tbuckley/cabot-search huggingface dataset:
HER2-Driven Breast Tumorigenesis Relies upon Interactions of the Estrogen Receptor with Coactivator MED1
Authors: Yongguang Yang, Marissa Leonard, Yijuan Zhang, Dan Zhao, Charif Mahmoud, Shugufta Khan, Jiang Wang, Elyse E. Lower, Xiaoting Zhang
Journal: Cancer Research (2017)

Studies of the estrogen receptor (ER) coactivator protein Mediator subunit 1 (MED1) have revealed its specific roles in pubertal mammary gland development and potential contributions to breast tumorigenesis, based on coamplification of MED1 and HER2 in certain breast cancers. In this study, we generated a mouse model of mammary tumorigenesis harboring the MMTV-HER2 oncogene and mutation of MED1 to evaluate its role in HER2-driven tumorigenesis. MED1 mutation in its ER-interacting LxxLL motifs was sufficient to delay tumor onset and to impair tumor growth, metastasis, and cancer stem-like cell formation in this model. Mechanistic investigations revealed that MED1 acted directly to regulate ER signaling through the downstream IGF1 pathway but not the AREG pathway. Our findings show that MED1 is critical for HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target.Significance: These findings identify an estrogen receptor-binding protein as a critical mediator of HER2-driven breast tumorigenesis, suggesting its candidacy as a disease-selective therapeutic target. Cancer Res; 78(2); 422-35. ©2017 AACR.
P2.07-028 Efficacy and Safety of Nivolumab in Non-Small Cell Lung Cancer Patients Who Relapse after Thoracic Radiotherapy
Authors: T. Yamaguchi, Y. Oya, Y. Kagawa, H. Furuta, N. Watanabe, J. Shimizu, Y. Horio, T. Uemura, S. Morikawa, K. Imaizumi, T. Hida
Journal: Journal of Thoracic Oncology (2017)
Inhaled Xenon Attenuates Myocardial Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest
Authors: Olli Arola, Antti Saraste, Ruut Laitio, Juhani Airaksinen, Marja Hynninen, Minna Bäcklund, Emmi Ylikoski, Johanna Wennervirta, Mikko Pietilä, Risto O. Roine, Veli-Pekka Harjola, Jussi Niiranen, Kirsi Korpi, Marjut Varpula, Harry Scheinin, Mervyn Maze, Tero Vahlberg, Timo Laitio, Sami Virtanen, Riitta Parkkola, Jani Saunavaara, Juha Martola, Heli Silvennoinen, Marjaana Tiainen, Juha Grönlund, Outi Inkinen, Päivi Silvasti, Eija Nukarinen, Klaus T. Olkkola
Journal: Journal of the American College of Cardiology (2017)
Abstract 17197: Contemporary Trends in the Use of Direct Oral Anticoagulants in Dialysis Patients With Atrial Fibrillation in the United States
Authors: Konstantinos Siontis, Ashley Eckard, Nicole Bhave, Kevin He, Austin Stack, Rajesh Balkrishnan, Rajiv Saran, Brahmajee Nallamothu
Journal: Circulation (2017)

Introduction:  End-stage renal disease (ESRD) patients on dialysis with atrial fibrillation (AF) are at high risk for both thrombotic complications and treatment-associated bleeding. Although direct oral anticoagulants (DOACs) reduce these risks in other populations, their use in dialysis patients is not well characterized and is discouraged due to a lack of empirical data.   Hypothesis:  We sought to characterize the utilization of DOACs in dialysis patients with AF requiring anticoagulation.   Methods:  We identified eligible dialysis patients continuously enrolled in the comprehensive US Renal Data System database who were prescribed warfarin or a DOAC (new start or switch from warfarin) from October 2010 (following initial FDA approval) to December 2015. Patients with valvular heart disease were excluded.   Results:  From a population of 1,313,637 patients with ESRD, 21,593 dialysis patients (female 48.5%, mean age 65.8 years) with a diagnosis of AF and a prescription for oral anticoagulation were identified. A total of 1,690 (7.8%) patients were prescribed DOACs (apixaban n=1,301, dabigatran n=201, rivaroxaban n=188; new start n=1,467, switch from warfarin=223), whereas 19,903 (92.2%) patients were prescribed warfarin only. DOACs were increasingly utilized relative to warfarin over the study period (p-for-trend    Conclusions:  Overall use of DOACs in dialysis patients with AF is increasing rapidly and exceeded over one-quarter of prescriptions in 2015. This highlights the need for further study of these drugs in this complex population that is typically excluded from clinical trials.
Palliative care in hematologic oncology: A needs assessment.
Authors: Gene Decastro, Bridget Earle
Journal: Journal of Clinical Oncology (2017)

