reducing doxorubicin penetration and the subsequent effect of doxorubicin on spheroids. Interestingly, however, knocking-out p21 in DLD-1/p53mut cells neither altered intracellular junctions nor affected doxorubicin penetration. These data indicate that the effect of p21 on IJ proteins and drug penetration is pertinent only in cells with wt p53. Overall, the data from our study suggest an intricate interplay between wt p53 and p21 in inducing cellular alterations that affect the sensitivity of cells to anti-cancer drugs in spheroids. Citation Format: Viswanath Das, Narendran Annadurai, Marián Hajdúch. An intricate role of p53 and p21 in cellular alterations and drug penetration in spheroids of colorectal cancer 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 4474.
Abstract 18321: Analysis of a Consanguineous Cohort to Identify and Characterize Human Knockouts
Authors: Danish Saleheen, Pradeep Nataranjan, Wei Zhao, Asif Rasheed, Sumeet Khetarpal, Eric Lander, Stacey Gabriel, Mark Daly, Philippe Frossard, John Danesh, Daniel Rader, Sekar Kathiresan
Journal: Circulation (2015)

Background: Experimental disruption of both gene copies (“knockout”) in model organisms has proven useful to understand gene function. Identification of “human knockouts” (i.e., individuals in which null mutations disrupt both copies of a given gene) should therefore provide valuable insights to a gene function that could be of direct relevance to humans. Objective and Methods: We leverage naturally-occurring null mutations and consanguinity in the human population in order to: 1) identify humans knocked out for genes; and 2) characterize the phenotypic consequences of complete gene disruption. We performed whole-exome sequencing in 7,078 individuals living in Pakistan, a region of the world with high levels of consanguinity, and tested whether knockouts differed from wild-type participants across a range of &gt;200 cardiometabolic traits. Results: Median length of genome-wide homozygosity among Pakistani participants was 6-7 times higher than participants of European (CEU, TSI), East Asian (CHB, JPT, CHD) and African ancestries (YRI, MKK), respectively. In Pakistanis, we were able to enumerate 47,656 mutations predicted to be null (nonsense, frameshift, or canonical splice-site); variants were further filtered based on MAF, transcript position, splice sites, and conservation to identify 36,850 “high-confidence” null mutations across 12,131 autosomal genes. Across all participants, 961 distinct genes were completely disrupted by homozygous null mutations. 1,306 participants (18.4%) had at least one gene knocked out. In a phenotypic screen, homozygosity for null mutations at APOC3 was associated with absent plasma apolipoprotein C-III levels; at PLAG27 , with absent enzymatic activity of lipoprotein-associated phospholipase A2 in the blood; at CYP2F1 , with higher plasma interleukin-8 concentrations; and at either A3GALT2 or NRG4 , with markedly reduced plasma insulin C-peptide concentrations. After physiologic challenge with oral fat, APOC3 knockouts, when compared to wild-type family members, displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Conclusion: These observations provide a roadmap to understand the consequences of complete disruption of a large fraction of genes in the human genome.
Abstract 2451: Long noncoding RNA OVAAL promotes melanoma cell proliferation through translational suppression of p27
Authors: YUNA YUAN ZHANG, Xu Guang Yan, Margaret Farrelly, Hamed Yari, Yuchen Feng, Ting La, Hessam Tabatabaee, Lei Jin, Xu Dong Zhang
Journal: Cancer Research (2018)

