The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.

Oncolytic viruses are generally designed to be cancer selective on the basis of a single genetic mutation. JX-594 is a thymidine kinase (TK) gene-inactivated oncolytic vaccinia virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and lac-Z transgenes that is designed to destroy cancer cells through replication-dependent cell lysis and stimulation of antitumoral immunity. JX-594 has demonstrated a favorable safety profile and reproducible tumor necrosis in a variety of solid cancer types in clinical trials. However, the mechanism(s) responsible for its cancer-selectivity have not yet been well described. We analyzed the replication of JX-594 in three model systems: primary normal and cancer cells, surgical explants, and murine tumor models. JX-594 replication, transgene expression, and cytopathic effects were highly cancer-selective, and broad spectrum activity was demonstrated. JX-594 cancer-selectivity was multi-mechanistic; replication was activated by epidermal growth factor receptor (EGFR)/Ras pathway signaling, cellular TK levels, and cancer cell resistance to type-I interferons (IFNs). These findings confirm a large therapeutic index for JX-594 that is driven by common genetic abnormalities in human solid tumors. This appears to be the first description of multiple selectivity mechanisms, both inherent and engineered, for an oncolytic virus. These findings have implications for oncolytic viruses in general, and suggest that their cancer targeting is a complex and multifactorial process.

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels.

Background Effective teamwork is critical for safe, high-quality care in the operating room (OR); however, teamwork interventions have not consistently resulted in the expected gains for patient safety or surgical culture. In order to optimize OR teamwork in a targeted and evidence-based manner, it is first necessary to conduct a comprehensive, theory-informed assessment of barriers and enablers from an interprofessional perspective. Methods This qualitative study was informed by the Theoretical Domains Framework (TDF). Volunteer, purposive and snowball sampling were conducted primarily across four sites in Ontario, Canada and continued until saturation was reached. Interviews were recorded, transcribed, and de-identified. Directed content analysis was conducted in duplicate using the TDF as the initial coding framework. Codes were then refined whereby similar codes were grouped into larger categories of meaning within each TDF domain, resulting in a list of domain-specific barriers and enablers. Results A total of 66 OR healthcare professionals participated in the study (19 Registered Nurses, two Registered Practical Nurses, 17 anaesthesiologists, 26 surgeons, two perfusionists). The most frequently identified teamwork enablers included people management, shared definition of teamwork, communication strategies, positive emotions, familiarity with team members, and alignment of teamwork with professional role. The most frequently identified teamwork barriers included others’ personalities, gender, hierarchies, resource issues, lack of knowledge of best practices for teamwork, negative emotions, conflicting norms and perceptions across professions, being unfamiliar with team members, and on-call/night shifts. Conclusions We identified key factors influencing OR teamwork from an interprofessional perspective using a theoretically informed and systematic approach. Our findings reveal important targets for future interventions and may ultimately increase their effectiveness. Specifically, achieving optimal teamwork in the OR may require a multi-level intervention that addresses individual, team and systems-level factors with particular attention to complex social and professional hierarchies.

A patient presumably acquired this illness after exposure to ticks in mountains near Los Angeles.

Background Despite substantial implications for healthcare provider practice and patient outcomes, gender has yet to be systematically explored with regard to interprofessional operating room (OR) teamwork. We aimed to explore and describe how gender and additional social identity factors shape experiences and perceptions of teamwork in the OR. Methods This study was a qualitative secondary analysis of semi-structured interviews with OR team members conducted between November 2018 and July 2019. Participants were recruited across hospitals in Ontario, Canada. We conducted both purposive and snowball sampling until data saturation was reached. Transcripts were analyzed thematically by two independent research team members, moving from open to axial coding. Results Sixty-six interviews of OR healthcare professionals were completed: anesthesia (n=17), nursing (n=19), perfusion (n=2), and surgery (n=26). Traditional gender roles, norms, and stereotypes were perceived and experienced by both women and men, but with different consequences. Both women and men participants described challenges that women face in the OR, such as being perceived negatively for displaying leadership behaviours. Participants also reported that interactions and behaviours vary depending on the team gender composition, and that other social identities, such as age and race, often interact with gender. Nevertheless, participants indicated a belief that the influence of gender in the OR may be modified. Conclusions The highly gendered reality of the OR creates an environment conducive to breakdowns in communuication and patient safety risks in addition to diminishing team morale, psychological safety, and provider well-being. Consequently, until teamwork interventions adequately account for gender, they are unlikely to be optimally effective or sustainable.

Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of SMA released exosomes containing reduced levels of SMN protein relative to normal controls. Cells overexpressing SMN protein released exosomes with dramatically elevated levels of SMN protein. We observed enhanced quantities of exosomes in the medium from SMN-depleted cells, and in serum from a mouse model of SMA and a patient with Type 3 SMA, suggesting that SMN-depletion causes a deregulation of exosome release or uptake. The quantity of SMN protein contained in the serum-derived exosomes correlated with the genotype of the animal, with progressively less protein in carrier and affected animals compared to wildtype mice. SMN protein was easily detectable in exosomes isolated from human serum, with a reduction in the amount of SMN protein in exosomes from a patient with Type 3 SMA compared to a normal control. Our results suggest that exosome-derived SMN protein may serve as an effective biomarker for SMA.

Vectors based on adenovirus (Ad) are one of the most commonly utilized platforms for gene delivery to cells in molecular biology studies and in gene therapy applications. Ad is also the most popular vector system in human clinical gene therapy trials, largely due to its advantageous characteristics such as high cloning capacity (up to 36 kb), ability to infect a wide variety of cell types and tissues, and relative safety due to it remaining episomal in transduced cells. The latest generation of Ad vectors, helper‑dependent Ad (hdAd), which are devoid of all viral protein coding sequences, can mediate high-level expression of a transgene for years in a variety of species ranging from rodents to non-human primates. Given the importance of histones and chromatin in modulating gene expression within the host cell, it is not surprising that Ad, a nuclear virus, also utilizes these proteins to protect the genome and modulate virus- or vector‑encoded genes. In this review, we will discuss our current understanding of the contribution of chromatin to Ad vector function.