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1.
J Pers Med ; 14(10)2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39452550

RESUMEN

BACKGROUND: Performing emergency surgery for bowel obstruction continues to place a significant strain on the healthcare system. Conventional assessment methods for outcomes in bowel obstruction cases often concentrate on isolated factors, and the evaluation of results for individuals with bowel obstruction remains poorly studied. This study aimed to examine the risk factors associated with major postoperative complications. METHODS: We retrospectively analyzed 99 patients undergoing surgery from 2015 to 2022. We divided the patients into two groups: (1) benign-related obstruction (n = 68) and (2) cancer-related obstruction (n = 31). We used logistic regression, KNN, and XGBOOST. We calculated the receiver operating characteristic curve and accuracy of the model. RESULTS: Colon obstructions were more frequent in the cancer group (p = 0.005). Operative time, intestinal resection, and stoma were significantly more frequent in the cancer group. Major complications were at 41% for the cancer group vs. 20% in the benign group (p = 0.03). Uni- and multivariate analysis showed that the significant risk factors for major complications were cancer-related obstruction and CRP. The best model was KNN, with an accuracy of 0.82. CONCLUSIONS: Colonic obstruction is associated with tumor-related blockage. Malignant cancer and an increase in C-reactive protein (CRP) are significant risk factors for patients who have undergone emergency surgery due to major complications. KNN could improve the process of counseling and the perioperative management of patients with intestinal obstruction in emergency settings.

2.
Drug Alcohol Depend ; 264: 112424, 2024 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-39288591

RESUMEN

BACKGROUND: Increasing evidence suggests that GLP-1 receptor agonists (GLP-1RA) have a potential use in addiction treatment. Few studies have assessed the impact of GLP-1RA on substance use disorder (SUD), particularly in humans. The study aimed to do systematic review of clinical trials to assess GLP-1RA's effect on reducing SUD in patients. METHODS: The scientific literature was reviewed using the MEDLINE, Scopus and Cochrane Library databases, following PRISMA guidelines. Studies including patients with a diagnosis of SU who were treated with GLP-1RA were selected. The primary outcome was GLP-1RA's therapeutic effect on SUD, and the secondary outcomes were therapeutic effects of GLP-1RA on weight, BMI and HbA1c. RESULTS: 1218 studies were retrieved, resulting in 507 papers after title and abstract screening. Following full-text review, only 5 articles met inclusion criteria. We incorporated a total of 630 participants utilizing Exenatide (n=3) and Dulaglutide (n=2) as GLP-1RAs. Therapeutic effect of GLP-1RA on SUD was assessed in 5 studies, with 3 demonstrating a significant decrease in SUD (alcohol and nicotine). GLP-1RA's impact on body weight, BMI, and HbA1c, was reported in 3 studies. These revealed a notable reduction in these parameters among the GLP-1RA treated group. CONCLUSION: This review will give an overview of current new findings in human studies; we suggest that the effects of GLP-1RA in SUD is a possible new option of therapy in addiction medicine.

3.
Life Sci Alliance ; 7(11)2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39209534

RESUMEN

Mitochondrial gene expression is a compartmentalised process essential for metabolic function. The replication and transcription of mitochondrial DNA (mtDNA) take place at nucleoids, whereas the subsequent processing and maturation of mitochondrial RNA (mtRNA) and mitoribosome assembly are localised to mitochondrial RNA granules. The bidirectional transcription of circular mtDNA can lead to the hybridisation of polycistronic transcripts and the formation of immunogenic mitochondrial double-stranded RNA (mt-dsRNA). However, the mechanisms that regulate mt-dsRNA localisation and homeostasis are largely unknown. With super-resolution microscopy, we show that mt-dsRNA overlaps with the RNA core and associated proteins of mitochondrial RNA granules but not nucleoids. Mt-dsRNA foci accumulate upon the stimulation of cell proliferation and their abundance depends on mitochondrial ribonucleotide supply by the nucleoside diphosphate kinase, NME6. Consequently, mt-dsRNA foci are profuse in cultured cancer cells and malignant cells of human tumour biopsies. Our results establish a new link between cell proliferation and mitochondrial nucleic acid homeostasis.


