tbuckley/cabot-search huggingface dataset:
Dynamics and functional interplay of histone lysine butyrylation, crotonylation, and acetylation in rice under starvation and submergence
Authors: Yue Lu, Qiutao Xu, Yuan Liu, Yue Yu, Zhong-Yi Cheng, Yu Zhao, Dao-Xiu Zhou
Journal: Genome biology (2018)

Histone lysine acylations by short-chain fatty acids are distinct from the widely studied histone lysine acetylation in chromatin, although both modifications are regulated by primary metabolism in mammalian cells. It remains unknown whether and how histone acylation and acetylation interact to regulate gene expression in plants that have distinct regulatory pathways of primary metabolism.We identify 4 lysine butyrylation (Kbu) sites (H3K14, H4K12, H2BK42, and H2BK134) and 45 crotonylation (Kcr) sites on rice histones by mass spectrometry. Comparative analysis of genome-wide Kbu and Kcr and H3K9ac in combination with RNA sequencing reveals 25,306 genes marked by Kbu and Kcr in rice and more than 95% of H3K9ac-marked genes are marked by both. Kbu and Kcr are enriched at the 5' region of expressed genes. In rice under starvation and submergence, Kbu and Kcr appear to be less dynamic and display changes in different sets of genes compared to H3K9ac. Furthermore, Kbu seems to preferentially poise gene activation by external stresses, rather than internal circadian rhythm which has been shown to be tightly associated with H3K9ac. In addition, we show that rice sirtuin histone deacetylase (SRT2) is involved in the removal of Kcr.Kbu, Kcr, and H3K9ac redundantly mark a large number of active genes but display different responses to external and internal signals. Thus, the proportion of rice histone lysine acetylation and acylation is dynamically regulated by environmental and metabolic cues, which may represent an epigenetic mechanism to fine-tune gene expression for plant adaptation.
Abstract 18472: Electrocardiographic and Imaging Predictors for Permanent Pacemaker (PPM) Implantation Following Transcatheter Aortic Valve Replacement (TAVR)
Authors: Jared M Routh, Lee Joseph, Brodie R Marthaler, Prashant Bhave
Journal: Circulation (2015)

Hypothesis: The purpose of this study was to identify predictors of permanent pacemaker (PPM) placement post-TAVR. Introduction: Cardiac conduction abnormalities requiring PPM are well-recognized complications of TAVR. Reliable predictors of post-TAVR PPM placement, however, remain elusive. Methods: A total of 114 patients who underwent trans-apical or trans-femoral TAVR using the balloon-expandable Edwards SAPIEN valve at the University of Iowa Hospitals and Clinics were identified. We then excluded patients with a pre-existing pacemaker and who required conversion to an open/salvage procedure. We performed a retrospective chart review aimed at abstracting raw data related to patient characteristics, EKG variables, imaging, procedural variables, outcomes, and follow-up data. Univariate and multivariate logistic regression was performed, with post-TAVR PPM implantation as the outcome. Results: A total of 100 patients were included in the study and PPM was placed in 9 patients (9%). AV block was the indication for all PPM. In univariate analysis, the ratio of valve size to diameter of Sinus of Valsalva was a significant predictor of PPM (84.1±9.3 vs 76.8±7.1, p=0.009) (Table 1). In multivariate analysis, using right bundle branch block (RBBB), sex and the ratio of valve size to diameter of Sinus of Valsalva as predictors, pre-existing (RBBB) (OR: 6.5, 95% CI: 1.1-37.1, p=0.035) was identified as a predictor of PPM and the ratio of valve size to diameter of Sinus of Valsalva (OR: 1.2, 95% CI: 1.03-1.3, p=0.012) was identified as a novel predictor of PPM. Conclusions: PPM placement was required in 9% of patients without pre-existing PPM who underwent TAVR. In addition to pre-existing RBBB, the ratio of valve size to diameter of Sinus of Valsalva was identified as a novel predictor of PPM after TAVR. Our findings differ from prior published manuscripts which reported valve size to LV outflow tract diameter ratio as a significant predictor of post-TAVR PPM implantation.
Sustaining safety and delivery of oral chemotherapy utilizing lean methodology.
Authors: Marc Steven Hoffmann, Adam Neiberger, Gloria Solis, Marshall Johnson, Debbie Fernandez
Journal: Journal of Clinical Oncology (2021)

