RESUMEN
The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.
Asunto(s)
Inmunoterapia/métodos , Linfocitos/inmunología , Neoplasias/terapia , Neovascularización Patológica/terapia , Microambiente Tumoral/inmunología , Secuencia de Aminoácidos , Animales , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/farmacología , Resistencia a Antineoplásicos/inmunología , Quimioterapia Combinada , Linfocitos/metabolismo , Ratones Endogámicos C3H , Ratones Transgénicos , Neoplasias/irrigación sanguínea , Neoplasias/inmunología , Neovascularización Patológica/inmunología , Péptidos/administración & dosificación , Péptidos/genética , Péptidos/farmacología , Análisis de Supervivencia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/química , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genéticaRESUMEN
Niche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.
Asunto(s)
Cabello , Melanocitos , Transducción de Señal , Animales , Ratones , Cabello/citología , Cabello/crecimiento & desarrollo , Folículo Piloso/citología , Folículo Piloso/fisiología , Receptores de Hialuranos/metabolismo , Melanocitos/citología , Melanocitos/metabolismo , Nevo/metabolismo , Nevo/patología , Osteopontina/metabolismo , Células Madre/citologíaRESUMEN
Metabolic dysfunction-associated steatohepatitis (MASH, previously termed non-alcoholic steatohepatitis (NASH)), is a major complication of obesity that promotes fatty liver disease. MASH is characterized by progressive tissue fibrosis and sterile liver inflammation that can lead to liver cirrhosis, cancer, and death. The molecular mechanisms of fibrosis in MASH and its systemic control remain poorly understood. Here, we identified the secreted-type pro-fibrotic protein, procollagen C-endopeptidase enhancer-1 (PCPE-1), as a brown adipose tissue (BAT)-derived adipokine that promotes liver fibrosis in a murine obesity-induced MASH model. BAT-specific or systemic PCPE-1 depletion in mice ameliorated liver fibrosis, whereas, PCPE-1 gain of function in BAT enhanced hepatic fibrosis. High-calorie diet-induced ER stress increased PCPE-1 production in BAT through the activation of IRE-1/JNK/c-Fos/c-Jun signaling. Circulating PCPE-1 levels are increased in the plasma of MASH patients, suggesting a therapeutic possibility. In sum, our results uncover PCPE-1 as a novel systemic control factor of liver fibrosis.
RESUMEN
The use of particle accelerators as photon sources has enabled advances in science and technology1. Currently the workhorses of such sources are storage-ring-based synchrotron radiation facilities2-4 and linear-accelerator-based free-electron lasers5-14. Synchrotron radiation facilities deliver photons with high repetition rates but relatively low power, owing to their temporally incoherent nature. Free-electron lasers produce radiation with high peak brightness, but their repetition rate is limited by the driving sources. The steady-state microbunching15-22 (SSMB) mechanism has been proposed to generate high-repetition, high-power radiation at wavelengths ranging from the terahertz scale to the extreme ultraviolet. This is accomplished by using microbunching-enabled multiparticle coherent enhancement of the radiation in an electron storage ring on a steady-state turn-by-turn basis. A crucial step in unveiling the potential of SSMB as a future photon source is the demonstration of its mechanism in a real machine. Here we report an experimental demonstration of the SSMB mechanism. We show that electron bunches stored in a quasi-isochronous ring can yield sub-micrometre microbunching and coherent radiation, one complete revolution after energy modulation induced by a 1,064-nanometre-wavelength laser. Our results verify that the optical phases of electrons can be correlated turn by turn at a precision of sub-laser wavelengths. On the basis of this phase correlation, we expect that SSMB will be realized by applying a phase-locked laser that interacts with the electrons turn by turn. This demonstration represents a milestone towards the implementation of an SSMB-based high-repetition, high-power photon source.
