The cuproptosis-related gene UBE2D2 functions as an immunotherapeutic and prognostic biomarker in pan-cancer.

BACKGROUND: Cuproptosis, as a unique modality of regulated cell death, requires the involvement of ubiquitin-binding enzyme UBE2D2. However, the prognostic and immunotherapeutic values of UBE2D2 in pan-cancer remain largely unknown. METHODS: Using UCSC Xena, TIMER, Clinical Proteomic Tumor Analysis Consortium (CPTAC), and Human Protein Atlas (HPA) databases, we aimed to explore the differential expression pattern of UBE2D2 across multiple cancer types and to evaluate its association with patient prognosis, clinical features, and genetic variations. The association between UBE2D2 and immunotherapy response was assessed by gene set enrichment analysis, tumor microenvironment, immune gene co-expression and drug half maximal inhibitory concentration (IC50) analysis. RESULTS: The mRNA and protein levels of UBE2D2 were markedly elevated in most cancer types, and UBE2D2 exhibited prognostic significance in liver hepatocellular carcinoma (LIHC), kidney chromophobe (KICH), uveal melanomas (UVM), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and kidney renal papillary cell carcinoma (KIRP). UBE2D2 expression was correlated with clinical features, tumor mutation burden, microsatellite instability, and anti-tumor drug resistance in several tumor types. Gene enrichment analysis showed that UBE2D2 was significantly associated with immune-related pathways. The expression level of UBE2D2 was correlated with immune cell infiltration, including CD4 + T cells、Macrophages M2、CD8 + T cells in pan-cancer. PDCD1, CD274 and CTLA4 expression levels were positively correlated with UBE2D2 level in multiple cancers. CONCLUSIONS: We comprehensively investigated the potential value of UBE2D2 as a prognostic and immunotherapeutic predictor for pan-cancer, providing a novel insight for cancer immunotherapy.

A novel prognostic model for predicting patient survival and immunotherapy responsiveness in hepatocellular carcinoma: insights into the involvement of T-cell proliferation.

BACKGROUND: The cancer-associated biological mechanisms and the implementation of immunotherapy are heavily impacted by the activities of T cells, consequently influencing the effectiveness of therapeutic interventions. Nevertheless, the mechanistic actions of T-cell proliferation in response to immunotherapy and the overall prognosis of individuals diagnosed with hepatocellular carcinoma (HCC) remains insufficiently understood. The present work seeks to present a comprehensive analysis immune landscape in the context of HCC. METHODS: To achieve this objective, both clinical data and RNA sequencing data were acquired from authoritative databases such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). RESULTS: Through the utilization of consensus clustering techniques, distinct molecular subtypes associated with T-cell proliferation were delineated. Following this, seven genes of prognostic significance were identified via a combination of Cox and Lasso regression analyses. By integrating these genes into a prognostic signature, the predictive capability of the model was verified through an examination of internal and external datasets. Moreover, immunohistochemistry and qRT-PCR tests have verified the reliability of prognostic markers. Notably, the high-risk group exhibited elevated expression of immune checkpoint genes as well as higher benefit in terms of drug sensitivity testing, as determined by the Chi-square test (P < 0.001). The risk score derived from the prognostic signature depicted considerable efficacy in predicting the survival outcomes of HCC cases. CONCLUSIONS: Overall, prognostic markers may become valuable predictive tool for individuals diagnosed with HCC, allowing for the prediction of their prognosis as well as the assessment of their immunological condition and response to immunotherapy.

Cancer cell-intrinsic STING is associated with CD8 + T-cell infiltration and might serve as a potential immunotherapeutic target in hepatocellular carcinoma.

