tbuckley/cabot-search huggingface dataset:
Abstract 156: Identifying novel therapeutics to inhibit the WNT self-renewal pathway in leukemia stem cells
Authors: Meghan Green Haney, Chunming Liu, Jessica Blackburn
Journal: Cancer Research (2018)

Abstract The relapse rate of pediatric Acute Lymphoblastic Leukemia (ALL) is 15-20%, and these patients have limited treatment options and a poor prognosis. Relapse rate is likely due to a small population of cells known as leukemia stem cells (LSCs), which have the ability to self-renew and can re-form a leukemia from a single cell. Additionally, a major clinical concern is whether these LSCs are effectively killed by conventional cytotoxic chemotherapies. Current efforts to study LSCs have faced serious limitations, which have impeded our understanding of this important population of cells. Prior work in our lab has established a zebrafish Myc-induced T-cell acute lymphoblastic leukemia (T-ALL) model that mimics the most aggressive and treatment resistant form of human T-ALL. Using this system, we isolated single LSCs through a novel transplantation strategy. Limiting dilution analysis showed significant differences in the rate of self-renewal between different LSCs, suggesting heterogeneity in LSC relapse potential. We generated a library of zebrafish T-ALL with high self-renewal rates (about 1 in 10 leukemia cells is a LSC) for use in bulk RNAseq, as well as single cell qPCR and single cell RNAseq to identify a self-renewal signature unique to LSCs. Single cell analyses showed a population of cells that expressed known self-renewal genes and clustered separately from the rest of the leukemia cells in the population. Ongoing work in our laboratory is focused on functionally testing whether this gene expression profile is linked with self-renewal. Additionally from this analysis, the Wnt pathway, more specifically ß-catenin, was enriched in the putative LSC population. These data support previous findings in mammalian models of ALL. We hypothesize that inhibitors of the Wnt pathway will inhibit self-renewal of LSCs and force them to terminally differentiate. However, there are no WNT inhibitors clinically available due to undesirable side-effects. We are currently using a 6xTCF/LEF:GFP zebrafish Wnt reporter model for high-throughput screens to identify new, less toxic Wnt pathway inhibitors. Thus far, several compounds have showed significantly decreased TCF/LEF activity after drug treatment, with no effects on animal health. Future studies will test these inhibitors in our zebrafish high LSC leukemia samples and patient derived xenograft models. Ultimately, these inhibitors may represent a potential therapeutic strategy for targeting treatment-resistant LSCs and preventing ALL relapse. Citation Format: Meghan Green Haney, Chunming Liu, Jessica Blackburn. Identifying novel therapeutics to inhibit the WNT self-renewal pathway in leukemia stem 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 156.
Abstract 1166: Identification of predictive markers for clinical efficacy of triple-negative breast cancer chemotherapy
Authors: Jihui Yun, Saem Hur, Wonyoung Kang, Deukchae Na, Jeesoo Chae, Jinjoo Kang, Ju-Hee Kim, Jiwoo Lee, Woohang Heo, Wonshik Han, Charles Lee, Dong-Young Noh, Hyeong-Gon Moon, Jong-Il Kim
Journal: Cancer Research (2018)

