RESUMO
BACKGROUND: Many guidelines have recommended renin-angiotensin system inhibitors (RASI) as the first-line treatment for patients with chronic kidney disease (CKD). We studied RASI prescription trends from 2010 to 2019, and analyzed the characteristics associated with RASI prescription in Chinese hospitalized CKD patients. AIM: To study the prescription of renin angiotensin system inhibitors in hospitalized patients with CKD in China. METHODS: It was retrospectively, cross-sectional reviewed RASI prescriptions in hospitalized CKD patients in China from 2010 to 2019. RASI prescribing trends were analyzed from 2010 to 2019, and bivariate and multivariate logistic regression analyses were conducted to identify characteristics associated with RASI prescription. RESULTS: A total of 35090 CKD patients were included, with 10043 (28.6%) RASI prescriptions. Among these patients, 18919 (53.9%) met the criteria for RASI treatments based on the 2012 kidney disease: Improving global outcomes guidelines. Of these, 7246 (38.3%) patients received RASI prescriptions. RASI prescriptions showed an initial rapid increase from 2011 to 2012, reached its peak around 2015 and 2016, and then exhibited a subsequent slight decreasing trend. Both bivariate and multivariate analyses showed that several characteristics, including the male gender, age less than 60-year-old, nephrology department admission, lower CKD stage, history of hypertension or diabetes, proteinuria, glomerulonephritis as the CKD etiology, and non-acute kidney injury were associated with RASI prescriptions. CONCLUSION: The frequency of RASI prescriptions showed an initial increase but a slight decreasing trend in more recent years. CKD patients with certain characteristics such as elderly age, advanced disease stage, surgery department admission, or acute kidney injury were less likely to receive RASI prescriptions. In the application of RASI in hospitalized CKD patients is insufficient. The actual clinical practice needs to be improved. The development of related research is helpful to guide the correct choice of clinical treatment strategy.
RESUMO
OBJECTIVE: Interferon-α (IFNα) therapy has been an integral part of the current treatment for hepatitis B virus (HBV) infection. However, the exact effect of IFNα antiviral therapy on liver function and iron metabolism in patients with chronic hepatitis B (CHB) remains unclear. Here, we investigated the characteristics of changes in liver function and iron metabolism indexes in patients with chronic hepatitis B before and after IFNα treatment. Additionally, we determined their predictive value for the therapeutic response of IFNα treatment. METHODS: In this study, 34 patients with CHB before and after IFNα treatment were enrolled. Serum levels of virological indicators, liver function, and iron metabolism markers were detected and analyzed in each patient. ROC curve analysis was performed to compare the predictive value of serum liver function and iron metabolism markers for the therapeutic response of IFN α treatment. RESULTS: A significant decrease in serum HBV DNA (P<0.001) and HBsAg (P<0.001) was observed before and after IFNα treatment. Compared to the patients before IFNα treatment, patients after IFNα treatment showed a significant increase in serum albumin (ALB) (P<0.05) and a significant decrease in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P=0.003 and P=0.034). These findings suggested that the synthetic function of the liver was improved, and liver inflammation was alleviated. Serum HEPC and serum ferritin (SF) levels in patients after IFNα treatment were significantly higher (P<0.001, P<0.001); however, serum iron (SI) levels were significantly lower (P=0.005) than those in patients before IFNα treatment. These findings indicate that IFNα treatment regulated iron metabolism homeostasis in CHB patients. Combined liver function and iron metabolism markers, including ALB, SI, SF, and HEPC, had the highest predictive value for the therapeutic response of IFNα treatment for CHB. CONCLUSION: IFNα treatment improved liver function and iron metabolism homeostasis in patients with CHB. Regular monitoring of serum ALB, SI, SF, and HEPC can help predict the therapeutic response of IFNα treatment for CHB.
