bluuebunny/crossref_metadata_2025_split huggingface dataset:
GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer
Authors: Bevill Samantha M. , Olivares-Quintero Jose F. , Sciaky Noah , Golitz Brian T. , Singh Darshan , Beltran Adriana S. , Rashid Naim U. , Stuhlmiller Timothy J. , Hale Andrew , Moorman Nathaniel J. , Santos Charlene M. , Angus Steven P. , Zawistowski Jon S. , Johnson Gary L. 
Published: April 2019

Abstract

Screening of an inhibitor library targeting kinases and epigenetic regulators identified several molecules having antiproliferative synergy with extraterminal domain (BET) bromodomain (BD) inhibitors (JQ1, OTX015) in triple-negative breast cancer (TNBC). GSK2801, an inhibitor of BAZ2A/B BDs, of the imitation switch chromatin remodeling complexes, and BRD9, of the SWI/SNF complex, demonstrated synergy independent of BRD4 control of P-TEFb–mediated pause-release of RNA polymerase II. GSK2801 or RNAi knockdown of BAZ2A/B with JQ1 selectively displaced BRD2 at promoters/enhancers of ETS-regulated genes. Additional displacement of BRD2 from rDNA in the nucleolus coincided with decreased 45S rRNA, revealing a function of BRD2 in regulating RNA polymerase I transcription. In 2D cultures, enhanced displacement of BRD2 from chromatin by combination drug treatment induced senescence. In spheroid cultures, combination treatment induced cleaved caspase-3 and cleaved PARP characteristic of apoptosis in tumor cells. Thus, GSK2801 blocks BRD2-driven transcription in combination with BET inhibitor and induces apoptosis of TNBC.

Implications:
Synergistic inhibition of BDs encoded in BAZ2A/B, BRD9, and BET proteins induces apoptosis of TNBC by a combinatorial suppression of ribosomal DNA transcription and ETS-regulated genes.
Circadian Rhythm of Vascular Function in Midlife Adults
Authors: Thosar Saurabh S. , Berman Alec M. , Herzig Maya X. , McHill Andrew W. , Bowles Nicole P. , Swanson Christine M. , Clemons Noal A. , Butler Matthew P. , Clemons Aaron A. , Emens Jonathan S. , Shea Steven A. 
Published: April 2019

Objective—
Adverse cardiovascular events occur more frequently in the morning than at other times of the day. Vascular endothelial function (VEF)—a robust cardiovascular risk marker—is impaired during this morning period. We recently discovered that this morning impairment in VEF is not caused by either overnight sleep or the inactivity that accompanies sleep. We determined whether the endogenous circadian system is responsible for this morning impairment in VEF. We also assessed whether the circadian system affects mechanistic biomarkers, that is, oxidative stress (malondialdehyde adducts), endothelin-1, blood pressure, and heart rate.

Approach and Results—

Twenty-one (11 women) middle-aged healthy participants completed a 5-day laboratory protocol in dim light where all behaviors, including sleep and activity, and all physiological measurements were evenly distributed across the 24-hour period. After baseline testing, participants underwent 10 recurring 5-hour 20-minute behavioral cycles of 2-hour 40-minute sleep opportunities and 2 hours and 40 minutes of standardized waking episodes. VEF, blood pressure, and heart rate were measured, and venous blood was sampled immediately after awakening during each wake episode. Independent of behaviors, VEF was significantly attenuated during the subjective night and across the morning (
P
=0.04). Malondialdehyde adducts and endothelin-1 exhibited circadian rhythms with increases across the morning vulnerable period and peaks around noon (
P
≤0.01). Both systolic (
P
=0.005) and diastolic blood pressure (
P
=0.04) were rhythmic with peaks in the late afternoon.