PURPOSE: The activation of stimulator of interferon genes (STING) pathway triggers the antitumor immunity by CD8 + T cells. However, the differentiated antitumor effects of STING activation in different cell types is still unclear. We aimed to investigate the expression and potential prognostic value of cancer cell-intrinsic STING in hepatocellular carcinoma (HCC), and whether STING could be a potential immunotherapeutic target of HCC was then evaluated. METHODS: We separately assessed the expression of STING in cancer cells and infiltrating immune cells in HCC tissues. The independent clinicopathological factors associated with survival outcomes were evaluated by the multivariable analysis. The HCC orthotopic mice model were used to confirm the immunotherapeutic effects of STING agonists, and CD8 + T-cell infiltration level was analyzed through immunofluorescence and flow cytometry. RESULTS: The expression of cancer cell-intrinsic STING was significantly reduced in HCC compared with adjacent tissues. Patients with low levels of cancer cell-intrinsic STING expression was associated with increased tumor volume (P = 0.009), higher serum AFP levels (P = 0.028), and decreased CD8 + T-cell infiltration (P = 0.002). Low levels of cancer cell-intrinsic STING expression indicated a poor overall survival (OS) and disease-free survival (DFS). Multivariate analysis demonstrated that low levels of cancer cell-intrinsic STING expression was an independent prognostic factor. Additionally, cancer cell-intrinsic STING expression was positively related with CD8 + T-cell infiltration levels in HCC patients (r = 0.308; P = 0.001). When mice with orthotopic HCC tumors treated with STING agonists, tumor growth was significantly reduced with enhanced levels of CD8 + T-cell infiltration. CONCLUSION: Cancer cell-intrinsic STING might affect HCC tumor progression through enhancing CD8 + T-cell infiltration and can be an immunotherapeutic target for HCC.

Sequencing of systemic treatment for hepatocellular carcinoma: Second line competitors.

During the last decades, further knowledge of hepatocellular carcinoma (HCC) molecular mechanisms has led to development of effective systemic treatments including tyrosine kinase inhibitors (TKIs) and immunotherapy. In this review, we describe first and second line systemic treatment options for advanced HCC. Several trials have evaluated new drugs for the treatment of HCC patients: In first line, lenvatinib resulted non-inferior to sorafenib and it can be used as alternative, even in the lack of evidence for sequential treatment options in second line after lenvatinib. Recently, atezolizumab plus bevacizumab have shown superiority over sorafenib in first-line. Sorafenib-regorafenib sequential administration in selected patients has opened a new paradigm of treatment in advanced HCC with a life expectancy exceeding two years. Other TKIs for second line treatment include cabozantinib and ramucirumab (specifically for patients with Alpha-fetoprotein values ≥ 400 ng/mL). The combination of TKIs with immunotherapy may represent a big step forward for these patients in the near future.

Natural killer cell receptor variants and chronic hepatitis B virus infection in the Vietnamese population.

OBJECTIVES: Genes of host immunity play an important role in disease pathogenesis and are determinants of clinical courses of infections, including hepatitis B virus (HBV). Killer-cell immunoglobulin-like receptor (KIR), expressed on the surface of natural killer cells (NK), regulate NK cell cytotoxicity by interacting with human leukocyte antigen (HLA) class I molecules and are candidates for influencing the course of HBV. This study evaluated whether variations in KIR gene content and HLA-C ligands are associated with HBV and with the development of liver cirrhosis and hepatocellular carcinoma. METHODS: A Vietnamese study cohort (HBV n = 511; controls n = 140) was genotyped using multiplex sequence-specific polymerase chain reaction (PCR-SSP) followed by melting curve analysis. RESULTS: The presence of the functional allelic group of KIR2DS4 was associated with an increased risk of chronic HBV (OR = 1.86, pcorr = 0.02), while KIR2DL2+HLA-C1 (OR = 0.62, pcorr = 0.04) and KIR2DL3+HLA-C1 (OR = 0.48, pcorr = 0.04) were associated with a decreased risk. The pair KIR2DL3+HLA-C1 was associated with liver cirrhosis (OR = 0.40, pcorr = 0.01). The presence of five or more activating KIR variants was associated with hepatocellular carcinoma (OR = 0.53, pcorr = 0.04). CONCLUSIONS: KIR gene content variation and combinations KIR-HLA influence the outcome of HBV infection.

