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1.
Am J Hosp Palliat Care ; : 10499091241247183, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38623845

RESUMO

OBJECTIVE: We wanted to examine the healthcare use and non-elective activity in the UK population of expected deaths over an 1-year period to highlight and examine the reasons for variation. We did this to identify areas to focus interventions or resources on to reduce unnecessary emergency care use at the end of life. METHODS AND ANALYSIS: We assembled a data set of approximately 400 000 adults who died in England in the financial year 2021/22 (April 2021-March 2022). Any adults classified as a 'sudden death' were excluded. We used available data to ensure outcome measures were relevant used expert consensus to agree what to examine. We recorded place of death and examined urgent care in terms of admissions in the last year and 90 days of life. We also used recorded hospital care days as elective and non-elective usage. RESULTS: There were over 400 000 decedents included in our regression models. Close to half died in hospital (44%). Three-quarters (77%) had at least one day of unplanned hospital care in the 90 days before they died, and half (56%) had at least one day of planned hospital care. CONCLUSION: Reliance on urgent care for those approaching end-of-life may indicate poor care planning and integration of services. A relatively modest increase in the amount of community care a person receives at end-of-life can substantially reduce the likelihood of dying in hospital. Those with a cancer cause of death are far less likely to die in hospital.

2.
Eur J Neurosci ; 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38654472

RESUMO

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss-of-function mutation in CDKL5 gene, encoding a serine-threonine kinase highly expressed in the brain. CDD manifests with early-onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock-in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre-treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long-term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild-type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G-coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild-type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder.

3.
Annu Rev Biomed Eng ; 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316063

RESUMO

Recent advances in single-cell and multicellular microfluidics technology have provided powerful tools for studying cancer biology and immunology. The ability to create controlled microenvironments, perform high-throughput screenings, and monitor cellular interactions at the single-cell level has significantly advanced our understanding of tumor biology and immune responses. We discuss cutting-edge multicellular and single-cell microfluidic technologies and methodologies utilized to investigate cancer-immune cell interactions and assess the effectiveness of immunotherapies. We explore the advantages and limitations in the wide range of 3D spheroid and single-cell microfluidic models recently developed, highlighting the various approaches in device generation and applications in immunotherapy screening for potential opportunities for point-of-care approaches. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 26 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

4.
Cell Death Dis ; 15(1): 18, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38195589

RESUMO

For over two decades, Rituximab and CHOP combination treatment (rCHOP) has remained the standard treatment approach for diffuse large B-cell lymphoma (DLBCL). Despite numerous clinical trials exploring treatment alternatives, few options have shown any promise at further improving patient survival and recovery rates. A wave of new therapeutic approaches have recently been in development with the rise of immunotherapy for cancer, however, the cost of clinical trials is prohibitive of testing all promising approaches. Improved methods of early drug screening are essential for expediting the development of the therapeutic approaches most likely to help patients. Microfluidic devices provide a powerful tool for drug testing with enhanced biological relevance, along with multi-parameter data outputs. Here, we describe a hydrogel spheroid-based microfluidic model for screening lymphoma treatments. We utilized primary patient DLBCL cells in combination with NK cells and rCHOP treatment to determine the biological relevance of this approach. We observed cellular viability in response to treatment, rheological properties, and cell surface marker expression levels correlated well with expected in vivo characteristics. In addition, we explored secretory and transcriptomic changes in response to treatment. Our results showed complex changes in phenotype and transcriptomic response to treatment stimuli, including numerous metabolic and immunogenic changes. These findings support this model as an optimal platform for the comparative screening of novel treatments.


Assuntos
Linfoma Difuso de Grandes Células B , Microfluídica , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Imunoterapia , Terapia Combinada , Reologia , Microambiente Tumoral
5.
J Card Fail ; 30(1): 64-77, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38065308

RESUMO

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.