Abstract Triple Negative Breast Cancer (TNBC) is uncommon type of invasive breast cancer accounting for about 10~20% of all breast cancers. TNBC is characterized by a lack of expression of estrogen receptors (ER), human epidermal growth factor receptor 2 (HER2) and progesterone receptors (PR). Due to this characteristic, common treatments including hormone therapy and drugs targeting these receptors are not effective against TNBC despite more aggressive clinical behavior when compared to other subtypes. Paclitaxel is one of the well-known chemotherapeutic agents used in treatment for patients with breast cancer. However, previous studies have reported that advanced breast cancer treated with paclitaxel often develop resistance to the paclitaxel. To understand molecular characteristics and mechanism associated with molecular adaption in cancer cell when treated with paclitaxel, we performed next generation sequencing (NGS) and in vivo experiment using patient derived xenograft (PDX) models. We established ten PDX models from two cases with TNBC each. Mice were divided into two group consisting of control (n=5) and paclitaxel treatment (n=5). We performed exome and transcriptome sequencing on three of five samples for each group. We didn't find significant differences between control and paclitaxel treatment groups in exome data. In transcriptome data, We identified 14 differentially expressed genes (DEGs) including members of CXCL gene family between control and paclitaxel treatment groups. Among these DEGs, 13 DEGs were up-regulated in paclitaxel treatment groups when compared to control group. We are conducting in vitro experiment for several genes among these 13 DEGs. Furthermore, we will perform transcriptome sequencing on PDX tumor samples of additional cases with TNBC for validation of the results so far achieved. Citation Format: Jihui Yun, Saem Hur, Wonyoung Kang, Deukchae Na, Jeesoo Chae, Jinjoo Kang, Ju-Hee Kim, Jiwoo Lee, Woohang Heo, Wonshik Han, Charles Lee, Dong-Young Noh, Hyeong-Gon Moon, Jong-Il Kim. Identification of predictive markers for clinical efficacy of triple-negative breast cancer chemotherapy [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 1166.
Consultant obstetrician and gynaecologist is struck off for groping four female colleagues
Authors: Clare Dyer
Journal: BMJ (2018)

A former professor of obstetrics and gynaecology at the University of Birmingham has been struck off the UK medical register for the “opportunistic” groping of four younger female colleagues, including a midwife who was in the middle of helping to deliver twins.

Khaled Ismail, 50, who was also a consultant with Birmingham Women’s NHS Foundation Trust, told a medical practitioners tribunal in Manchester that he denied the allegations, which related to incidents from 2013 to 2015. They were made by a junior doctor, called Dr A by the tribunal; by two nurses, named as Nurse B and Nurse C; and by a trustee with whom he had sat on a scientific committee, called Ms D in the case.

Ismail …
Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer
Authors: Corrine Ying Xuan Chua, Priya Jain, Antonia Susnjar, Jessica Rhudy, Marco Folci, Andrea Ballerini, April Gilbert, Shailbala Singh, Giacomo Bruno, Carly S. Filgueira, Cassian Yee, E. Brian Butler, Alessandro Grattoni
Journal: Journal of Controlled Release (2018)
DNMT1 in Six2 Progenitor Cells Is Essential for Transposable Element Silencing and Kidney Development
Authors: Szu-Yuan Li, Jihwan Park, Yuting Guan, Kiwung Chung, Rojesh Shrestha, Matthew B. Palmer, Katalin Susztak
Journal: Journal of the American Society of Nephrology (2019)

