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INTRODUCTION: Obstructive sleep apnoea (OSA) is a common, but underdiagnosed, sleep disorder. If untreated, it leads to poor health outcomes, including Alzheimer's disease, cancer, cardiovascular disease and all-cause mortality. Our aim is to determine the feasibility and cost-effectiveness of moving the testing for OSA into general practice and how general practitioner (GP)-based screening affects overall detection rates. METHODS AND ANALYSIS: Randomised controlled trial of case finding of OSA in general practice using a novel Medicines and Healthcare products Regulatory Agency-registered device (AcuPebble SA100) compared with usual care with internal feasibility phase. A diverse sample of general practices (approximately 40) from across the West Midlands Clinical Research Network will identify participants from their records. Eligible participants will be aged 50-70 years with body mass index >30 kg/m2 and diabetes (type 1 or 2) and/or hypertension (office blood pressure >145/90 mm Hg or on treatment). They will exclude individuals with known OSA or chronic obstructive pulmonary disease, or those they deem unable to take part. After eligibility screening, consent and baseline assessment, participants will be randomised to either the intervention or control group. Participants in the intervention arm will receive by post the AcuPebble sleep test kit. Those in the control arm will continue with usual care. Follow-up questionnaires will be completed at 6 months. The study is powered (90%) to detect a 5% difference and will require 606 patients in each arm (713 will be recruited to each arm to allow for attrition). Due to the nature of the intervention, participants and GPs will not be blinded to the allocation. OUTCOMES: Primary: Detection rate of moderate-to-severe OSA in the intervention group versus control group. Secondary: Time to diagnosis and time to treatment for intervention versus control group for mild, moderate and severe OSA; cost-effectiveness analysis comparing the different testing pathways. ETHICS AND DISSEMINATION: The trial started on 1 November 2022. Ethical approval was granted from the South Central Oxford A Research Ethics Committee on 9 June 2023 (23/SC/0188) (protocol amendment version 1.3; update with amendment and approval to renumber to V2.0 on 29 August 2023). Patient recruitment began on 7 January 2024; initial planned end date will be on 31 April 2025.Results will be uploaded to the ISRCTN register within 12 months of the end of the trial date, presented at conferences, submitted to peer-reviewed journals and distributed via our patient and public involvement networks.The University of Warwick will act as the trial sponsor. The trial will be conducted in accordance with the Sponsor and Primary Care Clinical Trials Unit standard operating procedures. TRIAL REGISTRATION NUMBER: ISRCTN 16982033.
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Análisis Costo-Beneficio , Atención Primaria de Salud , Apnea Obstructiva del Sueño , Humanos , Apnea Obstructiva del Sueño/terapia , Apnea Obstructiva del Sueño/diagnóstico , Persona de Mediana Edad , Anciano , Ensayos Clínicos Controlados Aleatorios como Asunto , Femenino , Masculino , Tamizaje Masivo/métodos , Estudios de FactibilidadRESUMEN
BACKGROUND: Bone metastasis is a common consequence of advanced prostate cancer. Bisphosphonates can be used to manage symptoms, but there are currently no curative treatments available. Altered tumour cell glycosylation is a hallmark of cancer and is an important driver of a malignant phenotype. In prostate cancer, the sialyltransferase ST6GAL1 is upregulated, and studies show ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate tumour growth and disease progression. METHODS: Here, we monitor ST6GAL1 in tumour and serum samples from men with aggressive prostate cancer and using in vitro and in vivo models we investigate the role of ST6GAL1 in prostate cancer bone metastasis. FINDINGS: ST6GAL1 is upregulated in patients with prostate cancer with tumours that have spread to the bone and can promote prostate cancer bone metastasis in vivo. The mechanisms involved are multi-faceted and involve modification of the pre-metastatic niche towards bone resorption to promote the vicious cycle, promoting the development of M2 like macrophages, and the regulation of immunosuppressive sialoglycans. Furthermore, using syngeneic mouse models, we show that inhibiting sialylation can block the spread of prostate tumours to bone. INTERPRETATION: Our study identifies an important role for ST6GAL1 and α2-6 sialylated N-glycans in prostate cancer bone metastasis, provides proof-of-concept data to show that inhibiting sialylation can suppress the spread of prostate tumours to bone, and highlights sialic acid blockade as an exciting new strategy to develop new therapies for patients with advanced prostate cancer. FUNDING: Prostate Cancer Research and the Mark Foundation For Cancer Research, the Medical Research Council and Prostate Cancer UK.
