tbuckley/cabot-search huggingface dataset:
P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes
Authors: Francesca D’Addio, Andrea Vergani, Luciano Potena, Anna Maestroni, Vera Usuelli, Moufida Ben Nasr, Roberto Bassi, Sara Tezza, Sergio Dellepiane, Basset El Essawy, Maria Iascone, Attilio Iacovoni, Laura Borgese, Kaifeng Liu, Gary Visner, Sirano Dhe-Paganon, Domenico Corradi, Reza Abdi, Randall C. Starling, Franco Folli, Gian Vincenzo Zuccotti, Mohamed H. Sayegh, Peter S. Heeger, Anil Chandraker, Francesco Grigioni, Paolo Fiorina
Journal: Journal of Clinical Investigation (2018)

Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on NLRP3 expression and function in T cells and led to NLRP3 dysregulation and Th17 skewing, delineating a high-risk group of cardiac-transplanted patients who may benefit from personalized therapy.
Abstract 417: Syndecan-4 Regulates the Effect of Osteopontin on Cardiac Fibroblast Function and Phenotype
Authors: Kate M Herum, Andreas Romaine, Arne Olav Melleby, Mari E Strand, Bjørn Braathen, Andrew D McCulloch, Cathrine R Carlson, Geir Christensen
Journal: Circulation Research (2017)

Pressure overload of the heart induces cardiac fibrosis due to excessive production of extracellular matrix by activated cardiac fibroblasts. This compromises cardiac function and may lead to heart failure. The transmembrane proteoglycan syndecan-4 is upregulated in response to pressure overload and can bind extracellular signaling proteins via its heparan sulfate glycosaminoglycan chains. The matricellular protein osteopontin is associated with fibrosis and contains a heparan binding domain that overlaps with its thrombin cleavage site. We here examine the role of the extracellular part of syndecan-4 in regulating proteolytic cleavage and pro-fibrotic activity of the matricellular protein osteopontin. Syndecan-4 and osteopontin mRNA displayed similar regulation patterns in response to left ventricular pressure overload induced by aortic banding in mice. Syndecan-4 and osteopontin bound to each other in left ventricles and fibroblasts as shown by native western blots, immunoprecipitation and immunofluorescent staining. Osteopontin was protected from cleavage by thrombin when pre-incubated with the extracellular domain of syndecan-4. Thrombin-cleaved osteopontin induced a pro-fibrotic phenotype when given to fibroblasts, whereas full-length osteopontin favored a more quiescent phenotype. Thus, our data suggest that the extracellular domain of syndecan-4 protects against the pro-fibrotic effects of osteopontin. Following the initial stage of extracellular remodeling, the extracellular part of syndecan-4 is shed from the cell surface. Accordingly, increased cleaved osteopontin was detected in hypertrophic pressure-overloaded left ventricles three days after aortic banding. Cleaved osteopontin was also detected in plasma from patients with aortic stenosis and displayed a higher cleaved/full-length ratio in the coronary sinus than the radial artery, suggestion that osteopontin is in fact cleaved locally in the heart. Our results indicate an anti-fibrotic effect of the extracellular part of syndecan-4 when it is still attached to the cell surface. Shedding of syndecan-4 from the cell surface at later stages of remodeling exposes osteopontin to cleavage by thrombin, enabling pro-fibrotic effects on cardiac fibroblasts.
Targeting sialic acid residues on lung cancer cells by inhalable boronic acid-decorated albumin nanocomposites for combined chemo/herbal therapy
Authors: Mayada M. Elgohary, Maged W. Helmy, Elsayeda-Zeinab A. Abdelfattah, Doaa M. Ragab, Sana M. Mortada, Jia-You Fang, Ahmed O. Elzoghby
Journal: Journal of Controlled Release (2018)
Challenges in Orphan Drug Development: Identification of Effective Therapy for Thyroid-Associated Ophthalmopathy
Authors: Terry J. Smith
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Thyroid-associated ophthalmopathy (TAO), the ocular manifestation of Graves’ disease, is a process in which orbital connective tissues and extraocular muscles undergo inflammation and remodeling. The condition seems to result from autoimmune responses to antigens shared by the thyroid and orbit. The thyrotropin receptor (TSHR), expressed at low levels in orbital tissues, is a leading candidate antigen. Recent evidence suggests that another protein, the insulin-like growth factor-I receptor (IGF-IR), is overexpressed in TAO, and antibodies against IGF-IR have been detected in patients with the disease. Furthermore, TSHR and IGF-IR form a physical and functional complex, and signaling initiated at TSHR requires IGF-IR activity. Identification of therapy for this rare disease has proven challenging and currently relies on nonspecific and inadequate agents, thus representing an important unmet need. A recently completed therapeutic trial suggests that inhibiting IGF-IR activity with a monoclonal antibody may be an effective and safe treatment for active TAO.
Abstract 15879: LCZ696, an Angiotensin-receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy and Fibrosis in a Rat Model of Chronic Kidney Disease
Authors: Yasunori Suematsu, Ane Nunes, Mahyar Khazaeli, Wanghui Jing, Moti L Kashyap, Nosratola D Vaziri, Hamid Moradi
Journal: Circulation (2016)

