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BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non-pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). OBJECTIVE: We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. METHODS: We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples. RESULTS: Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell-associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. CONCLUSION: A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.
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Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.
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Recent preclinical studies have shown that the intake of nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin and naproxen could be an effective intervention strategy against TMPRSS2-ERG fusion-driven prostate tumorigenesis. Herein, as a follow-up mechanistic study, employing TMPRSS2-ERG (fusion) positive tumors and plasma from TMPRSS2-ERG. Ptenflox/flox mice, we profiled the stage specific proteomic changes (focused on inflammatory circulating and prostate tissue/tumor-specific cytokines, chemokines, and growth factors/growth signaling-associated molecules) that contribute to prostate cancer (PCa) growth and progression in the TMPRSS2-ERG fusion-driven mouse model of tumorigenesis. In addition, the association of the protective effects of NSAIDs (aspirin 1400 ppm and naproxen 400 ppm) with the modulation of these specific molecular pathways was determined. A sandwich Elisa based membrane array-proteome profiler identifying 111 distinct signaling molecules was employed. Overall, the plasma and prostate tissue sample analyses identified 54 significant and differentially expressed cytokines, chemokines, and growth factors/growth signaling-associated molecules between PCa afflicted mice (TMPRSS2-ERG. Ptenflox/flox, age-matched noncancerous controls, NSAIDs-supplemented and no-drug controls). Bioinformatic analysis of the array outcomes indicated that the protective effect of NSAIDs was associated with reduced expression of (a) tumor promoting inflammatory molecules (M-CSF, IL-33, CCL22, CCL12, CX3CL1, CHI3L1, and CD93), (b) growth factors- growth signaling-associated molecules (Chemerin, FGF acidic, Flt-3 ligand, IGFBP-5, and PEDF), and (c) tumor microenvironment/stromal remodeling proteins MMP2 and MMP9. Overall, our findings corroborate the pathological findings that protective effects of NSAIDs in TMPSS2-ERG fusion-driven prostate tumorigenesis are associated with antiproliferative and anti-inflammatory effects and possible modulation of the immune cell enriched microenvironment.
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Antiinflamatorios no Esteroideos , Aspirina , Naproxeno , Neoplasias de la Próstata , Animales , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Antiinflamatorios no Esteroideos/farmacología , Aspirina/farmacología , Ratones , Naproxeno/farmacología , Proteómica/métodos , Inflamación/metabolismo , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Próstata/patología , Próstata/metabolismo , Próstata/efectos de los fármacos , Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Carcinogénesis/metabolismo , Proteoma/metabolismo , Humanos , Citocinas/metabolismo , Citocinas/sangreRESUMEN
Background: Cutaneous lichen planus (LP) is a recalcitrant, difficult-to-treat, inflammatory skin disease characterized by pruritic, flat-topped, violaceous papules on the skin. Baricitinib is an oral Janus kinase (JAK) 1/2 inhibitor that interrupts the signaling pathway of interferon (IFN)-γ, a cytokine implicated in the pathogenesis of LP. Methods: In this phase II trial, twelve patients with cutaneous LP received baricitinib 2 mg daily for 16 weeks, accompanied by in-depth spatial, single-cell, and bulk transcriptomic profiling of pre-and post-treatment samples. Results: An early and sustained clinical response was seen with 83.3% of patients responsive at week 16. Our molecular data identified a unique, oligoclonal IFN-γ, CD8+, CXCL13+ cytotoxic T-cell population in LP skin and demonstrate a rapid decrease in interferon signature within 2 weeks of treatment, most prominent in the basal layer of the epidermis. Conclusion: This study demonstrates the efficacy and molecular mechanisms of JAK inhibition in LP. Trial Registration Number : NCT05188521.
