115-402: Gladstone Institutes is an American independent, non-profit biomedical research organization whose focus is to better understand, prevent, treat and cure cardiovascular, viral and neurological conditions such as heart failure , HIV/AIDS and Alzheimer's disease . Its researchers study these diseases using techniques of basic and translational science . Another focus at Gladstone is building on
230-533: A Harvard / University of California, Los Angeles collaboration, and a group at MIT , published studies that substantially improved on the reprogramming approach, giving rise to iPSCs that were indistinguishable from ESCs. Unlike the first generation of iPSCs, these second generation iPSCs produced viable chimeric mice and contributed to the mouse germline, thereby achieving the 'gold standard' for pluripotent stem cells. These second-generation iPSCs were derived from mouse fibroblasts by retroviral-mediated expression of
345-405: A lentiviral system. Obtaining fibroblasts to produce iPSCs involves a skin biopsy, and there has been a push towards identifying cell types that are more easily accessible. In 2008, iPSCs were derived from human keratinocytes, which could be obtained from a single hair pluck. In 2010, iPSCs were derived from peripheral blood cells, and in 2012, iPSCs were made from renal epithelial cells in
460-606: A $ 25 million initiative around HIV and aging. Their research has included: In 2020, two new institutes were formed; the Gladstone Institute of Virology, and the Gladstone-UCSF Institute of Genomic Immunology, to study how viruses interact with human cells to cause disease. The Institute of Virology has been involved in research regarding the COVID-19 virus , including its long-term effects on
575-585: A cause (e.g., aortic stenosis ) or as a consequence (e.g., mitral regurgitation ) of heart failure. Reverse insufficiency of the left ventricle causes congestion in the blood vessels of the lungs so that symptoms are predominantly respiratory. Reverse insufficiency can be divided into the failure of the left atrium, the left ventricle, or both within the left circuit. Patients will experience shortness of breath (dyspnea) on exertion and, in severe cases, dyspnea at rest. Increasing breathlessness while lying down, called orthopnea , also occurs. It can be measured by
690-402: A complex organ, mimicking the process in fetal development . After growing in vitro for a few days, the liver buds were transplanted into mice where the 'liver' quickly connected with the host blood vessels and continued to grow. Most importantly, it performed regular liver functions including metabolizing drugs and producing liver-specific proteins. Further studies will monitor the longevity of
805-1131: A compliant cellular state for iPSC reprogramming. iPSC derivation is typically a slow and inefficient process, taking one–two weeks for mouse cells and three–four weeks for human cells, with efficiencies around 0.01–0.1%. However, considerable advances have been made in improving the efficiency and the time it takes to obtain iPSCs. Upon introduction of reprogramming factors, cells begin to form colonies that resemble pluripotent stem cells, which can be isolated based on their morphology, conditions that select for their growth, or through expression of surface markers or reporter genes . Induced pluripotent stem cells were first generated by Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University , Japan, in 2006. They hypothesized that genes important to embryonic stem cell (ESC) function might be able to induce an embryonic state in adult cells. They chose twenty-four genes previously identified as important in ESCs and used retroviruses to deliver these genes to mouse fibroblasts . The fibroblasts were engineered so that any cells reactivating
920-465: A decrease in intracardiac pressures or in ejection during systole , reducing cardiac output to the rest of the body. The filling failure and high intracardiac pressure can lead to fluid accumulation in ventricles of the heart. This manifests as water retention and swelling due to fluid accumulation ( edema ) called congestion . Impaired ejection can lead to inadequate blood flow to the body tissues, resulting in ischemia . Congestive heart failure
1035-613: A large-scale and high-throughput platform for cardiovascular drug safety screening. A proof-of-concept of using induced pluripotent stem cells (iPSCs) to generate human organ for transplantation was reported by researchers from Japan. Human ' liver buds' (iPSC-LBs) were grown from a mixture of three different kinds of stem cells: hepatocyte (for liver function) coaxed from iPSCs; endothelial stem cells (to form lining of blood vessels ) from umbilical cord blood ; and mesenchymal stem cells (to form connective tissue ). This new approach allows different cell types to self-organize into
1150-681: A myocardial infarction is suspected, various cardiac markers may be used. Blood tests routinely performed include electrolytes ( sodium , potassium ), measures of kidney function , liver function tests , thyroid function tests , a complete blood count , and often C-reactive protein if infection is suspected. Hyponatremia (low serum sodium concentration) is common in heart failure. Vasopressin levels are usually increased, along with renin, angiotensin II, and catecholamines to compensate for reduced circulating volume due to inadequate cardiac output. This leads to increased fluid and sodium retention in
1265-590: A normal ECG virtually excludes left ventricular systolic dysfunction. N-terminal pro-BNP (NT-proBNP) is the favored biomarker for the diagnosis of heart failure, according to guidelines published 2018 by NICE in the UK . Brain natriuretic peptide 32 (BNP) is another biomarker commonly tested for heart failure. An elevated NT-proBNP or BNP is a specific test indicative of heart failure. Additionally, NT-proBNP or BNP can be used to differentiate between causes of dyspnea due to heart failure from other causes of dyspnea. If
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#17327908302061380-419: A person with a failure of one ventricle lives long enough, it will tend to progress to failure of both ventricles. For example, left ventricular failure allows pulmonary edema and pulmonary hypertension to occur, which increases stress on the right ventricle. Though still harmful, right ventricular failure is not as deleterious to the left side. Since heart failure is a syndrome and not a disease, establishing
1495-485: A person with heart failure may have a reduced force of contraction due to overloading of the ventricle . In a normal heart, increased filling of the ventricle results in increased contraction force by the Frank–Starling law of the heart , and thus a rise in cardiac output . In heart failure, this mechanism fails, as the ventricle is loaded with blood to the point where heart muscle contraction becomes less efficient. This
