RESUMEN
BACKGROUND: Over the past decade, cancer immunotherapies have revolutionized the treatment of melanoma; however, responses vary across patient populations. Recently, baseline tumor size has been identified as an independent prognostic factor for overall survival in patients with melanoma receiving immune checkpoint inhibitors. MG1 is a novel oncolytic agent with broad tumor tropism that has recently entered early-phase clinical trials. The aim of this study was to characterize T-cell responses in human and mouse melanoma models following MG1 treatment and to establish if features of the tumor immune microenvironment (TIME) at two distinct tumor burdens would impact the efficacy of oncolytic virotherapy. METHODS: Human three-dimensional in vitro priming assays were performed to measure antitumor and antiviral T-cell responses following MG1 infection. T-cell receptor (TCR) sequencing, T2 killing assay, and peptide recall assays were used to assess the evolution of the TCR repertoire, and measure specific T-cell responses, respectively. In vivo, subcutaneous 4434 melanomas were characterized using RNA sequencing, immunohistochemistry, and flow cytometry. The effectiveness of intratumoral MG1 was assessed in advancing 4434 tumors and the generation of antitumor and antiviral T cells measured by splenocyte recall assays. Finally, combination MG1 and programmed cell death protein-1 antibody (αPD-1) therapy was investigated in advanced 4434 tumors. RESULTS: MG1 effectively supported priming of functional cytotoxic T cells (CTLs) against tumor-associated antigens as well as virus-derived peptides, as assessed using peptide recall and T2 killing assays, respectively. TCR sequencing revealed that MG1-primed CTL comprised larger clusters of similar CDR3 amino acid sequences compared with controls. In vivo testing of MG1 demonstrated that MG1 monotherapy was highly effective at treating early disease, resulting in 90% cures; however, the efficacy of MG1 reduced as the disease burden (local tumor size) increased, and the addition of αPD-1 was required to overcome resistance in more advanced disease. Differential gene expression profiles revealed that increased tumor burden was associated with an immunologically colder TIME. Furthermore, analysis of TCR signaling in advancing tumors demonstrated a different dynamic of TCR engagement compared with smaller tumors, in particular a shift in antigen recognition by CD4+ cells, from conventional to regulatory subsets. CONCLUSION: Addition of αPD-1 to MG1 is required to overcome viral therapy resistance in immunologically 'colder' more advanced melanoma, highlighting the importance of tumor burden to different types of immunotherapy.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Melanoma , Viroterapia Oncolítica , Virus Oncolíticos , Receptores de Antígenos de Linfocitos T , Humanos , Animales , Melanoma/inmunología , Melanoma/terapia , Melanoma/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Ratones , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Virus Oncolíticos/inmunología , Viroterapia Oncolítica/métodos , Transducción de Señal , Línea Celular Tumoral , Femenino , Microambiente Tumoral/inmunologíaRESUMEN
In June 2023, the UK Foundation Programme Office announced that the previous method of ranking students based on their educational performance measure and situational judgement test performance would be superseded by a preferencing algorithm that disregards academic merit. We outline our strong objections to this policy.
Asunto(s)
Evaluación Educacional , Humanos , Reino Unido , Rendimiento Académico , AlgoritmosRESUMEN
The extinction of the woolly rhinoceros (Coelodonta antiquitatis) at the onset of the Holocene remains an enigma, with conflicting evidence regarding its cause and spatiotemporal dynamics. This partly reflects challenges in determining demographic responses of late Quaternary megafauna to climatic and anthropogenic causal drivers with available genetic and paleontological techniques. Here, we show that elucidating mechanisms of ancient extinctions can benefit from a detailed understanding of fine-scale metapopulation dynamics, operating over many millennia. Using an abundant fossil record, ancient DNA, and high-resolution simulation models, we untangle the ecological mechanisms and causal drivers that are likely to have been integral in the decline and later extinction of the woolly rhinoceros. Our 52,000-y reconstruction of distribution-wide metapopulation dynamics supports a pathway to extinction that began long before the Holocene, when the combination of cooling temperatures and low but sustained hunting by humans trapped woolly rhinoceroses in suboptimal habitats along the southern edge of their range. Modeling indicates that this ecological trap intensified after the end of the last ice age, preventing colonization of newly formed suitable habitats, weakening stabilizing metapopulation processes, triggering the extinction of the woolly rhinoceros in the early Holocene. Our findings suggest that fragmentation and resultant metapopulation dynamics should be explicitly considered in explanations of late Quaternary megafauna extinctions, sending a clarion call to the fragility of the remaining large-bodied grazers restricted to disjunct fragments of poor-quality habitat due to anthropogenic environmental change.