Assuntos
Insuficiência Cardíaca , Humanos , Criança , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Lacunas de Evidências
6.
BMJ Open ; 13(11): e072938, 2023 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-37963701

RESUMO

INTRODUCTION: Invasive non-typhoidal Salmonellosis (iNTS) is mainly caused by Salmonella enterica serovars Typhimurium and Enteritidis and is estimated to result in 77 500 deaths per year, disproportionately affecting children under 5 years of age in sub-Saharan Africa. Invasive non-typhoidal Salmonellae serovars are increasingly acquiring resistance to first-line antibiotics, thus an effective vaccine would be a valuable tool in reducing morbidity and mortality from infection. While NTS livestock vaccines are in wide use, no licensed vaccines exist for use in humans. Here, a first-in-human study of a novel vaccine (iNTS-GMMA) containing S. Typhimurium and S. Enteritidis Generalised Modules for Membrane Antigens (GMMA) outer membrane vesicles is presented. METHOD AND ANALYSIS: The Salmonella Vaccine Study in Oxford is a randomised placebo-controlled participant-observer blind phase I study of the iNTS-GMMA vaccine. Healthy adult volunteers will be randomised to receive three intramuscular injections of the iNTS-GMMA vaccine, containing equal quantities of S. Typhimurium and S. Enteritidis GMMA particles adsorbed on Alhydrogel, or an Alhydrogel placebo at 0, 2 and 6 months. Participants will be sequentially enrolled into three groups: group 1, 1:1 randomisation to low dose iNTS-GMMA vaccine or placebo; group 2, 1:1 randomisation to full dose iNTS-GMMA vaccine or placebo; group 3, 2:1 randomisation to full dose or lower dose (dependant on DSMC reviews of groups 1 and 2) iNTS-GMMA vaccine or placebo.The primary objective is safety and tolerability of the vaccine. The secondary objective is immunogenicity as measured by O-antigen based ELISA. Further exploratory objectives will characterise the expanded human immune profile. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the South Central-Oxford A Research Ethics Committee (Ethics REF:22/SC/0059). Appropriate documentation and regulatory approvals have been acquired. Results will be disseminated via peer-reviewed articles and conferences. TRIAL REGISTRATION NUMBER: EudraCT Number: 2020-000510-14.


Assuntos
Infecções por Salmonella , Vacinas contra Salmonella , Adulto , Criança , Humanos , Pré-Escolar , Vacinas contra Salmonella/uso terapêutico , Hidróxido de Alumínio , Infecções por Salmonella/prevenção & controle , Infecções por Salmonella/tratamento farmacológico , Salmonella typhimurium , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase I como Assunto
7.
Public Health Nutr ; 26(12): 3088-3099, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37727877

RESUMO

OBJECTIVE: To evaluate the impact of increased availability of healthier options on purchasing of different types of vending snack products sold in English leisure (sports) centres. DESIGN: An evaluation of an intervention using pre-post methods and interrupted time series analysis. Products within the vending machines were altered over three phases to increase the availability of healthier options, using agreed nutrition criteria - Government Buying Standards for Food and Catering Services (GBSF) for England - as a guide, as well as product availability. The primary outcome was the change in mean weekly purchased energy between the first and third phase. Secondary outcomes included changes by phase and by week in weekly number of purchases, fats, sugars and salt for all products combined and by individual product categories. SETTING: Fifteen sports centres in the city of Leeds, West Yorkshire, UK. PARTICIPANTS: Snack products sold in eighteen vending machines. RESULTS: Energy purchased reduced from baseline to phase 2, for all product categories combined, by 47·25 MJ (95 % CI (-61·22, -33·27)) per machine and by 279 kJ, (95 % CI (-325, -266)) per product unit. There were reductions in most nutrients purchased in all individual product categories except chocolate confectionery. Nutrients per product unit decreased for all product categories except saturated fat in chocolate confectionery. Minimal underlying trends in the baseline phase were identified, indicating changes in outcomes were likely to be due to the intervention. CONCLUSIONS: Introducing standards to increase availability of healthier snack products in vending machines is feasible without substantially affecting sales.


