The lived experience of children and adolescents with cancer

Background The lived experience of children and adolescents diagnosed with cancer differs greatly from that of the adult cancer patient. A diagnosis of cancer disrupts almost every developmental life stage and continues to affect the child, and potentially their whole family, throughout adulthood. Objective While it is important to recognise the potential for posttraumatic growth, a considerable proportion of children and adolescents will experience poorer psychological, social, educational and quality-of-life outcomes. Parents, particularly mothers, have been shown to experience levels of post-traumatic distress even greater than that of survivors. As such, there exists a critical need to provide family-centred support from diagnosis through to long-term survivorship or bereavement. Discussion Ongoing surveillance, proactive management of chronic health conditions, and health behaviour education are critical to survivors' lifelong wellbeing and can be facilitated locally by general practitioners with support from tertiary healthcare teams in a shared-care arrangement

Patterns and Predictors of Healthcare Use among Adolescent and Young Adult Cancer Survivors versus a Community Comparison Group.

Healthcare use (HCU) during survivorship can mitigate adolescent and young adult (AYA) cancer survivors' (aged 15-39 years) risk of medical and psychosocial late effects, but this is understudied. We surveyed 93 Australian AYA post-treatment cancer survivors (Mage = 22.0 years, SD = 3.5; 55.9% female) and a comparison sample of 183 non-matched AYAs (Mage = 19.7, SD = 3.2; 70.5% female) on their HCU, medication use, depression/anxiety, and general functioning. Relative to our comparison AYAs, a higher proportion of our survivor group reported medical HCU (community-delivered: 65.6% versus 47.0%, p = 0.003; hospital-delivered: 31.2% versus 20.3%, p = 0.044) and mental HCU (53.8% vs. 23.5%; p < 0.0001) in the past six months. A higher proportion of our survivors reported taking medications within the past six months than our comparison AYAs (61.3% vs. 42.1%, p = 0.003) and taking more types (p < 0.001). Vitamin/supplement use was most common followed by psychotropic medications. Our survivor group reported lower depression (p = 0.001) and anxiety symptoms (p = 0.003), but similar work/study participation (p = 0.767) to our comparison AYAs. Across groups, psychological distress was associated with higher mental HCU (p = 0.001). Among survivors, those who were female, diagnosed with brain/solid tumors and who had finished treatment more recently reported greater HCU. Future research should establish whether this level of HCU meets AYAs' survivorship needs

Spatial transcriptomic characterization of COVID-19 pneumonitis identifies immune circuits related to tissue injury

Severe lung damage in COVID-19 involves complex interactions between diverse populations of immune and stromal cells. In this study, we used a spatial transcriptomics approach to delineate the cells, pathways and genes present across the spectrum of histopathological damage in COVID-19 lung tissue. We applied correlation network-based approaches to deconvolve gene expression data from areas of interest within well preserved post-mortem lung samples from three patients. Despite substantial inter-patient heterogeneity we discovered evidence for a common immune cell signaling circuit in areas of severe tissue that involves crosstalk between cytotoxic lymphocytes and pro-inflammatory macrophages. Expression of IFNG by cytotoxic lymphocytes was associated with induction of chemokines including CXCL9, CXCL10 and CXCL11 which are known to promote the recruitment of CXCR3+ immune cells. The tumour necrosis factor (TNF) superfamily members BAFF ( TNFSF13B ) and TRAIL ( TNFSF10 ) were found to be consistently upregulated in the areas with severe tissue damage. We used published spatial and single cell SARS-CoV-2 datasets to confirm our findings in the lung tissue from additional cohorts of COVID-19 patients. The resulting model of severe COVID-19 immune-mediated tissue pathology may inform future therapeutic strategies. One Sentence Summary Spatial analysis identifies IFNγ response signatures as focal to severe alveolar damage in COVID-19 pneumonitis

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

BACKGROUND: A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility. METHODS: Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated. FINDINGS: In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active. CONCLUSIONS: LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics

Online, Group-Based Psychological Support for Adolescent and Young Adult Cancer Survivors: Results from the Recapture Life Randomized Trial

