tbuckley/cabot-search huggingface dataset:
Abstract P5-14-06: Towards breast cancer prevention through reduced breast density: Suppressive effects of tamoxifen on normal breast epithelial cells
Authors: AH Rosendahl, L Puig Blasco, S Borgquist
Journal: Cancer Research (2018)

Abstract Background: Breast density is positively associated with risk of breast cancer and the local microenvironment in the normal breast is known to significantly impact breast cancer initiation and further progression. The selective estrogen receptor modulator tamoxifen, with beneficial clinical effects on breast cancer recurrence, has also been shown to reduce mammographic density potentially explaining the primary preventive effects of tamoxifen. Still, important gaps persist regarding the cellular and molecular basis of how tamoxifen modifies breast density and subsequently breast cancer risk. Purpose: To investigate the impact by tamoxifen on normal human breast epithelial cells (MCF-10A) with the additional ambition to mimic variations in breast density on the cellular level. Experimental design: Effects of tamoxifen on MCF-10A cells at different cellular densities were evaluated in vitro. Flow cytometry and the sulforhodamine-B assay were used to assess cell cycle distribution and proliferation. Cell adhesion to extracellular matrix proteins was analyzed using hexosaminidase assay. Modulation of integrin receptor levels was determined by Western immunoblotting. Results: Tamoxifen exposure resulted in impaired cell cycle progression of human breast epithelial cells with a dose-dependent G2/M-phase arrest and reduced cell proliferation. Irrespective of tamoxifen treatment, the percent cellular adhesion to fibronectin and collagen type I by MCF-10A cells was significantly greater in high-density models compared to low-density models. Following tamoxifen treatment the adhesion was reduced in all density models. Consistent with the tamoxifen-induced lower adhesion, the integrin α1 and β3 levels were reduced in a dose-dependent way. Conclusion: These data support the hypothesis that tamoxifen affects the normal breast epithelium and its adhesion capacity, which may contribute to the clinically observed decrease in breast density and a potential reduced risk of breast tumor establishment. Citation Format: Rosendahl AH, Puig Blasco L, Borgquist S. Towards breast cancer prevention through reduced breast density: Suppressive effects of tamoxifen on normal breast epithelial cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-14-06.
Handbook of Liaison Psychiatry
Authors: Lucy Watkin
Journal: BMJ (2008)

I thought this book was very interesting, but then I would as I am a psychiatrist. However, before flitting off to read the job pages and fantasise about a post researching sunshine in Hawaii please consider these facts.

Shocking news to some, but most diseases are attached to a patient, who is usually a living, feeling human being. The mind and the body are connected—sometimes this hits home as a reality only when we get ill ourselves.

Apologies for the flippancy, and you can rattle out a rapid response if you wish. However, some doctors, (not you, I am sure) insist on referring to patients as “the disease”—for example, “the fractured neck of femur” instead of Mrs Jones.

Yet people react to diagnoses in different ways, adjust for the disease healthily or not, or over-embrace an illness focused lifestyle. Every specialty has …
Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs
Authors: Jianyu Li, Eckhard Weber, Sabine Guth‐Gundel, Michael Schuleit, Andreas Kuttler, Christine Halleux, Nathalie Accart, Arno Doelemeyer, Anne Basler, Bruno Tigani, Kuno Wuersch, Mara Fornaro, Michaela Kneissel, Alexander Stafford, Benjamin R. Freedman, David J. Mooney
Journal: Advanced Healthcare Materials (2018)

Abstract Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin‐like growth factor‐1 mimetic protein (8 mg mL −1 ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine.
Role of Acid Sphingomyelinase and Ceramide in Mechano-Acoustic Enhancement of Tumor Radiation Responses
Authors: Ahmed El Kaffas, Azza Al-Mahrouki, Amr Hashim, Niki Law, Anoja Giles, Gregory J Czarnota
Journal: JNCI Journal of the National Cancer Institute (2018)