Asunto(s)
Ciclo Celular , Proliferación Celular , Homeostasis , Mitocondrias , ARN Bicatenario , ARN Mitocondrial , Humanos , Homeostasis/genética , ARN Mitocondrial/metabolismo , ARN Mitocondrial/genética , ARN Bicatenario/metabolismo , ARN Bicatenario/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Ciclo Celular/genética , Proliferación Celular/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Línea Celular Tumoral , Nucleósido-Difosfato Quinasa/metabolismo , Nucleósido-Difosfato Quinasa/genética , Transcripción Genética
4.
Leukemia ; 38(10): 2171-2182, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39179669

RESUMEN

JAK2V617F is the most recurrent genetic mutation in Philadelphia-negative chronic Myeloproliferative Neoplasms (MPNs). Since the JAK2 locus is located on Chromosome 9, we hypothesized that Chromosome 9 copy number abnormalities may be a disease modifier in JAK2V617F-mutant MPN patients. In this study, we identified a subset of MPN patients with partial or complete Chromosome 9 trisomy (+9p patients), who differ from JAK2V617F-homozygous MPN patients as they carry three JAK2 alleles as well as three copies of all neighboring gene loci, including CD274, encoding immunosuppressive Programmed death-ligand 1 (PD-L1) protein. Investigation of the clonal hierarchy revealed that the JAK2V617F occurs first, followed by +9p. Functionally, CD34+ cells from +9p MPN patients demonstrated increased clonogenicity, generating a greater number of primitive colonies, due to high OCT4 and NANOG expression, with knock-down of these genes leading to a genotype-specific decrease in colony numbers. Moreover, our analysis revealed increased PD-L1 surface expression in malignant monocytes from +9p patients, while analysis of the T cell compartment unveiled elevated levels of exhausted cytotoxic T cells. Overall, here we identify a distinct novel subgroup of MPN patients, who feature a synergistic interplay between +9p and JAK2V617F that shapes immune escape characteristics and increased stemness in CD34+ cells.


Asunto(s)
Cromosomas Humanos Par 9 , Janus Quinasa 2 , Mutación , Trastornos Mieloproliferativos , Trisomía , Humanos , Janus Quinasa 2/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Cromosomas Humanos Par 9/genética , Trisomía/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Agotamiento de Células T
5.
Am J Hematol ; 99(10): 1939-1950, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38953347

RESUMEN

Myeloproliferative neoplasms represent a group of clonal hematopoietic disorders of which myelofibrosis (MF) is the most aggressive. In the context of myeloid neoplasms, there is a growing recognition of the dysregulation of immune response and T-cell function as significant contributors to disease progression and immune evasion. We investigated cytotoxic T-cell exhaustion in MF to restore immune response against malignant cells. Increased expression of inhibitory receptors like CTLA-4 was observed on cytotoxic T cells from MF patients together with a reduced secretion of IFNɣ and TNFɑ. CTLA-4 ligands CD80 and CD86 were increased on MF granulocytes and monocytes highlighting a possible role for myeloid cells in suppressing T-cell activation in MF patients. Unlike healthy donors, the activation of cytotoxic T cells from MF patients was attenuated in the presence of myeloid cells and restored when T cells were cultured alone or treated with anti-CTLA-4. Moreover, anti-CTLA-4 treatment promoted elimination of neoplastic monocytes and granulocytes in a co-culture system with cytotoxic T cells. To test CTLA-4 inhibition in vivo, patient-derived xenografts were generated by transplanting MF CD34+ cells and by infusing homologous T cells in NSGS mice. CTLA-4 blockade reduced human myeloid chimerism and led to T-cell expansion in spleen and bone marrow. Overall, these findings shed light on T-cell dysfunction in MF and suggest that CTLA-4 blockade can boost the cytotoxic T cell-mediated immune response against tumor cells.