Over-expression of MiR-122 promotes apoptosis of hepatocellular carcinoma via targeting TLR4.

INTRODUCTION AND OBJECTIVE: MiR-122 has been regarded as a tumor suppressor. Toll-like receptor 4 (TLR4) has been found to be closely related to metastasis and immune escape of hepatocellular carcinoma (HCC). In the study, we sought to investigate the effect of miR-122 on HCC and the expression of TLR4. PATIENTS OR MATERIALS AND METHODS: Real-time PCR and Western blot were performed to detect the expressions of target factors. CCK-8 and flow cytometry analysis were employed to evaluate cell viability and apoptosis, respectively. Luciferase reporter assay was used to determine whether miR-122 could directly regulate the expression of TLR4. Enzyme-linked Immuno Sorbent Assay was adopted to detect the secretion of inflammatory cytokines. RESULTS: Both down-regulation of miR-122 and up-regulation of TLR4 were found to be correlated with low overall survival rate of HCC patients. TLR4 may be a direct target gene of miR-122. Over-expression of miR-122 induced apoptosis and inhibited cell viability of HCC by down-regulating TLR4, enhanced the expression of pro-apoptotic genes and suppressed the expression of anti-apoptotic genes. MiR-122 inhibited expressions and activities of inflammatory cytokines, including vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), cyclooxygenase-2 (Cox-2) and prostaglandin E2 (PGE2) and also reduced the expression of matrix metallopeptidase 9 (MMP-9). Furthermore, activities of phosphatidylinositide 3-kinases (PI3K), Akt and nuclear factor-kappa B (NF-κB) were suppressed by miR-122. CONCLUSIONS: Down-regulation of miR-122 facilitated the immune escape of HCC by targeting TLR4, which was related to PI3K/Akt/NF-κB signaling pathways. Our study may provide a possible strategy for the treatment of HCC.

Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response.

AIRmax and AIRmin mouse strains phenotypically selected for high and low acute inflammatory responsiveness (AIR) are, respectively, susceptible or resistant to developing hepatocellular carcinoma (HCC) induced by the chemical carcinogens urethane and diethylnitrosamine (DEN). Early production of TNF-α, IL-1ß, and IL-6 in the liver after DEN treatment correlated with tumor development in AIRmax mice. Transcriptome analysis of livers from untreated AIRmax and AIRmin mice showed specific gene expression profiles in each line, which might play a role in their differential susceptibility to HCC. Linkage analysis with SNP markers in F2 (AIRmax×AIRmin) intercross mice revealed two quantitative trait loci (QTL) in chromosomes 2 and 9, which are significantly associated with the number and progression of urethane-induced liver tumors. An independent linkage analysis with an intercross population from A/J and C57BL/6J inbred mice mapped regions in chromosomes 1 and 7 associated with the progression of urethane-induced liver tumors, evidencing the heterogeneity of HCC genetic control.

Immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is considered an immunogenic tumor that arises in chronically inflamed livers due to underlying chronic liver disease caused by viral and non-viral pathogenesis. This inflammation leads to tumor development and is associated to higher tumor immunogenicity. For this reason immunotherapeutic approaches may be suitable therapeutic strategies for HCC. Indeed, several preclinical and clinical data support this hypothesis showing that immunotherapy and even more their combination may be a good alternative candidate for the treatment of HCC patients. However, considering that the liver plays a central role in host defense as well as in the maintenance of self-tolerance, it is characterized by a strong intrinsic immune suppressive microenvironment as well as by a high immune evasion, which may represent a major impediment for an effective immune response against tumor. Furthermore, the low expression of tumor antigens on liver cancer cells leads to a lower T-cell activation and tumor infiltration, resulting in a less efficient control of the tumor growth and, consequently, in a worse clinical outcome. For this reason, strategies should be developed to counteract the different factors in the HCC tumor microenvironment playing a major role in reducing the effects of immunotherapy.

