Project description:From the bedside of patients contributing samples to large genome-wide association studies for atrial fibrillation (AF), over 100 AF risk loci have been identified. The top locus is near a gene implicated in pulmonary vein formation; the ostia of the pulmonary veins harbor initiating triggers of AF, and isolation of these areas is the cornerstone of ablation therapies for AF. Transcriptomic studies suggest that AF is associated with impaired or overwhelmed responses to cell stress. A dual risk model proposes that in genetically-susceptible individuals, inadequate transcriptional responses to stress predispose to AF in later life. Drugs targeting metabolic, oxidative, or protein handling stress may be novel upstream agents to bring back to the bedside for study in the prevention of AF.
Project description:Dexmedetomidine Diminishes Halothane Anesthetic Requirements in Rats Through a Postsynaptic Alpha 2 Adrenergic Receptor. By Segal IS, Vickery RG, Walton JK, Doze VA, and Maze M. ANESTHESIOLOGY 1988; 125:590-4. Abstract reprinted with permission.The effect of 4(5)-[1-(2,3-dimethylphenyl)ethyl]imidazole (medetomidine), the ?2 adrenergic agonist, on anesthetic requirements was investigated in rats anesthetized with halothane. Halothane MAC was determined before and after either dexmedetomidine (D-enantiomer) or levomedetomidine (L-enantiomer) 10, 30, and 100 ?g/kg, or vehicle intraperitoneally. There was a dose-dependent increase in MAC with the D-, but not the L-, stereoisomer. At the highest dose of dexmedetomidine (100 ?g/kg), halothane could be discontinued for up to 30?min with no response to tail clamping. To determine whether ?2 adrenoreceptors mediated this effect of dexmedetomidine on MAC, cohorts of rats were pretreated with idazoxan, 10?mg/kg intraperitoneally, a highly selective ?2 antagonist. This completely prevented the reduction of MAC caused by dexmedetomidine. To determine whether the reduction of MAC caused by dexmedetomidine was mediated in part through either opiate or adenosine receptors, groups of rats were pretreated with either naltrexone, 5?mg/kg intraperitoneally, an opiate antagonist, or 8-phenyltheophylline, 2.5?mg/kg intraperitoneally, an A1 adenosine antagonist. These two pretreatments did not alter the reduction of MAC by dexmedetomidine. To determine whether postsynaptic mechanisms mediate the anesthetic effect of dexmedetomidine, rats were depleted of central catecholamine stores with either n-(2-chloroethyl)-n-ethyl-2-bromobenzylamine or reserpine and ?-methyl-para-tyrosine, and MAC was determined before and after each dose of dexmedetomidine. While the catecholamine-depleted rats had a lower basal MAC than the vehicle controls, there was still a profound reduction in halothane MAC after administration of dexmedetomidine. The reduction of MAC by dexmedetomidine was blocked with idazoxan in the catecholamine-depleted rats. These data indicate that the reduction of MAC caused by dexmedetomidine is mediated through ?2 adrenoreceptors with no apparent involvement of either opiate or A1 adenosine receptors. Data from catecholamine-depleted rats suggest that the mediating mechanism must involve site(s) other than or in addition to the presynaptic ?2 adrenergic receptors on noradrenergic neurons. The authors conclude that central postsynaptic ?2 adrenergic receptors mediate a significant part of the reduction of anesthetic requirements caused by dexmedetomidine.
Project description:Retinopathy of prematurity (ROP), a vascular proliferative disease affecting preterm infants, is a leading cause of childhood blindness. Various studies have investigated the pathogenesis of ROP. Clinical experience indicates that oxygen levels are strongly correlated with ROP development, which led to the development of oxygen-induced retinopathy (OIR) as an animal model of ROP. OIR has been used extensively to investigate the molecular mechanisms underlying ROP and to evaluate the efficacy of new drug candidates. Large clinical trials have demonstrated the efficacy of anti-vascular endothelial growth factor (VEGF) agents to treat ROP, and anti-VEGF therapy is presently becoming the first-line treatment worldwide. Anti-VEGF therapy has advantages over conventional treatments, including being minimally invasive with a low risk of refractive error. However, long-term safety concerns and the risk of late recurrence limit this treatment. There is an unmet medical need for novel ROP therapies, which need to be addressed by safe and minimally invasive therapies. The recent progress in biotechnology has contributed greatly to translational research. In this review, we outline how basic ROP research has evolved with clinical experience and the subsequent emergence of new drugs. We discuss previous and ongoing trials and present the candidate molecules expected to become novel targets.
Project description:Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called "smoldering" MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients' survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.