High-dose radiotherapy (>8-10 Gy) causes rapid endothelial cell death via acid sphingomyelinase (ASMase)-induced ceramide production, resulting in biologically significant enhancement of tumor responses. To further augment or solicit similar effects at low radiation doses, we used genetic and chemical approaches to evaluate mechano-acoustic activation of the ASMase-ceramide pathway by ultrasound-stimulated microbubbles (USMB).Experiments were carried out in wild-type and acid sphingomyelinase (asmase) knockout mice implanted with fibrosarcoma xenografts. A cohort of wild-type mice received the ASMase-ceramide pathway inhibitor sphingosine-1-phosphate (S1P). Mice were treated with varying radiation doses, with or without a priori USMB exposure at different microbubble concentrations. Treatment response was assessed with quantitative 3D Doppler ultrasound and immunohistochemistry at baseline, and at three, 24, and 72 hours after treatment, with three to five mice per treatment group at each time point. All statistical tests were two-sided.Results confirmed an interaction between USMB and ionizing radiation at 24 hours (P < .001), with a decrease in tumor perfusion of up to 46.5% by three hours following radiation and USMB. This peaked at 24 hours, persisting for up to 72 hours, and was accompanied by extensive tumor cell death. In contrast, statistically nonsignificant and minimal tumor responses were noted in S1P-treated and asmase knockout mice for all treatments.This work is the first to confirm the involvement of the ASMase-ceramide pathway in mechanotransductive vascular targeting using USMB. Results also confirm that an acute vascular effect is driving this form of enhanced radiation response, and that it can be elicited at low radiation doses (<8-10 Gy) by a priori USMB exposure.
A YOUNG MALE WITH SHORT QT SYNDROME ON THE ELECTROCARDIOGRAM: SHOULD WE IMPLANT AN IMPLANTABLE CARDIAC DEFIBRILLATOR?
Authors: Juan Simon Rico Mesa, Andres F. Miranda-Arboleda, Megha Prasad, Rafael Correa, Juan Fernando Agudelo, Peter A. Brady, Juan Ramirez
Journal: Journal of the American College of Cardiology (2018)
P025 The diagnostic and prognostic value of autoantibodies in rheumatoid arthritis
Authors: D Sieghart, A Platzer, F Alasti, P Studenic, M Grundhuber, S Swiniarski, S Blueml, T Perkmann, J Smolen, G Steiner
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) are important diagnostic tools in rheumatoid arthritis (RA). These antibodies are predominantly of the IgM (RF) or IgG (ACPA) isotype. Other isotypes of both antibodies – like IgA – and other antibodies – like anti-RA33, which is directed to the nuclear antigen hnRNP-A2 – have been repeatedly reported but their diagnostic and prognostic value has still not been fully elucidated. <h3>Objectives</h3> Here we investigated (i) the prevalence of IgA-RF and IgA-ACPA as well as isotypes IgA, IgG and IgM of anti-RA33 antibody in patients with RA and (ii) their predictive value regarding therapeutic response to methotrexate (MTX). <h3>Methods</h3> Sera from 290 RA patients, 261 disease controls and 100 healthy subjects were tested for the presence of RF, ACPA and anti-RA33 IgG/A/M isotypes by EliA<sup>TM</sup> (Thermo Fisher Scientific). RF and ACPA were routinely measured by nephelometry and the anti-CCP EliA<sup>TM</sup>, respectively. For finding associations with American College of Rheumatology (ACR)20 and simplified disease activity score (SDAI)50 therapeutic responses, an inception cohort of 165 RA patients was analysed. <h3>Results</h3> Diagnostic specificity of antibodies was at least 95%. 185 (63.4%) of 290 RA patients tested positive for at least one routine marker (RF or ACPA) while 107 were negative for both antibodies (seronegative). Among these, 24 (8.2%) patients tested positive for IgG/A/M anti-RA33 and/or IgA-RF/ACPA. To determine the prognostic value regarding therapeutic responses a cross-validated combined model with an accuracy of 77% and an estimated <i>p</i>-value (k=10) of 0.00034 showed high levels (&gt;133 IU/ml) of IgM-RF to be associated with a favourable response to methotrexate (MTX). In case of low or no RF, the presence of IgG-RA33 antibody on the one hand, and the absence of IgA-ACPA on the other hand was associated with a favourable response. <h3>Conclusions</h3> Thus, these data suggest that determination of multiple antibodies increases the diagnostic power of serological testing and may be a feasible tool for the prediction of MTX response especially in combined models. <h3>Disclosure of interest</h3> D. Sieghart: None declared, A. Platzer: None declared, F. Alasti: None declared, P. Studenic: None declared, M. Grundhuber Employee of: Thermo Fisher Scientific – Phadia GmbH, S. Swiniarski Employee of: Thermo Fisher Scientific – Phadia GmbH, S. Blueml: None declared, T. Perkmann: None declared, J. Smolen: None declared, G. Steiner: None declared
The predictive role of estrogen receptor beta (ER-β) in androgen receptor (AR)-positive triple-negative breast cancer (TNBC)
Authors: A. Anestis, C. Mihailidou, S. Theocharis, D. Tryfonopoulos, A. Korogiannos, A. Koumarianou, E. Xingi, M. Kontos, A.G. Papavassiliou, M.V. Karamouzis
Journal: Annals of Oncology (2018)
Identification of RasGTPase activating protein as a potential cellular target of the novel tumor suppressor FUS1 in lung cancer by tandem affinity purification and mass spectrometry
Authors: Gitanjali Jayachandran, Jack Roth, Lin Ji
Journal: Cancer Research (2007)

