The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, ...making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.
► Phenformin is a mitochondrial inhibitor that selectively kills LKB1−/− NSCLC cells ► LKB1−/− NSCLC cells exhibit defective mitochondria and ROS following phenformin ► Phenformin improves tumors and survival in KrasG12DLkb1−/−, not KrasG12Dp53−/− mice ► eIF2α signaling markers are AMPK-independent biomarkers of biguanide treatment
Mucormycosis Reid, Gail; Lynch, 3rd, Joseph P; Fishbein, Michael C ...
Seminars in respiratory and critical care medicine,
02/2020, Letnik:
41, Številka:
1
Journal Article
Recenzirano
Mucormycosis is an infection caused by a group of filamentous molds within the order Mucorales. Infections may result from ingestion of contaminated food, inhalation of spores into the nares or ...lungs, or inoculation into disrupted skin or wounds. In developed countries, mucormycosis occurs primarily in severely immunocompromised hosts (e.g., those with hematological malignancies, organ transplantation, neutropenia, autoimmune disorders, or other impairments in immunity). Only 6 to 10% of cases occur in subjects with no underlying disease. In contrast, in developing countries, most cases of mucormycosis occur in persons with poorly controlled diabetes mellitus or in immunocompetent subjects following trauma. Mucormycosis exhibits a marked propensity to invade blood vessels, leading to thrombosis, necrosis, and infarction of tissue. Mortality associated with invasive mucormycosis is high (> 30-50%), with 90% mortality associated with disseminated disease. Mortality rates are much lower, though still significant (10-30%), among patients with localized cutaneous disease.The diagnosis of mucormycosis relies upon histopathology and culture. Blood tests are of limited diagnostic value. Even with disseminated disease, blood cultures are usually negative. Mucorales have a distinct histological appearance, with irregular, nonseptate hyphae that branch at right angles. Cultures and/or polymerase chain reaction (PCR) are important to identify the genera.Based on anatomic localization, mucormycosis can be classified as one of six forms: (1) rhino-orbital-cerebral mucormycosis (ROCM), (2) pulmonary, (3) cutaneous, (4) gastrointestinal (GI), (5) disseminated, and (6) mucormycosis of uncommon sites. Among diabetics, ROCM is the most common clinical presentation, whereas lung involvement is uncommon. In contrast, among organ transplant recipients or patients with hematological malignancies (HemeM), pulmonary and disseminated diseases are most common. Mucormycosis can progress rapidly, and delay in initiation of treatment by even a few days markedly worsens outcomes.Due to the rarity of mucormycosis, randomized controlled therapeutic trials have not been performed. Lipid formulations of amphotericin B (LFAB) are the mainstay of therapy, but the newer triazoles, posaconazole (POSA) and isavuconazole (ISAV) (the active component of the prodrug isavuconazonium sulfate), may be effective in patients refractory to or intolerant of LFAB. Early surgical debridement or excision plays an important adjunctive role. Additional studies are required to assess the optimal duration of therapy as well as the specific roles of LFAB and the triazoles in the treatment of mucormycosis.
Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). ...However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
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•IL-1β-driven increased intestinal permeability is observed in murine KD model•Blocking intestinal permeability or IgA production decreases murine KD vasculitis•IgA and IgA-C3 are observed in cardiovascular lesions of murine KD model•KD vasculitis may be a form of IgA vasculitis involving a gut-vascular axis
Kawasaki disease (KD) is the leading cause of acquired heart disease among children, and the etiology is unknown. Noval Rivas et al. demonstrate that a murine model of KD vasculitis is dependent on intestinal barrier dysfunction leading to secretory IgA leakage and IgA-C3 immune complex deposition in cardiovascular lesions.
Autonomic nervous system activation can induce significant and heterogeneous changes of atrial electrophysiology and induce atrial tachyarrhythmias, including atrial tachycardia and atrial ...fibrillation (AF). The importance of the autonomic nervous system in atrial arrhythmogenesis is also supported by circadian variation in the incidence of symptomatic AF in humans. Methods that reduce autonomic innervation or outflow have been shown to reduce the incidence of spontaneous or induced atrial arrhythmias, suggesting that neuromodulation may be helpful in controlling AF. In this review, we focus on the relationship between the autonomic nervous system and the pathophysiology of AF and the potential benefit and limitations of neuromodulation in the management of this arrhythmia. We conclude that autonomic nerve activity plays an important role in the initiation and maintenance of AF, and modulating autonomic nerve function may contribute to AF control. Potential therapeutic applications include ganglionated plexus ablation, renal sympathetic denervation, cervical vagal nerve stimulation, baroreflex stimulation, cutaneous stimulation, novel drug approaches, and biological therapies. Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future.
