RESUMEN
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
Asunto(s)
Células Estrelladas Hepáticas , Cirrosis Hepática , Humanos , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/patología , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Animales , Miofibroblastos/metabolismo , Miofibroblastos/patologíaRESUMEN
BACKGROUND: Colorectal cancer (CRC) is the 3rd most common cancer in the world and colonic carcinogenesis is a multifactorial disease that involves environmental and genetic factors. Gut microbiota plays a critical role in the regulation of intestinal homeostasis. Increasing evidence shows that the gut microbiome plays a role in CRC development and may be a biomarker for early diagnosis. OBJECTIVE: This study aimed to determine the clinical prognostic significance of gut microbiota in CRC patients in the Turkish population by metagenomic analysis and to determine the microbial composition in tumor tissue biopsy samples. METHODS: Tissue biopsies were taken from the participants with sterile forceps during colonoscopy and stored at -80 °C. Then, DNA isolation was performed from the tissue samples and the V3-V4 region of the 16 S rRNA gene was sequenced on the Illumina MiSeq platform. Quality control of the obtained sequence data was performed. Operational taxonomic units (OTUs) were classified according to the Greengenes database. Alpha diversity (Shannon index) and beta diversity (Bray-Curtis distance) analyses were performed. The most common bacterial species in CRC patients and healthy controls were determined and whether there were statistically significant differences between the groups was tested. RESULTS: A total of 40 individuals, 13 CRC patients and 20 healthy control individuals were included in our metagenomic study. The mean age of the patients was 64.83 and BMI was 25.85. In CRC patients, the level of Bacteroidetes at the phylum taxonomy was significantly increased (p = 0.04), the level of Clostridia at the class taxonomy was increased (p = 0.23), and the level of Enterococcus at the genus taxonomy was significantly increased (p = 0.01). When CRC patients were compared with the control group, significant increases were detected in the species of Gemmiger formicilis (p = 0.15), Prevotella copri (p = 0.02) and Ruminococcus bromii (p = 0.001) at the species taxonomy. CONCLUSIONS: Metagenomic analysis of intestinal microbiota composition in CRC patients provides important data for determining the treatment options for these patients. The results of this study suggest that it may be beneficial in terms of early diagnosis, poor prognosis and survival rates in CRC patients. In addition, this metagenomic study is the first study on the colon microbiome associated with CRC mucosa in the Turkish population.
RESUMEN
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2) continues to cause substantial morbidity and mortality. Most infections are mild; however, some patients experience severe and potentially fatal systemic inflammation, tissue damage, cytokine storm, and acute respiratory distress syndrome. Patients with chronic liver disease have been frequently affected, experiencing high morbidity and mortality. In addition, elevated liver enzymes may be a risk factor for disease progression, even in the absence of underlying liver disease. While the respiratory tract is a primary target of SARS-CoV-2, it has become evident that COVID-19 is a multisystemic infectious disease. The hepatobiliary system might be influenced during COVID-19 infection, ranging from a mild elevation of aminotransferases to the development of autoimmune hepatitis and secondary sclerosing cholangitis. Furthermore, the virus can promote existing chronic liver diseases to liver failure and activate the autoimmune liver disease. Whether the direct cytopathic effects of the virus, host reaction, hypoxia, drugs, vaccination, or all these risk factors cause liver injury has not been clarified to a large extent in COVID-19. This review article discussed the molecular and cellular mechanisms involved in the pathogenesis of SARS-CoV-2 virus-associated liver injury and highlighted the emerging role of liver sinusoidal epithelial cells (LSECs) in virus-related liver damage.