Assuntos
Preferências Alimentares , Lanches , Humanos , Estado Nutricional , Comércio , Inglaterra , Distribuidores Automáticos de Alimentos , Bebidas , Valor Nutritivo
9.
NPJ Vaccines ; 8(1): 100, 2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37443176

RESUMO

The pediatric population receives the majority of vaccines globally, yet there is a paucity of studies on the transcriptional response induced by immunization in this special population. In this study, we performed a systems-level analysis of immune responses to the trivalent inactivated influenza vaccine adjuvanted with MF-59 in children (15-24 months old) and in young, healthy adults. We analyzed transcriptional responses elicited by vaccination in peripheral blood, as well as cellular and antibody responses following primary and booster vaccinations. Our analysis revealed that primary vaccination induced a persistent transcriptional signature of innate immunity; booster vaccination induced a transcriptional signature of an enhanced memory-like innate response, which was consistent with enhanced activation of myeloid cells assessed by flow cytometry. Furthermore, we identified a transcriptional signature of type 1 interferon response post-booster vaccination and at baseline that was correlated with the local reactogenicity to vaccination and defined an early signature that correlated with the hemagglutinin antibody titers. These results highlight an adaptive behavior of the innate immune system in evoking a memory-like response to secondary vaccination and define molecular correlates of reactogenicity and immunogenicity in infants.

10.
Neurogastroenterol Motil ; 35(10): e14640, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37480191

RESUMO

BACKGROUND: A diet low in fermentable oligo-saccharides, di-saccharides, mono-saccharides and polyols (low FODMAP diet) is complex and clinical effectiveness is achieved with dietitian-led education, although dietitian availability in clinical practice varies. This study aimed to assess the feasibility of undertaking a trial to investigate the clinical and cost-effectiveness of different education delivery methods of the low FODMAP diet in patients with disorders of gut-brain interaction (DGBI). METHODS: In this feasibility randomized controlled trial, patients with DGBI requiring the low FODMAP diet were randomized to receive one of the following education delivery methods: booklet, app, or dietitian. Recruitment and retention rates, acceptability, symptoms, stool output, quality of life, and dietary intake were assessed. KEY RESULTS: Fifty-one patients were randomized with a recruitment rate of 2.4 patients/month and retention of 48 of 51 (94%). Nobody in the booklet group strongly agreed that this education delivery method enabled them to self-manage symptoms without further support, compared to 7 of 14 (50%) in the dietitian group (p = 0.013). More patients reported adequate relief of symptoms in the dietitian group (12, 80%) compared with the booklet group (7, 39%; p = 0.026), but not when compared to the app group (10, 63%, p > 0.05). There was a greater decrease in the IBS-SSS score in the dietitian group (mean -153, SD 90) compared with the booklet group (mean -90, SD 56; p = 0.043), but not when compared with the app group (mean -120, SD 62; p = 0.595). CONCLUSIONS & INFERENCES: Booklets were the least acceptable education delivery methods. Dietitian-led consultations led to high levels of clinical effectiveness, followed by the app, while the dietitian was superior to booklets alone. However, an adequately powered clinical trial is needed to confirm clinical effectiveness of these education delivery methods.


Assuntos
Dieta FODMAP , Qualidade de Vida , Humanos , Estudos de Viabilidade , Encéfalo
11.
PLoS Biol ; 21(7): e3002184, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37463136

RESUMO

The use of English as the common language of science represents a major impediment to maximising the contribution of non-native English speakers to science. Yet few studies have quantified the consequences of language barriers on the career development of researchers who are non-native English speakers. By surveying 908 researchers in environmental sciences, this study estimates and compares the amount of effort required to conduct scientific activities in English between researchers from different countries and, thus, different linguistic and economic backgrounds. Our survey demonstrates that non-native English speakers, especially early in their careers, spend more effort than native English speakers in conducting scientific activities, from reading and writing papers and preparing presentations in English, to disseminating research in multiple languages. Language barriers can also cause them not to attend, or give oral presentations at, international conferences conducted in English. We urge scientific communities to recognise and tackle these disadvantages to release the untapped potential of non-native English speakers in science. This study also proposes potential solutions that can be implemented today by individuals, institutions, journals, funders, and conferences. Please see the Supporting information files (S2-S6 Text) for Alternative Language Abstracts and Figs 5 and 6.


