tbuckley/cabot-search huggingface dataset:
<i>TP53</i> Mutation and Its Prognostic Significance in Waldenstrom's Macroglobulinemia
Authors: Stéphanie Poulain, Christophe Roumier, Elisabeth Bertrand, Aline Renneville, Aurélie Caillault-Venet, Emmanuelle Doye, Sandrine Geffroy, Sheherazade Sebda, Olivier Nibourel, Morgane Nudel, Charles Herbaux, Loic Renaud, Cécile Tomowiak, Stéphanie Guidez, Sabine Tricot, Catherine Roche-Lestienne, Bruno Quesnel, Claude Preudhomme, Xavier Leleu
Journal: Clinical Cancer Research (2017)

Purpose:TP53 is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and TP53 alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's macroglobulinemia (WM).Experimental Design: Here, we have explored the incidence of TP53 alteration using Sanger sequencing and ultradeep-targeted sequencing in 125 WM and 10 immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS), along with the clinical features and the associated genomic landscape using single-nucleotide polymorphism array and mutational landscape in an integrative study.Results: Overall, we have identified alteration of TP53 locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. TP53 mutation was acquired in 7.3% of patients with WM at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a-targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, PrimaMet, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.Conclusions: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice. Clin Cancer Res; 23(20); 6325-35. ©2017 AACR.
Abstract 1361: Characterization of TpeL, a RAS specific clostridial toxin
Authors: Maria T. Abreu-Blanco
Journal: Cancer Research (2017)

Abstract Clostridium perfringes lethal toxin (TpeL) belongs to the family of large clostridial glycosylating cytotoxins. Clostridial toxins are glycosyltransferases that modify and deactivate small GTPases of the RHO and RAS subfamily. TpeL mono-glycosylates in the switch I domain (Thr35) of RAC and RAS small GTPases. Glycosylation of RAS at Thr35 prevents binding to the primary effector, RAF kinase and results in a blockade RAS signal transduction. RAS family proteins function as key regulators of cell proliferation, differentiation, survival and gene expression. Moreover, mutations in RAS proteins are highly prevalent in human cancers. Considering the specificity of TpeL for RAS, we decided to investigate the biochemical interaction between TpeL and RAS, and potentially develop tools to disrupt the RAS signaling pathway. In order to assess the effect of TpeL in vivo, we use RAS-dependent MEFs expressing different KRAS mutations and BRAF V600E. We expect that proliferation should be inhibited in MEF cells expressing RAS isoforms, but MEF cells expressing BRAF V600E should not be affected by any toxin. We found that TpeL treatment did not affect the viability of the BRAF V600E cells and only induced toxicity in RAS expressing cells. Consistent with this result, TpeL treatment inhibited MAPK signal transduction in the RAS expressing cells, but not in the BRAF V600E cells. Surprisingly, both cell viability as well as pERK levels remained unaffected in the KRAS Q61R MEF cells treated with TpeL, suggesting that KRAS Q61R is resistant to glycosylation. This may be due in part to the relatively slow intrinsic rate of GTP hydrolysis and very high levels of KRAS-GTP in KRAS Q61R cells. We also developed and adapted biochemical assays to study TpeL-KRAS interaction in vitro. Based on Alpha Assay and UDP Glow, TpeL activity does not appear to be nucleotide specific, in contrast to previously reported findings. We are currently testing if TpeL RAS glycosylation is competitive with or is inhibited by other molecules that bind to switch I, such as the RBD domain of RAF1 or GEF/GAP proteins. These data may indicate that the lack of activity in KRAS Q61R expressing MEF cells is due not to the high levels of RAS-GTP, but to the constitutive binding to effector molecules, which prevent TpeL from accessing KRAS. We also hope to identify the critical residues required for TpeL binding and catalysis. By elucidating the mechanism of substrate binding and substrate specificity we may gain insight into novel binding pockets that could be exploited therapeutically. Citation Format: Maria T. Abreu-Blanco. Characterization of TpeL, a RAS specific clostridial toxin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1361. doi:10.1158/1538-7445.AM2017-1361
Abstract 1152: Lipid elongation: an unexplored therapeutic target in prostate cancer
Authors: Zeyad D. Nassar, Margaret M. Centenera, Jelle Machiels, Samuel J. Polacek, Katarzyna Bloch, Wayne D. Tilley, Luke A. Selth, Johannes V. Swinnen, Lisa Butler
Journal: Cancer Research (2017)