Asunto(s)
Extinción Biológica , Fósiles , Perisodáctilos , Dinámica Poblacional , Animales , Ecosistema , ADN Antiguo/análisis , PaleontologíaRESUMEN
The Arctic is among the most climatically sensitive environments on Earth, and the disappearance of multiyear sea ice in the Arctic Ocean is predicted within decades. As apex predators, polar bears are sentinel species for addressing the impact of environmental variability on Arctic marine ecosystems. By integrating genomics, isotopic analysis, morphometrics, and ecological modeling, we investigate how Holocene environmental changes affected polar bears around Greenland. We uncover reductions in effective population size coinciding with increases in annual mean sea surface temperature, reduction in sea ice cover, declines in suitable habitat, and shifts in suitable habitat northward. Furthermore, we show that west and east Greenlandic polar bears are morphologically, and ecologically distinct, putatively driven by regional biotic and genetic differences. Together, we provide insights into the vulnerability of polar bears to environmental change and how the Arctic marine ecosystem plays a vital role in shaping the evolutionary and ecological trajectories of its inhabitants.
Asunto(s)
Ursidae , Animales , Ecosistema , Cambio Climático , Evolución Biológica , Regiones Árticas , Cubierta de HieloRESUMEN
The Sahara region has experienced periodic wet periods over the Quaternary and beyond. These North African Humid Periods (NAHPs) are astronomically paced by precession which controls the intensity of the African monsoon system. However, most climate models cannot reconcile the magnitude of these events and so the driving mechanisms remain poorly constrained. Here, we utilise a recently developed version of the HadCM3B coupled climate model that simulates 20 NAHPs over the past 800 kyr which have good agreement with NAHPs identified in proxy data. Our results show that precession determines NAHP pacing, but we identify that their amplitude is strongly linked to eccentricity via its control over ice sheet extent. During glacial periods, enhanced ice-albedo driven cooling suppresses NAHP amplitude at precession minima, when humid conditions would otherwise be expected. This highlights the importance of both precession and eccentricity, and the role of high latitude processes in determining the timing and amplitude of the NAHPs. This may have implications for the out of Africa dispersal of plants and animals throughout the Quaternary.
RESUMEN
INTRODUCTION: Clostridioides difficile infection (CDI) is a globally recognized cause of morbidity and mortality with devastating effects on health-related quality of life (HRQoL). The objective of this study was to conduct the first systematic literature review (SLR) to assess the humanistic burden of CDI on patient experiences, including HRQoL and related constructs, and attitudes towards treatment alternatives. METHODS: An SLR was conducted to identify peer-reviewed articles that assessed CDI, including recurrent CDI (rCDI), and patient-reported outcomes or HRQoL. PubMed, Embase, and the Cochrane Collaboration abstracting services were used to conduct literature searches from 2010 to 2021 in the English language. This SLR was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) criteria. RESULTS: Of 511 identified articles, 21 met study inclusion criteria. The SLR showed CDI has a devastating impact on patients' overall HRQoL that continues well beyond infection clearance. The impact of CDI on physical, emotional, social, and professional well-being rivaled abdominal symptoms of uncontrollable diarrhea, being worse for patients with rCDI. Patients with CDI feel isolated, depressed, lonely, and continue to be frightened of recurrences as well as being contagious to others. Most believe that they will never be free of CDI. CONCLUSION: CDI and rCDI are debilitating conditions affecting physical, psychological, social, and professional functioning of patients' HRQoL, even long after the event has occurred. The results of this SLR suggest that CDI is a devastating condition in need of better prevention strategies, improved psychological support, and treatments that address the microbiome disruption to break the cycle of recurrence. Additional safe and effective therapies are needed to address this unmet medical need.