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The consumption of the non-steroidal anti-inflammatory drug (NSAID) aspirin is associated with a significant reduction in the risk of developing TMPRSS2-ERG (fusion)-positive prostate cancer (PCa) compared to fusion-negative PCa in population-based case-control studies; however, no extensive preclinical studies have been conducted to investigate and confirm these protective benefits. Thus, the focus of this study was to determine the potential usefulness of aspirin and another NSAID, naproxen, in PCa prevention, employing preclinical models of both TMPRSS2-ERG (fusion)-driven (with conditional deletion of Pten) and non-TMPRSS2-ERG-driven (Hi-Myc+/- mice) PCa. Male mice (n = 25 mice/group) were fed aspirin- (700 and 1400 ppm) and naproxen- (200 and 400 ppm) supplemented diets from (a) 6 weeks until 32 weeks of Hi-Myc+/- mice age; and (b) 1 week until 20 weeks post-Cre induction in the fusion model. In all NSAID-fed groups, compared to no-drug controls, there was a significant decrease in higher-grade adenocarcinoma incidence in the TMPRSS2-ERG (fusion)-driven PCa model. Notably, there were no moderately differentiated (MD) adenocarcinomas in the dorsolateral prostate of naproxen groups, and its incidence also decreased by ~79-91% in the aspirin cohorts. In contrast, NSAIDs showed little protective effect against prostate tumorigenesis in Hi-Myc+/- mice, suggesting that NSAIDs exert a specific protective effect against TMPRSS2-ERG (fusion)-driven PCa.
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Global expansion of marine renewable energy (MRE) technologies is needed to help address the impacts of climate change, to ensure a sustainable transition from carbon-based energy sources, and to meet national energy security needs using locally-generated electricity. However, the MRE sector has yet to realize its full potential due to the limited scale of device deployments (i.e., single devices or small demonstration-scale arrays), and is hampered by various factors including uncertainty about environmental effects and how the magnitude of these effects scale with an increasing number of devices. This paper seeks to expand our understanding of the environmental effects of MRE arrays using existing frameworks and through the adaptation and application of cumulative environmental effects terminology to key stressor-receptor interactions. This approach facilitates the development of generalized concepts for the scaling of environmental effects for key stressor-receptor interactions, identifying high priority risks and revealing knowledge gaps that require investigation to aid expansion of the MRE sector. Results suggest that effects of collision risk for an array may be additive, antagonistic, or synergistic, but are likely dependent on array location and configuration. Effects of underwater noise are likely additive as additional devices are deployed in an array, while the effects of electromagnetic fields may be dominant, additive, or antagonistic. Changes to benthic habitats are likely additive, but may be dependent on array configuration and could be antagonistic or synergistic at the ecosystem scale. Effects of displacement, entanglement, and changes to oceanographic systems for arrays are less certain because little information is available about effects at the current scale of MRE development.
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BACKGROUND: Prostate cancer (PCa) is the most diagnosed cancer in Australian men, and the number of survivors is growing with advances in diagnosis and treatment. Work participation following PCa diagnosis and treatment becomes a significant aspect of quality of life and survivorship. Using a qualitative phenomenological approach, we explored the work-related experiences of PCa survivors in Australia. METHODS: Semi-structured telephone interviews were conducted with 16 men (6 salaried employees, 10 self-employed; 8 diagnosed ≥ 5 years) purposively sampled from a community setting. Interviews were inductively analysed. RESULTS: Five main themes emerged: motivations to work; treatment decisions and work; the effects of PCa and its treatment on ability to participate in work; being an employee versus being self-employed; and personal agency. PCa and its treatment side-effects were detrimental to men's work capacity and ability, and could persist over an extended period. Most men expressed a strong desire to retain work or return to work. Discussions with healthcare professionals about work-related consequences were largely missing when treatment decisions were made. Self-employed men faced greater challenges than their salaried counterparts due to high financial burden and limited social and business support. Family, workplace and wider community support, and self-care, enhanced men's work participation experiences. CONCLUSIONS: PCa and its treatment substantially and persistently impacted men's working lives, and their experiences were diverse and multifaceted. Self-employed and long-term PCa survivors face greater challenges and are at high risk of poor work outcomes. A systematic approach and involvement of stakeholders at all levels is required to support ongoing work participation.
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Supervivientes de Cáncer , Neoplasias de la Próstata , Masculino , Humanos , Próstata , Calidad de Vida , Australia , Neoplasias de la Próstata/terapia , SobrevivientesRESUMEN
Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-ß response. In vitro, TGF-ß and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.