Asunto(s)
COVID-19 , Hepatopatías , Humanos , COVID-19/complicaciones , SARS-CoV-2 , Inflamación , Hepatopatías/etiologíaRESUMEN
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular entities, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), immune cells, myeloid-derived suppressor cells (MDSCs), immune checkpoint molecules and cytokines that promote cancer cell growth, as well as their drug resistance. HCC usually arises in the context of cirrhosis, which is always associated with an enrichment of activated fibroblasts that are owed to chronic inflammation. CAFs are a major component of the TME, providing physical support in it and secreting various proteins, such as extracellular matrices (ECMs), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (ILGF1/2) and cytokines that can modulate tumor growth and survival. As such, CAF-derived signaling may increase the pool of resistant cells, thus reducing the duration of clinical responses and increasing the degree of heterogeneity within tumors. Although CAFs are often implicated to be associated with tumor growth, metastasis and drug resistance, several studies have reported that CAFs have significant phenotypic and functional heterogeneity, and some CAFs display antitumor and drug-sensitizing properties. Multiple studies have highlighted the relevance of crosstalk between HCC cells, CAFs and other stromal cells in influence of HCC progression. Although basic and clinical studies partially revealed the emerging roles of CAFs in immunotherapy resistance and immune evasion, a better understanding of the unique functions of CAFs in HCC progression will contribute to development of more effective molecular-targeted drugs. In this review article, molecular mechanisms involved in crosstalk between CAFs, HCC cells and other stromal cells, as well as the effects of CAFs on HCC-cell growth, metastasis, drug resistance and clinical outcomes, are comprehensively discussed.
Asunto(s)
Fibroblastos Asociados al Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Citocinas/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Microambiente Tumoral/fisiología , Progresión de la EnfermedadRESUMEN
Macroautophagy/autophagy is an evolutionarily conserved cellular stress response mechanism. Autophagy induction in the tumor microenvironment (stroma) has been shown to support tumor metabolism. However, cancer cell-derived secreted factors that initiate communication with surrounding cells and stimulate autophagy in the tumor microenvironment are not fully documented. We identified CTF1/CT-1 (cardiotrophin 1) as an activator of autophagy in fibroblasts and breast cancer-derived carcinoma-associated fibroblasts (CAFs). We showed that CTF1 stimulated phosphorylation and nuclear translocation of STAT3, initiating transcriptional activation of key autophagy proteins. Additionally, following CTF1 treatment, AMPK and ULK1 activation was observed. We provided evidence that autophagy was important for CTF1-dependent ACTA2/α-SMA accumulation, stress fiber formation and fibroblast activation. Moreover, promotion of breast cancer cell migration and invasion by activated fibroblasts depended on CTF1 and autophagy. Analysis of the expression levels of CTF1 in patient-derived breast cancer samples led us to establish a correlation between CTF1 expression and autophagy in the tumor stroma. In line with our in vitro data on cancer migration and invasion, higher levels of CTF1 expression in breast tumors was significantly associated with lymph node metastasis in patients. Therefore, CTF1 is an important mediator of tumor-stroma interactions, fibroblast activation and cancer metastasis, and autophagy plays a key role in all these cancer-related events.Abbreviations: ACTA2/α-SMA: actin, alpha 2, smooth muscle CAFs: cancer- or carcinoma-associated fibroblasts CNT Ab.: control antibody CNTF: ciliary neurotrophic factor CTF1: cardiotrophin 1 CTF1 Neut. Ab.: CTF1-specific neutralizing antibody GFP-LC3 MEF: GFP-fused to MAP1LC3 protein transgenic MEF LIF: leukemia inhibitory factor IL6: interleukin 6 MEFs: mouse embryonic fibroblasts MEF-WT: wild-type MEFs OSM: oncostatin M TGFB/TGFß: transforming growth factor beta.
Asunto(s)
Autofagia , Neoplasias de la Mama , Citocinas , Animales , Ratones , Línea Celular Tumoral , Movimiento Celular , Fibroblastos/metabolismo , Interleucina-6/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Humanos , Femenino , Neoplasias de la Mama/metabolismo , Citocinas/metabolismoRESUMEN
Background and Aim: The aim of the present study was to examine the etiology of hepatocellular carcinoma (HCC) by underlying cause and determine the characteristics and clinical features of patients with HCC. Materials and Methods: The study comprised 1802 HCC patients diagnosed and followed up by Liver Diseases Outpatient Clinics in 14 tertiary centers in Turkey between 2001 and 2020. Results: The mean age was 62.3±10.7 years, and 78% of them were males. Of the patients, 82% had cirrhosis. Hepatitis B virus (HBV) infection was the most common etiology (54%), followed by hepatitis C virus (HCV) infection (19%) and nonalcoholic fatty liver disease (NAFLD) (10%). Of the patients, 56% had a single lesion. Macrovascular invasion and extrahepatic spread were present in 15% and 12% of the patients, respectively. The median serum alpha-fetoprotein level was 25.4 ng/mL. In total, 39% of the patients fulfilled the Milan Criteria. When we compared the characteristics of patients diagnosed before and after January 2016, the proportion of NAFLD-related HCC cases increased after 2016, from 6.6% to 13.4%. Conclusion: Chronic HBV and HCV infections remain the main causes of HCC in Turkey. The importance of NAFLD as a cause of HCC is increasing.
RESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve, emerging novel variants with spike protein mutations. Although most mutations emerged in the SARS-CoV-2 genome are neutral or mildly deleterious, a small number of mutations can affect virus phenotype that confers the virus a fitness advantage. These mutations can enhance viral replication, raise the risk of reinfection and blunt the potency of neutralizing antibodies triggered by previous infection and vaccination. Since December 2020, the SARS-CoV-2 has emerged five quickly spreading strains, designated variants of concern (VOCs), including the Alpha (B.1.1.7) variant, the Beta (B.1.351) variant, the Gamma (P.1) variant, the Delta (B.1.617.2) variant and the Omicron (B.1.1.529) variant. These variants have a high number of the mutations in the spike protein that promotes viral cell entry through the angiotensin-converting enzyme -2 (ACE2). Mutations that have arisen in the receptor binding domain (RBD) of the spike protein are of great concern due to their potential to evade neutralizing antibodies triggered by previous infection and vaccines. The Alpha variant emerged in the United Kingdom in the second half of 2020 that has spread quickly globally and acquired the E484K mutation in the United Kingdom and the United States. The Beta and Gamma variants emerged in South Africa and Brazil, respectively, that have additional mutations at positions E484 and K417 in the RBD. SARS-CoV-2 variants containing the combination of N501Y, E484K, and K417N/T mutations exhibit remarkably decreased sensitivity to neutralizing antibodies mediated by vaccination or previous infection. The Gamma variant may result in more severe disease than other variants do even in convalescent individuals. The Delta variant emerged in India in December 2020 and has spread to many countries including the United States and the United Kingdom. The Delta variant has 8 mutations in the spike protein, some of which can influence immune responses to the key antigenic regions of RBD. In early November 2021, the Omicron (B.1.1.529) variant was first detected in Botswana and South Africa. The Omicron variant harbors more than 30 mutations in the spike protein, many of which are located within the RBD, which have been associated with increased transmissibility and immune evasion after previous infection and vaccination. Additionally, the Omicron variant contains 3 deletions and one insertion in the spike protein. Recently, the Omicron variant has been classified into three sublineages, including BA.1, BA.2, and BA.3, with strikingly different genetic characteristics. The Omicron BA.2 sublineage has different virological landscapes, such as transmissibility, pathogenicity and resistance to the vaccine-induced immunity compared to BA.1 and BA.3 sublineages. Mutations emerged in the RBD of the spike protein of VOCs increase viral replication, making the virus more infectious and more transmissible and enable the virus to evade vaccine-elicited neutralizing antibodies. Unfortunately, the emergence of novel SARS-CoV-2 VOCs has tempered early optimism regarding the efficacy of COVID-19 vaccines. This review addresses the biological and clinical significance of SARS-CoV-2 VOCs and their impact on neutralizing antibodies mediated by existing COVID-19 vaccines.
RESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is known to be the most common liver disease in the world, and there are currently no approved pharmacological treatments to prevent or treat this condition. In addition to being associated with an increased risk of hepatocellular carcinoma and cirrhosis, NAFLD has now become the leading cause of liver failure-associated transplantation. The 16S rRNA gene which conserved regions can serve as universal primer binding sites for PCR amplification of gene fragments, while hypervariable regions contain significant sequence diversity useful for prokaryotic identification purposes. 16S rRNA gene sequences can be use by researchers to identify prokaryotic taxonomy found in clinical samples. As a result of increasing microbiota studies with developing technological developments, the role of intestinal microbiota in the pathogenesis of NAFLD is revealed in an important way. In this study, it was aimed to determine the clinical prognostic importance of gut microbiota in the pathogenesis of NAFLD and to determine the microbial composition with intestinal mucosal biopsy samples in NAFLD patients. MATERIAL AND METHOD: We included 20 patients diagnosed with NAFLD as a result of liver function tests, histological, ultrasonographic, biopsy evidence and 20 normal control groups created under exclusion criteria in this study. The healthy control group of the same age and gender as the patients were determined to be equal, and the age, gender, BMI, insulin resistance, AST, ALT levels of the individuals were recorded for analysis. Intestinal mucosal biopsy samples were taken from the individuals included in the study under sterile conditions. Microbial results were obtained as a result of 16S rRNA amplicon metagenomic processes. The region of approximately 1500 bp covering the V1-V9 region of the 16S rRNA gene was targeted to detect microbial diversity. The amplified regions were sequenced using next-generation sequencing. Operational Taxonomic Unit (OTU) value was obtained with bioinformatics software with the obtained sequence data. The analysis of the recorded parameters was done with the SPSS.19 statistical program. RESULTS: In the designed study, 16 phyla, 28 class, 56 order, 128 family, 415 genera, 1041 species microorganisms were analyzed taxonomically in a total of 40 individuals. In our study, Intestinal microbial diversity is lower in NAFLD patients compared to control group individuals. In addition, gram-negative bacteria were found to be more dominant in NAFLD patients. As a phylum, Proteobacteria increased in NAFLD group, Bacteroidetes and Actinobacteria in control group, while Firmicutes had equal distribution in both groups. BMI OR = 6.37, 95 %CI (0.39-0.40) p value was 0.001 in laboratory data, whereas Proteobacteria OR = 1.754, 95% CI (0.901-3.416), p value 0.05 in microbial profile. CONCLUSION: The 16S rRNA metagenomic study of intestinal microbiota using colonic mucosal biopsy samples in NAFLD disease was the first study in the Turkish population, and important data were obtained for other studies. In the data obtained, we think Proteobacteria, Ruminococcaceae, Escherichia coli and Bacilli are very important in both diagnostic and treatment options as a microbial profile in NAFLD.
Asunto(s)
Microbioma Gastrointestinal , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Biopsia , Microbioma Gastrointestinal/genética , Humanos , Neoplasias Hepáticas/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , ARN Ribosómico 16S/genéticaRESUMEN
Background: Large HCCs can often be associated with low levels of cirrhosis. However, inflammation is also regarded as a driver of HCC growth. Objectives: To compare patients with large >5 cm HCCs having high versus low serum inflammation parameters. Materials and methods: A Turkish patient HCC dataset with known survivals was retrospectively analyzed after dichotomization according to several clinical inflammation markers. Results: Amongst several parameters examined, only AST levels were significantly associated with elevated AFP levels and increased percent PVT and tumor multifocality. The dichotomization of the cohort according to high or low AST levels resulted in 2 subcohorts with a 5-fold difference in median survival. The 2 AST-dichotomised cohorts comprised patients with similar large-size HCCs, but which were significantly different with respect to serum AFP levels, percent PVT, and percent tumor multifocality. Conclusions: Two large-sized HCC phenotypes were identified. One had more aggressive HCC characteristics, higher inflammatory indices, and worse survival. The other had the opposite. Despite inflammation being important for the growth of some large tumors, others of a similar size likely have different growth mechanisms.
RESUMEN
The microbiome modulates key processes in metabolism, inflammation, and immunity and plays pivotal roles in many gastrointestinal and liver diseases. Recent experimental studies have demonstrated a key role of the microbiome in hepatocarcinogenesis. Dysfunctions of the gut bacterial flora have a significant effect on liver disease. Dysbiosis is found to be associated with chronic liver diseases. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related mortality. The majority of HCC develops in patients with chronic liver disease, caused by chronic viral hepatitis, nonalcoholic fatty liver disease (NAFLD), and alcohol-related fatty liver disease. This review discusses molecular mechanisms of gut microbiome-related hepatocarcinogenesis and the impact of dysbiosis on chronic liver disease progression.