Assuntos
Antivirais , Ferritinas , Hepatite B Crônica , Hepcidinas , Interferon-alfa , Ferro , Humanos , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/sangue , Hepatite B Crônica/virologia , Masculino , Feminino , Interferon-alfa/uso terapêutico , Antivirais/uso terapêutico , Ferro/sangue , Ferro/metabolismo , Adulto , Hepcidinas/sangue , Ferritinas/sangue , Pessoa de Meia-Idade , Albumina Sérica/metabolismo , Albumina Sérica/análise , Biomarcadores/sangue , Vírus da Hepatite B/efeitos dos fármacos , Resultado do Tratamento , Valor Preditivo dos Testes , Curva ROCRESUMO
BACKGROUND: The goal was to study the difference of virological, immunologic, and inflammatory indicators between Epstein-Barr associated infectious mononucleosis (EBV-IM) and EBV associated hemophagocytic lymphohistiocytosis (EBV-HLH) and to explore the evaluation indicators for monitoring the therapeutic efficacy of EBV-HLH. METHODS: Twenty children with EBV-IM (IM group) and 10 children with EBV-HLH (HLH group) were selected. Virology indicators were detected; the absolute count of lymphocyte, and lymphocyte subsets were detected; the levels of immunoglobulin and ferritin were assayed. RESULTS: Compared to the IM group, the HLH group showed a decrease in EBV-specific VCA-IgM antibody levels (U = 29.0, p = 0.006) and an increase in EBV-specific NA-IgG antibody levels (U = 17.0, p = 0.001), while there was no significant difference in EB-DNA loads (t = 0.417, p = 0.680). The counts of lymphocytes, and various lymphocyte subsets in the HLH group were lower than those in the IM group. Inflammatory markers in the HLH group were significantly higher than those in IM group. Dynamic monitoring of virological, immunological, and inflammatory indicators in HLH patients during treatment showed that EBV DNA gradually decreased in patients with good prognosis. Inflammatory indicators significantly decreased and returned to normal, lymphocyte count significantly increased and returned to normal during treatment. However, patients with poor prognosis showed rebound increase in EBV DNA and inflammatory indicators in the later stage of treatment, while lymphocyte count further decreased with the recurrence of the disease. CONCLUSIONS: Exhausted and damaged immune function in host by persistent stimulation of EB viral antigen is one of the main pathogeneses of EB-HLH. Lymphocyte count and serum ferritin level are effective indicators to monitor the therapeutic efficacy during the treatment to HLH.
Assuntos
Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Mononucleose Infecciosa , Linfo-Histiocitose Hemofagocítica , Humanos , Criança , Masculino , Feminino , Pré-Escolar , Herpesvirus Humano 4/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/virologia , Linfo-Histiocitose Hemofagocítica/sangue , Mononucleose Infecciosa/imunologia , Mononucleose Infecciosa/sangue , Mononucleose Infecciosa/virologia , Mononucleose Infecciosa/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por Vírus Epstein-Barr/sangue , DNA Viral/sangue , Inflamação/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Carga Viral , Ferritinas/sangue , Contagem de Linfócitos , Adolescente , Lactente , Subpopulações de Linfócitos/imunologiaRESUMO
BACKGROUNDS & AIMS: Given its ability to inhibit HBV replication, Interferon alpha (IFN-α) treatment has been confirmed to be effective in managing Chronic Hepatitis B (CHB). However, its underlying mechanisms are incompletely understood. METHODS: Herein, we investigated the antiviral properties of IFN-α by introducing IFN-α expression plasmids into a well-established HBV Hydrodynamic Injection (HDI) mouse model and examined the impact of IFN-α or hepcidin treatment on macrophages derived from THP-1 cells. The cytokine profiles were analyzed using the cytometry microsphere microarray technology, and flow cytometry was used to analyze the polarization of macrophages. Additionally, the IL-6/JAK2/STAT3 signaling pathway and the hepcidin-ferroportin axis were analyzed to better understand the macrophage polarization mechanism. RESULTS: As evidenced by the suppression of HBV replication, injection of an IFN-α expression plasmid and supernatants of IFN-α-treated macrophages exerted anti-HBV effects. The IFN-α treatment up-regulated IL-6 in mice with HBV replication, as well as in IFN-α-treated HepG2 cells and macrophages. Furthermore, JAK2/STAT3 signaling and hepcidin expression was promoted, inducing iron accumulation via the hepcidin-ferroportin axis, which caused the polarization of M1 macrophages. Furthermore, under the effect of IFN-α, IL-6 silencing or blockade downregulated the JAK2/STAT3 signaling pathway and hepcidin, implying that increased hepcidin expression under IFN-α treatment was dependent on the IL-6/JAK2/STAT3 pathway. CONCLUSION: The IL-6/JAK2/STAT3 signaling pathway is activated by IFN-α which induces hepcidin expression. The resulting iron accumulation then induces the polarization of M1 macrophages via the hepcidin-ferroportin axis, yielding an immune response which exerts antiviral effects against HBV replication.
