RESUMO
mTORC1 and GSK3 play critical roles in early stages of (macro)autophagy, but how they regulate late steps of autophagy remains poorly understood. Here we show that mTORC1 and GSK3-TIP60 signaling converge to modulate autophagosome maturation through Pacer, an autophagy regulator that was identified in our recent study. Hepatocyte-specific Pacer knockout in mice results in impaired autophagy flux, glycogen and lipid accumulation, and liver fibrosis. Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. Importantly, dephosphorylation of Pacer under nutrient-deprived conditions promotes TIP60-mediated Pacer acetylation, which facilitates HOPS complex recruitment and is required for autophagosome maturation and lipid droplet clearance. This work not only identifies Pacer as a regulator in hepatic autophagy and liver homeostasis in vivo but also reveals a signal integration mechanism involved in late stages of autophagy and lipid metabolism.
Assuntos
Autofagossomos/enzimologia , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Quinase 3 da Glicogênio Sintase/metabolismo , Metabolismo dos Lipídeos , Fígado/enzimologia , Lisina Acetiltransferase 5/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Transativadores/metabolismo , Acetilação , Animais , Autofagossomos/patologia , Proteínas Relacionadas à Autofagia/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Quinase 3 da Glicogênio Sintase/genética , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Gotículas Lipídicas/metabolismo , Fígado/patologia , Lisina Acetiltransferase 5/genética , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Ligação a Fosfato/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Transdução de Sinais , Transativadores/genética , Proteínas Supressoras de TumorRESUMO
Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity. Next, Pacer recruits PI3KC3 and HOPS complexes to the autophagosome for their site-specific activation by anchoring to the autophagosomal SNARE Stx17. Furthermore, Pacer is crucial for the degradation of hepatic lipid droplets, the suppression of Salmonella infection, and the clearance of protein aggregates. These results not only identify Pacer as a crucial multifunctional enhancer in autophagy but also uncover both the involvement of PI3KC3 and the mediators of HOPS's specific tethering activity in autophagosome maturation.
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Autofagossomos/enzimologia , Proteínas Relacionadas à Autofagia/metabolismo , Autofagia , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Qa-SNARE/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Proteínas Relacionadas à Autofagia/genética , Endossomos/enzimologia , Ativação Enzimática , Células HEK293 , Células HeLa , Células Hep G2 , Hepatócitos/enzimologia , Interações Hospedeiro-Patógeno , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Gotículas Lipídicas/metabolismo , Lisossomos/enzimologia , Fusão de Membrana , Agregados Proteicos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Qa-SNARE/genética , Interferência de RNA , Salmonella typhimurium/crescimento & desenvolvimento , Transdução de Sinais , Fatores de Tempo , Transfecção , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas de Transporte Vesicular/genéticaRESUMO
Malignant tumors including gastric cancer (GC) are the leading cause of deaths among reproductive women. Physiological morning sickness can mask the clinical manifestations of GC, whereas the clinical presence of metastatic tumors in the abdominal cavity may be easily mistaken for abdominal swelling caused by fetal growth. Pregnancy and delivery processes in young females could accelerate the growth of GC, leading to its rapid development and grave prognosis. Therefore, early diagnosis is critical and gastrointestinal endoscopy is recommended for any suspected pregnant woman with long-term morning sickness. Treatment strategies, including chemotherapy, resection surgery and radiotherapy, will be determined based on a comprehensive consideration of the status of both the fetus and the mother. Rational management, especially clinical multidisciplinary collaboration may significantly benefit such patients.
[Box: see text].
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Immunotherapy with immune checkpoint inhibitors (ICIs), including antibodies against programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represents a promising systematic treatment for advanced human malignancies. Transplantation remains the ultimate therapy for end-stage organ diseases. However, the efficacy of ICI treatment in solid organ transplant (SOT) recipients remains controversial. We established a transgenic primary liver cancer mouse model and performed allogeneic heterotopic heart transplantation. Different treatments were performed and survival curves were calculated. Graft samples were collected, and immune cells and the cell surface expression of PD-L1 were analysed by flow cytometry. Inflammatory cytokine levels in the serum were measured by an inflammatory array. The specificity of the histochemical techniques was tested by staining sections. A combination immunotherapy comprising a BET protein inhibitor (JQ1) and an immune checkpoint inhibitor (anti-PD-L1 antibody) was administered to primary liver cancer model mice bearing cardiac allografts. Interestingly, the combination immunotherapy effectively suppressed the progression of primary liver cancer but did not accelerate allograft rejection. In accordance with our previous findings, BET protein inhibition enhances the expression of a putative membrane transporter (Rab8A), which upregulates the expression of PD-L1 on the plasma membrane in a transgenic primary liver cancer mouse model. This may be a crucial mechanism of tumour progression arrest. Our data showed that heart transplantation upregulated the expression of the proinflammatory factor IFN-γ and suggested that BET protein inhibition (with JQ1) decreased PD-L1 expression in heart tissues after cardiac transplantation. This phenomenon was accompanied by enhanced infiltration of inflammatory IFN-γ. Our study provides a novel and efficient therapeutic strategy for SOT recipients.
