Convergent evolution in toxin detection and resistance provides evidence for conserved bacterial-fungal interactions.

Microbes rarely exist in isolation and instead form complex polymicrobial communities. As a result, microbes have developed intricate offensive and defensive strategies that enhance their fitness in these complex communities. Thus, identifying and understanding the molecular mechanisms controlling polymicrobial interactions is critical for understanding the function of microbial communities. In this study, we show that the gram-negative opportunistic human pathogen Pseudomonas aeruginosa, which frequently causes infection alongside a plethora of other microbes including fungi, encodes a genetic network which can detect and defend against gliotoxin, a potent, disulfide-containing antimicrobial produced by the ubiquitous filamentous fungus Aspergillus fumigatus. We show that gliotoxin exposure disrupts P. aeruginosa zinc homeostasis, leading to transcriptional activation of a gene encoding a previously uncharacterized dithiol oxidase (herein named as DnoP), which detoxifies gliotoxin and structurally related toxins. Despite sharing little homology to the A. fumigatus gliotoxin resistance protein (GliT), the enzymatic mechanism of DnoP from P. aeruginosa appears to be identical that used by A. fumigatus. Thus, DnoP and its transcriptional induction by low zinc represent a rare example of both convergent evolution of toxin defense and environmental cue sensing across kingdoms. Collectively, these data provide compelling evidence that P. aeruginosa has evolved to survive exposure to an A. fumigatus disulfide-containing toxin in the natural environment.

A novel treatment strategy utilizing panobinostat for high-risk and treatment-refractory hepatoblastoma.

BACKGROUND & AIMS: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To develop new therapeutic strategies for these patients, our laboratory has developed a preclinical testing pipeline. Given that histone deacetylase (HDAC) inhibition has been proposed for HB, we hypothesized that we could find an effective combination treatment strategy utilizing HDAC inhibition. METHODS: RNA sequencing, microarray, NanoString, and immunohistochemistry data of patient HB samples were analyzed for HDAC class expression. Patient-derived spheroids (PDSp) were used to screen combination chemotherapy with an HDAC inhibitor, panobinostat. Patient-derived xenograft (PDX) mouse models were developed and treated with the combination therapy that showed the highest efficacy in the PDSp drug screen. RESULTS: HDAC RNA and protein expression were elevated in HB tumors compared to normal livers. Panobinostat (IC50 of 0.013-0.059 µM) showed strong in vitro effects and was associated with lower cell viability than other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). All four models responded to VIP therapy with a decrease in tumor size compared to placebo. After 6 weeks of treatment, two models demonstrated necrotic cell death, with lower Ki67 expression, decreased serum alpha fetoprotein and reduced tumor burden compared to paired VI- and placebo-treated groups. CONCLUSIONS: Utilizing a preclinical HB pipeline, we demonstrate that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from patients with high-risk, relapsed, and treatment-refractory HB. IMPACT AND IMPLICATIONS: Patients with treatment-refractory hepatoblastoma have limited treatment options with survival rates of less than 50%. Our manuscript demonstrates that combination therapy with vincristine, irinotecan, and panobinostat reduces the size of high-risk, relapsed, and treatment-refractory tumors. With this work we provide preclinical evidence to support utilizing this combination therapy as an arm in future clinical trials.

Relationship between Hope and Quality of Life in Primary Care Patients: Vitality as a Mechanism.

The present study examined the role of vitality as a mediator of the association between dispositional hope and quality of life (QoL) (namely, physical health, psychological health, social relationships, and environment) in a sample of 101 adult primary care patients. Vitality was found to fully mediate the relationship between hope and physical health, social relationships, and environment. In addition, vitality was found to partially mediate the association between hope and psychological health. The present findings are consistent with a model in which vitality represents an important mechanism through which hope affects QoL in adults. Accordingly, these findings point to the importance of fostering both hope and vitality in efforts to promote positive QoL in adults.

Relationship between Future Orientation and Pain Severity in Fibromyalgia Patients: Self-Compassion as a Coping Mechanism.

The present study examined the relationship between future orientation and fibromyalgia-related pain severity in a sample of 287 adults with fibromyalgia. Specifically, authors examined dimensions of self-compassion (for example, self-kindness, isolation, mindfulness) as possible mechanisms through which future orientation might be associated with pain severity. Results of conducting a multiple mediator test with 10,000 bootstraps indicated that the significant negative association between future orientation and pain severity was mediated through one specific self-compassion dimension, namely, isolation. The article concludes with a discussion of the implications of the present findings for working with fibromyalgia patients, specifically the potential value of social workers working with fibromyalgia patients to build future orientation as a resilience factor to combat pain severity. Also discussed is the value of working with patients to develop a sustainable social support system that can disrupt experiences of social isolation and disconnectedness from others, and which appear to contribute to greater pain severity.