1610-423: A result of a blocked coronary artery . Cardiomyopathy refers specifically to problems within the heart muscle, and these problems can result in heart failure. Ischemic cardiomyopathy implies that the cause of muscle damage is coronary artery disease. Dilated cardiomyopathy implies that the muscle damage has resulted in enlargement of the heart. Hypertrophic cardiomyopathy involves enlargement and thickening of
1725-512: A result, coronary catheterization may be used to identify possibilities for revascularisation through percutaneous coronary intervention or bypass surgery . Heart failure is commonly stratified by the degree of functional impairment conferred by the severity of the heart failure, as reflected in the New York Heart Association (NYHA) functional classification . The NYHA functional classes (I–IV) begin with class I, which
1840-457: A type of pluripotent stem cell can be generated by subjecting the cells to certain types of stress (bacterial toxin, a low pH of 5.7, or physical squeezing); the resulting cells were called STAP cells, for stimulus-triggered acquisition of pluripotency . In light of difficulties that other labs had replicating the results of the surprising study, in March 2014, one of the co-authors has called for
1955-485: A variety of diseases. Managed by the University of Oxford , the effort pooled funds and resources from 10 pharmaceutical companies and 23 universities. The goal is to generate a library of 1,500 iPS cell lines which will be used in early drug testing by providing a simulated human disease environment. Furthermore, combining hiPSC technology and small molecule or genetically encoded voltage and calcium indicators provided
2070-440: A wide variety of human genetic diseases, including common disorders such as Down syndrome and polycystic kidney disease. In many instances, the patient-derived iPS cells exhibit cellular defects not observed in iPS cells from healthy subjects, providing insight into the pathophysiology of the disease. An international collaborated project, StemBANCC, was formed in 2012 to build a collection of iPS cell lines for drug screening for
2185-429: Is a pathophysiological condition in which the heart's output is insufficient to meet the needs of the body and lungs. The term "congestive heart failure" is often used because one of the most common symptoms is congestion or fluid accumulation in the tissues and veins of the lungs or other parts of a person's body. Congestion manifests itself particularly in the form of fluid accumulation and swelling (edema) , in
2300-420: Is a common, costly, and potentially fatal condition, and is the leading cause of hospitalization and readmission in older adults. Heart failure often leads to more drastic health impairments than the failure of other, similarly complex organs such as the kidneys or liver. In 2015, it affected about 40 million people worldwide. Overall, heart failure affects about 2% of adults, and more than 10% of those over
2415-702: Is a worsening of chronic heart failure symptoms, which can result in acute respiratory distress . High-output heart failure can occur when there is increased cardiac demand that results in increased left ventricular diastolic pressure which can develop into pulmonary congestion (pulmonary edema). Several terms are closely related to heart failure and may be the cause of heart failure, but should not be confused with it. Cardiac arrest and asystole refer to situations in which no cardiac output occurs at all. Without urgent treatment, these events result in sudden death. Myocardial infarction ("Heart attack") refers to heart muscle damage due to insufficient blood supply, usually as
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#17327908302062530-471: Is by the side of the heart involved (left heart failure versus right heart failure). Right heart failure was thought to compromise blood flow to the lungs compared to left heart failure compromising blood flow to the aorta and consequently to the brain and the remainder of the body's systemic circulation. However, mixed presentations are common, and left heart failure is a common cause of right heart failure. A more accurate classification of heart failure type
2645-421: Is caused by any condition that reduces the efficiency of the heart muscle, through damage or overloading . Over time, these increases in workload, which are mediated by long-term activation of neurohormonal systems such as the renin–angiotensin system and the sympathoadrenal system, lead to fibrosis , dilation, and structural changes in the shape of the left ventricle from elliptical to spherical. The heart of
2760-410: Is consistent with an international 2021 report termed "Universal Definition of Heart Failure". Score-based algorithms have been developed to help in the diagnosis of HFpEF , which can be challenging for physicians to diagnose. The AHA / ACC / HFSA defines heart failure as symptoms and signs consistent with heart failure in combination with shown "structural and functional alterations of the heart as
2875-432: Is defined as a person who experiences no limitation in any activities and has no symptoms from ordinary activities. People with NYHA class II heart failure have slight, mild limitations with everyday activities; the person is comfortable at rest or with mild exertion. With NYHA class III heart failure, a marked limitation occurs with any activity; the person is comfortable only at rest. A person with NYHA class IV heart failure
2990-491: Is due to the reduced ability to cross-link actin and myosin myofilaments in over-stretched heart muscle. No diagnostic criteria have been agreed on as the gold standard for heart failure, especially heart failure with preserved ejection fraction (HFpEF). In the UK , the National Institute for Health and Care Excellence recommends measuring N-terminal pro-BNP (NT-proBNP) followed by an ultrasound of
3105-605: Is exposure to certain toxins such as lead and cobalt . Additionally, infiltrative disorders such as amyloidosis and connective tissue diseases such as systemic lupus erythematosus have similar consequences. Obstructive sleep apnea (a condition of sleep wherein disordered breathing overlaps with obesity, hypertension, and/or diabetes) is regarded as an independent cause of heart failure. Recent reports from clinical trials have also linked variation in blood pressure to heart failure and cardiac changes that may give rise to heart failure. High-output heart failure happens when
3220-432: Is left unchanged, since the 12 common HLA-C alleles are enough to cover 95% of the world's population. A multipotent mesenchymal stem cell, when induced into pluripotence, holds great promise to slow or reverse aging phenotypes. Such anti-aging properties were demonstrated in early clinical trials in 2017. In 2020, Stanford University researchers concluded after studying elderly mice that old human cells when subjected to