218 Background: An oral chemotherapy safety event in 2017 prompted analysis of related workflows utilizing lean quality improvement methodology. Three kaizen workshops utilizing lean methodology with primary objectives to 1) develop safety standards for oral chemotherapy as rigorous as those for intravenous chemotherapy; 2) improve efficiency; and 3) design workflows that enable data collection and process control were conducted. Since 2017, our goal has been to sustain developed workflows to ensure oral chemotherapy patients have the right oral chemotherapy agent, at the right dose, at the right time, with independent and efficient safety checks by all care providers. Methods: After multidisciplinary teams participated in three kaizen workshops to develop workflows, education plans were developed and results were incorporated into the lean management system. The lean production method of Training Within Industry (TWI) was used to train physician, nursing, and pharmacy teams to the workflows. Results were communicated to key stakeholders weekly to monitor progress on workflow creation, spread, and process metrics designed to signal defects in the workflow. When processes were deemed ‘out of control,’ clinical team members provided regular and targeted interventions. Safety data were collected and correlated to surrogate outcomes for long-term impact assessment. Results: Interventions resulted in the following outcomes: 62 consecutive weeks with 99% reduction in oral chemotherapy defects reaching pharmacy. 86 consecutive weeks with 51% error reduction processing oral chemotherapy though a single EMR workflow. 57 consecutive weeks with 62% error reduction processing oral chemotherapy though a single EMR workflow. No serious safety events have occurred since 2017. Conclusions: Comprehensive quality improvement in our oral chemotherapy process has resulted in sustained safety, efficiency, and a data collection to signal when process defects occur. Multidisciplinary teams utilizing established lean methodology were critical to success.
Consumer demand and implementation of a scalp cooling program at a multi-site organization.
Authors: Ashley Featherstone, Karen Hernandez, Erica Fischer-Cartlidge, Mikel Ross, Curt Haase
Journal: Journal of Clinical Oncology (2018)

214 Background: Alopecia is so feared that patients may opt to forgo treatment or elect for a less effective treatment to prevent it. Consumer demand for scalp cooling has been on the rise recently and has escalated since the Food and Drug Administration cleared the use of scalp cooling machines to minimize chemotherapy-induced alopecia. This organization required a clinical support model to implement this unique intervention and to establish its own benchmarks for safety and quality. Methods: With no precedent for implementation, nursing, administration, facilities, information technology, finance and legal collaboratively established a process for integrating scalp cooling into current practice. Policies, patient education, staff training programs, billing codes and electronic documentation were created; technological solutions for tracking and scheduling patients at multiple sites were established; infection control and biomedical machine management systems were put into place. Results: Initially, eight sites offered scalp cooling for female breast cancer patients receiving alopecia-inducing chemotherapy. After expanded approval for all solid tumor patients, the program grew to all sites (n = 13) providing chemotherapy using one standard process. All sites implemented scalp cooling utilizing existing treatment space and schedules. To date, more than 800 cooling treatments have occurred. Conclusions: Patient priorities must be clinician priorities. A multi-site organization must respond to new research and consumer demand. Successful integration into the patient experience depends on alignment between providers, nursing, and support departments and forward thinking for scalability.
Qualitative study to understand the emotional response to a metastatic diagnosis in castration-resistant prostate cancer.
Authors: Claire Burbridge, Jason A Randall, Tara Symonds, Joe Lawson, Lindsay Dearden, Kelly McQuarrie, Byron M. Espina
Journal: Journal of Clinical Oncology (2018)