3167  FUS1 is a novel tumor suppressor identified in the human chromosome 3p21.3 region and allele loss or defective posttranslational modification are frequently found in most of human primary lung tumors. We used a tandem affinity purification (TAP) method to capture cellular proteins potentially interacting FUS1 proteins under physiological conditions and a ProteinChip-array-based SELDI-TOF-MS and tandem LC-MS/MS spectrometric analysis to subsequently identify the captured proteins. The cDNA encoding a wt-FUS1 or a c-terminal deletion mutant FUS1 protein was cloned into a plasmid vector and expressed as a fusion protein with tandem streptavidin and calmodulin binding tags at its N-termini, and used as a bait. The cell lysate was prepared from lung cancer cells transfected with the FUS1-TAP vector and then subjected to two successive purification steps for isolation of the protein complex binding to FUS1 proteins. The protein complex was subjected to SDS-PAGE to separate the interacting components in FUS1-binding complex. The individual protein-bands of interest were excised from the silver-stained gel and proteins were digested in gel by trypsin. The trypsin-digests were either applied to a ProteinChip array and analyzed by SELDI-TOF-MS or directly analyzed by a LC-MS/MS to identify the specific FUS1-interacting protein by peptide-mapping. We identified two candidate proteins namely, RasGAP (RasGTPase activating protein) and SFP1 (split zinc finger protein) to be interacting with wt-FUS1 under a physiological condition. We further confirmed the FUS1-RasGAP interaction using a magnetic bead based immuno-precipitation and immuno-blot analysis. The binding activity to RasGAP was diminished in the c-terminal deletion mutant of FUS1 protein, which is consistent with our previous studies that showed the involvement of a PDZ-binding motif at the c-terminal of FUS1 protein in FUS1-mediated protein-protein interaction. We also carried-out functional assays to understand the biological relevance of the Fus1-RasGAP interaction in lung cancer cells, using RasGAP- or FUS1-specific siRNAs. Inhibition of either FUS1 or RasGAP expression by siRNA resulted in a mutual down-regulation of the other protein component, suggesting an indispensable nature of this protein association in living cells. This work was supported by NIH/NCI SPORE grant P50 CA70907 and UO1 CA10535201.
Jonathan Fine: founder of Physicians for Human Rights
Authors: Joanna Lyall
Journal: BMJ (2018)

Credit: Ulrike Welsch/the Boston Globe /Getty Images

When Jonathan Fine was 6 years old, his father gave him five dollars and suggested that he send it to help blind children in China. “That was the first time I was aware of anything except three meals a day and summer camp somewhere nice,” he said.

“The knowledge opened up the world to me and influenced all my career choices,” said Fine, who has died at his home in Cambridge, Massachusetts, aged 86.

In 1981, when he was a director of a community health centre in Boston, Fine joined a medical delegation to Chile to investigate the case of three doctors who had disappeared during the Pinochet regime. He discovered where the doctors, supporters of Allende, were imprisoned and helped secure their release five weeks later. The delegation’s report, published in the New York Times , described the doctors’ detention as “a serious act of state repression.” “That was pretty heady. It showed me a few people could get a megaphone and make a difference,” he said.

In 1986, working with a group of other doctors, he founded and became the …
Role of <scp>IL</scp>‐13Rα2 in modulating <scp>IL</scp>‐13‐induced <scp>MUC</scp>5<scp>AC</scp> and ciliary changes in healthy and <scp>CRS</scp>w<scp>NP</scp> mucosa
Authors: J. Liu, Y. Y. Li, A. K. Andiappan, Y. Yan, K. S. Tan, H. H. Ong, K. T. Thong, Y. K. Ong, F. G. Yu, H. B. Low, Y. L. Zhang, L. Shi, D. Y. Wang
Journal: Allergy (2018)