Introduction: Chronic kidney disease (CKD) is associated with significant cardiovascular disease including uremic cardiomyopathy. LCZ696 (sacubitril/valsartan), is a promising new agent which has s...
Role of Cell Death in Toxicology: Does It Matter How Cells Die?
Authors: Sten Orrenius
Journal: The Annual Review of Pharmacology and Toxicology (2018)

My research activity started with studies on drug metabolism in rat liver microsomes in the early 1960s. The CO-binding pigment (cytochrome P450) had been discovered a few years earlier and was subsequently found to be involved in steroid hydroxylation in adrenal cortex microsomes. Our early studies suggested that it also participated in the oxidative demethylation of drugs catalyzed by liver microsomes, and that prior treatment of the animals with phenobarbital caused increased levels of the hemoprotein in the liver, and similarly enhanced rates of drug metabolism. Subsequent studies of cytochrome P450-mediated metabolism of toxic drugs in freshly isolated rat hepatocytes characterized critical cellular defense systems and identified mechanisms by which accumulating toxic metabolites could damage and kill the cells. These studies revealed that multiple types of cell death could result from the toxic injury, and that it is important to know which type of cell death results from the toxic injury.
2nd Rehabilitative Ultrasound Imaging Symposium in Physical Therapy, Madrid, Spain, 3–5 June 2016
Authors: Fernández-Carnero S, Calvo-Lobo C, Garrido-Marin A, Arias-Buría Jl
Journal: British Journal of Sports Medicine (2018)

Background The scientific evidence proposed by Ikai &amp; Fukunaga 1 may be considered as a key point to use other techniques different from conventional ultrasound, such as the ultrasound imaging in the physical therapy field. Since the first reported use of USI by physical therapists, there has been a significant growth in ways in which physical therapists are using USI technology 1 .
Abstract 19597: Cardiac Hypertrophy is Associated With Differential Protein Isoform Expression
Authors: Maggie P Lam, Yi Xing, Peipei Ping
Journal: Circulation (2016)

Introduction:  Alternative splicing contributes significantly to the diversification of the mammalian proteome by enabling one gene to give rise to multiple proteins, e.g., fetal and adult isoforms. Pathological cardiac hypertrophy is commonly associated with the re-expression of fetal genes, whereas mutations in splicing factors can cause cardiomyopathies. Advances in RNA-seq have led to the discovery of many novel isoform transcripts, but the protein-level existence and thus physiological functions of many isoforms are poorly understood.   Hypothesis:  Cardiac hypertrophy is associated with widespread differential alternative splicing, which can modulate cardiac phenotypes by altering the ratios of protein isoforms expressed in cardiac cells.   Methods:  We developed an integrated omics approach, which combines re-analysis of RNA-seq data, shotgun proteomics experiments, and computational algorithms to characterize proteome-wide alternative isoform expression. Splice isoforms specific to the C57BL/6J mouse heart were acquired from public ENCODE data (ENCSR000BYQ) and analyzed via a Bowtie-Tophat-rMATS pipeline. We then built a custom software tool to determine transcript translation frames and translate cell-type specific protein sequences. We then searched in-house proteomics datasets on mouse cardiac hypertrophy against the custom sequences to identify protein isoforms during disease progression.   Results:  We identified 816 distinct splice junction peptides in the mammalian heart proteome, including 41 instances in which unique peptides from both alternative isoforms are simultaneously identified. Our data present the first direct protein-level evidence for the existence of a number of alternative splicing events in the heart. We also observed differential expression of alternative isoforms, and present proteomics evidence of the isoform shift of pyruvate kinase (PKM1/2) and alpha-enolase (ENO1), etc., in cardiac hypertrophy.   Conclusions:  Integrated proteotranscriptomics approaches have the potential to expand the catalogue of known molecular changes during cardiac remodeling, and may be applied to identify novel disease drivers and drug targets in other heart disease models.
The Proteome of Prostate Cancer Bone Metastasis Reveals Heterogeneity with Prognostic Implications
Authors: Diego Iglesias-Gato, Elin Thysell, Stefka Tyanova, Sead Crnalic, Alberto Santos, Thiago S. Lima, Tamar Geiger, Jürgen Cox, Anders Widmark, Anders Bergh, Matthias Mann, Amilcar Flores-Morales, Pernilla Wikström
Journal: Clinical Cancer Research (2018)