137 Background: As patients with hematologic malignancies further enter the scope of practice for palliative medicine physicians, it is important to have an accurate view of their needs. Historically, there is a paucity of research examining symptom burden in this cohort. Even fewer studies explore the experience and perceptions of frontline hematology providers. As our Geriatrics and Palliative Medicine team at North Shore University Hospital (NSUH) embarked upon a collaborative Supportive Care model on our hospital’s dedicated Leukemia and Bone Marrow units, it was important to gain insight from providers about this population. Methods: We conducted a supportive care needs assessment survey of the staff (faculty, fellows, nurse practitioners, nurses, social workers, and case management) from the Leukemia and Bone Marrow units. The survey encompassed eighteen domains and attempted to assess their prevalence in patients according to the Hematology team. It included symptom burden, social and functional complexities, advance care planning, and goals of care. Free text responses were used to capture staff input about challenges in caring for this population Results: We received a response rate of 30% (30/101) with respondents primarily being nurses. It revealed the domains most commonly seen in this patient population by the team. Domains selected as “frequently” or “almost always” were fatigue (97%), nutritional issues (96%), gastrointestinal issues (93%), anxiety (80%), goals of care (69%), and advance directives (69%). We learned that symptom management was a challenge for the staff. They expressed that patients’ expectations about the impact of chemotherapy is a key area of importance. Lastly, communication with patients throughout treatment and caregiver support were consistent concerns from the team. Conclusions: Determining the four most prominent issues encountered by hematology staff were fatigue, nutritional, gastrointestinal, and anxiety can help to refine the symptom assessment. Moreover, communication and decision making concerns were important. These results underscore the necessity of assessing provider perspectives while treating those with hematologic malignancies to guide future initiatives.
Comorbid “treatable traits” in difficult asthma: Current evidence and clinical evaluation
Authors: T. R. Tay, M. Hew
Journal: Allergy (2017)

The care of patients with difficult-to-control asthma ("difficult asthma") is challenging and costly. Despite high-intensity asthma treatment, these patients experience poor asthma control and face the greatest risk of asthma morbidity and mortality. Poor asthma control is often driven by severe asthma biology, which has appropriately been the focus of intense research and phenotype-driven therapies. However, it is increasingly apparent that extra-pulmonary comorbidities also contribute substantially to poor asthma control and a heightened disease burden. These comorbidities have been proposed as "treatable traits" in chronic airways disease, adding impetus to their evaluation and management in difficult asthma. In this review, eight major asthma-related comorbidities are discussed: rhinitis, chronic rhinosinusitis, gastroesophageal reflux, obstructive sleep apnoea, vocal cord dysfunction, obesity, dysfunctional breathing and anxiety/depression. We describe the prevalence, impact and treatment effects of these comorbidities in the difficult asthma population, emphasizing gaps in the current literature. We examine the associations between individual comorbidities and highlight the potential for comorbidity clusters to exert combined effects on asthma outcomes. We conclude by outlining a pragmatic clinical approach to assess comorbidities in difficult asthma.
Exploring the relationship of self-reported lack of appetite to patient characteristics and symptom burden.
Authors: Kelly Hyland, Alyssa L Fenech, Diane Portman, Kristine A. Donovan
Journal: Journal of Clinical Oncology (2017)

187 Background: Cancer anorexia-cachexia syndrome (CACS) in patients is associated with decreases in lean body mass and body weight. Self-reported lack of appetite may be an important indicator for early identification of CACS. The current analyses examined the relationship of perceived lack of appetite to patient characteristics and overall symptom burden in a large mixed cancer sample referred to a palliative care clinic. Methods: We conducted a retrospective review of patients newly referred to an outpatient palliative care clinic over a two-year period. Data on demographic and clinical characteristics and patient-reported symptom scores on the Edmonton Symptom Assessment Scale (ESAS) were abstracted. Pearson’s correlations and ANOVAs were used to assess relationships between variables. Multiple regression analysis was used to evaluate the relative contribution of variables that were significantly correlated with lack of appetite at the univariate level. Results: Data on 544 patients ( M=53.7 years) showed that older age (r=12, p&lt;.01), not being married or in a marriage-like relationship (r=.09, p=.04), having insurance other than managed care insurance (r=.10, p=.02), lower body mass index (BMI; r=.11, p&lt;.01), marijuana use (r=.18, p&lt;.0001), and overall symptom burden (ESAS total score r=.52, p &lt; .0001) were associated with worse lack of appetite ( M=3.5, SD=3.1). Patients who were underweight (BMI &lt;18.5, 46.7%) reported significantly worse lack of appetite than patients who were normal weight, overweight, or obese ( M=3.9, SD=3.2, p&lt;.01). The final hierarchical regression model accounted for 34% of the variance in lack of appetite, with age, marital status, BMI, marijuana use, and total symptom burden remaining significant independent correlates (p’ s &lt;.01). Conclusions: Contrary to expectations, relatively few clinical correlates were associated with self-reported lack of appetite. Future research should explore inter-individual genetic factors to explain alterations in lean body mass and body weight that may contribute to poor appetite in patients. Such factors may be important indicators for early identification of CACS.
Association Between Inhaled Corticosteroid Use and Bone Fracture in Children With Asthma
Authors: Natasha Gray, Andrew Howard, Jingqin Zhu, Laura Y. Feldman, Teresa To
Journal: JAMA Pediatrics (2017)

