RESUMEN
Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.
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Células Dendríticas , Estrés del Retículo Endoplásmico , Endorribonucleasas , Enfermedad Injerto contra Huésped , Proteínas Serina-Treonina Quinasas , Proteína 1 de Unión a la X-Box , Animales , Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Ratones , Estrés del Retículo Endoplásmico/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Endorribonucleasas/genética , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo , Ratones Noqueados , Ratones Endogámicos C57BL , Trasplante de Células Madre Hematopoyéticas , Trasplante de Médula Ósea , Transducción de Señal , Diferenciación Celular/inmunología , Efecto Injerto vs Leucemia/inmunologíaRESUMEN
The gastrointestinal (GI) tract is a frequent target organ in acute graft-versus-host disease (aGVHD), which can determine the morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Donor T cells recognize allogeneic Ags presented by host APCs, proliferate, and differentiate into Th1 and Th17 cells that drive GVHD pathogenesis. IL-12 has been shown to play an important role in amplifying the allogeneic response in preclinical and clinical studies. This study demonstrates that IL-12Rß2 expression on recipient nonhematopoietic cells is required for optimal development of aGVHD in murine models of allo-HCT. aGVHD attenuation by genetic depletion of IL-12R signaling is associated with reduced MHC class II expression by intestinal epithelial cells and maintenance of intestinal integrity. We verified IL-12Rß2 expression on activated T cells and in the GI tract. This study, to our knowledge, reveals a novel function of IL-12Rß2 in GVHD pathogenesis and suggests that selectively targeting IL-12Rß2 on host nonhematopoietic cells may preserve the GI tract after allo-HCT.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Enfermedad Aguda , Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/genética , Intestinos/patología , Trasplante HomólogoRESUMEN
BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which there is an unmet need to understand the cellular composition of the affected liver and how it underlies disease pathogenesis. We aimed to generate a comprehensive atlas of the PSC liver using multi-omic modalities and protein-based functional validation. METHODS: We employed single-cell and single-nucleus RNA sequencing (47,156 cells and 23,000 nuclei) and spatial transcriptomics (one sample by 10x Visium and five samples with Nanostring GeoMx DSP) to profile the cellular ecosystem in 10 PSC livers. Transcriptomic profiles were compared to 24 neurologically deceased donor livers (107,542 cells) and spatial transcriptomics controls, as well as 18,240 cells and 20,202 nuclei from three PBC livers. Flow cytometry was performed to validate PSC-specific differences in immune cell phenotype and function. RESULTS: PSC explants with parenchymal cirrhosis and prominent periductal fibrosis contained a population of cholangiocyte-like hepatocytes that were surrounded by diverse immune cell populations. PSC-associated biliary, mesenchymal, and endothelial populations expressed chemokine and cytokine transcripts involved in immune cell recruitment. Additionally, expanded CD4+ T cells and recruited myeloid populations in the PSC liver expressed the corresponding receptors to these chemokines and cytokines, suggesting potential recruitment. Tissue-resident macrophages, by contrast, were reduced in number and exhibited a dysfunctional and downregulated inflammatory response to lipopolysaccharide and interferon-γ stimulation. CONCLUSIONS: We present a comprehensive atlas of the PSC liver and demonstrate an exhaustion-like phenotype of myeloid cells and markers of chronic cytokine expression in late-stage PSC lesions. This atlas expands our understanding of the cellular complexity of PSC and has potential to guide the development of novel treatments. IMPACT AND IMPLICATIONS: Primary sclerosing cholangitis (PSC) is a rare liver disease characterized by chronic inflammation and irreparable damage to the bile ducts, which eventually results in liver failure. Due to a limited understanding of the underlying pathogenesis of disease, treatment options are limited. To address this, we sequenced healthy and diseased livers to compare the activity, interactions, and localization of immune and non-immune cells. This revealed that hepatocytes lining PSC scar regions co-express cholangiocyte markers, whereas immune cells infiltrate the scar lesions. Of these cells, macrophages, which typically contribute to tissue repair, were enriched in immunoregulatory genes and demonstrated a lack of responsiveness to stimulation. These cells may be involved in maintaining hepatic inflammation and could be a target for novel therapies.
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Colangitis Esclerosante , Humanos , Cicatriz/metabolismo , Cicatriz/patología , Ecosistema , Hígado/patología , Cirrosis Hepática/patología , Citocinas/metabolismo , Inflamación/metabolismo , Perfilación de la Expresión GénicaRESUMEN
TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.
