tbuckley/cabot-search huggingface dataset:
Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells
Authors: Juli Liu, Sheng Liu, Hongyu Gao, Lei Han, Xiaona Chu, Yi Sheng, Weinian Shou, Yue Wang, Yunlong Liu, Jun Wan, Lei Yang
Journal: Genome biology (2020)

Abstract Background Early human heart and brain development simultaneously occur during embryogenesis. Notably, in human newborns, congenital heart defects strongly associate with neurodevelopmental abnormalities, suggesting a common gene or complex underlying both cardiogenesis and neurogenesis. However, due to lack of in vivo studies, the molecular mechanisms that govern both early human heart and brain development remain elusive. Results Here, we report ARID1A, a DNA-binding subunit of the SWI/SNF epigenetic complex, controls both neurogenesis and cardiogenesis from human embryonic stem cells (hESCs) through distinct mechanisms. Knockout-of-ARID1A (ARID1A −/− ) leads to spontaneous differentiation of neural cells together with globally enhanced expression of neurogenic genes in undifferentiated hESCs. Additionally, when compared with WT hESCs, cardiac differentiation from ARID1A −/− hESCs is prominently suppressed, whereas neural differentiation is significantly promoted. Whole genome-wide scRNA-seq, ATAC-seq, and ChIP-seq analyses reveal that ARID1A is required to open chromatin accessibility on promoters of essential cardiogenic genes, and temporally associated with key cardiogenic transcriptional factors T and MEF2C during early cardiac development. However, during early neural development, transcription of most essential neurogenic genes is dependent on ARID1A, which can interact with a known neural restrictive silencer factor REST/NRSF. Conclusions We uncover the opposite roles by ARID1A to govern both early cardiac and neural development from pluripotent stem cells. Global chromatin accessibility on cardiogenic genes is dependent on ARID1A, whereas transcriptional activity of neurogenic genes is under control by ARID1A, possibly through ARID1A-REST/NRSF interaction.
Covid-19: Government is criticised for “scandalous” £10bn spent on test and trace programme
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The UK government has spent £10bn (€11.2bn; $12.7bn) on its much derided covid-19 test and trace programme and £15bn on personal protective equipment for frontline healthcare staff, the Treasury disclosed this week.

It revealed the figures in a document summarising the substantial financial commitments made by the government in response to covid-19,1 published on 8 July as part of the chancellor’s plan for jobs. The Treasury also disclosed that, since mid-March, the government had spent £1bn on additional ventilators for the NHS and £5.5bn on other health spending, such as paying for extra capacity in private sector facilities.

Experts said that they were astonished at the size …
Abstract 11375: Chronic β3-Adrenergic Receptor Blockade Improves Cardiovascular Functional and Structural Responses in Aging Murine Model
Authors: Che Ping Cheng, Zhe Chen, Yixi Liu, Michael F Callahan, Satoshi Masutani, Peng Zhou, Zhi Zhang, Dalane Kitzman, David Zhao, Heng-Jie Cheng
Journal: Circulation (2018)

Background: Aging has a remarkable effect on the heart and arterial system. Although cardiovascular functional responses to aging have not been fully investigated, recent evidence suggests that car...
P-266 LDH levels as predictors of efficacy in second-line treatment for metastatic gastric cancer: The LINE study
Authors: A. Michelotti, E. Ongaro, L. Gerratana, M. De Scordilli, P. Di Nardo, L. Foltran, M. Guardascione, D. Basile, F. Cortiula, G. Miolo, A. Parnofiello, E. Bertoli, C. Lisanti, S. Buriolla, A. Buonadonna, F. Puglisi
Journal: Annals of Oncology (2020)
P-138 A comparison of the transcriptomic profiles of matched tissue from primary colorectal cancer and corresponding secondary lung metastases
Authors: S. Khakoo, S. Moorcraft, A. Pacis, M. Munter, M. Lathrop, F. Lefebvre, Y. Riazalhosseini, R. Shaikh, T. Jones, R. Begum, A. Wotherspoon, C. Saffery, E. Kalaitzaki, H. Anbunathan, S. Rao, D. Watkins, N. Starling, D. Cunningham, I. Chau, A. Bowcock
Journal: Annals of Oncology (2020)
A Web-Based Tool to Automate Portions of Pretest Genetic Counseling for Inherited Cancer
Authors: Deborah Cragun, Anne Weidner, Ann Tezak, Brenda Zuniga, Georgia L. Wiesner, Tuya Pal
Journal: Journal of the National Comprehensive Cancer Network (2020)

