tbuckley/cabot-search huggingface dataset:
Premature termination codon readthrough upregulates progranulin expression and improves lysosomal function in preclinical models of GRN deficiency
Authors: Jonathan Frew, Alireza Baradaran-Heravi, Aruna D. Balgi, Xiujuan Wu, Tyler D. Yan, Steve Arns, Fahimeh S. Shidmoossavee, Jason Tan, James B. Jaquith, Karen R. Jansen-West, Francis C. Lynn, Fen-Biao Gao, Leonard Petrucelli, Howard H. Feldman, Ian R. Mackenzie, Michel Roberge, Haakon B. Nygaard
Journal: Molecular Neurodegeneration (2020)

Abstract Background Frontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene ( GRN ) is an important cause of FTLD (FTLD- GRN ), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD. Methods We studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X −/− KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD- GRN . To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X. Results The R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X −/− KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X −/− KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X −/− KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV- GRN -R493X-V5 mice. Conclusions Taken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.
Inactivation of the Prolyl Isomerase Pin1 Sensitizes BRCA1-Proficient Breast Cancer to PARP Inhibition
Authors: Man-Li Luo, Fang Zheng, Wenying Chen, Zhi-Mei Liang, Gurushankar Chandramouly, Jianan Tan, Nicholas A. Willis, Chun-Hau Chen, Mateus de Oliveira Taveira, Xiao Zhen Zhou, Kun Ping Lu, Ralph Scully, Gerburg M. Wulf, Hai Hu
Journal: Cancer Research (2020)

PARP inhibitor monotherapies are effective to treat patients with breast, ovary, prostate, and pancreatic cancer with BRCA1 mutations, but not to the much more frequent BRCA wild-type cancers. Searching for strategies that would extend the use of PARP inhibitors to BRCA1-proficient tumors, we found that the stability of BRCA1 protein following ionizing radiation (IR) is maintained by postphosphorylational prolyl-isomerization adjacent to Ser1191 of BRCA1, catalyzed by prolyl-isomerase Pin1. Extinction of Pin1 decreased homologous recombination (HR) to the level of BRCA1-deficient cells. Pin1 stabilizes BRCA1 by preventing ubiquitination of Lys1037 of BRCA1. Loss of Pin1, or introduction of a BRCA1-mutant refractory to Pin1 binding, decreased the ability of BRCA1 to localize to repair foci and augmented IR-induced DNA damage. In vitro growth of HR-proficient breast, prostate, and pancreatic cancer cells were modestly repressed by olaparib or Pin1 inhibition using all-trans retinoic acid (ATRA), while combination treatment resulted in near-complete block of cell proliferation. In MDA-MB-231 xenografts and triple-negative breast cancer patient-derived xenografts, either loss of Pin1 or ATRA treatment reduced BRCA1 expression and sensitized breast tumors to olaparib. Together, our study reveals that Pin1 inhibition, with clinical widely used ATRA, acts as an effective HR disrupter that sensitizes BRCA1-proficient tumors to PARP inhibition. SIGNIFICANCE: PARP inhibitors have been limited to treat homologous recombination-deficient tumors. All-trans retinoic acid, by inhibiting Pin1 and destabilizing BRCA1, extends benefit of PARP inhibitors to patients with homologous recombination-proficient tumors.See related commentary by Cai, p. 2977.
CARE TRAJECTORY AND EARLY CLINICAL FEATURES AMONG PATIENTS WITH 99MTC-PYROPHOSPHATE POSITIVE TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM)
Authors: Andrew Abboud, Alexander Camacho, Austin Nguonly, Neyat Fiseha, Asher Bean, Michael T. Osborne, Nasrien E. Ibrahim, Cian P. McCarthy, Ahmed Tawakol, Frederick L. Ruberg, Reza Sadjadi, William S. David, Gregory D. Lewis, James L. Januzzi, Hanna Gaggin
Journal: Journal of the American College of Cardiology (2020)
Relationship of tumor and stromal autophagy and endocrine responsiveness in breast cancer tissues.