Cytosine methylation of regulatory regions, such as promoters and enhancers, plays a key role in regulating gene expression, however, its role in kidney development has not been analyzed.To identify functionally important epigenome-modifying enzymes and genome regions where methylation modifications are functionally important for kidney development, we performed genome-wide methylation analysis, expression profiling, and systematic genetic targeting of DNA methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) and Ten-eleven translocation methylcytosine hydroxylases (Tet2) in nephron progenitor cells (Six2Cre) in mice.Genome-wide methylome analysis indicated dynamic changes on promoters and enhancers during development. Six2CreDnmt3af/f, Six2CreDnmt3bf/f, and Six2CreTet2f/f mice showed no significant structural or functional renal abnormalities. In contrast, Six2CreDnmt1f/f mice died within 24 hours of birth, from a severe kidney developmental defect. Genome-wide methylation analysis indicated a marked loss of methylation of transposable elements. RNA sequencing detected endogenous retroviral transcripts. Expression of intracellular viral sensing pathways (RIG-I), early embryonic, nonrenal lineage genes and increased cell death contributed to the phenotype development. In podocytes, loss of Dnmt1, Dnmt3a, Dnmt3b, or Tet2 did not lead to functional or structural differences at baseline or after toxic injury.Genome-wide cytosine methylation and gene expression profiling showed that by silencing embryonic, nonrenal lineage genes and transposable elements, DNMT1-mediated cytosine methylation is essential for kidney development.
Abstract 3950: Small molecule NSC59984 synergizes with ROS-generating agents to induce cell death via reduced GSH in cancer cells
Authors: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract NSC59984 is a small molecule with a duel capability to induce mutant p53 degradation and restore p53 pathway signaling in cancer cells. NSC59984 requires reactive oxygen species (ROS) to induce mutant p53 degradation via ERK2. ROS regulates cell growth and death with tumor cells having higher ROS levels than normal cells. Increasing ROS level is a promising therapeutic strategy applied in cancer clinical trials. However, the toxicity of high ROS levels is a limitation that needs to be solved urgently. We investigated the synergy between NSC59984 and ROS in cancer cells. To increase ROS, cells were treated with BSO, an ROS-generating agent. Our data reveal that ROS sensitizes cells to NSC59984 treatment including enhanced-p53 restoration and mutant p53 degradation induced by NSC59984. Combination of NSC59984 and BSO shows a synergy to induce cell death in cancer cells with an antagonism observed in normal cells at the tested doses. Consistent with the in vitro experiments, our in vivo experiments show that the combination of NSC59984 and BSO significantly suppresses tumor growth. Immunohistochemical staining shows a decrease in Ki67 and an increase in cleaved caspase 3 in xenografted tumors following combination treatment, suggesting that the tumor suppression is due to the induction of cell death and the inhibition of cell growth. Furthermore, the combination of NSC59984 and BSO shows a significant reduction in glutathione (GSH) levels in cancer cells, suggesting that the synergy between NSC59984 and BSO is due to the inhibition of the antioxidant system in mutant p53-expressing cancer cells. Our data indicate that a high level of ROS can be considered as a biomarker for NSC59984 administration in cancer therapy and supports further evaluation of the combination of NSC59984 and ROS-generating agents. Citation Format: Shengliang Zhang, Lanlan Zhou, Wafik S. El-Deiry. Small molecule NSC59984 synergizes with ROS-generating agents to induce cell death via reduced GSH in 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 3950.
Adjunct rasagiline to treat Parkinson’s disease with motor fluctuations: a randomized, double-blind study in China
Authors: Zhenxin Zhang, Ming Shao, Shengdi Chen, Chunfeng Liu, Rong Peng, Yansheng Li, Jian Wang, Suiqiang Zhu, Qiumin Qu, Xiaoying Zhang, Haibo Chen, Xiangru Sun, Yanping Wang, Shenggang Sun, Baorong Zhang, Jimei Li, Xiaoping Pan, Gang Zhao
Journal: Translational Neurodegeneration (2018)

The use of adjunct rasagiline in levodopa-treated patients with Parkinson's disease and motor fluctuations is supported by findings from large-scale clinical studies. This study is to investigate the efficacy and safety of adjunct rasagiline in Chinese patients with Parkinson's disease, as a product registration study.This 16-week, randomized, double-blind, parallel-group, multicenter, placebo-controlled study of rasagiline 1 mg/day included levodopa-treated patients with Parkinson's disease and motor fluctuations. The primary efficacy endpoint was mean change from baseline in total daily OFF time over 16 weeks. Secondary endpoints were Clinical Global Impressions - Improvement (CGI-I), and change in Unified Parkinson's Disease Rating Scale (UPDRS) Activities of daily living (ADL) and Motor scores. Patient well-being (EQ-5D), and the frequency of adverse events were also assessed.In total, 324 levodopa-treated patients were randomized to rasagiline 1 mg/day (n = 165) or placebo (n = 159). Over 16 weeks, rasagiline statistically significantly reduced the mean [95% confidence interval] total daily OFF time versus placebo (- 0.5 h [- 0.92, - 0.07]; p = 0.023). There were also statistically significant improvements versus placebo in CGI-I (- 0.4 points [- 0.61, - 0.22]; p < 0.001), UPDRS-ADL OFF (- 1.0 points [- 1.75, - 0.27]; p = 0.008), and UPDRS-Motor ON (- 1.6 points [- 3.05, - 0.14]; p = 0.032) scores, as well as the EQ-5D utility index (p < 0.05). Rasagiline was safe and well tolerated.In levodopa-treated Chinese patients with Parkinson's disease and motor fluctuations, adjunct rasagiline 1 mg/day statistically significantly reduced OFF time, and improved daily function and overall well-being, versus placebo. Consistent with findings in other countries, adjunct rasagiline was proven efficacious and well tolerated in Chinese patients.NCT01479530. Registered 22 November 2011.
Intravenous iron sucrose versus oral iron administration for the postoperative treatment of post-bariatric abdominoplasty anaemia: an open-label, randomised, superiority trial in Brazil
Authors: Juan Carlos Montano-Pedroso, Elvio Bueno Garcia, Mariana Alcântara Rodrigues de Moraes, Daniela Francescato Veiga, Lydia Masako Ferreira
Journal: The Lancet Haematology (2018)
Abstract 812: New c-KIT mutations in GISTs: Bad for good
Authors: Erik Laurini, Suzana Aulic, Domenico Marson, Maurizio Fermeglia, Roberta Riboni, Marco Lucioni, Elena Dellera, Mario Alessiani, Vittorio Perfetti, Sabrina Pricl
Journal: Cancer Research (2018)

