tbuckley/cabot-search huggingface dataset:
Plant lamin-like proteins mediate chromatin tethering at the nuclear periphery
Authors: Bo Hu, Nan Wang, Xiuli Bi, Ezgi Süheyla Karaaslan, Anna-Lena Weber, Wangsheng Zhu, Kenneth Wayne Berendzen, Chang Liu
Journal: Genome biology (2019)

The nuclear envelope not only serves as a physical barrier separating nuclear content from the cytoplasm but also plays critical roles in modulating the three-dimensional organization of genomic DNA. For both plants and animals, the nuclear periphery is a functional compartment enriched with heterochromatin. To date, how plants manage to selectively tether chromatin at the nuclear periphery is unclear.By conducting dual-color fluorescence in situ hybridization experiments on 2C nuclei, we show that in Arabidopsis thaliana, specific chromatin positioning at the nuclear periphery requires plant lamin-like proteins CROWDED NUCLEI 1 (CRWN1), CRWN4, and DNA methylation in CHG and CHH contexts. With chromosome painting and Hi-C analyses, we show global attenuation of spatial chromatin compartmentalization and chromatin positioning patterns at the nuclear periphery in both the crwn1 and crwn4 mutants. Furthermore, ChIP-seq analysis indicates that CRWN1 directly interacts with chromatin domains localized at the nuclear periphery, which mainly contains non-accessible chromatin.In summary, we conclude that CRWN1 is a key component of the lamina-chromatin network in plants. It is functionally equivalent to animal lamins, playing critical roles in modulating patterns of chromatin positioning at the nuclear periphery.
Abstract 18086: Incidence and Predictors of Calcified Nodule in Patients With Coronary Artery Calcification: An Optical Coherence Tomography Study
Authors: Saki Iwai, Makoto Watanabe, Daisuke Kamon, Yoko Kita, Takuya Isojima, Tomoya Ueda, Tsunenari Soeda, Hiroyuki Kawata, Rika Kawakami, Hiroyuki Okura, Yoshihiko Saito
Journal: Circulation (2017)

Background: Calcified nodule (CN) is recognized as one of the pathogenic mechanisms of acute coronary syndrome (ACS) accounting for about 10% of the ACS. The aim of this study is to examine the inc...
Abstract 17316: Ventricular Myocardial Gene Expression in HFrEF Patients With Atrial Fibrillation (AF) vs. No AF, and Changes in Response to Beta-Blockade
Authors: Ryan G Aleong, David Kao, Brian D Lowes, Wayne Minobe, Michael Gilbert, Michael R Bristow
Journal: Circulation (2017)

Introduction: The co-existence of atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF) results in worse clinical outcomes than for either individual disorder, and the p...
Hard to explain
Authors: Eva Dumann
Journal: BMJ (2013)

Life as a half baked doctor can be tough. My naive hope that medical school would be filled with people who understand the secret workings of the body was soon destroyed—nobody seemed to, and I certainly don’t. Lay friends rub salt into these open wounds by asking questions about medical science that I can’t find answers to.

A magazine in a friend’s house recently brought on one of these struggles. My friend shows me a tiny print advertisement for vitamin preparations that have …
Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy
Authors: Qiang Cai, Shouhua Wang, Longyang Jin, Mingzhe Weng, Di Zhou, Jiandong Wang, Zhaohui Tang, Zhiwei Quan
Journal: Molecular Cancer (2019)

Abstract Background Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells. Methods We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA. Results The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate. Conclusions Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.
Abstract P2-01-23: Not presented
Authors: W Xing, Q Li, R Cao, G Sun, C Jiang
Journal: Cancer Research (2019)

Abstract This abstract was not presented at the conference. Citation Format: Xing W, Li Q, Cao R, Sun G, Jiang C. Not presented [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 P2-01-23.
Abstract P2-01-18: Withdrawn
Authors: A Abdullah, A Tao, MK Wendt
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Abdullah A, Tao A, Wendt MK. 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 P2-01-18.
Pharmacologic Inhibition of Epidermal Growth Factor Receptor Suppresses Nonalcoholic Fatty Liver Disease in a Murine Fast‐Food Diet Model
Authors: Bharat Bhushan, Swati Banerjee, Shirish Paranjpe, Kelly Koral, Wendy M. Mars, John W. Stoops, Anne Orr, William C. Bowen, Joseph Locker, George K. Michalopoulos
Journal: Hepatology (2019)

