Abstract: The disclosure is directed to methods for inhibiting toxic protein accumulation in cells by modulating the phosphorylation of carboxy terminus of heat shock cognate 70 interacting protein (CHIP), as well as a method for treating a disease caused by proteotoxicity in cells by increasing or inducing the activity of CHIP in a subject.

Abstract: Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.

Abstract: Provided herein are engineered tuberous sclerosis complex 2 (TSC2) polypeptides in which the ability of a residue corresponding to a serine residue in a wild type TSC2 polypeptide to be phosphorylated is altered. In some cases, an engineered TSC2 polypeptide cannot be phosphorylated (e.g., by substituting a serine residue with an alanine residue). In some cases, an engineered TSC2 polypeptide can act as if it is constitutively phosphorylated (e.g., by substituting a serine residue with a glutamic acid residue). Also provided herein are engineered immune cells including altered TSC2 polypeptides or including nucleic acid sequences encoding altered TSC2 polypeptides, and methods of making and using such engineered immune cells.

Abstract: Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.

Abstract: Administration of an HNO/NO? donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NO? donating compound isopropylamine (IPA)/NO (Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO? donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO· donors, administration of an HNO/NO? donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NO? exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Abstract: The present invention relates to methods for treating diastolic dysfunction or a disease, disorder or condition associated with diastolic dysfunction, methods for treating heart failure, methods for modulating SR Ca2+ release and/or uptake, methods for enhancing myocyte relaxation, preload or E2P hydrolysis, and methods for treating ventricular hypertrophy.

Abstract: Administration of an HNO/NO+ donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NO? donating compound isopropylamine (IPA)/NO (Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO? donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO? donors, administration of an HNO/NO? donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NO? exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Abstract: Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Abstract: Administration of an HNO/NO? donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NO? donating compound isopropylamine (IPA)/NO (Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO? donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO donors, administration of an HNO/NO? donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NO? exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Abstract: The present invention relates to the field of cardiology. More specifically, the present invention relates to the use of ?3 adrenoreceptor agonists to treat cardiac hypertrophy and heart failure. In a specific embodiment, a method for treating cardiac hypertrophy comprises the step of administering a therapeutically effective amount of a ?3 adrenoreceptor agonist to a patient diagnosed with cardiac hypertrophy. In a more specific embodiment, the method for treating cardiac hypertrophy comprises the step of administering a therapeutically effective amount of the ?3 adrenoreceptor agonist BRL 26830A to a patient diagnosed with cardiac hypertrophy. In a further embodiment, the present invention provides a method for treating a cardiovascular disease or condition associated with cardiac hypertrophy comprising the step of administering a therapeutically effective amount of a ?3 adrenoreceptor agonist to a patient diagnosed with cardiac hypertrophy.

Abstract: Administration of an HNO/NO? donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NO? donating compound isopropylamine (IPA)/NO (Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO? donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO? donors, administration of an HNO/NO? donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NO? exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Abstract: Administration of an HNO/NO? donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NO? donating compound isopropylamine (IPA)/NO(Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO? donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO? donors, administration of an HNO/NO? donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NO? exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Abstract: The present invention relates to methods for treating diastolic dysfunction or a disease, disorder or condition associated with diastolic dysfunction, methods for treating heart failure, methods for modulating SR Ca2+ release and/or uptake, methods for enhancing myocyte relaxation, preload or E2P hydrolysis, and methods for treating ventricular hypertrophy.

Abstract: Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Abstract: Administration of an HNO/NO? donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure Moreover, administration of the HNO/NO? donating compound isopropylamine (IPA)/NO (Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO? donating compound Angeli's salt.

Abstract: Administration of an HNO/NO− donating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure Moreover, administration of the HNO/NO− donating compound isopropylamine (IPA)/NO (Na(CH3)2CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NO− donating compound Angeli's salt. Additionally, in contrast to the effects observed with NO− donors, administration of an HNO/NO− donor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent Further, HNO/NO− exerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Abstract: Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Abstract: A novel method for estimating the end-systolic pressure-volume relationship (ESPVR) is presented. The method provides for accurate estimation of the ESPVR from a single beat of the cardiac cycle. The method is based on normalized human time varying elastance curves [E.sub.N (t.sub.N)]. The ESPVR is estimated from one beat using PV data measured at normalized time t.sub.N and end-systole (t.sub.max) to predict intercept: ##EQU1## and slope: E.sub.max(SB) =P(t.sub.max)/[V(t.sub.max)-V.sub.0(SB) ]. The present invention provides a method for ESPVR estimation which is non-invasive and particularly applicable for bedside applications.