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1.
Cell ; 180(1): 50-63.e12, 2020 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-31923399

RESUMEN

Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.


Asunto(s)
Inmunidad Mucosa/inmunología , Interleucina-18/inmunología , Mucosa Intestinal/inmunología , Animales , Citocinas/inmunología , Sistema Nervioso Entérico/inmunología , Sistema Nervioso Entérico/metabolismo , Células Epiteliales/inmunología , Femenino , Células Caliciformes/inmunología , Interleucina-18/biosíntesis , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/inmunología , Ratas , Ratas Sprague-Dawley , Infecciones por Salmonella/inmunología , Salmonella typhimurium/inmunología , Transducción de Señal/inmunología
2.
Cell ; 176(1-2): 334-347.e12, 2019 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-30580966

RESUMEN

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.


Asunto(s)
Antígenos CD/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiología , Animales , Antígenos CD/inmunología , Línea Celular , Fibrinógeno/inmunología , Fibrinógeno/metabolismo , Genes MHC Clase II/genética , Genes MHC Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunoterapia , Ligandos , Hígado/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Neoplasias/genética , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Proteína del Gen 3 de Activación de Linfocitos
4.
Nature ; 628(8006): 204-211, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38418880

RESUMEN

The eye, an anatomical extension of the central nervous system (CNS), exhibits many molecular and cellular parallels to the brain. Emerging research demonstrates that changes in the brain are often reflected in the eye, particularly in the retina1. Still, the possibility of an immunological nexus between the posterior eye and the rest of the CNS tissues remains unexplored. Here, studying immune responses to herpes simplex virus in the brain, we observed that intravitreal immunization protects mice against intracranial viral challenge. This protection extended to bacteria and even tumours, allowing therapeutic immune responses against glioblastoma through intravitreal immunization. We further show that the anterior and posterior compartments of the eye have distinct lymphatic drainage systems, with the latter draining to the deep cervical lymph nodes through lymphatic vasculature in the optic nerve sheath. This posterior lymphatic drainage, like that of meningeal lymphatics, could be modulated by the lymphatic stimulator VEGFC. Conversely, we show that inhibition of lymphatic signalling on the optic nerve could overcome a major limitation in gene therapy by diminishing the immune response to adeno-associated virus and ensuring continued efficacy after multiple doses. These results reveal a shared lymphatic circuit able to mount a unified immune response between the posterior eye and the brain, highlighting an understudied immunological feature of the eye and opening up the potential for new therapeutic strategies in ocular and CNS diseases.


Asunto(s)
Encéfalo , Ojo , Sistema Linfático , Animales , Femenino , Humanos , Masculino , Ratones , Conejos , Bacterias/inmunología , Encéfalo/anatomía & histología , Encéfalo/inmunología , Dependovirus/inmunología , Ojo/anatomía & histología , Ojo/inmunología , Glioblastoma/inmunología , Herpesvirus Humano 2/inmunología , Inyecciones Intravítreas , Sistema Linfático/anatomía & histología , Sistema Linfático/inmunología , Vasos Linfáticos/anatomía & histología , Vasos Linfáticos/inmunología , Macaca mulatta , Meninges/inmunología , Nervio Óptico/inmunología , Porcinos , Pez Cebra , Factor C de Crecimiento Endotelial Vascular/inmunología , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacología
5.
Nature ; 595(7866): 283-288, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34010947

RESUMEN

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses1-6. Although pathological innate immune activation is well-documented in severe disease1, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling7 to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.


Asunto(s)
Autoanticuerpos/análisis , Autoanticuerpos/inmunología , COVID-19/inmunología , COVID-19/metabolismo , Proteoma/inmunología , Proteoma/metabolismo , Animales , Antígenos de Superficie/inmunología , COVID-19/patología , COVID-19/fisiopatología , Estudios de Casos y Controles , Proteínas del Sistema Complemento/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Ratones , Especificidad de Órganos/inmunología
6.
Am J Hum Genet ; 110(7): 1162-1176, 2023 07 06.
Artículo en Inglés | MEDLINE | ID: mdl-37352861

RESUMEN

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.


Asunto(s)
Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patología , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Estudios de Asociación Genética , Polimorfismo de Nucleótido Simple/genética , Proteínas de Homeodominio/genética
7.
Nature ; 583(7817): 609-614, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32581358

RESUMEN

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials3. Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a 'decoy-resistant' IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8+ T cells, decreasing the prevalence of exhausted CD8+ T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1+ precursor CD8+ T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.