Epidermal growth factor receptor (EGFR) is a critical regulator of hepatocyte proliferation and liver regeneration. Our recent work indicated that EGFR can also regulate lipid metabolism during liver regeneration after partial hepatectomy. Based on these findings, we investigated the role of EGFR in a mouse model of nonalcoholic fatty liver disease (NAFLD) using a pharmacological inhibition strategy. C57BL6/J mice were fed a chow diet or a fast-food diet (FFD) with or without EGFR inhibitor (canertinib) for 2 months. EGFR inhibition completely prevented development of steatosis and liver injury in this model. In order to study if EGFR inhibition can reverse NAFLD progression, mice were fed the FFD for 5 months, with or without canertinib treatment for the last 5 weeks of the study. EGFR inhibition remarkably decreased steatosis, liver injury, and fibrosis and improved glucose tolerance. Microarray analysis revealed that ~40% of genes altered by the FFD were differentially expressed after EGFR inhibition and, thus, are potentially regulated by EGFR. Several genes and enzymes related to lipid metabolism (particularly fatty acid synthesis and lipolysis), which were disrupted by the FFD, were found to be modulated by EGFR. Several crucial transcription factors that play a central role in regulating these lipid metabolism genes during NAFLD, including peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1 (SREBF1), carbohydrate-responsive element-binding protein, and hepatocyte nuclear factor 4 alpha, were also found to be modulated by EGFR. In fact, chromatin immunoprecipitation analysis revealed that PPARγ binding to several crucial lipid metabolism genes (fatty acid synthase, stearoyl-coenzyme A desaturase 1, and perilipin 2) was drastically reduced by EGFR inhibition. Further upstream, EGFR inhibition suppressed AKT signaling, which is known to control these transcription factors, including PPARγ and SREBF1, in NAFLD models. Lastly, the effect of EGFR in FFD-induced fatty-liver phenotype was not shared by receptor tyrosine kinase MET, investigated using MET knockout mice. Conclusion: Our study revealed a role of EGFR in NAFLD and the potential of EGFR inhibition as a treatment strategy for NAFLD.
Phage therapy: Current status and perspectives
Authors: Andrzej Górski, Ryszard Międzybrodzki, Grzegorz Węgrzyn, Ewa Jończyk‐Matysiak, Jan Borysowski, Beata Weber‐Dąbrowska
Journal: Medicinal Research Reviews (2019)

Abstract The spread of antimicrobial resistant bacterial pathogens combined with the lack of new drug classes in the antibiotic pipeline causes a resurgence of the use of bacterial viruses (phages) to treat bacterial infections (phage therapy [PT]). There has been a substantial increase in patients subjected to this experimental therapy and emergence of new PT centers in Europe and the United States paralleled by one clinical trial completed in accord with good medical practice (GMP) requirements and a few others underway. What is more, evidence has been accumulating to suggest that phages can also exert anti‐inflammatory and immunomodulatory action which opens new pathways for the development of novel targets for PT. Here we present the status quo of the PT, recent regulatory, and clinical developments as well as new perspectives for its wider application in clinical medicine.
Timing of Angiography and Outcomes in High-Risk Patients With Non–ST-Segment–Elevation Myocardial Infarction Managed Invasively
Authors: Pierre Deharo, Gregory Ducrocq, Christoph Bode, Marc Cohen, Thomas Cuisset, Shamir R. Mehta, Charles Pollack, Stephen D. Wiviott, Yedid Elbez, Marc S. Sabatine, Philippe Gabriel Steg
Journal: Circulation (2017)