The IL-13 receptor α2 (IL-13Rα2) is a receptor for IL-13 which has conflicting roles in mediating IL-13 responses in the lower airway, with little known about its impact on upper airway diseases. We sought to investigate the expression of IL-13 receptors, IL-13Rα1 and IL-13Rα2, in chronically inflamed nasal epithelium, and explore IL-13-induced signaling pathways in an in vitro model of human nasal epithelial cells (hNECs).The protein and mRNA expression levels of IL-13 and its receptors in nasal biopsies of patients with nasal polyps (NP) and healthy controls were evaluated. We investigated goblet cell stimulation with mucus hypersecretion induced by IL-13 (10 ng/mL, 72 hours) treatment in hNECs using a pseudostratified epithelium in air-liquid interface (ALI) culture.There were significant increases in IL-13, IL-13Rα1, and IL-13Rα2 mRNA and protein levels in NP epithelium with healthy controls as baseline. MUC5AC mRNA positively correlated with IL-13Rα2 (r = .5886, P = .002) but not with IL-13Rα1 in primary hNECs. IL-13 treatment resulted in a significant increase in mRNA and protein levels of IL-13Rα2 only in hNECs. IL-13 treatment induced an activation of extracellular signal-regulated kinases (ERK)1/2 and an upregulation of C-JUN, where the IL-13-induced effects on hNECs could be attenuated by ERK1/2 inhibitor (50 μmol/L) or dexamethasone (10-4 -10-7 mol/L) treatment.IL-13Rα2 has a potential role in IL-13-induced MUC5AC and ciliary changes through ERK1/2 signal pathway in the nasal epithelium. IL-13Rα2 may contribute to airway inflammation and aberrant remodeling which are the main pathological features of CRSwNP.
Brexit negotiators must seek “closest possible regulatory alignment” to protect patients and industry
Authors: Adrian O’Dowd
Journal: BMJ (2018)

MPs have called on UK and EU negotiators involved in Brexit talks to protect patient safety by ensuring regulatory alignment and ongoing collaboration in clinical trials.

In a report published on 21 March the parliamentary health and social care committee emphasised the need to maintain patient safety on various fronts.1 MPs on the committee said that Brexit would affect many aspects of health, social care, and the life sciences sector both in the UK and the EU and that, to minimise harm to citizens, both sides had to secure the closest possible regulatory alignment as a priority in the next round of negotiations.

The …
The spatial molecular pattern of integrin recognition sites and their immobilization to colloidal nanobeads determine α2β1 integrin-dependent platelet activation
Authors: Augusto Martins Lima, Seraphine V. Wegner, Ana C. Martins Cavaco, Maria Inacia Estevão-Costa, Raquel Sanz-Soler, Stephan Niland, Georgii Nosov, Jürgen Klingauf, Joachim P. Spatz, Johannes A. Eble
Journal: Biomaterials (2018)
Corrigendum to ‘Comparative study between duct to mucosa and invagination pancreaticojejunostomy after pancreaticoduodenectomy: A prospective randomized study’International Journal of Surgery 16 (2015) 1–6
Authors: Ayman El Nakeeb, Mohamed El Hemaly, Waleed Askr, Mohamed Abd Ellatif, Hosam Hamed, Ahmed Elghawalby, Mohamed Attia, Tallat Abdallah, Mohamed Abd ElWahab
Journal: International Journal of Surgery (2018)
ASSOCIATION BETWEEN SPATIAL VENTRICULAR GRADIENT DIRECTION AND REGIONAL MYOCARDIAL DEFORMATION IN THE GENERAL POPULATION: THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY
Authors: Tor Biering-Sorensen, Jonathan Waks, Muammar Kabir, Golriz Sedaghat, Wendy Post, Elsayed Soliman, Alfred Buxton, Amil Shah, Scott Solomon, Larisa Tereshchenko
Journal: Journal of the American College of Cardiology (2018)
Multi-parametric MRI guided dose escalated radiotherapy for treatment of localized prostate cancer (PCa): Initial toxicity results of a prospective phase II trial.
Authors: Philip Blumenfeld, Mudit Chowdhary, Leslie A. Deane, Nick Pfanzelter, Stephanie Shors, Ryan Braun, Greg M White, Christopher Coogan, Jerome Hoeksema, Narenda Khare, Srinivas Vourganti, Julius Turian, Timothy Kuzel, Dian Wang
Journal: Journal of Clinical Oncology (2018)