Asunto(s)
Inmunoterapia , Péptidos y Proteínas de Señalización Intercelular/inmunología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucina-18/inmunología , Neoplasias/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Modelos Animales de Enfermedad , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Estimación de Kaplan-Meier , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/inmunología , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones , Receptores de Interleucina-18/metabolismo , Células Madre/citología , Células Madre/efectos de los fármacos , Células Madre/inmunología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología
8.
J Biol Chem ; 300(3): 105765, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38367667

RESUMEN

CLEC12A, a member of the C-type lectin receptor family involved in immune homeostasis, recognizes MSU crystals released from dying cells. However, the molecular mechanism underlying the CLEC12A-mediated recognition of MSU crystals remains unclear. Herein, we reported the crystal structure of the human CLEC12A-C-type lectin-like domain (CTLD) and identified a unique "basic patch" site on CLEC12A-CTLD that is necessary for the binding of MSU crystals. Meanwhile, we determined the interaction strength between CLEC12A-CTLD and MSU crystals using single-molecule force spectroscopy. Furthermore, we found that CLEC12A clusters at the cell membrane and seems to serve as an internalizing receptor of MSU crystals. Altogether, these findings provide mechanistic insights for understanding the molecular mechanisms underlying the interplay between CLEC12A and MSU crystals.


Asunto(s)
Lectinas Tipo C , Receptores Mitogénicos , Ácido Úrico , Humanos , Gota/metabolismo , Lectinas Tipo C/química , Lectinas Tipo C/inmunología , Receptores Mitogénicos/química , Receptores Mitogénicos/inmunología , Ácido Úrico/química , Ácido Úrico/inmunología , Dominios Proteicos , Cristalografía por Rayos X , Imagen Individual de Molécula , Línea Celular
9.
Nano Lett ; 24(15): 4400-4407, 2024 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-38568187

RESUMEN

We developed a magnesium/sodium (Mg/Na) hybrid battery using a hierarchical disk-whisker FeSe2 architecture (HD-FeSe2) as the cathode material and a modified dual-ion electrolyte. The polarizable Se2- anion reduced the Mg2+ migration barrier, and the 3D configuration possessed a large surface area, which facilitated both Mg2+/Na+ cation diffusion and electron transport. The dual-ion salts with NaTFSI in ether reduced the Mg plating/stripping overvoltage in a symmetric cell. The hybrid battery exhibited an energy density of 260.9 Wh kg-1 and a power density of 600.8 W kg-1 at 0.2 A g-1. It showed a capacity retention of 154 mAh g-1 and a Coulombic efficiency of over 99.5% under 1.0 A g-1 after 800 long cycles. The battery also displayed outstanding temperature tolerance. The findings of 3D architecture as cathode material and hybrid electrolyte provide a pathway to design a highly reliable Mg/Na hybrid battery.

10.
Genes Chromosomes Cancer ; 63(6): e23252, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39133763

RESUMEN

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive mature T-cell malignancy characterized by marked lymphocytosis, B symptoms, lymphadenopathy, and hepatosplenomegaly. There is no standard treatment approach, and in the absence of an allogeneic transplant, the prognosis remains poor. The disease-defining cytogenetic abnormality in T-PLL is the juxtaposition of the TCL1-family oncogene to the TCR gene enhancer locus primarily due to an inversion of chromosome 14, that is, inv(14). The application of next-generation sequencing technologies led to the discovery of highly recurrent gain-of-function mutations in JAK1/3 and STAT5B in over 70% of T-PLL providing opportunities for therapeutic intervention using small molecule inhibitors. Additional genetic mechanisms that may contribute to the pathogenesis of T-PLL remain unknown. Herein we describe the identification of a novel gene fusion SMCHD1::JAK2 resulting from a translocation between chromosome 9 and 18 involving SMCHD1 exon 45 and JAK2 exon 14 (t(9;18)(p24.1;p11.32)(chr9:g.5080171::chr18:g.2793269)), a previously undescribed genetic event in a patient with T-PLL harboring the key disease defining inv(14) resulting in rearrangement of TCL1 and TRA/D. In this manuscript, we describe the clinical and genetic features of the patient's disease course over a 25-month post-treatment duration using ruxolitinib and duvelisib.