Antigen-loaded dendritic cells triggers a specific cytotoxic T lymphocytes immune response against hepatocellular carcinoma: in vitro study.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the common malignancies, characterized by poor response to conventional therapeutic options. Immunotherapy with dendritic cells (DCs)-vaccines is one of the most successful strategies used for the treatment of HCC. However, the methods applied in the preparation of antigen-loaded DCs are important factors for optimization of DCs vaccines. PURPOSE: The present study was conducted to investigate the effect of HCC-whole tumor cell lysate prepared using rapid repetitive freeze-thaw cycles on the immunogenicity of DCs and evaluate the ability of whole tumor cell lysate-pulsed DCs vaccine to induce a specific cytotoxic T lymphocytes (CTLs) response against HepG2 cell line. METHODS: Immature DCs generated from peripheral blood monocytes were randomized into two groups: control DCs and whole tumor cell lysate-pulsed DCs. Phenotypic analysis of the DCs' cell maturation marker CD83 and co-stimulatory molecule CD86 was performed. HCC-specific cytotoxic activity of CD8+ CTLs was measured in vitro. RESULTS: Loading of DCs with necrotic whole cell lysate resulted in non-significant changes in DCs' expression of CD83, but a significant increase in expression of CD86. In addition, CD8+ CTLs stimulated with whole tumor cell lysate-pulsed DCs showed a high cytotoxic activity that specifically attack HepG2 cells. CONCLUSION: Our findings indicated that pulsation of DCs with whole tumor cell lysate prepared by repetitive freeze-thaw cycles could efficiently enhance the ability of DCs to induce proliferation and clonal expansion of CD8+ CTLs. Data herein, also indicated that whole tumor cell lysate-pulsed DCs triggers a specific CD8+ CTLs against HCC tumor cells.

Galectin-9: Diverse roles in hepatic immune homeostasis and inflammation.

Glycan-binding proteins, which include galectins, are involved at all stages of immunity and inflammation, from initiation through resolution. Galectin-9 (Gal-9) is highly expressed in the liver and has a wide variety of biological functions in innate and adaptive immunity that are instrumental in the maintenance of hepatic homeostasis. In the setting of viral hepatitis, increased expression of Gal-9 drives the expansion of regulatory T cells and contraction of effector T cells, thereby favoring viral persistence. The dichotomous nature of Gal-9 is evident in hepatocellular carcinoma, where loss of expression in hepatocytes promotes tumor growth and metastasis, whereas overexpression by Kupffer cells and endothelial cells inhibits the antitumor immune response. In nonalcoholic fatty liver disease, Gal-9 is involved indirectly in the expansion of protective natural killer T-cell populations. In ischemic liver injury, hepatocyte-derived Gal-9 is both diagnostic and cytoprotective. In drug-induced acute liver failure, plasma levels correlate with outcome. Here, we offer a synthesis of recent and emerging findings on Gal-9 in the regulation of hepatic inflammation. Ongoing studies are warranted to better elucidate the pathophysiology of hepatic immune-mediated diseases and to develop new therapeutic interventions using glycan-binding proteins. (Hepatology 2017;66:271-279).

HLA-G genetic variants and hepatocellular carcinoma: a meta-analysis.

Human leukocyte antigen (HLA)-G is a key tolerogenic molecule mainly expressed in the placenta and is crucial for implantation of the embryo and immunological tolerance of the fetus during pregnancy. However, under pathological conditions, such as cancer or viral infections, HLA-G can be expressed in other tissues. The gene coding for HLA-G (HLA-G, chromosome 6p21.3) presents numerous polymorphisms, some of them influencing its expression. One of the most studied, is the 14 bp ins/del (rs371194629) situated at the 3'-UTR of the gene. The insertion is thought to stabilize HLA-G mRNA. Different studies have analyzed the role of rs371194629 in hepatic injury, with either hepatotropic virus infection (i.e., HBV or HCV) or hepatocellular carcinoma (also induced by viral infection). Results from these studies are heterogeneous, differing with ethnicity and population age, and the role of rs371194629 is unclear. For these reasons, we decided to perform a meta-analysis of these results, concluding that the 14-bp ins/del polymorphism does not significantly contribute to hepatic injury.