3335-422: Is made by measuring ejection fraction , or the proportion of blood pumped out of the heart during a single contraction. Ejection fraction is given as a percentage with the normal range being between 50 and 75%. The types are: Heart failure may also be classified as acute or chronic. Chronic heart failure is a long-term condition, usually kept stable by the treatment of symptoms. Acute decompensated heart failure
3450-506: Is mentioned in the Ebers Papyrus around 1550 BCE. When the heart functions poorly as a pump and does not circulate blood adequately via the circulatory system to meet the demands of the body the term cardiovascular insufficiency is sometimes used. This generally leads to the syndrome of heart failure, a combination of signs and symptoms It develops when the heart fails to properly fill with blood during diastole , resulting in
3565-656: Is necessary to create universal iPSCs that can be transplanted independently of haplotypes of HLA . The current strategy for the creation of universal iPSCs has two main goals: to remove HLA expression and to prevent NK cells attacks due to deletion of HLA. Deletion of the B2M and CIITA genes using the CRISPR/Cas9 system has been reported to suppress the expression of HLA class I and class II, respectively. To avoid NK cell attacks. transduction of ligands inhibiting NK-cells, such as HLA-E and CD47 has been used. HLA-C
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3680-482: Is not specific for it. It is also indicated by congestion of the pulmonary circulation. Induced pluripotent stem cell Induced pluripotent stem cells (also known as iPS cells or iPSCs ) are a type of pluripotent stem cell that can be generated directly from a somatic cell . The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto , Japan , who together showed in 2006 that
3795-883: Is not the same as cardiac arrest , in which blood flow stops completely due to the failure of the heart to pump. Diagnosis is based on symptoms, physical findings, and echocardiography . Blood tests , and a chest x-ray may be useful to determine the underlying cause. Treatment depends on severity and case. For people with chronic, stable, or mild heart failure, treatment usually consists of lifestyle changes, such as not smoking , physical exercise , and dietary changes, as well as medications. In heart failure due to left ventricular dysfunction, angiotensin-converting-enzyme inhibitors , angiotensin II receptor blockers (ARBs), or angiotensin receptor-neprilysin inhibitors , along with beta blockers , mineralocorticoid receptor antagonists and SGLT2 inhibitors are recommended. Diuretics may also be prescribed to prevent fluid retention and
3910-603: Is still a critical need for blood for transfusion. In 2014, type O red blood cells were synthesized at the Scottish National Blood Transfusion Service from iPSC. The cells were induced to become a mesoderm and then blood cells and then red blood cells. The final step was to make them eject their nuclei and mature properly. Type O can be transfused into all patients. Human clinical trials were not expected to begin before 2016. The first human clinical trial using autologous iPSCs
4025-625: Is symptomatic at rest and becomes quite uncomfortable with any physical activity. This score documents the severity of symptoms and can be used to assess response to treatment. While its use is widespread, the NYHA score is not very reproducible and does not reliably predict walking distance or exercise tolerance on formal testing. In its 2001 guidelines, the American College of Cardiology / American Heart Association working group introduced four stages of heart failure: The ACC staging system
4140-416: Is that they only need to present for a brief amount of time in order for effective reprogramming to take place. Also in 2008, Yamanaka et al. found that they could transfer the four necessary genes with a plasmid. The Yamanaka group successfully reprogrammed mouse cells by transfection with two plasmid constructs carrying the reprogramming factors; the first plasmid expressed c-Myc, while the second expressed
4255-475: Is the X-ray imaging of blood vessels , which is done by injecting contrast agents into the bloodstream through a thin plastic tube ( catheter ), which is placed directly in the blood vessel. X-ray images are called angiograms. Heart failure may be the result of coronary artery disease, and its prognosis depends in part on the ability of the coronary arteries to supply blood to the myocardium (heart muscle). As
4370-494: Is the precipitating cause, and may manifest as regional wall motion abnormalities on echo. Chest X-rays are frequently used to aid in the diagnosis of CHF. In a person who is compensated, this may show cardiomegaly (visible enlargement of the heart), quantified as the cardiothoracic ratio (proportion of the heart size to the chest). In left ventricular failure, evidence may exist of vascular redistribution (upper lobe blood diversion or cephalization), Kerley lines , cuffing of
4485-434: Is the use of iPS cells derived from patients to identify therapeutic drugs able to rescue a phenotype. For instance, iPS cell lines derived from patients affected by ectodermal dysplasia syndrome (EEC), in which the p63 gene is mutated, display abnormal epithelial commitment that could be partially rescued by a small compound. An attractive feature of human iPS cells is the ability to derive them from adult patients to study
4600-589: Is theoretically no risk of rejection and that it eliminates the need to use embryonic stem cells. However, these iPSCs were derived from another person. New clinical trials involving iPSCs are now ongoing not only in Japan, but also in the US and Europe. Research in 2021 on the trial registry Clinicaltrials.gov identified 129 trial listings mentioning iPSCs, but most were non-interventional. To make iPSC-based regenerative medicine technologies available to more patients, it
4715-491: Is useful since stage A encompasses "pre-heart failure" – a stage where intervention with treatment can presumably prevent progression to overt symptoms. ACC stage A does not have a corresponding NYHA class. ACC stage B would correspond to NYHA class I. ACC stage C corresponds to NYHA class II and III, while ACC stage D overlaps with NYHA class IV. Histopathology can diagnose heart failure in autopsies . The presence of siderophages indicates chronic left-sided heart failure, but
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4830-569: The Sox gene family (Sox1, Sox2, Sox3, and Sox15) have been identified as crucial transcriptional regulators involved in the induction process whose absence makes induction impossible. Additional genes, however, including certain members of the Klf family (Klf1, Klf2, Klf4, and Klf5), the Myc family (c-myc, L-myc, and N-myc), Nanog , and LIN28 , have been identified to increase the induction efficiency. Although