Asunto(s)
Antígeno CTLA-4 , Mielofibrosis Primaria , Linfocitos T Citotóxicos , Humanos , Animales , Mielofibrosis Primaria/inmunología , Mielofibrosis Primaria/patología , Linfocitos T Citotóxicos/inmunología , Ratones , Femenino , Masculino , Anciano , Persona de Mediana Edad , Xenoinjertos , Activación de Linfocitos/efectos de los fármacos
6.
Sci Signal ; 17(834): eadj6603, 2024 04 30.
Artículo en Inglés | MEDLINE | ID: mdl-38687825

RESUMEN

The localization, number, and function of postsynaptic AMPA-type glutamate receptors (AMPARs) are crucial for synaptic plasticity, a cellular correlate for learning and memory. The Hippo pathway member WWC1 is an important component of AMPAR-containing protein complexes. However, the availability of WWC1 is constrained by its interaction with the Hippo pathway kinases LATS1 and LATS2 (LATS1/2). Here, we explored the biochemical regulation of this interaction and found that it is pharmacologically targetable in vivo. In primary hippocampal neurons, phosphorylation of LATS1/2 by the upstream kinases MST1 and MST2 (MST1/2) enhanced the interaction between WWC1 and LATS1/2, which sequestered WWC1. Pharmacologically inhibiting MST1/2 in male mice and in human brain-derived organoids promoted the dissociation of WWC1 from LATS1/2, leading to an increase in WWC1 in AMPAR-containing complexes. MST1/2 inhibition enhanced synaptic transmission in mouse hippocampal brain slices and improved cognition in healthy male mice and in male mouse models of Alzheimer's disease and aging. Thus, compounds that disrupt the interaction between WWC1 and LATS1/2 might be explored for development as cognitive enhancers.


Asunto(s)
Hipocampo , Péptidos y Proteínas de Señalización Intracelular , Plasticidad Neuronal , Fosfoproteínas , Proteínas Serina-Treonina Quinasas , Receptores AMPA , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Masculino , Humanos , Receptores AMPA/metabolismo , Receptores AMPA/genética , Ratones , Plasticidad Neuronal/fisiología , Hipocampo/metabolismo , Vía de Señalización Hippo , Serina-Treonina Quinasa 3 , Transducción de Señal , Memoria/fisiología , Proteínas Supresoras de Tumor/metabolismo , Proteínas Supresoras de Tumor/genética , Factor de Crecimiento de Hepatocito/metabolismo , Ratones Endogámicos C57BL , Enfermedad de Alzheimer/metabolismo , Fosforilación , Neuronas/metabolismo
7.
Obes Surg ; 34(4): 1366-1375, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38430321

RESUMEN

Increasing evidence suggests that bariatric surgery (BS) patients are at risk for substance abuse disorders (SUD). The purpose of this systematic review and meta-analysis was to determine the relationship between BS and the development of new-onset substance abuse disorder (SUDNO) in bariatric patients. On October 31, 2023, we reviewed the scientific literature following PRISMA guidelines. A total of 3242 studies were analyzed, 7 met the inclusion criteria. The pooled incidence of SUDNO was 4.28%. Patients' characteristics associated with SUDNO included preoperative mental disorders, high pre-BS BMI, and public health insurance. Surgical factors associated with new SUDNOs included severe complications in the peri- or postoperative period. The occurrence of SUDNOs is a non-negligeable complication after BS. Predisposing factors may be identified and preventive actions undertaken.


Asunto(s)
Cirugía Bariátrica , Obesidad Mórbida , Trastornos Relacionados con Sustancias , Humanos , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/estadística & datos numéricos , Trastornos Relacionados con Sustancias/epidemiología , Obesidad Mórbida/cirugía , Obesidad Mórbida/complicaciones , Factores de Riesgo , Complicaciones Posoperatorias/epidemiología , Incidencia , Femenino , Masculino , Adulto , Persona de Mediana Edad
8.
Nat Commun ; 15(1): 2635, 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38528004

RESUMEN

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation.