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Neoplasias Óseas , Ácido N-Acetilneuramínico , Neoplasias de la Próstata , Sialiltransferasas , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Humanos , Sialiltransferasas/metabolismo , Sialiltransferasas/genética , Animales , Neoplasias Óseas/secundario , Neoplasias Óseas/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Ratones , Ácido N-Acetilneuramínico/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Antígenos CD/metabolismo , Polisacáridos/farmacología , Glicosilación , beta-D-Galactósido alfa 2-6-SialiltransferasaRESUMEN
Despite an array of hypothesised implications for health, disease, and therapeutic development, antibodies against the non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) remain a subject of much debate. This systematic review of 114 publications aimed to generate a comprehensive overview of published studies in this field, addressing both the reported prevalence of anti-Neu5Gc antibodies in the human population and whether experimental variation accounts for the conflicting reports about the extent of this response. Absolute titres of anti-Neu5Gc antibodies, the reported prevalence of these antibodies, and the individual variation observed within experiments were analysed and grouped according to biological context ('inflammation', 'xenotransplantation', 'biotherapeutic use', 'cancer', and 'healthy populations'), detection method, target epitope selection, and choice of blocking agent. These analyses revealed that the experimental method had a notable impact on both the reported prevalence and absolute titres of anti-Neu5Gc antibodies in the general population, thereby limiting the ability to ascribe reported trends to genuine biological differences or the consequence of experimental design. Overall, this review highlights important knowledge gaps in the study of antibodies against this important xenoautoantigen and the need to establish a standardised method for their quantification if the extent of the importance of Neu5Gc in human health is to be fully understood.
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Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.
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Feniltiohidantoína , Neoplasias de la Próstata , beta-Galactosida alfa-2,3-Sialiltransferasa , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Benzamidas/farmacología , Nitrilos , LigandosRESUMEN
BACKGROUND: Ethnic minorities make up approximately 14% of the UK workforce. Despite the disproportionate burden of ill-health amongst ethnic minorities, and the increased interest in Diversity, Equity & Inclusion (DE&I) in the workplace, workplace health and wellbeing interventions are still most often designed for the ethnic majority. OBJECTIVE: The purpose of this scoping review was to explore the depth and breadth of evidence on the attitudes to and perceptions of health and wellbeing interventions in the workplace within ethnic minority groups in the UK, and to identify gaps in evidence that would provide direction for future research needs. METHODS: A scoping review with quality appraisal was undertaken, supplemented by a review of grey literature and a narrative review exploring related evidence from the knowledge bases related to community and cultural adaptation. RESULTS: Only three peer-reviewed studies met inclusion criteria, preventing broad conclusions. 14 papers from the community and cultural adaptation literature provided additional information about how health promotion may be approached effectively in the workplace, including the importance of culturally sensitive, people-centred design, and the use of established adaptation frameworks. CONCLUSION: The literature suggests a need for improvements in four key areas: (1) reporting of ethnic minorities in data relating to workplace health and wellbeing research, (2) more thorough review of perceptions and attitudes of ethnic minority workers in the UK, (3) design of culturally appropriate interventions that are tested for impact, and (4) testing of the effectiveness of culturally adapted interventions.
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BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type 2 diabetes and marked by hepatic inflammation, microvascular dysfunction, and fibrosis, impairing liver function and aggravating metabolic derangements. The liver homeostatic interactions disrupted in MASH are still poorly understood. We aimed to elucidate the plasticity and changing interactions of non-parenchymal cells associated with advanced MASH. METHODS: We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging murine and human livers, and via functional experiments in vivo and in vitro. RESULTS: The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells. CONCLUSION: We conclude that HSC-expressed NR1H4 and GSPCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and, through paracrine signals, overall sinusoidal health. Hence HSC activation in MASH not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals. IMPACT AND IMPLICATIONS: Homeostatic interactions between hepatic cell types and their deterioration in metabolic dysfunction-associated steatohepatitis are poorly characterized. In our current single cell-resolved study of advanced murine metabolic dysfunction-associated steatohepatitis, we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, stimulation of the identified signaling module is a promising therapeutic strategy to restore sinusoid function in chronic liver disease.
