RESUMEN
Astrocytes contribute to motor neuron death in amyotrophic lateral sclerosis (ALS), but whether they adopt deleterious features consistent with inflammatory reactive states remains incompletely resolved. To identify inflammatory reactive features in ALS human induced pluripotent stem cell (hiPSC)-derived astrocytes, we examined transcriptomics, proteomics, and glutamate uptake in VCP-mutant astrocytes. We complemented this by examining other ALS mutations and models using a systematic meta-analysis of all publicly-available ALS astrocyte sequencing data, which included hiPSC-derived astrocytes carrying SOD1, C9orf72, and FUS gene mutations as well as mouse ALS astrocyte models with SOD1G93A mutation, Tardbp deletion, and Tmem259 (also known as membralin) deletion. ALS astrocytes were characterized by up-regulation of genes involved in the extracellular matrix, endoplasmic reticulum stress, and the immune response and down-regulation of synaptic integrity, glutamate uptake, and other neuronal support processes. We identify activation of the TGFB, Wnt, and hypoxia signaling pathways in both hiPSC and mouse ALS astrocytes. ALS changes positively correlate with TNF, IL1A, and complement pathway component C1q-treated inflammatory reactive astrocytes, with significant overlap of differentially expressed genes. By contrasting ALS changes with models of protective reactive astrocytes, including middle cerebral artery occlusion and spinal cord injury, we uncover a cluster of genes changing in opposing directions, which may represent down-regulated homeostatic genes and up-regulated deleterious genes in ALS astrocytes. These observations indicate that ALS astrocytes augment inflammatory processes while concomitantly suppressing neuronal supporting mechanisms, thus resembling inflammatory reactive states and offering potential therapeutic targets.
Asunto(s)
Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , MutaciónRESUMEN
Amyotrophic lateral sclerosis is a rapidly progressive and fatal disease. Although astrocytes are increasingly recognized contributors to the underlying pathogenesis, the cellular autonomy and uniformity of astrocyte reactive transformation in different genetic forms of amyotrophic lateral sclerosis remain unresolved. Here we systematically examine these issues by using highly enriched and human induced pluripotent stem cell-derived astrocytes from patients with VCP and SOD1 mutations. We show that VCP mutant astrocytes undergo cell-autonomous reactive transformation characterized by increased expression of complement component 3 (C3) in addition to several characteristic gene expression changes. We then demonstrate that isochronic SOD1 mutant astrocytes also undergo a cell-autonomous reactive transformation, but that this is molecularly distinct from VCP mutant astrocytes. This is shown through transcriptome-wide analyses, identifying divergent gene expression profiles and activation of different key transcription factors in SOD1 and VCP mutant human induced pluripotent stem cell-derived astrocytes. Finally, we show functional differences in the basal cytokine secretome between VCP and SOD1 mutant human induced pluripotent stem cell-derived astrocytes. Our data therefore reveal that reactive transformation can occur cell autonomously in human amyotrophic lateral sclerosis astrocytes and with a striking degree of early molecular and functional heterogeneity when comparing different disease-causing mutations. These insights may be important when considering astrocyte reactivity as a putative therapeutic target in familial amyotrophic lateral sclerosis.
Asunto(s)
Esclerosis Amiotrófica Lateral , Células Madre Pluripotentes Inducidas , Esclerosis Amiotrófica Lateral/metabolismo , Astrocitos/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Mutación/genética , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genéticaRESUMEN
Reactive astrocytes are implicated in amyotrophic lateral sclerosis (ALS), although the mechanisms controlling reactive transformation are unknown. We show that decreased intron retention (IR) is common to human-induced pluripotent stem cell (hiPSC)-derived astrocytes carrying ALS-causing mutations in VCP, SOD1 and C9orf72. Notably, transcripts with decreased IR and increased expression are overrepresented in reactivity processes including cell adhesion, stress response and immune activation. This was recapitulated in public-datasets for (i) hiPSC-derived astrocytes stimulated with cytokines to undergo reactive transformation and (ii) in vivo astrocytes following selective deletion of TDP-43. We also re-examined public translatome sequencing (TRAP-seq) of astrocytes from a SOD1 mouse model, which revealed that transcripts upregulated in translation significantly overlap with transcripts exhibiting decreased IR. Using nucleocytoplasmic fractionation of VCP mutant astrocytes coupled with mRNA sequencing and proteomics, we identify that decreased IR in nuclear transcripts is associated with enhanced nonsense mediated decay and increased cytoplasmic expression of transcripts and proteins regulating reactive transformation. These findings are consistent with a molecular model for reactive transformation in astrocytes whereby poised nuclear reactivity-related IR transcripts are spliced, undergo nuclear-to-cytoplasmic translocation and translation. Our study therefore provides new insights into the molecular regulation of reactive transformation in astrocytes.