Assuntos
Antivirais , Vírus da Hepatite B , Hepcidinas , Interferon-alfa , Janus Quinase 2 , Macrófagos , Fator de Transcrição STAT3 , Hepcidinas/metabolismo , Hepcidinas/genética , Animais , Humanos , Interferon-alfa/farmacologia , Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Vírus da Hepatite B/fisiologia , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/imunologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Camundongos , Janus Quinase 2/metabolismo , Fator de Transcrição STAT3/metabolismo , Células Hep G2 , Transdução de Sinais/efeitos dos fármacos , Interleucina-6/metabolismo , Células THP-1 , Camundongos Endogâmicos C57BL , Replicação Viral/efeitos dos fármacos , Masculino , Hepatite B Crônica/imunologia , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Modelos Animais de Doenças , Hepatite B/imunologia , Hepatite B/tratamento farmacológico , Hepatite B/virologia , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genéticaRESUMO
BACKGROUND AND AIMS: Activation of the cGAS-STING pathway induces the production of type I interferons, initiating the antiviral immune response, which contributes to the clearance of pathogens. Previous studies have shown that STING agonists promote hepatitis B virus (HBV) clearance; however, few studies have investigated the effect of activating the cGAS-STING pathway in macrophages on HBV. METHODS: The polarization status of HBV particle-stimulated RAW264.7 macrophages was analyzed. After stimulation with HBV particles, the analysis focused on determining whether the DNA sensors in RAW264.7 macrophages recognized the viral double-stranded DNA (dsDNA) and evaluating the activation of the cGAS-STING pathway. Coculture of mouse macrophages and hepatocytes harboring HBV was used to study the antiviral activity of HBV-stimulated RAW264.7 macrophages. RESULTS: After stimulation with HBV particles, HBV relaxed circular DNA (rcDNA) was detected in RAW264.7 macrophages, and the protein expression of phospho-STING, phospho-TBK1, and phospho-IRF3 in the STING pathway was increased, as shown by Western blot analysis, which revealed that M1 polarization of macrophages was caused by increased expression of CD86. RT-PCR analyses revealed elevated expression of M1 macrophage polarization-associated cytokines such as TNFα, IL-1ß, iNOS, and IFNα/ß. In the coculture experiment, both HBsAg and HBeAg expression levels were significantly decreased in AML12-HBV1.3 cells cocultured with the supernatants of HBV-stimulated RAW264.7 macrophages. CONCLUSION: The results suggest that macrophages can endocytose HBV particles. Additionally, viral dsDNA can be recognized by DNA pattern recognition receptors, which in turn activate the cGAS-STING pathway, promoting the M1 polarization of macrophages, while no significant M2 polarization is observed. Macrophages stimulated with HBV particles exhibit enhanced antiviral activity against HBV.