Asunto(s)
Janus Quinasa 2 , Leucemia Prolinfocítica de Células T , Humanos , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/patología , Janus Quinasa 2/genética , Proteínas de Fusión Oncogénica/genética , Masculino , Translocación Genética , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Persona de Mediana Edad , Nitrilos/uso terapéutico , Cromosomas Humanos Par 9/genética
11.
Lancet Oncol ; 25(7): 901-911, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38823410

RESUMEN

BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Asunto(s)
Anticuerpos Biespecíficos , Receptores ErbB , Inmunoconjugados , Neoplasias , Receptor ErbB-3 , Humanos , Persona de Mediana Edad , Masculino , Femenino , Anticuerpos Biespecíficos/administración & dosificación , Anticuerpos Biespecíficos/efectos adversos , Anticuerpos Biespecíficos/uso terapéutico , Anciano , Adulto , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/inmunología , Receptor ErbB-3/antagonistas & inhibidores , Receptor ErbB-3/inmunología , Adulto Joven , Dosis Máxima Tolerada , Adolescente , Metástasis de la Neoplasia , China , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico
12.
J Proteome Res ; 23(7): 2619-2628, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38910295

RESUMEN

Chromatography-mass spectrometry-based lipidomics represents an essential tool for elucidating lipid dysfunction mechanisms and is extensively employed in investigating disease mechanisms and identifying biomarkers. However, the detection of low-abundance lipids in biological matrices, along with cumbersome operational procedures, complicates comprehensive lipidomic analyses, necessitating the development of highly sensitive, environmentally friendly, and automated methods. In this study, an online phase transition trapping-supercritical fluid extraction-chromatography-mass spectrometry (PTT-SFEC-MS/MS) method was developed and successfully applied to plasma lipidomics analysis in Type 1 diabetes (T1D) rats. The PTT strategy captured entire extracts at the column head by converting CO2 from a supercritical state to a gaseous state, thereby preventing peak spreading, enhancing peak shape for precise quantification, and boosting sensitivity without any sample loss. This method utilized only 5 µL of plasma and accomplished sample extraction, separation, and detection within 27 min. Ultimately, 77 differential lipids were identified, including glycerophospholipids, sphingolipids, and glycerolipids, in T1D rat plasma. The results indicated that the progression of the disease might be linked to alterations in glycerophospholipid and sphingolipid metabolism. Our findings demonstrated a green, highly efficient, and automated method for the lipidomics analysis of biological samples, providing a scientific foundation for understanding the pathogenesis and diagnosis of T1D.


Asunto(s)
Cromatografía con Fluido Supercrítico , Diabetes Mellitus Tipo 1 , Lipidómica , Espectrometría de Masas en Tándem , Animales , Lipidómica/métodos , Espectrometría de Masas en Tándem/métodos , Ratas , Cromatografía con Fluido Supercrítico/métodos , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/metabolismo , Lípidos/sangre , Lípidos/química , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratas Sprague-Dawley , Transición de Fase , Biomarcadores/sangre , Esfingolípidos/sangre , Esfingolípidos/análisis , Esfingolípidos/aislamiento & purificación
13.
Cancer Sci ; 115(1): 83-93, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37985391

RESUMEN

Autoantibodies (AAbs) in the blood of colorectal cancer (CRC) patients have been evaluated for tumor detection. However, it remains uncertain whether these AAbs are specific to tumor-associated antigens. In this study, we explored the IgG and IgM autoantibody repertoires in both the in situ tissue microenvironment and peripheral blood as potential tumor-specific biomarkers. We applied high-density protein arrays to profile AAbs in the tumor-infiltrating lymphocyte supernatants and corresponding serum from four patients with CRC, as well as in the serum of three noncancer controls. Our findings revealed that there were more reactive IgM AAbs than IgG in both the cell supernatant and corresponding serum, with a difference of approximately 3-5 times. Immunoglobulin G was predominant in the serum, while IgM was more abundant in the cell supernatant. We identified a range of AAbs present in both the supernatant and the corresponding serum, numbering between 432 and 780, with an average of 53.3% shared. Only 4.7% (n = 23) and 0.2% (n = 2) of reactive antigens for IgG and IgM AAbs, respectively, were specific to CRC. Ultimately, we compiled a list of 19 IgG AAb targets as potential tumor-specific AAb candidates. Autoantibodies against one of the top candidates, p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A (RPRD1A), were significantly elevated in 53 CRC patients compared to 119 controls (p < 0.0001). The project revealed that tissue-derived IgG AAbs, rather than IgM, are the primary source of tumor-specific AAbs in peripheral blood. It also identified potential tumor-specific AAbs that could be applied for noninvasive screening of CRC.