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Quimiocina CXCL10 , Esclerodermia Localizada , Humanos , Células Dendríticas/metabolismo , Fibroblastos/metabolismo , Interferón gamma/metabolismo , Factor de Crecimiento Transformador betaRESUMEN
Therapeutic targeting of RAS-mutated cancers is difficult, whereas prevention or interception (treatment before or in the presence of preinvasive lesions) preclinically has proven easier. In the A/J mouse lung model, where different carcinogens induce tumors with different KRAS mutations, glucocorticoids and retinoid X receptor (RXR) agonists are effective agents in prevention and interception studies, irrespective of specific KRAS mutations. In rat azoxymethane-induced colon tumors (45% KRAS mutations), cyclooxygenase 1/2 inhibitors and difluoromethylornithine are effective in preventing or intercepting KRAS-mutated or wild-type tumors. In two KRAS-mutant pancreatic models multiple COX 1/2 inhibitors are effective. Furthermore, combining a COX and an EGFR inhibitor prevented the development of virtually all pancreatic tumors in transgenic mice. In the N-nitroso-N-methylurea-induced estrogen receptor-positive rat breast model (50% HRAS mutations) various selective estrogen receptor modulators, aromatase inhibitors, EGFR inhibitors, and RXR agonists are profoundly effective in prevention and interception of tumors with wild-type or mutant HRAS, while the farnesyltransferase inhibitor tipifarnib preferentially inhibits HRAS-mutant breast tumors. Thus, many agents not known to specifically inhibit the RAS pathway, are effective in an organ specific manner in preventing or intercepting RAS-mutated tumors. Finally, we discuss an alternative prevention and interception approach, employing vaccines to target KRAS.
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Neoplasias Pancreáticas , Vacunas , Ratones , Ratas , Animales , Proteínas Proto-Oncogénicas p21(ras)/genética , Ratones Transgénicos , Mutación , Receptores ErbB , Prevención PrimariaRESUMEN
In eukaryotes and many aerobic prokaryotes, the final step of aerobic respiration is catalyzed by an aa3-type cytochrome c oxidase, which requires a modified heme cofactor, heme a. The conversion of heme b, the prototypical cellular heme, to heme o and ultimately to heme a requires two modifications, the latter of which is conversion of a methyl group to an aldehyde, catalyzed by heme a synthase (HAS). The N- and C-terminal halves of HAS share homology, and each half contains a heme-binding site. Previous reports indicate that the C-terminal site is occupied by a heme b cofactor. The N-terminal site may function as the substrate (heme o) binding site, although this has not been confirmed experimentally. Here, we assess the role of conserved residues from the N- and C-terminal heme-binding sites in HAS from prokaryotic (Shewanella oneidensis) and eukaryotic (Saccharomyces cerevisiae) species - SoHAS/CtaA and ScHAS/Cox15, respectively. A glutamate within the N-terminal site is found to be critical for activity in both types of HAS, consistent with the hypothesis that a carbocation forms transiently during catalysis. In contrast, the residue occupying the analogous C-terminal position is dispensable for enzyme activity. In SoHAS, the C-terminal heme ligands are critical for stability, while in ScHAS, substitutions in either heme-binding site have little effect on global structure. In both species, in vivo accumulation of heme o requires the presence of an inactive HAS variant, highlighting a potential regulatory role for HAS in heme o biosynthesis.
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Ácido Glutámico , Proteínas de Saccharomyces cerevisiae , Ácido Glutámico/metabolismo , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/metabolismo , Ferroquelatasa , Hemo/metabolismoRESUMEN
We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-ß-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations. PREVENTION RELEVANCE: Means to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/prevención & control , Células Endoteliales , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/prevención & control , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptor Toll-Like 4RESUMEN
Num1 is a multifunctional protein that both tethers mitochondria to the plasma membrane and anchors dynein to the cell cortex during nuclear inheritance. Previous work has examined the impact loss of Num1-based mitochondrial tethering has on dynein function in Saccharomyces cerevisiae; here, we elucidate its impact on mitochondrial function. We find that like mitochondria, Num1 is regulated by changes in metabolic state, with the protein levels and cortical distribution of Num1 differing between fermentative and respiratory growth conditions. In cells lacking Num1, we observe a reproducible respiratory growth defect, suggesting a role for Num1 in not only maintaining mitochondrial morphology, but also function. A structure-function approach revealed that, unexpectedly, Num1-mediated cortical dynein anchoring is important for normal growth under respiratory conditions. The severe respiratory growth defect in Δnum1 cells is not specifically due to the canonical functions of dynein in nuclear migration but is dependent on the presence of dynein, as deletion of DYN1 in Δnum1 cells partially rescues respiratory growth. We hypothesize that misregulated dynein present in cells that lack Num1 negatively impacts mitochondrial function resulting in defects in respiratory growth.
