The American Heart Association has recommended that palliative care be integrated into the care of all patients with advanced cardiac illnesses. Notwithstanding, the number of patients receiving specialist palliative intervention worldwide remains extremely small. This review examines the nature of palliative care and what is known about its delivery to patients with cardiac illness. Most of the published literature on the subject concern advanced heart failure; however, some data also exist regarding patients with heart transplantation, pulmonary hypertension, valvular disease, congenital heart disease, indwelling devices, mechanical circulatory support, and advanced coronary disease. In addition, outcome data, certification requirements, workforce challenges, barriers to implementation, and a potential caveat about palliative care will also be examined. Further work is required regarding appropriate means of implementation, quality control, and timing of intervention.

Advances in medical technology have begun to blur the lines between life and death as well as the lines between appropriate and inappropriate therapy. This review addresses the charged issue of the management of cardiac devices at or near the end of a patient's life, provides a summary of prior and current opinion with some historical context, and attempts to provide some modest guidance as to how to approach the various options to the patient's best advantage. Modalities to be addressed include indwelling electronic devices, the left ventricular assistance device, and extracorporeal mechanical oxygenation, and includes available outcome data as well as ethical analysis from a number of commentators. The expected further increase in technical sophistication of these devices is expected to render the various aspects of device deactivation more and more complex over the course of the next few years such that careful attention to and knowledge about this issue will continue to be more and more necessary.

Patients with heart failure are at risk for significant morbidity and mortality1 and can benefit from specialist palliative care (SPC). Currently, referrals are often inconsistent and made late in the illness trajectory.2,3 Chang et al4 conducted an international Delphi study in 2021 in which an expert panel identified a set of criteria for referral of patients with advanced heart failure for SPC. However, the timeliness of consults based on these referral criteria remained unclear. In this study, we examined the perceived timeliness of consults based on a list of criteria for SPC referral as determined by an international panel of experts.

Obesity-mediated metabolic syndrome remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves the heme oxygenase (HO) system, specifically its inducible form, HO-1. This review collects and updates much of the current knowledge relevant to pharmacology and clinical medicine concerning HO-1 in metabolic diseases and its effect on lipid metabolism. HO-1 has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin and leptin sensitivity. Recent reports indicate that HO-1 with its antioxidants via the effect of bilirubin increases formation of biologically active lipid metabolites such as epoxyeicosatrienoic acid (EET), omega-3 and other polyunsaturated fatty acids (PUFAs). Similarly, HO-1and bilirubin are potential therapeutic targets in the treatment of fat-induced liver diseases. HO-1-mediated upregulation of EET is capable not only of reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, a hallmark of the metabolic syndrome. This process involves browning of white fat tissue (i.e. formation of healthy adipocytes) and reduced lipotoxicity, which otherwise will be toxic to the heart. More importantly, this review examines the activity of EET in biological systems and a series of pathways that explain its mechanism of action and discusses how these might be exploited for potential therapeutic use. We also discuss the link between cardiac ectopic fat deposition and cardiac function in humans, which is similar to that described in obese mice and is regulated by HO-1-EET-PGC1α signaling, a potent negative regulator of the inflammatory adipokine NOV.

BACKGROUND Patients with advanced heart failure have substantial supportive care needs. Specialist palliative care can be beneficial, but it is unclear who is most appropriate for referral and when patients should be referred. OBJECTIVES We conducted a Delphi study of international experts to identify consensus referral criteria for specialist palliative care for patients with advanced heart failure. METHODS Clinicians from 5 continents with expertise in the integration of cardiology and palliative care were asked to rate 34 disease-based, 24 needs-based, and 9 time-based criteria over 3 rounds. Consensus was defined a priori as >= 70% agreement. A criterion was coded as major if the experts endorsed that meeting that criterion alone was adequate to justify a referral. RESULTS The response rate was 44 of 46 (96%), 41 of 46 (89%), and 43 of 46 (93%) in the first, second, and third rounds, respectively. Panelists reached consensus on 25 major criteria for specialist palliative care referral. The 25 major criteria were categorized under 6 topics, including "advanced/refractory heart failure, comorbidities, and complications" (eg, cardiac cachexia, cardiorenal syndrome) (n = 8), "advanced heart failure therapies" (eg, chronic inotropes, precardiac transplant) (n = 4), "hospital utilization" (eg, emergency room visits, hospitalization) (n = 2), "prognostic estimate" (n = 1), "symptom burden/distress" (eg, severe physical/emotional/spiritual distress) (n = 6), and "decision making/social support" (eg, goals-of-care discussions) (n = 4). The majority (68%) of major criteria had >= 90% agreement. CONCLUSIONS International experts reached consensus on a large number of criteria for referral to specialist palliative care. With further validation, these criteria may be useful for standardizing palliative care access in the inpatient and/or outpatient settings. (C) 2022 by the American College of Cardiology Foundation.