RESUMEN
Protein S-acyl transferases (PATs) catalyze S-acylation, a reversible post-translational modification critical for membrane association, trafficking, and stability of substrate proteins. Many plant proteins are potentially S-acylated but few have corresponding PATs identified. By using genomic editing, confocal imaging, pharmacological, genetic, and biochemical assays, we demonstrate that three Arabidopsis class C PATs positively regulate BR signaling through S-acylation of BRASSINOSTEROID-SIGNALING KINASE1 (BSK1). PAT19, PAT20, and PAT22 associate with the plasma membrane (PM) and the trans-Golgi network/early endosome (TGN/EE). Functional loss of all three genes results in a plethora of defects, indicative of reduced BR signaling and rescued by enhanced BR signaling. PAT19, PAT20, and PAT22 interact with BSK1 and are critical for the S-acylation of BSK1, and for BR signaling. The PM abundance of BSK1 was reduced by functional loss of PAT19, PAT20, and PAT22 whereas abolished by its S-acylation-deficient point mutations, suggesting a key role of S-acylation in its PM targeting. Finally, an active BR analog induces vacuolar trafficking and degradation of PAT19, PAT20, or PAT22, suggesting that the S-acylation of BSK1 by the three PATs serves as a negative feedback module in BR signaling.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Proteínas Serina-Treonina Quinasas , Acilación , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Brasinoesteroides/metabolismo , Regulación de la Expresión Génica de las Plantas , Transducción de Señal , Transferasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X or X::RAR::Y-type tripartite fusions in certain RARA- and all RARG-aAPL cases, with shared features and notable differences between these two disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.
RESUMEN
We have identified a protein, Kif24, that shares homology with the kinesin-13 subfamily of motor proteins and specifically interacts with CP110 and Cep97, centrosomal proteins that play a role in regulating centriolar length and ciliogenesis. Kif24 preferentially localizes to mother centrioles. Loss of Kif24 from cycling cells resulted in aberrant cilia assembly but did not promote growth of abnormally long centrioles, unlike CP110 and Cep97 depletion. We found that loss of Kif24 leads to the disappearance of CP110 from mother centrioles, specifically in cycling cells able to form cilia. Kif24 is able to bind and depolymerize microtubules in vitro. Remarkably, ectopically expressed Kif24 specifically remodels centriolar microtubules without significantly altering cytoplasmic microtubules. Thus, our studies have identified a centriolar kinesin that specifically remodels a subset of microtubules, thereby regulating cilia assembly. These studies also suggest mechanistic differences between the regulation of microtubule elongation associated with centrioles and cilia.
Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Centriolos/metabolismo , Cilios/metabolismo , Cinesinas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/metabolismo , Fosfoproteínas/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Humanos , Cinesinas/química , Datos de Secuencia Molecular , Alineación de SecuenciaRESUMEN
Targeted epigenome editing tools allow precise manipulation and investigation of genome modifications, however they often display high context dependency and variable efficacy between target genes and cell types. While systems that simultaneously recruit multiple distinct 'effector' chromatin regulators can improve efficacy, they generally lack control over effector composition and spatial organisation. To overcome this we have created a modular combinatorial epigenome editing platform, called SSSavi. This system is an interchangeable and reconfigurable docking platform fused to dCas9 that enables simultaneous recruitment of up to four different effectors, allowing precise control of effector composition and spatial ordering. We demonstrate the activity and specificity of the SSSavi system and, by testing it against existing multi-effector targeting systems, demonstrate its comparable efficacy. Furthermore, we demonstrate the importance of the spatial ordering of the recruited effectors for effective transcriptional regulation. Together, the SSSavi system enables exploration of combinatorial effector co-recruitment to enhance manipulation of chromatin contexts previously resistant to targeted editing.
