Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies.

Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replacement of muscle mass with fibrotic scarring. With the progression of these disorders, many patients suffer cardiomyopathies with fibrosis of the cardiac tissue.

Single cell analysis reveals satellite cell heterogeneity for proinflammatory chemokine expression.

The expression of proinflammatory signals at the site of muscle injury are essential for efficient tissue repair and their dysregulation can lead to inflammatory myopathies. Macrophages, neutrophils, and fibroadipogenic progenitor cells residing in the muscle are significant sources of proinflammatory cytokines and chemokines. However, the inducibility of the myogenic satellite cell population and their contribution to proinflammatory signaling is less understood.

Selective Insulin-like Growth Factor Resistance Associated with Heart Hemorrhages and Poor Prognosis in a Novel Preclinical Model of the Hematopoietic Acute Radiation Syndrome.

Although bone marrow aplasia has been considered for the past decades as the major contributor of radiation-induced blood disorders, cytopenias alone are insufficient to explain differences in the prevalence of bleeding. In this study, the minipig was used as a novel preclinical model of hematopoietic acute radiation syndrome to assess if factors other than platelet counts correlated with bleeding and survival. We sought to determine whether radiation affected the insulin-like growth factor-1 (IGF-1) pathway, a growth hormone with cardiovascular and radioprotective features.

Novel plasmids and resistance phenotypes in Yersinia pestis: unique plasmid inventory of strain Java 9 mediates high levels of arsenic resistance.

Growing evidence suggests that the plasmid repertoire of Yersinia pestis is not restricted to the three classical virulence plasmids. The Java 9 strain of Y. pestis is a biovar Orientalis isolate obtained from a rat in Indonesia.

An amino acid-based amphoteric liposomal delivery system for systemic administration of siRNA.

We demonstrate a systematic and rational approach to create a library of natural and modified, dialkylated amino acids based upon arginine for development of an efficient small interfering RNA (siRNA) delivery system. These amino acids, designated DiLA₂ compounds, in conjunction with other components, demonstrate unique properties for assembly into monodisperse, 100-nm small liposomal particles containing siRNA. We show that DiLA₂-based liposomes undergo a pH-dependent phase transition to an inverted hexagonal phase facilitating efficient siRNA release from endosomes to the cytosol.

RNAi-based therapeutics targeting survivin and PLK1 for treatment of bladder cancer.

Harnessing RNA interference (RNAi) to silence aberrant gene expression is an emerging approach in cancer therapy. Selective inhibition of an overexpressed gene via RNAi requires a highly efficacious, target-specific short interfering RNA (siRNA) and a safe and efficient delivery system. We have developed siRNA constructs (UsiRNA) that contain unlocked nucleobase analogs (UNA) targeting survivin and polo-like kinase-1 (PLK1) genes.

Improved specificity of gene silencing by siRNAs containing unlocked nucleobase analogs.

siRNAs confer sequence specific and robust silencing of mRNA. By virtue of these properties, siRNAs have become therapeutic candidates for disease intervention. However, their use as therapeutic agents can be hampered by unintended off-target effects by either or both strands of the siRNA duplex.

A potential therapeutic for pandemic influenza using RNA interference.

RNA interference (RNAi) involves sequence-specific downregulation of target genes, leading to gene silencing in vitro and in vivo. Synthetic small interfering RNAs (siRNAs), formulated with appropriate delivery agents, can serve as effective tools for RNAi-based therapeutics. The potential of siRNA to provide antiviral activity has been studied extensively in many respiratory viruses, including influenza virus, wherein specific siRNAs target highly-conserved regions of influenza viral genome, leading to potent inhibition of viral RNA replication.

Clinical laboratories, the select agent program, and biological surety (biosurety).

The threat of bioterrorism has led to increased concerns over the availability of biological select agents and toxins (BSAT). Congress has implemented several public laws that have led to the development of federal regulations by the Centers for Disease Control and Prevention (CDC) and the US Department of Agriculture. The CDC regulation 42 CFR 73 has a direct impact on all clinical laboratories that may at some time identify BSAT in a clinical specimen.

Intravitreal toxicology and duration of efficacy of a novel antiviral lipid prodrug of ganciclovir in liposome formulation.

Purpose: To evaluate the intraocular safety and antiviral treatment efficacy of the sustained lipid prodrug of ganciclovir, 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV), as an intravitreal injectable drug system for viral retinitis.

Methods: HDP-P-GCV was synthesized by coupling 1-O-hexadecyl-propanediol-3-phosphate to either free hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as catalyst. The compound was formulated into liposomes.

Treatment of herpes retinitis in an animal model with a sustained delivery antiviral drug, liposomal 1-O-octadecyl-SN-glycerol-3-phosphonoformate.

Purpose: To evaluate the clinical treatment efficacy of a long-lasting intravitreous injectable anti-cytomegalovirus (CMV) liposomal drug, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA).

Methods: Sixty-four pigmented rabbits were used for evaluation of the potency and duration of action of ODG-PFA after intravitreal injection using a herpes simplex virus (HSV)-1 retinitis model. For the potency evaluation, liposomal ODG-PFA was injected into rabbit vitreous at the same time that HSV-1 virus was inoculated onto the retina (simultaneous treatment).

Intravitreal pharmacokinetics in rabbits of the foscarnet lipid prodrug: 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA).

Purpose: To evaluate the intraocular distribution and metabolism of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3- phosphonoformate (ODG-PFA), following intravitreal administration.

Methods: Twenty rabbits received ODG-[14C]PFA intravitreal injection, yielding 0.632 mM resultant intravitreal concentration.

Epithelioid germinal centers in overwhelming childhood infections. The aftermath of nonspecific destruction of follicular B cells by natural killer cells.

The destruction of proliferating lymphoid cells within germinal centers with subsequent replacement by histiocytoid cells has been described in infants and children dying of viral and bacterial infections. The etiology and significance of "epithelioid germinal centers" (EGCs) are unknown. The cells implicated in forming EGCs have included histiocytes and dendritic reticulum cells.

Castleman's disease of the leptomeninges. Report of three cases.

Castleman's disease is a rare, benign lymphoproliferative disorder that usually arises in lymph nodes, most commonly in the mediastinum. The authors report the clinical and pathological features of three patients with localized Castleman's disease of the leptomeninges. There were two women, aged 63 and 82 years, and one 25-year-old man.

Radiation-induced neoplasms of the brain.

The histopathology of two patients with radiation-induced neoplasms of the brain following therapeutic irradiation for intracranial malignancies is described. The second neoplasms were an atypical meningioma and a polymorphous cell sarcoma, respectively. They occurred 12 and 23 years after irradiation (4000 rad), within the original field of irradiation.

Cutaneous necrotizing granulomatous vasculitis with evolution to T cell lymphoma.

The evolution of unusual cutaneous vasculitis to a systemic T cell lymphoma was observed over a 12-year period. Precise classification of the skin biopsy specimens during the course of this patient's illness was difficult. Different observers suggested malignant hemangioendothelioma, malignant lymphoma, regressing atypical histiocytosis, and granulomatous vasculitis.