Abstract Gastrointestinal stromal tumors are mesenchymal tumors arising in the stomach and small bowel and more rarely in the rectum, esophagus, peritoneum and retroperitoneum. These tumors are characterized by KIT or PDGFRA mutations. KIT mutations are all in frame and lead to constitutive tyrosine kinase domain activation without ligand binding. Mutations concern four exons (9, 11, 13 and 17) but mainly exon 11. In this work we report a case of a GIST patient with wild-type PDGFRA but bearing two mutations in KIT exon 9, i.e., the insertion mutation Y503_F504insAY and the missense mutation K509N. The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well. Accordingly, in silico experiments were performed to disclose the effects exerted by these new mutations on the protein structure, its thermodynamic stability, and the ability to promote/interfere with Imatinib binding. Direct drug binding thermodynamics and kinetics of the mutant KIT were measured using isothermal titration calorimetry. FInally, in vitro kinase assays were performed to monitor the phosphorylation status of this new mutant KIT. The prototypical KIT mutations Δ559 and T670I were also analyzed in parallel for comparison. To our knowledge, only AY 502-503 duplication/insertion and K509I substitution have been previously reported. Citation Format: Erik Laurini, Suzana Aulic, Domenico Marson, Maurizio Fermeglia, Roberta Riboni, Marco Lucioni, Elena Dellera, Mario Alessiani, Vittorio Perfetti, Sabrina Pricl. New c-KIT mutations in GISTs: Bad for good [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 812.
Abstract 36: Novel age-related tumor promoting and inhibiting genes in breast cancer
Authors: Bingzhi Wang, Xiang Gu, Haiyan Zhu, Luzhe Sun
Journal: Cancer Research (2018)

Abstract During aging, besides genetic alterations, genes with altered expression may promote breast cancer development. Using linear regression modeling, we identified 148 up-regulated and 189 down-regulated genes during aging, by analyzing the whole transcriptome profiling data of matched normal tissues from 82 female patients with age and menopausal status available from The Cancer Genome Atlas data. We also compared matched tumor and normal samples, 3356 up-regulated and 3124 down-regulated genes were identified to be affected by tumorigenesis. Overlapping of tumorigenesis-associated genes with age-dependent genes resulted in 14 up-regulated and 24 down-regulated genes with both age and tumorigenesis. These genes were significantly predictive in relapse free survival, indicative of their potential tumor promoting or suppressive functions respectively. To test this hypothesis, we selected two up-regulated genes-DYNLT3 and P4HA3, and two down-regulated genes-ALX4 and WDR86 to investigate their function in controlling breast cancer malignancy because they are novel genes to breast cancer. We found that knockdown of DYNLT3 or P4HA3, and overexpression of ALX4, significantly reduced breast cancer cell proliferation, migration and colony forming capacity in soft agar, while overexpression of WDR86 did not show any inhibitory activity in breast cancer cells. Consistent with the in vitro data, knockdown of DYNLT3, P4HA3 and overexpression of ALX4 inhibited tumor growth and lung metastasis when breast cancer cells were orthotopically implanted in mice, whereas such inhibition was not observed in mice when WDR86-overexpressing breast cancer cells were implanted. Taken together, our results support that some age-related genes harbor tumor promoting or inhibiting functions. Thus, proper modulation of their expression has potential to prevent or slow down the progression of breast cancer. Citation Format: Bingzhi Wang, Xiang Gu, Haiyan Zhu, Luzhe Sun. Novel age-related tumor promoting and inhibiting genes in 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 36.
Yann Le Meur #SportScienceInfographics
Authors: Alexandra Ross
Journal: British Journal of Sports Medicine (2018)