4945-436: The mesenchymal-epithelial transition (MET) process in which fibroblasts are pushed to a stem-cell like state, Ding's group identified two chemicals – ALK5 inhibitor SB431412 and MEK (mitogen-activated protein kinase) inhibitor PD0325901 – which was found to increase the efficiency of the classical genetic method by 100 fold. Adding a third compound known to be involved in the cell survival pathway, thiazovivin further increases
5060-616: The shortening fraction is the preferred measure of systolic function. Normally, the EF should be between 50 and 70%; in systolic heart failure, it drops below 40%. Echocardiography can also identify valvular heart disease and assess the state of the pericardium (the connective tissue sac surrounding the heart). Echocardiography may also aid in deciding specific treatments, such as medication, insertion of an implantable cardioverter-defibrillator , or cardiac resynchronization therapy . Echocardiography can also help determine if acute myocardial ischemia
5175-839: The Center for Comprehensive Alzheimer's Disease Research, while the Roddenberry Foundation helped launch the Roddenberry Stem Cell Center for Biology and Medicine. Also in 2011, the independent and philanthropic Gladstone Foundation formed with the mission of expanding the financial resources for the institutes. Gladstone Institutes consists of five institutes: Gladstone is also home to eight centers for researchers from different institutes to collaborate. These centers focus on stem and iPS cell research, as well as neurodegenerative disease research and therapeutics. Gladstone cardiovascular scientists research
5290-468: The DNA of skin and liver cells of mice, resulting in cells identical to ESCs. The adenovirus is unique from other vectors like viruses and retroviruses because it does not incorporate any of its own genes into the targeted host and avoids the potential for insertional mutagenesis. In 2009, Freed et al. demonstrated successful reprogramming of human fibroblasts to iPS cells. Another advantage of using adenoviruses
5405-732: The ESC-specific gene, Fbx15 , could be isolated using antibiotic selection. Upon delivery of all twenty-four factors, ESC-like colonies emerged that reactivated the Fbx15 reporter and could propagate indefinitely. To identify the genes necessary for reprogramming, the researchers removed one factor at a time from the pool of twenty-four. By this process, they identified four factors, Oct4, Sox2, cMyc, and Klf4, which were each necessary and together sufficient to generate ESC-like colonies under selection for reactivation of Fbx15. In June 2007, three separate research groups, including that of Yamanaka's,
5520-667: The Gladstone Institutes moved to a new facility in San Francisco's Mission Bay, San Francisco neighborhood. Dr. Mahley stepped down as president in 2010 to return to active research, and was replaced by R. Sanders Williams (former Dean of the School of Medicine at Duke University ). Deepak Srivastava became the institute's third president in January 2018. In 2011, the S.D. Bechtel, Jr. Foundation helped launch
5635-545: The Ministry of Health, Labor and Welfare on the same day. On May 16, 2018, the clinical research plan was approved by the Ministry of Health, Labor and Welfare's expert group with a condition. In October 2019, a group at Okayama University developed a model of ischemic heart disease using cardiomyocytes differentiated from iPS cells. Although a pint of donated blood contains about two trillion red blood cells and over 107 million blood donations are collected globally, there
5750-444: The administration or allegedly retaliatory actions against the complainants. These examples of antisemitic activities include: Current researchers at the institute include: Former researchers: Heart failure Heart failure ( HF ), also known as congestive heart failure ( CHF ), is a syndrome caused by an impairment in the heart 's ability to fill with and pump blood . Although symptoms vary based on which side of
5865-458: The affected retina where the degenerated RPE tissue was excised. Safety and vision restoration monitoring were to last one to three years. In March 2017, a team led by Masayo Takahashi completed the first successful transplant of iPS-derived retinal cells from a donor into the eye of a person with advanced macular degeneration. However it was reported that they are now having complications. The benefits of using autologous iPSCs are that there
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#17327908302065980-530: The age of 70. Rates are predicted to increase. The risk of death in the first year after diagnosis is about 35%, while the risk of death in the second year is less than 10% in those still alive. The risk of death is comparable to that of some cancers. In the United Kingdom, the disease is the reason for 5% of emergency hospital admissions. Heart failure has been known since ancient times in Egypt ; it
6095-453: The amount of blood pumped out is more than typical and the heart cannot keep up. This can occur in overload situations such as blood or serum infusions, kidney diseases, chronic severe anemia , beriberi (vitamin B 1 / thiamine deficiency), hyperthyroidism , cirrhosis , Paget's disease , multiple myeloma , arteriovenous fistulae , or arteriovenous malformations . Chronic stable heart failure may easily decompensate (fail to meet
6210-418: The areas around the bronchi , and interstitial edema. Ultrasound of the lung may also detect Kerley lines. An electrocardiogram (ECG or EKG) may be used to identify arrhythmias , ischemic heart disease , right and left ventricular hypertrophy , and presence of conduction delay or abnormalities (e.g. left bundle branch block ). Although these findings are not specific to the diagnosis of heart failure,
6325-656: The articles to be retracted. On 4 June 2014, the lead author, Obokata agreed to retract both the papers after she was found to have committed 'research misconduct' as concluded in an investigation by RIKEN on 1 April 2014. MicroRNAs are short RNA molecules that bind to complementary sequences on messenger RNA and block expression of a gene. Measuring variations in microRNA expression in iPS cells can be used to predict their differentiation potential. Addition of microRNAs can also be used to enhance iPS potential. Several mechanisms have been proposed. ES cell-specific microRNA molecules (such as miR-291, miR-294 and miR-295) enhance
6440-407: The blood , is a late sign of extremely severe pulmonary edema. Other signs of left ventricular failure include a laterally displaced apex beat (which occurs when the heart is enlarged) and a gallop rhythm (additional heart sounds), which may be heard as a sign of increased blood flow or increased intracardiac pressure. Heart murmurs may indicate the presence of valvular heart disease, either as