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Diabetes Mellitus Tipo 2 , Hígado Graso , Ratones , Humanos , Animales , Pericitos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hígado/patología , Transducción de Señal , Células Estrelladas Hepáticas/metabolismo , Hígado Graso/metabolismo , Cirrosis Hepática/patología , Factor 2 de Diferenciación de Crecimiento/metabolismoRESUMEN
Prostate cancer is the most common cancer in men and a major cause of cancer related deaths worldwide. Nearly all affected men develop resistance to current therapies and there is an urgent need to develop new treatments for advanced disease. Aberrant glycosylation is a common feature of cancer cells implicated in all of the hallmarks of cancer. A major driver of aberrant glycosylation in cancer is the altered expression of glycosylation enzymes. Here, we show that GCNT1, an enzyme that plays an essential role in the formation of core 2 branched O-glycans and is crucial to the final definition of O-glycan structure, is upregulated in aggressive prostate cancer. Using in vitro and in vivo models, we show GCNT1 promotes the growth of prostate tumours and can modify the glycome of prostate cancer cells, including upregulation of core 2 O-glycans and modifying the O-glycosylation of secreted glycoproteins. Furthermore, using RNA sequencing, we find upregulation of GCNT1 in prostate cancer cells can alter oncogenic gene expression pathways important in tumour growth and metastasis. Our study highlights the important role of aberrant O-glycosylation in prostate cancer progression and provides novel insights regarding the mechanisms involved.
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Neoplasias de la Próstata , Humanos , Masculino , Glicosilación , Polisacáridos/metabolismo , Próstata/patología , Neoplasias de la Próstata/patologíaRESUMEN
Prostate cancer progression is connected to the activity of conventional oncogenes and tumour suppressors and driven by circulating steroid hormones. A key issue has been how to identify and care for aggressively developing prostate tumours. Here we discuss how expression of the splicing regulators ESRP1 and ESRP2, and how their role as "masterminds" of epithelial splicing patterns, have been identified as markers of aggressively proliferating prostate primary tumours. We suggest that the origin of prostate cancer within epithelial cells, and the subsequent association of ESRP1 and ESRP2 expression with more aggressive disease progression, identify ESRP1 and ESRP2 as lineage survival oncogenes. To move this field on in the future it will be important to identify the gene expression targets controlled by ESRP1/2 that regulate prostate cancer proliferation. Potential future therapies could be designed to target ESRP1 and ESRP2 protein activity or their regulated splice isoforms in aggressive prostate tumours. Design of these therapies is potentially complicated by the risk of producing a more mesenchymal splicing environment that might promote tumour metastasis.
