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BACKGROUND: The risk of HCC is documented to be age-related. The outcomes of young HCC patients on postoperative prognosis are not well understood. The study aims to compare the characteristic differences between adolescent and young (AYA) and non-AYA HCC patients. METHODS: We performed a retrospective analysis of the clinical and pathological findings and the survival of 243 HCC patients who underwent operations between 2007 and 2018. RESULTS: The AYA group had a higher AFP level and a higher prevalence of family history of HCC or other cancers than the non-AYA group (P < 0.01 and P < 0.05). AYA patients had more unfavorable pathological characteristics including bigger lesion size, microvascular invasion, portal vein invasion, and hepatic capsule invasion. They also had a more unfavorable Edmondson grade and less tumor capsule formation (P < 0.01). Age was an independent predictor of survival in HCC patients. AYA patients had poorer disease-free and overall survival than non-AYA patients did (P < 0.01). Patients under 30 years old had an even poorer disease-free survival than those aged 30-40 (P = 0.047). CONCLUSIONS: AYA patients exhibited a higher recurrence rate and disease-related death rate with more unfavorable pathological characteristics. Enhanced follow-up for young HCC patients should be applied.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adolescente , Adulto , Carcinoma Hepatocelular/patología , Hepatectomía , Humanos , Neoplasias Hepáticas/patología , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios RetrospectivosRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a common type of pancreatic cancer with one of the worst survival rate of all malignancies. Recent studies have identified that immunosuppressive B cells could employ the PD-1/PD-L1 pathway to suppress antitumour T cell responses; hence, we examined the expression and function of PD-L1 in B cells. We found that the PD-L1 expression was significantly enriched in tumour-infiltrating (TI) B cells than in peripheral blood (PB) B cells from the same patients. Additionally, the PB B cells from stage III and stage IV PDAC patients presented significantly higher PD-L1 than the PB B cells from healthy controls. High PD-L1 expression in PB B cells could be achieved by stimulation via CpG and less effectively via anti-BCR plus CD40L, but not by coculture with pancreatic cancer cell lines in vitro. Also, STAT1 and STAT3 inhibition significantly suppressed PD-L1 upregulation in stimulated B cells. CpG-stimulated PB B cells could inhibit the IFN-γ expression and proliferation of CD8 T cells in a PD-L1-dependent manner. Also, TI CD8 T cells incubated with whole TI B cells presented significantly lower IFN-γ expression and lower proliferation, than TI CD8 T cells incubated with PD-L1+ cell-depleted TI B cells, suggesting that PD-L1+ B cells could also suppress CD8 T cells in the tumour. Overall, this study identified that B cells could suppress CD8 T cells via PD-L1 expression, indicating a novel pathway of immuno-regulation in pancreatic cancer.
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Antígeno B7-H1/metabolismo , Células Secretoras de Insulina/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Receptor de Muerte Celular Programada 1/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Unión ProteicaRESUMEN
Current treatment of intrahepatic cholangiocarcinoma (ICC) remains ineffective because knowledge of ICC carcinogenesis is unclear. Increasing evidence suggests that microRNAs (miRNAs), including miR-191, play an important role in tumorigenesis; but expression and biological functions of miR-191 in ICC remain to be established. This study investigated the functions and underlying mechanisms of miR-191 in ICC. ICC miRNA profiles were generated in five pairs of ICC and matched to normal bile duct tissues by next-generation sequencing technology; ICC miRNA profiles were verified in 18 pairs of ICC tissues and normal bile duct tissues by quantitative RT-PCR. The miR-191-associated mechanisms in ICC were investigated in vitro and in vivo, and clinical outcomes associated with miR-191 were correlated in 84 patients. Our results showed that miR-191 expression was significantly increased in ICC compared with the adjacent normal bile duct tissues (P < 0.001). Overexpression of miR-191 promoted proliferation, invasion, and migration of cholangiocarcinoma cells in vitro and in vivo. The elevated miR-191 expression reduced the expression level of ten-eleven translocation 1 (TET1)-a direct target gene of miR-191 in ICC, which catalyzes demethylation. The reduced TET1 expression level allowed the methylated CpG-rich regions at the p53 gene transcription start site stay methylated, leading to reduced p53 expression level, which compromises p53's anticancer vigor. Finally, miR-191 was found to be an independent risk factor for poor prognosis in patients with ICC (overall survival, hazard ratio = 3.742, 95% confidence interval 2.080-6.733, P < 0.001; disease-free survival, hazard ratio = 2.331, 95% confidence interval 1.346-4.037, P = 0.003). CONCLUSION: Our results suggest that overexpressed miR-191 is associated with ICC progression through the miR-191/TET1/p53 pathway. (Hepatology 2017;66:136-151).