Assuntos
Idioma , Linguística , Humanos , Inquéritos e Questionários
12.
Front Psychol ; 14: 1155617, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37333599

RESUMO

It is well-established that caregiver stress is linked to increased emotional distress among children, and recent evidence highlights similar associations between caregiver and child emotional well-being during the coronavirus (COVID-19) pandemic. Examining protective factors and coping mechanisms that are associated with resiliency in the face of pandemic-related stress can highlight potential strategies that may help children adapt to other unexpected hardships outside of a global pandemic. Previous research found that playing about the pandemic moderated an association between caregiver stress and children's emotional distress. However, few studies have explored "pandemic play" among children from low-income households, where pandemic-related stressors were often exacerbated. In the present study, 72 caregivers of Head Start preschoolers between 3 and 6 years of age were surveyed between late 2020 and early 2021. Results revealed that 32% of children engaged in pandemic play frequently. Caregiver stress was positively associated with child emotional distress, but only among children who did not engage in pandemic play frequently. These findings support the idea that child-directed play may be a developmentally appropriate and accessible coping mechanism to reduce the emotional burden of stressful events on children, regardless of economic context.

13.
J Prof Nurs ; 46: 134-140, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37188402

RESUMO

Nurses play a key role in the health of Americans. Unfortunately, the nation is expected to experience an increasing nursing shortage due to nurses retiring or leaving the profession and growing healthcare needs. In this context, it is important to prepare nursing students to be practice-ready graduates. To accomplish this goal, students must learn domain knowledge that is reflective of current nursing practices and have ample experiential learning opportunities, which require close collaboration between academia and practice in nursing education. Traditionally, faculty members who have developed nursing curriculum and the course content are mainly from within academia. The aims of the article are to describe prior efforts in academia-practice collaboration for baccalaureate-level nursing education and to propose the innovative Nursing Education and Practice Continuum model, which expands our team's successful collaborative projects. The model conceptualizes nursing education as a continuum between academia and practice, which constantly interact and evolve, and facilitates co-building and co-implementing nursing education courses for both students and practicing nurses. Nursing practice is also a continuum between experiential learning and practice after graduation. This continuum model can be implemented by aligning baccalaureate-level nursing education with the Nurse Residency Program curriculum. This article also addresses potential challenges and strategies during implementation.


Assuntos
Bacharelado em Enfermagem , Educação em Enfermagem , Estudantes de Enfermagem , Humanos , Aprendizagem Baseada em Problemas , Currículo
14.
J Infect ; 86(6): 574-583, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37028454

RESUMO

BACKGROUND: Heterologous COVID vaccine priming schedules are immunogenic and effective. This report aims to understand the persistence of immune response to the viral vectored, mRNA and protein-based COVID-19 vaccine platforms used in homologous and heterologous priming combinations, which will inform the choice of vaccine platform in future vaccine development. METHODS: Com-COV2 was a single-blinded trial in which adults ≥ 50 years, previously immunised with single dose 'ChAd' (ChAdOx1 nCoV-19, AZD1222, Vaxzevria, Astrazeneca) or 'BNT' (BNT162b2, tozinameran, Comirnaty, Pfizer/BioNTech), were randomised 1:1:1 to receive a second dose 8-12 weeks later with either the homologous vaccine, or 'Mod' (mRNA-1273, Spikevax, Moderna) or 'NVX' (NVX-CoV2373, Nuvaxovid, Novavax). Immunological follow-up and the secondary objective of safety monitoring were performed over nine months. Analyses of antibody and cellular assays were performed on an intention-to-treat population without evidence of COVID-19 infection at baseline or for the trial duration. FINDINGS: In April/May 2021, 1072 participants were enrolled at a median of 9.4 weeks after receipt of a single dose of ChAd (N = 540, 45% female) or BNT (N = 532, 39% female) as part of the national vaccination programme. In ChAd-primed participants, ChAd/Mod had the highest anti-spike IgG from day 28 through to 6 months, although the heterologous vs homologous geometric mean ratio (GMR) dropped from 9.7 (95% CI (confidence interval): 8.2, 11.5) at D28 to 6.2 (95% CI: 5.0, 7.7) at D196. The heterologous/homologous GMR for ChAd/NVX similarly dropped from 3.0 (95% CI:2.5,3.5) to 2.4 (95% CI:1.9, 3.0). In BNT-primed participants, decay was similar between heterologous and homologous schedules with BNT/Mod inducing the highest anti-spike IgG for the duration of follow-up. The adjusted GMR (aGMR) for BNT/Mod compared with BNT/BNT increased from 1.36 (95% CI: 1.17, 1.58) at D28 to 1.52 (95% CI: 1.21, 1.90) at D196, whilst for BNT/NVX this aGMR was 0.55 (95% CI: 0.47, 0.64) at day 28 and 0.62 (95% CI: 0.49, 0.78) at day 196. Heterologous ChAd-primed schedules produced and maintained the largest T-cell responses until D196. Immunisation with BNT/NVX generated a qualitatively different antibody response to BNT/BNT, with the total IgG significantly lower than BNT/BNT during all follow-up time points, but similar levels of neutralising antibodies. INTERPRETATION: Heterologous ChAd-primed schedules remain more immunogenic over time in comparison to ChAd/ChAd. BNT-primed schedules with a second dose of either mRNA vaccine also remain more immunogenic over time in comparison to BNT/NVX. The emerging data on mixed schedules using the novel vaccine platforms deployed in the COVID-19 pandemic, suggest that heterologous priming schedules might be considered as a viable option sooner in future pandemics. ISRCTN: 27841311 EudraCT:2021-001275-16.


