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A one-step, on-tissue chemical derivatisation method for MALDI mass spectrometry imaging was found to improve the detectability of aldehydes and ketones by charge-tagging. The developed reactive matrices, containing a UV-chromophore, ionisable moiety and hydrazide group, showed an equal or higher detection efficiency than Girard's reagent P, enabling improved imaging of brain metabolites without the need for additional co-matrices.
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Aldehídos , Hidrazinas , Cetonas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Aldehídos/química , Aldehídos/análisis , Cetonas/química , Cetonas/análisis , Hidrazinas/química , Hidrazinas/análisis , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , RatonesAsunto(s)
Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/inmunología , COVID-19/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/sangre , Anticuerpos Monoclonales/uso terapéutico , Tratamiento Farmacológico de COVID-19RESUMEN
Pediatric obstructive sleep apnea poses a significant health risk, with potential long-term consequences on cardiovascular health. This study explores the dichotomous nature of neonatal cardiac response to chronic intermittent hypoxia (CIH) between males and females, aiming to fill a critical knowledge gap in the understanding of sex-specific cardiovascular consequences of sleep apnea in early life. Neonates were exposed to CIH until p28 and underwent comprehensive in vivo physiological assessments, including whole-body plethysmography, treadmill stress-tests, and echocardiography. Results indicated that male CIH rats weighed 13.7% less than age-matched control males (p = 0.0365), while females exhibited a mild yet significant increased respiratory drive during sleep (93.94 ± 0.84 vs. 95.31 ± 0.81;p = 0.02). Transcriptomic analysis of left ventricular tissue revealed a substantial sex-based difference in the cardiac response to CIH, with males demonstrating a more pronounced alteration in gene expression compared to females (5986 vs. 3174 genes). The dysregulated miRNAs in males target metabolic genes, potentially predisposing the heart to altered metabolism and substrate utilization. Furthermore, CIH in males was associated with thinner left ventricular walls and dysregulation of genes involved in the cardiac action potential, possibly predisposing males to CIH-related arrhythmia. These findings emphasize the importance of considering sex-specific responses in understanding the cardiovascular implications of pediatric sleep apnea.
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Animales Recién Nacidos , Caracteres Sexuales , Transcriptoma , Masculino , Femenino , Animales , Ratas , Síndromes de la Apnea del Sueño/genética , Síndromes de la Apnea del Sueño/metabolismo , Síndromes de la Apnea del Sueño/fisiopatología , Ratas Sprague-Dawley , Hipoxia/metabolismo , Hipoxia/genética , Hipoxia/fisiopatología , MicroARNs/genética , MicroARNs/metabolismo , Factores Sexuales , Corazón/fisiopatologíaRESUMEN
Background: The aim of this study was to investigate the development of fatigue and mental illness between 3 and 12 months after critical COVID-19 and explore risk factors for long-lasting symptoms. Study Design and Methods: A prospective, multicenter COVID-19 study in southern Sweden, including adult patients (≥18 years) with rtPCR-confirmed COVID-19 requiring intensive care. Survivors were invited to a follow-up at 3 and 12 months, where patient-reported symptoms were assessed using the Modified Fatigue Impact Scale (MFIS), the Hospital Anxiety and Depression Scale (HADS) and the Posttraumatic Stress Disorder Checklist version 5 (PCL-5). The development between 3 and 12 months was described by changes in relation to statistical significance and suggested values for a minimally important difference (MID). Potential risk factors for long-lasting symptoms were analyzed by multivariable logistic regression. Results: At the 3-month follow-up, 262 survivors (87%) participated, 215 (72%) returned at 12 months. Fatigue was reported by 50% versus 40%, with a significant improvement at 12 months (MFIS; median 38 vs. 33, P < .001, MID ≥4). There were no significant differences in symptoms of mental illness between 3 and 12 months, with anxiety present in 33% versus 28%, depression in 30% versus 22%, and posttraumatic stress disorder in 17% versus 13%. A worse functional outcome and less sleep compared to before COVID-19 were risk factors for fatigue and mental illness at 12 months. Conclusions: Fatigue improved between 3 and 12 months but was still common. Symptoms of mental illness remained unchanged with anxiety being the most reported. A worse functional outcome and less sleep compared to before COVID-19 were identified as risk factors for reporting long-lasting symptoms.
