tbuckley/cabot-search huggingface dataset:
Abstract 15099: Suppression of Autophagic Flux by Sequestration of p62 Promotes RIP1-mediated Necroptosis in Cardiomyocytes
Authors: Makoto Ogasawara, Toshiyuki Yano, Takayuki Miki, Masaya Tanno, Atsushi Kuno, Hidemichi Kouzu, Toshiyuki Tobisawa, Shingo Muratsubaki, Kohei Ohno, Keitaro Nishizawa, Satoko Ishikawa, Tetsuji Miura
Journal: Circulation (2015)

Purpose: Necroptosis, a programmed form of necrosis, has been implicated in various pathological conditions including heart failure. Here we examined whether and how receptor-interacting protein kinase (RIP) 1-dependent necroptosis is functionally linked with autophagy in cardiomyocytes. Methods and results: In H9c2 cells, the necroptotic pathway was activated by TNF-α (TNF, 50 ng/ml) alone or by co-incubation of TNF with 20 mM z-VAD-fmk (zVAD), a pan-caspase inhibitor. TNF increased LDH activity in the culture medium from 26.6±4.3% of total LDH activity in the vehicle-treated control to 39.1±4.8%, suggesting induction of necrosis. Addition of zVAD to TNF (TNF/zVAD) further increased the LDH activity to 70.6±2.7%. The augmented cell death by TNF/zVAD was completely reversed by necrostatin-1 (39.4±4.0%), a RIP1 inhibitor, and was attenuated by rapamycin (10 nM), a promoter of autophagy (49.4±2.0%). Immunoblot analyses showed that TNF/zVAD significantly increased the level of LC3-II. The accumulation of LC3-II protein was not further increased by bafilomycin A1 (100 nM), an inhibitor of lysosomal degradation, indicating that accumulation of LC3-II by TNF/zVAD reflected suppression of autophagic flux. Immunoprecipitation experiments revealed that TNF/zVAD reduced interaction between LC3-II and p62, an autophagy adaptor protein, and conversely increased interaction between RIP1 and p62. The changes in p62 interactosomes by TNF/zVAD were reversed by pretreatment with rapamycin. On the other hand, TNF/zVAD-induced cell death when p62 was knocked down was still sensitive to necrostatin-1, indicating that a p62-independent pathway is also involved in RIP1-mediated necroptosis. Conclusions: Suppression of autophagic flux by p62 sequesteration from p62-LC3-II complexes and its recruitment to RIP1 promotes RIP1-dependent necroptosis by TNF/zVAD.
Combination of oximetry and sleep questionnaires as screening tools for CPAP initiation in patients with obstructive sleep apnea
Authors: A. Pataka, G. Kalamaras, E. Vlachogianni, P. Argyropoulou
Journal: Pulmonology (2018)

Obstructive sleep apnea syndrome (OSA) is a cause of high morbidity and mortality so diagnosis and treatment is essential. Questionnaires and oximetry have been used for OSA screening.To evaluate the clinical utility of different sleep questionnaires (Stop Bang (S-B), Berlin (BQ), Epworth Sleepiness Scale (ESS)) in deciding on treatment with Continuous Positive Airway Pressure (CPAP) and to examine whether the combination of the questionnaires alone or with oximetry improves their predictive value for CPAP initiation.Patients visiting a Sleep Clinic were prospectively studied. They completed the questionnaires. Home oximetry and in laboratory polysomnography (PSG) were performed within 3-20 days. Patients received CPAP if they were symptomatic with AHI≥5 or had AHI>15.204 patients were studied (77.5%males, mean age 51.8±13.8 years, BMI 32.8±6.2kg/m2). There was a good correlation between Oxygen Desaturation Index of oximetry (ODIox) and ODI of PSG (r=0.95, p<0.0001) and between ODIox and AHI (r=0.811, p<0.0001). ODIox≥15 presented sensitivity 89.3%, specificity 83.5%, PPV 87% NPV 86.4% for CPAP initiation. ESS had the best specificity (68.6%) and PPV (68.6%) and S-B had the highest sensitivity (98%) and NPV (80%) but the lowest specificity (11%) for CPAP initiation. The combination of different questionnaires or questionnaires with oximetry did not improve their predictive value for CPAP initiation.Oximetry accurately predicted CPAP initiation. Questionnaires alone had limited value as screening tools for CPAP initiation; the combination of oximetry with questionnaires did not improve their predictive value.
Addition of durvalumab (Dur) upon progression to bevacizumab (Bev) maintenance in advanced HER2-negative (HERNEG) breast cancer (BC): Safety, efficacy and biomarkers
Authors: M. Quintela-Fandino, L.M. Manso Sànchez, E. Holgado Martín, M.C. Moreno, S. Morales Murillo, B. Bermejo De Las Heras, D. Malon Gimenez, R. Colomer Bosch, L. Gonzalez Cortijo, J. Hornedo, S. Mouron, M. Muñoz, S. Escudero, R. Blanco, S. Mañes
Journal: Annals of Oncology (2018)
P10.15 Molecular Classification of Malignant Glioma
Authors: G. Johansson, T. Brännström, U. Andersson, I. Golovleva, B. Melin
Journal: Neuro-Oncology (2017)