Asunto(s)
Empalme Alternativo , Esclerosis Amiotrófica Lateral/genética , Astrocitos/metabolismo , Intrones , Animales , Astrocitos/efectos de los fármacos , Canales de Calcio/genética , Núcleo Celular/genética , Células Cultivadas , Citocinas/farmacología , Citoplasma/genética , Citoplasma/metabolismo , Proteínas de Unión al ADN/genética , Expresión Génica , Humanos , Ratones , Mutación , Superóxido Dismutasa-1/genética , Translocación Genética , Proteína que Contiene Valosina/genéticaRESUMEN
SARS-CoV-2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID-19 neurological injury. This is a cross-sectional exploratory prospective biomarker cohort study of 21 patients with COVID-19 neurological syndromes (Guillain-Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID-19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] É, interleukin [IL]-6, IL-1ß, IL-8). Patients with COVID-19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)-É (p = 0.004) and sAPPß (p = 0.03) as well as amyloid ß (Aß) 40 (p = 5.2 × 10-8 ), Aß42 (p = 3.5 × 10-7 ), and Aß42/Aß40 ratio (p = 0.005) compared to controls. Patients with COVID-19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPÉ and sAPPß. Conversely, GFAp was significantly reduced in COVID-19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPÉ and sAPPß. COVID-19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPÉ and sAPPß. A sensitivity analysis of COVID-19-associated GBS revealed a non-significant trend toward greater impairment of amyloid processing in COVID-19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID-19-associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.
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Enfermedad de Alzheimer , Amiloidosis , COVID-19 , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , COVID-19/complicaciones , Estudios de Cohortes , Estudios Transversales , Humanos , Proyectos Piloto , Estudios Prospectivos , SARS-CoV-2RESUMEN
We recently described aberrantly increased cytoplasmic SFPQ intron-retaining transcripts (IRTs) and concurrent SFPQ protein mislocalization as new hallmarks of amyotrophic lateral sclerosis (ALS). However, the generalizability and potential roles of cytoplasmic IRTs in health and disease remain unclear. Here, using time-resolved deep sequencing of nuclear and cytoplasmic fractions of human induced pluripotent stem cells undergoing motor neurogenesis, we reveal that ALS-causing VCP gene mutations lead to compartment-specific aberrant accumulation of IRTs. Specifically, we identify >100 IRTs with increased cytoplasmic abundance in ALS samples. Furthermore, these aberrant cytoplasmic IRTs possess sequence-specific attributes and differential predicted binding affinity to RNA binding proteins. Remarkably, TDP-43, SFPQ and FUS-RNA binding proteins known for nuclear-to-cytoplasmic mislocalization in ALS-abundantly and specifically bind to this aberrant cytoplasmic pool of IRTs. Our data are therefore consistent with a novel role for cytoplasmic IRTs in regulating compartment-specific protein abundance. This study provides new molecular insight into potential pathomechanisms underlying ALS and highlights aberrant cytoplasmic IRTs as potential therapeutic targets.