Conclusions—
The endogenous circadian system impairs VEF and increases malondialdehyde adducts and endothelin-1 in the morning vulnerable hours and may increase the risk of morning adverse cardiovascular events in susceptible individuals.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02202811.
Impaired Cholesterol‐Uptake Capacity of HDL Might Promote Target‐Lesion Revascularization by Inducing Neoatherosclerosis After Stent Implantation
Authors: Nagano Yuichiro , Otake Hiromasa , Toba Takayoshi , Kuroda Koji , Shinkura Yuto , Tahara Natsuko , Tsukiyama Yoshiro , Yanaka Kenichi , Yamamoto Hiroyuki , Nagasawa Akira , Onishi Hiroyuki , Sugizaki Yoichiro , Takeshige Ryo , Harada Amane , Murakami Katsuhiro , Kiriyama Maria , Oshita Toshihiko , Irino Yasuhiro , Kawamori Hiroyuki , Ishida Tatsuro , Toh Ryuji , Shinke Toshiro , Hirata Ken‐ichi 
Published: April 2019

Background
We evaluated the importance of high‐density lipoprotein (HDL) functionality for target‐lesion revascularization in patients treated with coronary stents using a rapid cell‐free assay system to evaluate the functional capacity of HDL to accept additional cholesterol (cholesterol‐uptake capacity; CUC).

Methods and Results

From an optical coherence tomography (OCT) registry of patients treated with coronary stents, 207 patients were enrolled and their HDL was functionally evaluated by measuring the CUC. Follow‐up OCT was performed (median duration, 24.5 months after stenting) to evaluate the presence of neoatherosclerosis. Clinical follow‐up was performed to assess target‐lesion revascularization for a median duration of 42.3 months after stent implantation. Neoatherosclerosis was identified in 37 patients (17.9%). Multivariate logistic regression analysis revealed that a decreased CUC was independently associated with neoatherosclerosis (odds ratio, 0.799;
P
<0.001). The CUC showed a significant inverse correlation with incidence of target‐lesion revascularization (odds ratio, 0.887;
P
=0.003) and with lipid accumulation inside stents, suggesting that neoatherosclerosis contributes to the association between CUC and target‐lesion revascularization.

Conclusions
Impaired HDL functionality, detected as decreased CUC, might lead to future stent failure by provoking atherogenic changes of the neointima within stents. Both quantitative and qualitative assessments of HDL might enable the improved prediction of clinical outcomes after stent implantation.
Predictive value of scoring systems for the diagnosis of acute appendicitis in emergency department patients: Is there an accurate one?
Authors: Ak Rohat , Doğanay Fatih , Unal Akoğlu Ebru , Akoğlu Haldun , Uçar Aslı Bahar , Kurt Erdem , Arslan Turan Cansu , Onur Ozge 
Published: April 2019

Background:Acute appendicitis is one of the challenging surgical conditions presented in the emergency departments. Clinical scoring systems were developed to reduce the negative appendectomy rate and also to avoid unnecessary diagnostic evaluation.Objectives:The primary aim was to compare the clinical adequacy of the Alvarado, Acute Inflammatory Response, and the Raja Isteri Pengiran Anak Saleha Appendicitis scores in patients with right lower quadrant pain for the diagnosis of acute appendicitis.Methods:This was a prospective and observational study. All patients over the age of 18 years who presented with a complaint of right lower quadrant pain were enrolled. The Alvarado, Acute Inflammatory Response, and Raja Isteri Pengiran Anak Saleha Appendicitis scoring systems were compared. The patients were either admitted or followed-up as out-patient. Face-to-face or telephone follow-up visits were arranged for the patients who did not have surgery and who were not admitted.Results:232 patients were included and 14 patients were excluded from the study. Of the 218 patients, 114 patients underwent surgery. Of the 114 patients, 107 patients were pathologically diagnosed with acute appendicitis. It was determined that Raja Isteri Pengiran Anak Saleha Appendicitis score was the most valuable score with 0.88 accuracy, followed by Acute Inflammatory Response (area under the curve = 0.79) and Alvarado (area under the curve = 0.71) scores.Conclusion:The accuracy of Raja Isteri Pengiran Anak Saleha Appendicitis scoring system was higher for the diagnosis of acute appendicitis than the other scores. The cut-off of the Raja Isteri Pengiran Anak Saleha Appendicitis score from a 7.5-point threshold provides a practical, non-invasive, rapid diagnostic method that increases acute appendicitis discriminative power in patients presenting with right lower quadrant pain.
Evaluation of appropriate use of bisphosphonates and denosumab in patients with cancer
Authors: Gyori Derek J , Bullington Susan M , Crawford Brooke S , Vernon Veronica P 
Published: April 2019