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Severe haematological diseases and lymphoid malignancies require bone marrow (BM)-suppressive treatments. Knowledge regarding the impact of BM-suppressive treatments on children's memory T cells is very limited. Memory T cells play a crucial role in defending against herpesviruses, which is particularly relevant in paediatric cancer care. We studied 53 children in total; 34 with cancer and 2 with severe haematological disorders, with some receiving BM-suppressive treatment with or without allogeneic-haematopoietic stem cell transplantation (allo-HSCT), alongside 17 healthy controls. We focused on peripheral blood proportions of memory T-cell subsets using flow cytometry and analysed cytokine-secreting T cells with a four-parameter FluoroSpot assay in response to T-cell mitogen and varicella zoster virus (VZV) peptides. Patients on BM-suppressive treatment showed increased clusters of differentiation (CD)4+ and CD8+ effector memory (TEM)/terminally differentiated effector (TEFF) T cells compared to the healthy controls. They also exhibited, amongst other things, when compared to the healthy controls, a reduced total number of cytokine-secreting cells, by means of interferon (IFN)-γ, interleukin (IL)-17A, IL-10, and IL-22, following mitogen activation. A diminished IFN-γ response among the children with BM-suppressive treatment was observed upon VZV-peptide stimulation, compared to the healthy children. Collectively, the findings herein indicate that the children who are undergoing or have finished BM-suppressive treatment display qualitative differences in their T-cell memory compartment, potentially increasing their susceptibility to severe viral infections and impacting their immunotherapy, which relies on the functional ability of autologous T cells.
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Herpesvirus Humano 3 , Interferón gamma , Humanos , Niño , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/fisiología , Masculino , Femenino , Interferón gamma/metabolismo , Preescolar , Adolescente , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/inmunología , Linfocitos T/metabolismo , Médula Ósea , Células T de Memoria/inmunologíaRESUMEN
In an era when population aging is increasing the burden of neurodegenerative conditions, deciphering the mechanisms underlying brain senescence is more important than ever. Here, we present a spatial metabolomics analysis of age-induced neurochemical alterations in the mouse brain using negative ionization mode mass spectrometry imaging. The age-dependent effects of the acetylcholinesterase inhibitor tacrine were simultaneously examined. For ultrahigh mass resolution analysis, we utilized a Fourier-transform ion cyclotron resonance spectrometer. To complement this, a trapped ion mobility spectrometry time-of-flight analyzer provided high speed and lateral resolution. The chosen approach facilitated the detection and identification of a wide range of metabolites, from amino acids to sphingolipids. We reported significant, age-dependent alterations in brain lipids which were most evident for sulfatides and lysophosphatidic acids. Sulfatide species, which are mainly localized to white matter, either increased or decreased with age, depending on the carbon chain length and hydroxylation stage. Lysophosphatidic acids were found to decrease with age in the detailed cortical and hippocampal subregions. An age-dependent increase in the glutamine/glutamate ratio, an indicator of glia-neuron interconnection and neurotoxicity, was detected after tacrine administration. The presented metabolic mapping approach was able to provide visualizations of the lipid signaling and neurotransmission alterations induced by early aging and can thus be beneficial to further elucidating age-related neurochemical pathways.