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Estudios de Asociación Genética , Pérdida Auditiva , Proteínas de la Membrana , Serina Endopeptidasas , Humanos , Femenino , Masculino , Serina Endopeptidasas/genética , Adulto , Proteínas de la Membrana/genética , Pérdida Auditiva/genética , Niño , Persona de Mediana Edad , Adolescente , Preescolar , Genotipo , Estudios de Cohortes , Fenotipo , Mutación Missense , Estudios Transversales , Adulto Joven , Estudios Retrospectivos , Anciano , Proteínas de NeoplasiasRESUMEN
Graft-versus-host disease (GVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation, a widely used therapy for hematologic malignancies and blood disorders. Here, we report an unexpected role of cytokine leukemia inhibitory factor (LIF) in protecting against GVHD development. Administrating recombinant LIF protein (rLIF) protects mice from GVHD-induced tissue damage and lethality without compromising the graft-versus-leukemia activity, which is crucial to prevent tumor relapse. We found that rLIF decreases the infiltration and activation of donor immune cells and protects intestinal stem cells to ameliorate GVHD. Mechanistically, rLIF downregulates IL-12-p40 expression in recipient dendritic cells after irradiation through activating STAT1 signaling, which results in decreased major histocompatibility complex II levels on intestinal epithelial cells and decreased donor T-cell activation and infiltration. This study reveals a previously unidentified protective role of LIF for GVHD-induced tissue pathology and provides a potential effective therapeutic strategy to limit tissue pathology without compromising antileukemic efficacy.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Factor Inhibidor de Leucemia , Leucemia , Animales , Ratones , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/terapia , Factor Inhibidor de Leucemia/genética , Trasplante HomólogoRESUMEN
The inner ear is derived from the otic placode, one of the numerous cranial sensory placodes that emerges from the pre-placodal ectoderm (PPE) along its anterior-posterior axis. However, the molecular dynamics underlying how the PPE is regionalized are poorly resolved. We used stem cell-derived organoids to investigate the effects of Wnt signaling on early PPE differentiation and found that modulating Wnt signaling significantly increased inner ear organoid induction efficiency and reproducibility. Alongside single-cell RNA sequencing, our data reveal that the canonical Wnt signaling pathway leads to PPE regionalization and, more specifically, medium Wnt levels during the early stage induce (1) expansion of the caudal neural plate border (NPB), which serves as a precursor for the posterior PPE, and (2) a caudal microenvironment that is required for otic specification. Our data further demonstrate Wnt-mediated induction of rostral and caudal cells in organoids and more broadly suggest that Wnt signaling is critical for anterior-posterior patterning in the PPE.
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Oído Interno , Vía de Señalización Wnt , Animales , Ratones , Reproducibilidad de los Resultados , Oído Interno/metabolismo , Diferenciación Celular , Ectodermo/metabolismo , Organoides , Células Madre , Regulación del Desarrollo de la Expresión GénicaRESUMEN
BACKGROUND: We analyzed the genetic causes of sensorineural hearing loss in racial and ethnic minorities of South Florida by reviewing demographic, phenotypic, and genetic data on 136 patients presenting to the Hereditary Hearing Loss Clinic at the University of Miami. In our retrospective chart review, of these patients, half self-identified as Hispanic, and the self-identified racial distribution was 115 (86%) White, 15 (11%) Black, and 6 (4%) Asian. Our analysis helps to reduce the gap in understanding the prevalence, impact, and genetic factors related to hearing loss among diverse populations. RESULTS: The causative gene variant or variants were identified in 54 (40%) patients, with no significant difference in the molecular diagnostic rate between Hispanics and Non-Hispanics. However, the total solve rate based on race was 40%, 47%, and 17% in Whites, Blacks, and Asians, respectively. In Non-Hispanic Whites, 16 different variants were identified in 13 genes, with GJB2 (32%), MYO7A (11%), and SLC26A4 (11%) being the most frequently implicated genes. In White Hispanics, 34 variants were identified in 20 genes, with GJB2 (22%), MYO7A (7%), and STRC-CATSPER2 (7%) being the most common. In the Non-Hispanic Black cohort, the gene distribution was evenly dispersed, with 11 variants occurring in 7 genes, and no variant was identified in 3 Hispanic Black probands. For the Asian cohort, only one gene variant was found out of 6 patients. CONCLUSION: This study demonstrates that the diagnostic rate of genetic studies in hearing loss varies according to race in South Florida, with more heterogeneity in racial and ethnic minorities. Further studies to delineate deafness gene variants in underrepresented populations, such as African Americans/Blacks from Hispanic groups, are much needed to reduce racial and ethnic disparities in genetic diagnoses.