Authors: Takayuki Ueno, Norikazu Masuda, Shigehira Saji, Katsumasa Kuroi, Nobuaki Sato, Hiroyuki Takei, Yutaka Yamamoto, Shinji Ohno, Hiroko Yamashita, Kazufumi Hisamatsu, Kenjiro Aogi, Hiroji Iwata, Hironobu Sasano, Masakazu Toi
Journal: Journal of Clinical Oncology (2013)

571 Background: Neoadjuvant endocrine therapy has been employed to improve surgical outcomes for endocrine responsive breast cancers in post-menopausal women. Endocrine responsiveness is estimated by the expression levels of hormone receptors although heterogeneity in the response is well recognized. To improve the clinical outcome, it is critical to understand how cancer tissues react to the endocrine treatment. Methods: Pre-treatment biopsy samples and post-treatment surgical samples were obtained from 116 patients enrolled onto the multicenter prospective study of neoadjuvant exemestane therapy, JFMC34-0601. Fifty-four paired samples were available for the study. Estrogen receptor, progesterone receptor, HER2, Ki-67 by immunohistochemistry and pathological response were centrally evaluated. Apoptosis was assessed by TUNEL (Roche Diagnostics, Mannheim) and M30 (Roche Diagnostics, Mannheim). Autophagy was assessed by anti-beclin 1 (Novus Biologicals, CO) and anti-LC3 (MBL, Nagoya). Clinical response was assessed based on the RECIST criteria. The Wilcoxon rank-sum test and chi-square test were used for the statistical analysis. Results: The expression of autophagy markers, beclin and LC3, in cancer cells showed significant increases by exemestane (beclin p=0.016; LC3 p=0.0004) whereas TUNEL did not show any change and M30 expression decreased (p=0.01). The increase of beclin expression was associated with the clinical response: responders showed an increase (p=0.039) while non-responders did not. Importantly, the treatment increased autophagy markers not only in cancer cells but in stromal cells (beclin p&lt;0.0001; LC3 p=0.024) while it did not change TUNEL in stromal cells. Patients with stromal beclin-positive showed poor clinical response (3/12) and poor pathological response (0/12) while those with stromal beclin-negative showed good clinical response (26/39) and good pathological response (16/38) (clinical response p=0.011; pathological response p=0.0064). Conclusions: This study suggested that exemestane induced autophagy in both cancer and stromal cells. In addition, stromal autophagy correlated with clinical and pathological response to the endocrine treatment.
MYOCARDIAL FIBROSIS RELATES TO ABNORMAL MYOCARDIAL MECHANICS IN PATIENTS WITH MITRAL VALVE PROLAPSE
Authors: Yasufumi Nagata, Philippe Bertrand, Jacob Dal-Bianco, Serguei Melnitchouk, Vinit Baliyan, Fred Holmvang, Russell A. Norris, Jose L. Guerrero, Michael A. Borger, Reece Moore, Lanqi Hua, Razia Sultana, Brian Yum, Tomas G. Neilan, Michael Picard, Jiwon Kim, Delling N. Francesca, Jonathan Weinsaft, Judy Hung, Robert A. Levine
Journal: Journal of the American College of Cardiology (2020)
PROGNOSTIC ACCURACY OF HEART SCORE IN PREDICTING MAJOR ADVERSE CARDIAC EVENTS IN 30, 90 AND 120 DAYS IN PATIENTS PRESENTING TO THE EMERGENCY DEPARTMENT WITH CHEST PAIN IN A COMMUNITY HEALTH SYSTEM
Authors: Luis Alonso Hernandez Mejia, Anmary Fernandez Betances, Manojna Nimmagadda, Sumit Sohal, Ruchie Bhattarai, Diana Miranda Ruiz, Luis Galindez, Chukwudumebi Okafor, Beulah Jyothy Koduru, Carlos Marin Ramirez, Karen O'Connor Perla, Ramon Checo, Dhiran Verguese
