tbuckley/cabot-search huggingface dataset:
Intracellular Delivery of an Antibody Targeting Gasdermin-B Reduces HER2 Breast Cancer Aggressiveness
Authors: Ángela Molina-Crespo, Ana Cadete, David Sarrio, Manuel Gámez-Chiachio, Lidia Martinez, Kinlin Chao, Ana Olivera, Andrea Gonella, Eva Díaz, José Palacios, Pradeep K. Dhal, Magnus Besev, Macarena Rodríguez-Serrano, María Laura García Bermejo, Juan Carlos Triviño, Amparo Cano, Marcos García-Fuentes, Osnat Herzberg, Dolores Torres, Maria José Alonso, Gema Moreno-Bueno
Journal: Clinical Cancer Research (2019)

Gasdermin B (GSDMB) overexpression/amplification occurs in about 60% of HER2 breast cancers, where it promotes cell migration, resistance to anti-HER2 therapies, and poor clinical outcome. Thus, we tackle GSDMB cytoplasmic overexpression as a new therapeutic target in HER2 breast cancers.We have developed a new targeted nanomedicine based on hyaluronic acid-biocompatible nanocapsules, which allow the intracellular delivery of a specific anti-GSDMB antibody into HER2 breast cancer cells both in vitro and in vivo.Using different models of HER2 breast cancer cells, we show that anti-GSDMB antibody loaded to nanocapsules has significant and specific effects on GSDMB-overexpressing cancer cells' behavior in ways such as (i) lowering the in vitro cell migration induced by GSDMB; (ii) enhancing the sensitivity to trastuzumab; (iii) reducing tumor growth by increasing apoptotic rate in orthotopic breast cancer xenografts; and (iv) diminishing lung metastasis in MDA-MB-231-HER2 cells in vivo. Moreover, at a mechanistic level, we have shown that AbGB increases GSDMB binding to sulfatides and consequently decreases migratory cell behavior and may upregulate the potential intrinsic procell death activity of GSDMB.Our findings portray the first evidence of the effectiveness and specificity of an antibody-based nanomedicine that targets an intracellular oncoprotein. We have proved that intracellular-delivered anti-GSDMB reduces diverse protumor GSDMB functions (migration, metastasis, and resistance to therapy) in an efficient and specific way, thus providing a new targeted therapeutic strategy in aggressive HER2 cancers with poor prognosis.
Abstract 18701: Temporary Mechanical Circulatory Support Using a Novel Minimally-Invasive Approach for Central VA-ECMO
Authors: Prashant Rao, Rinku Skaria, Jarrod Mosier, Joshua Malo, Richard Smith, Zain Khalpey
Journal: Circulation (2017)

Introduction: Early mechanical circulatory support may be beneficial in patients with refractory cardiogenic shock and circulatory collapse. Peripheral (p)VA-ECMO is increasingly considered because...
Abstract P3-09-03: RelB facilitates cell migration and invasion in breast cancer via MMP1 upregulation
Authors: M Wang, J Tang
Journal: Cancer Research (2019)