6555-604: The body first, causing foot and ankle swelling in people who are standing up and sacral edema in people who are predominantly lying down. Nocturia (frequent night-time urination) may occur when fluid from the legs is returned to the bloodstream while lying down at night. In progressively severe cases, ascites (fluid accumulation in the abdominal cavity causing swelling) and liver enlargement may develop. Significant liver congestion may result in impaired liver function ( congestive hepatopathy ), jaundice, and coagulopathy (problems of decreased or increased blood clotting). Dullness of
6670-457: The body's metabolic needs). This most commonly results from a concurrent illness (such as myocardial infarction (a heart attack) or pneumonia ), abnormal heart rhythms , uncontrolled hypertension , or a person's failure to maintain a fluid restriction, diet, or medication. Other factors that may worsen CHF include: anemia, hyperthyroidism, excessive fluid or salt intake, and medication such as NSAIDs and thiazolidinediones . NSAIDs increase
6785-412: The body; the rate of fluid retention is higher than the rate of sodium retention in the body, this phenomenon causes hypervolemic hyponatremia (low sodium concentration due to high body fluid retention). This phenomenon is more common in older women with low body mass. Severe hyponatremia can result in accumulation of fluid in the brain, causing cerebral edema and intracranial hemorrhage . Angiography
6900-478: The brain. Right-sided heart failure is often caused by pulmonary heart disease (cor pulmonale), which is typically caused by issues with pulmonary circulation such as pulmonary hypertension or pulmonic stenosis . Physical examination may reveal pitting peripheral edema, ascites, liver enlargement , and spleen enlargement . Jugular venous pressure is frequently assessed as a marker of fluid status, which can be accentuated by testing hepatojugular reflux . If
7015-407: The cellular basis of human disease. Since iPS cells are self-renewing and pluripotent, they represent a theoretically unlimited source of patient-derived cells which can be turned into any type of cell in the body. This is particularly important because many other types of human cells derived from patients tend to stop growing after a few passages in laboratory culture. iPS cells have been generated for
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#17327908302067130-516: The cost of) drug development. On November 22, 2024 the U.S House Education and Workforce and the House Energy and Commerce Committees announced they are jointly investigating the Gladstone Institutes for its handling of antisemitic incidents. The letter sent by the committee leadership to Deepak Srivastava and the Gladstone Institute cites several instances of antisemitic behavior conducted by faculty and staff, coupled with either no response from
7245-512: The development of induced pluripotent stem cell technology by one of its investigators, 2012 Nobel Laureate Shinya Yamanaka , to improve drug discovery, personalized medicine and tissue regeneration. Founded in 1979, Gladstone is academically affiliated with the University of California, San Francisco (UCSF), and located adjacent to UCSF's Mission Bay campus. The organization comprises five major institutes, as well as multiple centers focused on various areas of research. The current president of
7360-438: The earlier seminal work of Harold Weintraub on the role of myoblast determination protein 1 (MyoD) in reprogramming cell fate to a muscle lineage as an important precursor to the discovery of iPSCs. iPSCs are typically derived by introducing products of specific sets of pluripotency-associated genes, or "reprogramming factors", into a given cell type. The original set of reprogramming factors (also dubbed Yamanaka factors) are
7475-440: The effects of histone deacetylase (HDAC) inhibitor valproic acid. They found that it increased reprogramming efficiency 100-fold (compared to Yamanaka's traditional transcription factor method). The researchers proposed that this compound was mimicking the signaling that is usually caused by the transcription factor c-Myc. A similar type of compensation mechanism was proposed to mimic the effects of Sox2 . In 2008, Ding et al. used
7590-606: The effects of diuretic medications. Gossypol can increase the effects of diuretics, leading to toxicity. Gynura can cause low blood pressure. Licorice can worsen heart failure by increasing blood pressure and promoting fluid retention. Lily of the Valley can cause abnormally slow heart rates with mechanisms similar to those of digoxin. Tetrandrine can lower blood pressure by inhibiting L-type calcium channels . Yohimbine can exacerbate heart failure by increasing blood pressure through alpha-2 adrenergic receptor antagonism. Heart failure
7705-408: The efficiency by 200 fold. Using the combination of these three compounds also decreased the reprogramming process of the human fibroblasts from four weeks to two weeks. In April 2009, it was demonstrated that generation of iPS cells is possible without any genetic alteration of the adult cell: a repeated treatment of the cells with certain proteins channeled into the cells via poly-arginine anchors
7820-420: The efficiency of induced pluripotency by acting downstream of c-Myc. MicroRNAs can also block expression of repressors of Yamanaka's four transcription factors, and there may be additional mechanisms induce reprogramming even in the absence of added exogenous transcription factors. Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem cells, in many aspects, such as
7935-606: The expression of certain stem cell genes and proteins, chromatin methylation patterns, doubling time, embryoid body formation, teratoma formation, viable chimera formation, and potency and differentiability, but the full extent of their relation to natural pluripotent stem cells is still being assessed. Gene expression and genome-wide H3K4me3 and H3K27me3 were found to be extremely similar between ES and iPS cells. The generated iPSCs were remarkably similar to naturally isolated pluripotent stem cells (such as mouse and human embryonic stem cells, mESCs and hESCs, respectively) in
8050-483: The field of regenerative medicine . Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease. The most well-known type of pluripotent stem cell is the embryonic stem cell . However, since the generation of embryonic stem cells involves destruction (or at least manipulation) of
8165-429: The following respects, thus confirming the identity, authenticity, and pluripotency of iPSCs to naturally isolated pluripotent stem cells: The task of producing iPS cells continues to be challenging due to the six problems mentioned above. A key tradeoff to overcome is that between efficiency and genomic integration. Most methods that do not rely on the integration of transgenes are inefficient, while those that do rely on
8280-523: The force with which the heart ejects blood , thus are not recommended in people with heart failure with a reduced ejection fraction. Breast cancer patients are at high risk of heart failure due to several factors. After analyzing data from 26 studies (836,301 patients), the recent meta-analysis found that breast cancer survivors demonstrated a higher risk heart failure within first ten years after diagnosis (hazard ratio = 1.21; 95% CI: 1.1, 1.33). The pooled incidence of heart failure in breast cancer survivors