Background National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. Methods A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. Results A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. Conclusions Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.
Impact of the introduction of novel hormonal agents on metastatic castration-resistant prostate cancer treatment choice
Authors: Lahcene Halima , Aprikian Armen G , Vanhuyse Marie , Hu Jason , Bladou Franck , Cury Fabio , Kassouf Wassim , Perreault Sylvie , Dragomir Alice 
Published: April 2019

Background Docetaxel-based chemotherapy has been the cornerstone of the management of symptomatic metastatic castration-resistant prostate cancer (mCRPC) since 2004. This study aimed to describe how real-world clinical practice was changed with the public funding of novel hormonal agents (abiraterone and enzalutamide) in Quebec. Methods We conducted a retrospective cohort study in two McGill University hospitals. Hospital-based cancer registries were used to select mCRPC patients in medical oncology departments from January 2010 to June 2014. Two groups according to mCRPC diagnosis year were built, with 2012 chosen as the cut-off year, corresponding to the year abiraterone was approved for public reimbursement in second-line in Quebec. Kaplan–Meier analysis was used to estimate time to first docetaxel prescription since mCRPC diagnosis before and after 2012. Cox regression was used to identify predictive factors of docetaxel and novel hormonal agent use. Results In our cohort, 308 patients diagnosed with mCRPC were selected with 162 patients in the pre-2012 group and 146 patients in the post-2012 group. The median age at mCRPC was 74.0 years old. At 12 months from diagnosis, 69% of patients received a prescription for docetaxel in the pre-2012 group comparatively to 53% in the post-2012 group. Factors that decreased the likelihood of docetaxel utilization were: age older than 80 at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3–0.7), mCRPC diagnosis after 2012 (HR: 0.6; 95%CI: 0.4–0.8), and asymptomatic disease at mCRPC diagnosis (HR: 0.5; 95%CI: 0.3–0.7). Conclusion The introduction of novel hormonal agents reduced first-line and overall docetaxel utilization and delayed time to its initiation.
“I would prefer not to”: Assessing competence to consent in a case of refusal of cancer treatment
Authors: Castellana Gustavo B , Schraiber Lilia B , de Oliveira Talita R , de Barros Daniel M 
Published: April 2019

Background Based on an actual case in which a psychiatrist was called in to assess a patient’s capacity to refuse treatment, the aim of this study is to discuss how to manage this ethical and clinical issue and the dilemmas faced by the medical team. Case presentation: The case involved a 45-year-old female patient diagnosed with breast cancer who refused treatment. Since the mastology team had doubts about the patient’s mental state and given that she refused to consent to surgery, a forensic psychiatric consult was requested. Conclusion The forensic psychiatry team concluded that the patient’s decision-making capacity was preserved. The team suggested some actions to help the specialists deal with the ethical conflict. A reflection is proposed about the role of psychiatrists when an ethical dilemma involving decision-making capacity emerges in clinical situations, elucidating their work not only as physicians who determine diagnoses and conducts, but also as agents of transformation in the doctor–patient relationship.
No differences in effectiveness and safety between pipeline embolization device and stent-assisted coiling for the treatment of communicating segment internal carotid artery aneurysms
Authors: Enriquez-Marulanda Alejandro , Salem Mohamed M , Ascanio Luis C , Maragkos Georgios A , Gupta Raghav , Moore Justin M , Thomas Ajith J , Ogilvy Christopher S , Alturki Abdulrahman Y 
Published: April 2019