TNF-α and IL-10 polymorphisms increase the risk to hepatocellular carcinoma in HCV infected individuals.

Hepatitis C virus (HCV) is the major cause of hepatocellular carcinoma (HCC). The risk to develop HCC increases with the severity of liver inflammation and hepatic fibrosis. It is believed that a balance between the releases of pro- and anti-inflammatory cytokines will determine the clinical course of HCV and the risk to develop HCC. The inteleukin-10 (IL-10) and the tumor necrosis factor alpha (TNF-α) play key roles in the Th1 and Th2 balance during the inflammatory response against HCV. The aim of the present study was to investigate the association between polymorphisms in TNF-α -308 G>A (rs1800629), IL-10 -1082 G>A (rs1800896) and -819/-592 (rs1800871/rs1800872) with HCC risk in individuals with HCV. The present study evaluated 388 chronic HCV patients. Polymorphisms were determined by real-time PCR. Diplotypes associated with low IL-10 production and the TNF-α GG genotype were significantly associated with HCC occurrence after multivariate logistic regression analysis (P = 0.027 and P = 0.029, respectively). Additionally, the IL-10 -819 (-592) TT (AA) genotype was significantly associated with multiple nodules and HCC severity according to BCLC staging (P = 0.044 and P = 0.025, respectively). Patients carrying low production haplotypes of IL-10 and the TNF-α GG genotype have higher risk to develop HCC. J. Med. Virol. 88:1587-1595, 2016. © 2016 Wiley Periodicals, Inc.

Clinical research on dendritic cell vaccines to prevent postoperative recurrence and metastasis of liver cancer.

We aimed to evaluate dendritic cell (DC) tumor vaccines for preventing liver cancer recurrence and metastasis. DCs were induced from mononuclear cells in the peripheral blood with recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) and recombinant human interleukin 4 (rhIL-4), followed by sensitization with lysis of autologous liver cancer cells. One hundred and sixty patients with hepatocellular carcinoma were randomly divided into two groups of 80. One group was treated postoperatively with six cycles of the DC tumor vaccine. The other group was treated postoperatively with six cycles of FOLFOX 6, beginning 1 week after surgery. After treatment with DC tumor vaccines, the levels of CD3+, CD4+, and CD8+, the ratio of CD4+ to CD8+ DC, and the serum levels of IL-12 and IFN-γ were significantly increased both in comparison to the pre-treatment levels (P < 0.001) and to the chemotherapy group (P < 0.001). After a postoperative follow-up of 18 months, the metastatic recurrence rate in the DC tumor vaccine group was significantly lower than that in the chemotherapy group (17.50 vs 48.75%, P < 0.005), and the survival rate of the patients in the DC tumor vaccine group was higher than that of the chemotherapy treatment group (86.25 vs 52.50%, P < 0.005). Treatment with DC tumor vaccines was safe and feasible. It can enhance the immunity of the patients, reduce the rates of metastasis and recurrence, and improve survival rates. This is a promising treatment for the prevention of postoperative recurrence in patients with liver cancer.

Difficulties of familes in caring for children and adolescents with mental disorders: an integrative review / Dificultades de las familias en la atención a niños y jóvenes con trastorno mental: una revisión integral / Dificuldades das famílias no cuidado à criança e ao adolescente com transtorno mental: uma revisão integrativa

Objective To identify the difficulties of families with children and/or adolescents with mental disorder. Method This is an integrative review. In December 2013, an electronic search was performed on Latin American Caribbean Literature on Health Sciences databases (LILACS) and on Electronic Medicus Index of the National Library of Medicine (MEDLINE) indexed in the Health Virtual Library (BVS) using a combination of descriptors and boolean operators as follows: mental disorders and child or adolescent and caregivers and/not health staff. Results 557 studies were identified, of which 15 were selected for this study. The findings indicated difficulties related to the care for or to interaction with children/adolescents with mental disorder. Conclusion The studies revealed difficulties related to everyday practices of care and feelings expressed during care practices, as well as in relationships with children or adolescents with mental disorder.