201 Background: To explore the emotional response of men with a recent metastatic Castration Resistant Prostate Cancer (mCRPC) diagnosis, emotional burden of monitoring their condition prior to additional treatment for metastasis (“watch and wait”), and emotional impact on caregivers. Methods: In-depth, qualitative, one-to-one interviews with 25 men with a recent diagnosis of mCRPC from the US (n = 4), France (n = 12) and Germany (n = 9). Additional interviews were conducted with 12 of the participants’ primary support person (PSP) - a friend/family member who provided support to the participants emotionally and/or in everyday tasks; US (n = 2), France (n = 8), Germany (n = 4). Interviews were audio-recorded, transcribed and thematic analyzed. Results: Participants were 54-85 years old; 88% retired; mean time since metastatic diagnosis was 7.5 months (seven were within 12 weeks of metastasis, all others within 24 months of metastasis); and 19 experienced pain related to their CRPC. Symptoms and impacts associated with mCRPC were consistent across countries. The most frequent symptoms (reported by ≥75%) were fatigue/tiredness, sexual dysfunction and pain. Metastasis had a negative emotional impact, participants reported fear of what happens next. Some explicitly associated certain symptoms/impacts with metastasis, such as localized pain, diarrhea, blood in stool, and increased impact of activities of daily living. 72% highlighted that metastatic diagnosis impacted their emotional state, experiencing worry, anxiety, fear, low mood/depression and shock, with increased burden on PSP and strain on relationships. 80% highlighted that monitoring PSA values was important, and ten discussed the emotional impact of this: fear and worry when rising; glad, happy, and excited when falling. Most participants (80%) reported that, if a medication had been available to them to delay metastasis, they would have taken it, even if asymptomatic. Conclusions: Metastatic diagnosis was associated with a worsening of symptoms and both physical and emotional impacts. Rising PSA levels prior to metastasis had a negative emotional impact. Most participants were willing to take a medication to delay metastasis.
Assessment of Opioid Prescribing Practices Before and After Implementation of a Health System Intervention to Reduce Opioid Overprescribing
Authors: Barry R. Meisenberg, Jennifer Grover, Colson Campbell, Daniel Korpon
Journal: JAMA Network Open (2018)

Overprescribing of opioids has generated and sustains the opioid overdose epidemic. Health systems have a responsibility to lead the effort to reduce overprescribing.To measure the effects of multilevel interventions on opioid prescribing within a health system.Quality improvement study comparing a 6-month preintervention baseline with a 16-month postintervention period ending in April 2018. Inpatient and outpatient clinical activity within a regional health system including an acute care hospital, same-day surgery, and outpatient clinics. Opioid prescribing activity by hundreds of clinicians involving over a million clinical encounters was measured using a health system's electronic medical record.Multiple parallel interventions in different domains, including prescriber education and accountability, enhanced oversight via measurement of individual prescribers, tools to right-size postoperative discharge prescriptions, reduction of default amounts on standard opioid prescription orders, and professionally written patient and public education about opioid risks and alternatives.Morphine milligram equivalents (MME) per encounter per month, MME per opioid prescription, and rate of opioid prescriptions (opioid prescriptions per encounter per month).More than 44 000 clinical encounters per month were recorded. All baseline trends were not significantly different from 0. Total health system MME per encounter decreased 1.0 MME per encounter per month. At the end of the postintervention observation period, the monthly MME per encounter was 58% lower than the average of the 6-month baseline, the MME per opioid prescription per month was 34% less than the average of the baseline, and the opioid prescription rate was 38% lower than the average of the baseline.Opioid overprescribing was reduced with multifocal interventions targeting patient and public demand, creating prescriber awareness and accountability, and creating tools for clinical leadership accountability. The interventions described are adoptable by most organized health systems. Reducing total opioid supply within communities should be given high priority by those with a mission to protect and improve public health.
Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina
Authors: Thomas J. Ford, Bethany Stanley, Richard Good, Paul Rocchiccioli, Margaret McEntegart, Stuart Watkins, Hany Eteiba, Aadil Shaukat, Mitchell Lindsay, Keith Robertson, Stuart Hood, Ross McGeoch, Robert McDade, Eric Yii, Novalia Sidik, Peter McCartney, David Corcoran, Damien Collison, Christopher Rush, Alex McConnachie, Rhian M. Touyz, Keith G. Oldroyd, Colin Berry
Journal: Journal of the American College of Cardiology (2018)
Bone Flare to Androgen Deprivation Therapy in Metastatic, Hormone-Sensitive Prostate Cancer on 68Ga-Prostate-Specific Membrane Antigen PET/CT
Authors: Helle D. Zacho, Lars J. Petersen
Journal: Clinical Nuclear Medicine (2018)