Abstract Evading apoptosis and limitless replicative potential are two hallmarks of malignant cells. Here we report that melanoma cells surviving the induction of apoptosis by TNF-related apoptosis-inducing ligand (TRAIL) or the Mcl-1 inhibitor UMI-77 have even higher proliferative potential, and that this is associated with the increased expression of the long noncoding RNA (lncRNA) OVAAL which competes with p27 mRNA for binding to polypyrimidine tract binding protein 1 (PTBP1) and thus represses p27 mRNA translation. Prolonged exposure to TRAIL or Mcl-1 resulted in stable melanoma cell populations with increased proliferation activity. Comparative RNA-seq analysis identified OVAAL as the most significantly upregulated lncRNA in melanoma cells resistance to TRAIL and Mcl-1. ShRNA knockdown of OVVAL reversed the increased proliferative potential of resistant cells, and also inhibited proliferation in a subset of parental melanoma cell lines that constitutively expressed relatively high levels of OVAAL. RNA pulldown followed by Mass Spectrometry analysis revealed that among proteins that were physically associated with OVAAL was a protein called PTBP1 that bound to and enhanced the activity of the internal ribosomal entry site (IRES) in the 5' untranslated region (5'-UTR) of p27 mRNA. Indeed, OVAAL knockdown resulted in an increase in the association between PTBP1 and p27 IRES leading to upregulation of the p27 protein, whereas overexpression of OVAAL caused reduction in binding of PTBP1 to the IRES of p27. Furthermore, co-knockdown of PTBP1 abolished upregulation of p27 triggered by OVAAL knockdown. These results suggest that OVAAL competes with p27 mRNA for binding to PTBP1 and thus inhibits p27 expression and promotes cell proliferation. This was substantiated by binding assays using in vitro-synthesized biotin-labelled OVAAL, p27 IRES and purified PTBP1 in a cell-free system. Our results showed that the increased c-Myc activity was responsible for upregulation of OVAAL in melanoma cells selected for resistance to apoptosis induced by TRAIL or UMI-77. Collectively, these results identify the expression of OVAAL as an important mechanism promoting melanoma cell proliferation, with potential implications for targeting OVAAL in combination with apoptosis-inducing therapeutics in the treatment of melanoma. Citation Format: YUNA YUAN ZHANG, Xu Guang Yan, Margaret Farrelly, Hamed Yari, Yuchen Feng, Ting La, Hessam Tabatabaee, Lei Jin, Xu Dong Zhang. Long noncoding RNA OVAAL promotes melanoma cell proliferation through translational suppression of p27 [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 2451.
Abstract 2309: Increase in Cdk4 activity during progression of small intestinal neuroedocrine tumors
Authors: Tanupriya Contractor, Chris R. Harris
Journal: Cancer Research (2018)

Abstract In the USA, there are approximately 5000 new cases of small intestinal neuroendocrine tumors (SINETs) per year, many of which already show liver metastasis upon initial diagnosis. The genetic causes of SINETs have long been a mystery. The only known recurrent mutations are in the Cdkn1b gene, which is mutated in 8% of tumors. Cdkn1b encodes p27kip1, an inhibitor of Cdk4 and Cdk2. We analyzed proteins and genes linked to the function of Cdk4 in a set of early and late SINETs (pathological stages M0 or M1). Amplification of Cdk4 activators (CcnD1, CcnD2, CcnD3), or loss of copy of Cdk4 inhibitors (Cdkn1b as well as Cdkn2a), or mutation of Cdkn1b were uncommon events, but notably occurred almost exclusively in patients with late stage disease. Patients with late stage tumors also had genetic abnormalities in Phlda3, including loss of copy, loss of heterozygosity, or presence of the rs35383942 SNP. Altogether, more than 50 percent of the advanced tumors had one or more of these genetic events, compared to less than 15 percent of the early tumors. Phlda3 is known to affect Akt activity which in turn is known to repress p27kip1 by phosphorylation, and indeed we detected more p27kip1 phosphorylation in late stage tumors. Finally, advanced tumors showed higher expression of Cdk4 and increased phosphorylation of serine-807 or serine-811 of the Rb1 protein. Together, these data argue that there is genetic pressure to increase Cdk4 activity during progression of SINETs, and suggest that patients with advanced SINETs may respond to Cdk4 inhibitors. Citation Format: Tanupriya Contractor, Chris R. Harris. Increase in Cdk4 activity during progression of small intestinal neuroedocrine tumors [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 2309.
Roles of P-Selectin in Inflammation, Neointimal Formation, and Vascular Remodeling in Balloon-Injured Rat Carotid Arteries
Authors: Shin-ichiroHayashi, NoboruWatanabe, KohNakazawa, JunichiSuzuki, KenjiTsushima, TakuyaTamatani, ShinjiSakamoto, MitsuakiIsobe
Journal: Circulation (2000)