Interpersonal communication is key. As a member of a team of staff, you need to demonstrate your ability to cooperate with people of different disciplines, from different backgrounds and who may not have the same priorities as you. Be fair and keep challenging yourself. There is no place for lazy people.

For 10 years, I worked as a consultant for different French sporting federations for Beijing, London and Rio Olympic Games (triathlon, swimming, mountain-bike cycling and rugby sevens). My arrival at AS Monaco Football Club in 2016/2017 was a great opportunity to focus on just one team. It was the good moment to try something different and to keep learning by discovering a new environment.

7 am: wake-up.

8 am: meeting at the club with the staff.

9 am: welcoming the players and asking them how do they feel. Collecting some additional data to build a report which will be shared with the staff to eventually adjust the training content.

12 pm: analysing the training session and generating a report for the …
Abstract 1826: Oncogenic KRAS mediates resistance to MET targeted therapy in non-small cell lung cancer (NSCLC) with MET mutations that induce exon14 skipping
Authors: Ken Suzawa, Michael D. Offin, Christopher Kurzatkowski, Daniel Liu, Morana Vojnic, Roger S. Smith, Marissa Mattar, Inna Khodos, Elisa de Stanchina, Joshua K. Sabari, William W. Lockwood, Alexander E. Drilon, Marc Ladanyi, Romel Somwar
Journal: Cancer Research (2018)

Abstract Mutations in MET that induce skipping of exon 14 and lead to reduced ubiquitin ligase-mediated turnover of this receptor tyrosine kinase (RTK) are detected in 3-4% of non-small cell lung cancer (NSCLC), approaching the prevalence of ALK-rearranged lung cancers. Preclinical and clinical studies have revealed that MET exon14 alterations are actionable oncogenic drivers that are amenable to therapy with MET kinase inhibitors such as crizotinib. However, similar to most kinase-driven cancers, despite initial benefit, acquired resistance to therapy is inevitable. Next-generation sequencing (MSK-IMPACT 468 gene panel) was performed on samples from 81 NSCLC patients with MET exon14 alterations, including 7 with paired pre- and post-treatment tumor samples. A concurrent KRAS G12 mutation was identified in 5 patients. In 4 of these patients, the KRAS mutation was present prior to receiving crizotinib. The KRAS mutation was acquired post-crizotinib in the remaining patient. These findings implicate KRAS activation as a potential mechanism of acquired resistance. Using isogenic and patient-derived in vitro and in vivo models harboring MET exon14 skipping alteration, we confirmed that the KRAS mutation results in constitutive activation of RAS/ERK signaling and cells expressing both MET exon14 skipping and KRAS mutations are refractory to MET inhibition. Dual inhibition of MET and MEK with crizotinib and trametinib, respectively, has an additive effect in cell line and xenograft models. Whereas concurrent KRAS mutation is an extremely rare event in EGFR- and ALK-driven NSCLC, our findings confirm KRAS mutation as a recurrent mechanism of primary or secondary resistance to MET-directed therapies in lung cancers harboring MET exon14 alterations. We provide a new potential therapeutic strategy for NSCLC patients with both MET exon14 alterations and KRAS mutations. Citation Format: Ken Suzawa, Michael D. Offin, Christopher Kurzatkowski, Daniel Liu, Morana Vojnic, Roger S. Smith, Marissa Mattar, Inna Khodos, Elisa de Stanchina, Joshua K. Sabari, William W. Lockwood, Alexander E. Drilon, Marc Ladanyi, Romel Somwar. Oncogenic KRAS mediates resistance to MET targeted therapy in non-small cell lung cancer (NSCLC) with MET mutations that induce exon14 skipping [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 1826.