Journal: Journal of the American College of Cardiology (2020)
UTILIZATION OF TRANSESOPHAGEAL ECHOCARDIOGRAM IS ASSOCIATED WITH REDUCED MORTALITY IN PATIENT ADMITTED FOR INFECTIVE ENDOCARDITIS: A PROPENSITY SCORE MATCHING ANALYSIS OF THE NATIONAL INPATIENT SAMPLE
Authors: Lingling Wu, Kirtipal Bhatia, Catherine Teng, Yifeng Yang, Pengyang Li, Bing Yue, Karan Sud, Claire Huang Lucas, Yue Guo
Journal: Journal of the American College of Cardiology (2020)
ENRICHING ARTIFICIAL INTELLIGENCE ST-ELEVATION MYOCARDIAL INFARCTION (STEMI) DETECTION ALGORITHMS WITH DIFFERENTIAL DIAGNOSES
Authors: Sameer Mehta, Francisco Fernandez, Carlos Villagrán, Sebastián Niklitschek, Jorge Ávila, Roberto Botelho, Alejandra Frauenfelder, Daniel Vieira, Mariana Ceschim, Sohail Merchant, Akhil Vaid, Gladys Pinto, Isabella Vallenilla, Genesis Perez Del Nogal, Lilly Prieto, Maritza Luna, Daniela Bou Daher, Lorena Pisana, Juhee Lee
Journal: Journal of the American College of Cardiology (2020)
Coronavirus disease (COVID-19) in a paucisymptomatic patient: epidemiological and clinical challenge in settings with limited community transmission, Italy, February 2020
Authors: Emanuele Nicastri, Alessandra D’Abramo, Giovanni Faggioni, Riccardo De Santis, Andrea Mariano, Luciana Lepore, Filippo Molinari, Giancarlo Petralito, Silvia Fillo, Diego Munzi, Angela Corpolongo, Licia Bordi, Fabrizio Carletti, Concetta Castiletti, Francesca Colavita, Eleonora Lalle, Nazario Bevilacqua, Maria Letizia Giancola, Laura Scorzolini, Simone Lanini, Claudia Palazzolo, Angelo De Domenico, Maria Anna Spinelli, Paola Scognamiglio, Paolo Piredda, Raffaele Iacomino, Andrea Mone, Vincenzo Puro, Nicola Petrosillo, Antonio Battistini, Francesco Vairo, Florigio Lista, Giuseppe Ippolito
Journal: Eurosurveillance (2020)

Data concerning the transmission of the novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) in paucisymptomatic patients are lacking. We report an Italian paucisymptomatic case of coronavirus disease 2019 with multiple biological samples positive for SARS-CoV-2. This case was detected using the World Health Organization protocol on cases and contact investigation. Current discharge criteria and the impact of extra-pulmonary SARS-CoV-2 samples are discussed.
DIFFERENT SPECTRUM OF ADVERSE EVENTS IN PATIENTS WITH NONOBSTRUCTIVE VERSUS OBSTRUCTIVECORONARY ARTERY DISEASE: INSIGHTS FROM THE PROSPECTIVE MULTICENTER IMAGING STUDY FOR EVALUATION OF CHEST PAIN (PROMISE) TRIAL
Authors: Jana Taron, Borek Foldyna, Thomas Mayrhofer, Michael Thomas Osborne, Maros Ferencik, Neha J. Pagidipati, Pamela Douglas, Udo Hoffmann
Journal: Journal of the American College of Cardiology (2020)
INCIDENCE AND IMPLICATIONS OF PULMONARY ARTERY CATHETER USE IN REVASCULARIZED PATIENTS WITH MYOCARDIAL INFARCTION AND CARDIOGENIC SHOCK: INSIGHTS FROM LARGE US NATIONAL DATABASE
Authors: Said Ashraf, Tomo Ando, Oluwole Adegbala, Mohamed Shokr, John Dawdy, Carlos Oviedo, M. Chadi Alraies, Luis C. Afonso, Binita Shah
Journal: Journal of the American College of Cardiology (2020)
Downregulation of Sprouty2 protein in human squamous cell carcinoma of the head and neck and suppression of cell proliferation in vitro.