Abstract Dysregulated lipid metabolism is one of the hallmarks of cancer, particularly for prostate cancer (PCa). PCa cells exhibit distinctive metabolic features such as upregulation of enzymes involved in de novo synthesis, uptake and beta-oxidation of lipids, which promote prostate cancer growth, metastasis, and drug resistance. Androgen signalling is a major driver of both PCa growth and lipid metabolism in PCa cells, however the precise effects of androgens on cellular lipid composition and the molecular pathways by which androgens regulate lipid metabolism in PCa cells are yet to be elucidated. In this study we investigated the effect of androgens on the lipid composition of PCa cell membranes and the enzymes involved in lipid metabolism, and explored the influence of these enzymes on tumour cell behaviour such as cell migration, proliferation and attachment. PCa cell lines (AR positive and negative) were cultured in the absence or presence of androgens or the anti-androgen enzalutamide, and changes in intact phospholipid species were assessed by ESI-MS/MS-based lipidomics. This analysis revealed a complexity of changes in phospholipid profiles in response to androgen treatment. Strikingly, elongation of the fatty acyl chains was consistently observed for multiple phospholipid classes in response to the androgens mibolerone or 5α-dihydotestosterone, whereas inhibition of elongation was observed in the presence of enzalutamide. Transcriptional analysis of critical lipid metabolism pathways revealed that the enzymes that catalyse lipid elongation (ELOVLs) were markedly induced by androgens in multiple PCa cell lines, and siRNA depletion of these enzymes, either alone or in combination, reversed the androgen-induced fatty acyl elongation phenotype. The androgenic regulation of ELOVL enzymes was confirmed in clinical PCa cohorts and in primary tumours cultured as explants. Targeting ELOVL gene expression also significantly attenuated the tumorigenic properties of PCa cells. ELOVL downregulation decreased LNCaP cell migration, and adhesion to fibronectin. Furthermore, ELOVL knock down significantly decreased three-dimensional spheroid growth of LNCaP cells using a hang drop assay. The impact of these enzymes on the lipid profile of PCa cell membrane and cell viability, adhesion and migration suggests that they may represent promising and previously unexplored therapeutic targets. Citation Format: Zeyad D. Nassar, Margaret M. Centenera, Jelle Machiels, Samuel J. Polacek, Katarzyna Bloch, Wayne D. Tilley, Luke A. Selth, Johannes V. Swinnen, Lisa Butler. Lipid elongation: an unexplored therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1152. doi:10.1158/1538-7445.AM2017-1152
Impact of the International Recommendations for Electrocardiographic Interpretation on Cardiovascular Screening in Young Athletes
Authors: Harshil Dhutia, Aneil Malhotra, Gherardo Finocchiaro, Ahmed Merghani, Michael Papadakis, Huseyin Naci, Maite Tome, Sanjay Sharma
Journal: Journal of the American College of Cardiology (2017)
Trump demands Republicans continue effort to repeal Affordable Care Act
Authors: Michael McCarthy
Journal: BMJ (2017)

Over the weekend, US president Donald Trump demanded that Senate Republicans pass legislation to repeal the Affordable Care Act (ACA) before moving on to other business.

In a 29 July post on Twitter, the president wrote: “Unless the Republican Senators are total quitters, Repeal & Replace is not dead! Demand another vote before voting on any other bill!”

If Congress failed to repeal the law, the president said he would move to block the employer contributions the federal government provides to members of Congress and …
Abstract 5074: Therapeutic targeting of bromodomain and extra-terminal proteins degradation in triple-negative breast cancer
Authors: Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Shaomeng Wang
Journal: Cancer Research (2017)