Asunto(s)
Esclerosis Amiotrófica Lateral , Citoplasma/metabolismo , Intrones , Proteínas de Unión al ARN/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Humanos , Mutación , Proteína que Contiene Valosina/genéticaRESUMEN
BACKGROUND: Beta-blockers are widely used for many cardiovascular conditions; however, their efficacy in contemporary clinical practice remains uncertain. METHODS: We performed a prospectively designed, umbrella review of meta-analyses of randomised controlled trials (RCTs) investigating the evidence of beta-blockers in the contemporary management of coronary artery disease (CAD), heart failure (HF), patients undergoing surgery or hypertension (registration: PROSPERO CRD42016038375). We searched MEDLINE, EMBASE and the Cochrane Library from inception until December 2018. Outcomes were analysed as beta-blockers versus control for all-cause mortality, myocardial infarction (MI), incident HF or stroke. Two independent investigators abstracted the data, assessed the quality of the evidence and rated the certainty of evidence. RESULTS: We identified 98 meta-analyses, including 284 unique RCTs and 1,617,523 patient-years of follow-up. In CAD, 12 meta-analyses (93 RCTs, 103,481 patients) showed that beta-blockers reduced mortality in analyses before routine reperfusion, but there was a lack of benefit in contemporary studies where ≥ 50% of patients received thrombolytics or intervention. Beta-blockers reduced incident MI at the expense of increased HF. In HF with reduced ejection fraction, 34 meta-analyses (66 RCTs, 35,383 patients) demonstrated a reduction in mortality and HF hospitalisation with beta-blockers in sinus rhythm, but not in atrial fibrillation. In patients undergoing surgery, 23 meta-analyses (89 RCTs, 19,211 patients) showed no effect of beta-blockers on mortality for cardiac surgery, but increased mortality in non-cardiac surgery. In non-cardiac surgery, beta-blockers reduced MI after surgery but increased the risk of stroke. In hypertension, 27 meta-analyses (36 RCTs, 260,549 patients) identified no benefit versus placebo, but beta-blockers were inferior to other agents for preventing mortality and stroke. CONCLUSIONS: Beta-blockers substantially reduce mortality in HF patients in sinus rhythm, but for other conditions, clinicians need to weigh up both benefit and potential risk.
Asunto(s)
Antagonistas Adrenérgicos beta/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Antagonistas Adrenérgicos beta/farmacología , Humanos , Estudios ProspectivosRESUMEN
AIMS: The chemokine stromal derived factor-1α (SDF-1α) is known to protect the heart acutely from ischaemia-reperfusion injury via its cognate receptor, CXCR4. However, the timing and cellular location of this effect, remains controversial. METHODS AND RESULTS: Wild type male and female mice were subjected to 40â¯min LAD territory ischaemia in vivo and injected with either saline (control) or SDF-1α prior to 2â¯h reperfusion. Infarct size as a proportion of area at risk was assessed histologically using Evans blue and triphenyltetrazolium chloride. Our results confirm the cardioprotective effect of exogenous SDF-1α in mouse ischaemia-reperfusion injury and, for the first time, show protection when SDF-1α is delivered just prior to reperfusion, which has important therapeutic implications. The role of cell type was examined using the same in vivo ischaemia-reperfusion protocol in cardiomyocyte- and endothelial-specific CXCR4-null mice, and by Western blot analysis of endothelial cells treated in vitro. These experiments demonstrated that the acute infarct-sparing effect is mediated by endothelial cells, possibly via the signalling kinases Erk1/2 and PI3K/Akt. Unexpectedly, cardiomyocyte-specific deletion of CXCR4 was found to be cardioprotective per se. RNAseq analysis indicated altered expression of the mitochondrial protein co-enzyme Q10b in these mice. CONCLUSIONS: Administration of SDF-1α is cardioprotective when administered prior to reperfusion and may, therefore, have clinical utility. SDF-1α-CXCR4-mediated cardioprotection from ischaemia-reperfusion injury is contingent on the cellular location of CXCR4 activation. Specifically, cardioprotection is mediated by endothelial signalling, while cardiomyocyte-specific deletion of CXCR4 has an infarct-sparing effect per se.