Project description:Tongue squamous cell carcinoma is the most common malignancy in the oral cavity. Despite advances in diagnosis and treatment, the prognosis of advanced states has not significantly improved. Depth of invasion, pattern of invasion such as tumor budding grade, lingual lymph node metastasis in early stages, collective cell migration and circulating tumor cells in peripheral blood are some examples of the mechanisms that are currently receiving increasing attention in the evaluation of the prognosis of tongue cancers. Anatomic-based surgery showed that it is possible to improve loco-regional control of tongue cancer. In patients with a "T-N tract involvement", there is significantly more distant recurrence (40%) in patients undergoing a compartmental tongue surgery. In general, the neoplastic infiltration of the lingual muscles is traced back to the finding of neoplastic tissue along the course of a muscle; however, the muscle fibers, due to their spatial conformation and the organization of the extracellular matrix, could influence the movement of tumor cells through the muscle, leaving its three-dimensional structure unchanged. We need to exclude the possibility that tongue muscle fibers represent a mechanism for the diffusion of cancer cells without muscle invasion.
Project description:Heart failure is a major cause of global morbidity and mortality. Acute myocardial infarction (AMI) is a primary cause of heart failure due in large part to residual myocardial damage despite timely reperfusion therapy. Since the 1970's, multiple preclinical laboratories have tested whether reducing myocardial oxygen demand with a mechanical support pump can reduce infarct size in AMI. In the past decade, this hypothesis has been studied using contemporary circulatory support pumps. We will review the most recent series of preclinical studies in the field which led to the recently completed Door to Unload ST-segment Elevation Myocardial Infarction (DTU-STEMI) safety and feasibility pilot trial.
Project description:Sustained pharyngeal inflation (SPI) with pharyngeal oxygen flow and nasal closure (PhO2-NC) technique create positive inflation pressure in the airway. This study measured the peak inflation pressure (PIP) levels and image changes with SPI-assisted flexible bronchoscopy (SPI-FB) and compared the effects in the pharyngeal space and mid-tracheal lumen. This prospective study enrolled 20 participants aged 6 months to 3 years. Each participant underwent sequential SPI-FB of four different durations (0, 1s, 3s, and 5s) for three cycles. We used a 3.8 mm OD flexible bronchoscope to measure and analyze PIP levels, images, and lumen dimension scores. A total of 480 data were collected. The mean (SD) age and body weight were 12.0 (11.5) months and 7.8 (7.5) kg, respectively. The mean (IQR) PIPs were 4.2 (2.0), 18.5 (6.1), 30.6 (13.5), and 46.1 (25.0) cmH2O in the pharynx and 5.0 (1.6), 17.5 (6.5), 28.0 (12.3), 46.0 (28.5) cmH2O in the mid-trachea at SPI durations of 0, 1s, 3s, and 5s, respectively. The PIP levels had a positive correlation (p <0.001) with different SPI durations in both pharynx and trachea, and were nearly identical (p = 0.695, 0.787, and 0.725 at 1s, 3s, and 5s, respectively) at the same duration except the 0 s (p = 0.015). Lumen dimension scores also significantly increased with increasing SPI durations (p <0.05) in both locations. The identified lesions significantly increased as PIP levels increased (p <0.001). Conclusion: SPI-FB using PhO2-NC with durations up to 3s is safe and informative technique that provides controllable PIP, dilates airway lumens, and benefits lesion detection in the pharyngeal space and mid-tracheal lumen.
Project description:Spinal pain and associated disability is a leading cause of morbidity worldwide that has a strong association with degenerative disc disease (DDD). DDD can begin in early-late adolescence and has a variable course. Biologically based therapies to treat DDD face significant challenges posed by the unique milieu of the environment within the intervertebral discs. Many potential promising therapies are still in the early stages of development with a hostile microenvironment within the disc presenting unique challenges. The translational potential of this article: Patient selection, reasonable therapeutic goals, approach, and timing will need to be discerned in order to successfully translate potential therapeutics.
Project description:Retinal gene therapy has advanced considerably in the past three decades. Initial efforts have been devoted to comprehensively explore and optimize the transduction abilities of gene delivery vectors, define the appropriate intraocular administration routes and obtain evidence of efficacy in animal models of inherited retinal diseases (IRDs). Successful translation in clinical trials of the initial promising proof-of-concept studies led to the important milestone of the first approved product for retinal gene therapy in both US and Europe. The unprecedented clinical development observed during the last decade in the field is however highlighting new challenges that will need to be overcome to bring gene therapy to fruition to a larger patient population within and beyond the realm of IRDs.