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Envejecimiento , Metabolómica , Animales , Metabolómica/métodos , Envejecimiento/metabolismo , Envejecimiento/efectos de los fármacos , Ratones , Tacrina/farmacología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Inhibidores de la Colinesterasa/farmacología , Lisofosfolípidos/metabolismo , Sulfoglicoesfingolípidos/metabolismo , Espectrometría de Masas/métodosRESUMEN
The osteopontin-derived peptide FOL-005 stimulates hair growth. Using ligand-receptor glyco-capture technology we identified neuropilin-1 (NRP-1), a known co-receptor for vascular endothelial growth factor (VEGF) receptors, as the most probable receptor for FOL-005 and the more stable analogue FOL-026. X-ray diffraction and microscale thermophoresis analysis revealed that FOL-026 shares binding site with VEGF in the NRP-1 b1-subdomain. Stimulation of human umbilical vein endothelial cells with FOL-026 resulted in phosphorylation of VEGFR-2, ERK1/2 and AKT, increased cell growth and migration, stimulation of endothelial tube formation and inhibition of apoptosis in vitro. FOL-026 also promoted angiogenesis in vivo as assessed by subcutaneous Matrigel plug and hind limb ischemia models. NRP-1 knock-down or treatment of NRP-1 antagonist EG00229 blocked the stimulatory effects of FOL-026 on endothelial cells. Exposure of human coronary artery smooth muscle cells to FOL-026 stimulated cell growth, migration, inhibited apoptosis, and induced VEGF gene expression and VEGFR-2/AKT phosphorylation by an NRP-1-dependent mechanism. RNA sequencing showed that FOL-026 activated pathways involved in tissue repair. These findings identify NRP-1 as the receptor for FOL-026 and show that its biological effects mimic that of growth factors binding to the VEGF receptor family. They also suggest that FOL-026 may have therapeutical potential in conditions that require vascular repair and/or enhanced angiogenesis.
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Células Endoteliales de la Vena Umbilical Humana , Neovascularización Fisiológica , Neuropilina-1 , Osteopontina , Neuropilina-1/metabolismo , Humanos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Animales , Neovascularización Fisiológica/efectos de los fármacos , Osteopontina/metabolismo , Osteopontina/genética , Movimiento Celular/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Proliferación Celular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Masculino , Péptidos/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Unión Proteica , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Ratones , AngiogénesisRESUMEN
People who inject drugs are frequently colonized with Staphylococcus aureus and have an increased risk for skin and soft tissue infections. This longitudinal study aims to describe S. aureus carriage in this group and the risk for infections during a 1-year follow-up. We included 61 participants from the Malmö Needle Exchange Program. Mapping of S. aureus carriage was conducted by screening cultures every third month and S. aureus growth was semi-quantified. Data regarding infections and living conditions were collected from structured interviews. Statistics included univariate analysis with the Fischer's exact test, univariate logistic regression and multivariate logistic regression. S. aureus carriage was detected in 46-63% of participants, and 75% reported one or more infections during the study period. Self-reported infections were associated with carriage in perineum (OR 5.08 [95% CI 1.45-17.73]), in skin lesions (OR 1.48 [95% CI 1.21-1.81]), and unstable housing situation (OR 12.83 [95% CI 1.56-105.81]). Thus, people who inject drugs are frequent carriers of S. aureus and report a surprisingly high prevalence of skin and soft tissue infections. Homeless people and those with skin carriage seem to be at highest risk. Effective clinical interventions are needed, aiming at preventing infections in this vulnerable group.
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Portador Sano , Infecciones de los Tejidos Blandos , Staphylococcus aureus , Abuso de Sustancias por Vía Intravenosa , Humanos , Infecciones de los Tejidos Blandos/epidemiología , Infecciones de los Tejidos Blandos/microbiología , Masculino , Estudios Longitudinales , Femenino , Staphylococcus aureus/aislamiento & purificación , Adulto , Prevalencia , Abuso de Sustancias por Vía Intravenosa/complicaciones , Abuso de Sustancias por Vía Intravenosa/epidemiología , Portador Sano/epidemiología , Portador Sano/microbiología , Infecciones Cutáneas Estafilocócicas/epidemiología , Infecciones Cutáneas Estafilocócicas/microbiología , Persona de Mediana Edad , Infecciones Estafilocócicas/epidemiología , Infecciones Estafilocócicas/microbiología , Factores de RiesgoRESUMEN
INTRODUCTION: Small-cell lung cancer (SCLC) may be associated with neuronal autoantibodies and paraneoplastic neurological syndromes. It has been suggested that neuronal autoantibodies, especially antineuronal nuclear antibody type 1 (Hu) autoantibodies, are associated with longer survival of patients with SCLC. The objective of this study was to determine the frequency and distribution of neuronal autoantibodies at the time of diagnosis of SCLC patients and assess survival rates in relation to autoimmunity. METHODS: In this retrospective study, serum from 40 patients with biopsy-proven SCLC at the time of diagnosis was studied prior to treatment. The sera originated from a cancer registry at the Oncology Department, Vejle Hospital from 2007 to 2010. The sera were analyzed blindly to clinical status for the presence of neuronal autoantibodies. Medical records were reviewed for neurological symptoms. RESULTS: Neuronal autoantibodies were detected in 22/40 (55%) of the SCLC patients. A broad range of neurological symptoms was recorded in 28/40 (70%) patients, of which 14/28 (50%) were positive for neuronal autoantibodies. The most frequently detected autoantibodies were Hu (7/40, 17.5%) followed by GAD65 (6/22, 15.0%). Striational and P/Q- or N-type voltage-gated calcium channel antibodies were less common, with each found in five patients (12.5%). Eight patients (20%) had coexisting autoantibodies. Autoantibody-positivity was not associated with survival. CONCLUSION: Neuronal autoantibodies were at time of diagnosis found in approximately half of the treatment-naïve SCLC patients. Neither autoantibody positivity at diagnosis nor neurological manifestations correlated with survival and their clinical importance requires further studies in larger, prospective cohorts.