Purpose: Bone is the most predominant site of distant metastasis in prostate cancer, and patients have limited therapeutic options at this stage.Experimental Design: We performed a system-wide quantitative proteomic analysis of bone metastatic prostate tumors from 22 patients operated to relieve spinal cord compression. At the time of surgery, most patients had relapsed after androgen-deprivation therapy, while 5 were previously untreated. An extended cohort of prostate cancer bone metastases (n = 65) was used for immunohistochemical validation.Results: On average, 5,067 proteins were identified and quantified per tumor. Compared with primary tumors (n = 26), bone metastases were more heterogeneous and showed increased levels of proteins involved in cell-cycle progression, DNA damage response, RNA processing, and fatty acid β-oxidation; and reduced levels of proteins were related to cell adhesion and carbohydrate metabolism. Within bone metastases, we identified two phenotypic subgroups: BM1, expressing higher levels of AR canonical targets, and mitochondrial and Golgi apparatus resident proteins; and BM2, with increased expression of proliferation and DNA repair-related proteins. The two subgroups, validated by the inverse correlation between MCM3 and prostate specific antigen immunoreactivity, were related to disease prognosis, suggesting that this molecular heterogeneity should be considered when developing personalized therapies.Conclusions: This work is the first system-wide quantitative characterization of the proteome of prostate cancer bone metastases and a valuable resource for understanding the etiology of prostate cancer progression. Clin Cancer Res; 24(21); 5433-44. ©2018 AACR.
Facial-Aging App Availability in Waiting Rooms as a Potential Opportunity for Skin Cancer Prevention
Authors: Titus J. Brinker, Joachim Klode, Stefan Esser, Dirk Schadendorf
Journal: JAMA Dermatology (2018)

Facial-Aging App Availability in Waiting Rooms as a Potential Opportunity for Skin Cancer PreventionApproximately 90% of skin cancers are caused by UV exposure.Although dermatologists agree on the importance of primary prevention, busy clinicians often lack time and interventions at hand.Middle-aged men and HIV-positive patients undergoing immunosuppressive therapy are especially at risk of skin cancer, while research for these patient subgroups remains scarce. 1 A randomized clinical trial by Mahler et al 2 showed increased sun protection behavior associated with the use of UV photographs, which indicated the UV damage currently on the participant's face, among young adults at 4 to 5 months and 12 months of follow-up.However, the use of polaroid photography requires staff time, is outdated, does not illustrate future appearance, and is not readily available.Thus, in the waiting room of our HIV outpatient clinic, we provided a standalone version of a free facial-aging app called Sunface that was developed by one of the authors (T.J.B.).The app altered a 3-dimensional, animated selfie of the participant to approximate his or her future appearance based on UV exposure 3 (Figure 1).We aimed to develop a skin cancer prevention intervention that could be available to most patients visiting health care professionals and that would make salient the risks of UV exposure.
Impact of Cardiac Progenitor Cells on Heart Failure and Survival in Single Ventricle Congenital Heart Disease
Authors: Toshikazu Sano, Daiki Ousaka, Takuya Goto, Shuta Ishigami, Kenta Hirai, Shingo Kasahara, Shinichi Ohtsuki, Shunji Sano, Hidemasa Oh
Journal: Circulation Research (2018)