The pathogenesis and molecular pathways involved in non-alcoholic fatty liver disease (NAFLD) are reviewed, as well as what is known about mitochondrial dysfunction that leads to heart disease and the progression to steatohepatitis and hepatic fibrosis. We focused our discussion on the role of the antioxidant gene heme oxygenase-1 (HO-1) and its nuclear coactivator, peroxisome proliferator-activated receptor-gamma coactivator (PGC1-α) in the regulation of mitochondrial biogenesis and function and potential therapeutic benefit for cardiac disease, NAFLD as well as the pharmacological effect they have on the chronic inflammatory state of obesity. The result is increased mitochondrial function and the conversion of white adipocyte tissue to beige adipose tissue ("browning of white adipose tissue") that leads to an improvement in signaling pathways and overall liver function. Improved mitochondrial biogenesis and function is essential to preventing the progression of hepatic steatosis to NASH and cirrhosis as well as preventing cardiovascular complications.

Significance: Heme oxygenase (HO) plays a pivotal role in both vascular and metabolic functions and is involved in many physiological and pathophysiological processes in vascular endothelial cells (ECs) and adipocytes. Recent Advances: From the regulation of adipogenesis in adipose tissue to the adaptive response of vascular tissue in the ECs, HO plays a critical role in the capability of the vascular system to respond and adjust to insults in homeostasis. Recent studies show that HO-1 through regulation of adipocyte and adipose tissue functions ultimately aid not only in local but also in systemic maintenance of homeostasis. Critical Issues: Recent advances have revealed the existence of a cross talk between vascular ECs and adipocytes in adipose tissue. In the pathological state of obesity, this cross talk contributes to the condition's adverse chronic effects, and we propose that specific targeting of the HO-1 gene can restore signaling pathways and improve both vascular and adipose functions. Future Directions: A complete understanding of the role of HO-1 in regulation of cardiovascular homeostasis is important to comprehend the homeostatic regulation as well as in cardiovascular disease. Efforts are required to highlight the effects and the ability to target the HO-1 gene in models of obesity with an emphasis on the role of pericardial fat on cardiovascular health.

BACKGROUND:Patients with heart failure have significant symptom burden, care needs, and often a progressive course to end-stage disease. Palliative care referrals may be helpful but it is currently unclear when patients should be referred and by whom. We conducted a systematic review of the literature to examine referral criteria for palliative care among patients with heart failure.METHODS:We searched Ovid, MEDLINE, Ovid Embase, and PubMed databases for articles in the English language from the inception of databases to January 17, 2019 related to palliative care referral in patients with heart failure. Two investigators independently reviewed each citation for inclusion and then extracted the referral criteria. Referral criteria were then categorized thematically.RESULTS:Of the 1199 citations in our initial search, 102 articles were included in the final sample. We identified 18 categories of referral criteria, including 7 needs-based criteria and 10 disease-based criteria. The most commonly discussed criterion was physical or emotional symptoms (n=51 [50%]), followed by cardiac stage (n=46 [45%]), hospital utilization (n=38 [37%]), prognosis (n=37 [36%]), and advanced cardiac therapies (n=36 [35%]). Under cardiac stage, 31 (30%) articles suggested New York Heart Association functional class ≥III and 12 (12%) recommended New York Heart Association class ≥IV as cutoffs for referral. Prognosis of ≤1 year was mentioned in 21 (21%) articles as a potential trigger; few other criteria had specific cutoffs.CONCLUSIONS:This systematic review highlighted the lack of consensus regarding referral criteria for the involvement of palliative care in patients with heart failure. Further research is needed to identify appropriate and timely triggers for palliative care referral.