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Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/genética , Animales , Neoplasias de los Conductos Biliares/patología , Biopsia con Aguja , Movimiento Celular/genética , Proliferación Celular/genética , Colangiocarcinoma/patología , Estudios de Cohortes , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia/genética , Estudios Retrospectivos , Sensibilidad y Especificidad , Transducción de Señal , Células Tumorales CultivadasRESUMEN
BACKGROUND: Studies investigating the association between hepatitis C virus (HCV) infections and the occurrence of cholangiocarcinoma (CCA), especially intrahepatic cholangiocarcinoma (ICC), have shown inconsistent findings. Although previous meta-analyses referred to HCV and CCA, they mainly focused on ICC rather than CCA or extrahepatic cholangiocarcinoma (ECC). Since then, relevant new studies have been published on the association between HCV and ICC. Since the different anatomic locations of CCA have distinct epidemiologic features and different risk factors, it is necessary to evaluate the relationship between HCV infection and ICC, ECC, and CCA. METHODS: Relevant studies were identified by searching PUBMED, EMBASE, and MEDLINE databases prior to 1 August 2013. Pooled risk estimates were calculated with random-effects models using STATA 11.0. RESULTS: A total of 16 case-control studies were included in the final analysis. Pooled risk estimates showed a statistically significant increasing risk of CCA (odds ratio (OR) = 5.44, 95% CI, 2.72 to 10.89). The pooled risk estimate of ICC (OR = 3.38, 95% CI, 2.72 to 4.21) was higher than that of ECC (OR = 1.75, 95% CI, 1.00 to 3.05). In a subgroup analysis, the pooled risk estimate of ICC in studies from North America was obviously higher than in Asia (6.48 versus 2.01). The Begg funnel plot and Egger test showed no evidence of publication bias. CONCLUSIONS: HCV infection is associated with the increasing risk of CCA, especially ICC.
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Neoplasias de los Conductos Biliares/etiología , Conductos Biliares Extrahepáticos/virología , Conductos Biliares Intrahepáticos/virología , Colangiocarcinoma/etiología , Hepacivirus/patogenicidad , Hepatitis C/complicaciones , Neoplasias Hepáticas/etiología , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Estudios de Casos y Controles , Colangiocarcinoma/patología , Hepatitis C/virología , Humanos , Neoplasias Hepáticas/patología , PronósticoRESUMEN
BACKGROUND: Spleen-preserving laparoscopic distal pancreatectomy (SPLDP) can be performed with splenic vessel resection (SVR) or splenic vessel preservation (SVP). The purpose of this comparative study was to evaluate the clinical outcomes of patients who underwent SPLDP with SVR or SVP at a single institution. METHODS: We retrospectively reviewed the records of 246 patients who underwent SPLDP at Asan Medical Center, Seoul, Korea, for benign or low-grade malignant tumors found in the body or tail of the pancreas between November 2005 and November 2011. RESULTS: In total, 206 patients (83.7 %) were managed by SVP. SVR was performed in the remaining 40 (16.3 %) cases. There were no significant differences between the SVP and SVR groups in terms of intraoperative blood loss (378 ± 240 vs. 328 ± 204 ml, respectively; P = 0.240) and operating time (193.4 ± 59.1 vs. 204.4 ± 51.8 min, respectively; P = 0.492). Sixty-seven (32.5 %) and 10 patients (25 %) had complications in the SVP and SVR groups, respectively (P = 0.347). At 3 days after surgery, the rates of splenic infarction were 16.0 % (33/206) in the SVP group and 52.5 % (21/40) in the SVR group, but all recovered within 12 months on postoperative computed tomography. The time of recovery from splenic infarction was 3.6 ± 3.1 and 4.7 ± 3.7 months in the SVP and SVR groups, respectively. At 6 months, the rates of gastric varices were 1.9 % in the SVP group and 35 % in the SVR group (P < 0.001) with no progression at 12 months. No gastrointestinal bleeding occurred at a median follow-up of 34 months (range = 12-84). CONCLUSIONS: SPLDP with SVR can be used for patients with large and benign or low-grade malignant tumors that distort and compress vessel course, as the higher rate of early splenic ischemia and perigastric varices is acceptable.
