tbuckley/cabot-search huggingface dataset:
Abstract 4126: DNA methyltransferase inhibitors target a YES1-YAP1 signaling axis in childhood rhabdomyosarcoma
Authors: Katherine Slemmons, Choh Yeung, Josh Baumgart, Amy McCalla-Martin, Lee Helman
Journal: Cancer Research (2018)

Abstract We have previously shown that the SRC family kinase (SFK) member, YES1, is highly expressed and rapidly activated upon IGF-1R blockade in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and adolescents. YAP1 (YES-associated protein) is also highly expressed in human RMS tumors where it functions as an oncoprotein when the upstream Hippo tumor suppressor pathway is silenced, driving cell growth and survival. Thus far, efforts to pharmacologically inhibit YAP1 have been unsuccessful. One activator of the Hippo pathway, RASSF1a, is epigenetically silenced in many cancer types including sarcomas. Here we show a loss of RASSF1a expression in RMS cell lines via promoter methylation. Treatment with DNA methyltransferase inhibitors (DNMTis) can re-activate RASSF1a expression, resulting in YAP phosphorylation and inactivation. DNMTi treatment also significantly inhibits RMS cell growth, which can be rescued by overexpression of a constitutively active YAPS127A. In the alveolar variant (aRMS) in particular, DNMTis increase apoptosis and decrease both YES1 expression and activation. This suggests DNMTi treatment can inhibit both YAP1 and YES1 signaling. To further investigate the connection between YES1 and YAP1 we performed proximity ligation assays and discovered that YES1 and YAP1 interact in the nucleus of RMS cell lines. Furthermore, dasatinib treatment, a known SFK inhibitor, prevents YAP1 nuclear accumulation suggesting a role for YES1 in regulating YAP1 cellular localization. YAP1 is also tyrosine phosphorylated, which may be one way YES1 regulates YAP1. Lastly, cells expressing a constitutively active YAPS127A have increased activation of SFK suggesting a positive feedback loop whereby YAP1 activity can further activate YES1 through an unknown mechanism. These data uncover a signaling axis between the YES1 and YAP1 oncoproteins in RMS and suggest an alternative way to silence YES1 and YAP1 through use of DNMTis. We will further analyze this signaling through shRNA knockdown of YES1 and evaluate combination treatment of a DNMTi and dasatinib in vitro and in vivo. Citation Format: Katherine Slemmons, Choh Yeung, Josh Baumgart, Amy McCalla-Martin, Lee Helman. DNA methyltransferase inhibitors target a YES1-YAP1 signaling axis in childhood rhabdomyosarcoma [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 4126.
Acute Pressure Overload Could Induce Hypertrophic Responses in the Heart of Angiotensin II Type 1a Knockout Mice
Authors: KoichiroHarada, IsseiKomuro, YunzengZou, SumiyoKudoh, KazuhisaKijima, HiroakiMatsubara, TakeshiSugaya, KazuoMurakami, YoshioYazaki
Journal: Circulation Research (1998)

Abstract—Increasing evidence has suggested that locally produced angiotensin II (Ang II) plays an important role in the development of cardiac hypertrophy through the Ang II type 1 receptor (AT1). We and others have recently reported that Ang II is critical for mechanical stress–induced hypertrophic responses in vitro. Using AT1a knockout (KO) mice, we examined whether Ang II is indispensable for pressure overload–induced cardiac hypertrophy in the present study. Reverse-transcriptase polymerase chain reaction analysis revealed that AT1 mRNA levels were <10% in the heart of KO mice compared with wild-type (WT) mice, but the Ang II type 2 receptor gene was expressed at almost the same levels in the hearts of both mice. Intravenous infusion of subpressor dose of Ang II induced c-fos gene expression in the hearts of WT mice but not KO mice. Acute pressure overload, however, induced expressions of immediate-early response genes and activations of mitogen-activated protein kinases in the hearts of KO mice as w...
Abstract 5483: SIRT1 stabilization provides a therapeutic opportunity for reversing cachexia in pancreatic cancer
Authors: Aneesha Dasgupta, Enza Vernucci, Surendra K. Shukla, Scott E. Mulder, Ryan J. King, Jaime Abrego, Nina V. Chaika, Kyla Buettner, Pankaj K. Singh, Pankaj K. Singh
Journal: Cancer Research (2018)