Background—P-selectin plays key roles in mediating inflammation through promoting adherence of leukocytes to activated platelets and endothelium. This process is one of the initial events in atherosclerosis and restenosis after coronary angioplasty. Methods and Results—Using a rat balloon-injury model, we examined the role of P-selectin in vascular inflammatory processes. In the acute phase, immunohistochemistry revealed that P-selectin was intensely expressed on both activated platelets covering the denuded segment and endothelial cells of the inflamed adventitial small vessels. Treatment with an anti–P-selectin monoclonal antibody (MAb) for 8 consecutive days significantly inhibited neointimal formation at day 14 (42% inhibition; P<0.05), and this effect persisted at day 56 (40% inhibition; P<0.01) compared with the control group. Vascular shrinking accompanying adventitial fibrosis was also attenuated at day 56. Inhibition of both neointimal formation and vascular shrinking resulted in the lumen area o...
Pancytopaenia and breathlessness: Hickam’s Dictum prevails!
Authors: Andrew W Creamer, Rachel Protheroe, Harsha Gunawardena, Shaney L Barratt
Journal: Thorax (2018)

Dr Andrew W Creamer (AWC), Respiratory Registrar : A 70-year-old retired teacher was referred to the respiratory clinic with a 12-month history of progressive exertional dyspnoea and dry cough. He denied haemoptysis, constitutional symptoms or diurnal variation. He took omeprazole, amlodipine and ezetimibe for a long-standing history of dyspepsia, hypertension and hypercholesterolaemia. He was an ex-smoker with a 30 pack-year history.

He reported monophasic colour change in his fingers in the cold, but denied any other connective tissue disease (CTD) symptoms. He denied any significant environmental exposures such as organic dusts or moulds.

His vital signs were normal. There was evidence of mechanic’s hands (a hyperkeratotic eruption with fissuring and cracking on the palmar and radial aspects of the fingers, strongly associated with idiopathic inflammatory myopathies) but no other features of CTD or clubbing. Bibasal fine inspiratory crepitations were audible on chest auscultation. Cardiovascular examination was normal.

Initial investigations revealed pancytopenia (figure 1) with unremarkable liver and renal function, prompting referral to local haematology services for further assessment.



Figure 1 
Baseline blood tests at presentation. Abnormal values are highlighted in bold. Pancytopenia was evident, in the context of normal B12, folate and ferritin.



Lung function testing revealed a restrictive pattern with significantly reduced gas transfer (figure 2), while 6 min walk test demonstrated baseline saturations of 95% on air dropping to 77% on exertion, achieving 260 m (48% of theoretical distance).



Figure 2 
Lung function tests at baseline and 4-month follow-up. Spirometry demonstrated a restrictive pattern with reduction in gas transfer factor. KCO, carbon monoxide transfer coefficient; TLCO, transfer factor for carbon monoxide.



Chest X-ray showed prominent interstitial lung markings in the mid and lower zones (figure 3). High-resolution CT thorax (HRCT) demonstrated centrilobular emphysema throughout the lungs and a basally predominant interstitial process with features suggestive of non-specific interstitial pneumonia (NSIP) (figure …
Abstract 20191: Do Wearable Activity Trackers Improve Subjective Health Status, Physical Activity And Cardiometabolic Risk?
Authors: Luke J Burchill, Meike Niederhausen, Yuliang Wang, Sandra Colner, Douglas Bogia, Nora Fino, David Yanez, Jessica Minner, Prashant Shah, Saurabh Thosar, Steven Shea, Joaquin Cigarroa, Asha Nayak, Jodi Lapidus
Journal: Circulation (2016)

Introduction: We assessed the impact of a commercially available wearable activity tracker on health status, physical activity (PA) and cardiometabolic risk. Methods: Healthy volunteers used a wearable device for minute-by-minute recording and display of PA including steps / day and caloric expenditure. Activity goals were not prescribed. Health status (SF-12, GAD 7, PHQ-9, & the Satisfaction With Life Scale) and cardiometabolic risk [BMI, waist hip ratio, SBP, DBP, HBA1c and lipids] was assessed. Participants were asked whether PA increased during the study. Change in cardiometabolic risk factors was assessed via linear mixed models. Results: Of 431 volunteers, 322 had sufficient PA data. Average study duration was 5.2 ± 0.6 months. Measures of health status were unchanged, with the exception of the SF-12 vitality subscale (52 ± 8 at baseline vs 54 ± 8 at study end, p = 0.006). Over half (57%) reported a subjective increase in PA. However, wearable device data did not confirm objective increases in PA, w...
Abstract 3334: CREB is required forKRAS-driven lung tumorigenesis
Authors: Jong woo Lee, Frank J. Slack, Eric J. Nestler, Roy S. Herbst, Jaseok Peter Koo
Journal: Cancer Research (2018)