Abstract Triple negative breast cancer represents the most clinically challenging subtypes of breast cancer for which targeted therapeutics are still lacking. BET proteins have emerged as new therapeutic targets for human cancer and other diseases.We have developed a highly potent BET degrader, BETd-246, with an exceptional selectivity based upon a new class of BET inhibitor, BETi-211, and investigated its therapeutic potential and mechanisms of action in TNBC. BETd-246 induces degradation of BET proteins at low nanomolar concentrations within 1 hour, leading to potent anti-proliferative activity and strong apoptosis induction in the majority of TNBC cell lines, and is much more effective than the BETi-211 treatment. RNA-seq analysis reveals that degradation of BET proteins by BETd-246 elicits distinct transcriptional response than BET BD inhibition in TNBC cell lines. Transcriptomic analysis also shows a number of proliferation and survival-related genes were differentially regulated by BETd-246 and BETi-211 which were confirmed by quantitative RT-PCR. Mechanistically, down-regulation of MCL1 by BETd-246 plays a key role in the robust apoptosis induction in TNBC cell lines. In in vivo models, BETd-246 effectively degrades BET proteins and suppresses MCL1 expression in xenograft tumor tissues and exhibits a strong antitumor activity at well-tolerated dose-schedules in mice. Our data strongly suggest that targeting BET protein degradation is an exciting therapeutic strategy for TNBC. Citation Format: Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Shaomeng Wang. Therapeutic targeting of bromodomain and extra-terminal proteins degradation in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5074. doi:10.1158/1538-7445.AM2017-5074
Abstract 2960: Adipocytes sequester and metabolize daunorubicin
Authors: Xia Sheng, Jean-Hugues Parmentier, Jonathan Tucci, Hua Pei, Omar Cortez-Toledo, Christina Dieli-Conwright, Matthew Oberley, Michael Neely, Etan Orgel, Stan Louie, Steven D. Mittelman
Journal: Cancer Research (2017)

Abstract Obesity is associated with poorer outcome from many cancers, including childhood acute lymphoblastic leukemia (ALL). We have previously shown that adipocytes protect ALL cells from the anthracycline, daunorubicin (DNR). We therefore investigated whether adipocytes sequester and/or metabolize DNR in the ALL microenvironment. Using fluorescence and LC/MS measures, we demonstrated that adipocytes absorb DNR, reducing the intracellular DNR concentration in co-cultured BV173 ALL cells (after 48 hours, median fluorescent intensity of ALL cultured with adipocytes was 1.7±1.0 vs. 5.0±1.7 of those cultured alone, p&amp;lt;0.01). Mouse adipocytes convert DNR to the less active metabolite, daunorubicinol (DNR-ol); over 48 hours, media DNR decreased to 0.1±0.2 (vs. 24.8±8.76 ng/mL in control wells). At the same time, DNR-ol increased to 15.0±1.9 (vs. 0.7±0.6 in control wells; both p&amp;lt;0.05). Similar conversion of DNR to DNR-ol was observed in both mouse adipose explants and human adipose tissue biopsy samples ex vivo. qPCR confirmed human subcutaneous adipose tissue expresses several enzymes capable of metabolizing DNR, including AKR1A1, 1B1, 1C1, 1C2, 1C3, 7A2, and CBR1 and 3 (expression ranged between 20 and 195% β-actin). Using immunohistochemistry, we confirmed expression of AKR1C1, 1C2, and 1C3 in bone marrow adipocytes of children during the first month of treatment for ALL. Finally, two hours after an intravenous dose of DNR in mice, we found that the DNR-ol to DNR ratio was higher in subcutaneous (0.60±0.26) and omental (0.55±0.21) adipose than in white blood cells (0.16±0.11), bone marrow (undetectable DNR-ol), and spleen (undetectable DNR-ol). Together, these data demonstrate that adipocytes sequester and inactivate DNR, likely due to their expression of AKR and CBR enzymes. These findings uncover a novel and important mechanism which could promote local anthracycline resistance by cancer cells in microenvironment rich in adipocytes, such as bone marrow, omentum, and breast. Citation Format: Xia Sheng, Jean-Hugues Parmentier, Jonathan Tucci, Hua Pei, Omar Cortez-Toledo, Christina Dieli-Conwright, Matthew Oberley, Michael Neely, Etan Orgel, Stan Louie, Steven D. Mittelman. Adipocytes sequester and metabolize daunorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2017-2960
Abstract 5681: Utility of a targeted NSCLC genomic test for cfDNA variants in the community setting
Authors: Westen Hahn, Scott Thurston, Leisa Jackson, Amanda Weaver, Cherie Tschida, Brent Sage, Kristin Alexander, Tunee Pelletier, Nia Charrington, Samantha Cooper, Dianna Marr, Paul M. Bowling, Hestia Mellert, Gary Pestano
Journal: Cancer Research (2017)