Although much progress has been made in identifying the mechanisms that trigger endothelial activation and inflammatory cell recruitment during atherosclerosis, less is known about the intrinsic ...pathways that counteract these events. Here we identified NOTCH1 as an antagonist of endothelial cell (EC) activation. NOTCH1 was constitutively expressed by adult arterial endothelium, but levels were significantly reduced by high-fat diet. Furthermore, treatment of human aortic ECs (HAECs) with inflammatory lipids (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Ox-PAPC) and proinflammatory cytokines (TNF and IL1β) decreased Notch1 expression and signaling in vitro through a mechanism that requires STAT3 activation. Reduction of NOTCH1 in HAECs by siRNA, in the absence of inflammatory lipids or cytokines, increased inflammatory molecules and binding of monocytes. Conversely, some of the effects mediated by Ox-PAPC were reversed by increased NOTCH1 signaling, suggesting a link between lipid-mediated inflammation and Notch1. Interestingly, reduction of NOTCH1 by Ox-PAPC in HAECs was associated with a genetic variant previously correlated to high-density lipoprotein in a human genome-wide association study. Finally, endothelial Notch1 heterozygous mice showed higher diet-induced atherosclerosis. Based on these findings, we propose that reduction of endothelial NOTCH1 is a predisposing factor in the onset of vascular inflammation and initiation of atherosclerosis.
The autonomic nervous system regulates all aspects of normal cardiac function, and is recognized to play a critical role in the pathophysiology of many cardiovascular diseases. As such, the value of ...neuroscience‐based cardiovascular therapeutics is increasingly evident. This White Paper reviews the current state of understanding of human cardiac neuroanatomy, neurophysiology, pathophysiology in specific disease conditions, autonomic testing, risk stratification, and neuromodulatory strategies to mitigate the progression of cardiovascular diseases.
Cardiac allograft vasculopathy (CAV) is a major limitation to the long-term success of cardiac transplantation. Although there are published descriptions of the lesions, there have been no studies ...delineating the pathology of CAV in a large series of patients who underwent retransplantation for CAV.
We reviewed archival records and microscopic sections of surgically explanted hearts from 64 patients who underwent cardiac retransplantation: 54 adults (18 to 70 years old) and 10 children (3 to 15 years old). Vascular lesions were categorized as showing intimal fibromuscular hyperplasia, atherosclerosis and/or inflammation. The degree of luminal narrowing was estimated from gross descriptions and microscopic sections.
In total, 75% of hearts had evidence of acute cellular rejection, mostly mild. Intramyocardial arteries showed primarily intimal fibromuscular hyperplasia and inflammation with no atheromas present. Large and branch epicardial coronary arteries were narrowed in at least one artery of all hearts. Lesions in the epicardial coronary arteries were composed of intimal fibromuscular hyperplasia, atherosclerosis and/or inflammation affecting one or more vascular layers (intima, media and adventitia). Severe CAV with >75% luminal narrowing was seen in the LAD in 17% of hearts, the LCx in 17% and the RCA in 22% of hearts. Two hearts had severe narrowing of the left main coronary artery. Nineteen arteries had luminal thrombi. All hearts had narrowing of smaller epicardial branch coronary arteries that was often severe. Atheromas were present in arteries of adults and children; thus, not all atheromas could be considered pre-existing prior to transplantation. Both arteries and veins showed intimal hyperplasia and inflammation.
CAV is a pathologically multifaceted disorder that affects large and small epicardial coronary arteries of adults and children, with different types of lesions: intimal fibromuscular hyperplasia; atherosclerosis; and/or inflammation (vasculitis). Therapies to address this disease must take into account the protean nature of the vascular lesions.
Mitochondria are essential regulators of cellular energy and metabolism, and have a crucial role in sustaining the growth and survival of cancer cells. A central function of mitochondria is the ...synthesis of ATP by oxidative phosphorylation, known as mitochondrial bioenergetics. Mitochondria maintain oxidative phosphorylation by creating a membrane potential gradient that is generated by the electron transport chain to drive the synthesis of ATP
. Mitochondria are essential for tumour initiation and maintaining tumour cell growth in cell culture and xenografts
. However, our understanding of oxidative mitochondrial metabolism in cancer is limited because most studies have been performed in vitro in cell culture models. This highlights a need for in vivo studies to better understand how oxidative metabolism supports tumour growth. Here we measure mitochondrial membrane potential in non-small-cell lung cancer in vivo using a voltage-sensitive, positron emission tomography (PET) radiotracer known as 4-
Ffluorobenzyl-triphenylphosphonium (
F-BnTP)
. By using PET imaging of
F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse models of lung cancer, and find distinct functional mitochondrial heterogeneity within subtypes of lung tumours. The use of
F-BnTP PET imaging enabled us to functionally profile mitochondrial membrane potential in live tumours.
Purpose of Review
This discussion is intended to review the anatomy and pathology of the aortic valve and aortic root region, and to provide a basis for the understanding of and treatment of the ...important life-threatening diseases that affect the aortic valve.
Recent Findings
The most exciting recent finding is that less invasive methods are being developed to treat diseases of the aortic valve. There are no medical cures for aortic valve diseases. Until recently, open-heart surgery was the only effective method of treatment. Now percutaneous approaches to implant bioprosthetic valves into failed native or previously implanted bioprosthetic valves are being developed and utilized. A genetic basis for many of the diseases that affect the aortic valve is being discovered that also should lead to innovative approaches to perhaps prevent these disease. Sequencing of ribosomal RNA is assisting in identifying organisms causing endocarditis, leading to more effective antimicrobial therapy.
Summary
There is exciting, expanding, therapeutic innovation in the treatment of aortic valve disease.
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