Abstract The aberrant constitutive activation of the transcription factor, cyclic-AMP response element- binding (CREB) protein, has been associated with poor prognosis and chemotherapeutic resistance in KRAS-mutated human cancers, one of which includes non-small cell lung cancer (NSCLC). However, the role of CREB in KRAS-driven lung tumorigenesis has not been fully understood. Using adenoviral delivery of Cre specifically to the mouse lung, we generated a new transgenic lung cancer mouse model driven by Kras activating mutation G12D and concomitant with Creb loss (KrasLSL-G12D/+; CrebFlox/Flox). In this study, we used this model to show that a proto-oncogenic transcription factor CREB, is required for KRAS-driven lung tumorigenesis. Loss of Creb (Creb-/-) in the mice harboring Kras-mutated lung tumors significantly suppressed tumor development, and thus, dramatically prolonged mouse survival when compared to either wild (Creb+/+) or heterozygous (Creb+/-) deletion of Creb. Mechanistically, we identified a few novel CREB target gene. These data suggest that CREB is essential for KRAS-driven lung tumorigenesis and that CREB could be a potential target for therapeutic treatment for individuals suffering from KRAS-mutant lung cancers. Citation Format: Jong woo Lee, Frank J. Slack, Eric J. Nestler, Roy S. Herbst, Jaseok Peter Koo. CREB is required for KRAS-driven lung tumorigenesis [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 3334.
Circumferential Radiofrequency Ablation of Pulmonary Vein Ostia
Authors: CarloPappone, SalvatoreRosanio, GiuseppeOreto, MonicaTocchi, FilippoGugliotta, GabrieleVicedomini, AdrianoSalvati, CosimoDicandia, PatrizioMazzone, VincenzoSantinelli, SimoneGulletta, SergioChierchia
Journal: Circulation (2000)

Background—The pulmonary veins (PVs) and surrounding ostial areas frequently house focal triggers or reentrant circuits critical to the genesis of atrial fibrillation (AF). We developed an anatomic approach aimed at isolating each PV from the left atrium (LA) by circumferential radiofrequency (RF) lesions around their ostia. Methods and Results—We selected 26 patients with resistant AF, either paroxysmal (n=14) or permanent (n=12). A nonfluoroscopic mapping system was used to generate 3D electroanatomic LA maps and deliver RF energy. Two maps were acquired during coronary sinus and right atrial pacing to validate the lateral and septal PV lesions, respectively. Patients were followed up closely for ≥6 months. Procedures lasted 290±58 minutes, including 80±22 minutes for acquisition of all maps, and 118±16 RF pulses were deployed. Among 14 patients in AF at the beginning of the procedure, 64% had sinus rhythm restoration during ablation. PV isolation was demonstrated in 76% of 104 PVs treated by low peak-t...
Abstract NG02: NFS1 undergoes positive selection in lung tumors and protects cells from ferroptosis
Authors: Samantha W. Alvarez, Vladislav O. Sviderskiy, Erdem M. Terzi, Thales Papagiannakopoulos, Andre L. Moreira, Sylvia Adams, David M. Sabatini, Kıvanç Birsoy, Richard L. Possemato
Journal: Cancer Research (2018)