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Laparoscopía/métodos , Tratamientos Conservadores del Órgano/métodos , Pancreatectomía/métodos , Neoplasias Pancreáticas/cirugía , Bazo/irrigación sanguínea , Arteria Esplénica/cirugía , Vena Esplénica/cirugía , Adolescente , Adulto , Pérdida de Sangre Quirúrgica , Várices Esofágicas y Gástricas/etiología , Femenino , Estudios de Seguimiento , Humanos , Laparoscopía/efectos adversos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Tempo Operativo , Pancreatectomía/efectos adversos , Radiografía , Estudios Retrospectivos , Infarto del Bazo/diagnóstico por imagen , Infarto del Bazo/etiologíaRESUMEN
Liver metastasis stands as the primary contributor to mortality among patients diagnosed with colorectal cancer (CRC). Neutrophil extracellular traps (NETs) emerge as pivotal players in the progression and metastasis of cancer, showcasing promise as prognostic biomarkers. Our objective is to formulate a predictive model grounded in genes associated with neutrophil extracellular traps and identify novel therapeutic targets for combating CRLM. We sourced gene expression profiles from the Gene Expression Omnibus (GEO) database. Neutrophil extracellular trap-related gene set was obtained from relevant literature and cross-referenced with the GEO datasets. Differentially expressed genes (DEGs) were identified through screening via the least absolute shrinkage and selection operator regression and random forest modeling, leading to the establishment of a nomogram and subtype analysis. Subsequently, a thorough analysis of the characteristic gene CYP4F3 was undertaken, and our findings were corroborated through immunohistochemical staining. We identified seven DEGs (ATG7, CTSG, CYP4F3, F3, IL1B, PDE4B, and TNF) and established nomograms for the occurrence and prognosis of CRLM. CYP4F3 is highly expressed in CRC and colorectal liver metastasis (CRLM), exhibiting a negative correlation with CRLM prognosis. It may serve as a potential therapeutic target for CRLM. A novel prognostic signature related to NETs has been developed, with CYP4F3 identified as a risk factor and potential target for CRLM.
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Biomarcadores de Tumor , Neoplasias Colorrectales , Familia 4 del Citocromo P450 , Trampas Extracelulares , Neoplasias Hepáticas , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Familia 4 del Citocromo P450/genética , Familia 4 del Citocromo P450/metabolismo , Pronóstico , Trampas Extracelulares/metabolismo , Biomarcadores de Tumor/genética , Nomogramas , Perfilación de la Expresión Génica , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Neutrófilos/metabolismoRESUMEN
Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease characterized by inflammation and fibrosis of the pancreas. It is a systemic disease that can affect multiple organs, including the bile ducts, kidneys, lungs, and other organs. However, due to its complex presentation, AIP is often challenging to diagnose, and misdiagnosis with pancreatic tumors can occur. In our study, we reviewed three cases of atypical AIP where patients had normal serum IgG4 levels, leading to initial misdiagnosis with pancreatic tumors. Delayed diagnosis resulted in irreversible pathologies such as retroperitoneal fibrosis. All three patients had bile duct involvement, and imaging findings were similar to those of tumors, further complicating the diagnosis. The correct diagnosis was confirmed only after diagnostic therapy. Our study aims to raise awareness of atypical AIP and improve diagnostic efficiency by analyzing the clinical characteristics of these patients.