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Dineínas , Proteínas de Saccharomyces cerevisiae , Dineínas/genética , Dineínas/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Mitocondrias/metabolismo , Microtúbulos/metabolismoRESUMEN
The HLA-DRB1*03:01 allele is a major genetic risk factor in systemic lupus erythematosus (SLE), but the mechanistic basis of the association is unclear. Here we show that in the presence of interferon gamma (IFN-γ), a short DRB1*03:01-encoded allelic epitope activates a characteristic lupus transcriptome in mouse and human macrophages. It also triggers a cascade of SLE-associated cellular aberrations, including endoplasmic reticulum stress, unfolded protein response, mitochondrial dysfunction, necroptotic cell death, and production of pro-inflammatory cytokines. Parenteral administration of IFN-γ to naïve DRB1*03:01 transgenic mice causes increased serum levels of anti-double stranded DNA antibodies, glomerular immune complex deposition and histopathological renal changes that resemble human lupus nephritis. This study provides evidence for a noncanonical, antigen presentation-independent mechanism of HLA-disease association in SLE and could lay new foundations for our understanding of key molecular mechanisms that trigger and propagate this devastating autoimmune disease.
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Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico , Alelos , Animales , Epítopos/genética , Cadenas HLA-DRB1/genética , Humanos , Interferón gamma/genética , Lupus Eritematoso Sistémico/genética , RatonesRESUMEN
Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1ß, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc min/+ mouse model.
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In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Ptenflox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Ptenflox/flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed. Conversely, in the Hi-Myc+/- mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc+/- mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Ptenflox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis marker (CD-31). Importantly, there was a significant increase in immune cell infiltrations, which increased with the stage of tumorigenesis, in the TMPRSS2-ERG fusion-positive tumors relative to fusion negative tumors. Together, these findings are both novel and highly significant in establishing a working preclinical model for evaluating the efficacy of interventions during different stages of tumorigenesis in TMPRSS2-ERG fusion-driven PCa.
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Adenocarcinoma , Neoplasias de la Próstata , Adenocarcinoma/genética , Animales , Carcinogénesis/patología , Humanos , Masculino , Ratones , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología , Serina Endopeptidasas/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismoRESUMEN
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Primary care providers, including general practice teams (GPTs), are well positioned within the community to integrate cancer survivorship care into ongoing health management. However, roles of GPT members in delivery of cancer survivorship care have not been explored. The purpose of this study is to explore these roles from the perspectives of General Practitioners (GPs), Practice Nurses (PNs) and Practice Managers (PMs). An interpretive qualitative study using semi-structured in-depth telephone interviews with ten GPs, nine PNs and five PMs was conducted. Interviews were recorded, transcribed and analysed using grounded theory methods. Perspectives of roles in delivery of cancer survivorship care were highly variable. Variation was evident among perceptions of needs of cancer survivors, individual team members' scopes of practice, and individual professional knowledge and skills. A lack of clarity in roles and responsibilities of GPT members was thought to contribute to a lack of consistency in survivorship care. Reducing variations in perceptions of survivorship care in the primary care setting should be a priority. Such efforts may include development of practical guidance to support GPT members to clarify scopes of practice within the team. In addition to accessible comprehensive education programs, other innovative, tailored individualised education approaches may be helpful. System-level support in clarifying and supporting the roles of the primary care team is needed to facilitate a survivorship delivery system at general practice level where those within GPT can ensure that individual patients' needs are met in a timely and effective manner.