Background: Malignant glioma are devastating tumors with poor prognosis. In recent years, the classification of glioma have evolved greatly due to exploration of several molecular tools in addition to the traditional immunohistochemistry. Methods: To further evolve this classification, we thoroughly characterized the molecular and histological signature of 367 glioma patients from Sweden. We first obtained the full medical history and histological classification, along with matched blood samples and unstained tissue slides. We have performed extensive molecular characterization using genome wide association studies, methylation arrays and telomere length assays. We have extended the classification to include IDH1 mutations, chromosome 1p/19q co-deletion, EGFR amplification as well as the expression of two novel cell signaling regulators. The statistical analysis is ongoing and will reveal how well we can classify the tumors by combining the above mentioned techniques. Results: As expected we found EGFR upregulation in almost 50% of the patients with glioblastoma and one third of patients with anaplastic astrocytoma and anaplastic oligodendroglioma. No EGFR expression was found in any patient with low grade glioma. In consistence with previous studies 70% of the IDH1 mutated oligodendroglioma had 1p/19q co-deletion. In the IDH1 wildtype oligodendroglioma, about 50% of the low grade tumors had 1p/19q co-deletion. Interestingly, we found complete 1p/19q co-deletion in about 10% of the IDH1 wild type glioblastoma. Conclusion: Today, 1p/19q co-deletion is normally only studied in suspected oligodendroglioma and not in all types of glioma. Pending the clinical relevance of the 1p/19q co-deleted glioblastoma, it might be wise to expand the 1p/19q classification by including all types of glioma.
Premalignant and malignant oral mucosal lesions: Clinical and pathological findings
Authors: Mayra B.C. Maymone, Robert O. Greer, Jeffery Kesecker, Priya Cherukuri Sahitya, Lauren K. Burdine, Anh-Dao Cheng, Alexandre C. Maymone, Neelam A. Vashi
Journal: Journal of the American Academy of Dermatology (2018)
Abstract 9901: Cardiac Protection From Hypoxic Injury by a Novel Synthetic Peptide Targeting the Activator of G-Protein Signaling 8-Mediated Gβγ Signal
Authors: Motohiko Sato, Masahiro Hiraoka, Yukiko Yamane, Feng Xianfeng, Yoshihiro Ishikawa
Journal: Circulation (2011)

