tbuckley/cabot-search huggingface dataset:
High-resolution Repli-Seq defines the temporal choreography of initiation, elongation and termination of replication in mammalian cells
Authors: Peiyao A. Zhao, Takayo Sasaki, David M. Gilbert
Journal: Genome biology (2020)

DNA replication in mammalian cells occurs in a defined temporal order during S phase, known as the replication timing (RT) programme. Replication timing is developmentally regulated and correlated with chromatin conformation and local transcriptional potential. Here, we present RT profiles of unprecedented temporal resolution in two human embryonic stem cell lines, human colon carcinoma line HCT116, and mouse embryonic stem cells and their neural progenitor derivatives.
Transcatheter Edge-to-Edge Tricuspid Repair for Severe Tricuspid Regurgitation Reduces Hospitalizations for Heart Failure
Authors: Mathias Orban, Karl-Philipp Rommel, Edwin C. Ho, Matthias Unterhuber, Alberto Pozzoli, Kim A. Connelly, Simon Deseive, Christian Besler, Geraldine Ong, Daniel Braun, Jeremy Edwards, Mizuki Miura, Gökhan Gülmez, Lukas Stolz, Mara Gavazzoni, Michel Zuber, Martin Orban, Michael Nabauer, Francesco Maisano, Holger Thiele, Steffen Massberg, Maurizio Taramasso, Neil P. Fam, Philipp Lurz, Jörg Hausleiter
Journal: JACC Heart Failure (2020)
Abstract P4-12-16: A seven year single institution experience with IntrabeamTM intraoperative radiation therapy:recurrence rates and predictors of recurrence
Authors: Christina Munford, William E Burak, Krista Miller, Jennifer Davis, Nicole Neal, Caleb Price, Matthew Bertke, Michael Hasselle, Aaron Pederson
Journal: Cancer Research (2020)

Abstract Objectives: Patients undergoing single fraction intraoperative radiation therapy (IORT) for early stage breast cancer were analyzed to determine rates of local recurrence and to identify predictors of local recurrence. Materials and Methods: Patients who underwent intraoperative radiotherapy (IORT 20 Gray at 50kV using the INTRABEAMTM IORT system) have been analyzed over a 7 year period. The procedures were performed at a single institution by a single surgical and radiation oncology group. Post-operative whole breast radiotherapy (WBRT) was generally recommended in high risk patients with positive sentinel lymph nodes (SLN), lymphovascular invasion (LVI), extensive intraductal component (EIC), or positive margins requiring re-excision. Local recurrence was defined as any same breast recurrence during the follow-up period. Results: A total of 438 patients were included in the analysis. Median follow-up was 35 months. Median age was 68 years, mean tumor size on preoperative ultrasound was 1.2 cm. Patient characteristics are listed below: Patient/Tumor CharacteristicnGrade 1-232474.5%Grade 311125.5%Presence of LVI429.9%Presence of EIC4811.6%ER Negative429.7%PR Negative7918.4%DCIS only6514.4%Invasive Lobular only102.2%Positive SLN276.9%Re-excision performed6013.7% A total of 16 patients (3.7%) had a local or simultaneous local/regional recurrence. Median time to recurrence was 24.5 months. When analyzing associations between predictor variables and local recurrence using logistic regression, it was found that high tumor grade, EIC, LVI, DCIS or DCIS component, and need for re-excision were significant (p&amp;lt;0.05) predictors of local recurrence. Furthermore, there was a strong association with local recurrence and time to local recurrence when adjuvant endocrine therapy was recommended but the patient was either non-compliant or discontinued use due to side-effects (odds ratio 0.064, p&amp;lt;0.0005). Conclusions: INTRABEAMTM IORT can be used in select breast cancer patients with low local recurrence rates. Unfavorable tumor features and non-compliance with adjuvant endocrine therapy result in the highest risk of local recurrence. Better patient selection and pre-treatment education should minimize this risk. Citation Format: Christina Munford, William E Burak Jr, Krista Miller, Jennifer Davis, Nicole Neal, Caleb Price, Matthew Bertke, Michael Hasselle, Aaron Pederson. A seven year single institution experience with IntrabeamTM intraoperative radiation therapy:recurrence rates and predictors of recurrence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-16.
Risk of hospitalization and death due to infection in people with psoriasis: a population‐based cohort study using the Clinical Practice Research Datalink*
Authors: Z.Z.N. Yiu, R. Parisi, M. Lunt, R.B. Warren, C.E.M. Griffiths, S.M. Langan, D.M. Ashcroft
Journal: British Journal of Dermatology (2020)