Authors: Yin-Hsun Feng
Journal: Journal of Clinical Oncology (2013)

e17018 Background: Sprouty2 is known for its tumor-suppressing effect in various human malignant diseases. In head and neck squamous cell carcinoma (HNSCC), the role of sprouty2 in tumorigenesis and clinical implication is still unknown. Methods: Quantitative analysis of mRNA expression of sprouty2 was performed on frozen tumor samples from 42 patients with HNSCC and 19 oral verrucous hyperplasia (OVH). The expression of sprouty2 RNA was determined as the ratio of tested tumor sample and paired counterpart of normal mucosa , Sprouty2 expression and signaling in HNSCC cell lines were assessed by immunoblotting. In vitro proliferation was evaluated in HNSCC cell lines in response to enhanced expression of sprouty2 protein. Inhibition of cell proliferation by tyrosine kinase inhibitor, sorafenib, after modulation by expression of sprouty2 was measured by inhibition concentration. Results: Downregulation of sprouty2 expression was demonstrated in 79% of HNSCC samples compared with paired samples of normal mucosa, and in 58% of OVH samples compared with paired samples of normal mucosa. Low expression of sprouty2 was associated with invasiveness of huam HNSCC (p=0.03). Enhanced expression of sprouty2 protein suppressed the growth of HNSCC cells and signaling of the phosphorylated AKT pathway. After transfection of sprouty2 plasmid, HNSCC cells were more sensitive to sorafenib, a tyrosine kinase inhibitor of Raf and vascular endothelial growth factor receptor. Conclusions: Our data show that sprouty2 expression is down-regulated and behaves as a tumor suppressor in HNSCC. Sprouty2 expression in tumor cells enhances sensitivity to sorafenib.
CLINICAL CHARACTERISTICS AND OUTCOMES OF VENOUS THROMBOEMBOLISM DURING PREGNANCY AND PUERPERIUM INSIGHTS FROM A MULTICENTER REGISTRY
Authors: Islam Elgendy, Annemarie Fogerty, Ángeles Blanco-Molina, Vladimir Rosa, Sebastian Schellong, Andris Skride, Jose Portillo, Patricia Lopez-Miguel, Manuel Monreal, Ido Weinberg
Journal: Journal of the American College of Cardiology (2020)
STATIN TREATMENT PATTERNS AMONG PATIENTS WITH ACUTE MYOCARDIAL INFARCTION IN AN INTEGRATED HEALTHCARE SYSTEM
Authors: Yangyang Liu, Rasha Alkhatib, Yi Li, Abdelhadi Rifai, Pallavi Rane, Mohdhar Habib, Belinda Schludi, Rolin Wade, Catherine McGuiness, Neal Sawlani
Journal: Journal of the American College of Cardiology (2020)
ORBITAL ATHERECTOMY OF THE ILIO-FEMORAL ARTERIES FACILITATES LARGE-BORE ACCESS PRIOR TO TRANSFEMORAL TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Cezar Staniloae, Homam Ibrahim, Danielle Sin, Jorge Fuentes, Carlos Andres Gonzalez-Lengua, Illya Pushkar, Makoto Nakashima, Hasan Jilaihawi, Mathew Williams
Journal: Journal of the American College of Cardiology (2020)
PULMONARY HYPERTENSION CONFERS HIGHER MORTALITY IN PATIENTS WITH ATRIAL FIBRILLATION: A COMMUNITY-BASED STUDY
Authors: Rowlens Melduni, Kalkidan Bishu, Waldemar E. Wysokinski, Bernard J. Gersh, Vuyisile Tlhopane Nkomo, Eddie L. Greene, Garvan C. Kane, Jae K. Oh, Hon-Chi Lee
Journal: Journal of the American College of Cardiology (2020)
GLOBAL LONGITUDINAL STRAIN IS PROGNOSTIC IN LIGHT CHAIN AND TRANSTHYRETIN CARDIAC AMYLOIDOSIS WHILE THE APICAL SPARING RATIO OF LONGITUDINAL STRAIN IS NOT
Authors: Kathleen Zhang, Ray Zhang, Elena Deych, Yuko Soyama, Maria Karmpalioti, Peter Huntjens, Daniel Lenihan, John Gorcsan
Journal: Journal of the American College of Cardiology (2020)
The outcome of acute biphenotypic leukemias in childhood: A single center experience.