Assuntos
COVID-19 , Vacinas , Adulto , Feminino , Humanos , Masculino , Vacinas contra COVID-19 , ChAdOx1 nCoV-19 , Vacina BNT162 , Pandemias , Método Simples-Cego , COVID-19/prevenção & controle , Vacinação , Imunidade , Imunoglobulina G , Anticorpos Antivirais
15.
Nat Commun ; 14(1): 727, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36759624

RESUMO

In late June 2021 a heatwave of unprecedented magnitude impacted the Pacific Northwest region of Canada and the United States. Many locations broke all-time maximum temperature records by more than 5 °C, and the Canadian national temperature record was broken by 4.6 °C, with a new record temperature of 49.6 °C. Here, we provide a comprehensive summary of this event and its impacts. Upstream diabatic heating played a key role in the magnitude of this anomaly. Weather forecasts provided advanced notice of the event, while sub-seasonal forecasts showed an increased likelihood of a heat extreme with lead times of 10-20 days. The impacts of this event were catastrophic, including hundreds of attributable deaths across the Pacific Northwest, mass-mortalities of marine life, reduced crop and fruit yields, river flooding from rapid snow and glacier melt, and a substantial increase in wildfires-the latter contributing to landslides in the months following. These impacts provide examples we can learn from and a vivid depiction of how climate change can be so devastating.

16.
Neurosci Biobehav Rev ; 147: 105090, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36787871

RESUMO

Humans are the only species that engages in sustained, complex pretend play. As pretend play is practically ubiquitous across cultures, it might support or afford a context for developmental advances during the juvenile period that have implications for functioning in adulthood. Early in development, learning to separate our thoughts from reality is practiced in pretend play and is associated with changes not just in cognition, but in emotional and social domains as well. Specifically, pretend play affords opportunities to engage in abstractions that could support abilities such as perspective-taking, emotion recognition and regulation, and cooperation and negotiation in childhood. In turn, the abstraction skills promoted by early pretend play might underlie creativity, innovation, and our capacity to feel empathy and moral obligation to others in later childhood and adulthood. In fact, because pretend play affords sharing our abstractions with others, it might be an early context for behaviors that ultimately promote the shared abstractions of human culture itself.


Assuntos
Desenvolvimento Infantil , Jogos e Brinquedos , Humanos , Desenvolvimento Infantil/fisiologia , Cognição , Criatividade , Comportamento Social
17.
Sci Rep ; 12(1): 19735, 2022 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396956