Psoriasis is associated with risk factors for serious infections, but the independent relationship between psoriasis and serious infection is as yet unclear.To determine whether people with psoriasis have a higher risk of hospitalization due to any infection, respiratory infections, soft-tissue and skin infections, or a higher risk of death due to infection.We conducted a cohort study of people (≥ 18 years) with psoriasis using the UK Clinical Practice Research Datalink (CPRD GOLD) linked to Hospital Episode Statistics (HES) and Office for National Statistics (ONS) mortality records between 1 April 2003 and 31 December 2016, and matched with up to six comparators on age, sex and general practice. Hospitalization was ascertained from HES records; death was ascertained from ONS mortality records. Stratified Cox proportional hazard models were estimated, with stepwise adjustment in different models for potential confounders or mediators between psoriasis and serious infection.There were 69 315 people with psoriasis and 338 620 comparators who were followed up for a median (interquartile range) of 4·9 (5·9) and 5·1 (6·3) years, respectively. People with psoriasis had a higher incidence rate of serious infection [20·5 per 1000 person-years, 95% confidence interval (CI) 20·0-21·0, n = 7631] compared with those without psoriasis (16·1 per 1000 person-years, 95% CI 15·9-16·3, n = 30 761). The fully adjusted hazard ratio for the association between psoriasis and serious infection was 1·36 (95% CI 1·31-1·40), with similar results across the other outcomes.Psoriasis is associated with a small increase in the risk of serious infection. Further research is needed to understand how psoriasis predisposes to a higher risk of infection.
Hemostatic agents for prehospital hemorrhage control: a narrative review
Authors: Henry T. Peng
Journal: Military Medical Research (2020)

Abstract Hemorrhage is the leading cause of preventable death in combat trauma and the secondary cause of death in civilian trauma. A significant number of deaths due to hemorrhage occur before and in the first hour after hospital arrival. A literature search was performed through PubMed, Scopus, and Institute of Scientific Information databases for English language articles using terms relating to hemostatic agents, prehospital, battlefield or combat dressings, and prehospital hemostatic resuscitation, followed by cross-reference searching. Abstracts were screened to determine relevance and whether appropriate further review of the original articles was warranted. Based on these findings, this paper provides a review of a variety of hemostatic agents ranging from clinically approved products for human use to newly developed concepts with great potential for use in prehospital settings. These hemostatic agents can be administered either systemically or locally to stop bleeding through different mechanisms of action. Comparisons of current hemostatic products and further directions for prehospital hemorrhage control are also discussed.
EpCAM-high liver cancer stem cells resist natural killer cell–mediated cytotoxicity by upregulating CEACAM1
Authors: Dong Jun Park, Pil Soo Sung, Jung-Hee Kim, Gil Won Lee, Jeong Won Jang, Eun Sun Jung, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Natural killer (NK) cells can recognize and kill cancer cells directly, but their activity can be attenuated by various inhibitory molecules expressed on the surface. The expression of epithelial cell adhesion molecule (EpCAM), a potential marker for cancer stem cells (CSCs), is known to be strongly associated with poor clinical outcomes in hepatocellular carcinoma (HCC). NK cells targeting CSCs may be a promising strategy for anti-tumor therapy, but little is known about how they respond to EpCAM high CSCs in HCC. Methods EpCAM expression was assessed by immunohistochemistry in 280 human HCC tissues obtained from curative surgery. To investigate the functional activity of NK cells against liver CSCs, EpCAM high and EpCAM low Huh-7 cells were sorted by flow cytometry. The functional role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which is related to NK cells, was determined by in vitro co-culture of NK cells and hepatoma cells using Hepa1–6 mouse hepatoma cells, as well as in vivo experiments using C57/BL6 mice. Results The frequency of recurrence after curative surgery was higher in patients with positive EpCAM expression than in those with negative EpCAM expression. In subsequent analysis based on the anatomical location of EpCAM expression, patients with peritumoral EpCAM expression showed worse prognosis than those with pantumoral EpCAM expression. Co-culture experiments demonstrated that CEACAM1 was upregulated on the surface of EpCAM high HCC cells, resulting in resistance to NK cell-mediated cytotoxicity. Inversely, silencing CEACAM1 restored cytotoxicity of NK cells against EpCAM high Huh-7 cells. Moreover, neutralizing CEACAM1 on the NK cell surface enhanced killing of Huh-7 cells, suggesting that homophilic interaction of CEACAM1 is responsible for attenuated NK cell–mediated killing of CEACAM1 high cells. In mouse experiments with Hepa1–6 cells, EpCAM high Hepa1–6 cells formed larger tumors and showed higher CEACAM1 expression after NK cell depletion. NK-mediated cytotoxicity was enhanced after blocking CEACAM1 expression using the anti-CEACAM1 antibody, thereby facilitating tumor regression. Moreover, CEACAM1 expression positively correlated with EpCAM expression in human HCC tissues, and serum CEACAM1 levels were also significantly higher in patients with EpCAM + HCC. Conclusion Our data demonstrated that EpCAM high liver CSCs resist NK cell–mediated cytotoxicity by upregulation of CEACAM1 expression.
Imaging and quantifying drug delivery in skin – Part 2: Fluorescence andvibrational spectroscopic imaging methods
Authors: Ana-Maria Pena, Xueqin Chen, Isaac J. Pence, Thomas Bornschlögl, Sinyoung Jeong, Sébastien Grégoire, Gustavo S. Luengo, Philippe Hallegot, Peyman Obeidy, Amin Feizpour, Kin F. Chan, Conor L. Evans
Journal: Advanced Drug Delivery Reviews (2020)
Inhibition of post-trabeculectomy fibrosis via topically instilled antisense oligonucleotide complexes co-loaded with fluorouracil
Authors: Kuan Jiang, Junyi Chen, Lingyu Tai, Chang Liu, Xishan Chen, Gang Wei, Weiyue Lu, Weisan Pan
Journal: Acta Pharmaceutica Sinica B (2020)