Ischemia-reperfusion injury of the heart is associated with activation of multiple signaling pathways including those of heterotrimeric G-protein. We identified an ischemia-inducible G-protein activator, activator of G-protein signaling 8 (AGS8), which interacts directly with Gβγ and regulates Gβγ signaling in cells. The knockdown of AGS8 by siRNA dramatically blocked hypoxia-induced apoptosis of cardiomyocytes, suggesting AGS8 triggered a critical cascade leading to cell death, which could be a novel therapeutic target. To investigate this possibility further, we attempted to protect cardiomyocytes from hypoxia-induced apoptosis by utilizing a synthetic peptide which disrupts AGS8-mediated Gβγ signaling. We first developed a peptide (AGS8-peptide) that blocked the association of Gβγ with AGS8 based on amino acid sequences of the Gβγ binding domain of AGS8. We then investigated the effects of the AGS8-peptide on cardiomyocytes exposed to hypoxic stress. Cultured rat neonatal cardiomyocytes were exposed to hypoxia (6 h)/reoxygenation (18 h) following transfection with AGS8-peptide. Interestingly, AGS8-peptide effectively blocked apoptosis in cardiomyocytes, as determined by DNA end-labeling (9.7±1.5% of control, p&lt;0.05, mean±SEM) and an increase in cleaved caspase-3 (36.7±6.5% of control, p&lt;0.05, mean±SEM). Because AGS8-mediated Gβγ signaling influenced apoptosis of cardiomyocytes via channel protein connexin 43 (CX43), the effects of AGS8-peptide on permeability/localization of CX43 were examined. The permeability of CX43 following the exposure of cells to hypoxia, as determined by a flux of fluorescence dye (Lucifer yellow), was decreased (34.1±4.3%, p&lt;0.05 vs. normoxia control, mean±SEM). However, AGS8-peptide blocked the decrease of membrane permeability (93.0±12.3%, p&lt;0.05 vs. control group, mean±SEM). AGS8-peptide also blocked hypoxia-induced internalization of CX43 in cardiomyocytes (8.3±1.3% of control, p&lt;0.05, mean±SEM). These data indicate the importance of AGS8-mediated Gβγ signaling in cardiomyocytes and suggest that the targeted disruption of the AGS8 signal will provide a novel approach for protecting the myocardium against ischemic injury.
FDA Joins New Effort to Strengthen Medical Device Cybersecurity
Authors: Rebecca Voelker
Journal: JAMA (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 19762: MicroRNAs Predict Left Ventricular Reverse Remodeling in Chronic Systolic Heart Failure
Authors: Olivia Ziegler, Ravi Shah, Kirsty Danielson, Kristina Hanspers, Michael Tackett, Alex Pico, Saumya Das, James Januzzi
Journal: Circulation (2016)

Background: Current strategies to identify individuals who have LV reverse remodeling (LVRR) for subsequent treatment are limited. Plasma circulating microRNAs (miRNAs) represent an emerging area o...
Gels without Vapor Pressure: Soft, Nonaqueous, and Solvent‐Free Supramolecular Biomaterials for Prospective Parenteral Drug Delivery Applications
Authors: Anthony Tabet, Chun Wang
Journal: Advanced Healthcare Materials (2018)

Abstract The engineering advantages of soft, nonaqueous, solvent‐free supramolecular materials have resulted in their emerging transition and adoption from a predominantly food, cosmetics, and paint industry‐driven technology to biocompatible matrices for parenteral drug delivery. Factors that have contributed to this trend are the drastic increase of hydrophobic and combination drugs in the pharmaceutical pipeline and the limitations of hydrated drug delivery materials with regard to poorly soluble drugs and biologics. This review highlights examples of nonaqueous, soft supramolecular materials, illustrates molecular engineering principles that may give rise to novel structures and unique properties, and explores emerging opportunities of application of these materials in parenteral drug delivery.
United in Fight against prOstate cancer registry (UFO): Treatment patterns and quality of life from a large, multi-center, longitudinal cohort study in Asia
Authors: R. Kanesvaran, H. Uemura, D. Ye, E. Chiong, B. Lojanapiwat, Y.-S. Pu, S. Kumar Rawal, A.H.A. Razack, H. Zeng, B.H. Chung, Y.-S. Tsai, M.Y. Noor Ashani, Y. Liu, M. Asinas-Tan, W. Liu, G.K.M. Low, M. van Kooten Losio
Journal: Annals of Oncology (2018)
Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging
Authors: Vladimir Shalgunov, Aren van Waarde, Jan Booij, Martin C. Michel, Rudi A. J. O. Dierckx, Philip H. Elsinga
Journal: Medicinal Research Reviews (2018)