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Autoanticuerpos , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Masculino , Femenino , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Carcinoma Pulmonar de Células Pequeñas/inmunología , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Carcinoma Pulmonar de Células Pequeñas/sangre , Anciano , Persona de Mediana Edad , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/inmunología , Estudios Retrospectivos , Anciano de 80 o más Años , Adulto , Pronóstico , Neuronas/patología , Neuronas/inmunologíaRESUMEN
BACKGROUND: Two or more autoantibodies against either insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or zinc transporter 8 (ZnT8A) denote stage 1 (normoglycemia) or stage 2 (dysglycemia) type 1 diabetes prior to stage 3 type 1 diabetes. Automated multiplex Antibody Detection by Agglutination-PCR (ADAP) assays in two laboratories were compared to single plex radiobinding assays (RBA) to define threshold levels for diagnostic specificity and sensitivity. METHODS: IAA, GADA, IA-2A and ZnT8A were analysed in 1504 (54% females) population based controls (PBC), 456 (55% females) doctor's office controls (DOC) and 535 (41% females) blood donor controls (BDC) as well as in 2300 (48% females) patients newly diagnosed (1-10 years of age) with stage 3 type 1 diabetes. The thresholds for autoantibody positivity were computed in 100 10-fold cross-validations to separate patients from controls either by maximizing the χ2-statistics (chisq) or using the 98th percentile of specificity (Spec98). Mean and 95% CI for threshold, sensitivity and specificity are presented. FINDINGS: The ADAP ROC curves of the four autoantibodies showed comparable AUC in the two ADAP laboratories and were higher than RBA. Detection of two or more autoantibodies using chisq showed 0.97 (0.95, 0.99) sensitivity and 0.94 (0.91, 0.97) specificity in ADAP compared to 0.90 (0.88, 0.95) sensitivity and 0.97 (0.94, 0.98) specificity in RBA. Using Spec98, ADAP showed 0.92 (0.89, 0.95) sensitivity and 0.99 (0.98, 1.00) specificity compared to 0.89 (0.77, 0.86) sensitivity and 1.00 (0.99, 1.00) specificity in the RBA. The diagnostic sensitivity and specificity were higher in PBC compared to DOC and BDC. INTERPRETATION: ADAP was comparable in two laboratories, both comparable to or better than RBA, to define threshold levels for two or more autoantibodies to stage type 1 diabetes. FUNDING: Supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant number 2009-04078), the Swedish Foundation for Strategic Research (Dnr IRC15-0067) and the Swedish Research Council, Strategic Research Area (Dnr 2009-1039). AL was supported by the DiaUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and the Novo Nordisk Foundation.