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Objetivo Identificar las dificultades de las familias con niños y/o adolescentes con desórdenes mentales. Método Se trata de una revisión integradora. Una búsqueda electrónica se realizó en diciembre de 2013, en la base de datos de la literatura caribeña Latinoamericano de Ciencias de la Salud (LILACS) y en el Índice de Electronic Medicus de la Biblioteca Nacional de Medicina (MEDLINE) indexados en la Biblioteca Virtual en Salud (BVS), utilizando combinación de descriptores y operadores booleanos transtornos mentales and niño and adolescentes and cuidadores and/not personal de salud. Resultados Se identificaron 557 estudios, de los cuales 15 fueron considerados para este estudio. Los hallazgos indican dificultades relacionadas con la atención o estar con los niños o adolescentes con trastornos mentales. Conclusión Se evidenciaron las dificultades relacionadas con las prácticas cotidianas y con los sentimientos durante la atención de quien vive con un niño o adolescente con trastornos mentales.
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Objetivo Identificar as dificuldades das famílias de crianças ou adolescentes com transtornos mentais. Método Trata-se de uma revisão integrativa realizada nas bases de dados da Literatura Latino-Americana do Caribe em Ciências da Saúde (LILACS) e no Index Medicus Eletrônico da National Library of Medicine (MEDLINE) indexadas na Biblioteca Virtual em Saúde (BVS) utilizando a combinação dos descritores e operadores booleanos transtornos mentais and criança or adolescente and cuidadores and/not pessoal de saúde, em dezembro de 2013. Resultados Foram identificados 557 estudos, dos quais 15 foram selecionados para este estudo. Os achados evidenciaram dificuldades relacionadas ao cuidado ou convívio com crianças ou adolescentes com transtorno mental. Conclusão Foram evidenciadas dificuldades relacionadas às práticas cotidianas e aos sentimentos manifestos durante o convívio e o cuidado de crianças ou adolescentes com transtornos mentais.
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FoxO3a nuclear localization and its association with ß-catenin and Smads in IFN-α-treated hepatocellular carcinoma cell lines.

Interferon-α2b (IFN-α2b) reduces proliferation and increases apoptosis in hepatocellular carcinoma cells by decreasing ß-catenin/TCF4/Smads interaction. Forkhead box O-class 3a (FoxO3a) participates in proliferation and apoptosis and interacts with ß-catenin and Smads. FoxO3a is inhibited by Akt, IκB kinase ß (IKKß), and extracellular-signal-regulated kinase (Erk), which promote FoxO3a sequestration in the cytosol, and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (p38 MAPK). We analyzed FoxO3a subcellular localization, the participating kinases, FoxO3a/ß-catenin/Smads association, and FoxO3a target gene expression in IFN-α2b-stimulated HepG2/C3A and Huh7 cells. Total FoxO3a and Akt-phosphorylated FoxO3a levels decreased in the cytosol, whereas total FoxO3a levels increased in the nucleus upon IFN-α2b stimulus. IFN-α2b reduced Akt, IKKß, and Erk activation, and increased JNK and p38 MAPK activation. p38 MAPK inhibition blocked IFN-α2b-induced FoxO3a nuclear localization. IFN-α2b enhanced FoxO3a association with ß-catenin and Smad2/3/7. Two-step coimmunoprecipitation experiments suggest that these proteins coexist in the same complex. The expression of several FoxO3a target genes increased with IFN-α2b. FoxO3a knockdown prevented the induction of these genes, suggesting that FoxO3a acts as mediator of IFN-α2b action. Results suggest a ß-catenin/Smads switch from TCF4 to FoxO3a. Such events would contribute to the IFN-α2b-mediated effects on cellular proliferation and apoptosis. These results demonstrate new mechanisms for IFN-α action, showing the importance of its application in antitumorigenic therapies.