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Pérdida Auditiva Sensorineural , Humanos , Asiático/genética , Negro o Afroamericano/genética , ADN/genética , Florida/epidemiología , Pérdida Auditiva Sensorineural/epidemiología , Pérdida Auditiva Sensorineural/genética , Hispánicos o Latinos/genética , Péptidos y Proteínas de Señalización Intercelular , Estudios Retrospectivos , Blanco/genéticaRESUMEN
INTRODUCTION: Hearing loss is a common sensory disorder that impacts patients across the lifespan. Many genetic variants have been identified that contribute to non-syndromic hearing loss. Yet, genetic testing is not routinely administered when hearing loss is diagnosed, particularly in adults. In this study, genetic testing was completed in patients with known hearing loss. METHODS: 104 patients who were evaluated for hearing loss were enrolled and received genetic testing. RESULTS: Of those 104 patients, 39 had available genetic testing, 20 had one missing allele, and 45 yielded no genetic diagnosis. Of the 39 cases with genetic testing data, 24 were simplex cases and 15 were multiplex cases. A majority of patients presented with an autosomal recessive inheritance pattern (n=32), 26 of whom presented with congenital hearing loss. 38% of cases were positive for GJB2 mutation with c.35delG being the most common pathogenic variant. These findings are consistent with previous literature suggesting GJB2 mutations are the most common causes of non-syndromic hearing loss. CONCLUSION: Given the frequency of genetic variants in patients with hearing loss, genetic testing should be considered as a routine part of the hearing loss work-up, particularly as gene therapies are studied and become more widely available.
RESUMEN
Chronic inflammatory diseases like rheumatoid arthritis are characterized by a deficit in fully functional regulatory T cells. DNA-methylation inhibitors have previously been shown to promote regulatory T cell responses and, in the present study, we evaluated their potential to ameliorate chronic and acute animal models of rheumatoid arthritis. Of the drugs tested, decitabine was the most effective, producing a sustained therapeutic effect that was dependent on indoleamine 2,3-dioxygenase (IDO) and was associated with expansion of induced regulatory T cells, particularly at the site of disease activity. Treatment with decitabine also caused apoptosis of Th1 and Th17 cells in active arthritis in a highly selective manner. The molecular basis for this selectivity was shown to be ENT1, a nucleoside transporter, which facilitates intracellular entry of the drug and is up-regulated on effector T cells during active arthritis. It was further shown that short-term treatment with decitabine resulted in the generation of a population of regulatory T cells that were able to suppress arthritis upon adoptive transfer. In summary, a therapeutic approach using an approved drug is described that treats active inflammatory disease effectively and generates robust regulatory T cells with the IDO-dependent capacity to maintain remission.
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Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Decitabina/farmacología , Linfocitos T Reguladores/efectos de los fármacos , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Artritis Experimental/inmunología , Artritis Experimental/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Desmetilación del ADN/efectos de los fármacos , Tranportador Equilibrativo 1 de Nucleósido/genética , Tranportador Equilibrativo 1 de Nucleósido/inmunología , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Inducción de Remisión , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Células TH1/citología , Células TH1/inmunología , Células Th17/citología , Células Th17/inmunologíaRESUMEN
OBJECTIVE: To determine whether subjects who have recovered from COVID-19 smell and taste disturbance perform similarly to their COVID-naïve baseline, on gold-standard smell and taste tests. STUDY DESIGN: Prospective cross-sectional study. SETTING: University of Miami Department of Otolaryngology in Miami, FL between September 2021, and August 2022. METHODS: Those previously COVID-19 positive composed the experimental group, those who reported being COVID-naïve composed the control group. Mean total score for the UPSIT Smell Test, and the Burghart Taste Strip test were the primary outcome measures. RESULTS: 70 adult subjects (35 former COVID-positive, 35 COVID-naïve) were enrolled, with 21 females and 14 males in each group. 87 % of all subjects were white and were almost distributed evenly between Hispanic and non-Hispanic. Mean UPSIT total score for the experimental group was 30.6 (95 % CI 28.9-32.3), mean UPSIT total score for the control group was 31.2 (95 % CI 29.7-32.8). Mean Burghart total score for the experimental group was 11.3 (95 % CI 10.6-12.0), mean Burghart total score for the control group was 10.7 (95 % CI 9.7-11.8). These showed a significant overlap of the 95 % CI of the mean total score between the control group and the experimental group, suggesting no significant difference between the two groups. CONCLUSION: These results suggest that COVID-19 patients who experience smell and taste disturbance and recover, regain sensory ability similar to their pre-COVID ability. Further study is needed to validate these findings, but the results are promising in the long-term recovery of COVID-19.