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Aberrant glycosylation is a universal feature of cancer cells, and cancer-associated glycans have been detected in virtually every cancer type. A common change in tumour cell glycosylation is an increase in α2,6 sialylation of N-glycans, a modification driven by the sialyltransferase ST6GAL1. ST6GAL1 is overexpressed in numerous cancer types, and sialylated glycans are fundamental for tumour growth, metastasis, immune evasion, and drug resistance, but the role of ST6GAL1 in prostate cancer is poorly understood. Here, we analyse matched cancer and normal tissue samples from 200 patients and verify that ST6GAL1 is upregulated in prostate cancer tissue. Using MALDI imaging mass spectrometry (MALDI-IMS), we identify larger branched α2,6 sialylated N-glycans that show specificity to prostate tumour tissue. We also monitored ST6GAL1 in plasma samples from >400 patients and reveal ST6GAL1 levels are significantly increased in the blood of men with prostate cancer. Using both in vitro and in vivo studies, we demonstrate that ST6GAL1 promotes prostate tumour growth and invasion. Our findings show ST6GAL1 introduces α2,6 sialylated N-glycans on prostate cancer cells and raise the possibility that prostate cancer cells can secrete active ST6GAL1 enzyme capable of remodelling glycans on the surface of other cells. Furthermore, we find α2,6 sialylated N-glycans expressed by prostate cancer cells can be targeted using the sialyltransferase inhibitor P-3FAX -Neu5Ac. Our study identifies an important role for ST6GAL1 and α2,6 sialylated N-glycans in prostate cancer progression and highlights the opportunity to inhibit abnormal sialylation for the development of new prostate cancer therapeutics. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Neoplasias de la Próstata , Sialiltransferasas , Masculino , Humanos , Glicosilación , Polisacáridos/química , Polisacáridos/metabolismo , Reino Unido , beta-D-Galactósido alfa 2-6-Sialiltransferasa , Antígenos CD/metabolismoRESUMEN
The methyltransferase KMT5A has been proposed as an oncogene in prostate cancer and therefore represents a putative therapeutic target. To confirm this hypothesis, we have performed a microarray study on a prostate cancer cell line model of androgen independence following KMT5A knockdown in the presence of the transcriptionally active androgen receptor (AR) to understand which genes and cellular processes are regulated by KMT5A in the presence of an active AR. We observed that 301 genes were down-regulated whilst 408 were up-regulated when KMT5A expression was reduced. KEGG pathway and gene ontology analysis revealed that apoptosis and DNA damage signalling were up-regulated in response to KMT5A knockdown whilst protein folding and RNA splicing were down-regulated. Under these conditions, the top non-AR regulated gene was found to be CDC20, a key regulator of the spindle assembly checkpoint with an oncogenic role in several cancer types. Further investigation revealed that KMT5A regulates CDC20 in a methyltransferase-dependent manner to modulate histone H4K20 methylation within its promoter region and indirectly via the p53 signalling pathway. A positive correlation between KMT5A and CDC20 expression was also observed in clinical prostate cancer samples, further supporting this association. Therefore, we conclude that KMT5A is a valid therapeutic target for the treatment of prostate cancer and CDC20 could potentially be utilised as a biomarker for effective therapeutic targeting.
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A key challenge in the clinical management and cause of treatment failure of prostate cancer (PCa) is its molecular, cellular and clinical heterogeneity. Modelling systems that fully recapitulate clinical diversity and resistant phenotypes are urgently required for the development of successful personalised PCa therapies. The advent of the three-dimensional (3D) organoid model has revolutionised preclinical cancer research through reflecting heterogeneity and offering genomic and environmental manipulation that has opened up unparalleled opportunities for applications in disease modelling, high-throughput drug screening and precision medicine. Despite these remarkable achievements of organoid technology, several shortcomings in emulating the complex tumor microenvironment and dynamic process of metastasis as well as the epigenome profile limit organoids achieving true in vivo functionality. Technological advances in tissue engineering have enabled the development of innovative tools to facilitate the design of improved 3D cancer models. In this review, we highlight the current in vitro 3D PCa models with a special focus on organoids and discuss engineering approaches to create more physiologically relevant PCa organoid models and maximise their translational relevance that ultimately will help to realise the transformational power of precision medicine.
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Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Organoides/patología , Medicina de Precisión , Microambiente Tumoral/genéticaRESUMEN
The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies.
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Antineoplásicos , Neoplasias , Estados Unidos , Humanos , United States Food and Drug Administration , Neoplasias/tratamiento farmacológico , Biomarcadores , Oncología Médica , Aprobación de Drogas/métodos , Antineoplásicos/uso terapéuticoRESUMEN
Prostate cancer is the most common cancer in men and it is estimated that over 350,000 men worldwide die of prostate cancer every year. There remains an unmet clinical need to improve how clinically significant prostate cancer is diagnosed and develop new treatments for advanced disease. Aberrant glycosylation is a hallmark of cancer implicated in tumour growth, metastasis, and immune evasion. One of the key drivers of aberrant glycosylation is the dysregulated expression of glycosylation enzymes within the cancer cell. Here, we demonstrate using multiple independent clinical cohorts that the glycosyltransferase enzyme GALNT7 is upregulated in prostate cancer tissue. We show GALNT7 can identify men with prostate cancer, using urine and blood samples, with improved diagnostic accuracy than serum PSA alone. We also show that GALNT7 levels remain high in progression to castrate-resistant disease, and using in vitro and in vivo models, reveal that GALNT7 promotes prostate tumour growth. Mechanistically, GALNT7 can modify O-glycosylation in prostate cancer cells and correlates with cell cycle and immune signalling pathways. Our study provides a new biomarker to aid the diagnosis of clinically significant disease and cements GALNT7-mediated O-glycosylation as an important driver of prostate cancer progression.