Background Aneurysms arising from the communicating segment (C7) of the internal carotid artery (ICA) are one of the most frequent locations of intracranial aneurysms. Stent-assisted coiling (SAC) and flow diversion therapies are both endovascular strategies used for the treatment of ICA aneurysms occurring at the C7 segment. Objective The aim of this study is to compare both methods' angiographic and functional outcomes, and procedural complications. To our knowledge, this is the first study to compare both modalities for aneurysms at this location. Methods A retrospective review was performed of our prospectively collected database from 2008 until 2017 for patients treated with SAC and from 2013 until 2017 for patients treated with pipeline embolization devices (PEDs). Results We identified 35 patients for this cohort with 38 aneurysms; 17 treated with SAC and 21 with PED. Mean age was 59 years, and 30 patients were female (86%). Complete occlusion at last follow-up occurred in 70.6% of patients in the SAC group and in 81% in the PED group ( p = 0.45). Posterior communicating artery patency at last follow-up did not differ significantly between the two groups (94.1% vs 85.7%; p = 0.40). Good functional outcome at last follow-up (mRS 0–2) was achieved in 100% and 88.2% of patients, respectively. Additionally, there was no significant difference between the two groups for retreatment rates, procedural hemorrhagic, or thromboembolic complications. Conclusion SAC and PED are two equally efficacious modalities for endovascular treatment of ICA aneurysms arising at the communicating segment of the ICA.
Impact of Anterior Cruciate Ligament Reconstruction on NCAA FBS Football Players: Return to Play and Performance Vary by Position
Authors: Wise Patrick Martin , Gallo Robert A. 
Published: April 2019

Background: Anterior cruciate ligament (ACL) injuries are devastating for college football players. Although the change in functional performance of National Collegiate Athletic Association (NCAA) football players after reconstruction has been shown to be negligible, studies have failed to analyze the statistical performance of these players upon their return. Purpose/Hypothesis: The purpose of this study was to quantify the impact of ACL reconstruction on the statistical performance of collegiate football players. We hypothesized that statistical performance would vary by position and that running backs, wide receivers, and defensive backs, compared with preinjury and controls, would experience the largest decline in performance after returning from ACL reconstruction. Study Design: Descriptive epidemiology study. Methods: NCAA Football Bowl Subdivision (FBS) football players who experienced ACL tears between the years 2010 and 2015 were identified. The rates of return to play after surgery were determined for each position. Preinjury and postoperative performance statistics of each running back, receiver, defensive lineman, linebacker, and defensive back who met inclusion criteria were compared. A t-test analysis was used to compare the performance changes experienced by these players versus the performance changes of matched controls. Results: A total of 349 players were identified. Only 63.64% of eligible offensive linemen returned to play. Upon return, running backs experienced significant performance decreases compared with controls in carries (mean ± SD, –2.4 ± 2.7 vs 2.8 ± 1.6; P = .003), yards (–12.3 ± 15.5 vs 13.8 ± 7.8; P = .006), and receptions (–0.22 ± 0.32 vs 0.32 ± 0.23; P = .011) per game. Receivers displayed significant performance decreases compared with controls in number of touchdowns (–0.019 ± 0.110 vs 0.18 ± 0.06; P = .004), receptions (–0.11 ± 0.79 vs 1.2 ± 0.4; P = .004), and yards (–3.2 ± 10.6 vs 18.6 ± 5.4; P = .0009) per game. Linebackers demonstrated less improvement than controls in tackles for loss (0.007 ± 0.115 vs 0.31 ± 0.11; P = .0003) and sacks (0.001 ± 0.061 vs 0.10 ± 0.06; P = .026). Conclusion: Although offensive linemen were the least likely to return to play, running backs and receivers returned to play at a lower level of performance. The performance of defensive players was less affected by ACL reconstruction.
Neurosteroid Levels in the Orbital Frontal Cortex of Subjects With PTSD and Controls: A Preliminary Report
Authors: Cruz Dianne A. , Glantz Leisa A. , McGaughey Kara D. , Parke Gillian , Shampine Lawrence J. , Kilts Jason D. , Naylor Jennifer C. , Marx Christine E. , Williamson Douglas E. 
Published: April 2019