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Enfermedades Autoinmunes , Pancreatitis Autoinmune , Neoplasias Pancreáticas , Pancreatitis , Humanos , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/tratamiento farmacológico , Pancreatitis Autoinmune/diagnóstico , Diagnóstico Tardío , Diagnóstico Diferencial , Neoplasias Pancreáticas/diagnóstico , Pancreatitis/diagnóstico , Pancreatitis/tratamiento farmacológicoRESUMEN
Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF) is a transcription factor that activates the transcription of TNF-α and regulates the inflammatory response. LITAF has been found to have potential anti-cancer effects of in several tumors. However, the role of LITAF in colorectal cancer (CRC) remains unclear. Through a comprehensive pan-cancer analysis of the Cancer Genome Atlas (TCGA), LITAF was identified as a differentially downregulated gene in CRC. We hypothesized that LITAF may participate in the modulation of CRC progression. The present study was aimed to investigate the expression profile of LITAF in CRC and its effect on metastatic behavior and stemness as well as the underlying molecular mechanism. The expression profile of LITAF in CRC, and its relationship with the prognosis of CRC were explored using public databases. LITAF expression was detected by quantitative real-time PCR (qRT-PCR), western blot, and immunohistochemistry. Furthermore, the effects of overexpression or knockdown of LITAF on cell proliferation, apoptosis, migration, invasion, and stemness of CRC cells were investigated in vitro. The regulatory effect of LITAF on forkhead Box O 1 (FOXO1)-sirtuin 1 (SIRT1) signaling axis was also explored. In addition, a xenograft mouse model was used to investigate the in-vivo role of LITAF. LITAF was downregulated in tumor tissues and its expression was associated with the prognosis, pathological stage and liver metastasis. In-vitro experiments confirmed that LITAF inhibited tumor cell proliferation, migration, invasion and stemness, and induced cell apoptosis. In vivo experiments demonstrated that LITAF inhibited the tumorigenicity and liver metastasis in tumor-bearing mice. Additionally, LITAF promoted FOXO1-mediated SIRT1 inhibition, thus regulating cancer stemness and malignant phenotypes. LITAF was silenced in CRC and it participated in the progression of CRC by inhibiting CRC cell stemness, and malignant phenotypes. Therefore, LITAF may serve as a novel biomarker of CRC prognosis.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Animales , Ratones , Sirtuina 1/genética , Sirtuina 1/metabolismo , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Lipopolisacáridos , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/genética , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Movimiento Celular/genética , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
F-box and WD repeat domain containing 10 (FBXW10) is a member of the FBXW subgroup that contains the WD40 domain. FBXW10 has been rarely reported in colorectal cancer (CRC) and its mechanism is unclear. To investigate the role of FBXW10 in CRC, we conducted in vitro and in vivo experiments. Through the database and our clinical samples, we found that FBXW10 expression was up-regulated in CRC, and it was positively correlated with CD31 expression. CRC patients with high FBXW10 expression levels had a poor prognosis. Overexpression of FBXW10 up-regulated cell proliferation, migration and vascular formation, while knockdown of FBXW10 had the opposite effects. Studies on the mechanism of FBXW10 in CRC showed that FBXW10 could ubiquitinate large tumor suppressor kinase 2 (LATS2) and promote its degradation with the Fbox region of FBXW10 played an essential role in this process. In vivo studies demonstrated that knockout of FBXW10 inhibited tumor proliferation and reduced liver metastasis. In conclusion, our study proved that FBXW10 was significantly overexpressed in CRC and was involved in the pathogenesis of CRC by affecting angiogenesis and liver metastasis. Mechanistically, FBXW10 degraded LATS2 through ubiquitination. Therefore, FBXW10-LATS2 can be used as a therapeutic target for CRC in subsequent studies.