Abstract Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer patients but would also improve the patient survival. In the clinic, majority of the cancer patients are diagnosed at the refractory phase of cachexia, which cannot be reversed by dietary interventions. Till late therapies have not shown promising results in clinical trials. Hence, there is an urgent need to identify new targets to combat cancer cachexia. Sirtuins are protein deacetylases which affect the activity of various transcription factors and signaling components. The expression of all the sirtuins were analyzed after culturing mouse myotubes with tumor cell-conditioned media. The expression of SIRT1 decreased consistently upon treatment of myotubes with conditioned media from multiple human pancreatic cancer cell lines. Resveratrol, which is an activator of SIRT1 rescued the wasting phenotype in the myotubes. However, treatment of pancreatic cancer cells with resveratrol also decreased cell proliferation. Hence, we designed in vivo experiments to examine the effect of resveratrol on muscle wasting irrespective of its effects on tumor burden. We generated SIRT1 knockdown pancreatic cancer cell lines and orthotopically implanted them into the pancreas in athymic nude mice. The tumor-bearing mice were subjected to an oral delivery of resveratrol. These studies demonstrated that while resveratrol had limited effect on cancer cells due to SIRT1 knockdown, resveratrol treatment still protected the mice from muscle wasting by stabilizing SIRT1 in muscles. Hence, our results indicate that resveratrol-mediated stabilization of SIRT1 in muscles can revert wasting irrespective of its effects on tumor cells. Overall, our studies demonstrate the therapeutic potential of SIRT1 stabilization by resveratrol or related class of drugs in managing cancer-associated cachexia. Citation Format: Aneesha Dasgupta, Enza Vernucci, Surendra K. Shukla, Scott E. Mulder, Ryan J. King, Jaime Abrego, Nina V. Chaika, Kyla Buettner, Pankaj K. Singh, Pankaj K. Singh. SIRT1 stabilization provides a therapeutic opportunity for reversing cachexia in pancreatic 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 5483.
h<i>CALCRL</i> mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia
Authors: Duncan I. Mackie, Fuad Al Mutairi, Reema B. Davis, Daniel O. Kechele, Natalie R. Nielsen, Joshua C. Snyder, Marc G. Caron, Harvey J. Kliman, Jonathan S. Berg, John Simms, David R. Poyner, Kathleen M. Caron
Journal: The Journal of Experimental Medicine (2018)

We report the first case of nonimmune hydrops fetalis (NIHF) associated with a recessive, in-frame deletion of V205 in the G protein-coupled receptor, Calcitonin Receptor-Like Receptor (h
Corrigendum to molecular genetics and emerging therapies for retinitis pigmentosa: Basic research and clinical perspective progress in retinal and eye research (2018) Vol 63,107-131
Authors: Marina França Dias, Kwangsic Joo, Jessica A. Kemp, Silvia Ligório Fialho, Armando da Silva Cunha, Se Joon Woo, Young Jik Kwon
Journal: Progress in Retinal and Eye Research (2018)
Abstract 163: Glioblastoma, cancer stem cells, and reactive species balances: A case for GTP cyclohydrolase 1
Authors: Anh N. Tran, Kiera Walker, David G. Harrison, Wei Chen, James Mobley, Lauren Hocevar, James R. Hackney, Randee Sedaka, Jennifer Pollock, Matthew S. Goldberg, Dolores Hambardzumyan, Sara J. Cooper, G Yancey Gillespie, Anita B. Hjelmeland
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM), or grade IV astrocytoma, is a deadly disease due in part to the high degree of intratumoral heterogeneity that contributes to treatment failures. Previous studies have shown the importance of reactive species balances, partially controlled by the coupling of nitric oxide synthases (NOS) with their cofactor, in maintenance of glioma stem cell (GSC) phenotype as well as survival of cancer cells in general. In this study, we investigated the roles of GTP cyclohydrolase 1 (GCH1), which is the first and rate-limiting enzyme of the pathway producing of NOS cofactor producing pathway, in GBM stem cell phenotypes via redox balances. We found that GCH1 RNA and protein expression were increased in GSCs in comparison to non-GSCs, but that GCH1 was not exclusive to the GSC fraction. Indeed, GCH1 was elevated in GBM in comparison to normal brain. Overexpression of GCH1 in GBM cells increased cell growth in vitro and neurosphere-forming capability and decreased survival in an intracranial GBM mouse model. In contrast, GCH1 knockdown with short hairpin RNA in GBM cells led to growth inhibition in vitro as well as increased survival in animal models. GCH1 increased CD44 expression and was upregulated in the detrimental mesenchymal GBM subtype in which CD44 served as a marker. Mechanistically, we found that the expression of GCH1 increased BH4 production, as well as augmented multiple antioxidant pathways, including the expression of PARK7, was critical for controlling reactive species balance, including suppressing reactive oxygen species production. In silico analyses demonstrated that higher GCH1 levels in glioma patients correlate with higher glioma grade, recurrence and worse survival. Together, our data suggest that upregulation of GCH1 in GSCs promotes tumor maintenance and is a key regulator of reactive oxygen species in GBM, and GCH1 pathway is a potential target for therapy. Citation Format: Anh N. Tran, Kiera Walker, David G. Harrison, Wei Chen, James Mobley, Lauren Hocevar, James R. Hackney, Randee Sedaka, Jennifer Pollock, Matthew S. Goldberg, Dolores Hambardzumyan, Sara J. Cooper, G Yancey Gillespie, Anita B. Hjelmeland. Glioblastoma, cancer stem cells, and reactive species balances: A case for GTP cyclohydrolase 1 [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 163.
Abstract 1137: ANO1 confers the maintenance of stemness and radioresistance in glioma stem cells by stabilizing EGFRvIII
Authors: Dae-Hee Lee, Hee-Jin Kim, Jeong-Yub Kim, Jea-Yong Park, Myung-Jin Park
Journal: Cancer Research (2018)