Intracoronary administration of cardiosphere-derived cells (CDCs) in patients with single ventricles resulted in a short-term improvement in cardiac function.To test the hypothesis that CDC infusion is associated with improved cardiac function and reduced mortality in patients with heart failure.We evaluated the effectiveness of CDCs using an integrated cohort study in 101 patients with single ventricles, including 41 patients who received CDC infusion and 60 controls treated with staged palliation alone. Heart failure with preserved ejection fraction (EF) or reduced EF was stratified by the cardiac function after surgical reconstruction. The main outcome measure was to evaluate the magnitude of improvement in cardiac function and all-cause mortality at 2 years. Animal studies were conducted to clarify the underlying mechanisms of heart failure with preserved EF and heart failure with reduced EF phenotypes. At 2 years, CDC infusion increased ventricular function (stage 2: +8.4±10.0% versus +1.6±6.4%, P=0.03; stage 3: +7.9±7.5% versus -1.1±5.5%, P<0.001) compared with controls. In all available follow-up data, survival did not differ between the 2 groups (log-rank P=0.225), whereas overall patients treated by CDCs had lower incidences of late failure (P=0.022), adverse events (P=0.013), and catheter intervention (P=0.005) compared with controls. CDC infusion was associated with a lower risk of adverse events (hazard ratio, 0.411; 95% CI, 0.179-0.942; P=0.036). Notably, CDC infusion reduced mortality (P=0.038) and late complications (P<0.05) in patients with heart failure with reduced EF but not with heart failure with preserved EF. CDC-treated rats significantly reversed myocardial fibrosis with differential collagen deposition and inflammatory responses between the heart failure phenotypes.CDC administration in patients with single ventricles showed favorable effects on ventricular function and was associated with reduced late complications except for all-cause mortality after staged procedures. Patients with heart failure with reduced EF but not heart failure with preserved EF treated by CDCs resulted in significant improvement in clinical outcome.URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01273857 and NCT01829750.
Warner Slack: “Patients are the most underused resource”
Authors: Dave deBronkart, Daniel Z Sands
Journal: BMJ (2018)

Warner Slack, the visionary physician who wrote that the patient is the “largest and least utilised resource in healthcare,”1 died from pulmonary fibrosis on 23 June at the age of 85. Accolades have come in from scores of people who, like the authors, benefitted from his wisdom and generous mentoring.

Slack foresaw, with remarkable clarity, both the extent and the limitations of what computers could contribute to medicine. His 1997 book Cybermedicine: How Computing Empowers Doctors and Patients for Better Care 2 encapsulated his steadfast belief that information technology, “implemented wisely and well,” can empower both physicians and patients.

Technology was a lifelong aspect of Slack’s work. In 1966 he created software to take a patient’s medical history, saving physician time and improving accuracy. In the 1970s, Slack and Howard Bleich created the Center for Clinical Computing (CCC) at Harvard Medical School, now Division of Clinical …
A RIPK3-PGE2 Circuit Mediates Myeloid-Derived Suppressor Cell–Potentiated Colorectal Carcinogenesis
Authors: Guifang Yan, Huakan Zhao, Qi Zhang, Yu Zhou, Lei Wu, Juan Lei, Xiang Wang, Jiangang Zhang, Xiao Zhang, Lu Zheng, Guangsheng Du, Weidong Xiao, Bo Tang, Hongming Miao, Yongsheng Li
Journal: Cancer Research (2018)