Background: In patients with non–ST-segment–elevation myocardial infarction (NSTEMI) and GRACE (Global Registry of Acute Coronary Events) score &gt;140, coronary angiography (CAG) is recommended by European and American guidelines within 24 hours. We sought to study the association of very early (ie, ≤12 hours), early (12–24 hours), and delayed (&gt;24 hours) CAG in patients with NSTEMI with GRACE score &gt;140 with ischemic outcomes. Methods: The TAO trial (Treatment of Acute Coronary Syndrome With Otamixaban) randomized patients with NSTEMI and CAG scheduled within 72 hours to heparin plus eptifibatide versus otamixaban. In this post hoc analysis, patients with a GRACE score &gt;140 were categorized into 3 groups according to timing of CAG from admission (&lt;12, ≥12–&lt;24, and ≥24 hours). The primary ischemic outcome was the composite of all-cause death and myocardial infarction within 180 days of randomization. Results: CAG was performed in 4071 patients (&lt;12 hours, n=1648 [40.5%]; 12–24 hours, n=1420 [34.9%]; ≥24 hours, n=1003 [24.6%]). With CAG ≥24 hours as a reference, CAG from 12 to 24 hours was not associated with a lower risk of primary ischemic outcome at 180 days (odds ratio, 0.96; 95% confidence interval, 0.75–1.23), whereas CAG &lt;12 hours was associated with a lower risk of death and myocardial infarction (odds ratio, 0.71; 95% confidence interval, 0.55–0.91). Performing CAG &lt;12 hours was also associated with a lower risk of death and myocardial infarction (odds ratio, 0.76; 95% confidence interval, 0.61–0.94; P =0.01) compared with CAG performed at 12 to 24 hours. No difference was observed in bleeding complications. Conclusions: In patients with high-risk NSTEMI, undergoing CAG within the initial 12 hours after admission (as opposed to later, either 12–24 or ≥24 hours) was associated with lower risk of ischemic outcomes at 180 days.
Abstract 15017: Adipolin/C1q/Tnf-Related Protein 12 Serves as an Indicator of Coronary Artery Disease and Prevents the Progression of Pathological Vascular Remodeling
Authors: Hayato Ogawa, Koji Ohashi, Rei Shibata, Naoya Otaka, Hiroshi Kawanishi, Shukuro Yamaguchi, Toyoaki Murohara, Noriyuki Ouchi
Journal: Circulation (2017)

Obesity contributes to the development of cardiovascular disease. We have previously shown that adipolin, also known as C1q/Tnf-related protein 12, is an insulin sensitizing adipokine, which is dow...
General practice makes perfect
Authors: Alice James
Journal: BMJ (2013)

Around half of medical students will end up training to become GPs. Yet this career pathway is viewed by many students as a “soft option”—consigning you to a lifetime of colds and ingrown toenails. I recently heard a fellow medical student remark to another: “Don’t take this offensively, but I think you’d make a really good GP.” Where does this disregard for general practice as a career stem from, and why do some medical schools produce disproportionately fewer GPs?

In the latest UK Foundation Programme Office national F2 career destination survey,1 medical students from Bristol …
Whole-genome sequence analysis of a Pan African set of samples reveals archaic gene flow from an extinct basal population of modern humans into sub-Saharan populations
Authors: Belen Lorente-Galdos, Oscar Lao, Gerard Serra-Vidal, Gabriel Santpere, Lukas F. K. Kuderna, Lara R. Arauna, Karima Fadhlaoui-Zid, Ville N. Pimenoff, Himla Soodyall, Pierre Zalloua, Tomas Marques-Bonet, David Comas
Journal: Genome biology (2019)