Abstract Background: RelB is a subunit of the nuclear factor-κB (NF-κB) signaling famliy and appears aberrant expression in breast cancer. The aim of the present study was to further investigate the role of RelB in breast cancer and whether RelB might be a therapeutic target. Methods: 120 cases of breast cancer patients were collected from the Jiangsu Province Hospital during 2015-2017. Immunohistochemistry (IHC) was performed to detect RelB expression in breast cancer tissues and para-cancer tissues. The relationship between RelB expression and clinical pathologic parameters were investigated. Detection the expression of RelB in 4 kinds of human breast cancer cell lines (MCF-7, T47D, MDA-MB-231, BT-549) by Western blot and RT-qPCR.Knockout of RelB in TNBC cell lines (BT-549 and MDA-MB-231) was using the CRISPR/Cas9 genome editing system. CCK-8 and flow cytometry were performed to observe the proliferation, cycle and apoptosis of MDA-MB-231 and BT-549 after knockout of RelB. Transwell and wound healing experiments were performed to observe cell invasion and migration ability. RT-PCR and Western blotting were performed to detect the expression of mRNA and protein of EMT marker and MMP1 respectively. The luciferase reporter gene was performed to detect whether RelB binding with MMP1 promoter region. In vivo efficacy was tested using the xenograft model and lung metastasis model. Results: RelB was highly expressed in triple-negative breast cancer (TNBC) tissues compared with that in adjacent tissues. RelB levels were remarkably associated with the pTNM stage (p=0.01981) and ER expression (p=0.4689). RelB expressions in TNBC cell lines were higher than that of hormone receptor positive MCF-7 cells. In vitro studies showed that RelB deletion promoted apoptosis and suppressed breast cancer cell survival, migration and invasion by decreasing snail, vimentin and MMP1. RelB deletion inhibited cell cycle progression and G1/S transition by upregulating p21 and p27 expression. In vivo studies showed that 231-RelB-KO cells completely impaired tumor formation in xenograft models and lung metastasis model in nude mice. Conclusion: RelB is aberrant constitutive expressed in clinical specimens and cell lines of breast cancer, especially in TNBC. RelB regulates malignant phenotypes of breast cancer, including cell survival, migration and invasion, as well as apoptosis and the cell cycle. Moreover, RelB can induce MMP1, which facilitates the invasion of tumor. Collectively, our findings highlight that RelB might serve as a therapeutic target for triple negative breast cancer. Citation Format: Wang M, Tang J. RelB facilitates cell migration and invasion in breast cancer via MMP1 upregulation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-09-03.
The Legacy of Sexual Ancestors in Phenotypic Variability, Gene Expression, and Homoeolog Regulation of Asexual Hybrids and Polyploids
Authors: Oldřich Bartoš, Jan Röslein, Jan Kotusz, Jan Paces, Ladislav Pekárik, Miloslav Petrtýl, Karel Halačka, Eva Štefková Kašparová, Jan Mendel, Alicja Boroń, Dorota Juchno, Anna Leska, Olga Jablonska, Vladimir Benes, Monika Šídová, Karel Janko
Journal: Molecular Biology and Evolution (2019)

Hybridization and polyploidization are important evolutionary processes whose impacts range from the alteration of gene expression and phenotypic variation to the triggering of asexual reproduction. We investigated fishes of the Cobitis taenia-elongatoides hybrid complex, which allowed us to disentangle the direct effects of both processes, due to the co-occurrence of parental species with their diploid and triploid hybrids. Employing morphological, ecological, and RNAseq approaches, we investigated the molecular determinants of hybrid and polyploid forms. In contrast with other studies, hybridization and polyploidy induced relatively very little transgressivity. Instead, Cobitis hybrids appeared intermediate with a clear effect of genomic dosing when triploids expressed higher similarity to the parent contributing two genome sets. This dosage effect was symmetric in the germline (oocyte gene expression), interestingly though, we observed an overall bias toward C. taenia in somatic tissues and traits. At the level of individual genes, expression-level dominance vastly prevailed over additivity or transgressivity. Also, trans-regulation of gene expression was less efficient in diploid hybrids than in triploids, where the expression modulation of homoeologs derived from the "haploid" parent was stronger than those derived from the "diploid" parent. Our findings suggest that the apparent intermediacy of hybrid phenotypes results from the combination of individual genes with dominant expression rather than from simple additivity. The efficiency of cross-talk between trans-regulatory elements further appears dosage dependent. Important effects of polyploidization may thus stem from changes in relative concentrations of trans-regulatory elements and their binding sites between hybridizing genomes. Links between gene regulation and asexuality are discussed.
Abstract P5-04-04: Withdrawn
Authors: GM Das, S Kulkarni, C Oturkar, SB Edge, JH Wilton, J Wang, WM Swetzig, AA Adjei, R Bies, AD Hutson, CD Morrison, BA Kaipparettu, A Groman, S Kumar, H Capuccino
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Das GM, Kulkarni S, Oturkar C, Edge SB, Wilton JH, Wang J, Swetzig WM, Adjei AA, Bies R, Hutson AD, Morrison CD, Kaipparettu BA, Groman A, Kumar S, Capuccino H. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-04.
Endoscopic ultrasound-guided duodenojejunostomy for management of refractory benign hepaticojejunal anastomotic stricture
Authors: Gianfranco Donatelli, Fabrizio Cereatti, Serge Derhy
Journal: Endoscopy (2019)

A 45-year-old man was referred to our endoscopy unit because of a benign refractory hepaticojejunal anastomotic stricture. Previous transhepatic anastomotic dilations had failed to guarantee long-term patency. We proposed endoscopic ultrasound (EUS)-guided duodenojejunostomy created using a lumen-apposing metal stent (LAMS) to allow endoscopic management of the bilioenteric stricture.
Five truths about being a first year medical student and five rookie mistakes to avoid
Authors: George Gillett, Abhishek Kumar, Zak Tait
Journal: BMJ (2015)