Asunto(s)
Enfermedad de Alzheimer , Autofagia , Proteínas Cromosómicas no Histona , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedades Neuroinflamatorias , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Autofagia/genética , Proteínas Cromosómicas no Histona/metabolismo , Citocinas/metabolismo , Inflamasomas/metabolismo , Microglía/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo
11.
Front Public Health ; 11: 1108546, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37033069

RESUMEN

Background and objective: The fourth dose the COVID-19 vaccine was first proposed to immunocompromised patients. The aim of the article is to systematically review the literature and report the humoral response and outcomes after the fourth dose administration in people with impaired immune system. Methods: Published studies on the humoral response, efficacy and safety of the fourth dose of the COVID-19 vaccine were analyzed in various settings of immunocompromised patients. We conducted systematic searches of PubMed, Cochrane Library and WHO COVID-19 Research Database for series published through January 31, 2023, using the search terms "fourth dose" or "second booster" or "4th dose" and "Coronavirus" or "COVID-19" or "SARS-CoV-2." All articles were selected according to the PRISMA guidelines. Results: A total of 24 articles including 2,838 patients were comprised in the systematic review. All the studies involved immunocompromised patients, including solid organ transplant recipients, patients with autoimmune rheumatic disease, patients with human immunodeficiency virus (HIV) and patients with blood cancers or diseases. Almost all patients received BNT162b2 or mRNA-1273 as fourth dose. All the studies demonstrated the increase of antibody titers after the fourth dose, both in patients who had a serological strong response and in those who had a weak response after the third dose. No serious adverse events after the 4th dose have been reported by 13 studies. COVID-19 infection after the fourth dose ranged from 0 to 21%. Conclusion: The present review highlights the importance of the fourth dose of covid-19 vaccines for immunocompromised patients. Across the included studies, a fourth dose was associated with improved seroconversion and antibody titer levels. In particular, a fourth dose was associated with increasing immunogenicity in organ transplant recipients and patients with hematological cancers, with a very low rate of serious side effects.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , COVID-19/prevención & control , Vacuna BNT162 , SARS-CoV-2 , Huésped Inmunocomprometido
12.
bioRxiv ; 2023 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-37066393

RESUMEN

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. We demonstrate that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1ß release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1ß release, initiating an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D (GSDMD)-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of postmortem brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing new mechanistic insight into the biology of neuroinflammation.

13.
Acta Neuropathol ; 145(4): 439-459, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36729133

RESUMEN

Identification and characterisation of novel targets for treatment is a priority in the field of psychiatry. FKBP5 is a gene with decades of evidence suggesting its pathogenic role in a subset of psychiatric patients, with potential to be leveraged as a therapeutic target for these individuals. While it is widely reported that FKBP5/FKBP51 mRNA/protein (FKBP5/1) expression is impacted by psychiatric disease state, risk genotype and age, it is not known in which cell types and sub-anatomical areas of the human brain this occurs. This knowledge is critical to propel FKBP5/1-targeted treatment development. Here, we performed an extensive, large-scale postmortem study (n = 1024) of FKBP5/1, examining neocortical areas (BA9, BA11 and ventral BA24/BA24a) derived from subjects that lived with schizophrenia, major depression or bipolar disorder. With an extensive battery of RNA (bulk RNA sequencing, single-nucleus RNA sequencing, microarray, qPCR, RNAscope) and protein (immunoblot, immunohistochemistry) analysis approaches, we thoroughly investigated the effects of disease state, ageing and genotype on cortical FKBP5/1 expression including in a cell type-specific manner. We identified consistently heightened FKBP5/1 levels in psychopathology and with age, but not genotype, with these effects strongest in schizophrenia. Using single-nucleus RNA sequencing (snRNAseq; BA9 and BA11) and targeted histology (BA9, BA24a), we established that these disease and ageing effects on FKBP5/1 expression were most pronounced in excitatory superficial layer neurons of the neocortex, and this effect appeared to be consistent in both the granular and agranular areas examined. We then found that this increase in FKBP5 levels may impact on synaptic plasticity, as FKBP5 gex levels strongly and inversely correlated with dendritic mushroom spine density and brain-derived neurotrophic factor (BDNF) levels in superficial layer neurons in BA11. These findings pinpoint a novel cellular and molecular mechanism that has potential to open a new avenue of FKBP51 drug development to treat cognitive symptoms in psychiatric disorders.