Clostridioides difficile infection is a gut bacterial infection that can happen after a person has taken antibiotics to treat another infection. C. difficile infection can lead to other medical problems and death. This review of the literature aimed to understand how C. difficile infection (first, previous, and repeat occurrences), the severe diarrhea it causes, and available treatments (both old and new) for C. difficile infection can impact a person's quality of life, daily self-care activities, and attitudes toward treatment. Results from this review of 21 studies showed that C. difficile infection has a negative impact on the quality of life of patients, affecting their physical, mental, and social health. C. difficile infection also disrupted the professional lives of patients and their ability to perform work activities. This negative effect continued over time, long after the infection had cleared because patients feared it would come back again. Treating C. difficile infection improved quality of life. Findings suggest that C. difficile infection is a devastating condition that needs better prevention strategies, improved psychological support, and treatments that stop the cycle of repeated gut infections by restoring good gut flora.
RESUMEN
Our research group previously found that broccoli sprouts possess neuroprotective effects during pregnancy. The active compound has been identified as sulforaphane (SFA), obtained from glucosinolate and glucoraphanin, which are also present in other crucifers, including kale. Sulforaphene (SFE), obtained from glucoraphenin in radish, also has numerous biological benefits, some of which supersede those of sulforaphane. It is likely that other components, such as phenolics, contribute to the biological activity of cruciferous vegetables. Notwithstanding their beneficial phytochemicals, crucifers are known to contain erucic acid, an antinutritional fatty acid. The aim of this research was to phytochemically examine broccoli, kale, and radish sprouts to determine good sources of SFA and SFE to inform future studies of the neuroprotective activity of cruciferous sprouts on the fetal brain, as well as product development. Three broccoli: Johnny's Sprouting Broccoli (JSB), Gypsy F1 (GYP), and Mumm's Sprouting Broccoli (MUM), one kale: Johnny's Toscano Kale (JTK), and three radish cultivars: Black Spanish Round (BSR), Miyashige (MIY), and Nero Tunda (NT), were analyzed. We first quantified the glucosinolate, isothiocyanate, phenolics, and DPPH free radical scavenging activity (AOC) of one-day-old dark- and light-grown sprouts by HPLC. Radish cultivars generally had the highest glucosinolate and isothiocyanate contents, and kale had higher glucoraphanin and significantly higher sulforaphane content than the broccoli cultivars. Lighting conditions did not significantly affect the phytochemistry of the one-day-old sprouts. Based on phytochemistry and economic factors, JSB, JTK, and BSR were chosen for further sprouting for three, five, and seven days and subsequently analyzed. The three-day-old JTK and radish cultivars were identified to be the best sources of SFA and SFE, respectively, both yielding the highest levels of the respective compound while retaining high levels of phenolics and AOC and markedly lower erucic acid levels compared to one-day-old sprouts.