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Autoanticuerpos , Diabetes Mellitus Tipo 1 , Humanos , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Femenino , Masculino , Niño , Preescolar , Lactante , Transportador 8 de Zinc/inmunología , Sensibilidad y Especificidad , Proteínas Tirosina Fosfatasas Clase 8 Similares a Receptores/inmunología , Glutamato Descarboxilasa/inmunología , Curva ROC , Tamizaje Masivo/métodosRESUMEN
A major obstacle in improving survival in pediatric T-cell acute lymphoblastic leukemia is understanding how to predict and treat leukemia relapse in the CNS. Leukemia cells are capable of infiltrating and residing within the CNS, primarily the leptomeninges, where they interact with the microenvironment and remain sheltered from systemic treatment. These cells can survive in the CNS, by hijacking the microenvironment and disrupting normal functions, thus promoting malignant transformation. While the protective effects of the bone marrow niche have been widely studied, the mechanisms behind leukemia infiltration into the CNS and the role of the CNS niche in leukemia cell survival remain unknown. We identified a dysregulated gene expression profile in CNS infiltrated T-ALL and CNS relapse, promoting cell survival, chemoresistance, and disease progression. Furthermore, we discovered that interactions between leukemia cells and human meningeal cells induced epigenetic alterations, such as changes in histone modifications, including H3K36me3 levels. These findings are a step towards understanding the molecular mechanisms promoting leukemia cell survival in the CNS microenvironment. Our results highlight genetic and epigenetic alterations induced by interactions between leukemia cells and the CNS niche, which could potentially be utilized as biomarkers to predict CNS infiltration and CNS relapse.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Niño , Humanos , Supervivencia Celular , Linfocitos T/metabolismo , Recurrencia , Ciclo Celular , Microambiente TumoralRESUMEN
BACKGROUND AND OBJECTIVES: We aimed to evaluate the mortality of patients with AQP4 antibody-seropositive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) in Denmark compared with that in the general population. METHODS: We identified patients with AQP4-Ab+ NMOSD fulfilling the 2015 International Panel for Neuromyelitis Optica Diagnosis (IPND) criteria from multiple sources (laboratories and the Danish Multiple Sclerosis Registry). We obtained detailed information about patients from hospital records and about the general population matched on age, sex, and calendar year from Statistics Denmark. We calculated standardized mortality ratio (SMR), excess number of deaths per 1,000 person-years (EDR), and life expectancies compared with those of the matched general population. We examined predictive factors of mortality and the cause of death. RESULTS: Of 66 patients with AQP4-Ab+ NMOSD between 2008 and 2020, 15 died. Overall, the SMR was 2.54 (95% CI 1.47-4.09), and the EDR was 16.8 (95% CI 4.6-34.3). The median life expectancy for patients with AQP4-Ab+ NMOSD was 64.08 years (95% CI 53.02-83.9), compared with 83.07 years for the general population. Risk of death over time was increased in the patient population with a hazard ratio (HR) of 2.22 (1.34-3.68; p = 0.002). The cause of death was directly related to NMOSD in 93% of the cases. The age at disease onset was an independent predictor of death (HR 1.042; 95% CI 1.006-1.079; p = 0.02). DISCUSSION: AQP4-Ab+ NMOSD is associated with increased mortality and shorter life expectancy compared with that in the general population, underlining the need for highly effective treatment approaches.
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Esclerosis Múltiple , Neuromielitis Óptica , Humanos , Neuromielitis Óptica/diagnóstico , Acuaporina 4 , Anticuerpos , Esclerosis Múltiple/complicaciones , Dinamarca/epidemiología , AutoanticuerposRESUMEN
The immune system of neonates is immature and therefore knowledge of possible early-life protection against SARS-CoV-2 infection, such as breastfeeding, is of great importance. Few studies have investigated the presence and duration of SARS-CoV-2 antibodies in breastmilk in relation to the trimester of maternal infection during pregnancy, and none with successful participation from all three trimesters. This study has dual objectives (1) in relation to the trimester of infection to examine the frequency, concentration and duration of IgA and IgG antibodies in breastmilk and blood serum in the third and sixth month post-partum in former SARS-CoV-2-infected mothers and (2) to examine the association in pediatric emergency admission of children within the first six months of life compared to children of non-SARS-CoV-2-infected women. The first objective is based on a prospective cohort and the second is based on a nested case-control design. The study participants are women with a former SARS-CoV-2 infection during pregnancy, whose serology IgG tests at delivery were still positive. Maternal blood and breastmilk samples were collected at three and six months postpartum. Serum IgA frequency three months pp was 72.7% (50%, 90% and 60% in the first, second and third trimester) and 82% six months pp (67%, 91% and 82% in the first, second and third trimester). Breastmilk IgA frequency three months pp was 27% (16.6%, 36% and 20% in first, second and third trimester) and 28% six months pp (0%, 38% and 28% in the first, second and third trimester). The highest IgA concentration in breastmilk was found six months post-partum with infection in the third trimester. Serum IgA was detectable more than 400 days post infection, and serum IgG above threshold was found 430 days after date of infection. We found no correlation between serum IgA and breastmilk IgA, nor between serum IgG and breastmilk IgA regardless of the trimester of infection.