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Antineoplásicos , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Antígeno B7-H1/metabolismo , Interferon gama , Imunoterapia/métodos , Aloenxertos/metabolismoRESUMO
Development of cancer has been linked to chronic inflammation, particularly via interleukin-23 (IL-23) and IL-17 signaling pathways. However, the cellular source of IL-17 and underlying mechanisms by which IL-17-producing cells promote human colorectal cancer (CRC) remain poorly defined. Here, we demonstrate that innate γδT (γδT17) cells are the major cellular source of IL-17 in human CRC. Microbial products elicited by tumorous epithelial barrier disruption correlated with inflammatory dendritic cell (inf-DC) accumulation and γδT17 polarization in human tumors. Activated inf-DCs induced γδT17 cells to secrete IL-8, tumor necrosis factor alpha, and GM-CSF with a concomitant accumulation of immunosuppressive PMN-MDSCs in the tumor. Importantly, γδT17 cell infiltration positively correlated with tumor stages and other clinicopathological features. Our study uncovers an inf-DC-γδT17-PMN-MDSC regulatory axis in human CRC that correlates MDSC-meditated immunosuppression with tumor-elicited inflammation. These findings suggest that γδT17 cells might be key players in human CRC progression and have the potential for treatment or prognosis prediction.
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Neoplasias Colorretais/imunologia , Interleucina-17/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Células Th17/imunologia , Proliferação de Células , Células Dendríticas/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Inflamação/imunologia , Interleucina-8/metabolismo , Ativação Linfocitária/imunologia , Células Mieloides/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Hepatocellular carcinoma (HCC) represents the majority of liver cancer and is the fourth most common cause of cancer-related death. Although advances in molecular targeted therapy have shown promise, none of these agents has yet demonstrated significant clinical benefit. Bromo- and extraterminal domain (BET) protein inhibitors have been considered potential therapeutic drugs for HCC but the biological activity remains unclear. This study found that BET protein inhibition did not effectively suppress the progression of HCC, using a transgenic HCC mouse model. Mechanistically, the BET protein inhibitor JQ1 upregulated the expression of programmed cell death-ligand 1 (PD-L1) on the plasma membrane in vivo and in vitro. Moreover, JQ1 enhanced the expression of Rab8A, which upregulated the expression of PD-L1 on the plasma membrane. This study also showed that JQ1 combined with anti-PD-L1 Ab effectively suppressed HCC progression, and this benefit was obtained by enhancing the activation and cytotoxic capabilities of CD8 T cells. These results revealed the crucial role and regulation of BET protein inhibition on the expression of PD-L1 in HCC. Thus, combining BET protein inhibition with immune checkpoint blockade offers an efficient therapeutic approach for HCC.
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Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/terapia , Proteínas/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Antígeno B7-H1/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Células Hep G2 , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular/métodos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
Lymphoma-associated haemophagocytic lymphohistiocytosis (L-HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L-HLH, was initiated between 2016 and 2018. Fifty-seven adult lymphoma patients were enrolled - 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L-HLH by a quantitative mass spectrometric approach. Soluble V-set and immunoglobulin domain-containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L-HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme-linked immunosorbent assay to be significantly increased in lymphoma patients with L-HLH. When it was exploited for the diagnosis of lymphoma patients with L-HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut-off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one-year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L-HLH.