Abstract A 69-year-old man with newly diagnosed prostate cancer PSA 274 ng/mL, Gleason 4+3, T-stage 3b) underwent 68 Ga-PSMA PET/CT for staging with follow-up scans 6 and 13 weeks after androgen deprivation therapy (ADT) initiation. Six weeks after ADT initiation, lymph node metastases observed at staging showed metabolic and radiological regression, whereas the skeleton showed increased PSMA uptake in existing bone metastases and several new PSMA-avid lesions. Skeletal PSMA uptake decreased after 13 weeks of ADT, and prostate-specific antigen decreased to 16 ng/mL. These findings suggest the presence of the flare phenomenon to ADT in bone metastases seen on PSMA PET/CT.
Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial
Authors: Guy Meyer, Benjamin Besse, Hélène Doubre, Anaïs Charles-Nelson, Sandro Aquilanti, Armine Izadifar, Reza Azarian, Isabelle Monnet, Corinne Lamour, Renaud Descourt, Gérard Oliviero, Laurent Taillade, Christos Chouaid, Frederique Giraud, Pierre-Emmanuel Falcoz, Marie-Pierre Revel, Virginie Westeel, Adrien Dixmier, Jean Tredaniel, Stéphanie Dehette, Chantal Decroisette, Alain Prevost, Eric Pichon, Elizabeth Fabre, Jean-Charles Soria, Sylvie Friard, Jean-Baptiste Stern, Laurence Jabot, Georges Dennewald, Gérard Pavy, Patrick Petitpretz, Jean-Marc Tourani, Marco Alifano, Gilles Chatellier, Philippe Girard
Journal: European Respiratory Journal (2018)

The anti-tumour and anti-metastatic properties of heparins have not been tested in patients with early stage cancer. Whether adjuvant low molecular weight heparin (LMWH) tinzaparin impacts the survival of patients with resected non-small cell lung cancer (NSCLC) was investigated. Patients with completely resected stage I, II or IIIA NSCLC were randomly allocated to receive subcutaneous tinzaparin 100 IU·kg −1 once a day for 12 weeks or no treatment in addition to standard of care. The trial was open-label with blinded central adjudication of study outcomes. The primary outcome was overall survival. In 549 patients randomised to tinzaparin (n=269) or control (n=280), mean± sd age was 61.6±8.9 years, 190 (34.6%) patients had stage II−III disease, and 220 (40.1%) patients received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in overall survival between groups (hazard ratio (HR) 1.24, 95% CI 0.92–1.68; p=0.17). There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94, 95% CI 0.68–1.30; p=0.70). Adjuvant tinzaparin had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I−IIIA NSCLC. These results do not support further clinical evaluation of LMWHs as anti-tumour agents.
Clinical pathway creation and adherence at a large hybrid cancer center.
Authors: Matthew Carnell, Martin D. Fleming, David Craig Portnoy, Matthew T. Ballo, Kristopher Fisher, Bradley G. Somer, Kurt W. Tauer, Cheryl A. Prince, Ari M. Vanderwalde
Journal: Journal of Clinical Oncology (2018)