25 Background: Multi-parametric MRI (mpMRI) of PCa uses advanced sequences to detect aggressive, high grade and bulky lesions. Given known advantages of hypofractionated radiotherapy (RT) to treat PCa (low a/b ratio), we conducted a phase II trial to escalate a high dose to mpMRI lesion(s) via Image-Guided (IG)-RT/Volumetric Arc Therapy (VMAT)/Stereotactic Body Radiotherapy (SBRT) technology. We present the acute toxicity results of this novel approach. Methods: 22 pts with mpMRI lesion(s) were prospectively treated to a course of IGRT/VMAT to the prostate &amp; seminal vesicle +/- pelvic lymph nodes (PLN) to a dose of 45 Gy in 25 fractions followed by SBRT boost, 18 Gy in 3 fraction to the prostate with a simultaneous integrated boost 21 Gy in 3 fractions (EQD2 = 85.2 Gy using a/b 3 or 93.4 Gy using a/b 1.5) to the mpMRI prostatic lesion(s). Placement of 3 polymer based fiducial markers visible in both CT and MRI for image co-registration and treatment guidance was performed. Genitourinary (GU) and gastrointestinal (GI) adverse events (AE) were scored using CTCAE v4. DSMC approved reporting of acute AE results prior to completion of trial accrual as an interim safety assessment prior to final trial accrual. Results: Median age was 66.5 years (range: 57-80). All patients had PI-RADS grade 3-5 mpMRI lesion(s); 41.0%, 45.4% and 13.6% having 1, 2 and 3 lesions respectively. Ten (45%) pts had Gleason Score (GS) 8-10 and 12 had GS 7 disease. Median PSA was 8.97 (range: 4.0-77.9). Eleven (50%), 10 (46%), and 1 (5%) pts had stage T1, T2, and T3 tumor, respectively. Nine pts received treatment to the PLN and 15 received androgen deprivation therapy. All patients completed the protocol treatment without reporting acute GI or GU AEs grade ≥3 during treatment or at follow up. Grade 2 GI (diarrhea) and GU toxicity (frequency) was seen in 2 (9%) and 9 (41%) pts, respectively, during treatment. Of the 16 pts (71%) with least 3 months follow-up all grade 2 GI and 55.5% GU toxicities had resolved. Conclusions: Early results of this prospective Phase II study suggest that high-dose RT for localized PCa via mpMRI-guided RT/VMAT and SBRT boost is tolerable with a favorable acute toxicity profile.
Abstract MP78: Long-term Antibiotic Use and Risks of All-Cause and Cause-Specific Mortality among Women: Prospective Cohort Study
Authors: Yoriko Heianza, Wenjie Ma, Yin Cao, Andrew T Chan, Eric B Rimm, Frank B Hu, Kathryn M Rexrode, JoAnn E Manson, Lu Qi
Journal: Circulation (2018)

Introduction: Antibiotic exposure is associated with a long-lasting alteration in gut microbiota, and may be related to subsequent major chronic diseases such as cardiovascular diseases and cancer. No previous prospective cohort study has investigated associations between duration of antibiotic use during adulthood with mortality from major chronic diseases among populations at usual risk. Hypothesis: We investigated whether a longer duration of antibiotic use was associated with elevated risks of all-cause and cause-specific deaths among women. Methods: This study included 37,510 women aged ≥60 y who were initially free of cardiovascular diseases or cancer from the Nurses’ Health Study. The present analysis included women who reported data on antibiotic use on the 2004 questionnaire when the information was first assessed. We calculated hazard ratios (HR) for all-cause mortality, and deaths from cardiovascular disease (ICD-8 [international classification of diseases, eighth revision, ICD-8], codes 390 to 458) and cancer (ICD-8, 140-209) according to total days of antibiotic use per year (none, less than 15 days, 15 days to less than 2 months, or ≥2 months) in late adulthood (age 60 or older). Follow-up time was calculated from the return date of the 2004 questionnaire until the date of death, or end of follow-up (June 30, 2012), whichever occurred first. Results: During 287,474 person-years of follow-up, we documented 2908 deaths from any cause (including 474 cardiovascular deaths and 906 cancer deaths). Longer duration of antibiotic use was significantly associated with higher risk of death from any cause after adjusted for dietary intake, lifestyle factors, hypertension, hypercholesterolemia, diabetes ( P trend &lt;0.0001), other medication use (such as aspirin, statin, H2 blockers, proton pump inhibitors) ( P trend =0.001), and other characteristics ( P trend =0.038). As compared to women who did not use antibiotics, those who used for ≥2 months in late adulthood had significantly increased risks of all-cause mortality (multivariate-adjusted HR 1.27; 95% CI, 1.07, 1.49) and cardiovascular mortality (HR 1.58; 95% CI, 1.02, 2.46), but not cancer mortality (HR=0.86; 95% CI, 0.63, 1.16). The association between long-term antibiotic use in late adulthood and an elevated risk of all-cause death was more evident among women who also used antibiotics in middle adulthood (during age 40-59) ( P trend =0.002) than among those who did not use during this life stage. Conclusions: Long-term duration of antibiotic exposure especially in late adulthood was associated with increased all-cause and cardiovascular mortality in women.