Dendritic cells transfected with hepatocellular carcinoma (HCC) total RNA induce specific immune responses against HCC in vitro and in vivo.

BACKGROUND: Immunotherapy is an effective method for preventing metastasis and recurrence of carcinoma. Hepatocellular carcinoma (HCC) is a common malignancy with a high rate of recurrence, and has not successfully been introduced to immunotherapy. METHODS: Peripheral blood mononuclear cells were isolated from whole blood of HCC patients and stimulated to transform into dendritic cells (DCs). These DCs were then transfected with RNA extracted from HepG-2 hepatoma cells to induce expression of specific antigens. RESULTS: The transfected DCs stimulated T lymphocytes to produce cytotoxic T lymphocytes, which specifically attacked HepG-2 cells. Injection of T lymphocytes from HCC patients and transfected DCs into severe combined immunodeficiency mice limited the growth of HepG-2 tumors. CONCLUSION: A specific immune response against hepatoma can be generated in vivo by administering DCs transfected with RNA from a specific tumor. This method may have therapeutic application in humans to reduce recurrence of HCC.

Evaluation of a histocompatibility antigen related to hepatitis B virus in patients with hepatocellular carcinoma in the western Brazilian Amazon.

Hepatocellular carcinoma is an infection of variable incidence that can be caused by hepatitis B virus (HBV), which is endemic in the Amazon region. The diagnosis of HBV can be performed through the use of serum markers such as the hepatitis B surface antigen. The chronic HBV can cause mutagenesis and carcinogenesis, being the susceptibility of infection due to allele human leukocyte antigen (HLA). Thus, we evaluated the clinical, molecular and laboratory profile (histocompatibility complex) of HBV in 22 patients with hepatocellular carcinoma in Amazonia, including 18 males and 4 females, using a blood sample for generic HLA class II. The results showed increased frequency of disease evolution in adults between 25 and 64 years old, who comprised 19 of the 22 patients studied. Most patients (16/22) presented high levels of alpha-fetoprotein and transaminases (14/22). The most common HLA alleles were DRB1 04 (8/44), DRB1 08 (9/44), DRB 03 (16/44), and DQB1 04 (9/44). When we compared specific phenotype frequencies of HLA-DRB1 between patients and controls, we found that patients had a significantly higher frequency of allele DRB1 08 and a significantly lower frequency of DRB1 07 and DRB1 12 compared to previous studies on Asian and Amazonian populations suggesting ethnic differences. We suggest that alleles HLA-DRB 08, HLA-DRB 03 and HLA-DQB1 04 may be risk factors for hepatocellular carcinoma in Amazon.

Single nucleotide polymorphisms in CXCR1 gene and its association with hepatitis B infected patients in Saudi Arabia.

BACKGROUND/AIM: This study aims to investigate whether the SNPs of CXCR1 gene, could predict the likelihood of viral persistence and/or disease progression. MATERIAL AND METHODS: We investigated the association of two different SNPs (rs2234671, and rs142978743) in 598 normal healthy controls and 662 HBV patients from a Saudi ethnic population. The HBV patients were categorized into inactive carriers (n = 428), active carriers (n = 162), cirrhosis (n = 54) and Cirrhosis-HCC (n = 18) sub-groups. Genetic variants in CXCR1 were determined by polymerase chain reaction (PCR)-based DNA direct sequencing. RESULTS: The frequency of the risk allele 'C' for the SNP, rs2234671 was found to be insignificant when the patient group was compared to the uninfected control group, however, a significant distribution of the allele 'C' of rs2234671 was observed among active HBV carriers + cirrhosis + cirrhosis - HCC vs. inactive HBV carriers with an OR = 1.631 (95% C.I. 1.016-2.616) and p = 0.032. However, no significant association was observed for rs142978743 when the distribution of risk allele was analyzed among the different patient groups (i.e. inactive carriers, active carriers, cirrhosis and HCC). Furthermore, the most common haplotype, Haplo-1 (AG), was found to have an insignificant frequency distribution between HBV cases and controls, while the same haplotype was found to be significantly distributed when active carriers + cirrhosis + cirrhosis - HCC patients were compared to inactive HBV carriers with a frequency of 0.938 and p = 0.0315. Haplo-2 (AC) was also found to be significantly associated with a frequency of 0.058 and p = 0.0163. CONCLUSION: The CXCR1 polymorphism, rs2234671 was found to be associated with chronic HBV infection and may play a role in disease activity.