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Biomarcadores Tumorais/sangue , Linfo-Histiocitose Hemofagocítica , Linfoma , Proteínas de Neoplasias/sangue , Receptores de Complemento/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfoma/sangue , Linfoma/complicações , Linfoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
The bromo- and extra-terminal domain (BET) signaling pathway plays an important role in cell proliferation, immune responses, and pro-inflammatory events. JQ1 as a first-in-class potent and selective inhibitor of the BRD4 signaling pathway is widely used for tumor biology studies. It was found that JQ1 could potently reduce cancer cell viability in vitro and in vivo. The underlying mechanisms include an effect on cell cycle arrest in the G1 phase and a decrease in the percentage of cells in the S phase. Furthermore, JQ1 could alter cytokines expressions not only in T cells but also in dendritic cells (DCs). Apoptosis of tumor cells was induced by JQ1 through downregulation of E2f1 protein expression. In addition, JQ1 exhibited a potent suppressive effect on ERα and androgen receptor (AR) signaling pathways in breast and prostate cancers. Accumulating evidence supports the notion of BRD4 suppression as a target of therapeutic intervention in clinical oncology. Our present review article advances the understanding of the role of the JQ1 / BRD4 protein.
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Antineoplásicos/farmacologia , Azepinas/farmacologia , Neoplasias/tratamento farmacológico , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptor alfa de Estrogênio/antagonistas & inibidores , Humanos , Terapia de Alvo Molecular , Neoplasias/patologia , Proteínas Nucleares/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidoresRESUMO
OBJECTIVE: To investigate the effects of siRNAs targeting CD97 immune epitopes on proliferation, infiltration, apoptosis and cell cycle of breast cancer cells. METHODS: siRNA sequences targeting CD97EGF and CD97Stalk immune epitopes were designed according to Gene Bank NM_001025160.2 with smart siCatchTM siRNA design software. CD97siRNAs were transfected into MDA-MB231 cells in which CD97 was highly expressed. Highest sensitive CD97EGF and CD97Stalk siRNA were screened by Western blotting. Inverted microscope was used to observe the growth of CD97siRNAs-transfected MDA-MB231 cells; the proliferation activity of MDA-MB231 cells was detected by MTT method; the wound healing assay and Transwell migration test were performed to examine the migration and infiltration ability of CD97EGF and CD97Stalk siRNA-transfected MDA-MB231 cells; the effects of CD97EGF siRNA and CD97Stalk siRNA on cell apoptosis and cell cycle of MDA-MB231 cells were detected by TUNEL and flow cytometry. RESULTS: The growth and proliferation activity of CD97siRNAs-transfected MDA-MB231 cells were significantly lower than those in the control groups, and such differences were more significant in CD97Stalk siRNA-transfected group (all P<0.05); scratch test showed that the wound healing rate was lower in CD97siRNAs-transfected groups, especially in CD97Stalk siRNA-transfected group (all P<0.05); Transwell migration showed that the number of MDA-MB231 cells crossing through chambers were less in CD97siRNAs-transfected groups, especially in CD97Stalk siRNA-transfected group (all P<0.05); no significant difference in cell apoptosis was observed between CD97siRNAs-transfected groups and control groups; cell cycle detection showed that CD97siRNAs-transfected groups had less cells in G0/G1 phase and more cells in S phase compared with the control groups, and such effect on cell cycle was more marked in CD97Stalk siRNA-transfected group (all P<0.05). CONCLUSIONS: CD97 plays an important role in the cell growth, proliferation, migration and invasion of breast cancer MDA-MB231 cells, and compared with CD97EGF, CD97Stalk may have more effective inhibitory effects on cellular malignant behaviors.
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Antígenos CD , Epitopos , RNA Interferente Pequeno , Antígenos CD/genética , Antígenos CD/imunologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Epitopos/genética , Humanos , Invasividade Neoplásica , RNA Interferente Pequeno/farmacologia , Receptores Acoplados a Proteínas GRESUMO
OBJECTIVE: To study the funding and achievements in the field of organ transplantation support by the National Natural Science Foundation of China (NSFC). METHODS: A search of NSFC database was made by using the key word "transplantation" and excluding "bone marrow transplantation" for the projects funded between 1988 and 2013. SCI indexed publications that marked with NSFC project number were collected by searching each grant number in the database of the Web of Science. RESULTS: Six hundreds fifty-five projects were identified and received about 220 million yuan in grant funding. These funded research projects were distributed among 25 provinces and autonomous regions, however, which were mainly in the developed coastal areas; of them, 43 (6.56%) projects were granted in xenotransplantation and 17 projects (2.60%) were funded in the field of traditional Chinese medicine-related organ transplantation; Transplantation on blood vessels, heart, kidney, liver, lung, small intestine, pancreatic, cornea, trachea, skin, etc. were primarily performed in research. Nine hundreds and sixty-one SCI-indexed publications were achieved. CONCLUSIONS: Magnitude and intensity of NSFC funding, output of SCI publications have been increasing, suggesting that NSFC positively promotes the development of organ transplantation. Although a great progress of transplantation has been made, basic and translational studies should be vigorously strengthened.