Abstract The concept of the high‐affinity state postulates that a certain subset of G‐protein‐coupled receptors is primarily responsible for receptor signaling in the living brain. Assessing the abundance of this subset is thus potentially highly relevant for studies concerning the responses of neurotransmission to pharmacological or physiological stimuli and the dysregulation of neurotransmission in neurological or psychiatric disorders. The high‐affinity state is preferentially recognized by agonists in vitro. For this reason, agonist tracers have been developed as tools for the noninvasive imaging of the high‐affinity state with positron emission tomography (PET). This review provides an overview of agonist tracers that have been developed for PET imaging of the brain, and the experimental paradigms that have been developed for the estimation of the relative abundance of receptors configured in the high‐affinity state. Agonist tracers appear to be more sensitive to endogenous neurotransmitter challenge than antagonists, as was originally expected. However, other expectations regarding agonist tracers have not been fulfilled. Potential reasons for difficulties in detecting the high‐affinity state in vivo are discussed.
NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study
Authors: Morgane Cheminant, Julie Bruneau, Georgia Malamut, David Sibon, Nicolas Guegan, Tom van Gils, Sascha Cording, Amélie Trinquand, Virginie Verkarre, Ludovic Lhermitte, Nicole Brousse, Anne-Sophie Jannot, Sherine Khater, Laurent Frenzel, Richard Delarue, Felipe Suarez, Ambroise Marçais, Chris JJ Mulder, Elizabeth Macintyre, Vahid Asnafi, Laurent Pouyet, Cécile Bonnafous, Florence Lhospice, Thierry Jo Molina, Bertrand Meresse, Christophe Cellier, Nadine Cerf-Bensussan, Olivier Hermine
Journal: Gut (2018)

Objectives Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). Design NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. Results NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of &gt;25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo . Conclusion NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.
White button mushrooms and prostate cancer prevention
Authors: Sheryl Phung, Jingjing Ye, Gene Hur, Sharon Kwok, Ki Lui, Shiuan Chen
Journal: Cancer Research (2005)

5174  A series of in vitro and in vivo experiments have been carried out to demonstrate that white button mushrooms can be a chemopreventing agent against prostate cancer. A 20% methanol extract of white button mushrooms has been found to contain phytochemicals that suppress steroid 5alpha-reductase and aromatase. Steroid 5alpha-reductase converts testosterone to dihydrotestosterone (DHT) and has been shown to play an important role in the development of prostate cancer and benign prostate hyperplasia. The use of steroid 5alpha-reductase inhibitors has been found to decrease the incidence of prostate cancer. Aromatase is the enzyme that converts androgen to estrogen. This enzyme is expressed in prostate cancer cells and has been suggested to play a role in androgen-independent prostate cancer. Cell culture experiments involving cells treated with mushroom extract for ten days, have been carried out. Through these experiments, we have revealed that white button mushroom extract has the ability to suppress the growth of hormone resistant prostate cancer cells such as PC-3 and DU145 as well as hormone dependent LNCaP cells in a dose dependent manner. The mushroom extract was found not to affect the proliferation of normal prostate epithelial cells. We have also carried out in vivo chemoprevention studies using prostate cancer cell-implanted male athymic nude mouse models. There were two groups of mice gavaged with two different concentrations of mushroom extract and also a pair-fed control group that was gavaged with water. From this in vivo study, we demonstrated that our mushroom extract decreased tumor size in a dose dependent manner. Pathology results indicated that there was significant increase in apoptosis compared to the control as well as decrease in cell proliferation. Therefore, our findings on white button mushrooms indicate that the intake of mushrooms could reduce the incidence of prostate cancer. An effective chemopreventive agent should not significantly alter quality of life, and is ideally inexpensive, safe and well tolerated. This prevention method should be readily available and affordable to the general population including underserved populations (*These authors contributed equally to this work).
Increasing Safe Outpatient Management of Emergency Department Patients With Pulmonary Embolism
Authors: David R. Vinson, Dustin G. Mark, Uli K. Chettipally, Jie Huang, Adina S. Rauchwerger, Mary E. Reed, James S. Lin, Mamata V. Kene, David H. Wang, Dana R. Sax, Tamara S. Pleshakov, Ian D. McLachlan, Cyrus K. Yamin, Andrew R. Elms, Hilary R. Iskin, Ridhima Vemula, Donald M. Yealy, Dustin W. Ballard
Journal: Annals of Internal Medicine (2018)