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COVID-19 , Trastornos del Olfato , Adulto , Masculino , Femenino , Humanos , Estudios Transversales , Trastornos del Olfato/etiología , Estudios Prospectivos , Recuperación de la Función , Olfato , DisgeusiaRESUMEN
Removal of heavy metals using the electrokinetic (EK) remediation technology is restricted by soils containing a fraction of clay particles above 12%. Furthermore, it is also affected by hydroxide precipitation (focusing phenomenon) close to the cathode. A modified EK reactor containing a permeable reactive barrier (PRB) was proposed herein where the enzyme-induced carbonate precipitation (EICP) treatment was incorporated into the PRB. Despite that, NH4+-N pollution induced by the urea hydrolysis resulting from the EICP treatment causes serious threats to surrounding environments and human health. There were four types of tests applied to the present work, including CP, TS1, TS2, and TS3 tests. CP test neglected the bio-PRB, while TS1 test considered the bio-PRB. TS2 test based on TS1 test tackled NH4+-N pollution using the struvite precipitation technology. TS3 test based on TS2 test applied EDDS to enhance the removal of Cu and Pb. In CP test, the removal efficiency applied to Cu and Pb removals was as low as approximately 10%, presumably due to the focusing phenomenon. The removal efficiency was elevated to approximately 24% when the bio-PRB and the electrolyte reservoir were involved in TS1 test. TS2 test indicated that the rate of struvite precipitation was 40 times faster than the ureolysis rate, meaning that the struvite precipitate had sequestered NH4+ before it started threatening surrounding environments. The chelation between Cu2+ and EDDS took place when EDDS played a part in TS3 test. It made Cu2+ negatively surface charged by transforming Cu2+ into EDDSCu2-. The chelation caused those left in S4 and S4 to migrate toward the bio-PRB, whereas it also caused those left in S1 and S2 to migrate toward the anode. Due to this reason, the fraction of Cu2+ removed by the bio-PRB and the electrolyte reservoir is raised to 32% and 26% respectively, and the fraction of remaining Cu was reduced to 41%. Also, the removal efficiency applied to Pb removal was raised to 50%. Results demonstrate the potential of struvite and EDDS-assisted EK-PRB technology as a cleanup method for Cu- and Pb-contaminated loess.
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Cobre , Plomo , Estruvita , Cobre/química , Plomo/química , Estruvita/química , Suelo/química , Succinatos/química , Contaminantes del Suelo/químicaRESUMEN
P2RX2 encodes the P2X2 receptor, which is an adenosine triphosphate (ATP) gated (purinoreceptor) ion channel. P2RX2 c. 178G > T (p.V60L) mutation was previously identified in two unrelated Chinese families, as the cause of human DFNA41, a form of dominant, early-onset and progressive sensorineural hearing loss. We generated and characterized a knock-in mouse model based on human p.V60L mutation that recapitulates the human phenotype. Heterozygous KI mice started to exhibit hearing loss at 21-day-old and progressed to deafness by 6-month-old. Vestibular dysfunction was also observed in mutant mice. Abnormal morphology of the inner hair cells and ribbon synapses was progressively observed in KI animals suggesting that P2rx2 plays a role in the membrane spatial location of the ribbon synapses. These results suggest that P2rx2 is essential for acoustic information transfer, which can be the molecular mechanism related to hearing loss.