Asunto(s)
Epigenoma , Edición Génica , Cromatina/genética , Sistemas CRISPR-Cas , Epigénesis Genética , Edición Génica/métodos , Regulación de la Expresión GénicaRESUMEN
BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Quimioradioterapia , Quimioterapia de Inducción , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Persona de Mediana Edad , Masculino , Femenino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/tratamiento farmacológico , Adulto , China/epidemiología , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/terapia , Quimioradioterapia/métodos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anciano , Cisplatino/uso terapéutico , Cisplatino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Gemcitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Desoxicitidina/administración & dosificación , Adulto Joven , Adolescente , Supervivencia sin ProgresiónRESUMEN
Interactions between Tumor microenvironment (TME) cells shape the unique growth environment, sustaining tumor growth and causing the immune escape of tumor cells. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the identification of cancer-related TME cells. Here, we proposed a novel network-based computational method, named as iATMEcell, to identify the abnormal TME cells associated with the biological outcome of interest based on a cell-cell crosstalk network. In the method, iATMEcell first manually collected TME cell types from multiple published studies and obtained their corresponding gene signatures. Then, a weighted cell-cell crosstalk network was constructed in the context of a specific cancer bulk tissue transcriptome data, where the weight between cells reflects both their biological function similarity and the transcriptional dysregulated activities of gene signatures shared by them. Finally, it used a network propagation algorithm to identify significantly dysregulated TME cells. Using the cancer genome atlas (TCGA) Bladder Urothelial Carcinoma training set and two independent validation sets, we illustrated that iATMEcell could identify significant abnormal cells associated with patient survival and immunotherapy response. iATMEcell was further applied to a pan-cancer analysis, which revealed that four common abnormal immune cells play important roles in the patient prognosis across multiple cancer types. Collectively, we demonstrated that iATMEcell could identify potentially abnormal TME cells based on a cell-cell crosstalk network, which provided a new insight into understanding the effect of TME cells in cancer. iATMEcell is developed as an R package, which is freely available on GitHub (https://github.com/hanjunwei-lab/iATMEcell).
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Microambiente Tumoral , Fenómenos Fisiológicos Celulares , Comunicación CelularRESUMEN
Hepatic ischemia-reperfusion injury (HIRI) represents a major risk factor in liver transplantation and resection surgeries. Kupffer cells (KCs) produce proinflammatory cytokines and lead to hepatic neutrophil infiltration in the liver, which is one of the leading causes of HIRI. Mid1 is involved in immune infiltration, but the role of Mid1 remains poorly understood. Herin, our study aimed to investigate the effect of Mid1 on HIRI progression. Male C57BL/6 mice aged 6 weeks were used for the HIRI model established. The function of Mid1 on liver injury and hepatic inflammation was evaluated. In vitro, KCs were used to investigate the function and mechanism of Mid1 in modulating KC inflammation upon lipopolysaccharide (LPS) stimulation. We found that Mid1 expression was up-regulated upon HIRI. Mid1 inhibition alleviated liver damage, as evidenced by neutrophil infiltration, intrahepatic inflammation, and hepatocyte apoptosis. In vitro experiments further revealed that Mid1 knockdown reduced the secretion of proinflammatory cytokines and chemokines in KCs. Moreover, silenced-Mid1 suppressed proinflammatory responses by the inhibition of NF-κB, JNK, and p38 signaling pathways. Taken together, Mid1 contributes to HIRI via regulating the proinflammatory response of KCs and inducing neutrophil infiltration. Targeting Mid1 may be a promising strategy to protect against HIRI.
Asunto(s)
Macrófagos del Hígado , Hígado , Ratones Endogámicos C57BL , Daño por Reperfusión , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/inmunología , Ratones , Masculino , Macrófagos del Hígado/metabolismo , Hígado/patología , Hígado/metabolismo , Infiltración Neutrófila , Citocinas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , FN-kappa B/metabolismo , Apoptosis , Inflamación/metabolismo , Inflamación/patología , Transducción de SeñalRESUMEN
Cigarette smoking behaviors are harmful and cause one out of ten deaths due to cardiovascular disease. As population sizes grow and number of cigarette smokers increases, it is vital that we understand the mechanisms leading to heart failure in cigarette smokers. We have reported that metabolic regulation of a histone deacetylase, SIRT1, modulates cardiovascular and mitochondrial function under stress. Given this conclusion, we hypothesized that chronic cigarette smoking led to cardiovascular dysfunction via a reduction SIRT1. Mice were randomly organized into smoking or nonsmoking groups, and the smoking group received cigarette smoke exposure for 16 weeks. Following 16-week exposure, diastolic function of the heart was impaired in the smoking group as compared to sham, indicated by a significant increase in E/e'. The electrical function of the heart was also impaired in the smoking group compared to the sham group, indicated by increased PR interval and decreased QTc interval. This diastolic dysfunction was not accompanied by increased fibrosis in mouse hearts, although samples from human chronic smokers indicated increased fibrosis compared to their nonsmoker counterparts. As well as diastolic dysfunction, mitochondria from the 16-week smoking group showed significantly impaired function, evidenced by significant decreases in all parameters measured by the mitochondrial stress test. We further found biochemical evidence of a significantly decreased level of SIRT1 in left ventricles of both mouse and human smoking groups compared to nonsmoking counterparts. Data from this study indicate that decreased SIRT1 levels by cigarette smoking are associated with diastolic dysfunction caused by compromised mitochondrial integrity.