Assuntos
DNA Viral , Vírus da Hepatite B , Macrófagos , Proteínas de Membrana , Nucleotidiltransferases , Transdução de Sinais , Vírus da Hepatite B/fisiologia , Vírus da Hepatite B/imunologia , Animais , Nucleotidiltransferases/metabolismo , Camundongos , Macrófagos/imunologia , Macrófagos/virologia , Macrófagos/metabolismo , Proteínas de Membrana/metabolismo , Células RAW 264.7 , Hepatite B/imunologia , Hepatite B/virologia , Humanos , Ativação de Macrófagos/imunologia , Hepatócitos/virologia , Hepatócitos/imunologia , Hepatócitos/metabolismo , Fator Regulador 3 de Interferon/metabolismoRESUMO
Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are antigenically related flaviviruses that co-circulate in many countries/territories. The interaction between the two viruses needs to be determined. Recent findings by ourselves and other labs showed that JEV-elicited antibodies (Abs) and CD8+T cells exacerbate and protect against subsequent ZIKV infection, respectively. However, the impact of JEV envelope (E) protein domain III (EDIII)-induced immune responses on ZIKV infection is unclear. We show here that sera from JEV-EDIII-vaccinated mice cross-react with ZIKV-EDIII in vitro, and transfer of the same sera to mice significantly decreases death upon lethal ZIKV infection at a dose-dependent manner. Maternally acquired anti-JEV-EDIII Abs also significantly reduce the mortality of neonatal mice born to JEV-EDIII-immune mothers post ZIKV challenge. Similarly, transfer of ZIKV-EDIII-reactive IgG purified from JEV-vaccinated humans increases the survival of ZIKV-infected mice. Notably, transfer of an extremely low volume of JEV-EDIII-immune sera or ZIKV-EDIII-reactive IgG does not mediate the Ab-mediated enhancement (ADE) of ZIKV infection. Similarly, transfer of JEV-EDIII-elicited CD8+T cells protects recipient mice against ZIKV challenge. These results demonstrate that JEV-EDIII-induced immune components including Abs and T cells have protective roles in ZIKV infection, suggesting EDIII is a promising immunogen for developing effective and safety JEV vaccine.
Assuntos
Anticorpos Antivirais , Linfócitos T CD8-Positivos , Proteção Cruzada , Vírus da Encefalite Japonesa (Espécie) , Proteínas do Envelope Viral , Infecção por Zika virus , Zika virus , Animais , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/imunologia , Linfócitos T CD8-Positivos/imunologia , Zika virus/imunologia , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Proteínas do Envelope Viral/imunologia , Camundongos , Vírus da Encefalite Japonesa (Espécie)/imunologia , Proteção Cruzada/imunologia , Feminino , Reações Cruzadas , Encefalite Japonesa/prevenção & controle , Encefalite Japonesa/imunologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Modelos Animais de Doenças , ImunizaçãoRESUMO
BACKGROUND: Diabetic patients with cataracts encounter specific difficulties during cataract surgery due to alterations in microcirculation, blood supply, metabolism, and the microenvironment. Traditional phacoemulsification may not fully tackle these issues, especially in instances with substantial preoperative astigmatism. The utilization of femtosecond laser-assisted phacoemulsification, in conjunction with Toric intraocular lens (IOL) implantation, offers a potentially more efficient strategy. This research seeks to evaluate the efficacy and possible complications of this approach in diabetic cataract patients. AIM: To investigate the clinical efficacy and complications of femtosecond laser-assisted phacoemulsification combined with Toric IOL implantation in diabetic cataract patients, comparing it with traditional phacoemulsification methods. METHODS: This retrospective study enrolled 120 patients with diabetes cataract from May 2019 to May 2021. The patients were divided into two groups: the control group underwent traditional phacoemulsification and Toric IOL implantation, while the treatment group received Len Sx femtosecond laser-assisted treatment. Outcome measures included naked eye vision, astigmatism, high-level ocular phase difference detection, clinical efficacy, and complication. RESULTS: There were no significant preoperative differences in astigmatism or naked eyesight between the two groups. However, postoperative improvements were observed in both groups, with the treatment group showing greater enhancements in naked eye vision and astigmatism six months after the procedure. High-level corneal phase difference tests also indicated significant differences in favor of the treatment group. CONCLUSION: This study suggests that femtosecond laser-assisted phacoemulsification combined with Toric IOL implantation appears to be more effective in enhancing postoperative vision in diabetic cataract patients compared to traditional methods offering valuable insights for clinical practice.
RESUMO
BACKGROUND: To avoid acute variceal bleeding in cirrhosis, current guidelines recommend screening for high-risk esophageal varices (EVs) by determining variceal size and identifying red wale markings. However, visual measurements of EV during routine endoscopy are often inaccurate. AIM: To determine whether biopsy forceps (BF) could be used as a reference to improve the accuracy of binary classification of variceal size. METHODS: An in vitro self-made EV model with sizes ranging from 2 to 12 mm in diameter was constructed. An online image-based survey comprising 11 endoscopic images of simulated EV without BF and 11 endoscopic images of EV with BF was assembled and sent to 84 endoscopists. The endoscopists were blinded to the actual EV size and evaluated the 22 images in random order. RESULTS: The respondents included 48 academic and four private endoscopists. The accuracy of EV size estimation was low in both the visual (13.81%) and BF-based (20.28%) groups. The use of open forceps improved the ability of the endoscopists to correctly classify the varices by size (small ≤ 5 mm, large > 5 mm) from 71.85% to 82.17% (P < 0.001). CONCLUSION: BF may improve the accuracy of EV size assessment, and its use in clinical practice should be investigated.