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Pérdida Auditiva Sensorineural/genética , Receptores Purinérgicos P2X2/genética , Adenosina Trifosfato/metabolismo , Animales , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Células Ciliadas Auditivas Internas/patología , Pérdida Auditiva Sensorineural/patología , Heterocigoto , Humanos , Ratones , Mutación/genética , Linaje , Fenotipo , Sinapsis/genética , Sinapsis/patología , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/patologíaRESUMEN
It is an essential task to construct brain templates and analyze their anatomical structures in neurological and cognitive science. Generally, templates constructed from magnetic resonance imaging (MRI) of a group of subjects can provide a standard reference space for analyzing the structural and functional characteristics of the group. With recent development of artificial intelligence (AI) techniques, it is desirable to explore AI registration methods for quantifying age-specific brain variations and tendencies across different ages. In this article, we present an AI-based age-specific template construction (called ASTC) framework for longitudinal structural brain analysis using T1-weighted MRIs of 646 subjects from 18 to 82 years old collected from four medical centers. Altogether, 13 longitudinal templates were constructed at a 5-year age interval using ASTC, and tissue segmentation and substructure parcellation were performed for analysis across different age groups. The results indicated consistent changes in brain structures along with aging and demonstrated the capability of ASTC for longitudinal neuroimaging study.
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Inteligencia Artificial , Encéfalo , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Inteligencia , Factores de Edad , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
MiR-1283 has been identified as a tumor suppressor in some malignancies. Whereas, the role of miR-1283 in HER2-positive (HER2+) breast cancer, particularly its role in regulating cell proliferation, one of the most significant features of tumor progression, is unclear. The related microRNA screened by the breast cancer sample GSE131599 dataset were detected in HER2+ breast cancer tissues and cell lines. Then, the obtained miR-1283 was overexpressed in SKBR3 and BT-474 cells followed by relevant functional assays concerning cell proliferation and apoptosis. The xenograft mouse model was induced and the effect of miR-1283 on tumor growth and cell proliferation was examined. The target of miR-1283 and the transcription factor regulating miR-1283 were predicted and identified. Finally, the influence of transcription factor KLF14 on cell proliferation and apoptosis was investigated. An integrated analysis confirmed that miR-1283 expression was significantly decreased in HER2+ breast cancer tissues. Also, by q-RT-PCR detection, miR-1283 expression was markedly reduced in HER2+ breast cancer tissues and cell lines. The miR-1283 overexpression prevented the proliferation and enhanced apoptosis of HER2+ breast cancer cells, as well as inhibited tumor growth. Mechanistically, miR-1283 inhibited TFAP2C expression by targeting the 3'-untranslated regions of TFAP2C messenger RNA, and the KLF14 enhanced miR-1283 level via binding to its promoter. The result subsequently confirmed the KLF14/miR-1283 signaling suppressed cell proliferation in HER2+ breast cancer. Our results suggested that the KLF14/miR-1283/TFAP2C axis inhibited HER2+ breast cancer progression, which might provide novel insight into mechanical exploration for this disease.
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Neoplasias de la Mama , MicroARNs , Humanos , Animales , Ratones , Femenino , Línea Celular Tumoral , Neoplasias de la Mama/metabolismo , MicroARNs/metabolismo , Proliferación Celular/genética , Factores de Transcripción/genética , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factor de Transcripción AP-2/genéticaRESUMEN
Friend leukemia virus integration 1 (Fli-1) is an ETS transcription factor and a critical regulator of inflammatory mediators, including MCP-1, CCL5, IL-6, G-CSF, CXCL2, and caspase-1. GM-CSF is a regulator of granulocyte and macrophage lineage differentiation and a key player in the pathogenesis of inflammatory/autoimmune diseases. In this study, we demonstrated that Fli-1 regulates the expression of GM-CSF in both T cells and endothelial cells. The expression of GM-CSF was significantly reduced in T cells and endothelial cells when Fli-1 was reduced. We found that Fli-1 binds directly to the GM-CSF promoter using chromatin immunoprecipitation assay. Transient transfection assays indicated that Fli-1 drives transcription from the GM-CSF promoter in a dose-dependent manner, and mutation of the Fli-1 DNA binding domain resulted in a significant loss of transcriptional activation. Mutation of a known phosphorylation site within the Fli-1 protein led to a significant increase in GM-CSF promoter activation. Thus, direct binding to the promoter and phosphorylation are two important mechanisms behind Fli-1-driven activation of the GM-CSF promoter. In addition, Fli-1 regulates GM-CSF expression in an additive manner with another transcription factor Sp1. Finally, we demonstrated that a low dose of a chemotherapeutic drug, camptothecin, inhibited expression of Fli-1 and reduced GM-CSF production in human T cells. These results demonstrate novel mechanisms for regulating the expression of GM-CSF and suggest that Fli-1 is a critical druggable regulator of inflammation and immunity.