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Neoplasias Colorrectales , Proteínas F-Box , Neoplasias Hepáticas , Humanos , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Neoplasias Hepáticas/genética , Ubiquitinación , Proliferación Celular/genética , Neoplasias Colorrectales/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas F-Box/genética , Proteínas F-Box/metabolismoRESUMEN
Background: Cholangiocarcinoma is characterized by significant cellular heterogeneity and complex intercellular communication, which contribute to its progression and therapeutic resistance. Therefore, unraveling this complexity is essential for the development of effective treatments. Methods: We employed single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and intercellular communication in cholangiocarcinoma and adjacent normal tissues from two patients. Distinct cell types were identified, and gene ontology analyses were conducted to determine enriched pathways. Moreover, cell-cell communications were analyzed using CellChat, a computational framework. Additionally, we performed sub-clustering analysis of T cells and fibroblasts. Results: The scRNA-seq analysis revealed distinct cell clusters and diverse cellular compositions of cholangiocarcinoma. CellChat analysis underscored an amplified outgoing signal from fibroblasts within the tumor, suggesting their pivotal role in the tumor microenvironment. Furthermore, T cell sub-clustering analysis revealed an active immune response within the tumor and new tumor-specific T cell clonotypes, suggesting scope for targeted immunotherapies. Moreover, fibroblast sub-clustering analysis indicated distinct functional states and highlighted the role of activated fibroblasts in shaping intercellular communication, particularly via CD99 and FN1 signaling. Conclusion: Our findings reveal the intricate cellular heterogeneity and dynamic intercellular communication in cholangiocarcinoma, providing valuable insights into disease progression and potential therapeutic strategies.
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Background: Nodal status is a vital prognostic factor for ampullary adenocarcinoma. This study was designed to evaluate the clinical significance of the positive nodes in this disease. Methods: Data from 110 patients who underwent curative pancreatoduodenectomy for ampullary adenocarcinoma between January 2007 and December 2018 were retrospectively collected and analyzed. Results: The median number of lymph nodes per patient was 32 (20-46). Metastatic lymph nodes were found in 84 (76.4%) patients. In patients with positive nodules, the most commonly involved nodes were the #13 (80.1%) and #17 (78.6%) nodes, followed by #12 (69.0%) and #8 nodes (57.1%). Patients with 3-4 positive nodes among #13, #17, #12, and #8 had lower survival rates than those with 0 or 1-2 nodes. Conclusion: Ampullary adenocarcinoma commonly spreads to #13, #17, #12, and #8 lymph nodes. These nodes affected the patients' survival rates dramatically.
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Objective: Tumor recurrence remains the main dilemma after surgical treatment of ampulla of Vater carcinoma. This study was designed to identify the prognostic factors and evaluate the recurrence patterns of ampulla of Vater cancer. Methods: A total of 286 patients who underwent surgical resection of ampulla of Vater cancer in two medical centers from January 2000 to October 2016 were collected. Data on clinicopathologic factors, survival rate, and recurrence patterns were retrospectively analyzed. Results: A total of 158 patients (55.2%) survived without evidence of recurrence (non-recurrence), whereas 65 (22.7%) and 63 patients (22.1%) suffered from recurrence of the disease within 12 months (early recurrence) and after 12 months (late recurrence), respectively. Early-recurrence patients exhibited a more advanced disease (advanced tumor stage, lymph node involvement, pancreas invasion, and late TNM stage) than late-recurrence patients. The first or primary location of cancer recurrence in 33 patients (25.8%) was locoregional. Metastasis developed in the liver in 30 patients (23.4%), peritoneum in 13 patients (10.2%), lungs in 10 patients (7.8%), and para-aortic or superior mesenteric artery lymph node in 10 patients (7.8%). Multiple metastases were observed in 26 patients (20.3%). Conclusion: The most common patterns of postoperative recurrence are locoregional and recurrent liver metastasis. The recurrence patterns with the worst prognosis are peritoneal and multiple metastases.