Asunto(s)
Quimiocina CXCL12/genética , Corazón/efectos de los fármacos , Receptores CXCR4/genética , Daño por Reperfusión/terapia , Animales , Quimiocina CXCL12/farmacocinética , Modelos Animales de Enfermedad , Endotelio/efectos de los fármacos , Endotelio/patología , Corazón/fisiopatología , Humanos , Ratones , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Sustancias Protectoras , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Transducción de Señal/efectos de los fármacosRESUMEN
Current myocarditis guidelines do not advocate treatment to prevent myocardial injury and scar deposition in patients with myocarditis and normal left ventricular ejection fraction. We aimed to ascertain the utility of beta blockers, calcium channel blockers and antagonists of the renin-angiotensin system in ameliorating myocardial injury, scar formation and calcification in animal in vivo models of myocarditis. The project was prospectively registered with the PROSPERO database of systematic reviews (CRD42018089336). Primary outcomes (necrosis, fibrosis and calcification) were meta-analysed with random-effects modelling. 52 studies were systematically reviewed. Meta-analysis was performed compared with untreated controls. In each study, we identified all independent comparisons of treatment versus control groups. The pooled weighted mean difference (WMD) indicated treatment reduced necrosis by 16.9% (71 controlled analyses, 95% CI 13.2-20.7%; P < 0.001), however there was less evidence of an effect after accounting for publication bias. Treatment led to a 12.8% reduction in fibrosis (73 controlled analyses, 95% CI 7.6-18.0%; P < 0.001). After accounting for publication bias this was attenuated to 7.8% but remained significant. Treatment reduced calcification by 4.1% (28 controlled analyses, 95% CI 0.2-8.0%; P < 0.0395). We observed significant heterogeneity in effect size in all primary endpoints, which was predominantly driven by differences between drug categories. Beta blockers and angiotensin-converting enzyme (ACE) inhibitors were the only agents that were effective for both necrosis and fibrosis, while only ACE inhibitors had a significant effect on calcification. This study provides evidence for a role for ACE inhibitors and beta blockers to prevent myocardial injury and scar deposition in in vivo models of myocarditis. There is a need for further well-designed studies to assess the translational application of these treatments.
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Antagonistas Adrenérgicos beta/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Cardiomiopatías/prevención & control , Miocarditis/tratamiento farmacológico , Animales , Calcinosis , Cardiomiopatías/etiología , Modelos Animales de Enfermedad , Fibrosis , Miocarditis/complicaciones , Miocardio/patología , Necrosis/etiología , Necrosis/prevención & controlRESUMEN
OBJECTIVE: Whether statins increase the risk of intracerebral haemorrhage (ICH) in patients with a previous stroke remains uncertain. This study addresses the evidence of statin therapy on ICH and other clinical outcomes in patients with previous ischaemic stroke (IS) or ICH. METHODS: A systematic literature review and meta-analysis was performed in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assess observational and randomised studies comparing statin therapy with control (placebo or no treatment) in patients with a previous ICH or IS. The risk ratios (RR) for the primary outcome (ICH) and secondary outcomes (IS, any stroke, mortality and function) were pooled using random effects meta-analysis according to stroke subtype. RESULTS: Forty-three studies with a combined total of 317 291 patient-years of follow-up were included. In patients with previous ICH, statins had no significant impact on the pooled RR for recurrent ICH (1.04, 95% CI 0.86 to 1.25; n=23 695); however, statins were associated with significant reductions in mortality (RR 0.49, 95% CI 0.36 to 0.67; n=89 976) and poor functional outcome (RR 0.71, 95% CI 0.67 to 0.75; n=9113). In patients with previous IS, statins were associated with a non-significant increase in ICH (RR 1.36, 95% CI 0.96 to 1.91; n=103 525), but significantly lower risks of recurrent IS (RR 0.74, 95% CI 0.66 to 0.83; n=53 162), any stroke (RR 0.82, 95% CI 0.67 to 0.99; n=55 260), mortality (RR 0.68, 95% CI 0.50 to 0.92; n=74 648) and poor functional outcome (RR 0.83, 95% CI 0.76 to 0.91; n=34 700). CONCLUSIONS: Irrespective of stroke subtype, there were non-significant trends towards future ICH with statins. However, this risk was overshadowed by substantial and significant improvements in mortality and functional outcome among statin users. TRIAL REGISTRATION NUMBER: CRD42017079863.
