Hospital-Acquired Sacral Pressure Ulcer Complicated by a Spinal Epidural Abscess.

A spinal epidural abscess is a rare condition characterized by the accumulation of pus between the dura mater and vertebral column, often caused by hematogenous spread from a distant site or local spread from infection in nearby structures. The abscess leads to compression of the spinal cord and can result in neurological damage, including dysfunction or permanent neurological deficits. Treatment of spinal epidural abscesses should not be delayed and requires a combination of decompression by surgical drainage and antibiotic therapy.

Complex Cardiovascular Morbidities in Prader-Willi Syndrome: A Multidisciplinary Approach.

This case emphasizes the complexity of Prader-Willi syndrome (PWS), the need for a collaborative approach from specialists, and a closer look at the various cardiovascular complexities associated with this syndrome. While current treatments focus on managing symptoms, ongoing genetic research offers hope for more favorable outcomes. Further studies are crucial to gauge the effectiveness of these treatments for PWS patients.

Small tissue chips with big opportunities for space medicine.

The spaceflight environment, including microgravity and radiation, may have considerable effects on the health and performance of astronauts, especially for long-duration and Martian missions. Conventional on-ground and in-space experimental approaches have been employed to investigate the comprehensive biological effects of the spaceflight environment. As a class of recently emerging bioengineered in vitro models, tissue chips are characterized by a small footprint, potential automation, and the recapitulation of tissue-level physiology, thus promising to help provide molecular and cellular insights into space medicine.

Retargeting FX-binding-ablated HAdV-5 to vascular cells by inclusion of the RGD-4C peptide in hexon hypervariable region 7 and the HI loop.

Recent studies have generated interest in the function of human adenovirus serotype 5 (HAdV-5) hexon:  factor X (FX) binding and subsequent hepatocyte transduction and interaction with the immune system. Here, we retargeted adenovirus serotype 5 vectors, ablated for FX interaction, by replacing amino acids in hexon HVR7 with RGD-4C or inserting the peptide into the fibre HI loop. These genetic modifications in the capsid were compatible with virus assembly, and could efficiently retarget transduction of the vector via the αvβ3/5 integrin-mediated pathway, but did not alter immune recognition by pre-existing human neutralizing anti-HAdV-5 antibodies or by natural antibodies in mouse serum.

Structures of Adenovirus Incomplete Particles Clarify Capsid Architecture and Show Maturation Changes of Packaging Protein L1 52/55k.

Unlabelled: Adenovirus is one of the most complex icosahedral, nonenveloped viruses. Even after its structure was solved at near-atomic resolution by both cryo-electron microscopy and X-ray crystallography, the location of minor coat proteins is still a subject of debate. The elaborated capsid architecture is the product of a correspondingly complex assembly process, about which many aspects remain unknown.

Capsid modification strategies for detargeting adenoviral vectors.

Adenoviral vectors hold immense potential for a wide variety of gene therapy based applications; however, their efficacy and toxicity is dictated by "off target" interactions that preclude cell specific targeting to sites of disease. A number of "off target" interactions have been described in the literature that occur between the three major capsid proteins (hexon, penton, and fiber) and components of the circulatory system, including cells such as erythrocytes, white blood cells, and platelets, as well as circulatory proteins including complement proteins, coagulation factors, von Willebrand Factor, p-selectin as well as neutralizing antibodies. Thus, to improve efficacious targeting to sites of disease and limit nonspecific uptake of virus to non-target tissues, specifically the liver and the spleen, it is necessary to develop suitable strategies for genetically modifying the capsid proteins to preclude these interactions.

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile.

Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.

Integrase-deficient lentiviral vectors mediate efficient gene transfer to human vascular smooth muscle cells with minimal genotoxic risk.

We have previously shown that injury-induced neointima formation was rescued by adenoviral-Nogo-B gene delivery. Integrase-competent lentiviral vectors (ICLV) are efficient at gene delivery to vascular cells but present a risk of insertional mutagenesis. Conversely, integrase-deficient lentiviral vectors (IDLV) offer additional benefits through reduced mutagenesis risk, but this has not been evaluated in the context of vascular gene transfer.

Vector systems for prenatal gene therapy: principles of adenovirus design and production.