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MicroRNA-542-3p (miR-542-3p) functions as a tumor suppressor in many human cancers, but its biological roles in hepatocellular carcinoma (HCC) remains to be further explored. In our study, we revealed that miR-542-3p was frequently down-expressed in HCC cell lines and tissues using real-time quantitative reverse-transcription PCR (qRT-PCR). Overexpression of miR-542-3p inhibits the proliferation of HCC cells via induction of apoptosis and cell cycle arrest. Furthermore, we confirmed that survivin was a direct target of miR-542-3p in HCC cells, and overexpression of survivin attenuated the miR-542-3p-induced inhibition of HCC cell proliferation. A negative association between miR-542-3p and survivin mRNA levels was also found in HCC tissues. These findings showed that miR-542-3p inhibits the proliferation of HCC cells by targeting survivin, indicating that miR-542-3p/survivin signaling axis might serve as a potential therapeutic target in the treatment of HCC.
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Carcinoma Hepatocelular/patología , Proteínas Inhibidoras de la Apoptosis/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , Animales , Apoptosis/genética , Carcinoma Hepatocelular/genética , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Survivin , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4+CXCR5+ follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4+CXCR5+ T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype. We further demonstrated that a host of microbial motifs, including Pam3CSK4, poly(I:C), LPS, imiquimod, and CpG, could significantly stimulate IFN-γ, IL-17, and/or IL-21 from circulating CD4+CXCR5+ T cells in PBC patients, especially in the presence of monocytes and B cells. Whole bacterial cells of Escherichia coli, Novosphingobium aromaticivorans, and Mycobacterium gordonae, could also potently stimulate IFN-γ, IL-17, and/or IL-21 production from circulating CD4+CXCR5+ T cells. But interestingly, while the whole cell could potently stimulate circulating CD4+CXCR5+ T cells from both healthy controls and PBC patients, the cell protein lysate could only potently stimulate circulating CD4+CXCR5+ T cells from PBC patients, but not those from healthy controls, suggesting that circulating CD4+CXCR5+ T cells in PBC patients had distinctive antigen-specificity from those in healthy individuals. Together, these data demonstrated that bacterial antigen stimulation is a potential source of aberrant Tfh cell activation in PBC patients.
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Antígenos Bacterianos/inmunología , Linfocitos B/inmunología , Colangitis/inmunología , Cirrosis Hepática Biliar/inmunología , Monocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Bacterias/inmunología , Células Cultivadas , Citocinas/metabolismo , Femenino , Humanos , Activación de Linfocitos , Receptores CXCR5/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. In this system, FA was attached to the terminal of the hydrophilic segment of poly(lactic acid)-poly(L-lysine) (PLA-PLL), and PLL was modified by a citric acid group. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency. STATEMENT OF SIGNIFICANCE: Negatively charged nano-carriers prolonged anti-cancer drugs' blood circulation. However it is difficult to be internalised. Therefore, a negative-to-positive charged micelle surface could improve selectivity for tumour cells and increase uptake chance. In this study, we developed a folate (FA)-conjugated and pH-responsive active targeting micellar system for anti-cancer drug delivery. The FA receptor-mediated active targeting and electrostatic interaction between micelles and cell membrane due to a negative-to-positive charge reversal was combined in one micellar anti-cancer drug delivery system to enhance the tumour targeting and cellular internalisation of micelles. In vitro and in vivo anti-cancer studies demonstrated that the doxorubicin-loaded, FA-conjugated and pH-responsive polymeric micelles possess an enhanced and effective cancer efficiency.