### You won’t be able to watch medical dramas on television without cringing

You’ll never be able to watch Holby City again without noticing an inaccurate medical reference or irresponsible procedure. Whether it is doctors living in caravans in hospital car parks, medical staff performing operations on their parents, or clinicians being able to diagnose patients at first sight, real medicine simply isn’t like that. Likewise, don’t be fooled by the endless tracheostomies that screenwriters entertain viewers with—you’ll probably see more in one episode than in your entire time at medical school.

### Nobody knows the right way to use a stethoscope

Whether it is which way to position the earpieces, or telling which side is the diaphragm or bell, at some point everyone gets flummoxed by this pesky medical essential. It might be the symbol of your medical student status, but that won’t prevent you being left prodding at a patient’s thorax, desperately trying to hear anything that resembles a heartbeat.

### Family and friends will ask you for medical advice

Even though you’ll only have covered a term’s worth of material when you go home at Christmas, people will assume that you are …
Metabolic reprogramming toward oxidative phosphorylation identifies a therapeutic target for mantle cell lymphoma
Authors: Liang Zhang, Yixin Yao, Shaojun Zhang, Yang Liu, Hui Guo, Makhdum Ahmed, Taylor Bell, Hui Zhang, Guangchun Han, Elizabeth Lorence, Maria Badillo, Shouhao Zhou, Yuting Sun, M. Emilia Di Francesco, Ningping Feng, Randy Haun, Renny Lan, Samuel G. Mackintosh, Xizeng Mao, Xingzhi Song, Jianhua Zhang, Lan V. Pham, Philip L. Lorenzi, Joseph Marszalek, Tim Heffernan, Giulio Draetta, Philip Jones, Andrew Futreal, Krystle Nomie, Linghua Wang, Michael Wang
Journal: Science Translational Medicine (2019)

Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clinical specimens, we show that metabolic reprogramming toward oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton's tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), a B cell lymphoma subtype with poor clinical outcomes. Inhibition of OXPHOS with a clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in marked growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.
Abstract P6-14-02: Withdrawn
Authors: MR Esser, JJ Rowe, ML McCann, M Nicholas-Alexander, EP Helck, SM Lewis
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Esser MR, Rowe JJ, McCann ML, Nicholas-Alexander M, Helck EP, Lewis SM. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-14-02.
Paediatrics and politics
Authors: Terence Stephenson
Journal: BMJ (2013)

In 1798 Edward Jenner first described “vaccination.” The British government awarded Jenner £30 000 in recompense for his time, the equivalent of £1m (€1.2m; $1.5m) today. Exactly 200 years later in 1998 Andrew Wakefield claimed a link between MMR (measles, mumps, rubella) vaccination and autism. From early experimental medicine, as we would now describe Jenner’s observational study, and then his “first in man, proof of principle” experiment on a child; through some of the largest efficacy studies ever conducted in the 20th century; to a case series that involved selection bias, non-reproducible results, and fraud, evidence based medicine has come through two centuries, the past 25 years of which I witnessed at close quarters.

In 1986, as …
David Oliver: Pensions policy and public relations
Authors: David Oliver
Journal: BMJ (2019)

BerkshireChanges to pension tax rules for doctors have hit the news in recent months.In particular, changes to the lifetime allowance (LTA) for pension pots and the annual allowance (AA) for total annual contributions have caused consternation. 1 2The mainstream media have covered this issue, and Josephine Cumbo, pensions correspondent for the Financial Times, has written extensively about it. [3]4][5] It was also raised in Money Box on BBC Radio 4 6 and in a Westminster Hall debate. 7 But the Treasury has said that senior NHS workers will not be exempt and that reducing pension
The American Cancer Society 2035 challenge goal on cancer mortality reduction
Authors: Jiemin Ma, Ahmedin Jemal, Stacey A. Fedewa, Farhad Islami, J. Leonard Lichtenfeld, Richard C. Wender, Kevin J. Cullen, Otis W. Brawley
Journal: CA A Cancer Journal for Clinicians (2019)