8395-509: The form of peripheral edema (causing swollen limbs and feet) and pulmonary edema (causing difficulty breathing) and ascites (swollen abdomen). Pulse pressure , which is the difference between the systolic ("top number") and diastolic ("bottom number") blood pressures, is often low/narrow (i.e. 25% or less of the level of the systolic) in people with heart failure, and this can be an early warning sign. Symptoms of heart failure are traditionally divided into left-sided and right-sided because
8510-678: The formation of prostaglandins , NSAIDs may exacerbate heart failure through several mechanisms, including promotion of fluid retention, increasing blood pressure , and decreasing a person's response to diuretic medications. Similarly, the ACC/AHA recommends against using COX-2 inhibitor medications in people with heart failure. Thiazolidinediones have been strongly linked to new cases of heart failure and worsening of pre-existing congestive heart failure due to their association with weight gain and fluid retention. Certain calcium channel blockers, such as diltiazem and verapamil , are known to decrease
8625-739: The heart if positive. In Europe , the European Society of Cardiology , and in the United States, the AHA / ACC / HFSA , recommend measuring NT-proBNP or BNP followed by an ultrasound of the heart if positive. This is recommended in those with symptoms consistent with heart failure such as shortness of breath . The European Society of Cardiology defines the diagnosis of heart failure as symptoms and signs consistent with heart failure in combination with "objective evidence of cardiac structural or functional abnormalities". This definition
8740-666: The heart is affected, HF typically presents with shortness of breath , excessive fatigue , and bilateral leg swelling . The severity of the heart failure is mainly decided based on ejection fraction and also measured by the severity of symptoms. Other conditions that have symptoms similar to heart failure include obesity , kidney failure , liver disease , anemia , and thyroid disease . Common causes of heart failure include coronary artery disease , heart attack , high blood pressure , atrial fibrillation , valvular heart disease , excessive alcohol consumption , infection , and cardiomyopathy . These cause heart failure by altering
8855-535: The heart muscle. An echocardiogram ( ultrasound of the heart) is commonly used to support a clinical diagnosis of heart failure. This can determine the stroke volume (SV, the amount of blood in the heart that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF). In pediatrics,
8970-599: The heart's myocardial tissue (termed myocarditis ) can similarly contribute to the development of heart failure. Genetic predisposition plays an important role. If more than one cause is present, progression is more likely and prognosis is worse. Heart damage can predispose a person to develop heart failure later in life and has many causes including systemic viral infections (e.g., HIV ), chemotherapeutic agents such as daunorubicin , cyclophosphamide , trastuzumab and substance use disorders of substances such as alcohol , cocaine , and methamphetamine . An uncommon cause
9085-703: The heart, and studying samples of SARS-CoV-2 variations appearing in California, and their resistances to the Moderna and Pfizer vaccines . Research at Gladstone focuses on major neurological diseases including: Alzheimer's disease , Parkinson's disease , frontotemporal dementia (FTD), Huntington's disease , amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease) and multiple sclerosis . This research incorporates animal models, electrophysiology , behavioral testing and automated high-throughput analyses. In addition, Gladstone investigators seek to accelerate
9200-577: The high-quality, multipotent vascular stem cells. After the iPS cells were injected directly into the vitreous of the damaged retina of mice, the stem cells engrafted into the retina, grew and repaired the vascular vessels . Labelled iPSCs-derived NSCs injected into laboratory animals with brain lesions were shown to migrate to the lesions and some motor function improvement was observed. Beating cardiac muscle cells, iPSC-derived cardiomyocytes , can be mass-produced using chemically defined differentiation protocols. These protocols typically modulate
9315-546: The idea of selling cardiomyocytes to pharmaceutical companies and universities to help develop new drugs for heart disease. On March 9, 2018, the Specified Regenerative Medicine Committee of Osaka University officially approved the world's first clinical research plan to transplant a "myocardial sheet" made from iPS cells into the heart of patients with severe heart failure. Osaka University announced that it had filed an application with
9430-466: The inhibition of histone methyl transferase (HMT) with BIX-01294 in combination with the activation of calcium channels in the plasma membrane in order to increase reprogramming efficiency. Deng et al. of Beijing University reported in July 2013 that induced pluripotent stem cells can be created without any genetic modification. They used a cocktail of seven small-molecule compounds including DZNep to induce
9545-475: The institute is Deepak Srivastava. Gladstone Institutes was founded in 1979 as a research and training facility housed at San Francisco General Hospital . Under inaugural president Robert Mahley—a cardiovascular scientist recruited from the National Institutes of Health—the institutes was launched with a $ 8 million trust from the late commercial real estate developer, J. David Gladstone. In 2004
9660-530: The integration of transgenes face the problems of incomplete reprogramming and tumor genesis, although a vast number of techniques and methods have been attempted. Another large set of strategies is to perform a proteomic characterization of iPS cells. Further studies and new strategies should generate optimal solutions to the five main challenges. One approach might attempt to combine the positive attributes of these strategies into an ultimately effective technique for reprogramming cells to iPS cells. Another approach
9775-415: The introduction of four specific genes (named Myc , Oct3/4 , Sox2 and Klf4 ), collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." Pluripotent stem cells hold promise in
9890-430: The left and right ventricles supply different parts of the circulation. In biventricular heart failure, both sides of the heart are affected. Left-sided heart failure is the more common. The left side of the heart takes oxygen-rich blood from the lungs and pumps it to the rest of the circulatory system in the body (except for the pulmonary circulation ). Failure of the left side of the heart causes blood to back up into