RESUMO
The main objective of this study was to investigate the potential probiotic properties of Lacticaseibacillus rhamnosus VHProbi®M15 (M15). This study examined the effects of M15 on sucralfate-induced constipation in a mouse model. The BALB/c mice were randomly divided into four groups: the normal group (NOR) was without any treatment, while the constipation (CON), phenolphthalein (PHE), and probiotic (PRO) treatment groups were fed with sucralfate until the appearance of constipation symptoms. Afterward, the NOR and CON groups were given 1 ml saline orally every day until the end of the experiment; the PHE and PRO groups were given phenolphthalein or M15 suspension in 1 ml orally, respectively. Compared with the CON group, the fecal water content and intestinal peristalsis improved in the PRO group. Here, intake of M15 effectively attenuated sucralfate-induced constipation, recuperated colonic epithelial integrity, and increased serum levels of gastrointestinal excitatory neurotransmitters (motilin, gastrin, substance P). Analysis of the intestinal microbiota of mice by 16S rRNA metagenomic revealed an increase in the relative abundance of Bacteroides and a decrease in Sclerotinia, Verrucosa and Proteus in the PRO group. Compared with the CON group, the constipation-induced intestinal microecological changes were partially recovered in the PHE and PRO groups. These results demonstrate that M15 enhanced gastrointestinal transit and alleviated in mice with sucralfate-induced constipation.
Assuntos
Galanina/análogos & derivados , Lacticaseibacillus rhamnosus , Probióticos , Substância P/análogos & derivados , Camundongos , Animais , Sucralfato/efeitos adversos , RNA Ribossômico 16S , Constipação Intestinal/induzido quimicamente , Constipação Intestinal/tratamento farmacológico , Probióticos/farmacologia , Probióticos/uso terapêutico , Fenolftaleínas/efeitos adversosRESUMO
This study is to investigate the regulation of TRIM3/FABP4 on colorectal cancer (CRC) cell migration and lipid metabolism. After transfection of HCT116, LoVo, or SW480 cells, the expression of FABP4, TRIM3, N-cadherin, Vimentin, E-cadherin, and lipid droplet (LD) formation-related genes was measured by qRT-PCR or western blot assays. Wound healing and Transwell assays were applied to detect CRC cell migration and invasion abilities. The levels of triglyceride (TG) and total cholesterol (TC) were measured and the formation of LDs was observed. Additionally, the relationship between FABP4 and TRIM3 was confirmed by Co-IP and ubiquitination assays. Furthermore, a liver metastasis model of CRC was established to explore the effect of FABP4 on CRC tumor metastasis in vivo. FABP4 was upregulated in CRC cells. Downregulation of FABP4 or upregulation of TRIM3 resulted in repressed cell migration and invasion, decreased TG and TC levels, and reduced numbers of LDs. In nude mice, knockdown of FABP4 reduced metastatic nodules in the liver. Mechanistically, TRIM3 combined FABP4 and decreased its protein expression by ubiquitination. Overexpressed FABP4 reversed the influence of TRIM3 upregulation on CRC cell migration and LD formation. In conclusion, underexpressed TRIM3 suppressed FABP4 ubiquitination and accelerated CRC cell migration and LD formation.