Daily use of inhaled corticosteroids is a widely recommended treatment for mild persistent asthma in children. There is concern that, similar to systemic corticosteroids, inhaled corticosteroids may have adverse effects on bone health.To determine whether there is an increased risk of bone fracture associated with inhaled corticosteroid use in children with asthma.In this population-based nested case-control study, we used health administrative databases to identify a cohort of children aged 2 to 18 years with a physician diagnosis of asthma between April 1, 2003, and March 31, 2014, who were eligible for public drug coverage through the Ontario Drug Benefit Program (Ontario, Canada). We matched cases of first fracture after asthma diagnosis to fracture-free controls (ratio of 1 to 4) based on date of birth (within 1 year), sex, and age at asthma diagnosis (within 2 years). We used a 1-year lookback period to ascertain history of inhaled corticosteroid use. Multivariable conditional logistic regression was used to obtain an odds ratio (OR) with 95% confidence interval for fracture, comparing no inhaled corticosteroid use vs current, recent, and past use.Inhaled corticosteroid use during the child's 1-year lookback period, measured as current user if the prescription was filled less than 90 days prior to the index date, recent user (91-180 days), past user (181-365 days), or no use.First emergency department visit for fracture after asthma diagnosis, identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes.This study included 19 420 children (61.0% male; largest proportion of children, 31.5%, were aged 6-9 years at their index date). The multivariable regression results did not show a significant association between first fracture after asthma diagnosis and current use (OR, 1.07; 95% CI, 0.97-1.17), recent use (OR, 0.96; 95% CI, 0.86-1.07), or past use (OR, 1.00; 95% CI, 0.91-1.11) of inhaled corticosteroids, compared with no use, while adjusting for sociodemographic factors and other medication use. However, use of systemic corticosteroids in the 1-year lookback period resulted in greater odds of fracture (OR, 1.17; 95% CI, 1.04-1.33).Systemic corticosteroids, but not inhaled corticosteroids, were significantly associated with increased odds of fracture in the pediatric asthma population.
Abstract 11939: Long-Term Evaluation of a Novel Autologous Valve Substitute (Biovalve) With a Stent for Transcatheter Implantation
Authors: Yoshiaki Takewa, Yasuhide Nakayama, Yuichi Atsuta, Satoru Kishimoto, Kazuma Date, Hirohito Sumikura, Masashi Yamanami, Keiichi Kanda, Tsutomu Tajikawa, Takaharu Tanaka, Yoshiyuki Taenaka, Eisuke Tatsumi
Journal: Circulation (2013)

Purpose:  A novel autologous aortic valve with a metallic stent (Biovalve Stent) was developed, using simple, safe and economical in-body tissue engineering. In this study, the long-term evaluation of the Biovalve Stent for transcatheter implantation was investigated in a goat model.   Methods:  Biovalve Stents were prepared by 2-month embedding of the molds, assembled using plastic rods and a metallic stent, in the subcutaneous spaces of goats. After extracting the molds and removing the plastic rods only, Biovalve Stents with tri-leaflets similar to those of the native aortic valves were constituted from completely autologous connective tissues. Ten out of fourteen Biovalve Stents were implanted in the aorta in situ and other four Biovalve Stents were implanted in the pulmonary artery (PA) in situ with transcatheter technique.   Results:  In both aortic and PA cases, the Biovalve Stents were successfully implanted. Angiography showed smooth movement of the leaflets with a little regurgitation under the systemic and pulmonary circulation. The Biovalve Stents were extracted 1, 2 or 5 months after implantation. The leaflets of the Biovalve kept their shape and elasticity even after 5 months and neither calcification nor thrombi were observed. Histological examination showed the cell populations inside the valves and endothelial cells covering the laminar surface of the valve leaflets.   Conclusion:  The Biovalve Stent satisfied the higher requirements of systemic and pulmonary circulation in goats for 5 months with the potential for transcatheter implantation.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years
Authors: Luiz Sérgio F. de Carvalho, Alessandra M. Campos, Andrei C. Sposito
Journal: Diabetes Care (2017)