Asunto(s)
Carcinoma Hepatocelular/etiología , Microbioma Gastrointestinal , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/etiología , Animales , Carcinogénesis , Carcinoma Hepatocelular/patología , Disbiosis/complicaciones , Humanos , Neoplasias Hepáticas/patología , RatonesRESUMEN
Covid-19 Pneumonia of SARS-CoV-2 pandemic infection, persists to have high disease burden especially in cancer patients. Increased inflammation and thromboembolic processes are blamed to influence cancer patients more than the others but due to lack of knowledge regarding the pathophysiology of the both the virus itself and the response of the host, more basic and translational disease modeling research is needed to understand Cancer-Covid-19 interaction. In this study, serum samples from the patients, who were hospitalized due to Covid-19 pneumonia, applied to different cancer cells and cytotoxicity, motility, proliferation and gene expression analysis were performed. Serum samples derived from healthy volunteers and the fetal bovine serum that is used regularly in cell culture experiments used as controls. Hospitalized Covid-19 patients who had also cancer, were retrospectively screened, and their clinical course were recorded. Overall 12 Patient (PS) and 4 healthy serums (CS) were included in the experiments. PS applied cells showed increased motility in A549 cells as well as lost cell to cell connection in MCF7 and HCT116 cells, and induced expression of VIM, ZEB1 and SNAIL2 mRNA levels. Eight cancer diagnosed patients who were hospitalized due to Covid-19 between April and September 2020 were also reviewed retrospectively, which 5 of them were dead during SARS-CoV-2 infection. Thorax CT images of the 2 patients showed increased metastatic nodules in the lungs as of January 2021. The results of the study indicate that metastasis may be one of the prolonged consequences of COVID-19 pandemic in cancer sufferers.
Asunto(s)
COVID-19/inmunología , Transición Epitelial-Mesenquimal/fisiología , Sueros Inmunes , Neoplasias/patología , Adulto , Anciano , COVID-19/complicaciones , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Citotoxicidad Inmunológica , Femenino , Humanos , Sueros Inmunes/efectos adversos , Sueros Inmunes/toxicidad , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/virología , Masculino , Persona de Mediana Edad , Neoplasias/inmunologíaRESUMEN
ABSTRACT: We aimed to elucidate the frequency of polymorphic genotypes and alleles of patatin-like phospholipase domain containing 3 rs738409 polymorphism and its possible associations with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis in a cohort from Turkey.We enrolled 200 patients diagnosed with NAFLD and genotyped for rs738409 I148M polymorphism by real-time polymerase chain reaction, particularly by melting curve analysis. SPSS analysis software was used for statistical significance. Continuous variable values were expressed as meanâ±âstandard deviation. Significant statistical level was chosen as pâ =â0.05.Our results demonstrate in a cohort from Turkey that rs738409 Câ>âG polymorphism (I148M) of patatin-like phospholipase domain containing 3 gene is significantly able to affect individuals to have NAFLD in unadjusted regression model.Consistent with the previous studies in other populations, our study group showed a significantly higher risk of having NAFLD in unadjusted regression model but not in the adjusted model indicating that non-genetic factors such as age and sex may be responsible for the association. However, independent studies need to validate our findings with a larger group of NAFLD patients, as well as in different ethnic cohorts.