Asunto(s)
Autoanticuerpos , Neoplasias Colorrectales , Humanos , Biomarcadores de Tumor , Inmunoglobulina G , Inmunoglobulina M , Microambiente Tumoral , Proteínas Represoras , Proteínas de Ciclo Celular
14.
Cancer Sci ; 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39192543

RESUMEN

Plasma levels of oncofetal chondroitin sulfate (ofCS)-modified CD44 have emerged as a promising biomarker for multi-cancer detection. Here, we explored its potential to predict the survival of patients with lung cancer. A prospective observational cohort was conducted involving 274 newly diagnosed patients with lung cancer at the Sun Yat-sen University Cancer Center from 2013 to 2015. The plasma levels of ofCS-modified CD44 were measured, and Cox regression analysis was performed to assess the association between plasma-modified CD44 levels and overall survival (OS) as well as other prognostic outcomes. Prognostic nomograms were constructed based on plasma ofCS-modified CD44 levels to predict survival outcomes for patients with lung cancer. Patients with high expression ofCS-modified CD44 exhibited significantly worse outcomes in terms of OS (HR = 1.61, 95%CI = 1.13-2.29, p = 0.009) and progression-free survival (PFS). These findings were consistent across various analyses. The concordance index of the prognostic nomogram for predicting OS in both the training set and validation set were 0.723 and 0.737, respectively. Additionally, time-dependent receiver operating characteristic (ROC) curves showed that the nomogram could serve as a useful tool for predicting OS in patients with lung cancer. Plasma ofCS-modified CD44 may serve as an independent prognosis marker for patients with lung cancer. Further validation of its predictive value could enhance prognostic assessment and guide personalized treatment strategies for patients with lung cancer.

15.
EMBO J ; 39(10): e103111, 2020 05 18.
Artículo en Inglés | MEDLINE | ID: mdl-32187724

RESUMEN

The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Beclina-1/metabolismo , Quinasa de Punto de Control 2/metabolismo , Accidente Cerebrovascular Isquémico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Autofagia , Línea Celular , Modelos Animales de Enfermedad , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Ratones , Estrés Oxidativo , Fosforilación
16.
Mol Med ; 30(1): 70, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38789926

RESUMEN

BACKGROUND: The development of pulmonary fibrosis involves a cascade of events, in which inflammation mediated by immune cells plays a pivotal role. Chemotherapeutic drugs have been shown to have dual effects on fibrosis, with bleomycin exacerbating pulmonary fibrosis and bortezomib alleviating tissue fibrotic processes. Understanding the intricate interplay between chemotherapeutic drugs, immune responses, and pulmonary fibrosis is likely to serve as the foundation for crafting tailored therapeutic strategies. METHODS: A model of bleomycin-induced pulmonary fibrosis was established, followed by treatment with bortezomib. Tissue samples were collected for analysis of immune cell subsets and functional assessment by flow cytometry and in vitro cell experiments. Additionally, multi-omics analysis was conducted to further elucidate the expression of chemokines and chemokine receptors, as well as the characteristics of cell populations. RESULTS: Here, we observed that the expression of CXCL16 and CXCR6 was elevated in the lung tissue of a pulmonary fibrosis model. In the context of pulmonary fibrosis or TGF-ß1 stimulation in vitro, macrophages exhibited an M2-polarized phenotype and secreted more CXCL16 than those of the control group. Moreover, flow cytometry revealed increased expression levels of CD69 and CXCR6 in pulmonary CD4 T cells during fibrosis progression. The administration of bortezomib alleviated bleomycin-induced pulmonary fibrosis, accompanied by reduced ratio of M2-polarized macrophages and decreased accumulation of CD4 T cells expressing CXCR6. CONCLUSIONS: Our findings provide insights into the key immune players involved in bleomycin-induced pulmonary fibrosis and offer preclinical evidence supporting the repurposing strategy and combination approaches to reduce lung fibrosis.