Abstract Anoctamin-1 (ANO1), also known as TMEM16A, is a Ca2+-activated chloride channel known to mediate a number of physiologic functions such as mediating acute and chronic pain and regulating blood vessels and airway smooth muscle. In particular, ANO1 expression is amplified in a variety of cancers, and overexpression of ANO1 is not favorable for clinical prognosis. Previous studies have reported that ANO1 is associated with tumorigenesis, proliferation, migration, and invasion of cancer cells, but the mechanism is not clear yet. In this study, we examined role of ANO1 in the maintenance of stemness and radio-resistance in glioma stem cells (GSCs). Knockdown of ANO1 with shRNA and treatment of ANO1 specific inhibitors (CaCCAo1 and TAO1) suppressed the expression of Notch intracellular domain, Nestin and EGFRvIII and decreased self-renewal activity and invasion in GSCs. Suppression of ANO1 increased radiation sensitivity by inducing ROS-mediated GSCs death. However, inhibition of chloride channel activity, the main function of ANO1, was found to be unaffected in this event. Interestingly, we found that ANO1 retained stemness by direct binding to EGFRvIII, which is specifically expressed in GSCs, and that the chaperone property of ANO1 function may affect the stability of EGFRvIII. In intracranial mouse model of GSCs, knockdown of ANO1 increased the survival rate of mice by suppressing tumor formation. Taken together, we suggest that ANO1 is a crucial molecule involved in the maintenance of stemness and radiation resistance in GSCs and may be a good therapeutic target for treating glioblastoma. Citation Format: Dae-Hee Lee, Hee-Jin Kim, Jeong-Yub Kim, Jea-Yong Park, Myung-Jin Park. ANO1 confers the maintenance of stemness and radioresistance in glioma stem cells by stabilizing EGFRvIII [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 1137.
Abstract 17432: Specific Care Process Implementation Associated With Improved Reperfusion Times Across Multiple STEMI Networks: Insights From The AHA Mission: Lifeline STEMI Accelerator Program
Authors: Christopher B Fordyce, Hussein R Al-Khalidi, James G Jollis, Mayme L Roettig, Akshay Bagai, Peter B Berger, Claire C Corbett, Harold L Dauerman, Kathleen Fox, J. L Garvey, Joan Gu, Timothy D Henry, Ivan C Rokos, Matthew W Sherwood, B H Wilson, Christopher B Granger
Journal: Circulation (2015)