10005-441: The lung fields when percussed and reduced breath sounds at the base of the lungs may suggest the development of a pleural effusion (fluid collection between the lung and the chest wall ). Though it can occur in isolated left- or right-sided heart failure, it is more common in biventricular failure because pleural veins drain into both the systemic and pulmonary venous systems. When unilateral, effusions are often right-sided. If
10120-446: The lungs, causing breathing difficulties and fatigue due to an insufficient supply of oxygenated blood. Common respiratory signs include increased respiratory rate and labored breathing (nonspecific signs of shortness of breath). Rales or crackles are heard initially in the lung bases and when severe in all lung fields indicate the development of pulmonary edema (fluid in the alveoli ). Cyanosis , indicates deficiency of oxygen in
10235-510: The main strategies for avoiding problems (1) and (2) has been to use small molecules that can mimic the effects of transcription factors. These compounds can compensate for a reprogramming factor that does not effectively target the genome or fails at reprogramming for another reason; thus they raise reprogramming efficiency. They also avoid the problem of genomic integration, which in some cases contributes to tumor genesis. Key studies using such strategy were conducted in 2008. Melton et al. studied
10350-436: The methods pioneered by Yamanaka and others have demonstrated that adult cells can be reprogrammed to iPS cells, there are still challenges associated with this technology: The table on the right summarizes the key strategies and techniques used to develop iPS cells in the first five years after Yamanaka et al.'s 2006 breakthrough. Rows of similar colors represent studies that used similar strategies for reprogramming. One of
10465-441: The mouse somatic cells into stem cells which they called CiPS cells with the efficiency – at 0.2% – comparable to those using standard iPSC production techniques. The CiPS cells were introduced into developing mouse embryos and were found to contribute to all major cells types, proving its pluripotency. Ding et al . demonstrated an alternative to transcription factor reprogramming through the use of drug-like chemicals. By studying
10580-475: The movement of basic science discoveries into clinical trials with efforts to bridge the so-called "Valley of Death". The research features an emphasis on the common threads linking the various diseases and treatments for them. Current research programs include: Another focus at Gladstone is building on the development of induced pluripotent stem cell technology by one of its senior investigators, 2012 Nobel Laureate Shinya Yamanaka . In 2006, Yamanaka discovered
10695-575: The number of pillows required to lie comfortably, with extreme cases of orthopnea forcing the patient to sleep sitting up. Another symptom of heart failure is paroxysmal nocturnal dyspnea : a sudden nocturnal attack of severe shortness of breath, usually occurring several hours after falling asleep. There may be " cardiac asthma " or wheezing . Impaired left ventricular forward function can lead to symptoms of poor systemic perfusion such as dizziness , confusion , and cool extremities at rest. Loss of consciousness may also occur due to loss of blood supply to
10810-452: The original iPSC method, and James Thomson of University of Wisconsin-Madison who was the first to derive human embryonic stem cells. With the same principle used in mouse reprogramming, Yamanaka's group successfully transformed human fibroblasts into iPSCs with the same four pivotal genes, Oct4, Sox2, Klf4, and cMyc, using a retroviral system, while Thomson and colleagues used a different set of factors, Oct4, Sox2, Nanog, and Lin28, using
10925-564: The other three factors ( Oct4 , Klf4 , and Sox2 ). Although the plasmid methods avoid viruses, they still require cancer-promoting genes to accomplish reprogramming. The other main issue with these methods is that they tend to be much less efficient compared to retroviral methods. Furthermore, transfected plasmids have been shown to integrate into the host genome and therefore they still pose the risk of insertional mutagenesis. Because non-retroviral approaches have demonstrated such low efficiency levels, researchers have attempted to effectively rescue
11040-520: The pre-implantation stage embryo, there has been much controversy surrounding their use. Patient-matched embryonic stem cell lines can now be derived using somatic cell nuclear transfer (SCNT). Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without
11155-503: The resulting shortness of breath. Depending on the case, an implanted device such as a pacemaker or implantable cardiac defibrillator may sometimes be recommended. In some moderate or more severe cases, cardiac resynchronization therapy (CRT) or cardiac contractility modulation may be beneficial. In severe disease that persists despite all other measures, a cardiac assist device ventricular assist device , or, occasionally, heart transplantation may be recommended. Heart failure
11270-403: The right ventricular pressure is increased, a parasternal heave which causes the compensatory increase in contraction strength may be present. Backward failure of the right ventricle leads to congestion of systemic capillaries. This generates excess fluid accumulation in the body. This causes swelling under the skin ( peripheral edema or anasarca ) and usually affects the dependent parts of
11385-410: The risk of immune rejection. While the iPSC technology has not yet advanced to a stage where therapeutic transplants have been deemed safe, iPSCs are readily being used in personalized drug discovery efforts and understanding the patient-specific basis of disease. Yamanaka named iPSCs with a lower case "i" due to the popularity of the iPod and other products. In his Nobel seminar, Yamanaka cited
11500-626: The risk twofold. A number of medications may cause or worsen the disease. This includes NSAIDs , COX-2 inhibitors , a number of anesthetic agents such as ketamine , thiazolidinediones, some cancer medications , several antiarrhythmic medications , pregabalin , alpha-2 adrenergic receptor agonists , minoxidil , itraconazole , cilostazol , anagrelide , stimulants (e.g., methylphenidate ), tricyclic antidepressants , lithium , antipsychotics , dopamine agonists , TNF inhibitors , calcium channel blockers (especially verapamil and diltiazem ), salbutamol , and tamsulosin . By inhibiting
11615-618: The same developmental signaling pathways required for heart development . These iPSC-cardiomyocytes can recapitulate genetic arrhythmias and cardiac drug responses, since they exhibit the same genetic background as the patient from which they were derived. In June 2014, Takara Bio received technology transfer from iHeart Japan, a venture company from Kyoto University's iPS Cell Research Institute, to make it possible to exclusively use technologies and patents that induce differentiation of iPS cells into cardiomyocytes in Asia. The company announced