Adenoviruses have many attributes, which have made them one of the most widely investigated vectors for gene therapy applications. These include ease of genetic manipulation to produce replication-deficient vectors, ability to readily generate high titer stocks, efficiency of gene delivery into many cell types, and ability to encode large genetic inserts. Recent advances in adenoviral vector engineering have included the ability to genetically manipulate the tropism of the vector by engineering of the major capsid proteins, particularly fiber and hexon.

Biodistribution and inflammatory profiles of novel penton and hexon double-mutant serotype 5 adenoviruses.

The use of adenovirus serotype 5 (Ad5) vectors in the clinical setting is severely hampered by the profound liver tropism observed after intravascular delivery coupled with the pronounced inflammatory and innate immune response elicited by these vectors. Liver transduction by circulating Ad5 virions is mediated by a high-affinity interaction between the capsid hexon protein and blood coagulation factor X (FX), whilst penton-α(v)integrin interactions are thought to contribute to the induction of anti-Ad5 inflammatory and innate immune responses. To overcome these limitations, we sought to develop and characterise for the first time novel Ad5 vectors possessing mutations ablating both hexon:FX and penton:integrin interactions.

Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension.

Serotonin is produced by pulmonary arterial endothelial cells (PAEC) via tryptophan hydroxylase-1 (Tph1). Pathologically, serotonin acts on underlying pulmonary arterial cells, contributing to vascular remodeling associated with pulmonary arterial hypertension (PAH). The effects of hypoxia on PAEC-Tph1 activity are unknown.

Tropism-modification strategies for targeted gene delivery using adenoviral vectors.

Achieving high efficiency, targeted gene delivery with adenoviral vectors is a long-standing goal in the field of clinical gene therapy. To achieve this, platform vectors must combine efficient retargeting strategies with detargeting modifications to ablate native receptor binding (i.e.

Altering the Ad5 packaging domain affects the maturation of the Ad particles.

We have previously described a new family of mutant adenoviruses carrying different combinations of attB/attP sequences from bacteriophage PhiC31 flanking the Ad5 packaging domain. These novel helper viruses have a significantly delayed viral life cycle and a severe packaging impairment, regardless of the presence of PhiC31 recombinase. Their infectious viral titers are significantly lower (100-1000 fold) than those of control adenovirus at 36 hours post-infection, but allow for efficient packaging of helper-dependent adenovirus.

Biodistribution and retargeting of FX-binding ablated adenovirus serotype 5 vectors.

A major limitation for adenoviral transduction in vivo is the profound liver tropism of adenovirus type 5 (Ad5). Recently, we demonstrated that coagulation factor X (FX) binds to Ad5-hexon protein at high affinity to mediate hepatocyte transduction after intravascular delivery. We developed novel genetically FX-binding ablated Ad5 vectors with lower liver transduction.

Identification of coagulation factor (F)X binding sites on the adenovirus serotype 5 hexon: effect of mutagenesis on FX interactions and gene transfer.

Recent studies have demonstrated the importance of coagulation factor X (FX) in adenovirus (Ad) serotype 5-mediated liver transduction in vivo. FX binds to the adenovirus hexon hypervariable regions (HVRs). Here, we perform a systematic analysis of FX binding to Ad5 HVRs 5 and 7, identifying domains and amino acids critical for this interaction.

Advances in helper-dependent adenoviral vector research.

The immunogenicity and cytotoxicity associated with early generations of adenoviral vectors provided a strong incentive for the development of helper-dependent adenovirus, a last generation of adenoviral vectors that is devoid of all viral coding sequences. These vectors have shown to mediate longer high-level transgene expression in vivo with reduced toxicity and thus offer enormous potential for human gene therapy. In addition, they possess a considerably larger cloning capacity than conventional adenoviral vectors making the transfer of large cDNAs, multiple transgenes and longer tissue-specific or regulable promoters possible.

Differential amplification of adenovirus vectors by flanking the packaging signal with attB/attP-PhiC31 sequences: implications for helper-dependent adenovirus production.

Current strategies to amplify helper-dependent adenovirus, based on excision of the packaging signal, do not routinely reduce helper adenovirus contamination below 1%. Here, we have tested if reducing the efficiency of the packaging process of the helper adenovirus could impair its packaging without affecting helper-dependent adenovirus production. Interestingly, insertion of attB/attP-PhiC31 sequences flanking the packaging signal significantly lengthens adenovirus cycle up to 60 h without reducing virus viability or production yield.