Authors: O. Bulent Zulfikar, Betul Cakir, Basak Koc
Journal: Journal of Clinical Oncology (2013)

e18006 Background: Acute biphenotypic leukemias is a rare type of leukemia in childhood, expressing both myeloid and lymphoid markers. We evaluated 22 patients having biphenotype leukemia to document the characteristics and outcome. Methods: We reviewed the files of the children with acute leukemia referred to Istanbul University Oncology Institute between May 2000 – May 2011. Results: There were 21 (22%) patients, 11 girls and 10 boys, having biphenotypic features among 93 acute leukemia patients. Of these, 15 were B-lymhoid/myeloid, 6 were T-lymphoid/myeloid patients. Genetic analysis was performed in 18 patients. Two had t(12;21) positivity; philadelphia chromosome or myeloid translocations including 16 inv., t(8;21), t(15;17) were negative. Median follow up time was 65 months (21-109). All the patients were treated with COG high risk acute lymphoblastic leukemia protocols and achieved remission except 2 patients who required myeloid induction treatment (MRC 10 Protocol). Two of the patients relapsed at 30 th and 34 th months of follow-up. Conclusions: In our series, all the patients are in remission including two relapsed patients who are disease free with stem cell transplantation. The outcome of biphenotypic leukemia patients treated with lymphoblastic leukemia protocols were not lower than acute lymphoblastic leukemia patients. These patients need special care and prompt approach due to their problems during treatment.
Morphine alters respiratory control but not other key obstructive sleep apnoea phenotypes: a randomised trial
Authors: Rodrigo T. Martins, Jayne C. Carberry, David Wang, Luke Rowsell, Ronald R. Grunstein, Danny J. Eckert
Journal: European Respiratory Journal (2020)

Accidental opioid-related deaths are increasing. These often occur during sleep. Opioids such as morphine may worsen obstructive sleep apnoea (OSA). Thus, people with OSA may be at greater risk of harm from morphine. Possible mechanisms include respiratory depression and reductions in drive to the pharyngeal muscles to increase upper airway collapsibility. However, the effects of morphine on the four key phenotypic causes of OSA (upper airway collapsibility (pharyngeal critical closure pressure; P crit ), pharyngeal muscle responsiveness, respiratory arousal threshold and ventilatory control (loop gain) during sleep) are unknown. 21 males with OSA (apnoea–hypopnoea index range 7–67 events·h −1 ) were studied on two nights (1-week washout) according to a double-blind, randomised, cross-over design (ACTRN12613000858796). Participants received 40 mg of MS-Contin on one visit and placebo on the other. Brief reductions in continuous positive airway pressure (CPAP) from the therapeutic level were delivered to induce airflow limitation during non-rapid eye movement (REM) sleep to quantify the four phenotypic traits. Carbon dioxide was delivered via nasal mask on therapeutic CPAP to quantify hypercapnic ventilatory responses during non-REM sleep. Compared to placebo, 40 mg of morphine did not change P crit (−0.1±2.4 versus −0.4±2.2 cmH 2 O, p=0.58), genioglossus muscle responsiveness (−2.2 (−0.87 to −5.4) versus −1.2 (−0.3 to −3.5) μV·cmH 2 O −1 , p=0.22) or arousal threshold (−16.7±6.8 versus −15.4±6.0 cmH 2 O, p=0.41), but did reduce loop gain (−10.1±2.6 versus −4.4±2.1, p=0.04) and hypercapnic ventilatory responses (7.3±1.2 versus 6.1±1.5 L·min −1 , p=0.006). Concordant with recent clinical findings, 40 mg of MS-Contin does not systematically impair airway collapsibility, pharyngeal muscle responsiveness or the arousal threshold in moderately severe OSA patients. However, consistent with blunted chemosensitivity, ventilatory control is altered.