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Pesquisa Biomédica/economia , Fundações , Transplante , China , Apoio Financeiro , HumanosRESUMO
Harness of sensitized transplantation remains a clinical challenge particularly in parallel with prolonged cold ischemia time (PCI)-mediated injury. Our present study was to test the role of myeloid-derived suppressor cells (MDSCs) in mouse pre-sensitized transplantation. Our findings revealed that CD11b+Gr1(low) MDSC was shown to have strong suppressive activity. MDSCs subsets from the tolerated mice exhibited higher suppressive capacities compared with counterparts from naive (untreated) mice. Depletion of Tregs could not affect splenic CD11b+Gr1(-low) MDSC frequency, but increase peripheral and intragraft CD11b+Gr1(-low) frequency. Intriguingly, boost of Tregs remarkably caused an increase of CD11b+Gr1(-low) frequency in the graft, peripheral blood, and spleen. Furthermore, peripheral CD11b+Gr1(-low) cells were massively accumulated at the early stage when allogeneic immune response was enhanced. Taken together, MDSCs could prevent grafts from PCI-mediated injury independent on Tregs in the pre-sensitized transplant recipients. Utilization of MDSC subset particularly CD11b+Gr1(-low) might provide a novel insight into improving graft outcome under such clinical scenarios.
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Transplante de Coração , Células Mieloides/imunologia , Animais , Antígeno CD11b/metabolismo , Contagem de Células , Isquemia Fria/efeitos adversos , Modelos Animais de Doenças , Sobrevivência de Enxerto/imunologia , Imunofenotipagem , Terapia de Imunossupressão , Masculino , Camundongos , Células Mieloides/metabolismo , Receptores de Quimiocinas/metabolismo , Transplante de Pele , Baço/citologia , Baço/imunologiaRESUMO
OX40 is a T cell costimulatory molecule that belongs to the TNFR superfamily. In the absence of immune activation, OX40 is selectively expressed by Foxp3(+) regulatory T cells (Tregs), but not by resting conventional T cells. The exact role of OX40 in Treg homeostasis and function remains incompletely defined. In this study, we demonstrate that OX40 engagement in vivo in naive mice induces initial expansion of Foxp3(+) Tregs, but the expanded Tregs have poor suppressive function and exhibit features of exhaustion. We also show that OX40 enables the activation of the Akt and Stat5 pathways in Tregs, resulting in transient proliferation of Tregs and reduced levels of Foxp3 expression. This creates a state of relative IL-2 deficiency in naive mice that further impacts Tregs. This exhausted Treg phenotype can be prevented by exogenous IL-2, as both OX40 and IL-2 agonists drive further expansion of Tregs in vivo. Importantly, Tregs expanded by both OX40 and IL-2 agonists are potent suppressor cells, and in a heart transplant model, they promote long-term allograft survival. Our data reveal a novel role for OX40 in promoting immune tolerance and may have important clinical implications.
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Receptores OX40/fisiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Tolerância ao Transplante/imunologia , Animais , Proliferação de Células , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/biossíntese , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Transplante de Coração/patologia , Imunidade Celular/genética , Interleucina-2/deficiência , Interleucina-2/fisiologia , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ligante OX40 , Receptores OX40/deficiência , Receptores OX40/metabolismo , Linfócitos T Reguladores/transplante , Tolerância ao Transplante/genética , Fatores de Necrose Tumoral/metabolismoRESUMO
OBJECTIVE: We assessed NOX4 expression in gastric cancer (GC), its prognostic significance, and underlying mechanisms, focusing on promoting ferroptosis through increased ROS production. METHODS: We evaluated NOX4 expression in GC tissues via immunohistochemistry and analyzed correlations with clinicopathological characteristics using TCGA and clinical data. Impacts of manipulating NOX4 levels on GC cell invasiveness, proliferation, and sensitivity to ferroptosis inducers were investigated. RESULTS: Significantly higher NOX4 expression in GC tissues versus normal adjacent tissues correlated with decreased overall survival and increased tumor aggressiveness. NOX4 was an independent predictor of poor prognosis. Functionally, NOX4 manipulation influenced ROS levels, with overexpression enhancing production. Inhibition of NOX4 or application of antioxidants reduced cancer cell invasion and proliferation. Importantly, NOX4-overexpressing cells showed increased sensitivity to ferroptosis inducers, indicating synergistic effects between NOX4 and ferroptosis in suppressing GC progression. CONCLUSION: Our findings highlight NOX4's potential as a therapeutic target in GC, where modulation can enhance efficacy of ferroptosis-inducing treatments, offering a promising strategy for combating this malignancy.