Asunto(s)
Brassica , Raphanus , Glucosinolatos/química , Brassica/química , Raphanus/química , Isotiocianatos/farmacología , Radicales Libres/farmacologíaRESUMEN
BACKGROUND: The interruption of oxygen and blood supply to the newborn brain around the time of birth is a risk factor for hypoxic-ischemic encephalopathy and may lead to infant mortality or lifelong neurological impairments. Currently, therapeutic hypothermia, the cooling of the infant's head or entire body, is the only treatment to curb the extent of brain damage. NEW METHOD: In this study, we designed a focal brain cooling device that circulates cooled water at a steady state temperature of 19 ± 1 °C through a coil of tubing fitted onto the neonatal rat's head. We tested its ability to selectively decrease brain temperature and offer neuroprotection in a neonatal rat model of hypoxic-ischemic brain injury. RESULTS: Our method cooled the brain to 30-33 °C in conscious pups, while keeping the core body temperature approximately 3.2 °C warmer. Furthermore, the application of the cooling device to the neonatal rat model demonstrated a reduction in brain volume loss compared to pups maintained at normothermia and achieved a level of brain tissue protection the same as that of whole-body cooling. COMPARISON WITH EXISTING METHODS: Prevailing methods of selective brain hypothermia are designed for adult animal models rather than for immature animals such as the rat as a conventional model of developmental brain pathology. Contrary to existing methods, our method of cooling does not require surgical manipulation or anaesthesia. CONCLUSION: Our simple, economical, and effective method of selective brain cooling is a useful tool for rodent studies in neonatal brain injury and adaptive therapeutic interventions.
Asunto(s)
Lesiones Encefálicas , Hipotermia Inducida , Hipotermia , Hipoxia-Isquemia Encefálica , Animales , Ratas , Animales Recién Nacidos , Hipotermia/patología , Hipotermia/terapia , Hipotermia Inducida/métodos , Encéfalo/patología , Hipoxia-Isquemia Encefálica/terapia , Lesiones Encefálicas/patologíaRESUMEN
Objective: To conduct a systematic review of published real-world evidence describing the cost and healthcare resource use for Clostridiodes difficile infection (CDI) in the United States. Methods: A systematic literature review was conducted searching for terms for CDI and healthcare costs. Titles of articles and abstracts were reviewed to identify those that met study criteria. Studies were evaluated to examine overall design and comparison groups in terms of healthcare resource use and cost for CDI. Results: In total, 28 articles met the inclusion criteria. Moreover, 20 studies evaluated primary CDI or did not specify, and 8 studies1-8 evaluated both primary CDI and recurrent (rCDI). Data from Medicare were used in 6 studies. Nearly all studies used a comparison group, either controls without CDI (N = 20) or comparison between primary CDI and rCDI (N = 7). Two studies examined costs of rCDI by the number of recurrences. Overall, the burden of CDI is significant, with higher aggregate costs for patients with rCDI. Compared with non-CDI controls, hospital length of stay increased in patients with both primary and rCDI compared to patients without CDI. Patients with primary CDI cost healthcare systems $24,000 more than patients without CDI. Additionally, 2 studies that evaluated the impact of recurrence among those patients with an index case of CDI demonstrated significantly higher direct all-cause medical costs among those with rCDI compared to those without. Conclusion: CDI, and particularly rCDI, is a costly condition with hospitalizations being the main cost driver.
RESUMEN
Background and aim Ward-round documentation is important for clinical communication and patient safety. Standardized checklists have improved ward-round documentation in surgical and medical settings. This quality improvement project aimed to introduce a standardized ward round proforma to improve documentation in a UK specialist stroke unit. Methods Ward round entries were assessed against internally agreed standardized criteria. A stroke-specific ward round proforma was designed and introduced with input from the multidisciplinary team. A repeat audit was performed, including assessment of the use of different proforma sections. Multidisciplinary team members were invited to provide feedback via an anonymous online survey. Results A total of 111 ward round entries were reviewed before the proforma was introduced. Ninety-five ward round entries were reviewed following introduction of the proforma, and 84.2% of these used the proforma for documentation. Overall documentation of standardized criteria improved from 48.7% to 62.1% with substantial improvement seen in documentation of neurological examination, presence/absence of mechanical venous thromboembolism prophylaxis, and blood test results. Multidisciplinary team feedback was positive. Conclusions The stroke-specific ward round proforma improved the quality and consistency of documentation in the unit. An updated proforma was designed using these results and multidisciplinary team feedback.