Canadian national retrospective chart review comparing the long term effect of cyclosporine vs. tacrolimus on clinical outcomes in patients with post-liver transplantation hepatitis C virus infection.

The transition from regular use of cyclosporine to the newer calcineurin-inhibitors, such as tacrolimus, has been suggested as a contributing factor to the "era effect" of worsening outcomes of post-transplant HCV recurrence. This retrospective medical chart review of 458 patients was undertaken to evaluate the role of immunosuppressant choice (cyclosporine vs. tacrolimus) in determining virologic response and clinical outcomes of post-liver transplant HCV infection recurrence. Our results showed that patients undergoing interferon-based treatment taking cyclosporine have significantly better odds (OR: 2.59, P = 0.043) of presenting a sustained viral response (66.7%) compared to tacrolimus (52.8%). This did not result in a significant effect on post-liver transplantation clinical events including HCV-related deaths, graft loss, fibrosing cholestatic hepatitis, hepatocellular carcinoma or graft rejection. Other variables, which showed a significant relationship with the achievement of sustained viral response included donor age (OR 0.96, P = 0.001) and HCV genotype 1 infection (OR 0.05, P < 0.001). The observed significant increase in the odds of acute/hyperacute (OR 6.49, P = 0.001) and chronic rejection (OR 10.45, P < 0.001) in the cyclosporine to tacrolimus switch group, accompanied by an increase in the odds of HCV-related death (OR 2.30, P < 0.047) compared to tacrolimus merits further study. A significant increase (P < 0.044) in new-onset diabetes mellitus with tacrolimus (28.3%) compared to cyclosporine (18.7%) was also observed. Pre-transplant diabetes mellitus was associated with a significantly increased likelihood of graft fibrosis (HR 1.95, P = 0.003).

Hepatic local micro-environmental immune status in hepatocellular carcinoma and cirrhotic tissues / Estatus inmune microambiental local hepático en el carcinoma hepatocelular y los Tejidos Cirróticos

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours in the world, especially in Guangxi, China. The causes and mechanism of its tumourigenesis and development have not been completely clarified Some studies revealed that the hepatic local cellular immune function was one of the factors. In the present study, the local micro-environmental immune status was explored by investigating the number, distribution and function of CD3, CD57, CD20, CD68, and granzyme B (GrB) positive cells in 60 patients with HCC and 62 patients with liver cirrhosis (LC) and its relationship with the prognosis of the patients. The results showed that the number of T and B lymphocytes and natural killer (NK) cells in the liver of HCC patients was significantly higher than that in the LC and normal controls; while the number of macrophages (Mphi) was significantly lower The number of Mphi in the tissues decreased successively with the decrease of HCC differentiation; GrB-expressing cells in the liver predominantly consisted of CD57 positive cells. The number of NK cells, B lymphocytes and GrB-expressing cells in the cancerous tissues of stage I and II was significantly higher than that of stages III and IV. The number of T lymphocytes, NK cells, Mphi, and GrB-expressing lymphocytes in HCC cases without metastasis in 15 months was significantly higher than in the metastatic counterparts. The number of T and B lymphocytes, NK cells, and GrB-expressing cells decreased in patients with the progression of the HCC. These results suggest that the number of T and B lymphocytes, NK cells, Mphi and GrB-positive lymphocytes might be important markers in the estimation of hepatic local immune status and be useful factors for predicting the prognosis of HCC patients.