Abstract Time to treatment can have significant impact on progression of cancer, and treatment decisions rely heavily upon genomic and proteomic testing. However, multiple factors can delay the availability of molecular diagnostic test results, including the use of tissue-based testing. Almost one third of patients with non-small cell lung cancer (NSCLC) are either not candidates for biopsies, or have insufficient tissue samples from their initial biopsy. Additionally, most physicians in the community setting want to initiate treatment quickly but do not have access to on-site molecular testing at their practice. As a result, physicians may delay their decision to commence treatment with specific targeted therapies or treat before the mutation status is known. The goal of this study was to assess the utility of a blood-based cell-free (cf) nucleic acid Laboratory Developed Test (LDT) in the community setting. The tests utilize Droplet Digital™ PCR (ddPCR) technology to detect the EGFR sensitizing mutations L858R and exon 19 deletion (E746 - A750), the EGFR resistance mutation (T790M), the KRAS mutations G12C, G12V and G12D, and the BRAF V600E mutation. Patient samples for testing were collected and shipped at ambient room temperature using a Biodesix® whole blood sample collection kit and processed at the Biodesix laboratory. Metrics were reviewed from the real-time measurement of established molecular diagnostic markers in the plasma of patients with NSCLC. For this study we analyzed results from greater than 4,000 patient cases (~24,000 individual variants). Greater than 70% of test orders were received from physician practices that self-identified as community based. Test mutation status results were reported within 72 hours of sample receipt from the physician’s office (95%). The percentage of tests requested that were positive for each variant category were 9% for EGFR sensitizing, 9% for EGFR resistance, 11% for KRAS, and 1% for BRAF. Notably, we generated test results successfully for 98% of tests submitted. We have developed fast, highly robust and sensitive blood-based assays to expedite time to treatment and expand the laboratory testing options for patients with NSCLC. Citation Format: Westen Hahn, Scott Thurston, Leisa Jackson, Amanda Weaver, Cherie Tschida, Brent Sage, Kristin Alexander, Tunee Pelletier, Nia Charrington, Samantha Cooper, Dianna Marr, Paul M. Bowling, Hestia Mellert, Gary Pestano. Utility of a targeted NSCLC genomic test for cfDNA variants in the community setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5681. doi:10.1158/1538-7445.AM2017-5681
Abstract LB-263: P53 promotes replication genome stability by epigenetics-enabled MRE11 restart
Authors: Katharina Schlacher, Sunetra Roy, Karl-Heinz Tomaszowski
Journal: Cancer Research (2017)

Abstract DNA damage activates p53, the most frequently mutated tumor suppressor, to guard the genome and control gene transcription, epigenetics and apoptosis. Yet, how p53 suppresses genome instability remains ill-defined and is clouded by its genome-wide alterations. Here, enabled by our kPOND technology for single-cell nascent DNA/protein interactions and single-molecule DNA spreading, we define p53’s role in promoting genomic stability by enabling replication restart of stalled replication forks. Mechanistically, p53 enables MRE11 nuclease recruitment for stalled replication fork restart via control of epigenetic factor. We find an apoptosis-proficient and tumor promoting p53 mutant allele to be replication restart defective, while an apoptosis defective and poorly tumor-promoting murine p53 allele remains mostly restart proficient, revealing an improved correlation of restart functions with tumorigenesis compared to apoptosis functions. Importantly, both null and p53 gain-of-function (GOF) mutant cells show restart defects resulting in replication dependent genomic instability, uncovering a common function defect aside gene transcription. Both mutant and p53 null cells show increased recruitment of error-prone repair factors and DNA polymerases, providing a mechanism for genomic instability observed in these cells by pathway homeostasis imbalance. Collective results unveil a common transcription-independent pathway defect for both p53 null and GOF mutants laying groundwork for new targeting strategies of p53 defects in cancer. Note: This abstract was not presented at the meeting. Citation Format: Katharina Schlacher, Sunetra Roy, Karl-Heinz Tomaszowski. P53 promotes replication genome stability by epigenetics-enabled MRE11 restart [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-263. doi:10.1158/1538-7445.AM2017-LB-263
Preventing exacerbations in chronic obstructive pulmonary disease
Journal: BMJ (2011)