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Proliferação de Células , Ferroptose , NADPH Oxidase 4 , Invasividade Neoplásica , Espécies Reativas de Oxigênio , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ferroptose/efeitos dos fármacos , NADPH Oxidase 4/metabolismo , NADPH Oxidase 4/genética , Espécies Reativas de Oxigênio/metabolismo , Linhagem Celular Tumoral , Feminino , Masculino , Pessoa de Meia-Idade , Prognóstico , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND: Uncontrolled ulcer bleeding of duodenal ulcer (DU) after endoscopic therapy often needs surgery. At present, cutting the bottom of the ulcer with ligation and performing its excision-lesion are the common ways to achieve immediate efficacy in stopping bleeding. For the problem of its great trauma, we seek an easy and useful technical method to reach the same therapeutic effect to stop acute bleeding. METHODS: We determined the distribution of the lesion and its innervated blood vessels under the guidance of the endoscopy and then performed suture and hemostasis on the external surface of the stomach and duodenum. RESULTS: An immediate efficacy in stopping bleeding was shown and the hemoglobin (Hb) level returned to normal after operation with no recurrence of bleeding. CONCLUSION: We created a successful and novel strategy for laparotomy-endoscopic assisted suture for DU emergency hemostasis without duodenectomy.
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BACKGROUND: Gastric cancer (GC) is a common malignancy of the digestive system. According to global 2018 cancer data, GC has the fifth-highest incidence and the third-highest fatality rate among malignant tumors. More than 60% of GC are linked to infection with Helicobacter pylori (H. pylori), a gram-negative, active, microaerophilic, and helical bacterium. This parasite induces GC by producing toxic factors, such as cytotoxin-related gene A, vacuolar cytotoxin A, and outer membrane proteins. Ferroptosis, or iron-dependent programmed cell death, has been linked to GC, although there has been little research on the link between H. pylori infection-related GC and ferroptosis. AIM: To identify coregulated differentially expressed genes among ferroptosis-related genes (FRGs) in GC patients and develop a ferroptosis-related prognostic model with discrimination ability. METHODS: Gene expression profiles of GC patients and those with H. pylori-associated GC were obtained from The Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases. The FRGs were acquired from the FerrDb database. A ferroptosis-related gene prognostic index (FRGPI) was created using least absolute shrinkage and selection operator-Cox regression. The predictive ability of the FRGPI was validated in the GEO cohort. Finally, we verified the expression of the hub genes and the activity of the ferroptosis inducer FIN56 in GC cell lines and tissues. RESULTS: Four hub genes were identified (NOX4, MTCH1, GABARAPL2, and SLC2A3) and shown to accurately predict GC and H. pylori-associated GC. The FRGPI based on the hub genes could independently predict GC patient survival; GC patients in the high-risk group had considerably worse overall survival than did those in the low-risk group. The FRGPI was a significant predictor of GC prognosis and was strongly correlated with disease progression. Moreover, the gene expression levels of common immune checkpoint proteins dramatically increased in the high-risk subgroup of the FRGPI cohort. The hub genes were also confirmed to be highly overexpressed in GC cell lines and tissues and were found to be primarily localized at the cell membrane. The ferroptosis inducer FIN56 inhibited GC cell proliferation in a dose-dependent manner. CONCLUSION: In this study, we developed a predictive model based on four FRGs that can accurately predict the prognosis of GC patients and the efficacy of immunotherapy in this population.
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Pretreatment is a key process restricting the development of biorefinery. This work developed a pretreatment process based on an ethanolamine/acetamide alkaline deep eutectic solvent (ADES). Under microwave assistance, pure ADES pretreatment at 100 °C for 10 min achieved 95.9 % delignification and 95.2 % hemicellulose removal of bamboo shoot shells (BSS). Further, when 75 % water was added to pure DES to prepare hydrated DES (75 %-HADES), impressive delignification (93.2 %), hemicellulose removal (92.2 %) and cellulose recovery (94.8 %) were still achieved. The cellulose digestibility of the 75 %-HADES pretreated solid residue was significantly increased from 12.2 % (the control) to 91.2 %. Meanwhile, the structural features of hemicellulose and lignin macromolecules fractionated by 75 %-HADES pretreatment were well preserved, offering opportunities for downstream utilization. Overall, this work proposes an effective pretreatment strategy with the potential to enable the utilization of all major components of bamboo shoot shells.