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COVID-19 , Recién Nacido , Embarazo , Humanos , Femenino , Niño , Masculino , SARS-CoV-2 , Leche Humana , Estudios Prospectivos , Periodo Posparto , Anticuerpos Antivirales , Inmunoglobulina G , Madres , Inmunoglobulina ARESUMEN
Neuropeptides are bioactive peptides that are synthesized and secreted by neurons in signaling pathways in the brain. Peptides and proteins are extremely vulnerable to proteolytic cleavage when their biological surrounding changes. This makes neuropeptidomics challenging due to the rapid alterations that occur to the peptidome after harvesting of brain tissue samples. For a successful neuropeptidomic study, the biological tissue sample analyzed should resemble the living state as much as possible. Heat stabilization has been proven to inhibit postmortem degradation by denaturing proteolytic enzymes, hence increasing identification rates of neuropeptides. Here, we describe two different stabilization protocols for rodent brain samples that increase the number of intact mature neuropeptides and minimize interference from degradation products of abundant proteins. Additionally, we present an extraction protocol that aims to extract a wide range of hydrophilic and hydrophobic neuropeptides by sequentially using an aqueous and an organic extraction medium.
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Neuropéptidos , Neuropéptidos/metabolismo , Péptidos/metabolismo , Proteolisis , Péptido Hidrolasas/metabolismo , Encéfalo/metabolismoRESUMEN
The Convention on the Rights of Persons with Disabilities (CRPD) sets out a new vision for mental health care with equality and self-determination as its core standards. The CRPD fundamentally challenges long-standing practices in Sweden including the use of involuntary hospitalization, treatment without consent, and the use of restraints. This article discusses the impact of this new vision on Swedish mental health law and policy. An examination of mental health law inquiries from 2008 to 2023 reveals a notable lack of attention from policymakers towards the CRPD. Nevertheless, the Convention has emerged as a vital advocacy instrument for disability organizations and others opposing proposals that seek to broaden doctors' authority to employ coercion. In addition, the many efforts undertaken to reduce the use of coercion and to enhance the involvement of individuals with psychosocial disabilities in policy development align seamlessly with the principles of the Convention. This article concludes with a reflection on why the CRPD has not assumed a more prominent role in shaping mental health law in Sweden and calls on the government to seriously consider the CRPD's call for equality.
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Personas con Discapacidad , Salud Mental , Humanos , Suecia , Naciones Unidas , Derechos HumanosRESUMEN
Background: Advances in treatment of childhood malignancies have improved overall cure rates to 80%. Nevertheless, cancer is still the most common cause of childhood mortality in Sweden. The prognosis is particularly poor for relapse of high-risk malignancies. In the international INFORM registry, tumor tissue from patients with relapsed, refractory, or progressive pediatric cancer as well as from very-high risk primary tumors is biologically characterized using next-generation sequencing to identify possible therapeutic targets. We analyzed data from Swedish children included in the INFORM registry concerning patient characteristics, survival, sequencing results and whether targeted treatment was administered to the children based on the molecular findings. Methods: A registry-based descriptive analysis of 184 patients included in the INFORM registry in Sweden during 2016-2021. Results: The most common diagnoses were soft tissue and bone sarcomas followed by high grade gliomas [including diffuse intrinsic pontine glioma (DIPG)]. Complete molecular analysis was successful for 203/212 samples originating from 184 patients. In 88% of the samples, at least one actionable target was identified. Highly prioritized targets, according to a preset scale, were identified in 48 (24%) samples from 40 patients and 24 of these patients received matched targeted treatment but only six children within a clinical trial. No statistically significant benefit in terms of overall survival or progression free survival was observed between children treated with matched targeted treatment compared to all others. Conclusion: This international collaborative study demonstrate feasibility regarding sequencing of pediatric high-risk tumors providing molecular data regarding potential actionable targets to clinicians. For a few individuals the INFORM analysis was of utmost importance and should be regarded as a new standard of care with the potential to guide targeted therapy.