RESUMEN
Antioxidants and anti-inflammatory compounds are potential candidates to prevent age-related chronic diseases. Broccoli sprouts (BrSp) are a rich source of sulforaphane-a bioactive metabolite known for its antioxidant and anti-inflammatory properties. We tested the effect of chronic BrSp feeding on age-related decline in cardiometabolic health and lifespan in rats. Male and female Long-Evans rats were fed a control diet with or without dried BrSp (300 mg/kg body weight, 3 times per week) from 4 months of age until death. Body weight, body composition, blood pressure, heart function, and glucose and insulin tolerance were measured at 10, 16, 20, and 22 months of age. Behavioral traits were also examined at 18 months of age. BrSp feeding prolonged life span in females, whereas in males the positive effects on longevity were more pronounced in a subgroup of males (last 25% of survivors). Despite having modest effects on behavior, BrSp profoundly affected cardiometabolic parameters in a sex-dependent manner. BrSp-fed females had a lower body weight and visceral adiposity while BrSp-fed males exhibited improved glucose tolerance and reduced blood pressure when compared to their control counterparts. These findings highlight the sex-dependent benefits of BrSp on improving longevity and delaying cardiometabolic decline associated with aging in rats.
Asunto(s)
Brassica , Enfermedades Cardiovasculares , Insulinas , Animales , Ratas , Masculino , Femenino , Ratas Long-Evans , Longevidad , Antioxidantes , Glucosa , Peso CorporalRESUMEN
The purpose of this study was to conduct a systematic review to evaluate the cost-effectiveness evidence of herpes zoster vaccines in the U.S. A systematic literature review was undertaken for U.S. studies focused on the cost-effectiveness of herpes zoster vaccines. Eligibility criteria included studies that evaluated the cost-effectiveness of the recombinant zoster vaccine (RZV) and zoster vaccine live (ZVL) and were published between 2015 and 2021. Article titles and abstracts were reviewed to identify relevant publications. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) criteria for economic evaluations were used to evaluate the studies. Eleven published studies met inclusion and exclusion criteria. Seven studies compared RZV and ZVL. Four studies compared ZVL dosing regimens with or without a no vaccine option. All studies incorporated health system costs. Ten out of eleven (90.9%) studies conducted their analyses from a societal perspective and included indirect costs. For measurements of effectiveness, ten of eleven (90.9%) studies estimated quality-adjusted life years, four (36.4%) used shingles cases averted, two (18.2%) employed deaths prevented, and one (9.1%) measured life years saved. All studies that compared RZV with no vaccine found RZV to be a cost-effective strategy to prevent both shingles and post-herpetic neuralgia. Additionally, these analyses showed that RZV consistently dominated ZVL. Compliance with the second RZV dose was important for full benefit of the vaccine. The studies identified in this systematic review identified well-constructed cost-effectiveness analyses of herpes zoster vaccines in the U.S. RZV was more cost-effective than no vaccine or ZVL. This systematic review supports removal of ZVL from the U.S. market.
RESUMEN
BACKGROUND: Combination herpes simplex virus (HSV) oncolytic virotherapy and BRAF inhibitors (BRAFi) represent promising immunogenic treatments for BRAF mutant melanoma, but an improved understanding of the immunobiology of combinations is needed to improve on the benefit of immune checkpoint inhibitors (ICI). METHODS: Using a BRAFV600E-driven murine melanoma model, we tested the immunogenicity of HSV/BRAFi in immunocompetent C57BL mice. In addition to standard FACS analysis, we used the 'Timer of Cell Kinetics and Activity' system, which can analyze the temporal dynamics of different T cell subsets. This immune data was used to inform the selection of ICI for triple combination therapy, the effects of which were then further characterized using transcriptomics. RESULTS: Adding BRAFi treatment to HSV improved anti-tumor effects in vivo but not in vitro. Immune characterization showed HSV or dual therapy led to fewer intratumoral Treg, although with a more activated phenotype, together with more effector CD8 +T cells. Tocky analysis further showed that HSV/BRAFi dual treatment reduced the Tocky signal (reflecting engagement with cognate antigen), in both Treg and conventional subsets of CD4+, but not in CD8 +cells. However, a higher percentage of Treg than of conventional CD4 +maintained frequent engagement with antigens on treatment, reflecting a predominance of suppressive over effector function within the CD4 +compartment. The only T cell subset which correlated with a reduction in tumor growth was within Tocky signal positive conventional CD4+, supporting their therapeutic role. Targeting CD25 high, antigen-engaged Treg with a depleting anti-CD25 ICI, achieved complete cures in 100% of mice with triple therapy. Transcriptomic analysis confirmed reduction in Foxp3 on addition of anti-CD25 to HSV/BRAFi, as well as increases in expression of genes reflecting interferon signaling and cytotoxic activity. CONCLUSIONS: Combination HSV/BRAFi is an immunogenic therapy for BRAF mutant melanoma, but cannot fully control tumors. Dual therapy results in changes in T cell dynamics within tumors, with relatively maintained antigen signaling in Treg compared with conv CD4+. Antigen-engaged CD4 +effectors correlate with tumor growth control, and depletion of Treg by addition of an anti-CD25 ICI, releasing suppression of conventional CD4 +effectors by Treg, enhances survival and activates immune signaling within tumors.