Asunto(s)
Isquemia Encefálica/epidemiología , Hemorragia Cerebral/epidemiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Accidente Cerebrovascular/epidemiología , Humanos , Factores de Riesgo , Prevención SecundariaRESUMEN
Atrial fibrillation (AF) is the most common arrhythmia worldwide. The prevalence of AF in persons older than 55 years is at least 33.5 million globally and is predicted to more than double in the next half-century. Anticoagulation, heart rate control, and heart rhythm control comprise the 3 main treatment strategies in AF. Anticoagulation is aimed at preventing debilitating stroke, systemic embolism, and associated mortality. Historically, anticoagulation in AF was achieved with a vitamin K antagonist such as warfarin, which is supported by evidence demonstrating reduced incident stroke and all-cause mortality. However, warfarin has unpredictable pharmacokinetics with many drug-drug interactions that require regular monitoring to ensure patients remain in the therapeutic anticoagulant range. Non-vitamin K antagonist oral anticoagulants including dabigatran, rivaroxaban, apixaban, and edoxaban provide a possible solution to these issues with their more predictable pharmacokinetics, rapid onset of action, and greater specificity. Results from large randomized, controlled trials indicate that these agents are at least noninferior to warfarin in prevention of stroke. These trials also demonstrate a consistently lower incidence of intracranial hemorrhage, almost always all life-threatening bleeds, and many forms of major bleeds with the possible exception of gastrointestinal and some other forms of mucosal bleeding, compared with warfarin. Patients with AF are a heterogeneous population with diverse risk of stroke and bleeding, and different subgroups respond differently to anticoagulation. Important clinical questions have arisen regarding optimal anticoagulation drug selection in distinct populations such as those with renal impairment, older age, coronary artery disease, and heart failure as well as those at particularly high risk for bleeding or thromboembolism. In this review, treatment strategies in AF management are discussed in the context of different individual subgroups of patients.
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Anticoagulantes/uso terapéutico , Fibrilación Atrial/complicaciones , Tromboembolia , Salud Global , Humanos , Incidencia , Tromboembolia/epidemiología , Tromboembolia/etiología , Tromboembolia/prevención & controlRESUMEN
BACKGROUND: Some previous studies have reported that survivors of childhood cancer are at an increased risk of developing long-term mental health morbidity, whilst others have reported that this is not the case. Therefore, we analysed 5-year survivors of childhood cancer using the British Childhood Cancer Survivor Study (BCCSS) to determine the risks of aspects of long-term mental health dysfunction. PROCEDURE: Within the BCCSS, 10 488 survivors completed a questionnaire that ascertained mental health-related information via 10 questions from the Short Form-36 survey. Internal analyses were conducted using multivariable logistic regression to determine risk factors for mental health dysfunction. External analyses were undertaken using direct standardisation to compare mental health dysfunction in survivors with UK norms. RESULTS: This study has shown that overall, childhood cancer survivors had a significantly higher prevalence of mental health dysfunction for 6/10 questions analysed compared to UK norms. Central nervous system (CNS) and bone sarcoma survivors reported the greatest dysfunction, compared to expected, with significant excess dysfunction in 10 and 6 questions, respectively; the excess ranged from 4.4-22.3% in CNS survivors and 6.9-15.9% in bone sarcoma survivors. Compared to expected, excess mental health dysfunction increased with attained age; this increase was greatest for reporting 'limitations in social activities due to health', where the excess rose from 4.5% to 12.8% in those aged 16-24 and 45+, respectively. Within the internal analyses, higher levels of educational attainment and socio-economic classification were protective against mental health dysfunction. CONCLUSIONS: Based upon the findings of this large population-based study, childhood cancer survivors report significantly higher levels of mental health dysfunction than those in the general population, where deficits were observed particularly among CNS and bone sarcoma survivors. Limitations were also observed to increase with age, and thus it is important to emphasise the need for mental health evaluation and services across the entire lifespan. There is evidence that low educational attainment and being unemployed or having never worked adversely impacts long-term mental health. These findings provide an evidence base for risk stratification and planning interventions.