We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC-1α, HO-1 levels, insulin receptor phosphorylation and improved mitochondrial function, theses beneficial effect were reversed by deletion of PGC-1α. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreased cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome.

Previously we demonstrated that an EET‐agonist has pleiotropic effects including inhibition of Soluble Epoxide Hydrolase expression and reversed cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that an EET agonist would increase PGC‐1α, which controls mitochondrial function and HO‐1 induction and negatively regulates the expression of the proinflammatory adipokine NOV in both cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular systolic function as well as increase insulin receptor phosphorylation. The effect of an EET agonist was measured in cardiac and pericardial adipose tissues in db/db mice on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins. Control db/db mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist decreased pericardial adipose tissue expression of NOV, normalized FS, increased PGC‐1α, HO‐1 levels, insulin receptor phosphorylation and improved mitochondrial function. HO‐1‐ derived carbon monoxide (CO) levels, mitochondrial function (p<0.01), insulin receptor phosphorylation (p<0.05), ATP levels and VO2 (p<0.05). Deletion of PGC‐1α reversed all of the above beneficial effects, increasing the expression of NOV and inflammatory cytokines in pericardial adipose tissue. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreases cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome. Further, this study demonstrated that EET‐mediated inhibition of NOV is a potential therapeutic target for the prevention of heart failure and the development of metabolic syndrome.Support or Funding InformationNational Institutes of Health grant (HL34300 to NGA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BackgroundObesity is a global epidemic and a major risk factor in the development of metabolic syndrome, diabetes and associated complications such as cardiovascular disease, kidney disease, hypertension, and neuropathies. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid generated by a super family of cytochrome P450 (CYP) monooxygenases and epoxygenases. Hypertension caused by chronic obesity in leptin receptor deficient mice, may be linked to mitochondrial dysfunction. Previously we and others have reported the beneficial effects of epoxyeicosatrienoic acid in renal and adipose tissue function, as well as its vasodilatory action, it increases insulin sensitivity and inhibits inflammation and reactive oxygen species (ROS). We hypothesized that EET attenuates obesity‐induced renal dysfunction by improving sodium excretion, reducing the sodium‐chloride cotransporter NCC, lowering blood pressure and increasing mitochondrial and thermogenic gene levels in PGC1α dependent mice.MethodsSixteen week‐old db/db mice were divided into 3 treatment groups for an additional 16‐wk experiment; Control, EET‐A 1.5 mg/100g BW i.p. 3x/week, and EET‐A‐Ln‐PGC‐1α shRNA (Ln‐PGC‐1 α shRNA suppressed PGC‐1α protein levels in renal tissue by >50%). After 16‐wks pf treatment oxygen consumption (VO2), visceral fat and fasting blood glucose levels were determined; urine was collected and renal tissues were harvested to measure: type 2 Na‐K‐Cl cotransporters (NKCC2), epithelial Na channels‐alpha subunit (ENac), NaCl cotransporters (NCC), PGC‐1α, HO‐1, and mitochondrial biogenesis markersResultsEET‐agonist normalized glucose metabolism, renal ENaC and NCC protein expression, urinary sodium excretion and blood pressure in obese mice. EET‐agonist improved mitochondrial integrity, thermogenic genes, and PGC1α‐HO‐1‐adiponectin signaling. Knockout of PGC1α in EET‐treated mice resulted in a reversal of these beneficial effects including a decrease in sodium excretion, elevation of blood pressure and an increase in NOV. Effects of EET on perirenal adipose tissue included EET increased adiponectin, mitochondrial integrity and thermogenic genes and decreased NOV, i.e. ‘Browning’ perirenal adipose phenotype that occurs under high fat diets.ConclusionTreatment with an EET‐agonist led to the recruitment of PGC‐1α‐HO‐1, enhanced mitochondrial function, decreased perirenal fat‐derived NOV, and the downregulation of NCC channels resulting in a decrease in sodium retention in chronically obese mice. EET has the potential to serve as a powerful therapeutic agent in the treatment of obesity‐induced hypertension.Support or Funding InformationNational Institutes of Health grant (HL34300 to NGA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Background.: We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on renal and adipose tissue function, in addition to its vasodilatory action; it increases insulin sensitivity and inhibits inflammation. In an examination of the signaling mechanisms by which EET reduces renal and peri-renal fat function, we hypothesized that EET ameliorates obesity-induced renal dysfunction by improving sodium excretion, reducing the sodium-chloride cotransporter NCC, lowering blood pressure, and enhancing mitochondrial and thermogenic gene levels in PGC-1 alpha dependent mice. Methods: EET-agonist treatment normalized glucose metabolism, renal ENaC and NCC protein expression, urinary sodium excretion and blood pressure in obese (db/db) mice. A marked improvement in mitochondrial integrity, thermogenic genes, and PGC-1 alpha HO-1-adiponectin signaling occurred. Knockout of PGC-1 alpha in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in sodium excretion, elevation of blood pressure and an increase in the pro-inflammatory adipokine nephroblastoma overexpressed gene (NOV). In the elucidation of the effects of EET on peri-renal adipose tissue, EET increased adiponectin, mitochondrial integrity, thermogenic genes and decreased NOV, i.e. "Browning' peri-renal adipose phenotype that occurs under high fat diets. Taken together, these data demonstrate a critical role of an EET agonist in the restoration of healthy adipose tissue with reduced release of inflammatory molecules, such as AngII and NOV, thereby preventing their detrimental impact on sodium absorption and NCC levels and the development of obesity-induced renal dysfunction.