Asunto(s)
Trastornos Mentales , Neocórtex , Humanos , Trastornos Mentales/genética , Envejecimiento/genética , Neuronas , Genotipo , Polimorfismo de Nucleótido Simple
14.
Clin Exp Med ; 23(4): 1171-1180, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36495369

RESUMEN

The trajectory of B cell development goes through subsequent steps governed by complex genetic programs, strictly regulated by multiple transcription factors. Interferon regulatory factor 4 (IRF4) regulates key points from pre-B cell development and receptor editing to germinal center formation, class-switch recombination and plasma cell differentiation. The pleiotropic ability of IRF4 is mediated by its "kinetic control", allowing different IRF4 expression levels to activate distinct genetic programs due to modulation of IRF4 DNA-binding affinity. IRF4 is implicated in B cell malignancies, acting both as tumor suppressor and as tumor oncogene in different types of precursors and mature B cell neoplasia. Here, we summarize the complexity of IRF4 functions related to different DNA-binding affinity, multiple IRF4-specific target DNA motif, and interactions with transcriptional partners. Moreover, we describe the unique role of IRF4 in acute leukemias and B cell mature neoplasia, focusing on pathogenetic implications and possible therapeutic strategies in multiple myeloma and chronic lymphocytic leukemia.


Asunto(s)
Centro Germinal , Neoplasias , Humanos , Diferenciación Celular , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , ADN/metabolismo
16.
Cell Rep ; 41(10): 111766, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36476872

RESUMEN

Learning and memory rely on changes in postsynaptic glutamergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type receptor (AMPAR) number, spatial organization, and function. The Hippo pathway component WW and C2 domain-containing protein 1 (WWC1) regulates AMPAR surface expression and impacts on memory performance. However, synaptic binding partners of WWC1 and its hierarchical position in AMPAR complexes are largely unclear. Using cell-surface proteomics in hippocampal tissue of Wwc1-deficient mice and by generating a hippocampus-specific interactome, we show that WWC1 is a major regulatory platform in AMPAR signaling networks. Under basal conditions, the Hippo pathway members WWC1 and large tumor-suppressor kinase (LATS) are associated, which might prevent WWC1 effects on synaptic proteins. Reduction of WWC1/LATS binding through a point mutation at WWC1 elevates the abundance of WWC1 in AMPAR complexes and improves hippocampal-dependent learning and memory. Thus, uncoupling of WWC1 from the Hippo pathway to AMPAR-regulatory complexes provides an innovative strategy to enhance synaptic transmission.


Asunto(s)
Proteómica , Receptores AMPA , Animales , Ratones
17.
Front Immunol ; 13: 832263, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35371054

RESUMEN

The indoleamine 2,3-dioxygenase 1 (IDO1) metabolic circuitry, comprising the first tryptophan (Trp) catabolite L-kynurenine (Kyn) and the aryl hydrocarbon receptor (AHR), has emerged as a mechanism of cancer immune evasion. Here, we investigated the functional role of the IDO1/Kyn/AHR axis in chronic lymphocytic leukemia (CLL). Our data show that CLL cells expressed an active form of the IDO1 enzyme and microenvironmental stimuli can positively modulate its expression. Interferon (IFN)-γ induces IDO1 expression through the Jak/STAT1 pathway and mediates Kyn production concomitantly with Trp consumption in CLL-conditioned media, while INCB018424 (ruxolitinib), a JAK1/2 inhibitor, impaired both effects. To characterize the involvement of IDO1 in leukemic cell maintenance, we overexpressed IDO1 by vector transfection measuring enhanced resistance to spontaneous apoptosis. IDO1 pro-survival influence was confirmed by treating CLL cells with Kyn, which mediated the increase of induced myeloid leukemia cell differentiation protein (MCL1). Conversely, AHR silencing or its blockade via CH-223191 improved the apoptosis of leukemic clones and mitigated MCL1 expression. Moreover, Kyn-treated CLL cells are less affected by the pro-apoptotic effect of ABT-199 (venetoclax), while CH-223191 showed synergistic/additive cytotoxicity with this drug. Lastly, targeting directly MCL1 in CLL cells with AMG-176, we abrogate the pro-survival effect of Kyn. In conclusion, our data identify IDO1/Kyn/AHR signaling as a new therapeutic target for CLL, describing for the first time its role in CLL pathobiology.