Asunto(s)
Fumar Cigarrillos , Ratones Endogámicos C57BL , Mitocondrias Cardíacas , Sirtuina 1 , Animales , Ratones , Sirtuina 1/metabolismo , Fumar Cigarrillos/efectos adversos , Masculino , Humanos , Mitocondrias Cardíacas/metabolismo , Femenino , Persona de Mediana Edad , Diástole , Miocardio/metabolismo , Miocardio/patologíaRESUMEN
Thromboinflammation is a complex pathology associated with inflammation and coagulation. In cases of cardiovascular disease, in particular ischemia-reperfusion injury, thromboinflammation is a common complication. Increased understanding of thromboinflammation depends on an improved concept of the mechanisms of cells and proteins at the axis of coagulation and inflammation. Among these elements are activated protein C and platelets. This review summarizes the complex interactions of activated protein C and platelets regulating thromboinflammation in cardiovascular disease. By unraveling the pathways of platelets and APC in the inflammatory and coagulation cascades, this review summarizes the role of these vital mediators in the development and perpetuation of heart disease and the thromboinflammation-driven complications of cardiovascular disease. Furthermore, this review emphasizes the significance of the counteracting effects of platelets and APC and their combined role in disease states.
Asunto(s)
Coagulación Sanguínea , Plaquetas , Inflamación , Daño por Reperfusión Miocárdica , Proteína C , Humanos , Plaquetas/metabolismo , Plaquetas/patología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Inflamación/metabolismo , Inflamación/patología , Coagulación Sanguínea/fisiología , Proteína C/metabolismo , AnimalesRESUMEN
Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.
Asunto(s)
Fibrosis Pulmonar Idiopática , Defensa del Paciente , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , National Institutes of Health (U.S.) , Calidad de Vida , Reproducibilidad de los Resultados , Estados Unidos , Capacidad Vital , Ensayos Clínicos como AsuntoRESUMEN
Schizophrenia is a severe psychological disorder. The current diagnosis mainly relies on clinical symptoms and lacks laboratory evidence, which makes it very difficult to make an accurate diagnosis especially at an early stage. Plasma protein profiles of schizophrenia patients were obtained and compared with healthy controls using 4D-DIA proteomics technology. Furthermore, 79 DEPs were identified between schizophrenia and healthy controls. GO functional analysis indicated that DEPs were predominantly associated with responses to toxic substances and platelet aggregation, suggesting the presence of metabolic and immune dysregulation in patients with schizophrenia. KEGG pathway enrichment analysis revealed that DEPs were primarily enriched in the chemokine signaling pathway and cytokine receptor interactions. A diagnostic model was ultimately established, comprising three proteins, namely, PFN1, GAPDH and ACTBL2. This model demonstrated an AUC value of 0.972, indicating its effectiveness in accurately identifying schizophrenia. PFN1, GAPDH and ACTBL2 exhibit potential as biomarkers for the early detection of schizophrenia. The findings of our studies provide novel insights into the laboratory-based diagnosis of schizophrenia.