Background Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD ( n = 18) and controls ( n = 35). Methods Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography-tandem mass spectrometry. Results Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone ( p = 0.03) compared to control males, and females with PTSD had significantly increased levels of pregnenolone ( p = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone ( t46 = 2.37, p = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone ( t46 = −2.25, p = 0.03) relative to control females. Conclusions To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC.
Comparative risks of chronic inhaled corticosteroids and macrolides for bronchiectasis
Authors: Henkle Emily , Curtis Jeffrey R. , Chen Lang , Chan Benjamin , Aksamit Timothy R. , Daley Charles L. , Griffith David E. , Winthrop Kevin L. 
Published: April 2019

IntroductionNon-cystic fibrosis (CF) bronchiectasis (“bronchiectasis”) is a chronic airway disease for which little data exist to inform treatment decisions. We sought to compare the risks of respiratory infections in chronic users of inhaled corticosteroids (ICSs)versusmacrolide monotherapy.MethodsWe identified a cohort of US Medicare enrollees with a bronchiectasis diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 494.0 or 494.1) between 2006 and 2014, excluding CF. We defined chronic new use as the first ≥28-day prescription of ICS therapy or macrolide monotherapy. We compared the characteristics of the exposure cohorts using standardised mean differences (SMDs) and computed a propensity score (PS) to account for treatment differences. The risks of acute exacerbation, hospitalised respiratory infection, all-cause hospitalisation and mortality were compared using PS decile-adjusted Cox regression models.ResultsWe identified 83 589 new users of ICSs and 6500 new users of macrolides from 285 043 included Medicare enrollees with bronchiectasis. The crude incidence of hospitalised respiratory infection was 12.6 (ICS therapy) and 10.3 (macrolide monotherapy) per 100 patient-years. The PS-adjusted HRs comparing ICS with macrolide new users were 1.39 (95% CI 1.23–1.57) for hospitalised respiratory infection, 1.56 (95% 1.49–1.64) for acute exacerbation and 1.09 (95% 0.95–1.25) for mortality.InterpretationAmong patients with bronchiectasis, the use of ICSs was associated with an increased risk of hospitalised respiratory infections compared with macrolide monotherapy.
Dual mechanism of action of T2 inhibitor therapies in virally induced exacerbations of asthma: evidence for a beneficial counter-regulation
Authors: Efthimiou John , Poll Chris , Barnes Peter J. 
Published: April 2019

Biological agents such as omalizumab and monoclonal antibodies (mAbs) that inhibit type 2 (T2) immunity significantly reduce exacerbations, which are mainly due to viral infections, when added to inhaled corticosteroids in patients with severe asthma. The mechanisms for the therapeutic benefit of T2 inhibitors in reducing virally induced exacerbations, however, remain to be fully elucidated. Pre-clinical and clinical evidence supports the existence of a close counter-regulation of the high-affinity IgE receptor and interferon (IFN) pathways, and a potential dual mechanism of action and therapeutic benefit for omalizumab and other T2 inhibitors that inhibit IgE activity, which may enhance the prevention and treatment of virally induced asthma exacerbations. Similar evidence regarding some novel T2 inhibitor therapies, including mAbs and small-molecule inhibitors, suggests that such a dual mechanism of action with enhancement of IFN production working through non-IgE pathways might also exist. The specific mechanisms for this dual effect could be related to the close counter-regulation between T2 and T1 immune pathways, and potential key underlying mechanisms are discussed. Further basic research and better understanding of these underlying counter-regulatory mechanisms could provide novel therapeutic targets for the prevention and treatment of virally induced asthma exacerbations, as well as T2- and non-T2-driven asthma. Future clinical research should examine the effects of T2 inhibitors on IFN responses and other T1 immune pathways, in addition to any effects on the frequency and severity of viral and other infections and related exacerbations in patients with asthma as a priority.