tbuckley/cabot-search huggingface dataset:
Rosemary Radley-Smith: paediatric cardiologist who cofounded the charity Chain of Hope
Authors: Penny Warren
Journal: BMJ (2020)

Photo credit: Courtesy of Chain of Hope

In 1964 Magdi Yacoub was a senior registrar working at the Royal Brompton Hospital in London. He said, “I was doing my round late at night, preparing for the following day, and I found a young doctor reviewing the notes. We got talking and she told me ‘I have studied every patient on the ward and your patient has x, y, and z.’” The young woman was cardiologist Rosemary Radley-Smith, and she and Yacoub were to forge a close working partnership that lasted nearly 50 years.

Born in 1939 in Epsom, Surrey, Radley-Smith was the eldest of four children. Her father, Eric, was a neurosurgeon and her mother, Eileen, was a nurse at King’s College Hospital. After studying at Trevelyan School in Hayward’s Heath and Cheltenham Ladies’ College, Radley-Smith went to the Royal Free Hospital in London to study medicine, qualifying in 1963. Anxious, according to colleagues, to free herself from her father’s shadow and to prove her …
Abstract 1443: Inhibiting HMG-CoA reductase suppresses non-small cell lung carcinogenesis
Authors: Qiushi Wang, Tianshun Zhang, Ruihua Bai, Keke Wang, Xiang Li, Kangdong Liu, Ting Wang, Xiaoyu Chang, Weiya Ma, Ann Bode, Qingxin Xia, Yongping Song, Zigang Dong
Journal: Cancer Research (2020)

Abstract 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) is a rate-limiting enzyme in the mevalonate pathway and is associated with the development of several tumor types. However, the role of HMGCR in non-small cell lung cancer (NSCLC) is still unknown. In the present study, we found that HMGCR is overexpressed in human lung adenocarcinoma tissues compared with normal tissues. Knockdown of HMGCR in NSCLC cells attenuated growth and induced apoptosis in vitro and in vivo. Furthermore, we found that fluvastatin, an inhibitor of HMGCR, suppressed NSCLC cell growth and induced apoptosis. Intriguingly, fluvastastin functions by inhibiting the HMGCR-driven Braf/MEK/ERK1/2 and Akt signaling pathways. Notably, fluvastatin attenuated tumor growth in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis and in a patient-derived xenograft (PDX) lung tumor model. Overall, our findings suggest that fluvastatin might be promising chemopreventive or potential therapeutic drug against NSCLC tumorigenesis, providing hope for rapid clinical translation. Citation Format: Qiushi Wang, Tianshun Zhang, Ruihua Bai, Keke Wang, Xiang Li, Kangdong Liu, Ting Wang, Xiaoyu Chang, Weiya Ma, Ann Bode, Qingxin Xia, Yongping Song, Zigang Dong. Inhibiting HMG-CoA reductase suppresses non-small cell lung carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1443.
Abstract 4836: Diagnostic and prognostic significance of microRNA modulation in oral cancer
Authors: Luca Falzone, Silvia Vivarelli, Salvatore Crimi, Alberto Bianchi, Saverio Candido, Massimo Libra
Journal: Cancer Research (2020)