Background: Increasing demand for genetic testing for inherited cancer risk coupled with a shortage of providers trained in genetics highlight the potential for automated tools embedded in the clinic process to meet this demand. We developed and tested a scalable, easy-to-use, 12-minute web-based educational tool that included standard pretest genetic counseling elements related to panel-based testing for multiple genes associated with cancer risk. Methods: The tool was viewed by new patients at the Vanderbilt Hereditary Cancer Clinic before meeting with a board-certified genetics professional. Pre- and post-tool surveys measured knowledge, feeling informed/empowered to decide about testing, attitudinal values about genetic testing, and health literacy. Of the initial 100 participants, 50 were randomized to only have knowledge measured on the post-tool survey to assess for a priming effect. Results: Of 360 patients approached, 305 consented and completed both the pre- and post-tool surveys, with a mean age of 47 years, including 80% female patients and 48% patients with cancer. Survey results showed an increase in knowledge and feeling informed/empowered after viewing the tool ( P &lt;.001), but no significant change in attitude ( P =.64). Post-tool survey data indicated no difference in median knowledge between low and high health literacy groups ( P =.30). No priming effect was present among the initial 100 participants ( P =.675). Conclusions: Viewing the educational tool resulted in significant gains in knowledge across health literacy levels, and most individuals felt informed and empowered to decide about genetic testing. These findings indicate that the use of an automated pretest genetic counseling tool may help streamline the delivery of genetic services.
A novel mechanism of tumor suppressor gene re-expression: Nonsense mutation read through
Authors: Westley J. Friesen, Ellen Welch, Yuki Tomizawa, Jin Zhuo, Thomas Davis, Neil Almstead, Rich Wilde, James Takasugi, Young-Choon Moon, Marla Weetall, Holly McAdams, Joseph Colacino, John Babiak, Stuart Peltz
Journal: Cancer Research (2004)

4002  The occurrence of a premature stop codon arrests translation at the site of the nonsense mutation. Nonsense mutations can appear in critical genes in a large number of the most common forms of cancers and are known to either cause the disease (e.g., familial adenomatous polyposis) or to occur during the progression of the disease (e.g., p53 gene). Nonsense mutations can affect other tumor suppressor and regulatory genes including BRCA1, BRCA2, PTEN, NF1, NF2, MLH1, MSH2, VHL, WT1, TSC1, TSC2, and ATM. We are developing new small molecular weight compounds to treat genetic diseases and cancers resulting from nonsense mutations. A subset of aminoglycoside antibiotics, such as gentamicin, has been shown to promote read-through of the nonsense mutations in genes encoding for proteins, the absence of which results in Cystic Fibrosis (CF), Hurlers Syndrome or Duchenne Muscular Dystrophy (DMD). These studies provide proof of concept that small molecules can promote nonsense suppression to produce functional, full-length proteins which can then reverse the disease phenotype. We have identified chemical scaffolds that are more potent and efficacious in promoting read-through of premature termination codons than aminoglycosides. Such compounds are able to suppress multiple nonsense mutations in the p53 gene, thus restoring full-length, transcriptionally active p53. p53 induced by nonsense suppression appears to drive cancer cells into apoptosis as well as sensitize them to DNA damaging oncolytics. As an example, in a xenograft model, a compound from one of our scaffolds significantly and dose-dependently impeded growth of human ovarian cancer tumors containing a nonsense-mutation in the p53 gene. A 30 mg/kg dose administered once per week completely inhibited growth of the implanted tumors for >80days. We are currently conducting dose response studies to determine a typical minimal effective dose in the xenograft model. We are also investigating the effects of these compounds on additional cell lines harboring nonsense mutations in other tumor suppressor genes such as APC, NF1, and NF2.
Eye Disease in Children
Authors: K. Wybar
Journal: BMJ (1965)