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Based on disappointing results of stem cell-based application in clinical trials for patients with critical limb ischemia, we hypothesized that the acidic environment might be the key factor limiting cell survival and function. In the present study, we used microdialysis to determine presence of acidosis and metabolic imbalance in critical ischemia. Moreover, we explored the effect of extracellular acidosis on adipose-derived stem cells (ADSCs) at molecular and transcriptional level. Our data demonstrate that low pH negatively regulates cell proliferation and survival, also, it results in cell cycle arrest, mitochondrial dynamics disorder, DNA damage as well as the impairment of proangiogenic function in a pH-dependent manner. Further transcriptome profiling identified the pivotal signaling pathways and hub genes in response to acidosis. Collectively, these findings provide strong evidences for a critical role of acidosis in ADSCs impairment with ischemic condition and suggest treatments focus on tissue pH balance and acidosis-mediated hub genes may have therapeutic potential in stem cell-based application.
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Linking clinical multi-omics with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling demonstrates a close relationship with undifferentiated sarcomas. In two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, indicating stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.
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Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Multiómica , Medicina de Precisión , Factores de Transcripción/genética , Sarcoma/genética , Sarcoma/terapia , Sarcoma/diagnóstico , Proteína EWS de Unión a ARN/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/terapia , Proteínas Tirosina Quinasas Receptoras , Biomarcadores de Tumor/genética , Proteínas de Fusión Oncogénica/genética , Proteína-Arginina N-Metiltransferasas , Proteínas de Unión al ADN/genéticaRESUMEN
Inotuzumab Ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin. The Phase 1B of the ITCC-059 trial tested InO combined with chemotherapy in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Relapsed /refractory CD22+ BCP-ALL pediatric patients were enrolled. The primary objective was to establish the Recommended Phase 2 Dose (RP2D). Secondary objectives included preliminary efficacy and tolerability. InO was combined with 1.5 mg/m2 of vincristine (days 3, 10, 17, 24), 20 mg/m2 of dexamethasone (two 5-day blocks, then amended), and intrathecal therapy. A rolling-6 design was used testing InO from 0.8 to 1.8 mg/m2/cycle. Between May-2020 and Apr-2022, 30 patients were treated, and 29 were evaluable for dose limiting toxicities (DLTs). At 1.1 mg/m2/cycle, two out of four patients had DLTs (liver toxicity). InO was de-escalated to 0.8 mg/m2/cycle (n=6) without DLTs while awaiting a protocol amendment to reduce dexamethasone dose to 10 mg/m2. Post amendment, InO was re-escalated to 1.1 mg/m2/cycle (n=6, 1 DLT), then to 1.4 mg/m2/cycle (n=3, no DLTs), and finally to 1.8 mg/m2/cycle (n=7, 1 DLT). Three additional patients were treated in an expansion cohort. The pooled response rate was 80% (24/30; 95%CI: 61.4% to 92.3%) and, among responders, 66.7% achieved minimal residual disease negativity. The RP2D of InO combined with vincristine, dexamethasone and IT therapy was declared at 1.8 mg/m2/cycle (1.5 mg/m2/cycle after remission) in a fractionated schedule. This combination showed an response rate similar to the single agent cohorts of this trial, with liver toxicity issues at the initial higher dexamethasone dose. #NTR5736.
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OBJECTIVES: The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins. METHODS: This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel). RESULTS: Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p<0.05), of which 10 proteins were elevated in PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, and IL-2. In the FMT group, levels of 12 proteins changed significantly across all timepoints (tumour necrosis factor (TNF), CDCP1, IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences in protein levels between FMT and sham-treated patients were observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell factor (p=0.024), matrix metalloproteinase-1 (p=0.038), and SLAMF1 (p=0.042). FMT had the largest positive effect on IFN-γ, Axin-1 and CCL25 and the largest negative effect on CCL19 and IL-6. CONCLUSIONS: Patients with active PsA have a distinct immunological plasma protein signature compared with HC pre-FMT. FMT affects several of these disease markers, including sustained elevation of IFN-γ. TRIAL REGISTRATION NUMBER: NCT03058900.