Asunto(s)
Biomarcadores , Profilinas , Proteómica , Esquizofrenia , Esquizofrenia/metabolismo , Esquizofrenia/diagnóstico , Esquizofrenia/sangre , Humanos , Biomarcadores/sangre , Biomarcadores/metabolismo , Proteómica/métodos , Profilinas/metabolismo , Femenino , Masculino , Adulto , Estudios de Casos y Controles , Gliceraldehído-3-Fosfato Deshidrogenasa (Fosforilante)/metabolismo , Persona de Mediana Edad , Proteínas Sanguíneas/análisis , Proteoma/análisisRESUMEN
Hair follicle stem cells (HFSCs) are maintained in a quiescent state until activated to grow, but the mechanisms that reactivate the quiescent HFSC reservoir are unclear. Here, we find that loss of Sirt7 in mice impedes hair follicle life-cycle transition from telogen to anagen phase, resulting in delay of hair growth. Conversely, Sirt7 overexpression during telogen phase facilitated HSFC anagen entry and accelerated hair growth. Mechanistically, Sirt7 is upregulated in HFSCs during the telogen-to-anagen transition, and HFSC-specific Sirt7 knockout mice (Sirt7f/f ;K15-Cre) exhibit a similar hair growth delay. At the molecular level, Sirt7 interacts with and deacetylates the transcriptional regulator Nfatc1 at K612, causing PA28γ-dependent proteasomal degradation to terminate Nfatc1-mediated telogen quiescence and boost anagen entry. Cyclosporin A, a potent calcineurin inhibitor, suppresses nuclear retention of Nfatc1, abrogates hair follicle cycle delay, and promotes hair growth in Sirt7-/- mice. Furthermore, Sirt7 is downregulated in aged HFSCs, and exogenous Sirt7 overexpression promotes hair growth in aged animals. These data reveal that Sirt7 activates HFSCs by destabilizing Nfatc1 to ensure hair follicle cycle initiation.
Asunto(s)
Folículo Piloso/enzimología , Sirtuinas/metabolismo , Células Madre/enzimología , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Senescencia Celular/efectos de los fármacos , Ciclosporina/farmacología , Ratones , Ratones Noqueados , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Sirtuinas/genéticaRESUMEN
Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
Asunto(s)
Proteína 61 Rica en Cisteína/metabolismo , Neurogénesis/fisiología , Transducción de Señal , Células Madre Adultas/fisiología , Animales , Encéfalo , Proteína 61 Rica en Cisteína/genética , Epéndimo/citología , Epéndimo/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismoRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. METHODS: We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. RESULTS: A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. CONCLUSIONS: The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.
Asunto(s)
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Receptor ErbB-2 , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidad , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Receptor ErbB-2/metabolismo , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Ensayos Clínicos Fase III como Asunto , Biomarcadores de Tumor/metabolismoRESUMEN
The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.
Asunto(s)
Neoplasias Pulmonares , Mutación , Neoplasias Primarias Múltiples , Receptores de Antígenos de Linfocitos T , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Masculino , Femenino , Persona de Mediana Edad , AncianoRESUMEN
Uncontrolled and excessive photothermal heating in photothermal therapy (PTT) inevitably causes thermal damage to surrounding normal tissues, severely limiting the universality and safety of PTT. To address this issue, an intelligent cooling thermal-responsive (ICTR) gel containing poly(N-isopropylacrylamide-co-acrylamide) (P(NIPAM-AM))microgel is applied onto the skin to realize intelligent PTT, which can avoid excessive heating and accidental injury. The high near-infrared (NIR) light transmittance (> 95%) of the ICTR gel ensures effective light delivery at low temperatures, while the refractive index of the P(NIPAM-AM) microgel increases remarkably when the temperature exceeds a predetermined threshold, resulting in progressively enhanced light scattering and weakened photothermal conversion. In animal studies, the negative feedback regulation of ICTR gel on light transmittance and photothermal heating allows the photothermal temperature in the lesion site to be stabilized within the effective therapeutic range (45 °C) while ensuring that the skin surface temperature does not exceed 35 °C. Compared with the severe skin thermal damage found in the histological staining of mice skin receiving conventional PTT, the mice skin receiving the ICTR gel-enabled intelligent PTT remains in good condition. This study establishes an intelligent and universal paradigm for PTT thermal regulation, which is of great significance for achieving safe and effective PTT.