Abstract A summary evaluation of the 2015 American Cancer Society (ACS) challenge goal showed that overall US mortality from all cancers combined declined 26% over the period from 1990 to 2015. Recent research suggests that US cancer mortality can still be lowered considerably by applying known interventions broadly and equitably. The ACS Board of Directors, therefore, commissioned ACS researchers to determine challenge goals for reductions in cancer mortality by 2035. A statistical model was used to estimate the average annual percent decline in overall cancer death rates among the US general population and among college‐educated Americans during the most recent period. Then, the average annual percent decline in the overall cancer death rates of college graduates was applied to the death rates in the general population to project future rates in the United States beginning in 2020. If overall cancer death rates from 2020 through 2035 nationally decline at the pace of those of college graduates, then death rates in 2035 in the United States will drop by 38.3% from the 2015 level and by 54.4% from the 1990 level. On the basis of these results, the ACS 2035 challenge goal was set as a 40% reduction from the 2015 level. Achieving this goal could lead to approximately 1.3 million fewer cancer deaths than would have occurred from 2020 through 2035 and 122,500 fewer cancer deaths in 2035 alone. The results also show that reducing the prevalence of risk factors and achieving optimal adherence to evidence‐based screening guidelines by 2025 could lead to a 33.5% reduction in the overall cancer death rate by 2035, attaining 85% of the challenge goal.
Ikaros tumor suppressor function includes induction of active enhancers and super-enhancers along with pioneering activity
Authors: Yali Ding, Bo Zhang, Jonathon L. Payne, Chunhua Song, Zheng Ge, Chandrika Gowda, Soumya Iyer, Pavan K. Dhanyamraju, Glenn Dorsam, Mark E. Reeves, Dhimant Desai, Suming Huang, Kimberly J. Payne, Feng Yue, Sinisa Dovat
Journal: Leukemia (2019)

Ikaros encodes a transcription factor that functions as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). The mechanisms through which Ikaros regulates gene expression and cellular proliferation in T-ALL are unknown. Re-introduction of Ikaros into Ikaros-null T-ALL cells resulted in cessation of cellular proliferation and induction of T-cell differentiation. We performed dynamic, global, epigenomic, and gene expression analyses to determine the mechanisms of Ikaros tumor suppressor activity. Our results identified novel Ikaros functions in the epigenetic regulation of gene expression: Ikaros directly regulates de novo formation and depletion of enhancers, de novo formation of active enhancers and activation of poised enhancers; Ikaros directly induces the formation of super-enhancers; and Ikaros demonstrates pioneering activity by directly regulating chromatin accessibility. Dynamic analyses demonstrate the long-lasting effects of Ikaros DNA binding on enhancer activation, de novo formation of enhancers and super-enhancers, and chromatin accessibility. Our results establish that Ikaros' tumor suppressor function occurs via global regulation of the enhancer and super-enhancer landscape and through pioneering activity. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and Ikaros-induced enhancers, and that are responsible for the cessation of proliferation and induction of T-cell differentiation in T-ALL cells.
Lipoprotein(a) and Cardiovascular Outcomes in Patients With Coronary Artery Disease and Prediabetes or Diabetes
Authors: Jing-Lu Jin, Ye-Xuan Cao, Hui-Wen Zhang, Di Sun, Qi Hua, Yan-Fang Li, Yuan-Lin Guo, Na-Qiong Wu, Cheng-Gang Zhu, Ying Gao, Qiu-Ting Dong, Hui-Hui Liu, Qian Dong, Jian-Jun Li
Journal: Diabetes Care (2019)

