tbuckley/cabot-search huggingface dataset:
The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis
Authors: Pit Ullmann, Fabien Rodriguez, Martine Schmitz, Steffen K. Meurer, Komal Qureshi-Baig, Paul Felten, Aurélien Ginolhac, Laurent Antunes, Sonia Frasquilho, Nikolaus Zügel, Ralf Weiskirchen, Serge Haan, Elisabeth Letellier
Journal: Cancer Research (2018)

Abstract The vast majority of colorectal cancer–related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. Significance: These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg. Cancer Res; 78(14); 3793–808. ©2018 AACR.
Association of Timing of Aortic Valve Replacement Surgery After Stroke With Risk of Recurrent Stroke and Mortality
Authors: Charlotte Andreasen, Mads Emil Jørgensen, Gunnar H. Gislason, Andreas Martinsson, Robert D. Sanders, Jawdat Abdulla, Per Føge Jensen, Christian Torp-Pedersen, Lars Køber, Charlotte Andersson
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> Timing of surgical aortic valve replacement (SAVR) in patients with aortic valve stenosis and previous stroke for the risk of recurrent stroke is insufficiently investigated. <h3>Objective</h3> To evaluate the association of time elapsed between previous stroke and SAVR with the risk of recurrent perioperative stroke, major adverse cardiovascular events (MACE), and mortality among patients with aortic valve stenosis. <h3>Design, Setting, and Participants</h3> This cohort study using data from Danish administrative registries included all patients with aortic valve stenosis older than 18 years who underwent SAVR between 1996 and 2014 (n = 14 030). Patients who received simultaneous mitral, tricuspid, or pulmonary valve surgery and patients with endocarditis 1 year prior to surgery were excluded. Data were analyzed from March 2017 to January 2018. <h3>Exposures</h3> Time elapsed between prior stroke and SAVR (&lt;3 months, 3-&lt;12 months, ≥12 months, and no prior stroke). <h3>Main Outcomes and Measures</h3> Thirty-day risks of MACE, ischemic stroke, and all-cause mortality reported as absolute events and multivariable adjusted odds ratios with 95% confidence intervals. Restricted cubic spline regression models were additionally applied on the subgroup with prior stroke. <h3>Results</h3> Of the 14 030 included patients, 616 patients (190 [30.8%] women; mean [SD] age, 72.0 [9.1] years) with prior stroke underwent surgery, and 13 414 (4837 [36.1%] women; mean [SD] age, 69.8 [10.8] years) without prior stroke underwent surgery. The absolute risk of ischemic stroke was significantly increased in patients with stroke less than 3 months prior to surgery compared with patients with no prior stroke (18.4% [37 of 201] vs 1.2% [160 of 13 219]; odds ratio, 14.69; 95% CI, 9.69-22.27). Likewise, compared with patients without stroke, patients with stroke less than 3 months prior surgery were at significantly increased risk of MACE (23.3% [53 of 227] vs 5.7% [768 of 13 414]; odds ratio, 4.57; 95% CI, 3.24-6.44) but not all-cause mortality (6.8% [50 of 730] vs 3.6% [374 of 10 370]; odds ratio, 1.45; 95% CI, 0.83-2.54). Spline analyses supported a declining risk over time, reaching nadir after 2 to 4 months. <h3>Conclusions and Relevance</h3> Previous stroke is a major risk factor of recurrent ischemic stroke and MACE in patients undergoing SAVR, especially if time elapsed between previous stroke and surgery is less than 3 months.