Trabeculectomy is the mainstay of surgical glaucoma treatment, while the success rate was unsatisfying due to postoperative scarring of the filtering blebs. Clinical countermeasures for scar prevention are intraoperative intervention or repeated subconjunctival injections. Herein, we designed a co-delivery system capable of transporting fluorouracil and anti-TGF-β2 oligonucleotide to synergistically inhibit fibroblast proliferation via topical instillation. This co-delivery system was built based on a cationic dendrimer core (PAMAM), which encapsulated fluorouracil within hydrophobic cavity and condensed oligonucleotide with surface amino groups, and was further modified with hyaluronic acid and cell-penetrating peptide penetratin. The co-delivery system was self-assembled into nanoscale complexes with increased cellular uptake and enabled efficient inhibition on proliferation of fibroblast cells. In vivo studies on rabbit trabeculectomy models further confirmed the anti-fibrosis efficiency of the complexes, which prolonged survival time of filtering blebs and maintained their height and extent during wound healing process, exhibiting an equivalent effect on scar prevention compared to intraoperative infiltration with fluorouracil. Qualitative observation by immunohistochemistry staining and quantitative analysis by Western blotting both suggested that TGF-β2 expression was inhibited by the co-delivery complexes. Our study provided a potential approach promising to guarantee success rate of trabeculectomy and prolong survival time of filtering blebs.
Nurses’ professional judgment: appropriate care for people according to their stage of life
Authors: David Reilly
Journal: BMJ (2020)

The loss of a valuable nurse because of an irrational decision by the Nursing and Midwifery Council (NMC) is a shameful event. I agree with Oliver that this will damage nurses’ confidence in the NMC and increase the number of inappropriate cardiopulmonary resuscitation (CPR) attempts.1 We have seen the same punitive attitude from the General Medical Council, with a similar inability to see …
Human neonatal hepatocytes have higher viability, higher function and lower innate immunogenicity than adult hepatocytes, making them an ideal cell for transplantation
Authors: Charlotte A. Lee, Sharon Lehec, Anil Dhawan, Shirin E. Khorsandi, Ragai R. Mitry, Valeria Iansante, Simon Walker, Paradzai Chitongo, Raquel Fernandez-Dacosta, Celine Filippi, Nigel Heaton, Sanjay Bansal, Emer Fitzpatrick
Journal: Hepatology (2016)
Abstract 17325: Initial False Positive Episodes and Outcomes of Programming Changes With a Novel Implantable Loop Recorder
Authors: Ethan Hacker, Tawseef Dar, Bharath Yarlagadda, Valay Parikh, Brandon Wise, Y. Madhu Reddy, Rhea Pimentel, Loren Berenbom, Martin Emert, Raghu Dendi, Seth H Sheldon
Journal: Circulation (2018)