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Celulose , Solventes Eutéticos Profundos , Solventes/química , Biomassa , Hidrólise , Lignina/químicaRESUMO
Metal-organic frameworks (MOFs) are characterised by high porosity levels and controllable structures, making them ideal adsorbents for wastewater. However, obtaining substrate materials with mechanical stability, excellent pore accessibility, and good processability for compositing MOF crystal powders to adsorb multiple pollutants in complex aqueous environments is challenging. In this study, porous MOFs@ modified cellulose sponge (MCS) composites were fabricated using MCS as a scaffold to provide anchoring sites for the coordination of Zr4+ ions and further in situ synthesis of MOFs, namely UiO-66@MCS and UiO-66-NH2@MCS, which effectively removed heavy metal ions and organic dyes. MOFs@MCS composites exhibit excellent water and dimensional stability, maintaining the pore structure by ambient drying during reuse. Compared with UiO-66@MCS composite, UiO-66-NH2@MCS composite exhibited a higher adsorption capacity of 224.5 mg·g-1 for Hg2+ and 400.9 mg·g-1 for methylene blue (MB). The adsorption of Hg2+ onto the MOFs@MCS composites followed the Langmuir and pseudo-second-order models, whereas the Freundlich and pseudo-second-order models were more suitable for MB adsorption. Moreover, the MOFs@MCS composites exhibited excellent reusability and were selective for the removal of Hg2+. Overall, this approach effectively combines Zr-based MOFs with mechanically and dimensionally stable porous cellulose sponges, rendering the approach suitable for purifying complex wastewater.
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Purpose: Although allergic diseases in children are on the rise, there has been no comprehensive investigation of the allergens affecting children with allergic diseases in central China. Therefore, we aimed to analyze the distribution of serum allergen species among children with allergic conditions in central China to inform the prevention, diagnosis, and treatment of childhood allergies. Patients and Methods: A total of 9213 children (5543 males with 2.88 ± 0.04 years old and 3670 females with 2.91 ± 0.05 years old) underwent allergen screening, and serum allergen-specific IgE (sIgE) antibodies were detected using an automated fluorescent enzyme immunoassay system. Results: Our findings revealed a total sIgE-positive rate (sIgE-PR) of 57.83%, with mixed food (42.10%), egg whites (30.83%), milk (28.97%), mixed dust mites (24.57%), and mixed molds (23.20%) being the most prevalent source of allergens. The sIgE-PR for common sources of allergens exhibited significant sex-based differences, with males having greater susceptibility than females (p<0.05). Dust mites were the primary source of inhaled allergens, whereas egg white was the predominant source of food allergens. Sources of food allergens were most dominant among infants (0-3 years old); sIgE-PRs for most source of food allergens decreased with age, whereas those for most source of inhaled allergens increased. The autumn sIgE-PRs for mixed molds, weed pollen combinations, and tree pollen combinations were significantly higher than those found in other seasons (p<0.05). Conclusion: Our findings suggest that sources of allergens profiles in children with allergies vary across age groups and seasons. Understanding these patterns can improve the effective prevention of childhood allergies.
RESUMO
Paragangliomas (PGLs) are rare neuroendocrine tumors which overproduce catecholamines (CAs). They are extra-adrenal, catecholamine-secreting tumors occurring outside the adrenal glands. Gastric PGLs originating from extra-adrenal paraganglia are exceptionally rare, and their presentation in geriatric patients further adds to the complexity of diagnosis and management. A 72-year-old male patient presented with enduring left upper abdominal pain and anemia persisting for over a year, and hypertension for six months. Physical examination revealed epigastric discomfort and pallor. Computed tomography scans revealed enlarged lymph nodes in the lesser curvature of the stomach and thickening of the gastric antrum wall with concavity. The patient underwent three cycles of neoadjuvant therapy before radical gastrectomy for gastric cancer. These imaging findings were confirmed during surgery and intraoperative blood pressure was in fluctuation. After the successful resection of the tumor, postoperative pathology confirmed paraganglioma. During postoperative examination, it was observed that the patient's CAs and their metabolites had returned to within the normal range. Combined with the existing ten literatures, we retrospective report the clinical and pathological characteristics and treatment strategies of the rare gastric paraganglioma.