Asunto(s)
Lipasa/genética , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Adulto , Glucemia , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Reacción en Cadena en Tiempo Real de la Polimerasa , Turquía/epidemiologíaRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of the coronavirus disease 2019 (COVID-19), has been identified in China in late December 2019. SARS-CoV-2 is an enveloped, positive-sense, single-stranded RNA betacoronavirus of the Coronaviridae family. Coronaviruses have genetic proofreading mechanism that corrects copying mistakes and thus SARS-CoV-2 genetic diversity is extremely low. Despite lower mutation rate of the virus, researchers have detected a total of 12,706 mutations in the SARS-CoV-2 genome, the majority of which were single nucleotide polymorphisms. Sequencing data revealed that the SARS-CoV-2 accumulates two-single nucleotide mutations per month in its genome. Recently, an amino acid aspartate (D) to glycine (G) (D614G) mutation due to an adenine to guanine nucleotide change at position 23,403 at the 614th amino-acid position of the spike protein in the original reference genotype has been identified. The SARS-CoV-2 viruses that carry the spike protein D614G mutation have become dominant variant around the world. The D614G mutation has been found to be associated with 3 other mutations in the spike protein. Clinical and pseudovirus experimental studies have demonstrated that the spike protein D614G mutation alters the virus phenotype. However, the impact of the mutation on the rate of transmission between people, disease severity and the vaccine and therapeutic development remains unclear. Three variants of SARS-CoV-2 have recently been identified. They are B.1.1.7 (UK) variant, B.1.351 (N501Y.V2, South African) variant and B.1.1.28 (Brazilian) variant. Epidemiological data suggest that they have a higher transmissibility than the original variant. There are reports that some vaccines are less efficacious against the B.1.351 variant. This review article discusses the effects of novel mutations in the SARS-CoV-2 genome on transmission, clinical outcomes and vaccine development.
RESUMEN
INTRODUCTION: Hepatocellular carcinoma is associated with several chronic inflammatory conditions. It is increasingly understood that the inflammation may be part of the carcinogenic process and prognostically important. OBJECTIVE: To evaluate the serum levels of three inflammation markers in relation to survival in HCC patients. METHODS: We retrospectively examined the serum levels of CRP, albumin and ESR, both singly and in combination, in relation to patient survival. RESULTS: Survival worsened with increase in CRP or ESR or decrease in albumin levels. Combinations of CRP plus albumin or CRP plus ESR were associated with an even greater range of survival (3-fold), together with significant differences in maximum tumor diameter (PVT) and percent of patients with portal vein thrombosis (PVT). The triplet of CRP plus albumin plus ESR was associated with a sevenfold difference in survival, comparing low vs high parameter levels. These significant differences were found in patients with small or large tumors. CONCLUSIONS: Combinations of CRP with albumin or ESR or all three parameters together significantly related to differences in survival and to differences in MTD and percent PVT, in patients with both small and large size HCCs.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Albúminas , Biomarcadores , Proteína C-Reactiva , Humanos , Estudios RetrospectivosRESUMEN
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is often associated with metabolic syndrome (type 2 diabetes, hypertension, hypertriglyceridemia, insulin resistance, and obesity). NAFLD is multi-factorial in pathogenesis with some genetic predisposition. The variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) is known to be an independent risk factor for hepatocellular cancer (HCC). The aim of this study was to investigate the role of PNPLA3 polymorphism as the risk factor for NAFLD. METHODOLOGY: Patients had histological, ultrasonographic, biopsy evidence of NAFLD (n=248) and 81 controls were studied for PNPLA3 polymorphism. PNPLA3 genotyping was done from peripheral blood DNA by real-time polymerase chain reaction (RT-PCR). RESULTS: PNPLA3 genotyping of the groups NAFLD (CC [n = 76], CG [n = 83], GG [n = 89]) and control (CC [n= 42], CG [n = 22], GG [n = 17]) was determined. In the patient group, the G allele was 261 (52.63%) and the C allele was 235 (47.37%), whereas in the control group, the G allele was 56 (34.54%) and the C allele was 106 (65.43%). In our study, 53 out of 174 women had GG allele and 54 out of 155 men had GG allele. CONCLUSION: The findings suggest that there is a predominant relationship between men with PNPLA3 I148M variant with NAFLD in women. Patients with NAFLD carrying PNPLA3 rs738409 G>C variant are at higher risk of NAFLD.