Asunto(s)
Trastornos Mentales/etiología , Neoplasias/psicología , Sobrevivientes/psicología , Adolescente , Adulto , Femenino , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Neoplasias/patología , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Structural learning theory suggests that experiencing motor task variation enables the central nervous system to extract general rules regarding tasks with a similar structure - rules that can subsequently be applied to novel situations. Complex minimally invasive surgery (MIS) requires different port sites, but switching ports alters the limb movements required to produce the same endpoint control of the surgical instrument. The purpose of the present study was to determine if structural learning theory can be applied to MIS to inform training methods. METHODS: A tablet laptop running bespoke software was placed within a laparoscopic box trainer and connected to a monitor situated at eye level. Participants (right-handed, non-surgeons, mean age = 23.2 years) used a standard laparoscopic grasper to move between locations on the screen. There were two training groups: the M group (n = 10) who trained using multiple port sites, and the S group (n = 10) who trained using a single port site. A novel port site was used as a test of generalization. Performance metrics were a composite of speed and accuracy (SACF) and normalized jerk (NJ; a measure of movement 'smoothness'). RESULTS: The M group showed a statistically significant performance advantage over the S group at test, as indexed by improved SACF (p < 0.05) and NJ (p < 0.05). CONCLUSIONS: This study has demonstrated the potential benefits of incorporating a structural learning approach within MIS training. This may have practical applications when training junior surgeons and developing surgical simulation devices.
Asunto(s)
Simulación por Computador , Educación Médica/métodos , Laparoscopios , Laparoscopía/educación , Procedimientos Quirúrgicos Mínimamente Invasivos/educación , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
OBJECTIVE: A right and left hepatic trisectionectomy and an extended trisectionectomy are the largest liver resections performed for malignancy. This report analyses a series of 23 patients who had at least one repeat resection after a hepatic trisectionectomy for colorectal liver metastasis (CRLM). METHODS: A retrospective analysis of a single-centre prospective liver resection database from May 1996 to April 2009 was used for patient identification. Full notes, radiology and patient reviews were analysed for a variety of factors with respect to survival. RESULTS: Twenty-three patients underwent up to 3 repeat hepatic resections after 20 right and 3 left hepatic trisectionectomies. In 18 patients the initial surgery was an extended trisectionectomy. Overall 1-, 3- and 5-year survival rates after a repeat resection were 100%, 46% and 32%, respectively. No factors predictive for survival were identified. CONCLUSION: A repeat resection after a hepatic trisectionectomy for CRLM can offer extended survival and should be considered where appropriate.
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Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Neoplasias Colorrectales/patología , Hepatectomía , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Metastasectomía , Adenocarcinoma/mortalidad , Adulto , Anciano , Quimioterapia Adyuvante , Neoplasias Colorrectales/mortalidad , Inglaterra , Femenino , Hepatectomía/efectos adversos , Hepatectomía/mortalidad , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/mortalidad , Imagen por Resonancia Magnética , Masculino , Metastasectomía/efectos adversos , Metastasectomía/mortalidad , Persona de Mediana Edad , Terapia Neoadyuvante , Reoperación , Estudios Retrospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Chronic catecholamine production is associated with desensitisation and down-regulation of adrenergic receptors and occurs in conditions, such as heart failure and myocardial infarction. The effects of further acute adrenergic stimulation, which may occur during exercise, and their subsequent effects on chemosensitivity and ventilation are unclear. Chronic isoprenaline (ISO) increased ventilation by 50 % (P < 0.05) yet the sensitivity to graded hypoxia was preserved. Acute noradrenaline (NA) in control animals led to a doubling of ventilation in hyperoxia (P < 0.001), and this difference was preserved in graded hypoxia (P < 0.001). Yet, combination of NA + ISO did not increase ventilation beyond ISO at baseline or in hypoxia. ISO, NA, and NA + ISO all induced a metabolic acidosis (P < 0.05) with enhanced ventilation in partial compensation. Carotid sinus nerve (CSN) section led to a partial loss of catecholamine-induced augmentation in ventilation (P < 0.05), yet direct recording from CSN in vitro suggests catecholamine is inhibitory for CSN discharge. These observations suggest that chronic catecholamine exposure may result in decreased exercise performance as a direct consequence of the hyperpnea to compensate for an increased metabolic rate coupled with acidosis and leading to increased central chemosensitivity. A limited contribution from peripheral chemoreceptors was noted but was not a consequence of catecholamine stimulation of the carotid body.