Assuntos
Neoplasias Colorretais , Gotículas Lipídicas , Animais , Camundongos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Camundongos NusRESUMO
The material basis and mechanism of Chaenomelis Fructus in the treatment of rheumatoid arthritis(RA) were explored by network pharmacology, and the potential anti-RA targets of Chaenomelis Fructus were verified by molecular docking and animal experiments. The active components and targets of Chaenomelis Fructus were searched against the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform. GeneCards, DisGeNET, and OMIM were used to obtain RA-related targets. The common targets shared by Chaenomelis Fructus and RA were considered as the potential targets of Chaenomelis Fructus in the treatment of RA. Cytoscape 3.9.0 was employed to establish a "traditional Chinese medicine-active component-common target-disease" network. The protein-protein interaction(PPI) network was established by STRING, and the core genes were visualized by RStudio 4.1.0. DAVID was used for Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment to predict and visualize the involved signaling pathways. Molecular docking was carried out with the active components screened out as ligands and RA core genes as the targets. Finally, the prediction results were verified by animal experiments. Four main active components of Chaenomelis Fructus were obtained, which corresponded to 137 targets. Chaenomelis Fructus and RA shared 37 common targets. GO annotation yielded 239 terms(P<0.05), and KEGG pathway enrichment analysis screened out 94 signaling pathways(P<0.05), mainly involving interleukin-17(IL-17), tumor necrosis factor, Toll-like receptor, and nuclear factor-kappa B(NF-κB) signaling pathways. Molecular docking results showed that the main active components of Chaenomelis Fructus bound well with the core targets of RA. The results of animal experiments proved that Chaenomelis Fructus can alleviate joint swelling in the mice with RA. The results of ELISA showed that Chaenomelis Fructus lowered the levels of interleukin-6(IL-6) and interleukin-1ß(IL-1ß). Western blot showed that Chaenomelis Fructus down-regulated the protein level of vascular endothelial growth factor A(VEGFA). Chaenomelis Fructus exerts anti-inflammatory effect and reduces pannus formation by regulating the core targets such as VEGFA, IL-1ß, and IL6 in the treatment of RA. The findings of this study provide new ideas for the future treatment of RA with Chaenomelis Fructus.
Assuntos
Artrite Reumatoide , Medicamentos de Ervas Chinesas , Animais , Camundongos , Farmacologia em Rede , Fator A de Crescimento do Endotélio Vascular , Simulação de Acoplamento Molecular , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Fator de Necrose Tumoral alfa , NF-kappa B , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Medicina Tradicional ChinesaRESUMO
Although some progress has been made in tumor treatment, gliomas remain one of the tumors that can still seriously threaten human life and health. Due to the particularity of the immune microenvironment of the central nervous system and the strong invasiveness of tumors, the treatment of gliomas remains a major challenge. Currently, researchers have explored a large number of immunotherapy programs to improve the survival and prognosis of glioma patients, including tumor vaccines, immune checkpoint inhibitors, adoptive cell transfer therapy, viral vector therapy, and genetic engineering therapy. The goal of these programs is to activate or change the immunosuppressive environment and target tumor cells through drugs, combined with surgical resection, radiotherapy, chemotherapy, and anti-angiogenesis drugs, to achieve the purpose of treating glioma. This review briefly describes the immunosuppressive microenvironment of gliomas and summarizes recent immunotherapeutic strategies and their progress. The aim is to summarize the latest immunotherapies for the treatment of gliomas and provide new research directions.
Assuntos
Glioma , Imunoterapia , Humanos , Glioma/terapia , Sistema Nervoso Central , Microambiente TumoralRESUMO
Malignant rhabdoid tumors (MRTs) are rare tumors with high mortality rates and poor prognoses. MRTs occur mainly in the central nervous system, kidneys, and soft tissues, but rarely in the omentum. MRTs occur more commonly in infants and children and less frequently in adults. Here, we report the first observed case of MRT in an adult omentum. A 35-year-old man with abdominal distension and pain was admitted to the emergency department. Previously, several hospitals considered patients with cirrhosis who had not received active treatment. Computed tomography and magnetic resonance imaging revealed diffuse omental thickening and massive ascites. The surgery was performed at our hospital, and the pathological diagnosis was MRT with a SMARCB1(INI-1) deletion. Postoperatively, his symptoms improved, and he underwent five cycles of chemotherapy. However, 6 months after surgery, the tumor developed liver metastases, and the patient subsequently died. Primary MRT of the greater omentum is rare, and its pathological diagnosis usually requires extensive clinicopathological evaluation of various differential diagnoses and an appropriate work-up to exclude other malignancies associated with SMARCB1 deletion. At the same time, the lack of specific signs of omental MRT and its rapid progression should alert clinicians.
RESUMO
Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors - but not catalytic inhibitors - reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1's catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1's noncatalytic function may be a promising treatment strategy for NEPC.