Asunto(s)
Herpes Simple , Melanoma , Virus Oncolíticos , Animales , Linfocitos T CD4-Positivos , Humanos , Inmunidad , Melanoma/tratamiento farmacológico , Ratones , Ratones Endogámicos C57BL , Virus Oncolíticos/fisiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
BACKGROUND: Neonatal hypoxic-ischemic encephalopathy arises from a reduction of oxygen and blood supply to the infant brain and can lead to severe brain damage and life-long disability. The damage is greatest at the irreversibly injured necrotic core, whereas the penumbra is the surrounding, potentially salvageable tissue populated with a mix of alive and dying cells. To date, there exists no method for targeting drugs to the brain damage. METHODS AND MAJOR RESULTS: Bacteriophages are viruses that propagate in bacteria but are biocompatible in humans and also amenable to genetic and chemical modification in a manner distinctive from conventional therapeutic nanoparticles. Here, a library of M13 bacteriophage was administered into a rat model of hypoxic-ischemic encephalopathy, and unique bacteriophage clones were confirmed to localize in healthy brain tissue versus the core and penumbra zones of injury. CONCLUSIONS: For the first time, there is a potential to directly deliver therapeutics to different regions of the neonatal brain injury.
Asunto(s)
Bacteriófagos , Hipoxia-Isquemia Encefálica , Animales , Bacteriófagos/genética , Encéfalo , Hipoxia-Isquemia Encefálica/terapia , RatasRESUMEN
BACKGROUND: Perinatal brain injury results in neurodevelopmental disabilities (neuroDDs) that include cerebral palsy, autism, attention deficit disorder, epilepsy, learning disabilities and others. Commonly, injury occurs when placental circulation, that is responsible for transporting nutrients and oxygen to the fetus, is compromised. Placental insufficiency (PI) is a reduced supply of blood and oxygen to the fetus and results in a hypoxic-ischemic (HI) environment. A significant HI state in-utero leads to perinatal compromise, characterized by fetal growth restriction and brain injury. Given that over 80% of perinatal brain injuries that result in neuroDDs occur during gestation, prior to birth, preventive approaches are needed to reduce or eliminate the potential for injury and subsequent neuroDDs. Sulforaphane (SFA) derived from cruciferous vegetables such as broccoli sprouts (BrSps) is a phase-II enzyme inducer that acts via cytoplasmic Nrf2 to enhance the production of anti-oxidants in the brain through the glutathione pathway. We have previously shown a profound in vivo neuro-protective effect of BrSps/SFA as a dietary supplement in pregnant rat models of both PI and fetal inflammation. Strong evidence also points to a role for SFA as treatment for various cancers. Paradoxically, then SFA has the ability to enhance cell survival, and with conditions of cancer, enhance cell death. Given our findings of the benefit of SFA/Broccoli Sprouts as a dietary supplement during pregnancy, with improvement to the fetus, it is important to determine the beneficial and toxic dosing range of SFA. We therefore explored, in vitro, the dosing range of SFA for neuronal and glial protection and toxicity in normal and oxygen/glucose deprived (OGD) cell cultures. METHODS: OGD simulates, in vitro, the condition experienced by the fetal brain due to PI. We developed a cell culture model of primary cortical neuronal, astrocyte and combined brain cell co-cultures from newborn rodent brains. The cultures were exposed to an OGD environment for various durations of time to determine the LD50 (duration