Asunto(s)
Quinurenina , Leucemia Linfocítica Crónica de Células B , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Quinurenina/metabolismo , Leucemia Linfocítica Crónica de Células B/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Triptófano/metabolismo
18.
Cells ; 11(6)2022 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-35326454

RESUMEN

In recent years, the introduction of new drugs targeting Bruton's tyrosine kinase (BTK) has allowed dramatic improvement in the prognosis of patients with chronic lymphocytic leukemia (CLL) and other B-cell neoplasms. Although these small molecules were initially considered less immunosuppressive than chemoimmunotherapy, an increasing number of reports have described the occurrence of unexpected opportunistic fungal infections, in particular invasive aspergillosis (IA). BTK represents a crucial molecule in several signaling pathways depending on different immune receptors. Based on a variety of specific off-target effects on innate immunity, namely on neutrophils, monocytes, pulmonary macrophages, and nurse-like cells, ibrutinib has been proposed as a new host factor for the definition of probable invasive pulmonary mold disease. The role of platelets in the control of fungal growth, through granule-dependent mechanisms, was described in vitro almost two decades ago and is, so far, neglected by experts in the field of clinical management of IA. In the present study, we confirm the antifungal role of platelets, and we show, for the first time, that the exposure to BTK inhibitors impairs several immune functions of platelets in response to Aspergillus fumigatus, i.e., the ability to adhere to conidia, activation (as indicated by reduced expression of P-selectin), and direct killing activity. In conclusion, our experimental data suggest that antiplatelet effects of BTK inhibitors may contribute to an increased risk for IA in CLL patients.


Asunto(s)
Aspergilosis , Infecciones Fúngicas Invasoras , Leucemia Linfocítica Crónica de Células B , Agammaglobulinemia Tirosina Quinasa/metabolismo , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/metabolismo , Plaquetas/metabolismo , Humanos , Infecciones Fúngicas Invasoras/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico
20.
Am J Psychiatry ; 179(5): 375-387, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34698522

RESUMEN

OBJECTIVE: A fine-tuned balance of glucocorticoid receptor (GR) activation is essential for organ formation, with disturbances influencing many health outcomes. In utero, glucocorticoids have been linked to brain-related negative outcomes, with unclear underlying mechanisms, especially regarding cell-type-specific effects. An in vitro model of fetal human brain development, induced human pluripotent stem cell (hiPSC)-derived cerebral organoids, was used to test whether cerebral organoids are suitable for studying the impact of prenatal glucocorticoid exposure on the developing brain. METHODS: The GR was activated with the synthetic glucocorticoid dexamethasone, and the effects were mapped using single-cell transcriptomics across development. RESULTS: The GR was expressed in all cell types, with increasing expression levels through development. Not only did its activation elicit translocation to the nucleus and the expected effects on known GR-regulated pathways, but also neurons and progenitor cells showed targeted regulation of differentiation- and maturation-related transcripts. Uniquely in neurons, differentially expressed transcripts were significantly enriched for genes associated with behavior-related phenotypes and disorders. This human neuronal glucocorticoid response profile was validated across organoids from three independent hiPSC lines reprogrammed from different source tissues from both male and female donors. CONCLUSIONS: These findings suggest that excessive glucocorticoid exposure could interfere with neuronal maturation in utero, leading to increased disease susceptibility through neurodevelopmental processes at the interface of genetic susceptibility and environmental exposure. Cerebral organoids are a valuable translational resource for exploring the effects of glucocorticoids on early human brain development.


Asunto(s)
Células Madre Pluripotentes Inducidas , Receptores de Glucocorticoides , Encéfalo/metabolismo , Dexametasona/metabolismo , Dexametasona/farmacología , Femenino , Glucocorticoides/efectos adversos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Organoides/metabolismo , Embarazo , Receptores de Glucocorticoides/genética
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