Assuntos
Adenocarcinoma , Neoplasias da Próstata , Humanos , Masculino , Adenocarcinoma/genética , Linhagem Celular Tumoral , Histona Desmetilases/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Oxaliplatin (OXA) is a standard agent for colorectal cancer (CRC) adjuvant chemotherapy. However, acquired and intrinsic OXA resistance is a primary challenge for CRC treatment. This study investigates the function of the Kruppel-like factor 5/fatty acid binding proteins 6 (KLF5/FABP6) axis in CRC proliferation, lipid droplet formation and OXA resistance. OXA-resistant CRC cell lines were constructed, and FABP6 and KLF5 expression was assessed in parental and OXA-resistant CRC cells. Subsequent to gain- and loss-of-function experiments, CRC cell proliferation was assessed by cell counting kit-8 (CCK-8) and clone formation assays, the intracellular lipid synthesis by oil red O staining and the protein expression of lipid metabolism genes by western blot. OXA resistance of CRC cells was assessed by CCK-8 assay. The binding of KLF5 to FABP6 was analyzed by the dual-luciferase reporter and ChIP assays. A tumorigenicity assay in nude mice was adopted to examine the impact of KLF5 on CRC tumor growth and OXA resistance in vivo . FABP6 and KLF5 expression was high in CRC cell lines. Downregulation of FABP6 or KLF5 restrained CRC cell proliferation and lipid droplet formation in vitro . FABP6 and KLF5 expression was elevated in OXA-resistant CRC cells. Downregulation of FABP6 or KLF5 repressed the OXA resistance of OXA-resistant CRC cells. Mechanistically, KLF5 facilitated the transcription of FABP6. FABP6 overexpression counteracted the suppressive effects of KLF5 downregulation on CRC cell growth, lipid droplet formation and OXA resistance. KLF5 downregulation restrained CRC tumor growth and OXA resistance in vivo . In conclusion, KLF5 knockdown reduced FABP6 transcription to protect against proliferation, lipid droplet formation and OXA resistance in CRC.
Assuntos
Neoplasias Colorretais , Proteínas de Ligação a Ácido Graxo , Fatores de Transcrição Kruppel-Like , Gotículas Lipídicas , Animais , Camundongos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas de Ligação a Ácido Graxo/genética , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/patologia , Camundongos Nus , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Fatores de Transcrição/metabolismoRESUMO
To explore the efficiency of nutritional support therapy . Pharmacists led the construction of an individualized nutritional computing system and were involved in the process of treatment. After obtaining relevant professional knowledge and instruction on how to operate the system, MDT members intervened in the incorrect treatment process during nutritional support therapy. The Department of Radiation Oncology and the Intensive Care Unit (ICU) were selected as pilot departments to compare and analyze the rationality of nutrition risk screening and the use of enteral nutrition (EN) and parenteral nutrition (PN) in treatment before and after intervention. The individualized nutritional computing system significantly improved work efficiency, promoted nutrition risk screening, and saved 10-15 minutes in the treatment of each patient. After intervention in the Department of Radiation Oncology, the use rate of Total Nutrient Admixture (TNA) increased by 7.17%, and the single-bottle infusion rate of PN preparation decreased by 17.94% in patients at risk of malnutrition. The use rate of EN and single-bottle infusion rate of PN preparation in patients without risk of malnutrition decreased by 15.17% and 20.81%, respectively. Overall, 98.75% of ICU patients were at risk of malnutrition. The use rates of EN and TNA increased by 12.79% and 12.14%, respectively, and the single-bottle infusion rate of PN preparation decreased by 10.06%. Streamlined and mobile MDT, the use of an individualized nutritional computing system, and the effective work of pharmacists in the process significantly improved the efficiency and rationality of nutritional support therapy .