Asunto(s)
Bleomicina , Bortezomib , Linfocitos T CD4-Positivos , Quimiocina CXCL16 , Fibrosis Pulmonar , Receptores CXCR6 , Animales , Masculino , Ratones , Antígenos CD , Antígenos de Diferenciación de Linfocitos T/metabolismo , Bleomicina/efectos adversos , Bortezomib/farmacología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Quimiocina CXCL16/metabolismo , Quimiotaxis/efectos de los fármacos , Modelos Animales de Enfermedad , Lectinas Tipo C , Macrófagos/metabolismo , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/tratamiento farmacológico , Receptores CXCR6/metabolismo
17.
Anal Chem ; 96(28): 11189-11197, 2024 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-38965741

RESUMEN

Lipids play integral roles in biological processes, with carbon-carbon double bonds (C═C) markedly influencing their structure and function. Precise characterization and quantification of unsaturated lipids are crucial for understanding lipid physiology and discovering disease biomarkers. However, using mass spectrometry for these purposes presents significant challenges. In this study, we developed a microwave-assisted magnesium monoperoxyphthalate hexahydrate (MMPP) epoxidation reaction, coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS), to analyze unsaturated lipids. Microwave irradiation expedited the MMPP epoxidation, achieving complete derivatization in 10 min without byproducts. A diagnostic ion pair, displaying a 16 Da mass difference, effectively identified the location of the C═C bond in mass spectra. Microwave irradiation also significantly facilitated the epoxidation reaction of polyunsaturated lipids, achieving yields greater than 85% and yielding a complete epoxidation product. This simplifies chromatographic separation and aids in accurate quantification. Additionally, a purification process was implemented to remove excess derivatization reagents, significantly reducing mass spectrometry response suppression and enhancing analytical reproducibility. The method's effectiveness was validated by analyzing unsaturated lipids in rat plasma from a type I diabetes model. We quantified nine unsaturated lipids and characterized 42 fatty acids and glycerophospholipids. The results indicated that unsaturated fatty acids increased in diabetic plasma while unsaturated glycerophospholipids decreased. Furthermore, the relative abundances of Δ9/Δ11 isomer pairs also exhibited a close association with diabetes. In conclusion, microwave-assisted MMPP epoxidation coupled with LC-MS/MS provides an effective strategy for characterization and quantification of polyunsaturated lipids, offering deeper insight into the physiological impact of unsaturated lipids in related diseases.


Asunto(s)
Microondas , Espectrometría de Masas en Tándem , Animales , Ratas , Espectrometría de Masas en Tándem/métodos , Compuestos Epoxi/química , Masculino , Ácidos Grasos Insaturados/química , Ácidos Grasos Insaturados/análisis , Ácidos Grasos Insaturados/sangre , Cromatografía Liquida/métodos , Ratas Sprague-Dawley
18.
Cancer Immunol Immunother ; 73(5): 76, 2024 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-38554213

RESUMEN

BACKGROUND: Tumor microenvironment actually reduces antitumor effect against the immune attack by exclusion of CD8+T cells. Progranulin (PGRN) is a multifunctional growth factor with significant pathological effects in multiple tumors; however, its role in immunity evasion of breast cancer (BCa) is not completely understood. METHODS: We depleted GRN (PGRN gene) genetically in mice or specifically in PY8119 murine BCa cell line, and mouse models of orthotopic or subcutaneous transplantation were used. Chimeric mice-deficient of PGRN (Grn-/-) in bone marrow (BM) compartment was also generated. Association of PGRN expression with chemokine production or BCa development was investigated by histological and immunological assays. RESULTS: We found PGRN was involved in exhaustion of cytotoxic CD8+T cell in BCa with the increasing expressions of M2 markers and intercellular cell adhesion molecule-1 (ICAM-1) on macrophages. Specifically, ablation of PGRN in PY8119 cells reduced tumor burden, accompanied by the infiltrating of cytotoxic CD8+T cells into tumor nests. Moreover, our result revealed that blockade of PD-1 in PGRN-depleted tumors exhibited better antitumor effect in vivo and significantly decreased tumor burden. CONCLUSION: These findings suggest that inhibition of PGRN may act as a potential immune-therapeutic strategy by recovering infiltration of CD8+T cell in BCa tissue and thereby enhancing the response to anti-PD-1 therapy.