Acute exacerbations of chronic obstructive pulmonary disease (COPD) are associated with significant morbidity and mortality. Patients with frequent exacerbations have high levels of anxiety and depression, significantly impaired health status and faster disease progression.1 2 Exacerbations are also the most common cause of emergency respiratory admissions to UK hospitals3 and are costly to health services.2 Here we assess whether and how drug and non-drug interventions can help in preventing exacerbations.

COPD is defined by the Global Initiative for Chronic Lung Disease (GOLD) as “a preventable and treatable disease . . . characterised by airflow limitation that is not fully reversible. It is a progressive systemic disease that results in debility over time.”4 Cigarette smoking is the most important causal factor for the development of the disease and smoking cessation is a crucial intervention that can both reduce the rate of decline in lung function and improve survival.5 6 The severity of COPD is defined in terms of the reduction in forced expiratory volume in 1 second (FEV1) relative to that predicted for age, height, and sex. This measure is considered the most significant (but not only) predictor of prognosis in the disease.7 Mild COPD is defined as an FEV1 of 50-79% of predicted, moderate as 30-49%, and severe as below 30%.8

There is no standard definition for an exacerbation. GOLD describes it as “an event in the natural course of the disease characterised by a change in the patient’s baseline dyspnoea, cough, and/or sputum production that is beyond normal day-to-day variation, is acute in onset, and may warrant a change in regular medication.”4 COPD exacerbations develop because of complex interactions between respiratory viruses, airway bacteria, ambient air pollution, and host factors, which then result in an inflammatory cascade. Consequences of …
Abstract 4472: A subunit of splicing factor 3b, SF3B4, functions as driver of liver cancer via aberrant splicing activity on tumor suppressorKLF4
Authors: Qingyu Shen, Jung Woo Eun, Hyung Seok Kim, Hee Doo Yang, Sang Yean Kim, Suk Woo Nam
Journal: Cancer Research (2017)

Abstract Alternative splicing is one of the crucial mechanism that contribute to proteome diversity and, as reported, up to 90% of genes are alternatively spliced in human. In the last few years, a large number of mRNA isoforms revealed to contribute many cellular development and disease, including cancer. SF3B4 is one of six subunits of the splicing factor 3b (SF3b) complex which is an important protein complex in U2 snRNP super complex. In this study, we show that SF3B4 expression was overexpressed in a large cohort of human hepatocellular carcinoma (HCC) patients. SF3B4 knockdown caused G1/S cell cycle arrest by recovering p27 expression and simultaneously suppressing cyclins, and CDKs in liver cancer cell. Consistently, Spliceostatin A, a SF3b complex inhibitor, also suppressed liver cancer cell growth with similar effect on cell cycle regulation. In addition, sustained suppression of SF3B4 reduced the in vivo tumor growth rate in mouse xenograft models. Furthermore, SF3B4 knockdown repressed in vitro tumor cell motility and invasion of liver cancer cells. Notably, we observed that SF3B4 knockdown increased alternative transcript splicing event of a large number of genes in liver cancer cells. From this, we found that SF3B4 knockdown caused induction of wildtype KLF4 transcript expression, and thereby exerted anti-tumor growth effect on liver cancer cells. Indeed, ectopic expression of KLF4 mimicked SF3B4 knockdown effect on same cells. Our results suggest that aberrant regulation of SF3B4 contribute to malignant transformation and growth of liver cancer cells by repression of tumor suppressor via unmodulated alternative splicing activity during liver tumorigenesis. Citation Format: Qingyu Shen, Jung Woo Eun, Hyung Seok Kim, Hee Doo Yang, Sang Yean Kim, Suk Woo Nam. A subunit of splicing factor 3b, SF3B4, functions as driver of liver cancer via aberrant splicing activity on tumor suppressor KLF4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4472. doi:10.1158/1538-7445.AM2017-4472