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Doxorrubicina , Ácido Láctico , Micelas , Neoplasias Experimentales/tratamiento farmacológico , Ácido Poliglicólico , Células A549 , Animales , Ácido Cítrico/química , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Preparaciones de Acción Retardada/farmacología , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Células HeLa , Células Hep G2 , Humanos , Concentración de Iones de Hidrógeno , Ácido Láctico/química , Ácido Láctico/farmacocinética , Ácido Láctico/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Ácido Poliglicólico/química , Ácido Poliglicólico/farmacocinética , Ácido Poliglicólico/farmacología , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although the combination of cisplatin and gemcitabine (GEM) is considered the standard first-line chemotherapy against unresectable hilar cholangiocarcinoma (HC), its efficacy is discouraging. The present randomized open-label clinical trial aimed to evaluate the efficacy and safety of the GEM plus S-1 (GEM-S-1) combination against unresectable HC. Twenty-five patients per group were randomly assigned to receive GEM, S-1 or GEM-S-1. Neutropenia (56%) and leukopenia (40%) were the most common chemotherapy-related toxicities in the GEM-S-1 group. Median overall survival (OS) in the GEM-S-1, GEM and S-1 groups was 11, 10 and 6 months, respectively. GEM plus S-1 significantly improved OS compared to S-1 monotherapy (OR=0.68; 95%CI, 0.50-0.90; P=0.008). Median progression-free survival (PFS) times in the GEM-S-1, GEM and S-1 groups were 4.90, 3.70 and 1.60 months, respectively. GEM plus S-1 significantly improved PFS compared to S-1 monotherapy (OR=0.50; 95%CI, 0.27-0.91; P=0.024). Response rates were 36%, 24% and 8% in the GEM-S-1, GEM and S-1 groups, respectively. A statistically significant difference was found in response rates between the gemcitabine-S-1 and S-1 groups (36% vs 8%, P=0.017). Patients with CA19-9<466 U/ml were more responsive to chemotherapeutic agents than those with CA19-9≥571 U/ml (88.9% vs 0%, P<0.001). We conclude that the combination of GEM plus S-1 provides a better OS, PFS and response rate than S-1 monotherapy, but it did not significantly differ from GEM monotherapy. (ChiCTR-TRC-14004733).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Tumor de Klatskin/tratamiento farmacológico , Adulto , Anciano , Neoplasias de los Conductos Biliares/mortalidad , Antígeno CA-19-9/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Combinación de Medicamentos , Femenino , Humanos , Estimación de Kaplan-Meier , Tumor de Klatskin/mortalidad , Masculino , Persona de Mediana Edad , Ácido Oxónico/administración & dosificación , Ácido Oxónico/efectos adversos , Tegafur/administración & dosificación , Tegafur/efectos adversos , GemcitabinaRESUMEN
Heme oxygenase-1 has been identified to protect allograft from ischemia/reperfusion and immunologic rejection. Activity of heme oxygenase-1 is regulated by a guanine-thymine dinucleotide length polymorphism in the heme oxygenase-1 gene promoter. In this study, we aimed to explore the impact of the heme oxygenase-1 gene promoter polymorphism of donors and recipients on the orthotopic liver graft function after transplantation. Sixty recipients and their accompanying donors of orthotopic liver allografts were included retrospectively in this study. Heme oxygenase-1 gene promoter polymorphism was assessed using genomic DNA isolated from cryopreserved splenocytes or peripheral blood mononuclear cells and analyzed by genetic analyzer. Small allele of the donor heme oxygenase-1 gene polymorphism significantly prolonged the graft survival (p = 0.017). Recipients of allografts from a class of small-allele carrier had significantly lower serum total bilirubin compared with recipients of a nonclass small-allele donor liver (p < 0.01). Additionally, in recipients of small-carrier allografts, cold ischemia time (<10 h or ≥10 h) did not affect the total bilirubin significantly. Our study suggested a protective function of donor-derived heme oxygenase-1 gene promoter polymorphism on orthotopic liver allograft function after transplantation.
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Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is one of the most common cancers in HBV-endemic regions, with irreversible progression and poor prognosis. HBV-related HCC patients lack effective antiviral/antitumor B cell antibody responses. We hypothesize that dysregulation of PD-1-expressing follicular helper T (Tfh) cell, induced by intrahepatic/intratumoral PD-L1 expression in HCC, could contribute to the defects in B cell immunity. The Tfh responses in healthy control (HC) subjects, chronic hepatitis B (HepB) patients, and HBV-related HCC patients were examined. Compared to HC and HepB individuals, HCC patients showed reduced ICOS expression, IL-10 and IL-21 secretion, and proliferation in Tfh cells. Tfh cells from stage III patients demonstrated increased impairment than those from stage I and stage II patients. Compared to Tfh cells from HC and HepB subjects, those from stage III HCC patients were significantly less effective at inducing the differentiation of naive B cells toward plasmablasts. HCC is known to upregulate hepatic PD-L1 expression, which could suppress Tfh responses. Blocking PD-1 partially rescued the Tfh functions in stage I and stage II HCC subjects but not in stage III HCC patients, while treatment with recombinant PD-L1 strongly suppressed Tfh functions in all HCC stages. Moreover, the level of IL-10 and IL-21 expression by Tfh cells was inversely correlated with the intensity of PD-L1 expression in resected tumors. Together, our results demonstrated an HCC-specific Tfh exhaustion, which might have resulted from elevated PD-1 and PD-L1 signaling.