Pattern of progression determines post-progression survival in patients with hepatocellular carcinoma treated with Radioembolization
Authors: C. Jordan, M. de la Torre, A.C. Gardini, J.I. Bilbao, M. Rodriguez-Fraile, L.S. Rodriguez, D. D’avola, M. Iñarrairaegui, J.I. Herrero, J. Quiroga, B. Sangro
Journal: Journal of Hepatology (2018)
Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor–Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5
Authors: Mitch Dowsett, Ivana Sestak, Meredith M. Regan, Andrew Dodson, Giuseppe Viale, Beat Thürlimann, Marco Colleoni, Jack Cuzick
Journal: Journal of Clinical Oncology (2018)

Purpose Estimating risk of late distant recurrence (DR) is an important goal for managing women with hormone receptor–positive breast cancer after 5 years of endocrine treatment without recurrence. We developed and validated a simple clinicopathologic tool (Clinical Treatment Score post–5 years [CTS5]) to estimate residual risk of DR after 5 years of endocrine treatment. Patients and Methods The ATAC (Arimidex, Tamoxifen, Alone or in Combination) data set (N = 4,735) was used to create a prognostic score for post–5-year risk of DR. Validity of CTS5 (ATAC) was tested in the BIG 1-98 data set (N = 6,711). Time to late DR, 5 years after finishing scheduled endocrine therapy, was the primary end point. Cox regression models estimated the prognostic performance of CTS5 (ATAC). Results CTS5 (ATAC) was significantly prognostic for late DR in the ATAC cohort (hazard ratio, 2.47; 95% CI, 2.24 to 2.73; P &lt; .001) and BIG 1-98 validation cohort (hazard ratio, 2.07; 95% CI, 1.88 to 2.28; P &lt; .001). CTS5 (ATAC) risk stratification defined in the training cohort as low (&lt; 5% DR risk, years 5 to 10), intermediate (5% to 10%), or high (&gt; 10%) identified 43% of the validation cohort as low risk, with an observed DR rate of 3.6% (95% CI, 2.7% to 4.9%) during years 5 to 10. From years 5 to 10, 63% of node-negative patients were low risk, with a DR rate of 3.9% (95% CI, 2.9% to 5.3%), and 24% with one to three positive nodes were low risk, with a DR rate of 1.5% (95% CI, 0.5% to 3.8%). A final CTS5 for future use was derived from pooled data from ATAC and BIG 1-98. Conclusion CTS5 is a simple tool based on information that is readily available to all clinicians. CTS5 was validated as highly prognostic for late DR in the independent BIG 1-98 study. The final CTS5 algorithm identified 42% of women with &lt; 1% per-year risk of DR who could be advised of the limited potential value of extended endocrine therapy.
Subanalysis of the LOWR HDV-2 study reveals high response rates to Lonafarnib in patients with low viral loads
Authors: C. Yurdaydin, C. Kalkan, F. Karakaya, A. Caliskan, S. Karatayli, O. Keskin, R. Idilman, M. Bozdayi, C. Koh, T. Heller, J. Glenn
Journal: Journal of Hepatology (2018)
From “Longshot” to “Fantasy”: Obligations to Pediatric Patients and Families When Last-Ditch Medical Efforts Fail
Authors: Elliott Mark Weiss, Autumn Fiester
Journal: The American Journal of Bioethics (2018)

Clinicians at quaternary centers see part of their mission as providing hope when others cannot. They tend to see sicker patients with more complex disease processes. Part of this mission is offering longshot treatment modalities that are unlikely to achieve their stated goal, but conceivably could. When patients embark on such a treatment plan, it may fail. Often treatment toward an initial goal continues beyond the point at which such a goal is feasible. We explore the progression of care from longshot to fantasy using two pediatric cases. This progression may be differentiated into four distinct stages of care related to the potential of achieving the initial goals of care. Physicians are often ill prepared for the progression of treatments from a longshot hope to an unfeasible and, therefore, typically unjustified intervention. We present a structured approach to guide clinicians at referral institutions where these situations may be common. The transition of care from "longshot" to "fantasy" is an inherent part of quaternary care for the sickest of patients that has been underexplored. Physicians are often poorly equipped to approach that transition. We advocate this approach to the shift from longshot to fantasy with the belief that such a structured method will have multiple benefits, including: reduced suffering for the patient; decreased emotional burden on patient and family; decreased provider moral distress; increased likelihood of seeking high quality palliative care earlier; and provision of honest and straightforward information to patients and their families.