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Neoplasias de la Próstata , Masculino , Humanos , Regulación hacia Arriba , Glicosilación , Neoplasias de la Próstata/metabolismo , Transducción de Señal , Activación TranscripcionalRESUMEN
Importance: Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered. Observations: Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021. Conclusions and Relevance: Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.
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Antineoplásicos , Productos Biológicos , Estados Unidos , Humanos , Aprobación de Drogas , Antineoplásicos/efectos adversos , Oncología Médica , United States Food and Drug AdministrationRESUMEN
The role of allogeneic hematopoietic cell transplantation (allo-HCT) followed by maintenance therapy in high-risk multiple myeloma (MM) remains controversial. We evaluated the efficacy of ixazomib maintenance therapy after reduced-intensity conditioning allo-HCT from HLA-matched donors in patients with high-risk MM. The primary study endpoint was progression-free survival (PFS) postrandomization, treated as a time to event. Secondary endpoints were grade II-IV and grade II-IV acute graft-versus-host-disease (GVHD), chronic GVHD, best response, disease progression, nonrelapse mortality (NRM), overall survival (OS), toxicity, infection, and health-related quality of life. In this phase 2, double-blinded, prospective multicenter trial, we randomized patients with high-risk MM (ie, those with poor-risk cytogenetics, plasma cell leukemia, or relapsing within 24 months after autologous HCT) to ixazomib (3 mg on days 1, 8, and 15) or placebo after allo-HCT. The conditioning regimen included fludarabine/melphalan/bortezomib with tacrolimus plus methotrexate for GVHD. Fifty-seven patients were enrolled, of whom 52 (91.2%) underwent allo-HCT and 43 (82.7%) were randomized to ixazomib versus placebo. At 21 months postrandomization, the ixazomib and placebo groups had similar PFS (55.3% versus 59.1%; P = 1.00) and OS (94.7% versus 86.4%; P = .17). The cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% versus 0%) and chronic GVHD at 12 months (68.6% versus 63.6%) also were similar in the 2 groups. The secondary analysis showed that at 24 months post-allo-HCT, PFS and OS were 52% and 82%, respectively, with a corresponding NRM of 11.7%. These results demonstrate the safety and durable disease control with allo-HCT in high-risk MM patients. We could not adequately assess the efficacy of ixazomib maintenance because the trial terminated early owing to enrollment delays, but there was no indication of any impact on outcomes.
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Enfermedad Injerto contra Huésped , Mieloma Múltiple , Humanos , Mieloma Múltiple/tratamiento farmacológico , Médula Ósea , Estudios Prospectivos , Calidad de Vida , Trasplante Homólogo/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & controlRESUMEN
Postbiotics are a new category of biotics that have the potential to confer health benefits but, unlike probiotics, do not require living cells to induce health effects and thus are not subject to the food safety requirements that apply to live microorganisms. Postbiotics are defined as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Postbiotic components include short-chain fatty acids, exopolysaccharides, vitamins, teichoic acids, bacteriocins, enzymes and peptides in a non-purified inactivated cell preparation. While research into postbiotics is in its infancy, there is increasing evidence that postbiotics have the potential to modulate human health. Specifically, a number of postbiotics have been shown to improve gut health by strengthening the gut barrier, reducing inflammation and promoting antimicrobial activity against gut pathogens. Additionally, research is being conducted into the potential application of postbiotics to other areas of the body, including the skin, vagina and oral cavity. The purpose of this review is to set out the current research on postbiotics, demonstrate how postbiotics are currently used in commercial products and identify a number of knowledge gaps where further research is needed to identify the potential for future applications of postbiotics.