OBJECTIVE Like mutations with loss of function in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, inhibitors of PCSK9 (PCSK9i) may potentially favor the manifestation of diabetes. RESEARCH DESIGN AND METHODS A meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i versus placebo in the primary hypercholesterolemia setting. Statins and ezetimibe were used in 98.4% of these studies and balanced between PCSK9i and placebo. We calculated relative risks (RRs) and 95% CIs using random- and fixed-effect models. RESULTS We included 68,123 participants (20 RCTs) with median follow-up of 78 weeks. PCSK9i increased fasting blood glucose (weighted mean difference 1.88 mg/dL [95% CI 0.91–2.68]; I2 = 0%; P &amp;lt; 0.001) and HbA1c (0.032% [0.011–0.050]; I2 = 15.5%; P &amp;lt; 0.001) when compared with placebo. This effect was not sufficient to increase incidence of diabetes (RR 1.04 [0.96–1.13]; I2 = 0%; P = 0.427). Exploratory meta-regression analyses indicated an association between the increased risk of diabetes and the potency (P = 0.029) and duration (P = 0.026) of PCSK9i treatment. CONCLUSIONS In the short term, PCSK9i therapy favors a small but significant increase in plasma glycemia and HbA1c.
Urgent versus post-stabilisation antiretroviral treatment in hospitalised HIV-infected children in Kenya (PUSH): a randomised controlled trial
Authors: Irene N Njuguna, Lisa M Cranmer, Vincent O Otieno, Cyrus Mugo, Hellen M Okinyi, Sarah Benki-Nugent, Barbra Richardson, Joshua Stern, Elizabeth Maleche-Obimbo, Dalton C Wamalwa, Grace C John-Stewart
Journal: The Lancet HIV (2017)
2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death
Authors: Sana M. Al-Khatib, William G. Stevenson, Michael J. Ackerman, William J. Bryant, David J. Callans, Anne B. Curtis, Barbara J. Deal, Timm Dickfeld, Michael E. Field, Gregg C. Fonarow, Anne M. Gillis, Christopher B. Granger, Stephen C. Hammill, Mark A. Hlatky, José A. Joglar, G. Neal Kay, Daniel D. Matlock, Robert J. Myerburg, Richard L. Page
Journal: Circulation (2017)
Treatment of Epstein Barr-positive nasopharyngeal carcinoma with adoptively transferred cytotoxic T cells
Authors: Chrystal U. Louis, Karin Straathof, Victoria Torrano, Catherine Bollard, Helen Huls, M. Victoria Gresik, Heidi Weiss, Adrian Gee, Malcolm Brenner, Cliona Rooney, Helen Heslop, Stephen Gottschalk
Journal: Cancer Research (2006)

4000  Background: The majority of undifferentiated nasopharyngeal carcinomas (NPC) are Epstein Barr virus (EBV) positive, and EBV antigens expressed in NPC are attractive targets for the adoptive immunotherapy with antigen-specific cytotoxic T lymphocytes (CTL). We are evaluating the safety and efficacy of EBV-specific CTL (EBV-CTL) in two Phase I clinical trials. In the first clinical trial, EBV-CTL are given alone (Straathof et al.; Blood 2005; 105:1898). The aim of the second trial is to enhance the in vivo expansion of infused EBV-CTL by lymphodepletion prior to cell infusion. Lymphodepletion should result in homeostatic proliferation of the infused T cells that are restoring the lymphoid compartment. A pair of monoclonal antibodies targeted to the CD45 antigen (CD45 Mabs), which have been used in the past to lymphodeplete patients prior to stem cell transplantation, are being used for lymphodepletion prior to EBV-CTL infusions. Study design: The primary objective of these Phase I clinical trials is to determine the safety of escalating doses of EBV-specific CTL with or without CD45 Mabs infusion in EBV-positive NPC patients. The secondary objective is to determine the expansion, persistence and anti-tumor effects of infused EBV-specific CTL. Results: Eighteen patients with advanced NPC have been treated with autologous EBV-CTL (2x107-2x108 cells/m2 per infusion). Patients received between 1 and 5 CTL infusions, which were well tolerated, although one patient developed transient swelling at the site of pre-existing disease. Prior to CTL infusion, 6 patients were in remission (5CR/1CRu) and 12 had refractory/relapsed disease. All 6 patients treated in remission remain in remission 1 to 50 months post-CTL infusion. Ten of 12 patients with disease have been followed for more than 3 months post-CTL infusion; 2 had complete responses and remain in remission 48 months after CTL infusion; 3 had stable disease for 7 - 27 months; 1 had a partial response for 12 months; 4 had progressive disease. Five of 12 patients with relapsed/refractory disease received anti-CD45 Mabs followed by EBV-CTL. Infusion of anti-CD45 Mabs resulted in a transient period of neutropenia (ANC
Abstract 20928: Non-Invasive Mitochondrial Modulation: A Novel Approach to Reduce Brain Injury Following Cardiac Arrest
Authors: Thomas H Sanderson, Joseph M Wider, Erin Gruley, Christian A Reynolds, Karin Przyklenk, Icksoo Lee, Maik Huttemann
Journal: Circulation (2017)