Introduction: Management of voluminous data from implantable cardiac devices is resource intensive. False positive events can be especially problematic with implantable loop recorders (ILRs). We sought to describe our early experience with a novel ILR. Hypothesis: Sensitivity adjustment to &lt;=0.10 mV may reduce false positive ILR detection of bradycardia/pauses. Methods: A single center retrospective study was performed in patients with the Abbott Confirm RX ILR. Tachycardia, atrial fibrillation (AF), bradycardia, and pause events were reviewed to determine whether they were true or false positives. Results: The study included 13 patients (age 67 ±15.8 years, 62% men). The reasons for implant included: AF (n=7, 54%), syncope(n=3, 23%), palpitations (n=2, 15%), and stroke (n=1, 8%). The median follow-up duration was 3.1 months (IQR 1.3-4.4 months). There was no change in serial R waves during mean follow-up of 0.58 months (pre 0.62±0.22 mV, post 0.63±0.22 mV, p=0.52). Tachycardia detection occurred in 6 patients (46%), with only 1 patient having a false positive episode. AF detection occurred in 8 patients (62%), with only 2 patients having true AF episodes. Pause/bradycardia episodes were detected in 5 patients (39%), with false positive episodes in 4 patients. There was no difference in R waves at implant among patients with and without false positive bradycardia/pauses episodes (0.66 ±0.27 vs. 0.44 ± 0.28 mV, p=0.21). The max sensitivity was higher among patients with than without false positive bradycardia/pause episodes (0.14 ±0.01, 0.07 ±0.02 mV, p&lt;0.0001). No patients programmed to sensitivity &lt;=0.10 mV had false positive bradycardia/pause episodes. The sensitivity was adjusted to &lt;=0.10 mV in 3 of 4 patients with false positive bradycardia/pause episodes which eliminated future false positive episodes and did not result in false positive tachycardia/AF episodes. The overall mean monthly rate of false positive bradycardia/pause events was reduced from 387 events/month to zero in these patients. Conclusion: Programming the novel ILR to a sensitivity of &lt;=0.10 mV resulted in a marked reduction in false positive bradycardia/pause episodes without an increase in false positive tachycardia/AF episodes.
Studies on Starling's Law of the Heart
Authors: JOHN ROSS, EUGENE BRAUNWALD
Journal: Circulation (1964)

The acute circulatory responses to impeding venous return to the heart by the inflation of a balloon in the inferior vena cava were determined in 14 patients undergoing left heart catheterization. In the five patients without clinical or hemodynamic evidence of impaired left ventricular function, left ventricular end-diastolic pressure fell, and the decrease was accompanied by reductions in the cardiac index, left ventricular stroke volume, and left ventricular stroke work. In nine patients with impaired left ventricular function, directionally similar responses were noted, although the left ventricular function curves relating left ventricular end-diastolic pressure to left ventricular stroke work were generally flatter and lower than those in the patients without left ventricular disease. In none of the patients did a significant increase in cardiac index, stroke volume, or left ventricular stroke work occur during inflation of the balloon. It is concluded that the Starling relationship appears to operate in a directionally similar manner both in the normal and the depressed human left ventricle, and that the left ventricles of patients with impaired function are not on a descending limb of the curve. However, a descending limb of the left ventricular Starling curve may become apparent when an additional work load is imposed on the diseased ventricle.
A Novel Cardioprotective Therapy That Also Improves Glycemia
Authors: Bruce Neal, Clare Arnott
Journal: JAMA (2020)

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Abstract P5-02-14: The MAPK pathway is variably active across breast cancer subtypes, and increased activity may be associated with hormonal therapy resistance
Authors: Anja van de Stolpe, Laurent Holtzer, Yvonne Wesseling-Rozendaal, Wim Verhaegh
Journal: Cancer Research (2020)