<h3>Rationale:</h3> Chronic obstructive pulmonary disease (COPD) is associated with a 2–3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association are not clear and appear to be independent of smoking history. <h3>Objective:</h3> We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls. <h3>Methods:</h3> In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry. <h3>Results:</h3> Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p&lt;0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM). <h3>Conclusions:</h3> Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.
Impact of Plaque Composition on Slow flow/No Reflow Phenomena in Patients with Acute Reperfused Myocardial Infarction-Virtual Histology IVUS Analysis-
Authors: Ohshima Kousei, Ikeda Shuntaro, Yamane Kenichi, Ishibashi Ken, Aono Jun, Ohshima Kiyotaka, Watanabe Koki, Hamada Mareomi
Journal: Circulation (2008)
Abstract 160: Interval From Collapse to Reaching Target Temperature Had No Impact for the Neurological Outcome in Post Cardiac Arrest Victims, Retrospective Cohort Study of J-Pulse-Hypo Registry
Authors: Tadashi Kaneko, Shunji Kasaoka, Yoshio Tahara, Ken Nagao, Naohiro Yonemoto, Hiroyuki Yokoyama, Hiroshi Nonogi
Journal: Circulation (2019)

Introduction: Currently, the ICEREA study, randomized controlled study of comparison between intravascular and surface cooling for post cardiac arrest syndrome (PCAS), did not show significant advantage of intravascular cooling to improve neurological outcome (Odds ratio 1.41, P = 0.07) (Circulation 2015;132:182-93). However, the study showed that intravascular cooling group showed significant shorter interval to reach 34 0 C (5.5 hr v.s. 8.5 hr, P&lt;0.001). These results indicated the possibility of shorter cooling interval could improve neurological outcome of PCAS cases. Hypothesis: Shorter cooling interval could improve neurological outcome in PCAS cases. Methods: Inclusion criteria was witnessed, 34 0 C of target temperature (TT), and within 12 hr interval from collapse to reach TT. Three hundred were selected as eligible cases for this study from participants with J-PULSE-Hypo study database. The 300 cases were divided into 4 groups (A: interval from collapse to reach TT within 180 min, B: 181-360 min, C: 363-540 min, D: 541-720 min), and compared the favorable neurological outcome (CPC 1-2) by univariate and multivariate analysis. Results: Groups were A: 88 cases, B: 114 cases, C: 74 cases, and D: 24 cases. 477 participants were analyzed. The comparison of each groups for favorable neurological outcome, were not significant difference (A: 46%, B: 62%, C: 61%, and D: 63%, univariate: P = 0.109, multivariate: P = 0.812). Conclusions: Shorter cooling interval could not show advantage to improve neurological outcome in PCAS cases.
Endoscopic retrograde transabdominal ultrasound-guided bile duct drainage during COVID-19 pandemic
Authors: Klaus Mönkemüller, Peter Rauh, Steffen Rickes
Journal: Endoscopy (2020)

Suppurative cholangitis is a life-threatening condition requiring urgent decompression of the biliary tree [1]. Currently, endoscopic retrograde cholangiopancreatography (ERCP) is the standard method to drain the bile ducts. Herein, we present a novel method of radiation-free, direct endoscopic drainage of the common bile duct using transabdominal ultrasound.
Inhibiting Mcl-1 with an antisense oligonucleotide induces cell death in acute myeloid leukemia cells
Authors: Bing Z. Carter, Duncan Mak, Wendy Schober, Erich Koller, Nicholas M. Dean, Eric G. Marcusson, Brett P. Monia, Michael Andreeff
Journal: Cancer Research (2006)