Abstract Oral cancer is one of the leading causes of cancer death worldwide. Despite the availability of screening programs, oral cancer is often not correctly diagnosed resulting in a significant fraction of late diagnosis.Currently, there are not effective biomarkers for the early diagnosis of oral cancer and for the definition of patients' prognosis. Therefore, the identification of new effective diagnostic and prognostic biomarkers is one of the main challenges for the management of this tumor. Our preliminary analyses of GEO DataSets and TCGA miRNA profiling datasets identified a set of microRNAs (miRNAs) significantly de-regulated in oral cancer. In addition, through the use of different bioinformatics tools (miRCancerdb, GO PANTHER, STRING and DIANA-mirPath), the diagnostic and prognostic significance of selected miRNAs, as well as the modulated molecular pathways and genes were predicted.Starting from these preliminary bioinformatics results, the aim of the present study was to validate the sensitivity and specificity of selected miRNAs in oral cancer patients and healthy controls. For this purpose, the expression levels of selected miRNAs were determined in plasma and matched saliva samples from a subset of oral cancer patients and healthy controls by using specific miRNA TaqMan probes and droplet digital PCR (ddPCR).The ddPCR results showed that the selected miRNAs can be easily detected in both plasma and saliva samples with concordant expression levels and that the expression levels of miRNAs were significantly different in oral cancer patients compared to healthy controls as predicted in the bioinformatics analyses. Furthermore, the comparison of the molecular data with the clinical-pathological features of patients allowed us to establish the prognostic significance of selected miRNAs. Citation Format: Luca Falzone, Silvia Vivarelli, Salvatore Crimi, Alberto Bianchi, Saverio Candido, Massimo Libra. Diagnostic and prognostic significance of microRNA modulation in oral cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4836.
Abstract 2136: RegTools: Integrative analysis of genomic and transcriptomic data to identify splice altering mutations across 35 cancer types
Authors: Kelsy C. Cotto, Yang-Yang Feng, Zachary L. Skidmore, Avinash Ramu, Jason Kunisaki, Donald F. Conrad, Yiing Lin, William Chapman, Ravindra Uppaluri, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith
Journal: Cancer Research (2020)

Abstract The interpretation of variants in cancer is often focused on genomic alterations that have a known coding consequence. This analysis strategy excludes somatic mutations in non-coding regions of the genome and even exonic mutations may have unidentified non-coding consequences. To address this issue, we created RegTools, a free, open-source software package that integrates analysis of variant calls from genomic data with evidence of expressed splice junctions from transcriptomic data to efficiently identify variants that may cause aberrant splicing in tumors. To date, we have applied RegTools to over 9,000 samples from TCGA and the McDonnell Genome Institute in an effort to identify somatic variants that are associated with alternative splicing patterns within these tumors. For each mutation, we defined a set of control samples in the same cancer cohort that lacked the particular mutation. We then determined putative splicing-relevant mutations by identifying novel splice isoforms whose expression was significantly elevated in the presence of the associated mutation. To further characterize these somatic variants and their associated splice isoforms, we annotated them with the Variant Effect Predictor (VEP), SpliceAI, and Genotype-Tissue Expression (GTEx) junction counts. While some of these mutations would have been predicted by VEP or SpliceAI to be splicing relevant, our analysis provides additional detail by specifically associating a mutation with an altered junction or junctions, including ones not predicted by VEP/SpliceAI or observed within GTEx normal tissue data. RegTools is freely available and open source (www.regtools.org) and all analysis scripts are provided within the project's GitHub repo (https://github.com/griffithlab/regtools). Citation Format: Kelsy C. Cotto, Yang-Yang Feng, Zachary L. Skidmore, Avinash Ramu, Jason Kunisaki, Donald F. Conrad, Yiing Lin, William Chapman, Ravindra Uppaluri, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith. RegTools: Integrative analysis of genomic and transcriptomic data to identify splice altering mutations across 35 cancer types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2136.
Abstract 3475: CYP3A5 inhibitor bergamottin present in grape fruit extract blocks prostate cancer cell growth
Authors: Opalina Vetrichelvan, Priyatham Gorjala, Oscar Goodman, Ranjana Mitra
Journal: Cancer Research (2020)