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Microbioma Gastrointestinal , Probióticos , Humanos , Ácidos Grasos Volátiles , Vitaminas , InflamaciónRESUMEN
Gastrostomy fed children traditionally have a Formulae diet (FD), which fulfills nutritional requirements; however, many families are adopting Blended diets (BD), which are what the whole family would eat. We undertook an observational investigation of the colonic microbiota and metabonome in a small group of gastrostomy fed children, who were either on an FD or BD, and compared, where possible to their siblings (17 FD, 28 BD, 19 HS). There was no increase in complications in tube blockage or infection rates, but a significant improvement in the prevalence of bowel problems, a reduction in medication and an increase in quality of life. Metataxonomic analysis showed that the FD group was significantly different to the Sibling group, and that families did not cluster together. Whole sample metabonomics showed no differences between groups; however, univariate analysis of biologically important metabolites did differ. Changing to a BD resulted in no increase in complications or risks, but improved the overall quality of life for the children and families.
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Microbioma Gastrointestinal , Microbiota , Niño , Humanos , Gastrostomía/métodos , Nutrición Enteral/métodos , Calidad de Vida , DietaRESUMEN
BACKGROUND: Medical students are at risk of burnout and reduced quality of life (QoL). The risk of burnout doubles from third to sixth year of medical school, and medical students have an 8%-11% lower QoL than nonmedical students. It is imperative to prevent this, as burnout and reduced QoL is independently associated with errors in practice. This systematic review aims to examine whether physical activity/exercise is associated with burnout and/or QoL in medical students. METHODS: Articles were identified through database searches of Embase, Medline, PsycINFO, Scopus and Web of Science. Studies were included if both physical activity/exercise and burnout or QoL were measured and limited to those focussing on medical students. Risk of bias was assessed using accredited cohort and cross-sectional checklists. A narrative synthesis was conducted due to heterogeneity in the dataset. FINDINGS: Eighteen studies were included, comprising 11,500 medical students across 13 countries. Physical activity was negatively associated with burnout and positively associated with QoL. Furthermore, the findings were suggestive of a dose-response effect of physical activity on both burnout and QoL; higher intensities and frequencies precipitated greater improvements in outcomes. CONCLUSIONS: This multinational review demonstrates that physical activity is associated with reduced burnout and improved QoL in medical students. It also identifies a paucity of research into the optimal intensity, frequency, volume and mode of physical activity. Further research, building on this review, is likely to inform the long overdue development of evidence-based, well-being curricula. This could involve incorporating physical activity into medical education which may improve well-being and better prepare students for the demands of medical practice.
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Agotamiento Profesional , Estudiantes de Medicina , Humanos , Calidad de Vida , Estudios Transversales , Agotamiento Profesional/epidemiología , Agotamiento Profesional/prevención & control , Agotamiento Psicológico/epidemiología , Ejercicio FísicoRESUMEN
Prostate cancer is the most common cancer in men, and it is primarily driven by androgen steroid hormones. The glycosylation enzyme EDEM3 is controlled by androgen signalling and is important for prostate cancer viability. EDEM3 is a mannosidase that trims mannose from mis-folded glycoproteins, tagging them for degradation through endoplasmic reticulum-associated degradation. Here, we find that EDEM3 is upregulated in prostate cancer, and this is linked to poorer disease-free survival. Depletion of EDEM3 from prostate cancer cells induces an ER stress transcriptomic signature, and EDEM3 overexpression is cyto-protective against ER stressors. EDEM3 expression also positively correlates with genes involved in the unfolded protein response in prostate cancer patients, and its expression can be induced through exposure to radiation. Importantly, the overexpression of EDEM3 promotes radio-resistance in prostate cancer cells and radio-resistance can be reduced through depletion of EDEM3. Our data thus implicate increased levels of EDEM3 with a role in prostate cancer pathology and reveal a new therapeutic opportunity to sensitise prostate tumours to radiotherapy.