Population demography and gene flow among African groups, as well as the putative archaic introgression of ancient hominins, have been poorly explored at the genome level. Here, we examine 15 African populations covering all major continental linguistic groups, ecosystems, and lifestyles within Africa through analysis of whole-genome sequence data of 21 individuals sequenced at deep coverage. We observe a remarkable correlation among genetic diversity and geographic distance, with the hunter-gatherer groups being more genetically differentiated and having larger effective population sizes throughout most modern-human history. Admixture signals are found between neighbor populations from both hunter-gatherer and agriculturalists groups, whereas North African individuals are closely related to Eurasian populations. Regarding archaic gene flow, we test six complex demographic models that consider recent admixture as well as archaic introgression. We identify the fingerprint of an archaic introgression event in the sub-Saharan populations included in the models (~ 4.0% in Khoisan, ~ 4.3% in Mbuti Pygmies, and ~ 5.8% in Mandenka) from an early divergent and currently extinct ghost modern human lineage. The present study represents an in-depth genomic analysis of a Pan African set of individuals, which emphasizes their complex relationships and demographic history at population level.
Abstract P4-08-31: Withdrawn
Authors: T Loughman, C-JA Wang, P Dynoodt, B Fender, C Lopez-Ruiz, S Barron, S Stapleton, D O'Leary, A Fabre, C Quinn, B Nodin, K Jirström, A Bracken, WM Gallagher
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Loughman T, Wang C-JA, Dynoodt P, Fender B, Lopez-Ruiz C, Barron S, Stapleton S, O'Leary D, Fabre A, Quinn C, Nodin B, Jirström K, Bracken A, Gallagher WM. 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 P4-08-31.
Making sense of it all
Authors: Matthew Billingsley
Journal: BMJ (2016)

Welcome to a new term, and if you’re a fresher, we have two articles to help you acclimatise to medical student life. Firstly, Aemun Reza, a final year student at Imperial College London, points out some of the tell tale signs that prove you’re morphing into a medical student. Can you chat casually about bowel surgery while eating lasagne? Have you been told off by nurses for loitering? Do mistakes in medical television dramas now infuriate you? Find out how many signs you display on page 10.

Secondly, what medical school tribe do you fit into? Katy Bettany, foundation year 1 doctor and former editor of Student …
Abstract P4-10-19: Withdrawn
Authors: IT Gram, T Braaten, E Lund, I Licaj
Journal: Cancer Research (2019)

Abstract This abstract was withdrawn by the authors. Citation Format: Gram IT, Braaten T, Lund E, Licaj I. 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 P4-10-19.
Abstract P5-11-08: Genetic landscape of prior and resistance to CDK4/6 inhibition in targeted NGS panel analysis of palbociclib or abemaciclib and endocrine versus placebo and endocrine
Authors: J Xu, T Sun, X Wang
Journal: Cancer Research (2019)

Abstract Background: CDK4/6 inhibition combined with endocrine therapy is now a standard of care for advanced estrogen receptor (ER) positive breast cancer. Predictive genetic landscape and mechanisms of resistance to CDK4/6 inhibitors have not been described clearly because of limited evidence from clinical samples. We investigated the genetic landscape and mechanisms of resistance to CDK4/6 inhibitors (palbociclib or abemaciclib). Methods: Using driver mutation targeted sequencing, we conducted longitudinal ctDNA analysis in 39 pairs of baseline of primary tumor and end of treatment or monitoring plasma samples. DNA were extracted and the genomic profiles were analyzed based on NGS. Results: In our cohort, the most frequence mutations were PIK3CA (38.5%), TP53(17.9%), CCND1, ZNF703, FGFR1, MAP2K4, RB1, ARID1A, ATRX, DNMT3A. In five paitents harboring RB1 mutations prior to CDK4/6 inhibitor, only one case occured progressing early with 4mos of PFS, and the others were 5.5+, 6.5+, 13.5+, 21+months, it represented different from pre-clinical results that RB1 mutation was associated with resistance to CDK4/6 inhibitor. Interesting, patients with PIK3CA/PTEN/AKT1 mutations (n=15) were likely sensitivity to CDK4/6 inhibitor than those (n=11) with wild type (median PFS: 17 mos vs. 9.5mos, P=0.046). In another cohort of everolimus, new driver mutations emerged in both FGFR1 and ERBB3 at end of everolimus and significantly disappeared in AKT1 mutation. Three patients used palbociclib after progress disease of everolimus, the prognosis were poor with PFS of 1, 6, 9 mos. Evolution of driver gene mutations was uncommon in patients progressing on CDK4/6 inhibitors treatment, but common in patients progressing on everolimus treatment. Conclusions: De novo PIK3CA/PTEN/AKT1 mutations were likely better prognosis biomarkers with the treatment of CDK4/6 inhibitor. RB1 mutation are common and may not contribute to CDK4/6 inhibitor resistance differ from PALOMA3 ctDNA analysis. Our small sample finding indicate it may be a bad stragegy for CDK4/6 inhibitor after progress disease with mTOR inhibitor everolimus. Citation Format: Xu J, Sun T, Wang X. Genetic landscape of prior and resistance to CDK4/6 inhibition in targeted NGS panel analysis of palbociclib or abemaciclib and endocrine versus placebo and endocrine [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 P5-11-08.
Is More Better? Promising Biological Effects of Double-Dose Alpha 1-Antitrypsin Therapy
Authors: Irina Petrache
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