11730-535: The same four transcription factors (Oct4, Sox2, cMyc, Klf4). However, instead of using Fbx15 to select for pluripotent cells, the researchers used Nanog , a gene that is functionally important in ESCs. By using this different strategy, the researchers created iPSCs that were functionally identical to ESCs. Reprogramming of human cells to iPSCs was reported in November 2007 by two independent research groups: Shinya Yamanaka of Kyoto University, Japan, who pioneered
11845-509: The spectrum of cardiovascular disease, utilizing developmental, chemical, and stem cell biology approaches, as well as genomics techniques, across a variety of research programs and institutes. Their research has included: In 1991, Gladstone expanded its focus to include virology and immunology in response to the HIV/AIDS crisis. Since then the institute has also studied hepatitis C , Zika virus , and COVID-19 . In 2011, Gladstone launched
11960-436: The structure or the function of the heart or in some cases both. There are different types of heart failure: right-sided heart failure , which affects the right heart , left-sided heart failure , which affects the left heart , and biventricular heart failure, which affects both sides of the heart. Left-sided heart failure may be present with a reduced ejection fraction or with a preserved ejection fraction . Heart failure
12075-507: The technique with what is known as the PiggyBac Transposon System . Several studies have demonstrated that this system can effectively deliver the key reprogramming factors without leaving footprint mutations in the host cell genome. The PiggyBac Transposon System involves the re-excision of exogenous genes, which eliminates the issue of insertional mutagenesis. In January 2014, two articles were published claiming that
12190-486: The technology, by which ordinary differentiated adult cells (such as fibroblasts from skin) could be "reprogrammed" into a pluripotent state—i.e., a state similar to embryonic stem cells , which are capable of developing into virtually any cell type in the human body. His discovery of induced pluripotent stem cells, or iPS cells, has since revolutionized the fields of developmental biology, stem cell research and both personalized and regenerative medicine. In 2012 Yamanaka
12305-439: The transcription factors Oct4 (Pou5f1), Sox2 , Klf4 and cMyc . While this combination is most conventional in producing iPSCs, each of the factors can be functionally replaced by related transcription factors, miRNAs , small molecules, or even non-related genes such as lineage specifiers. It is also clear that pro-mitotic factors such as C-MYC/L-MYC or repression of cell cycle checkpoints, such as p53, are conduits to creating
12420-591: The transplanted organ in the host body (ability to integrate or avoid rejection ) and whether it will transform into tumors . In 2021, a switchable Yamanaka factors- reprogramming -based approach for regeneration of damaged heart without tumor-formation was demonstrated in mice and was successful if the intervention was carried out immediately before or after a heart attack. Embryonic cord-blood cells were induced into pluripotent stem cells using plasmid DNA. Using cell surface endothelial/pericytic markers CD31 and CD146 , researchers identified 'vascular progenitor',
12535-541: The underlying cause for the clinical presentation", for HFmrEF and HFpEF specifically requiring "evidence of spontaneous or provokable increased left ventricle filling pressures". The European Society of Cardiology has developed a diagnostic algorithm for HFpEF , named HFA-PEFF. HFA-PEFF considers symptoms and signs, typical clinical demographics (obesity, hypertension, diabetes, elderly, atrial fibrillation), and diagnostic laboratory tests, ECG, and echocardiography. One historical method of categorizing heart failure
12650-565: The underlying cause is vital to diagnosis and treatment. In heart failure, the structure or the function of the heart or in some cases both are altered. Heart failure is the potential end stage of all heart diseases. Common causes of heart failure include coronary artery disease , including a previous myocardial infarction (heart attack), high blood pressure , atrial fibrillation , valvular heart disease , excess alcohol use , infection , and cardiomyopathy of an unknown cause. In addition, viral infection and subsequent inflammation of
12765-434: The urine. Other considerations for starting cell type include mutational load (for example, skin cells may harbor more mutations due to UV exposure), time it takes to expand the population of starting cells, and the ability to differentiate into a given cell type. The generation of induced pluripotent cells is crucially dependent on the transcription factors used for the induction. Oct-3/4 and certain products of
12880-488: Was 4.44 (95% CI 3.33-5.92) per 1000 person-years of follow-up. Certain alternative medicines carry a risk of exacerbating existing heart failure, and are not recommended. This includes aconite , ginseng , gossypol , gynura , licorice , lily of the valley , tetrandrine , and yohimbine . Aconite can cause abnormally slow heart rates and abnormal heart rhythms such as ventricular tachycardia. Ginseng can cause abnormally low or high blood pressure and may interfere with
12995-774: Was approved by the Japan Ministry Health and was to be conducted in 2014 at the Riken Center for Developmental Biology in Kobe . However the trial was suspended after Japan's new regenerative medicine laws came into effect in November 2015. More specifically, an existing set of guidelines was strengthened to have the force of law (previously mere recommendations). iPSCs derived from skin cells from six patients with wet age-related macular degeneration were reprogrammed to differentiate into retinal pigment epithelial (RPE) cells. The cell sheet would be transplanted into
13110-720: Was awarded the Nobel Prize in Physiology or Medicine. Since Yamanaka's discovery, scientists at Gladstone have used iPS technology to research solutions for Huntington's disease and Alzheimer's disease, as well as create a new model for testing HIV/AIVD vaccines. Other work at the Data Science & Biotechnology Institute include: The Gladstone Center for Translational Advancement was formed in 2017, and focuses on drug repositioning ; repurposing already-approved drugs for new uses and clinical trials, to speed up (and lower
13225-429: Was sufficient to induce pluripotency. The acronym given for those iPSCs is piPSCs (protein-induced pluripotent stem cells). Another key strategy for avoiding problems such as tumorgenesis and low throughput has been to use alternate forms of vectors: adenoviruses , plasmids , and naked DNA or protein compounds. In 2008, Hochedlinger et al. used an adenovirus to transport the requisite four transcription factors into
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