Abstract Background: Previous research has revealed that the androgen receptor (AR), which upon activation goes to the nucleus, is the driving force of prostate cancer growth. Once activated, AR promotes transcription of genes responsible for promoting cancer growth. Previous studies have shown that inhibition of CYP3A5 blocks the activation process of the AR. CYP3A5 is a liver enzyme and together with CYP3A4 processes 50% of all commonly prescribed drugs. CYP3A5 is the extrahepatic form expressed in both normal and malignant prostate. Bergamottin, a compound found in grapefruit juice, is a known CYP3A4/5 inhibitor. Based on CYP3A5's ability to regulate AR activation, we tested the effects of bergamottin on AR activation to see if the compound can be utilized as a dietary supplement to reduce prostate cancer growth. Methods: Western blotting, cell fractionation, and immunofluorescence were used to observe the effects of bergamottin on AR, amount of AR in nucleus/cytoplasm, and cellular localization of AR, respectively. MTT based cell growth measurement was used to see how prostate cancer cell growth was affected by bergamottin. Results: Cell growth assay revealed that bergamottin reduced prostate cancer cell growth. The IC50 for LNCaP cells was observed to be 2.4 μM. Growth of RWPE1 cells (non transformed prostate epithelium) was not effected at the same concentration of bergamottin. Western blot analysis showed that total AR protein expression was downregulated in the bergamottin treated LNCaP and MDAPCa2b cells. Cell fractionation assay revealed that bergamottin significantly reduced nuclear AR after DHT induction compared to non-treated cells. Immunofluorescence assay confirmed reduced nuclear AR in the bergamottin treated LNCaP and MDAPCa2b cells. Furthermore, bergamottin reduced PSA levels both inside the cells and in the growth media indicating that it inhibits AR downstream signaling. Conclusion: Our results concluded that bergamottin successfully blocked AR activation and downstream signaling, and consequently slowed down prostate cancer cell growth. The implication of this experiment is the potential use of bergamottin as a food supplement alongside other prostate cancer treatments in order to aid in blocking prostate cancer growth. Citation Format: Opalina Vetrichelvan, Priyatham Gorjala, Oscar Goodman Jr, Ranjana Mitra. CYP3A5 inhibitor bergamottin present in grape fruit extract blocks prostate cancer cell growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3475.
Abstract 2809: Pancreatic cancer patient-derived organoids as a tool for personalized medicine
Authors: Herve Tiriac
Journal: Cancer Research (2020)

Abstract Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemo-sensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemo-sensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemo-refractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Citation Format: Herve Tiriac. Pancreatic cancer patient-derived organoids as a tool for personalized medicine [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2809.
Abstract 3616: Somatic mutation profiling of colorectal cancer by targeted next generation sequencing
Authors: Amira Salah El-Din Youssef, Ahmed Moustafa, Ahmed Osama Touny, Zeinab K. Hassan, Mohammed Mohey Eldin, Mai M. Lotfy, Auhood Nassar, ola sayed, Abdel-Rahman N. Zekri
Journal: Cancer Research (2020)