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Endotelio/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Proteína Proto-Oncogénica c-fli-1/metabolismo , Linfocitos T/fisiología , Animales , Camptotecina/farmacología , Endotelio/patología , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Humanos , Células Jurkat , Ratones , Terapia Molecular Dirigida , Células 3T3 NIH , Regiones Promotoras Genéticas/genética , Proteína Proto-Oncogénica c-fli-1/genética , ARN Interferente Pequeño/genética , Factor de Transcripción Sp1/genética , Linfocitos T/efectos de los fármacos , Inhibidores de Topoisomerasa I/farmacologíaRESUMEN
Lead (Pb) accumulation can lead to serious threats to surrounding environments and damage to the liver and kidneys. In the past few years, microbial-induced carbonate precipitation (MICP) technology has been widely applied to achieve Pb immobilization due to its environmentally friendly nature. However, harsh pH conditions can cause the instability of the carbonate precipitation to degrade or dissolve, increasing the potential of Pb2+ migration into nearby environments. In this study, microcapsule-based self-healing microbial-induced calcium carbonate (MICC) materials were applied to prevent Pb migration. The highest sporulation rate of 95.8% was attained at 7 g/L yeast extract, 10 g/L NH4Cl, and 3.6 g/L Mn2+. In the germination phase, the microcapsule not only prevented the bacterial spores from being threatened by the acid treatment but secured their growth and reproduction. Micro analysis also revealed that cerussite, calcite, and aragonite minerals were present, while extracellular polymeric substances (EPSs) were identified via Fourier transform infrared spectroscopy (FTIR). These results confirm their involvement in combining Pb2+ and Ca2+. The immobilization efficiency of above 90% applied to MICC materials was attained, while it of below 5% applied to no MICC use was attained. The findings explore the potential of applying microcapsule-based self-healing MICC materials to prevent Pb ion migration when the calcium carbonate degrades under harsh pH conditions.
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Carbonato de Calcio , Plomo , Carbonato de Calcio/química , Carbonato de Calcio/metabolismo , Cápsulas , Carbonatos , MineralesRESUMEN
BACKGROUND: The value of radiomics features from the adrenal gland and periadrenal fat CT images for predicting disease progression in patients with COVID-19 has not been studied extensively. We assess the value of radiomics features from the adrenal gland and periadrenal fat CT images in predicting COVID-19 disease exacerbation. METHODS: A total of 1,245 patients (685 moderate and 560 severe patients) were enrolled in a retrospective study. We proposed a 3D V-net to segment adrenal glands in onset CT images automatically, and periadrenal fat was obtained using inflation operation around the adrenal gland. Next, we built a clinical model (CM), three radiomics models (adrenal gland model [AM], periadrenal fat model [PM], and fusion of adrenal gland and periadrenal fat model [FM]), and radiomics nomogram (RN) after radiomics features extracted. RESULTS: The auto-segmentation framework yielded a dice value 0.79 in the training set. CM, AM, PM, FM, and RN obtained AUCs of 0.717, 0.716, 0.736, 0.760, and 0.833 in the validation set. FM and RN had better predictive efficacy than CM (P < 0.0001) in the training set. RN showed that there was no significant difference in the validation set (mean absolute error [MAE] = 0.04) and test set (MAE = 0.075) between predictive and actual results. Decision curve analysis showed that if the threshold probability was between 0.4 and 0.8 in the validation set or between 0.3 and 0.7 in the test set, it could gain more net benefits using RN than FM and CM. CONCLUSIONS: Radiomics features extracted from the adrenal gland and periadrenal fat CT images are related to disease exacerbation in patients with COVID-19.