of OGD required for 50% cell death). Using the LD50 as the time point, we evaluated the efficacy of varying doses of SFA for neuroprotective and neurotoxicity effects. Control cultures were exposed to normal media without OGD, and cytotoxicity of varying doses of SFA was also evaluated. Immunofluorescence (IF) and Western blot analysis of cell specific markers were used for culture characterization, and quantification of LD50. Efficacy and toxicity effect of SFA was assessed by IF/high content microscopy and by AlamarBlue viability assay, respectively. RESULTS: We determined the LD50 to be 2 hours for neurons, 8 hours for astrocytes, and 10 hours for co-cultures. The protective effect of SFA was noticeable at 2.5 µM and 5 µM for neurons, although it was not significant. There was a significant protective effect of SFA at 2.5 µM (p<0.05) for astrocytes and co-cultures. Significant toxicity ranges were also confirmed in OGD cultures as ≥ 100 µM (p<0.05) for astrocytes, ≥ 50 µM (p<0.01) for co-cultures, but not toxic in neurons; and toxic in control cultures as ≥ 100 µM (p<0.01) for neurons, and ≥ 50 µM (p<0.01) for astrocytes and co-cultures. One Way ANOVA and Dunnett's Multiple Comparison Test were used for statistical analysis. CONCLUSIONS: Our results indicate that cell death shows a trend to reduction in neuronal and astrocyte cultures, and is significantly reduced in co-cultures treated with low doses of SFA exposed to OGD. Doses of SFA that were 10 times higher were toxic, not only under conditions of OGD, but in normal control cultures as well. The findings suggest that: 1. SFA shows promise as a preventative agent for fetal ischemic brain injury, and 2. Because the fetus is a rapidly growing organism with profound cell multiplication, dosing parameters must be established to insure safety within efficacious ranges. This study will influence the development of innovative therapies for the prevention of childhood neuroDD.
Asunto(s)
Glucosa/deficiencia , Isotiocianatos/farmacología , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Oxígeno/metabolismo , Sulfóxidos/farmacología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Células Cultivadas , Técnicas de Cocultivo , Dosificación Letal Mediana , Neuronas/efectos de los fármacos , Ratas Long-EvansRESUMEN
INTRODUCTION: Perinatal arterial ischemic stroke (PAIS) underlies approximately 10% of infantile spasms (IS). We aim to identify patterns of brain injury in ischemic stroke that may predispose infants to infantile spasms. METHODS: Sixty-four perinatal arterial ischemic stroke patients were identified meeting the following inclusion criteria: term birth, magnetic resonance imaging (MRI) showing ischemic stroke or encephalomalacia in an arterial distribution, and follow-up records. Patients who developed infantile spasms (PAIS-IS) were analyzed descriptively for ischemic stroke injury patterns and were compared to a seizure-free control group (PAIS-only). Stroke injury was scored using the modified pediatric ASPECTS (modASPECTS). RESULTS: The PAIS-IS (n = 9) group had significantly higher modASPECTS than the PAIS-only (n = 16) group (P = .002, Mann-Whitney). A greater proportion of PAIS-IS patients had injury to deep cerebral structures (67%) than PAIS-only (25%). CONCLUSION: Infarct size was significantly associated with infantile spasms development. Results support theories implicating deep cerebral structures in infantile spasms pathogenesis. This may help identify perinatal arterial ischemic stroke patients at risk of infantile spasms, facilitating more timely diagnosis.