Introduction: The STEMI Accelerator Program occurred in 16 U.S. metropolitan regions and resulted in more patients receiving timely reperfusion. We assessed whether implementing key care processes was associated with shorter reperfusion times. Methods: Hospitals (n=167 with 23,498 STEMI patients) were surveyed pre- (02/2012) and post- (08/2014) intervention with a standardized care process questionnaire. Survey data were then merged with patient-level clinical data over the same time period. For reperfusion times, hospitals were stratified by whether they implemented a specific process of care, had a pre-existing process, or never implemented the process. Results: Uptake of several care processes increased following intervention: pre-hospital activation (62% to 91% of hospitals; p&lt;0.001), single call transfer protocol from an outside facility (45% to 70%; p&lt;0.001) and emergency department (ED) bypass for both direct presenters via paramedics (48% to 59%; p=0.002) and transfer patients (56% to 79%; p=0.001). There were significant differences in median first medical contact-to-device (FMC) times (Figure) among patients treated at hospitals that implemented pre-activation compared to non-implementers (88 min for implementers; vs 89 min for pre-existing; vs 98 min for non-implementers; p&lt;0.001 for group comparisons). Similarly, patients treated at hospitals implementing single call transfer protocols had shorter median FMC times (112 min vs 128 min vs 152 min; p&lt;0.001). ED bypass was also associated with shorter FMC times for both direct presenters (84 min vs 88 min vs 94 min; p&lt;0.001) and transfers (123 min vs 127 min vs 167 min; p&lt;0.001). Conclusions: The STEMI Accelerator program increased the uptake of key care processes, which were in turn associated with shorter median reperfusion times. These findings support ongoing efforts to implement regional STEMI networks focused upon pre-hospital activation, single call transfer protocols and ED bypass.
Rate of depressive episode in Peruvian oncologic outpatients.
Authors: Luis Furuya, Erick Infanzon, Diego Venegas
Journal: Journal of Clinical Oncology (2012)

e12043 Background: Depression in Lima, Peru has a prevalence rate of 6.7% and lifetime prevalence of 19%. The relationship between depression and cancer has been widely studied, affects approximately 15% to 25% of cancer patients. However, there is little research in latin population. We report the results of evaluate the frequency of depressive disorder in Peruvian oncologic outpatients and describe clinical and epidemiological features Methods: A descriptive transversal study was performed to 70 patients that attended to oncology clinic at the Hospital Nacional Cayetano Heredia. Data was collected through a survey that included a clinical demographic record and the spanish version – ICD 10 of the Mini International Neuropsychiatric Interview for the diagnosis of depressive episode. Results: The 52% of the participants were females. The mean age was 57 years (18- 83 y) Breast cancer (21%) and lymphoma non Hodgkin (21%) were the most common types of cancer. The mean period from diagnosis was 5 month. The frequency of depressive episode was 21.4%. The 33.3% of women with breast cancer had depression, while patients with NHL had only 13.3% of frequency. We founded two factors with statistically significant association: poor financial status (p =0.041) and advance clinical stages (III and IV) (p = 0.026; OR: 6.8) Conclusions: The frequency of depressive episode was similar to other reports in the literature, the poor financial status and advanced stage are most associated with depression in our population
Dynamic Trajectories of Left Ventricular Ejection Fraction in Heart Failure
Authors: Josep Lupón, Giovana Gavidia-Bovadilla, Elena Ferrer, Marta de Antonio, Alexandre Perera-Lluna, Jorge López-Ayerbe, Mar Domingo, Julio Núñez, Elisabet Zamora, Pedro Moliner, Patricia Díaz-Ruata, Javier Santesmases, Antoni Bayés-Genís
Journal: Journal of the American College of Cardiology (2018)
Abstract 1307: Effect of tumor purity on somatic mutation detection using next-generation sequencing technology: A benchmarking study
Authors: Wendell Jones, Wenming Xiao
Journal: Cancer Research (2018)