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Catecolaminas/farmacología , Hipoxia/fisiopatología , Respiración/efectos de los fármacos , Acidosis/inducido químicamente , Animales , Arterias Carótidas/inervación , Masculino , Conducción Nerviosa/efectos de los fármacos , Nervios Periféricos/fisiología , Ratas , Ratas Wistar , Estrés FisiológicoRESUMEN
Since the initial reporting of the successful reversal of hyperglycemia through the transplantation of pancreatic islets, significant research efforts have been conducted in elucidating the process of revascularization and the influence of engraftment site on graft function and survival. During the isolation process the intrinsic islet vascular networks are destroyed, leading to impaired revascularization after transplant. As a result, in some cases a significant quantity of the beta cell mass transplanted dies acutely following the infusion into the portal vein, the most clinically used site of engraftment. Subsequently, despite the majority of patients achieving insulin independence after transplant, a proportion of them recommence small, supplemental exogenous insulin over time. Herein, this review considers the process of islet revascularization after transplant, its limiting factors, and potential strategies to improve this critical step. Furthermore, we provide a characterization of alternative transplant sites, analyzing the historical evolution and their role towards advancing transplant outcomes in both the experimental and clinical settings.
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Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/irrigación sanguínea , Animales , Microambiente Celular , Humanos , Microcirculación , Neovascularización FisiológicaRESUMEN
Amyotrophic lateral sclerosis (ALS) is characterized by nucleocytoplasmic mislocalization of the RNA-binding protein (RBP) TDP-43. However, emerging evidence suggests more widespread mRNA and protein mislocalization. Here, we employed nucleocytoplasmic fractionation, RNA sequencing, and mass spectrometry to investigate the localization of mRNA and protein in induced pluripotent stem cell-derived motor neurons (iPSMNs) from ALS patients with TARDBP and VCP mutations. ALS mutant iPSMNs exhibited extensive nucleocytoplasmic mRNA redistribution, RBP mislocalization, and splicing alterations. Mislocalized proteins exhibited a greater affinity for redistributed transcripts, suggesting a link between RBP mislocalization and mRNA redistribution. Notably, treatment with ML240, a VCP ATPase inhibitor, partially restored mRNA and protein localization in ALS mutant iPSMNs. ML240 induced changes in the VCP interactome and lysosomal localization and reduced oxidative stress and DNA damage. These findings emphasize the link between RBP mislocalization and mRNA redistribution in ALS motor neurons and highlight the therapeutic potential of VCP inhibition.
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Esclerosis Amiotrófica Lateral , Humanos , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , ARN Mensajero/metabolismo , Neuronas Motoras/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteína que Contiene Valosina/genéticaRESUMEN
Amyotrophic Lateral Sclerosis (ALS) causes motor neuron degeneration, with 97% of cases exhibiting TDP-43 proteinopathy. Elucidating pathomechanisms has been hampered by disease heterogeneity and difficulties accessing motor neurons. Human induced pluripotent stem cell-derived motor neurons (iPSMNs) offer a solution; however, studies have typically been limited to underpowered cohorts. Here, we present a comprehensive compendium of 429 iPSMNs from 15 datasets, and 271 post-mortem spinal cord samples. Using reproducible bioinformatic workflows, we identify robust upregulation of p53 signalling in ALS in both iPSMNs and post-mortem spinal cord. p53 activation is greatest with C9orf72 repeat expansions but is weakest with SOD1 and FUS mutations. TDP-43 depletion potentiates p53 activation in both post-mortem neuronal nuclei and cell culture, thereby functionally linking p53 activation with TDP-43 depletion. ALS iPSMNs and post-mortem tissue display enrichment of splicing alterations, somatic mutations, and gene fusions, possibly contributing to the DNA damage response.