We have previously reported that epoxyeicosatrienoic acid (EET) has multiple beneficial effects on vascular function; in addition to its antiapoptotic action, it increases insulin sensitivity and inhibits inflammation. To uncover the signaling mechanisms by which EET reduces cardiomyopathy, we hypothesized that EET infusion might ameliorate obesity-induced cardiomyopathy by improving heme oxygenase (HO)-1, Wnt1, thermogenic gene levels, and mitochondrial integrity in cardiac tissues and improved pericardial fat phenotype. EET reduced levels of fasting blood glucose and proinflammatory adipokines, including nephroblastoma overexpressed (NOV) signaling, while increasing echocardiographic fractional shortening and O2 consumption. Of interest, we also noted a marked improvement in mitochondrial integrity, thermogenic genes, and Wnt 1 and HO-1 signaling mechanisms. Knockout of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in EET-treated mice resulted in a reversal of these beneficial effects including a decrease in myocardial Wnt1 and HO-1 expression and an increase in NOV. To further elucidate the effects of EET on pericardial adipose tissues, we observed EET treatment increases in adiponectin, PGC-1α, phospho-AMP-activated protein kinase, insulin receptor phosphorylation, and thermogenic genes, resulting in a “browning” pericardial adipose phenotype under high-fat diets. Collectively, these experiments demonstrate that an EET agonist increased Wnt1 and HO-1 signaling while decreasing NOV pathways and the progression of cardiomyopathy. Furthermore, this report presents a portal into potential therapeutic approaches for the treatment of heart failure and metabolic syndrome. NEW & NOTEWORTHY The mechanism by which EET acts on obesity-induced cardiomyopathy is unknown. Here, we describe a previously unrecognized function of EET infusion that inhibits nephroblastoma overexpressed (NOV) levels and activates Wnt1, hence identifying NOV inhibition and enhanced Wnt1 expression as novel pharmacological targets for the prevention and treatment of cardiomyopathy and heart failure. Listen to this article's corresponding podcast at http://ajpheart.physiology.org/content/early/2017/05/31/ajpheart.00093.2017 .