Loss of oxygen delivery to the brain during cardiac arrest can promote significant brain injury. While prompt resuscitation is critical, the reintroduction of oxygen can potentiate injury by promoting reactive oxygen species (ROS) generation. While mitigating ROS damage may serve as a therapeutic avenue for cerebral reperfusion injury, traditional attempts to scavenge ROS have failed. This failure is thought to be due to inherent difficulties with delivery to the brain and sub-cellular targets within the early minutes of reflow. We found that specific infrared light (IRL) wavelengths penetrate the brain and reversibly reduce the activity of cytochrome c oxidase (CcO). Accordingly, we developed a non-pharmacologic therapy using specific IRL wavelengths to non-invasively modulate CcO and circumvent these delivery barriers. Our previous data shows that IRL wavelengths that reduce CcO activity also directly modulate mitochondrial respiratory rate and membrane potential, block mitochondrial ROS production, and limit neuronal death following oxygen-glucose deprivation. We hypothesized that these wavelengths could be used to inhibit ROS generation following resuscitation from cardiac arrest and thus, provide neuroprotection. IRL therapy was first evaluated for neuroprotection in the rat model of global brain ischemia (bilateral carotid occlusion and systemic hypotension - 8 minutes). Rats were randomly enrolled into IRL treatment groups, initiated immediately upon reperfusion. After 14 days, animals subjected to ischemia demonstrated an 86% loss of neurons in the CA1 hippocampus. Strikingly, for the IRL-treated animals, loss of neurons was significantly less, ranging from 17% with the best treatment to 35% with the least efficacious regimen (n=8-12, p&lt;0.05) and preserved neurologic function, assessed by radial arm maze (n = 10, p&lt;0.05). Finally, preliminary data from a swine model of cardiac arrest/resuscitation show a reduction in neurologic deficit score (0-150 scale 0=no deficit, 150=brain dead) with IRL treatment (Cardiac Arrest/Resuscitation = 112, Cardiac Arrest/Resuscitation + IRL treatment = 1: N = 4-6/group). These data demonstrate that IRL therapy may provide a novel strategy for the treatment of post-cardiac arrest brain injury.
Maternal high fat diet and its consequence on the gut microbiome: A rat model
Authors: Phyllis E. Mann, Kevin Huynh, Giovanni Widmer
Journal: Gut Microbes (2017)

The biological changes that occur during pregnancy in the female mammal include shifts in hormonal regulation in preparation for parturition and lactation, and changes in energy metabolism. In women, studies have also shown that during pregnancy there is a reduction in bacterial species richness in the gut. In the current experiment rats were used to model the interaction of diet, reproductive status, and intestinal bacterial microbiota during pregnancy and lactation. In Experiment 1 rats were exposed to either standard chow or high-fat chow (60%) and were divided into two groups: unmated (NULL) or mated (RE). In Experiment 2, both NULL and RE rats were exposed to high-fat chow for a 30-day period. High-throughput sequencing of the 16S rRNA gene revealed that pregnancy impacted the gut microbiota in a similar manner to humans. The impact of reproductive status on microbiota composition, however, was stronger in rats fed a high-fat (HF) diet. Diet-induced changes replicated some of the changes observed in humans, such as increasing the Firmicutes/Bacteroidetes ratio. However, in contrast to humans, pregnancy in rats did not increase β-diversity between microbiota from different animals. These results indicate that during pregnancy in rats, the gut microbiota is altered in a similar manner to that which occurs in women, and that these changes are further exaggerated by exposure to a HF diet. Thus, the rat may allow modelling the effects of consumption of HF food during pregnancy and enable future studies to determine the risks of HF diets during pregnancy and its consequences on the offspring.