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OBJECTIVES: We hypothesized that the combination of APACHE II and Model for End-Stage Liver Disease systems would work satisfactorily in patients admitted to intensive care unit after living-donor liver transplant. MATERIALS AND METHODS: Data were retrospectively collected from the database of our surgical team. The study included 38 patients (hepatitis B virus cirrhosis, 47.4%; hepatocellular carcinoma, 28.9%; other diseases, 23.7%). Laboratory values were obtained. Vital signs, Glasgow Coma scale scores, and urine output were abstracted. Variables included age, sex, acute physiology score, APACHE II score, APACHE II-predicted intensive care unit and hospital mortality, predicted length of intensive care unit, and hospital stay. Patients' actual length of intensive care unit and hospital stays, intensive care unit and hospital discharge status, and discharge location were recorded. Standardized mortality ratios were calculated. Discrimination and calibration of APACHE II were assessed. All patients were divided into 3 groups: Model for End-Stage Liver Disease score: >25, 18 to 25, and <18. Predicted hospital mortality was calculated and compared. RESULTS: Mean APACHE II scores of survivors and non-survivors were 13.03 and 23.67. Mean risk of death was 7.05% and 25.07%. APACHE II scores and risk of death between survivors and non-survivors was significantly different (P <.001). The cutoff value of APACHE II score and Model for End-Stage Liver Disease score in the receiving operating characteristic curve was 20 and 25. Patients with APACHE II scores greater than 20 or Model for End-Stage Liver Disease scores greater than 25 had higher predicted hospital mortality after living-donor liver transplant. CONCLUSIONS: The modified APACHE II model provides an accurate prognosis of patients receiving a living-donor liver transplant. The combined application of Model for End-Stage Liver Disease score and APACHE II score can improve the predictive accuracy.
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APACHE , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/métodos , Donadores Vivos , Complicaciones Posoperatorias/diagnóstico , Adolescente , Adulto , Anciano , Área Bajo la Curva , Niño , Preescolar , Enfermedad Hepática en Estado Terminal/diagnóstico , Enfermedad Hepática en Estado Terminal/mortalidad , Femenino , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/mortalidad , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Severe acute pancreatitis (SAP) as a common acute abdomen due to complicated causes is characterized by lots of morbidities, difficult treatment, and high mortality. This study was designed to investigate the role of individually staged nutritional support (ISNS) in the treatment of SAP. METHODS: One hundred patients with SAP admitted to our hospital from January 1997 to October 2002 were randomly divided into total parenteral nutrition group (TPN group, 50 patients) and individually staged nutrition group (individualized group, 50 patients), between which the therapeutic outcome and the incidence of complications were carefully analyzed. RESULTS: Compared with the TPN group, the individualized group had less complications (62 vs 94 patients) including incubation related complications (2% vs 16%), superinfections (8% vs 30%), hepatic functional insufficiency (4% vs 24%) and intra-peritoneal infections (4% vs 12%), in addition to a sooner restoring of oral nutrition (18.5 vs 24.8 days, P<0.05), a shorter hospital stay (24.5 vs 30.2 days) and a lower hospital cost (4.1 vs 5.8 10,000 yuan, P<0.05). CONCLUSION: ISNS, which provides SAP patients with sufficient energy and nutrients according to their true pathological status, is an ideal nutrition planning with lowered incidence of complications, shortened hospital stay and lightened financial burden.