Telehealth interventions offer a practical platform to support adolescent and young adult (AYA) cancer survivors' mental health needs after treatment, yet efficacy data are lacking. We evaluated an online, group-based, videoconferencing-delivered cognitive-behavioral therapy (CBT) intervention ('Recapture Life') in a 3-arm randomized-controlled trial comparing Recapture Life with an online peer-support group, and a waitlist control, with the aim of testing its impact on quality of life, emotional distress and healthcare service use. Forty AYAs (Mage = 20.6 years) within 24-months of completing treatment participated, together with 18 support persons. No groupwise impacts were measured immediately after the six-week intervention. However, Recapture Life participants reported using more CBT skills at the six-week follow-up (OR = 5.58, 95% CI = 2.00-15.56, p = 0.001) than peer-support controls. Recapture Life participants reported higher perceived negative impact of cancer, anxiety and depression at 12-month follow-up, compared to peer-support controls. Post-hoc analyses suggested that AYAs who were further from completing cancer treatment responded better to Recapture Life than those who had completed treatment more recently. While online telehealth interventions hold promise, recruitment to this trial was challenging. As the psychological challenges of cancer survivorship are likely to evolve with time, different support models may prove more or less helpful for different sub-groups of AYA survivors at different times

Influence of Ecto-Nucleoside Triphosphate Diphosphohydrolase Activity on Trypanosoma cruzi Infectivity and Virulence

The protozoan Trypanosoma cruzi is the causative agent of Chagas disease, an endemic zoonosis present in some countries of South and Central Americas. The World Health Organization estimates that 100 million people are at risk of acquiring this disease. The infection affects mainly muscle tissues in the heart and digestive tract. There are no vaccines or effective treatment, especially in the chronic phase when most patients are diagnosed, which makes a strong case for the development of new drugs to treat the disease. In this work we evaluate a family of proteins called Ecto-Nucleoside-Triphosphate-Diphosphohydrolase (Ecto-NTPDase) as new chemotherapy target to block T. cruzi infection in mammalian cells and in mice. We have used inhibitors and antibodies against this protein and demonstrated that T. cruzi Ecto-NTPDases act as facilitators of infection in mammalian cells and virulence factors in mice model. Two of the drugs used in this study (Suramin and Gadolinium) are currently used for other diseases in humans, supporting the possibility of their use in the treatment of Chagas disease

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with &#60;5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Structure, mechanism, and inhibition of Hedgehog acyltransferase

The Sonic Hedgehog (SHH) morphogen pathway is fundamental for embryonic development and stem cell maintenance and is implicated in various cancers. A key step in signaling is transfer of a palmitate group to the SHH N terminus, catalyzed by the multi-pass transmembrane enzyme Hedgehog acyltransferase (HHAT). We present the high-resolution cryo-EM structure of HHAT bound to substrate analog palmityl-coenzyme A and a SHH-mimetic megabody, revealing a heme group bound to HHAT that is essential for HHAT function. A structure of HHAT bound to potent small-molecule inhibitor IMP-1575 revealed conformational changes in the active site that occlude substrate binding. Our multidisciplinary analysis provides a detailed view of the mechanism by which HHAT adapts the membrane environment to transfer an acyl chain across the endoplasmic reticulum membrane. This structure of a membrane-bound O-acyltransferase (MBOAT) superfamily member provides a blueprint for other protein-substrate MBOATs and a template for future drug discovery

Free backbone carbonyls mediate rhodopsin activation

Conserved prolines in the transmembrane helices of G-protein-coupled receptors (GPCRs) are often considered to function as hinges that divide the helix into two segments capable of independent motion. Depending on their potential to hydrogen-bond, the free C=O groups associated with these prolines can facilitate conformational flexibility, conformational switching or stabilization of the receptor structure. To address the role of conserved prolines in family A GPCRs through solid-state NMR spectroscopy, we focus on bovine rhodopsin, a GPCR in the visual receptor subfamily. The free backbone C=O groups on helices H5 and H7 stabilize the inactive rhodopsin structure through hydrogen-bonds to residues on adjacent helices. In response to light-induced isomerization of the retinal chromophore, hydrogen-bonding interactions involving these C=O groups are released, thus facilitating repacking of H5 and H7 onto the transmembrane core of the receptor. These results provide insights into the multiple structural and functional roles of prolines in membrane proteins