Asunto(s)
Lesiones Encefálicas/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Espasmos Infantiles/epidemiología , Lesiones Encefálicas/diagnóstico por imagen , Femenino , Humanos , Lactante , Recién Nacido , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Espasmos Infantiles/diagnósticoRESUMEN
Stressors during the fetal and postnatal period affect the growth and developmental trajectories of offspring, causing lasting effects on physiologic regulatory systems. Here, we tested whether reduced uterine artery blood flow in late pregnancy would alter body composition in the offspring, and whether feeding offspring a western diet (WD) would aggravate these programming effects. Pregnant rats underwent bilateral uterine artery ligation (BUAL) or sham surgery on gestational day (GD)18 (term = GD22). At weaning, offspring from each group received either a normal diet (ND) or a WD. BUAL surgery increased fetal loss and caused offspring growth restriction, albeit body weights were no longer different at weaning, suggesting postnatal catch-up growth. BUAL did not affect body weight gain, fat accumulation, or plasma lipid profile in adult male offspring. In contrast, while ND-fed females from BUAL group were smaller and leaner than their sham-littermates, WD consumption resulted in excess weight gain, fat accumulation, and visceral adiposity. Moreover, WD increased plasma triglycerides and cholesterol in the BUAL-treated female offspring without any effect on sham littermates. These results demonstrate that reduced uterine artery blood flow during late pregnancy in rodents can impact body composition in the offspring in a sex-dependent manner, and these effects may be exacerbated by postnatal chronic WD consumption.
Asunto(s)
Dieta Occidental , Metabolismo de los Lípidos , Arteria Uterina/patología , Adipocitos/patología , Animales , Animales Recién Nacidos , Composición Corporal , Peso Corporal , Tamaño de la Célula , Femenino , Prueba de Tolerancia a la Glucosa , Ligadura , Lípidos/sangre , Masculino , Obesidad Abdominal/sangre , Obesidad Abdominal/patología , Tamaño de los Órganos , Embarazo , Ratas Long-EvansRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Introduction: Immune checkpoint inhibitors (ICI) have dramatically improved the outcome for cancer patients across multiple tumor types. However the response rates to ICI monotherapy remain relatively low, in part due to some tumors cultivating an inherently 'cold' immune microenvironment. Oncolytic viruses (OV) have the capability to promote a 'hotter' immune microenvironment which can improve the efficacy of ICI.Areas covered: In this article we conducted a literature search through Pubmed/Medline to identify relevant articles in both the pre-clinical and clinical settings for combining OVs with ICIs and discuss the impact of this approach on treatment as well as changes within the tumor microenvironment. We also explore the future directions of this novel combination strategy.Expert opinion: The imminent results of the Phase 3 study combining pembrolizumab with or without T-Vec injection are eagerly awaited. OV/ICI combinations remain one of the most promising avenues to explore in the success of cancer immunotherapy.
Asunto(s)
Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/terapia , Viroterapia Oncolítica/métodos , Adenoviridae/fisiología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Terapia Combinada , Enterovirus/fisiología , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Orthoreovirus/fisiología , Virus Vaccinia/fisiologíaRESUMEN
We present a continuous land-based climate reconstruction dataset extending back 60 kyr from 0 BP (1950) at 0.5° resolution on a monthly timestep for 0°N to 90°N. It has been generated from 42 discrete snapshot simulations using the HadCM3B-M2.1 coupled general circulation model. We incorporate Dansgaard-Oeschger (DO) and Heinrich events to represent millennial scale variability, based on a temperature reconstruction from Greenland ice-cores, with a spatial fingerprint based on a freshwater hosing simulation with HadCM3B-M2.1. Interannual variability is also added and derived from the initial snapshot simulations. Model output has been downscaled to 0.5° resolution (using simple bilinear interpolation) and bias corrected. Here we present surface air temperature, precipitation, incoming shortwave energy, minimum monthly temperature, snow depth, wind chill and number of rainy days per month. This is one of the first open access climate datasets of this kind and can be used to study the impact of millennial to orbital-scale climate change on terrestrial greenhouse gas cycling, northern extra-tropical vegetation, and megaflora and megafauna population dynamics.