Background: Many low-risk patients with acute pulmonary embolism (PE) in the emergency department (ED) are eligible for outpatient care but are hospitalized nonetheless. One impediment to home discharge is the difficulty of identifying which patients can safely forgo hospitalization. Objective: To evaluate the effect of an integrated electronic clinical decision support system (CDSS) to facilitate risk stratification and decision making at the site of care for patients with acute PE. Design: Controlled pragmatic trial. (ClinicalTrials.gov: NCT03601676) Setting: All 21 community EDs of an integrated health care delivery system (Kaiser Permanente Northern California). Patients: Adult ED patients with acute PE. Intervention: Ten intervention sites selected by convenience received a multidimensional technology and education intervention at month 9 of a 16-month study period (January 2014 to April 2015); the remaining 11 sites served as concurrent controls. Measurements: The primary outcome was discharge to home from either the ED or a short-term (<24-hour) outpatient observation unit based in the ED. Adverse outcomes included return visits for PE-related symptoms within 5 days and recurrent venous thromboembolism, major hemorrhage, and all-cause mortality within 30 days. A difference-in-differences approach was used to compare pre–post changes at intervention versus control sites, with adjustment for demographic and clinical characteristics. Results: Among 881 eligible patients diagnosed with PE at intervention sites and 822 at control sites, adjusted home discharge increased at intervention sites (17.4% pre- to 28.0% postintervention) without a concurrent increase at control sites (15.1% pre- and 14.5% postintervention). The difference-in-differences comparison was 11.3 percentage points (95% CI, 3.0 to 19.5 percentage points; P = 0.007). No increases were seen in 5-day return visits related to PE or in 30-day major adverse outcomes associated with CDSS implementation. Limitation: Lack of random allocation. Conclusion: Implementation and structured promotion of a CDSS to aid physicians in site-of-care decision making for ED patients with acute PE safely increased outpatient management. Primary Funding Source: Garfield Memorial National Research Fund and The Permanente Medical Group Delivery Science and Physician Researcher Programs.
Whole-body Imaging of Cell Death Provides a Systemic, Minimally Invasive, Dynamic, and Near-real Time Indicator for Chemotherapeutic Drug Toxicity
Authors: Steven E. Johnson, Andrey Ugolkov, Chad R. Haney, Gennadiy Bondarenko, Lin Li, Emily A. Waters, Raymond Bergan, Andy Tran, Thomas V. O'Halloran, Andrew Mazar, Ming Zhao
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Response to toxicity in chemotherapies varies considerably from tissue to tissue and from patient to patient. An ability to monitor the tissue damage done by chemotherapy may have a profound impact on treatment and prognosis allowing for a proactive management in understanding and mitigating such events. For the first time, we investigated the feasibility of using whole-body imaging to map chemotherapeutic drug–induced toxicity on an individual basis. Experimental Design: In a preclinical proof-of-concept, rats were treated with a single clinical dose of cyclophosphamide, methotrexate, or cisplatin. In vivo whole-body imaging data were acquired using 99mTc-duramycin, which identifies dead and dying cells as an unambiguous marker for tissue injury in susceptible organs. Imaging results were cross-validated using quantitative ex vivo measurements and histopathology and compared with standard blood and serum panels for toxicology. Results: The in vivo whole-body imaging data detected widespread changes, where spatially heterogeneous toxic effects were identified across different tissues, within substructures of organs, as well as among different individuals. The signal changes were consistent with established toxicity profiles of these chemotherapeutic drugs. Apart from generating a map of susceptible tissues, this in vivo imaging approach was more sensitive compared with conventional blood and serum markers used in toxicology. Also, repeated imaging during the acute period after drug treatment captured different kinetics of tissue injury among susceptible organs in males and females. Conclusions: This novel and highly translational imaging approach shows promise in optimizing therapeutic decisions by detecting and managing drug toxicity on a personalized basis. Toxicity to normal tissues is a significant limitation in chemotherapies. This work demonstrated an in vivo imaging-based approach for characterizing toxicity-induced tissue injury in a systemic, dynamic, and near-real time fashion. This novel approach shows promise in optimizing therapeutic decisions by monitoring drug toxicity on a personalized basis.