4075  The apoptotic cascade is regulated by multiple families of both pro- and anti-apoptotic proteins. Mcl-1 is a member of the antiapoptotic Bcl-2 family of proteins which is highly expressed in various types of solid and hematological cancers, and has recently been shown to be an important survival factor for hematopoietic stem cells. We have identified and characterized a potent antisense oligonucleotide (ASO) inhibitor of Mcl-1. Transfection of this ASO results in the decreased expression of Mcl-1 protein and the induction of apoptosis in multiple cell types, including HL-60. In this study, we investigated the regulation of Mcl-1 expression and its potential as a therapeutic target in AML cells. We found that Mcl-1 protein level is significantly decreased by MEK inhibition in HL-60 and OCI-AML2 cells suggesting that Mcl-1 expression is regulated through MAPK signaling. Downregulation of Mcl-1 by its antisense oligonucleotide induced cell death accompanied by decreases in mitochondrial membrane potential (MMP), caspase activation and annexin-V positivity, indicating that Mcl-1 is essential for survival in HL-60 cells. By itself, the MEK inhibitor primarily induced G0/G1 cell cycle block. When combined with Mcl-1-ASO, MEK inhibition further decreased Mcl-1 protein level and cell death induced by Mcl-1-ASO was significantly enhanced. These results show that Mcl-1 has the potential to be a good drug target for AML as well as other cancer types. In vivo studies in mouse models of cancer are being performed with this ASO to better understand this potential.
Association Between Oral Corticosteroid Bursts and Severe Adverse Events
Authors: Tsung-Chieh Yao, Ya-Wen Huang, Sheng-Mao Chang, Shun-Yu Tsai, Ann Chen Wu, Hui-Ju Tsai
Journal: Annals of Internal Medicine (2020)

Long-term use of oral corticosteroids has known adverse effects, but the risk from brief oral steroid bursts (≤14 days) is largely unknown.To examine the associations between steroid bursts and severe adverse events, specifically gastrointestinal (GI) bleeding, sepsis, and heart failure.Self-controlled case series.Entire National Health Insurance Research Database of medical claims records in Taiwan.Adults aged 20 to 64 years with continuous enrollment in the National Health Insurance program from 1 January 2013 to 31 December 2015.Incidence rates of severe adverse events in steroid burst users and non-steroid users, as well as incidence rate ratios (IRRs) for severe adverse events within 5 to 30 and 31 to 90 days after initiation of steroid therapy.Of 15 859 129 adult participants, 2 623 327 who received a single steroid burst were included. The most common indications were skin disorders and respiratory tract infections. The incidence rates per 1000 person-years in steroid bursts were 27.1 (95% CI, 26.7 to 27.5) for GI bleeding, 1.5 (CI, 1.4 to 1.6) for sepsis, and 1.3 (CI, 1.2 to 1.4) for heart failure. Rates of GI bleeding (IRR, 1.80 [CI, 1.75 to 1.84]), sepsis (IRR, 1.99 [CI, 1.70 to 2.32]), and heart failure (IRR, 2.37 [CI, 2.13 to 2.63]) significantly increased within 5 to 30 days after steroid therapy initiation and attenuated during the subsequent 31 to 90 days.Persons younger than 20 years or older than 64 years were not included.Oral corticosteroid bursts are frequently prescribed in the general adult population in Taiwan. The highest rates of GI bleeding, sepsis, and heart failure occurred within the first month after initiation of steroid therapy.National Health Research Institutes, Ministry of Science and Technology of Taiwan, Chang Gung Medical Foundation, and Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Controllable drug delivery by light-activated nanoimpellers for cancer therapy
Authors: Jie lu, Eunshil Choi, Jeffrey Zink, Fuyu Tamanoi
Journal: Cancer Research (2008)

5601  Controllable delivery and on-demand release of chemotherapeutic drugs by nanoparticles provide a promising approach for cancer therapy, because the conventional drug delivery brings severe toxic side-effect to surrounding normal tissues as well. In our previous study, we have successfully synthesized and used the mesoporous silica nanoparticles to overcome the problem of hydrophobicity of anticancer drugs which is one of major obstacles for chemotherapy. Here we report synthesis construction of mesoporous silica nanoparticles that are equipped with nanoimpeller system for controllable drug delivery. This was accomplished by tethering azobenzene derivatives to the interiors of mesopores. When excited by light with a specific wavelength, a constant cis-trans isomerization reaction of N=N bonds occurs, which causes continual dynamic wagging of the untethered terminus and therefore impels out the guest molecules through the pore. The release of anticancer drugs inside of the mesopores to cancer cells can be actuated by light-irradiation at a specific wavelength on a time and power-dependent manner. The anticancer drug camptothecin (CPT) was loaded in and released only under light excitation, and induced apoptosis of cancer cells was observed. This cancer-targeting controllable delivery of chemotherapeutic drugs is the first step towards a novel platform for a new generation of nanotherapeutics with both spatial and temporal external control to attack malignant tumors while sparing the normal tissues. Our nanoparticles provide a new cancer-targeting vehicle that achieves controllable approaches for cancer therapy.
P-272 Sarcopenia in metastatic colorectal cancer patients during first-line chemotherapy
Authors: C. Maddalena, A. Ponsiglione, L. Camera, L. Santarpia, F. Pasanisi, D. Bruzzese, C. Panico, G. Fiore, S. Camardella, T. Caramia, A. Farinaro, S. De Placido, C. Carlomagno
Journal: Annals of Oncology (2020)
Obstetric issues in preterm birth
Authors: Deirdre J Murphy, Peter W Fowlie, William McGuire
Journal: BMJ (2004)