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COVID-19 , Humanos , Estudios Retrospectivos , COVID-19/diagnóstico por imagen , Glándulas Suprarrenales/diagnóstico por imagen , Progresión de la Enfermedad , Atención a la Salud , Tomografía Computarizada por Rayos XRESUMEN
To develop a deep learning-based model for detecting rib fractures on chest X-Ray and to evaluate its performance based on a multicenter study. Chest digital radiography (DR) images from 18,631 subjects were used for the training, testing, and validation of the deep learning fracture detection model. We first built a pretrained model, a simple framework for contrastive learning of visual representations (simCLR), using contrastive learning with the training set. Then, simCLR was used as the backbone for a fully convolutional one-stage (FCOS) objective detection network to identify rib fractures from chest X-ray images. The detection performance of the network for four different types of rib fractures was evaluated using the testing set. A total of 127 images from Data-CZ and 109 images from Data-CH with the annotations for four types of rib fractures were used for evaluation. The results showed that for Data-CZ, the sensitivities of the detection model with no pretraining, pretrained ImageNet, and pretrained DR were 0.465, 0.735, and 0.822, respectively, and the average number of false positives per scan was five in all cases. For the Data-CH test set, the sensitivities of three different pretraining methods were 0.403, 0.655, and 0.748. In the identification of four fracture types, the detection model achieved the highest performance for displaced fractures, with sensitivities of 0.873 and 0.774 for the Data-CZ and Data-CH test sets, respectively, with 5 false positives per scan, followed by nondisplaced fractures, buckle fractures, and old fractures. A pretrained model can significantly improve the performance of the deep learning-based rib fracture detection based on X-ray images, which can reduce missed diagnoses and improve the diagnostic efficacy.
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Fracturas de las Costillas , Humanos , Fracturas de las Costillas/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Rayos X , Radiografía , Estudios RetrospectivosRESUMEN
Although the electrokinetic (EK) remediation has drawn great attention because of its good maneuverability, the focusing phenomenon near the cathode and low removal efficiency remain to be addressed. In this study, a novel EK reactor was proposed to remediate Cu and Pb contaminated loess where a biological permeable reactive barrier (bio-PRB) was deployed to the middle of the EK reactor. For comparison, three test configurations, namely, CG, TG-1, and TG-2, were available. CG considered the multiple enzyme-induced carbonate precipitation (EICP) treatments, while TG-1 considered both the multiple EICP treatments and pH regulation. TG-2 further considered NH4+ recovery based on TG-1. CG not only improved Cu and Pb removals by the bio-PRB but also depressed the focusing phenomenon. TG-1 causes more Cu2+ and Pb2+ to migrate toward the bio-PRB and aggravates Cu and Pb removals by the bio-PRB, depressing the focusing phenomenon. TG-2 depressed the focusing phenomenon the most because Cu2+ and Pb2+ can combine with not only CO32- but PO43-. The removal efficiency of Cu and Pb is 34% and 36%, respectively. A NH4+ recovery of about 100% is attained.
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Restauración y Remediación Ambiental , Contaminantes del Suelo , Plomo , Tecnología , Contaminantes del Suelo/análisis , SueloRESUMEN
Objective This consensus aims to provide evidence-based recommendations on common questions in the diagnosis and treatment of acute respiratory failure (ARF) for critically ill cancer patients.Methods We developed six clinical questions using the PICO (Population, Intervention, Comparison, and Outcome) principle in diagnosis and treatment for critical ill cancer patients with ARF. Based on literature searching and meta-analyses, recommendations were devised. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) method was applied to each question to reach consensus in the expert panel. Results The panel makes strong recommendations in favor of (1) metagenomic next-generation sequencing (mNGS) tests may aid clinicians in rapid diagnosis in critically ill cancer patients suspected of pulmonary infections; (2) extracorporeal membrane oxygenation (ECMO) therapy should not be used as a routine rescue therapy for acute respiratory distress syndrome in critically ill cancer patients but may benefit highly selected patients after multi-disciplinary consultations; (3) cancer patients who have received immune checkpoint inhibitor therapy have an increased incidence of pneumonitis compared with standard chemotherapy; (4) critically ill cancer patients who are on invasive mechanical ventilation and estimated to be extubated after 14 days may benefit from early tracheotomy; and (5) high-flow nasal oxygen and noninvasive ventilation therapy can be used as a first-line oxygen strategy for critically ill cancer patients with ARFs. A weak recommendation is: (6) for critically ill cancer patients with ARF caused by tumor compression, urgent chemotherapy may be considered as a rescue therapy only in patients determined to be potentially sensitive to the anticancer therapy after multidisciplinary consultations. Conclusions The recommendations based on the available evidence can guide diagnosis and treatment in critically ill cancer patients with acute respiratory failure and improve outcomes.