Abstract Aim: This study aimed to sequence custom 96 genes of tumor suppressor genes and oncogenes frequently associated with colorectal cancer (CRC) to identify the frequency of the detected genetic mutations in the disease progression of CRC patients and to develop personalized therapy in those somatic mutation carriers. Material and methods: Biopsy samples were collected from Egyptian patients classified into inflammatory bowel disease (IBD) (n=20), colonic polyp (CP) (n=38) and CRC (n=60) patients as well as subjects with chronic non-specific colitis served as a control group (n=20). The libraries were performed using Qiaseq UMI-based targeted panel and sequenced via Ion proton sequencer. The detected genetic variants with an average coverage of 500x were annotated against Cosmic and dbSNP and Clinvar databases. Results: Analysis revealed that 52 genes harbor 128, 47 genes harbor 111, 40 genes harbor 71 and 39 genes harbor 66 somatic variants were detected in the CRC, CP, IBD and control groups; respectively. ARID1A (c.5548dupG (5%)), ATM (c.2572T&amp;gt;C (10%)), AXIN2 (c.1975C&amp;gt;T (5%)), FLCN (c.1285dupC (8%)), KRAS (c.35G&amp;gt;T (8%)), MSH6 (c.3261dupC (5%)), SLC9A9 (c.1765A&amp;gt;G (10%)), TP53 (c.1024C&amp;gt;T (5%)) were found to be the highly frequently detected pathogenic CRC specific variants. We also identified 29 genes harbor 43 common variants. The highly frequently common detected variants were ACVR2A (c.1310delA), ATM (c.5557G&amp;gt;A), BRCA1 (c.3548A&amp;gt;G, c.2612C&amp;gt;T), BRCA2 (c.1114A&amp;gt;C), IGF2 (c.677delG), KIT (c.1621A&amp;gt;C), MLH1 (c.655A&amp;gt;G), MLK4 (c.2223G&amp;gt;T, c.2182G&amp;gt;A), PIK3CA (c.1173A&amp;gt;G), PTPN12 (c.964G&amp;gt;A), RET (c.2071G&amp;gt;A), TP53 (c.121delG, c.215C&amp;gt;G) Conclusion: Our data showed that our Egyptian genetic makeup is different from other population. Also, the identified somatic mutations are crucial for understanding cancer predisposition and developing personalized therapies for the Egyptian colorectal cancer patients. Citation Format: Amira Salah El-Din Youssef, Ahmed Moustafa, Ahmed Osama Touny, Zeinab K. Hassan, Mohammed Mohey Eldin, Mai M. Lotfy, Auhood Nassar, ola sayed, Abdel-Rahman N. Zekri. Somatic mutation profiling of colorectal cancer by targeted next generation sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3616.
Abstract 509: Discovery of novel small molecule inhibitors of Wnt signaling through <i>in silico</i> molecular docking
Authors: Joo-Leng Low, Weina Du, Tenzin Gocha, Oguz Gokce, Xiaoqian Zhang, Daniel G. Yim, Adaikalavan Ramasamy, Hao Fan, Ramanuj DasGupta
Journal: Cancer Research (2020)

Abstract Canonical Wnt signaling is one of the crucial pathways involved in embryonic development and tissue homeostasis. However this pathway is often dysregulated in cancers and thus developing effective inhibitors of Wnt signaling is of great interest in the field. Our strategy for inhibition of Wnt signaling involves disruption of the β-catenin (β-cat)-Tcf4 protein-protein interaction (PPI) complex, which is the key effector for nuclear Wnt signaling activity. Towards this goal, we developed a computational model of β-cat for predicting small molecule binders. Application of our computational model to an in silico screen against a library of more than 10,000 compounds predicted 27 compounds as good binders to β-cat. Through in vitro validation experiments such as Wnt reporter assays, co-immunoprecipitation, and surface plasmon resonance (SPR) studies, we identified compound GB1874 as our most promising candidate for inhibiting the β-cat-Tcf4 PPI. Compound GB1874 also affected the proliferation of Wnt-addicted colorectal cancer (CRC) cells in vitro and in tumor xenograft models in vivo. Notably the in vivo efficacy was associated with minimal systemic toxicity. In summary, we report the identification of a novel disruptor of β-cat-Tcf4 interaction, GB1874, which can serve as a promising small molecule candidate for a Wnt signaling inhibitor. Moreover, our study demonstrates the feasibility of using computational modeling to identify new inhibitors of PPI. Citation Format: Joo-Leng Low, Weina Du, Tenzin Gocha, Oguz Gokce, Xiaoqian Zhang, Daniel G. Yim, Adaikalavan Ramasamy, Hao Fan, Ramanuj DasGupta. Discovery of novel small molecule inhibitors of Wnt signaling through in silico molecular docking [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 509.
Abstract 4896: Transcriptomic alterations by HPV-human fusion transcripts in HPV+ HNSCC cell lines
Authors: Lisa M. Pinatti, Hana Sinha, Chad Brenner, Heather M. Walline, Thomas E. Carey
Journal: Cancer Research (2020)