ENDOSONOGRAPHIC MEASUREMENTS OF TUMOR THICKNESS AND SURFACE AREA TO PREDICT TUMOR RESPONSE AFTER NEOADJUVANT CHEMORADIOTHERAPY IN PATIENTS WITH ESOPHAGEAL CANCER; A MULTICENTER PROSPECTIVE COHORT STUDY
Authors: RD van der Bogt, BJ Noordman, KK Krishnadath, CAM Roumans, EJ Schoon, LE Oostenbrug, PD Siersema, FP Vleggaar, JJB van Lanschot, MCW Spaander
Journal: Endoscopy (2018)

Endosonography (EUS) is an accurate method for initial staging in esophageal cancer, but does not accurately assess T stage after neoadjuvant chemoradiotherapy (nCRT). EUS maximum tumor thickness (MTT) and maximum tumor area (MTA) have been shown to correlate well with histopathologic residual tumor volume. This study assessed the predictive value of EUS-based measurement by using both MTT and MTA for detection of residual disease after completion of nCRT.
COLD SNARE POLYPECTOMY VERSUS ENDOSCOPIC SUBMUCOSAL DISSECTION FOR SMALL SUPERFICIAL NON-AMPULLARY DUODENAL EPITHELIAL TUMOR
Authors: K Takizawa, N Kakushima, M Tanaka, N Kawata, M Yoshida, K Imai, S Ito, H Ishiwatari, K Hotta, H Matsubayashi, H Ono
Journal: Endoscopy (2018)

The aim of this study was to comparatively assess outcomes of cold snare polypectomy (CSP) and endoscopic submucosal dissection (ESD) for small superficial non-ampullary duodenal epithelial tumor (SNADET).
Cervical Pessary and Spontaneous Preterm Birth—Reply
Authors: Pasquale Martinelli, Gabriele Saccone
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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial
Authors: Susanne Saussele, Johan Richter, Joelle Guilhot, Franz X Gruber, Henrik Hjorth-Hansen, Antonio Almeida, Jeroen J W M Janssen, Jiri Mayer, Perttu Koskenvesa, Panayiotis Panayiotidis, Ulla Olsson-Strömberg, Joaquin Martinez-Lopez, Philippe Rousselot, Hanne Vestergaard, Hans Ehrencrona, Veli Kairisto, Katerina Machová Poláková, Martin C Müller, Satu Mustjoki, Marc G Berger, Alice Fabarius, Wolf-Karsten Hofmann, Andreas Hochhaus, Markus Pfirrmann, Francois-Xavier Mahon, Gert Ossenkoppele, Maria N. Pagoni, Stina Söderlund, Martine Escoffre-Barbe, Gabriel Etienne, Jolanta Dengler, Francoise Huguet, Nikolas von Bubnoff, Hana Klamova, Edgar Faber, Francois Guilhot, Kourosh Lotfi, Delphine Rea, Tim H. Brümmendorf, Gorgine E. de Greef, Leif Stenke, Franck E. Nicolini, Laurence Legros, Andreas Burchert, Jaroslava Voglova, Aude Charbonnier, Emmanuel Gyan, Volker Kunzmann, Peter E. Westerweel
Journal: The Lancet Oncology (2018)
Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials
Authors: M.A.E. de van der Schueren, A. Laviano, H. Blanchard, M. Jourdan, J. Arends, V.E. Baracos
Journal: Annals of Oncology (2018)

Driven by reduced nutritional intakes and metabolic alterations, malnutrition in cancer patients adversely affects quality of life, treatment tolerance and survival. We examined evidence for oral nutritional interventions during chemo(radio)therapy.We carried out a systematic review of randomized controlled trials (RCT) with either dietary counseling (DC), high-energy oral nutritional supplements (ONS) aiming at improving intakes or ONS enriched with protein and n-3 polyunsaturated fatty acids (PUFA) additionally aiming for modulation of cancer-related metabolic alterations. Meta-analyses were carried out on body weight (BW) response to nutritional interventions, with subgroup analyses for DC and/or high-energy ONS or high-protein n-3 PUFA-enriched ONS.Eleven studies were identified. Meta-analysis showed overall benefit of interventions on BW during chemo(radio)therapy (+1.31 kg, 95% CI 0.24-2.38, P = 0.02, heterogeneity Q = 21.1, P = 0.007). Subgroup analysis showed no effect of DC and/or high-energy ONS (+0.80 kg, 95% CI -1.14 to 2.74, P = 0.32; Q = 10.5, P = 0.03), possibly due to limited compliance and intakes falling short of intake goals. A significant effect was observed for high-protein n-3 PUFA-enriched intervention compared with isocaloric controls (+1.89 kg, 95% CI 0.51-3.27, P = 0.02; Q = 3.1 P = 0.37). High-protein, n-3 PUFA-enriched ONS studies showed attenuation of lean body mass loss (N = 2 studies) and improvement of some quality of life domains (N = 3 studies). Overall, studies were limited in number, heterogeneous, and inadequately powered to show effects on treatment toxicity or survival.This systematic review suggests an overall positive effect of nutritional interventions during chemo(radio)therapy on BW. Subgroup analyses showed effects were driven by high-protein n-3 PUFA-enriched ONS, suggesting the benefit of targeting metabolic alterations. DC and/or high-energy ONS were less effective, likely due to cumulative caloric deficits despite interventions. We highlight the need and provide recommendations for well-designed RCT to determine the effect of nutritional interventions on clinical outcomes, with specific focus on reaching nutritional goals and providing the right nutrients, as part of an integral supportive care approach.