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Supervivientes de Cáncer , Medicina General , Neoplasias , Australia , Humanos , Investigación Cualitativa , SupervivenciaRESUMEN
OBJECTIVE: The COVID-19 pandemic has resulted in health professionals facing unprecedented challenges and changes in practice. Responding to humanitarian crises involves saving lives and reducing suffering and as such, palliative care is an essential component of the response to COVID-19. This study aimed to explore health professionals' perspectives of the role of palliative care during the COVID-19 pandemic by analyzing their views and experiences expressed in articles and blogs located via Twitter. METHOD: Qualitative content analysis of 33 online articles and blogs written by health professionals from 1 February 2020 to 30 June 2020. Online articles and blogs were included if the URL was posted on Twitter. The consolidated criteria for reporting qualitative research (COREQ) guided data collection and reporting. RESULTS: The health professionals whose viewpoints were analyzed were from Europe, North America, Oceania and Asia. The themes derived from content analysis were (a) the recognized value of palliative care during the pandemic, (b) positioning palliative care as every health professional's responsibility and (c) specialist palliative care supporting and guiding health professionals. CONCLUSIONS: This study utilizes a unique approach to exploring the perspectives of health professionals from several countries during a global pandemic. The study emphasizes the value of palliative care and identifies gaps in end-of-life care provision including resource allocation. This brings to light the urgent need to equip all health professionals with palliative care knowledge and skills, including discussing and planning care. Specialist palliative care teams are well placed to support health professionals to provide quality care.
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COVID-19 , Medios de Comunicación Sociales , Personal de Salud , Humanos , Cuidados Paliativos , Pandemias , Investigación Cualitativa , SARS-CoV-2RESUMEN
PURPOSE: Financial toxicity (FT) describes financial distress or hardship as an outcome of cancer and its treatment. Minimising the impact of FT requires early assessment and intervention. General practice plays a significant role in the support of a person with cancer and may have an important role in the management of FT. The purpose of this study was to understand perspectives of general practitioners (GP) on addressing FT in the primary care setting, which may then help inform strategies to further support collaborative efforts to address FT. METHODS: A qualitative interpretive approach was utilised for this study. GPs were recruited through a GP conference and other professional networks using purposive, snowballing sampling techniques. Data collection continued until sufficient rich data had been obtained. Interviews were recorded and transcribed verbatim. The data were analysed using inductive analysis techniques. RESULTS: Twenty (n = 20) GPs participated in semi-structured in-depth telephone interviews. GPs identified that their role positions them well to provide some FT support, but there are limitations. Perceptions and philosophies about cancer management were drivers of referrals and financial conversations. Priorities for care of FT by GPs included improved cost information provision and accessible support. CONCLUSION: GPs can play an important role in helping to address FT associated with cancer and its treatments if supported with the right information.
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Medicina General , Médicos Generales , Neoplasias , Actitud del Personal de Salud , Estrés Financiero , Humanos , Neoplasias/terapia , Atención Primaria de Salud , Investigación CualitativaRESUMEN
LAY ABSTRACT: Children with an autism spectrum disorder (autism) often have negative experiences within the surgical setting. We conducted individual interviews with 8 parents of children with autism who had recently undergone surgery, and 15 healthcare providers (HCPs) with experience caring for children with autism. We asked open-ended questions on the approaches used to support children with autism around the time of surgery, how effective they were, suggestions for improvement, and the barriers and facilitators to improvement. Three main themes emerged within an overarching metaphor of a balancing act. The first theme, finding your footing through an uncertain journey, described individual factors (e.g. anticipatory anxiety) that set the foundation for experiences. The second theme, relationships can help to keep everyone steady, highlighted how personal interactions (e.g. collaboration and empathy) influence the experience. Finally, the systems shape the experience theme captured how systemic factors (e.g. the hospital environment) affected the balancing act. These findings enriched our understanding of the surgical experiences of children with autism, families, and HCPs by demonstrating the importance of individual characteristics, relationships, and systemic factors. Future interventions should consider this complexity and intervene not just with children, but also their parents, healthcare providers, and in policy to improve experiences.