Asunto(s)
Lipasa/genética , Proteínas de la Membrana/genética , Mutación , Enfermedad del Hígado Graso no Alcohólico/genética , Carcinoma Hepatocelular , Decepción , Humanos , Neoplasias Hepáticas , Síndrome Metabólico , Factores de RiesgoAsunto(s)
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Estudio de Asociación del Genoma Completo/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologíaRESUMEN
AIM: Hepatitis C virus (HCV) affects approximately 250 million people worldwide. If patients are untreated, 80% of patients with chronic HCV develop liver failure, liver cirrhosis (LC), and hepatocellular carcinoma (HCC). HCV genotype 1 is the most prevalent among the infected individuals with HCV. Hepatic steatosis is known as accumulation of lipid molecules in hepatocytes, and its prevalence is approximately 55% in CHC infection. The reason of HCV-related hepatic steatosis in CHC infection is mainly HCV core protein. HCV core protein inhibits activities of microsomal triglyceride transfer protein (MTP) which is a lipid transfer protein expressed in the liver. The -493G/T polymorphism in the promoter region of MTP gene has been associated with HCV-related hepatic steatosis. This polymorphism in MTP gene influences MTP mRNA expression, therefore which might also affect lipid transfer. We evaluated the association between MTP gene polymorphism and the risk of HCV genotype 1-related hepatic steatosis. METHODS: In the current study, MTP gene polymorphism was explored in 144 biopsy-proven chronic HCV genotype 1 patients by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The results showed that there were no any difference between the steatosis and the non-steatosis groups for the allele and genotype frequencies of the -493G/T polymorphism (Pâ¯>â¯.05). Moreover, MTP genotypes (GG vs. TGâ¯+â¯TT) were not associated with BMI, fibrosis stages and the levels of biochemical parameters. Additionally, there were statistically significant differences in the biochemical parameters including triglyceride, total cholesterol, LDL, VLDL levels between the two groups (Pâ¯<â¯.05). CONCLUSIONS: In conclusion, the current study demonstrates for the first time that MTP gene -493G/T polymorphism has not a major effect on the risk of HCV genotype 1-related hepatic steatosis in Turkish population. Further studies are imperative to clarify the association of this polymorphism with HCV genotype 1 infection in HCV-related hepatic steatosis.
Asunto(s)
Proteínas Portadoras/genética , Hígado Graso/genética , Hepacivirus/genética , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Hepatitis C/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
INTRODUCTION: Several markers of systemic inflammation, including blood C-reactive protein, platelet lymphocyte ratio (PLR) and neutrophil lymphocyte ratio (NLR) have been identified as independent prognosticators for hepatocellular carcinoma (HCC). METHODS: To attempt to understand the significance of these markers, they were examined in relation to 4 tumour parameters, namely maximum tumour diameter (MTD), tumour multifocality, portal vein thrombosis (PVT) and blood alpha-fetoprotein (AFP) levels. RESULTS: Using linear and logistic regression models, we found that C-reactive protein and PLR on single variables, were statistically significantly related to the tumour parameters. In a logistic regression final model, CRP was significantly related to MTD, AFP and PVT, and the Glasgow Index significantly related to MTD and AFP. Results of the area under the receiver operating characteristic curves (ROC), showed that the areas for PLR and CRP were statistically significant for high versus low MTD and for presence versus absence of PVT. CRP alone was significant for high versus low AFP. CONCLUSIONS: These analyses suggest that the prognostic usefulness of the inflammatory markers PLR and CRP (but not NLR) may be due to their reflection of parameter values for tumour growth and invasiveness.
RESUMEN
The hepatocellular carcinoma (HCC) tumor marker alpha-fetoprotein (AFP) is only elevated in about half of the HCC patients, limiting its usefulness in following the effects of therapy or screening. New markers are needed. It has been previously noted that the inflammation markers C-reactive protein (CRP) and platelet-lymphocyte ratio (PLR) are prognostically important and may reflect HCC aggressiveness. We therefore examined these 2 markers in a low-AFP HCC cohort and found that for HCCs > 2 cm, both markers significantly rise with an increasing maximum tumor diameter (MTD). We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Youden index value for each marker, and their area-under-the-curve values for each MTD group. Patients were dichotomized into 2 groups based on the CRP and PLR from the receiver-operating characteristic curve analysis. In the logistic regression models of the 4 different MTD patient groups, CRP and PLR levels were statistically significant to estimate MTD in univariate logistic regression models of MTD groups > 2 cm. CRP and PLR were then combined, and the combination was statistically significant to estimate MTD groups of 3-, 4-, and 5-cm cutoffs. CRP and PLR thus have potential as tumor markers for low-AFP HCC patients, and possibly for screening.