Adjunctive Intranasal Esketamine in Treatment-Resistant Depression
Authors: Anish Shouan, Sandeep Grover
Journal: JAMA Psychiatry (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 Psychiatry HomeNew OnlineCurrent IssueFor Authors Podcast 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 Psychiatry journal
P457Monophosphorylation of cardiac troponin-I at Ser23/24 regulates cardiac myofibrillar Ca2+ sensitivity and modulates calpain-induced proteolysis
Authors: J C Kentish, A Martin-Garrido, B J Biesiadecki, H E Salhi, Y Shaifta, C Dos Remedios, S Ayaz-Guner, W Cai, Y Ge, M Avkiran
Journal: Cardiovascular Research (2018)

Materials and methods of research.The study included 19 patients with primary a STEMI the average age was 59 6 17 years.All patients underwent PCI with reperfusion of the infarctionrelated coronary artery.The mean recanalization time was 5 (4, 6) h.Using EchoCG, final systolic volume (CSR), terminal diastolic volume (BWW), LV ejection fraction (LVEF) was msured admission, 3rd, 7th and 21st day of STEMI.The CD133þ cells level was determined by flow cytometry of venous blood samples in the same periods.There was a control group of healthy volunteers (6 males) the average age was 41 6 9 years (absolutely healthy).Results: Carrying out an individual analysis of CD 133þ cells level circulating in patients with acute myocardial infarction, they found a multidirectional, nonlinear dynamics of their content by the 3rd day of MI.Due to this dynamics, all patients were divided into 2 subgroups: the 1st subgroup consisted of the patients with initially low level and it's further increasing on the 3rd day of MI, the 2nd subgroup -patients with a decrease level to a 3-m day of illness.Intragroup and intergroup differences were revealed on different days of the disease (p <0.05).A positive correlation was established between the relative amount of CD133þ cells in patients of the 2nd subgroup on the 7th day of MI and LVEF on the 21st day (R ¼ 0.7, p ¼ 0.02).Also, a relationship was found between the low absolute amount of CD 133þ cells in the first day of acute myocardial infarction and signs of chronic heart failure (CHF) after 6 months of the disease (p <0.05).Namely: in patients of the first subgroup, 6 months after of acute MI, minimal clinical manifestations of CHF were observed.This fact confirms that a high release of CD133þ cells into the peripheral channel is associated with a favorable course and disease prognosis. Conclusion:We showed the response of marrow to acute myocardial infarction, as release of CD133þ cells into the blood.It was found that the high mobilization of these cells both on the 1st day of MI and during the whole observation period was associated with a favorable course and disease prognosis, according to improvement of clinical and echocardiographic parameters.