Abstract Next generation sequencing (NGS) is becoming an essential tool for clinical cancer care. Whole genome sequencing (WGS), whole exome sequencing (WES), and targeted gene sequencing (TGS) have emerged as important tools and are critical for advancing precision oncology to meaningfully impact patient lives. To enable this goal, we must first thoroughly characterize the complexities of using NGS to identify somatic mutations in samples with tumor heterogeneity and variable tissue sample purity. Here, we applied both experiment and in silico approaches to determine the effects of tumor heterogeneity on somatic mutation detection. First, we systematically investigated somatic mutation events in paired cell lines (breast carcinoma and matched normal) using a myriad of NGS platforms and protocols. Then, we applied machine learning algorithms to define high confidence mutation calls with datasets from the combination of all platforms and pipelines. Finally, we performed whole genome sequencing from tumor DNA samples titrated with matched normal cells to create a gradient of tumor purities from 100%, 75%, 50%, 20%, 10%, 5%, and 0%. We also created a series of in silico mixes by pooling reads from tumor and normal cell lines at respective ratios. With somatic variation “ground truth” established by multiple orthogonal sequencing platforms and multiple analysis tools, we evaluated performance of individual software tools for tumor purity assessment and for mutation detection. Our experimental design allowed us to systematically evaluate accuracy, specificity and sensitivity of mutation detection across a range of tumor purities, as well as conduct a head-to-head comparison of in silico approaches versus experimental approaches. This comprehensive study will help to clarify our understanding of experimental and analytical challenges that arise when confronted with tumor heterogeneity in patient care clinical decisions. In addition, data generated in this study will be used as a benchmark resource for the community to develop and improve tools to meet clinical challenges. Citation Format: Wendell Jones, Wenming Xiao, Somatic Mutation Working Group, SEQC2 Consortium. Effect of tumor purity on somatic mutation detection using next-generation sequencing technology: A benchmarking study [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 1307.
Within-Gene Shine–Dalgarno Sequences Are Not Selected for Function
Authors: Adam J Hockenberry, Michael C Jewett, Luís A N Amaral, Claus O Wilke
Journal: Molecular Biology and Evolution (2018)

The Shine-Dalgarno (SD) sequence motif facilitates translation initiation and is frequently found upstream of bacterial start codons. However, thousands of instances of this motif occur throughout the middle of protein coding genes in a typical bacterial genome. Here, we use comparative evolutionary analysis to test whether SD sequences located within genes are functionally constrained. We measure the conservation of SD sequences across Enterobacteriales, and find that they are significantly less conserved than expected. Further, the strongest SD sequences are the least conserved whereas we find evidence of conservation for the weakest possible SD sequences given amino acid constraints. Our findings indicate that most SD sequences within genes are likely to be deleterious and removed via selection. To illustrate the origin of these deleterious costs, we show that ATG start codons are significantly depleted downstream of SD sequences within genes, highlighting the constraint that these sequences impose on the surrounding nucleotides to minimize the potential for erroneous translation initiation.
Association between age, deprivation and specific comorbid conditions and the receipt of major surgery in patients with non-small cell lung cancer in England: A population-based study
Authors: Aurélien Belot, Helen Fowler, Edmund Njeru Njagi, Miguel-Angel Luque-Fernandez, Camille Maringe, Winnie Magadi, Aimilia Exarchakou, Manuela Quaresma, Adrian Turculet, Michael D Peake, Neal Navani, Bernard Rachet
Journal: Thorax (2018)

Introduction We investigated socioeconomic disparities and the role of the main prognostic factors in receiving major surgical treatment in patients with lung cancer in England. Methods Our study comprised 31 351 patients diagnosed with non-small cell lung cancer in England in 2012. Data from the national population-based cancer registry were linked to Hospital Episode Statistics and National Lung Cancer Audit data to obtain information on stage, performance status and comorbidities, and to identify patients receiving major surgical treatment. To describe the association between prognostic factors and surgery, we performed two different analyses: one using multivariable logistic regression and one estimating cause-specific hazards for death and surgery. In both analyses, we used multiple imputation to deal with missing data. Results We showed strong evidence that the comorbidities ‘congestive heart failure’, ‘cerebrovascular disease’ and ‘chronic obstructive pulmonary disease’ reduced the receipt of surgery in early stage patients. We also observed gender differences and substantial age differences in the receipt of surgery. Despite accounting for sex, age at diagnosis, comorbidities, stage at diagnosis, performance status and indication of having had a PET-CT scan, the socioeconomic differences persisted in both analyses: more deprived people had lower odds and lower rates of receiving surgery in early stage lung cancer. Discussion Comorbidities play an important role in whether patients undergo surgery, but do not completely explain the socioeconomic difference observed in early stage patients. Future work investigating access to and distance from specialist hospitals, as well as patient perceptions and patient choice in receiving surgery, could help disentangle these persistent socioeconomic inequalities.