RESUMO

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential nutrients that can affect inflammatory responses. While n-3 PUFAs are generally considered beneficial for cardiovascular disease and obesity, the effects on asthma, the most common inflammatory lung disease are unclear. While prenatal dietary n-3 PUFAs decrease the risk for childhood wheezing, postnatal dietary n-3 PUFAs can worsen allergic airway inflammation. Sphingolipid metabolism is also affected by dietary n-3 PUFAs. Decreased sphingolipid synthesis leads to airway hyperreactivity, besides inflammation, a cardinal feature of asthma, and common genetic asthma risk alleles lead to lower sphingolipid synthesis. We investigated the effect of dietary n-3 PUFAs on sphingolipid metabolism and airway reactivity. Comparing a fish-oil diet with a high n-3 PUFA content (FO) to an isocaloric coconut oil-enriched diet (CO), we found an n-3 PUFA-dependent effect on increased airway reactivity, that was not accompanied by inflammation. Lung and whole blood content of dihydroceramides, ceramides, sphingomyelins, and glucosylceramides were lower in mice fed the n-3 PUFA enriched diet consistent with lower sphingolipid synthesis. In contrast, phosphorylated long chain bases such as sphingosine 1-phosphate were increased. These findings suggest that dietary n-3 PUFAs affect pulmonary sphingolipid composition to favor innate airway hyperreactivity, independent of inflammation, and point to an important role of n-3 PUFAs in sphingolipid metabolism.


Assuntos
Asma , Ácidos Graxos Ômega-3 , Gravidez , Feminino , Animais , Camundongos , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos , Dieta , Ácidos Graxos Insaturados/metabolismo , Inflamação/metabolismo , Esfingolipídeos
18.
Nat Commun ; 13(1): 4674, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945217

RESUMO

The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.


Assuntos
Apoptose , Glutamina , Apoptose/genética , Linhagem Celular Tumoral , Ciclo do Ácido Cítrico , Fibroblastos/metabolismo , Glutamina/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
19.
Ann Thorac Surg ; 2022 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-35934067

RESUMO

BACKGROUND: Children undergoing orthotopic heart transplant (OHT) may require complex reconstruction of superior vena cava (SVC) anomalies. SVC anatomy and mode of reconstruction are potential risk factors for SVC obstruction. METHODS: A retrospective single-center review was conducted of patients undergoing initial OHT between January 1, 1990, and July 1, 2021. Simple SVC anatomy included a single right SVC to the right atrium or bilateral SVCs with a left SVC to an intact coronary sinus, without prior superior cavopulmonary connection. Presence of anomalous SVC anatomy, superior cavopulmonary connection, or previous atrial switch operation defined complex anatomy. Reconstructive strategies included atrial anastomosis; direct SVC-to-SVC anastomosis; and augmented SVC anastomosis using innominate vein, patch, cavopulmonary connection, or interposition graft. The primary outcome was reintervention for SVC obstruction. RESULTS: Of 288 patients, pretransplant diagnoses included congenital heart disease (n = 155 [54%]), cardiomyopathy (n = 125 [43%]), and other (n = 8 [3%]). Most (n = 208 [72%]) had simple SVC anatomy compared with complex SVC anatomy (80 [28%]). Reintervention for SVC obstruction occurred in 15 of 80 (19%) with complex anatomy and 1 of 208 (0.5%) with simple anatomy (P = .0001). Reintervention was more common when innominate vein or a patch was used (9/25 [36%]) compared with an interposition graft (1/7 [14%]) or direct anastomosis (6/82 [7%]; χ2 = 13.1; P = .001). Most reinterventions occurred within 30 days of OHT (14/16 [88%]). CONCLUSIONS: Patients with complex SVC anatomy have a higher rate of reintervention for SVC obstruction after OHT compared with those with simple SVC anatomy. In cases of complex SVC anatomy, interposition grafts may be associated with less reintervention compared with complex reconstructions using donor tissue.

20.
Am J Case Rep ; 23: e937680, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35788133

RESUMO

Retraction Notice: The manuscript contains inaccurate regulatory details about the treatment used in this case. Reference: Serhat Gumrukcu, Tung X. Nguyen, Rachel L. White, Gregory T. Howell, Phillip Musikanth. Allogeneic Natural Killer and Cytomegalovirus (CMV)-pp65 Pulsed Dendritic Cells Induced Complete Response Through 15 Months in a Patient with Recurrent Glioblastoma: A Case Study. Am J Case Rep. 2021; 22: e931030. DOI: 10.12659/AJCR.931030.

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