A multicenter, randomized, double-blind, PLB-controlled trial of Galectin-3 inhibitor (GR-MD-02) in patients with NASH cirrhosis and portal hypertension
Authors: N. Chalasani, G. Garcia-Tsao, Z. Goodman, E. Lawitz, M. Abdelmalek, M. Rinella, M. Ryan, M. Noureddin, C. Jue, M. Pyko, A. Allgood, H. Shlevin, R. Horton, E. Zomer, P. Traber, R. Loomba, B. Tetri, A. Sanyal, S. Harrison
Journal: Journal of Hepatology (2018)
Transarterial-chemoembolization and hepatocellular carcinoma. A regular interval approach avoids the 10% of the procedures and an optimal survival with the transition to systemic therapy in 80% of the patients
Authors: M.S. Zamparelli, M. Burrel, A. Darnell, V. Sapena, M. Barrufet, A. Sotomayor, N. Llarch, G. Iserte, A. Diaz-Gonzalez, E. Belmonte, A. Forner, J. Rimola, C. Ayuso, M. Reig, J. Bruix
Journal: Journal of Hepatology (2018)
Pruning of the Pulmonary Vasculature in Asthma. The Severe Asthma Research Program (SARP) Cohort
Authors: Samuel Y. Ash, Farbod N. Rahaghi, Carolyn E. Come, James C. Ross, Alysha G. Colon, Juan Carlos Cardet-Guisasola, Eleanor M. Dunican, Eugene R. Bleecker, Mario Castro, John V. Fahy, Sean B. Fain, Benjamin M. Gaston, Eric A. Hoffman, Nizar N. Jarjour, David T. Mauger, Sally E. Wenzel, Bruce D. Levy, Raul San Jose Estepar, Elliot Israel, George R. Washko
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Loss of the peripheral pulmonary vasculature, termed vascular pruning, is associated with disease severity in patients with chronic obstructive pulmonary disease.Objectives: To determine if pulmonary vascular pruning is associated with asthma severity and exacerbations.Methods: We measured the total pulmonary blood vessel volume (TBV) and the blood vessel volume of vessels less than 5 mm2 in cross-sectional area (BV5) and of vessels less than 10 mm2 (BV10) in cross-sectional area on noncontrast computed tomographic scans of participants from the Severe Asthma Research Program. Lower values of the BV5 to TBV ratio (BV5/TBV) and the BV10 to TBV ratio (BV10/TBV) represented vascular pruning (loss of the peripheral pulmonary vasculature).Measurements and Main Results: Compared with healthy control subjects, patients with severe asthma had more pulmonary vascular pruning. Among those with asthma, those with poor asthma control had more pruning than those with well-controlled disease. Pruning of the pulmonary vasculature was also associated with lower percent predicted FEV1 and FVC, greater peripheral and sputum eosinophilia, and higher BAL serum amyloid A/lipoxin A4 ratio but not with low-attenuation area or with sputum neutrophilia. Compared with individuals with less pruning, individuals with the most vascular pruning had 150% greater odds of reporting an asthma exacerbation (odds ratio, 2.50; confidence interval, 1.05–5.98; P = 0.039 for BV10/TBV) and reported 45% more asthma exacerbations during follow-up (incidence rate ratio, 1.45; confidence interval, 1.02–2.06; P = 0.036 for BV10/TBV).Conclusions: Pruning of the peripheral pulmonary vasculature is associated with asthma severity, control, and exacerbations, and with lung function and eosinophilia.
P523Activation of RISK signaling pathway is involved in age-dependent cardioprotective effect of remote ischemic preconditioning in SHR rats
Authors: V Ledvenyiova-Farkasova, L Griecsova, M Murarikova, S Carnicka, M Ferko, T Rajtik, A Szobi, A Adameova, I Bernatova, T Ravingerova
Journal: Cardiovascular Research (2018)

the number (DADinc¼ 4.7260.6#/min) and amplitude of DAD (DADampl¼2.760.4 mV) as well as the number of spontaneous APs in myocytes from the MI adjacent region, without affecting the overall global Ca2þ transient kinetics in both regions.Conclusion: Both in vitro and in vivo studies showed the peri-infarct region having a higher arrhythmogenic potential compared to the non-infarcted remote region.Hyperactive non-coupled RyRs are at the origin of these spontaneous Ca2þ releases and are responsive to drug treatment without affecting the overall global Ca2þ transient.