the age of a worldwide increase in antibiotic resistance, it is questionable whether the broad use of antibiotics as maintenance treatment for chronic diseases is a wise decision, as antibiotic resistance is closely correlated to infectious disease-related mortality.King Arthur and the Knights of the Round Table died, and the Holy Grail was lost forever.Even though this is only a Welsh tale, it should be a lesson.
How to . . . become a general practitioner
Authors: Jacqui Wise
Journal: BMJ (2019)

The BMJ General practice is a challenging, rewarding, and varied vocation that offers stability, family friendly working hours, and great career opportunities.A GP needs excellent personal skills, a broad knowledge base, and familiarity with a large number of acronyms.To become a GP in the UK you need a minimum of three years of GP specialty training on a programme approved by the General Medical Council.This normally consists of 18 months in an approved training practice with a further 18 months in approved hospital posts.There are, however, an increasing number of four year options available.
Early squamous cell lung carcinoma: prognostic biomarkers for the many
Authors: Francesco Pezzella
Journal: Thorax (2019)

When Aschoff published his landmark textbook Pathologische Anatomie in 1909,1 lung carcinomas were barely mentioned. Their classification into histological subtypes was also very basic as they were simply described as being ‘usually made up by cylindrical cells, rarely being medullary, colloid or cancroid’.2 Since then a lot has changed because of our increased knowledge and, unfortunately, because of a dramatic increase of cases of lung carcinoma following the epidemic of cigarette smoking. Now we know that, under the umbrella of lung carcinomas, there are several different neoplastic diseases.3 Squamous cell carcinomas (SCC) represent one of the major types of lung epithelial neoplasm, and three histological subtypes of invasive SCC are identified in the most recent WHO classification: keratinising, non-keratinising and basaloid3 plus the preinvasive ‘in situ’ type.

Despite our advances in understanding the biology of these tumours, treatment for the largest group, the non-small cell lung carcinomas (NSCLC) of which SCC are part, it is still mainly guided by the tumour-node-metastasis (TNM) staging system, with surgery as first-line choice in early carcinomas (stages I, II and II according to the TNM system).4 Although curative in a number of people, surgical treatment eventually still fails in a large number of cases. Only 67% of patients with Stage IA survive 5 years, while just 25% are still alive, at the same time, if the stage is IIIA.5 The number of clinical trials evaluating the effect of adjuvant postoperative chemotherapy is therefore increasing to try to improve the outcome of surgery; however, the results are, so far, modest. When evaluating a patient for adjuvant treatment, the main predictive factor so far identified and currently used in clinical practice is still the TNM stage. Despite an increasing number of studies performed, no prognostic and/or predictive biomarkers have been …
The art of intelligent spending
Authors: Isabella Laws
Journal: BMJ (2013)

The NHS has been under some scrutiny lately over inconsistency in the procurement of medical products. For example where one NHS trust paid £1109 (€1317; $1756) for knee implants, another paid just £634 for an identical product.1 Analysts have blamed a “lack of transparency in the market.” It is natural, however, that the companies that make the supplies aim to make as large a profit as possible. So, why hasn’t the NHS put policies in place to ensure more critical spending?

I believe that it is the attitude …
A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip
Authors: Sasan Jalili-Firoozinezhad, Francesca S. Gazzaniga, Elizabeth L. Calamari, Diogo M. Camacho, Cicely W. Fadel, Amir Bein, Ben Swenor, Bret Nestor, Michael J. Cronce, Alessio Tovaglieri, Oren Levy, Katherine E. Gregory, David T. Breault, Joaquim M. S. Cabral, Dennis L. Kasper, Richard Novak, Donald E. Ingber
Journal: Nature Biomedical Engineering (2019)