Abstract Receptor-interacting protein kinase 3 (RIPK3) is essential for mucosal repair in inflammatory bowel diseases (IBD) and colorectal cancer. However, its role in tumor immunity is unknown. Here, we report that decreased RIPK3 in colorectal cancer correlates with the accumulation of myeloid-derived suppressor cells (MDSC). Deficiency of RIPK3 boosted tumorigenesis via accumulation and immunosuppressive activity of MDSCs. Reduction of RIPK3 in MDSC and colorectal cancer cells elicited NFκB-transcribed COX-2, which catalyzed the synthesis of prostaglandin E2 (PGE2). PGE2 exacerbated the immunosuppressive activity of MDSCs and accelerated tumor growth. Moreover, PGE2 suppressed RIPK3 expression while enhancing expression of NFκB and COX-2 in MDSCs and colorectal cancer cells. Inhibition of COX-2 or PGE2 receptors reversed the immunosuppressive activity of MDSCs and dampened tumorigenesis. Patient databases also delineated the correlation of RIPK3 and COX-2 expression with colorectal cancer survival. Our findings demonstrate a novel signaling circuit by which RIPK3 and PGE2 regulate tumor immunity, providing potential ideas for immunotherapy against colorectal cancer. Significance: A novel signaling circuit involving RIPK3 and PGE2 enhances accumulation and immunosuppressive activity of MDSCs, implicating its potential as a therapeutic target in anticancer immunotherapy. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5586/F1.large.jpg. Cancer Res; 78(19); 5586–99. ©2018 AACR.
PPARγ Ligand Inhibits Osteopontin Gene Expression Through Interference With Binding of Nuclear Factors to A/T-Rich Sequence in THP-1 Cells
Authors: YukoOyama, NobuhiroAkuzawa, RyozoNagai, MasahikoKurabayashi
Journal: Circulation Research (2002)

Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily that acts as a key player in adipocyte differentiation, glucose metabolism, and macrophage differentiation. Osteopontin (OPN), a component of extracellular matrix, is elevated during neointimal formation in the vessel wall and is synthesized by macrophages in atherosclerotic plaques. In the present study, we investigated the molecular mechanisms regulating OPN gene expression by PPARγ in THP-1 cells, a cell line derived from human monocytic leukemia cells. Northern and Western blot analyses showed that exposure of THP-1 cells to PMA (phorbol 12-myristate 13-acetate) increases OPN mRNA and protein levels in a time-dependent manner. PMA-induced OPN expression was significantly decreased by troglitazone (Tro) and other PPARγ ligands. Transient transfection assays of the human OPN promoter/luciferase construct showed that PPARγ represses OPN promoter activity, and the PPARγ-responsive region within the OPN pro...
Abstract 17980: Irisin Protects Against Hypoxia and Reoxygenation Injury Through Hdac4
Authors: Yu T Zhao, Jianfeng Du, Hao Wang, Ling Zhang, Ting C Zhao
Journal: Circulation (2016)

Introduction: Irisin is a recently identified myokine that brings increases in energy expenditure and contributes to the beneficial effects of exercise on the browning of white adipose tissues. How...
Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to-Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT)
Authors: M. Loredana Marcovecchio, Scott T. Chiesa, Jane Armitage, Denis Daneman, Kim C. Donaghue, Timothy W. Jones, Farid H. Mahmud, Sally M. Marshall, H. Andrew W. Neil, R. Neil Dalton, John Deanfield, David B. Dunger, Carlo Acerini, Fran Ackland, Binu Anand, Tim Barrett, Virginia Birrell, Fiona Campbell, Marietta Charakida, Tim Cheetham, Scott Chiesa, Chris Cooper, Ian Doughty, Atanu Dutta, Julie Edge, Alastair Gray, Julian Hamilton-Shield, Nick Mann, M. Loredana Marcovecchio, Gerry Rayman, Jonathon Mark Robinson, Michelle Russell-Taylor, Vengudi Sankar, Anne Smith, Nandu Thalange, Chandan Yaliwal, Paul Benitez-Aguirre, Fergus Cameron, Andrew Cotterill, Jennifer Couper, Maria Craig, Elizabeth Davis, Kim Donaghue, Timothy W. Jones, Charles Verge, Phil Bergman, Christine Rodda, Cheril Clarson, Jacqueline Curtis, Denis Daneman, Farid Mahmud, Etienne Sochett, Sally Marshall, Jane Armitage, Polly Bingley, William Van’t Hoff, David Dunger, Neil Dalton, Denis Daneman, Andrew Neil, John Deanfield, Tim Jones, Kim Donaghue, Colin Baigent, Jon Emberson, Marcus Flather, Rudy Bilous
Journal: Diabetes Care (2018)

Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10-16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2-4-year AdDIT study.One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study.After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log-rank P < 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08-8.85]) and HbA1c (1.37 [1.10-1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], P = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group (P < 0.05).ACR at the higher end of the normal range at the age of 10-16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA1c.