Jian Cao, Shailendra P. Singh, John A. McClung, Gregory Joseph, Luca Vanella, Ignazio Barbagallo, Houli Jiang, John R. Falck, Michael Arad, Joseph I. Shapiro, and Nader G. Abraham Departments of Medicine and Pharmacology, New York Medical College, Valhalla, New York; Chinese PLA General Hospital, Beijing, China; Department of Drug Science/Section of Biochemistry, University of Catania, Catania, Italy; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas; Leviev Heart Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel; and Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia

Native valvular emergencies are nearly always regurgitant in nature, whereas acute prosthetic valve dysfunction can be either regurgitant or stenotic. Regardless of the etiology, the presentation of acute valvular pathology differs significantly from chronic disease in both clinical presentation and in its appearance on diagnostic modalities, and appropriate recognition is critical to the choice of the appropriate therapeutic modality. Intrinsic to the recognition of a valvular emergency is a knowledge of those conditions for which a high index of suspicion must be maintained. This article addresses the etiologies, presentation, and diagnosis of these conditions and presents the relevant data that bears on which therapy may be most appropriate for which condition.

Introduction: Diabetes mellitus type 2 (DM2) is associated with cardiovascular complications, which are characterized by increased oxidative stress (ROS) and inhibition of anti-oxidant genes such as heme oxygenase (HO-1), Super oxide dismutase (SOD2) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The latter that controls mitochondrial biogenesis, oxidative metabolism, and increased degradation of epoxyeicosatrienoic acids (EETs). Inhibition of these genes leads to increased myocardial stiffness and the development of cardiac hypertrophy and diastolic dysfunction. Aim: To assess whether PGC-1α plays a significant role in the development of diabetic cardiomyopathy in chronically obese mice. Methods: Leptin resistant (db/db) mice develop cardiomyopathy at the age of 5-6 month. Mice were treated with the EET agonist (EET-A) and with either lentivirus (Ln)- PGC-1α (Sh) or EET-A-Ln-PGC-1α scrambled for 3 additional months. Results: db mice exhibited impaired glucose tolerance, increased fasting blood glucose (366±21.9mg/dL vs.112±9.2 mg/dL, p<0.004), decreased oxygen consumption (VO 2 ) (25.09±1.1ml/min vs. 55.37±5.92ml/min, p<0.002) and heart weight (0.17±0.02g vs.0.12±0.006g, p<0.05) compared to WT mice. EET agonists treatments improved fasting glucose levels (366±21.9mg/dL vs. 134±18.4 mg/dL, p<0.007) and oxygen consumption (25.09±1.1ml/min vs. 33.7±3.75ml/min, p<0.018), and reduced heart weight (0.17±0.02g vs.0.13±0.002g, p<0.0026). HO-1 levels were increased in cardiac tissue 22-fold (p<0.016). The beneficial effects of EET were reversed inhibition of PGC-1α in the EET-A-Ln PGC-1α (Sh) not in EET-A-Ln-PGC-1α scrambled group. The inhibition of PGC-1α (52% reduction, p<0.022) resulted in a reduction in the beneficial effects of EET-A as manifested by weight gain, the development of severe dilated cardiomyopathy and the attenuation of HO-1 and SOD2 (90% and 76% reduction respectively, p<0.02) and a decrease in mitochondrial fusion proteins Mfn1, 2 and OPa1. Conclusion: EET mediated restoration of mitochondrial function by PGC1α is essential for the enhancement of HO-1-myocyte contraction and the prevention of LV dysfunction in chronic obesity.

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

Cardiovascular disease remains the leading cause of death worldwide. Among many potential targets for pharmacological intervention, a promising strategy involves epoxyeicosatrienoic acid (EET) and soluble epoxide hydroxylase (sEH) inhibition. sEH is the enzyme that converts EET to its less potent metabolite; therefore, EET is upregulated by its inhibitor. EET has pleotropic effects that collectively reduce inflammation, while increasing vasodilation and insulin sensitivity. Recent reports indicate that EET agonists and sEH inhibitors are capable of not only reversing endothelial dysfunction and hypertension, but also of reversing cardiac remodeling, which is a hallmark of cardiomyopathy and the metabolic syndrome. EET agonists and sEH inhibitors are in development as potential therapies, and at least one drug is already in clinical trials. This review examines the activity of EET in biological systems, proposes a series of pathways to explain its mechanism of action, and discusses how these might be exploited for potential therapeutic use.