POTENTIAL ROLE OF ADHESION MOLECULES P, E, AND L-SELECTINS IN THE PATHOGENESIS OF PULMONARY EMBOLISM
Authors: Iman Darwish, Yevgeniy Brailovsky, Amir Darki, Debra A. Hoppensteadt, Brett Slajus, Emily Bontekoe, Frank De Stefano, Jawed Fareed
Journal: Journal of the American College of Cardiology (2020)
WARFARIN TIME IN THERAPEUTIC RANGE TRAJECTORIES IN POTENTIAL SWITCHERS TO DIRECT ORAL ANTICOAGULANTS
Authors: Krishna Pundi, Alexander Perino, Jun Fan, Susan Schmitt, Mitra Kothari, Karolina Szummer, Mariam Askari, Paul A. Heidenreich, Mintu Turakhia
Journal: Journal of the American College of Cardiology (2020)
Influenza-induced acute respiratory distress syndrome during the 2010-2016 seasons: bacterial co-infections and outcomes by virus type and subtype
Authors: A. Bal, J.S. Casalegno, C. Melenotte, F. Daviet, L. Ninove, S. Edouard, F. Morfin, M. Valette, X. De Lamballerie, B. Lina, L. Papazian, A. Nougairède, S. Hraiech
Journal: Clinical Microbiology and Infection (2020)
AN ENSEMBLE-BASED APPROACH TO THE DEVELOPMENT OF CLINICAL PREDICTION MODELS FOR FUTURE-ONSET HEART FAILURE AND CORONARY ARTERY DISEASE USING MACHINE LEARNING
Authors: Karim Taha, Heather Joan Ross, Mohammad Peikari, Brigitte Mueller, Chun-Po Steve Fan, Edgar Crowdy, Cedric Manlhiot
Journal: Journal of the American College of Cardiology (2020)
Natriuretic peptide analogues with distinct vasodilatory or renal activity: integrated effects in health and experimental heart failure
Authors: Miriam T Rademaker, Nicola J A Scott, Cho Yeow Koh, R Manjunatha Kini, A Mark Richards
Journal: Cardiovascular Research (2020)

Management of acute decompensated heart failure (ADHF) requires disparate treatments depending on the state of systemic/peripheral perfusion and the presence/absence of expanded body-fluid volumes. There is an unmet need for therapeutics that differentially treat each aspect. Atrial natriuretic peptide (ANP) plays an important role in blood pressure and volume regulation. We investigate for the first time the integrated haemodynamic, endocrine and renal effects of human ANP analogues, modified for exclusive vasodilatory (ANP-DRD) or diuretic (ANP-DGD) activities, in normal health and experimental ADHF.We compared the effects of incremental infusions of ANP analogues ANP-DRD and ANP-DGD with native ANP, in normal (n = 8) and ADHF (n = 8) sheep. ANP-DRD administration increased plasma cyclic guanosine monophosphate (cGMP) in association with dose-dependent reductions in arterial pressure in normal and heart failure (HF) sheep similarly to ANP responses. In contrast to ANP, which in HF produced a diuresis/natriuresis, this analogue was without significant renal effect. Conversely, ANP-DGD induced marked stepwise increases in urinary cGMP, urine volume, and sodium excretion in HF comparable to ANP, but without accompanying vasodilatory effects. All peptides increased packed cell volume relative to control in both states, and in HF, decreased left atrial pressure. In response to ANP-DRD-induced blood pressure reductions, plasma renin activity rose compared to control only during the high dose in normals, and not at all in HF-suggesting relative renin inhibition, with no increase in aldosterone in either state, whereas renin and aldosterone were both significantly reduced by ANP-DGD in HF.These ANP analogues exhibit distinct vasodilatory (ANP-DRD) and diuretic/natriuretic (ANP-DGD) activities, and therefore have the potential to provide precision therapy for ADHF patients with differing pathophysiological derangement of pressure-volume homeostasis.