298 Background: Clinical pathways are valuable in reducing treatment variation, improving outcomes, and reducing costs in an oncology setting. With input of clinical stakeholders at West Cancer Center, we created and implemented a melanoma clinical pathway to improve care and facilitate standardization between melanoma sub-specialists and general oncologists. Retrospective pathway adherence was assessed to inform quality improvement goals. Methods: Using national guidelines and expert literature review, we developed a pathway defining a center-wide algorithmic approach to treat melanoma. Prior adherence to the pathway was retrospectively assessed by evaluating treatment during 1 year across 8 metrics. All patients who received systemic melanoma therapy during the study period at a large cancer center ( &gt; 5000 new patients annually) were included in the assessment. Of the included patients, metric adherence was only measured when applicable. Adherence rates were described for predefined melanoma subspecialists versus predefined general oncologists without a declared subspecialty in melanoma. Significance was assessed with fisher exact test. Results: The following metrics were defined by the expert team as essential components of melanoma pathway; receipt of wide local excision; receipt of sentinel lymph node biopsy; presentation at multidisciplinary conference; molecular profiling before treatment of metastatic disease; treatment with preferred regimens in 1 st line, 2 nd line, and 3 rd line; and clinical trial participation. Ninety patients were evaluated. Conclusions: Most differences in pathway adherence were found to be not significant. Clinical trial accrual was higher among melanoma subspecialists compared to general oncologists. Clinical pathways allow patients treated by general oncologists to benefit from the expertise of subspecialists and improve quality of care.[Table: see text]
Promoter Methylation-Regulated miR-145-5p Inhibits Laryngeal Squamous Cell Carcinoma Progression by Targeting FSCN1
Authors: Wei Gao, Chunming Zhang, Wenqi Li, Huizheng Li, Jiangwei Sang, Qinli Zhao, Yunfeng Bo, Hongjie Luo, Xiwang Zheng, Yan Lu, Yong Shi, Dongli Yang, Ruiping Zhang, Zhenyu Li, Jiajia Cui, Yuliang Zhang, Min Niu, Jun Li, Zhongqiang Wu, Huina Guo, Caixia Xiang, Juan Wang, Juan Hou, Lu Zhang, Rick F. Thorne, Yongping Cui, Yongyan Wu, Shuxin Wen, Binquan Wang
Journal: Molecular Therapy (2018)

Laryngeal squamous cell carcinoma (LSCC) is a common form of head and neck cancer with poor prognosis. However, the mechanism underlying the pathogenesis of LSCC remains unclear. Here, we demonstrated increased expression of fascin actin-bundling protein 1 (FSCN1) and decreased expression of microRNA-145-5p (miR-145-5p) in a clinical cohort of LSCC. Luciferase assay revealed that miR-145-5p is a negative regulator of FSCN1. Importantly, low miR-145-5p expression was correlated with TNM (tumor, node, metastasis) status and metastasis. Moreover, cases with low miR-145-5p/high FSCN1 expression showed poor prognosis, and these characteristics together served as independent prognostic indicators of survival. Gain- and loss-of-function studies showed that miR-145-5p overexpression or FSCN1 knockdown inhibited LSCC migration, invasion, and growth by suppressing the epithelial-mesenchymal transition along with inducing cell-cycle arrest and apoptosis. Additionally, hypermethylation of the miR-145-5p promoter suggested that repression of miR-145-5p arises through epigenetic inactivation. LSCC tumor growth in vivo could be inhibited by using miR-145-5p agomir or FSCN1 small interfering RNA (siRNA), which highlights the potential for clinical translation. Collectively, our findings indicate that miR-145-5p plays critical roles in inhibiting the progression of LSCC by suppressing FSCN1. Both miR-145-5p and FSCN1 are important potential prognostic markers and therapeutic targets for LSCC.Graphical abstract
Erratum: Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice (Nature Medicine (2004) 10 (1208-1215))
Authors: N. Komazawa, M. Matsuda, G. Kondoh, W. Mizunoya, M. Iwaki, T. Takagi, Y. Sumikawa, K. Inoue, A. Suzuki, T. W. Mak, T. Nakano, T. Fushiki, J. Takeda, I. Shimomura
Journal: Nature Medicine (2005)
Systems Pharmacology: Defining the Interactions of Drug Combinations
Authors: J.G. Coen van Hasselt, Ravi Iyengar
Journal: The Annual Review of Pharmacology and Toxicology (2018)

The majority of diseases are associated with alterations in multiple molecular pathways and complex interactions at the cellular and organ levels. Single-target monotherapies therefore have intrinsic limitations with respect to their maximum therapeutic benefits. The potential of combination drug therapies has received interest for the treatment of many diseases and is well established in some areas, such as oncology. Combination drug treatments may allow us to identify synergistic drug effects, reduce adverse drug reactions, and address variability in disease characteristics between patients. Identification of combination therapies remains challenging. We discuss current state-of-the-art systems pharmacology approaches to enable rational identification of combination therapies. These approaches, which include characterization of mechanisms of disease and drug action at a systems level, can enable understanding of drug interactions at the molecular, cellular, physiological, and organismal levels. Such multiscale understanding can enable precision medicine by promoting the rational development of combination therapy at the level of individual patients for many diseases.