Abstract Background: Based on preclinical research, the MAPK growth factor pathway is thought to be an oncogenic pathway driving breast cancer, potentially in association with the ER pathway. In patients it is unclear how functional activity of the MAPK pathway activity relates to activity of the ER pathway to drive cancer growth. We have reported before on the development of assays, e.g. for the ER pathway, that enable quantitative measurement of activity of signal transduction pathways based on Bayesian computational model inference of pathway activity from measurements of mRNA levels of target genes of the ER transcription factor (Cancer Res., 2014, vol. 74, no. 11, pp. 2936-2945). We now present (1) development of the MAPK-AP1 pathway model, (2) MAPK-AP1 pathway activity and its relation to ER pathway activity in breast cancer; (3) emergence of MAPK pathway activity associated with hormonal therapy resistance. Methods: The MAPK-AP1 pathway model was developed and biologically validated on Affymetrix mRNA data from samples (different cell types) with a known MAPK pathway activity. MAPK-AP1 and ER pathway activity scores were measured on Affymetrix expression data of primary untreated breast cancer samples (GSE45827, n=141) and of fulvestrant sensitive and resistant MCF7 cell line clones (GSE74391). Results: In clinical breast cancer samples, average MAPK pathway activity was increased in all subtypes compared to normal breast tissue, with a large dynamic range indicating that in each subtype there are samples with high and with low pathway activity; ER pathway activity in Luminal A and B subtypes ranged from high to low, and was low in all other subtypes. MAPK-AP1 pathway activity did not correlate with ER pathway activity. Fulvestrant-sensitive MCF7 cells had high ER and low MAPK pathway activity scores, while resistant MCF7 clones exhibited increased MAPK pathway activity and complete loss of ER pathway activity, explaining therapy resistance. Discussion: The MAPK-AP1 pathway is frequently activated in all breast cancer subtypes, independent of ER pathway activity. We hypothesize that in case of resistance to hormonal therapy measurement of both pathway activities may be informative as to the underlying resistance mechanism, i.e. loss of ER pathway activity and/or gain of MAPK pathway activity. Future clinical studies are needed to confirm the role of these signaling pathways in hormonal resistance. Citation Format: Anja van de Stolpe, Laurent Holtzer, Yvonne Wesseling-Rozendaal, Wim Verhaegh. The MAPK pathway is variably active across breast cancer subtypes, and increased activity may be associated with hormonal therapy resistance [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-02-14.
Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes
Authors: Ali Muhammed Ali, Robert Martinez, Hussein Al-Jobori, John Adams, Curtis Triplitt, Ralph DeFronzo, Eugenio Cersosimo, Muhammad Abdul-Ghani
Journal: Diabetes Care (2020)

OBJECTIVE To examine the effect of combination therapy with canagliflozin plus liraglutide on HbA1c, endogenous glucose production (EGP), and body weight versus each therapy alone. RESEARCH DESIGN AND METHODS Forty-five patients with poorly controlled (HbA1c 7–11%) type 2 diabetes mellitus (T2DM) on metformin with or without sulfonylurea received a 9-h measurement of EGP with [3-3H]glucose infusion, after which they were randomized to receive 1) liraglutide 1.2 mg/day (LIRA), 2) canagliflozin 100 mg/day (CANA), or 3) liraglutide 1.2 mg plus canagliflozin 100 mg (CANA/LIRA) for 16 weeks. At 16 weeks, the EGP measurement was repeated. RESULTS The mean decrease from baseline to 16 weeks in HbA1c was −1.67 ± 0.29% (P = 0.0001), −0.89 ± 0.24% (P = 0.002), and −1.44 ± 0.39% (P = 0.004) in patients receiving CANA/LIRA, CANA, and LIRA, respectively. The decrease in body weight was −6.0 ± 0.8 kg (P &amp;lt; 0.0001), −3.5 ± 0.5 kg (P &amp;lt; 0.0001), and −1.9 ± 0.8 kg (P = 0.03), respectively. CANA monotherapy caused a 9% increase in basal rate of EGP (P &amp;lt; 0.05), which was accompanied by a 50% increase (P &amp;lt; 0.05) in plasma glucagon-to-insulin ratio. LIRA monotherapy reduced plasma glucagon concentration and inhibited EGP. In CANA/LIRA-treated patients, EGP increased by 15% (P &amp;lt; 0.05), even though the plasma insulin response was maintained at baseline and the CANA-induced rise in plasma glucagon concentration was blocked. CONCLUSIONS These results demonstrate that liraglutide failed to block the increase in EGP caused by canagliflozin despite blocking the rise in plasma glucagon and preventing the decrease in plasma insulin concentration caused by canagliflozin. The failure of liraglutide to prevent the increase in EGP caused by canagliflozin explains the lack of additive effect of these two agents on HbA1c.