OBJECTIVE The aim of the current study is to determine the impact of elevated lipoprotein(a) [Lp(a)] on cardiovascular events (CVEs) in stable coronary artery disease (CAD) patients with different glucose metabolism status. RESEARCH DESIGN AND METHODS In this multicenter study, we consecutively enrolled 5,143 patients from March 2011 to February 2015. Patients were categorized according to status of glucose metabolism (diabetes mellitus [DM], pre–diabetes mellitus [pre-DM], and normal glucose regulation [NGR]) levels and further classified into 12 groups by Lp(a) levels. CVE end points included nonfatal acute myocardial infarction (MI), stroke, and cardiovascular mortality. All subjects were followed up for the occurrence of the CVEs. RESULTS During a median of 6.1 years’ follow-up, 435 (8.5%) CVEs occurred. No significant difference in occurrence of CVEs was observed between NGR and pre-DM groups (hazard ratio 1.131 [95% CI 0.822–1.556], P &amp;gt; 0.05). When status of glucose metabolism was incorporated in stratifying factors, 30 ≤ Lp(a) &amp;lt; 50 mg/dL and Lp(a) ≥50 mg/dL were associated with significantly higher risk of subsequent CVEs in pre-DM (2.181 [1.099–4.327] and 2.668 [1.383–5.415], respectively; all P &amp;lt; 0.05) and DM (3.088 [1.535–5.895] and 3.470 [1.801–6.686], all P &amp;lt; 0.05). Moreover, adding Lp(a) to the Cox model increased the C-statistic by 0.022 and 0.029 in pre-DM and DM, respectively, while the C-statistic was not statistically improved when Lp(a) was included for CVEs prediction in NGR. CONCLUSIONS Our findings, for the first time, indicated that elevated Lp(a) levels might affect the prognosis in patients with pre-DM with stable CAD, suggesting that Lp(a) may help further stratify stable CAD patients with mild impaired glucose metabolism.
Abstract ES6-1: Oxidative stress responses in cancer
Authors: J Brugge
Journal: Cancer Research (2019)

Abstract Generation of reactive oxygen species (ROS), a natural byproduct of oxygen metabolism, occurs in all aerobic organisms at a controlled rate. Cancer cells are subjected to numerous cellular insults, including dysregulated oncogenes and loss of their natural extracellular matrix (ECM) interactions, that lead to the generation of high levels of ROS and selection for upregulation of anti-oxidant programs that allow adaptation to elevated ROS. Although cancer cells possess enhanced canonical antioxidant programs that neutralize ROS, they nevertheless exhibit prominent ROS levels in response to these insults, suggesting the existence of additional programs that allow cancer cells to tolerate elevated ROS. My presentation will include a discussion of the evolving concepts about the role of oxidative stress and anti-oxidants in distinct processes associated with tumor initiation and progression and the potential for targeting anti-oxidants for therapeutic intervention. In addition, I will describe studies from our laboratory using 3-dimensional culture systems to model early events in breast cancer which have highlighted the critical role of oxidative stress in eliminating aberrantly proliferating breast epithelial cells, as well as the role of endogenous anti-oxidants in promoting proliferation and survival of pre-malignant cells. I will also discuss studies providing evidence for an unconventional mechanism whereby cancer cells co-opt the ROS-activated neuronal Ca2+-permeable TRPA1 channel in order to adapt to oxidative environments. Citation Format: Brugge J. Oxidative stress responses in cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES6-1.
Abstract P4-12-05: First implementation of the International Consortium of Health Outcomes Measurement standard for breast cancer at a major German university hospital using a web-based tool to measure patient reported outcomes
Authors: MM Karsten, D Speiser, C Hartmann, K Lippold, V Kirchberger, J-U Blohmer
Journal: Cancer Research (2019)

Abstract Purpose: Collecting patient reported outcome (PRO) data in a systematic way enables an objective evaluation of treatments and its related outcomes. By using the disease specific questionnaires developed by the International Consortium of Health Outcome Measurement (ICHOM) this allows for comparison between physicians, hospitals and even different countries. Methods In November 2016 we implemented a web-based system to collect PRO data at the breast center at Charité University hospital using the ICHOM data set. All new patients who are seen at the breast center are enrolled and are answering a predefined set of questions using a tablet computer. Once they start their treatment at Charité automated emails are sent to the patient at predefined treatment points. Those emails contain a web-based link through which they can access their questionnaires. Results Until now we have enrolled 834 patients and initiated 2470 questionnaires. 9.44% of patients were under 40 years of age, 49.7% between 40 and 60, 39.6% between 60-80 and 1.3% over the age of 80 years. The average return rate of questionnaires is 72% without any additional intervention. When asked about preference regarding paper versus online 7.9% of the patients 50 to 60 years of age would prefer paper, 18% in the 60-70 years of age group and 21.2 % in the age group over 70 years. Conclusion Measuring PRO in breast cancer patients in an automated electronic version is possible across all age ranges while simultaneously achieving a high return rate. Citation Format: Karsten MM, Speiser D, Hartmann C, Lippold K, Kirchberger V, Blohmer J-U. First implementation of the International Consortium of Health Outcomes Measurement standard for breast cancer at a major German university hospital using a web-based tool to measure patient reported outcomes [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-12-05.