Abstract Human papillomavirus (HPV) genomic integration is frequently seen in oropharyngeal squamous cell carcinoma (OPSCC). Integration into cellular genes can cause the generation of HPV-host fusion transcripts, which have been associated with altered gene expression of critical cellular pathways and worse survival in OPSCC patients. The mechanism of these transcriptomic alterations by fusion transcripts and how they contribute to poor outcome are unknown. We began our analysis by investigating whether our cell lines models of HPV+ OPSCC recapitulate these gene expression alterations using a qRT-PCR profiling system. We compared the expression of 128 genes in relevant pathways in four fusion transcript positive cell lines versus two fusion transcript negative cell lines and found a number of genes that were differentially expressed between the two groups. This suggests that these cell lines are appropriate models to study the mechanism of fusion transcript-dependent transcriptional regulation. To confirm our results in another system, we created fusion transcript positive/negative cell lines by cloning two pairs of either an HPV-human fusion transcript or an HPV only transcript into normal keratinocytes. These cloned cells were then run through the same qRT-PCR profiling system, and we saw differentially expressed genes between the two groups. There was an overlapping set of gene pathways between the HPV+ OPSCC cell lines and cloned keratinocytes, suggesting HPV-human fusion transcripts are sufficient to alter cellular gene expression. Subsequent in-depth molecular characterization and in vitro studies will help clarify the mechanism of these changes and their effects on cancer formation and metastasis. These studies will advance our understanding of how fusion transcripts lead to worse patient survival and help develop new therapies for these patients. Citation Format: Lisa M. Pinatti, Hana Sinha, Chad Brenner, Heather M. Walline, Thomas E. Carey. Transcriptomic alterations by HPV-human fusion transcripts in HPV+ HNSCC cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4896.
Abstract 1652: Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model
Authors: Xuyi Yue, Yangchun Xin, Hua Li, Zhiqin Li, Hancheng Cai, Sigrid A. Langhans
Journal: Cancer Research (2020)

Abstract In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)-L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. 1-L-[18F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice using a Perkin-Elmer G4 PET-X-Ray scanner. Medulloblastoma tumors showed significant and specific accumulation of 1-L-[18F]FETrp. 1-L-[18F]FETrp also showed significantly higher tumor uptake than its D-enantiomer 1-D-[18F]FETrp. The uptake of 1-L-[18F]FETrp in normal brain tissue was low, suggesting that 1-L-[18F]FETrp may prove a valuable PET imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors. Citation Format: Xuyi Yue, Yangchun Xin, Hua Li, Zhiqin Li, Hancheng Cai, Sigrid A. Langhans. Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1652.
Abstract 5080: Prognostic immune subtypes in glioblastoma
Authors: Anna Joy, Xishuang Dong, Seungchan Kim
Journal: Cancer Research (2020)

Abstract Variations in the tumor immune microenvironment between Glioblastoma (GBM) patients complicates development and testing of immunotherapies. We used publicly available single cell RNA sequencing data of GBM patients to extract pan immune-specific genes in GBM. Interrogating bulk GBM sequencing or microarray data with pan immune-specific genes should allow examination of the immune component. We used these genes to investigate subtypes of GBM immune microenvironments. Consensus clustering using these genes on GBM TCGA RNAseq data gave 4 distinct subtypes while 12% of tumors were not assigned to any of those subtypes. Immune subtypes had distinct clinical outcomes. Differences in median survival (16.6 vs 5.8 months; longest vs. shortest survival; p &amp;lt; 1e-05 Logrank, Wald and Likelihood ratio tests) suggests the immune microenvironment significantly impacts clinical course. Cox univariate analysis indicates age had no contribution to risk (HR = 1.034; 95% confidence interval 1.017-1.052). We propose that immune-subtyping of GBM with pan immune-specific genes will lead to biomarkers that predict immunotherapeutic response. It will also help to identify molecular pathways and targets that suppress the immune anti-tumor response. Citation Format: Anna Joy, Xishuang Dong, Seungchan Kim. Prognostic immune subtypes in glioblastoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5080.