Abstract Environmental nutrient levels impact cancer cell metabolism, resulting in context-dependent gene essentiality. Here, using RNAi-based loss of function screening, we identify environmental oxygen level as a major driver of differential essentiality between in vitro model systems and in vivo tumours. Above the 3-8% oxygen concentration typical of most tissues, we find that cancer cells depend on high levels of the iron-sulfur cluster (ISC) biosynthetic enzyme NFS1. Accordingly, mammary or subcutaneous tumours grow despite NFS1 suppression, while metastatic or primary lung tumours do not. Consistent with a role in surviving the high oxygen environment of incipient lung tumours, NFS1 lies in a region of genomic amplification present in lung adenocarcinoma and is most highly expressed in well-differentiated adenocarcinomas. NFS1 activity is particularly important for maintaining the ISC cofactors present in multiple cell-essential proteins upon exposure to O2 compared to other forms of oxidative damage. Additionally, insufficient ISC maintenance robustly activates the iron-starvation response and, in combination with glutathione biosynthesis inhibition, triggers ferroptosis, a non-apoptotic form of cell death. Suppression of NFS1 cooperates with inhibition of cysteine transport to trigger ferroptosis in vitro and slow tumour growth. Therefore, lung adenocarcinomas select for expression of a pathway that confers resistance to high oxygen tension and protects cells from undergoing ferroptosis in response to oxidative damage. These observations lead to the tantalizing hypothesis that one can trick cancer cells into taking up large quantities of iron and releasing intracellular iron stores via modulation of NFS1 or downstream effectors, such as IRPs, leaving them at increased risk for ROS-mediated cell death mechanisms such as ferroptosis. Citation Format: Samantha W. Alvarez, Vladislav O. Sviderskiy, Erdem M. Terzi, Thales Papagiannakopoulos, Andre L. Moreira, Sylvia Adams, David M. Sabatini, Kıvanç Birsoy, Richard L. Possemato. NFS1 undergoes positive selection in lung tumors and protects cells from ferroptosis [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 NG02.
Abstract 2955: A radiomic-based MRI phenotype is uniquely associated with hypermutated genotype in gliomas
Authors: Islam Hassan, Aikaterini Kotrotsou, Carlos Kamiya Matsuoka, Kristin D. Alfaro-Munoz, Nabil Elshafeey, Nancy El Shafei, Pascal O. Zinn, John F. de Groot, Rivka R. Colen
Journal: Cancer Research (2018)

Abstract INTRODUCTION Hypermutation is the excessive accumulation of DNA mutation in cancer cells. This specific hypermutated genotype has been reported in low and high grade gliomas, specifically post-temozolomide treatment and is associated with treatment-resistance. Herein, we sought to identify an imaging-based signature for hypermutated gliomas using a radiomics-based approach. MATERIALS AND METHODS In this IRB-approved retrospective study, we analyzed a total of 101 patients with primary gliomas from the University of Texas MD Anderson Cancer Center. Next generation sequencing (NGS) platforms (T200 and Foundation 1) were used to determine the Mutation burden status in post-biopsy (stereotactic/excisional). Patients were dichotomized based on their mutation burden; 77 hypomutated (&amp;lt;30 mutations) and 24 hypermutated (&amp;gt;=30 mutations or &amp;lt;30 with MMR gene or POLE/POLD gene mutations). Radiomic analysis was performed on the conventional MR images (FLAIR and T1 post-contrast) obtained prior to tumor tissue surgical sampling; and a total of 2480 rotation-invariant radiomic features were extracted using: (i) the first-order histogram and (ii) grey level co-occurrence matrix. The Maximum Relevance Minimum Redundancy technique was used to select the most relevant radiomic features. ROC analysis and leave-one-out cross-validation (LOOCV) were used to assess the performance of the Support Vector Machine (SVM) classifier as and AUC, Sensitivity, Specificity, and p-value were obtained. RESULTS We found 100 radiomic features that can discriminate between hypermutated versus hypomutated gliomas, AUC 96.3% (CI: 90.2%-98.9%), Sensitivity 100%, Specificity 95%, p-value=3.769e-6. CONCLUSION Hypermutated gliomas has a unique radiomic quantitative signature that can be used to predict mutation burden regardless of tumor grade or histopathology. Citation Format: Islam Hassan, Aikaterini Kotrotsou, Carlos Kamiya Matsuoka, Kristin D. Alfaro-Munoz, Nabil Elshafeey, Nancy El Shafei, Pascal O. Zinn, John F. de Groot, Rivka R. Colen. A radiomic-based MRI phenotype is uniquely associated with hypermutated genotype in gliomas [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 2955.