Predicting and preventing preterm labour and choosing the safest method of delivery are important challenges in reducing the number of preterm births and improving outcomes for mother and baby. This article covers the predictive tests, methods of prevention, maternal and fetal indications for preterm birth, and various approaches to delivery.

Most preterm deliveries follow spontaneous onset of preterm labour or preterm prelabour rupture of the amniotic membranes (pPROM). Much work has been done (with limited success) to find diagnostic tests that predict accurately if a woman who is at risk of preterm delivery will go on to deliver preterm. For these women, who may have a history of preterm birth or clinical signs of preterm labour, such tests would allow early and targeted use of antenatal interventions. These interventions, especially antenatal corticosteroids, improve neonatal and long term outcomes for preterm infants.

View this table:

Antenatal corticosteroids



The most common clinical tests used to determine the risk of preterm labour are transvaginal sonography (to measure the length of the endocervix) and the cervicovaginal fetal fibronectin test. These tests have high negative predictive values—that is, if results are negative then the women probably will not progress to preterm delivery. Although there does not seem to be a role for routine use of the fibronectin test or transvaginal sonography to screen women for preterm birth, women thought to be at high risk can be reassured by negative results. This may help women to avoid unnecessary interventions such as antenatal transfer to a distant perinatal unit.

View this table:

Cervicovaginal fetal fibronectin test



Current medical approaches to preventing preterm labour include the use of tocolytic drugs, antibiotic treatment, and cervical cerclage.

### Tocolytic drugs

Tocolytic drugs can delay the progress of preterm labour in the short term but maternal side effects include hypotension, …
A transcriptomic continuum of differentiation arrest identifies myeloid interface acute leukemias with poor prognosis
Authors: Jonathan Bond, Aleksandra Krzywon, Ludovic Lhermitte, Christophe Roumier, Anne Roggy, Mohamed Belhocine, Alexander Abdulkader Kheirallah, Patrick Villarese, Guillaume Hypolite, Francine Garnache-Ottou, Sylvie Castaigne, Nicolas Boissel, Vahid Asnafi, Claude Preudhomme, Hervé Dombret, Elisa Laurenti, Elizabeth Macintyre
Journal: Leukemia (2020)

Abstract Classification of acute lymphoblastic and myeloid leukemias (ALL and AML) remains heavily based on phenotypic resemblance to normal hematopoietic precursors. This framework can provide diagnostic challenges for immunophenotypically heterogeneous immature leukemias, and ignores recent advances in understanding of developmental multipotency of diverse normal hematopoietic progenitor populations that are identified by transcriptional signatures. We performed transcriptional analyses of a large series of acute myeloid and lymphoid leukemias and detected significant overlap in gene expression between cases in different diagnostic categories. Bioinformatic classification of leukemias along a continuum of hematopoietic differentiation identified leukemias at the myeloid/T-lymphoid interface, which shared gene expression programs with a series of multi or oligopotent hematopoietic progenitor populations, including the most immature CD34+CD1a−CD7− subset of early thymic precursors. Within these interface acute leukemias (IALs), transcriptional resemblance to early lymphoid progenitor populations and biphenotypic leukemias was more evident in cases originally diagnosed as AML, rather than T-ALL. Further prognostic analyses revealed that expression of IAL transcriptional programs significantly correlated with poor outcome in independent AML patient cohorts. Our results suggest that traditional binary approaches to acute leukemia categorization are reductive, and that identification of IALs could allow better treatment allocation and evaluation of therapeutic options.