Asunto(s)
Molécula 1 de Adhesión Intercelular , Neoplasias , Animales , Ratones , Linfocitos T CD8-positivos , Línea Celular Tumoral , Molécula 1 de Adhesión Intercelular/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Progranulinas/genética , Microambiente Tumoral
19.
BMC Plant Biol ; 24(1): 547, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38872092

RESUMEN

BACKGROUND: Plant growth and development are severely threatened by drought and salt stresses. Compared with structural genes, transcription factors (TFs) play more pivotal roles in plant growth and stress adaptation. However, the underlying mechanisms of sorghum adapting to drought and salt are insufficient, and systematic analysis of TFs in response to the above stresses is lacking. RESULTS: In this study, TFs were identified in sorghum and model plants (Arabidopsis thaliana and rice), and gene number and conserved domain were compared between sorghum and model plants. According to syntenic analysis, the expansion of sorghum and rice TFs may be due to whole-genome duplications. Between sorghum and model plants TFs, specific conserved domains were identified and they may be related to functional diversification of TFs. Forty-five key genes in sorghum, including four TFs, were likely responsible for drought adaption based on differently expression analysis. MiR5072 and its target gene (Sobic.001G449600) may refer to the determination of sorghum drought resistance according to small RNA and degradome analysis. Six genes were associated with drought adaptation of sorghum based on weighted gene co-expression network analysis (WGCNA). Similarly, the core genes in response to salt were also characterized using the above methods. Finally, 15 candidate genes, particularly two TFs (Sobic.004G300300, HD-ZIP; Sobic.003G244100, bZIP), involved in combined drought and salt resistance of sorghum were identified. CONCLUSIONS: In summary, the findings in this study help clarify the molecular mechanisms of sorghum responding to drought and salt. We identified candidate genes and provide important genetic resource for potential development of drought-tolerant and salt-tolerant sorghum plants.


Asunto(s)
Sequías , ARN Mensajero , Sorghum , Factores de Transcripción , Sorghum/genética , Sorghum/fisiología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulación de la Expresión Génica de las Plantas , Oryza/genética , Oryza/fisiología , Estrés Salino/genética , ARN de Planta/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genes de Plantas , Análisis de Secuencia de ARN
20.
BMC Med ; 22(1): 390, 2024 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-39272142

RESUMEN

BACKGROUND: Sleep and physical activity (PA) are thought to be interconnected with the development of rheumatoid arthritis (RA). However, the precise nature and extent of these relationships have yet to be fully quantified. This study aimed to quantify the longitudinal effects of sleep behaviors, PA, and genetic susceptibility on the incidence of RA and to estimate the combined effects and interactions among these exposures. METHODS: A total of 363,211 adults were derived from a large European cohort. We incorporated five sleep behaviors (sleep duration, insomnia, snoring, chronotype, and daytime sleepiness) to generate sleep patterns, which were defined based on healthy sleep scores. Multivariate-adjusted Cox proportional hazard models were conducted to assess the individual and combined associations of sleep patterns, PA, and genetic susceptibility with the risk of RA occurrence. Multiplicative and additive interactions were estimated by Pinteraction and relative excess risk due to interaction (RERI) between each of the two exposures. RESULTS: During a follow-up of 12.5 years, 4262 RA cases were ascertained. A healthy sleep pattern was associated with a decreased risk of RA in a dose-response manner, with an adjusted hazard ratio (HR) of 0.79 (95% confidence interval [CI] = 0.75-0.84), independent of traditional risk factors and genetic predisposition. Under the restricted cubic splines model, a non-linear association was detected for PA and RA risk. Participants in the intermediate quintile 3 showed the lowest risk for developing RA, with a HR 95% CI of 0.84 (0.76-0.92). Moreover, there was an additive interaction effect of intermediate sleep pattern and PA, with a 0.45 (95% CI = 0.02-0.87) RERI of developing RA. Additionally, individuals at high genetic risk had the greatest 10-year absolute risk reduction (10.58 per 1000 person-years) when adopting both favorable behaviors. CONCLUSIONS: A healthy sleep pattern and moderate PA were associated with a reduced risk of developing RA, which can offset the deleterious effects of predisposing genetic components. Implementing these modifiable lifestyle factors into public health practices is beneficial for RA prevention.


Asunto(s)
Artritis Reumatoide , Ejercicio Físico , Predisposición Genética a la Enfermedad , Sueño , Humanos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/genética , Masculino , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Sueño/fisiología , Adulto , Ejercicio Físico/fisiología , Incidencia , Anciano , Factores de Riesgo , Europa (Continente)/epidemiología , Estudios de Cohortes
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