RESUMO
Backgrounds & aims: Epstein-Barr virus (EBV) infection occurs commonly in children and may cause acute infectious mononucleosis (AIM) and various malignant diseases. Host immune responses are key players in the resistance to EBV infection. We here assessed the immunological events and laboratory indicators of EBV infection, as well as determined the clinical usefulness of evaluating the severity and efficacy of antiviral therapy in AIM patients. Methods: We enrolled 88 children with EBV infection. The immune environment was defined by immunological events such as frequencies of lymphocyte subsets, phenotypes of T cells, and their ability to secrete cytokines, and so on. This environment was analyzed in EBV-infected children with different viral loads and in children in different phases of infectious mononucleosis (IM) from disease onset to convalescence. Results: Children with AIM had higher frequencies of CD3+ T and CD8+ T cells, but lower frequencies of CD4+ T cells and CD19+ B cells. In these children, the expression of CD62L was lower and that of CTLA-4 and PD-1 was higher on T cells. EBV exposure induced granzyme B expression, but reduced IFN-γ secretion, by CD8+ T cells, whereas NK cells exhibited reduced granzyme B expression and increased IFN-γ secretion. The frequency of CD8+ T cells was positively correlated with the EBV DNA load, whereas the frequencies of CD4+ T cells and B cells were negatively correlated. During the convalescent phase of IM, CD8+ T cell frequency and CD62L expression on T cells were restored. Moreover, patient serum levels of IL-4, IL-6, IL-10, and IFN-γ were considerably lower throughout the convalescent phase than throughout the acute phase. Conclusion: Robust expansion of CD8+ T cells, accompanied by CD62L downregulation, PD-1 and CTLA-4 upregulation on T cells, enhanced granzyme B production, and impaired IFN-γ secretion, is a typical characteristic of immunological events in children with AIM. Noncytolytic and cytolytic effector functions of CD8+ T cells are regulated in an oscillatory manner. Furthermore, the AST level, number of CD8+ T cells, and CD62L expression on T cells may act as markers related to IM severity and the effectiveness of antiviral treatment.
RESUMO
Four new steroids, chouchunsteride A-D (1-4), together with four known steroids (5-8), were isolated from the leaves of Ailanthus altissima (Mill.) Swingle. Their structures were elucidated based on spectroscopic data analysis, while the relative and absolute configurations were determined via acetonide analysis and quantum chemical ECD calculations. All isolated steroids were evaluated for their cytotoxic activity against two hepatoma carcinoma cell lines (HepG2, Hep3B). Among them, 1 exhibited the most potent cytotoxicity against HepG2 cells with an IC50 value of 4.03 µM.
Assuntos
Ailanthus , Humanos , Ailanthus/química , Folhas de Planta , Células Hep G2 , Esteroides/farmacologiaRESUMO
[This corrects the article on p. 2921 in vol. 19, PMID: 23704825.].
RESUMO
The androgen receptor (AR) signaling pathway is critical for growth and differentiation of prostate cancer cells. For that reason, androgen deprivation therapy with medical or surgical castration is the principal treatment for metastatic prostate cancer. More recently, new potent AR signaling inhibitors (ARSIs) have been developed. These drugs improve survival for men with metastatic castration-resistant prostate cancer (CRPC), the lethal form of the disease. However, ARSI resistance is nearly universal. One recently appreciated resistance mechanism is lineage plasticity or switch from an AR-driven, luminal differentiation program to an alternate differentiation program. Importantly, lineage plasticity appears to be increasing in incidence in the era of new ARSIs, strongly implicating AR suppression in this process. Lineage plasticity and shift from AR-driven tumors occur on a continuum, ranging from AR-expressing tumors with low AR activity to AR-null tumors that have activation of alternate differentiation programs versus the canonical luminal program found in AR-driven tumors. In many cases, AR loss coincides with the activation of a neuronal program, most commonly exemplified as therapy-induced neuroendocrine prostate cancer (t-NEPC). While genetic events clearly contribute to prostate cancer lineage plasticity, it is also clear that epigenetic events-including chromatin modifications and DNA methylation-play a major role. Many epigenetic factors are now targetable with drugs, establishing the importance of clarifying critical epigenetic factors that promote lineage plasticity. Furthermore, epigenetic marks are readily measurable, demonstrating the importance of clarifying which measurements will help to identify tumors that have undergone or are at risk of undergoing lineage plasticity. In this review, we discuss the role of AR pathway loss and activation of a neuronal differentiation program as key contributors to t-NEPC lineage plasticity. We also discuss new epigenetic therapeutic strategies to reverse lineage plasticity, including those that have recently entered clinical trials.