Liver Hepatocellular Carcinoma Research Articles

Single-cell RNA sequencing revealed potential targets for immunotherapy studies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a solid tumor prone to chemotherapy resistance, and combined immunotherapy is expected to bring a breakthrough in HCC treatment. However, the tumor and tumor microenvironment (TME) of HCC is highly complex and heterogeneous, and there are still many unknowns regarding tumor cell stemness and metabolic reprogramming in HCC. In this study, we combined single-cell RNA sequencing data from 27 HCC tumor tissues and 4 adjacent non-tumor tissues, and bulk RNA sequencing data from 374 of the Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) samples to construct a global single-cell landscape atlas of HCC. We analyzed the enrichment of signaling pathways of different cells in HCC, and identified the developmental trajectories of cell subpopulations in the TME using pseudotime analysis. Subsequently, we performed transcription factors regulating different subpopulations and gene regulatory network analysis, respectively. In addition, we estimated the stemness index of tumor cells and analyzed the intercellular communication between tumors and key TME cell clusters. We identified novel HCC cell clusters that specifically express HP (HCC_HP), which may lead to higher tumor differentiation and tumor heterogeneity. In addition, we found that the HP gene expression-positive neutrophil cluster (Neu_AIF1) had extensive and strong intercellular communication with HCC cells, tumor endothelial cells (TEC) and cancer-associated fibroblasts (CAF), suggesting that clearance of this new cluster may inhibit HCC progression. Furthermore, ErbB signaling pathway and GnRH signaling pathway were found to be upregulated in almost all HCC tumor-associated stromal cells and immune cells, except NKT cells. Moreover, the high intercellular communication between HCC and HSPA1-positive TME cells suggests that the immune microenvironment may be reprogrammed. In summary, our present study depicted the single-cell landscape heterogeneity of human HCC, identified new cell clusters in tumor cells and neutrophils with potential implications for immunotherapy research, discovered complex intercellular communication between tumor cells and TME cells.

Hepatocyte FBXW7-dependent activity of nutrient-sensing nuclear receptors controls systemic energy homeostasis and NASH progression in male mice

Nonalcoholic steatohepatitis (NASH) is epidemiologically associated with obesity and diabetes and can lead to liver cirrhosis and hepatocellular carcinoma if left untreated. The intricate signaling pathways that orchestrate hepatocyte energy metabolism and cellular stress, intrahepatic cell crosstalk, as well as interplay between peripheral tissues remain elusive and are crucial for the development of anti-NASH therapies. Herein, we reveal E3 ligase FBXW7 as a key factor regulating hepatic catabolism, stress responses, systemic energy homeostasis, and NASH pathogenesis with attenuated FBXW7 expression as a feature of advanced NASH. Multiomics and pharmacological intervention showed that FBXW7 loss-of-function in hepatocytes disrupts a metabolic transcriptional axis conjointly controlled by the nutrient-sensing nuclear receptors ERRα and PPARα, resulting in suppression of fatty acid oxidation, elevated ER stress, apoptosis, immune infiltration, fibrogenesis, and ultimately NASH progression in male mice. These results provide the foundation for developing alternative strategies co-targeting ERRα and PPARα for the treatment of NASH.

Serum wisteria floribunda agglutinin-positive human Mac-2 binding protein is unsuitable as a diagnostic marker of occult hepatocellular carcinoma in end-stage liver cirrhosis.

Serum glycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) is a marker of liver fibrosis and hepatocellular carcinoma (HCC). In this study, we aimed to evaluate the diagnostic ability of WFA+-M2BP for occult HCC, which current diagnostic imaging tests fail to detect. Patients who underwent hepatectomy for liver transplantation (LT) and whose whole liver could be sliced and subjected to histological examination between 2010 and 2018 were eligible for this study (n = 89). WFA+-M2BP levels were measured in samples collected before the LT. Comparison of the postoperative histological test results with the preoperative imaging data grouped the patients into histologically no group (N), histologically detected group (D), histologically increased group (I), and histologically decreased or same group (DS), and the results were compared with the WFA+-M2BP values. In addition, comparisons were made between each data with and without HCC, including occult HCC, and total tumor diameter. Irrespective of underlying hepatic disease conditions, there were 6 patients in the N group, 10 in the D group, 41 in the I group, and 32 in the DS group. The median of the serum WFA+-M2BP level for each group was as follows: N group, 8.05 (1.25-11.9); D group, 11.025 (1.01-18.21); I group, 9.67 (0.29-17.83); and DS group, 9.56 (0.28-19.44) confidence of interval. We found no significant differences between the pairings. Comparison of underlying hepatic diseases revealed that liver cirrhosis due to hepatitis B and C and non-B and -C liver cirrhosis had no significant differences. AFP levels, on the other hand, had significant relationships in comparison between the presence or absence of histological HCC, in correlation between total tumor diameter, and in the ROC analysis for the diagnosis of HCC including occult HCC. Serum WFA+-M2BP cannot help diagnose occult HCC that is already undetected using imaging tests in decompensated liver cirrhosis patients requiring LT.

Hepatocellular carcinoma and sarcopenia: a narrative review.

Hepatocellular carcinoma (HCC) affects millions of people each year and is associated with high mortality and morbidity. Sarcopenia, a condition of muscle wasting, and decreased muscle performance is common among aging adults, and is associated with poor clinical outcomes. Individuals with HCC and chronic liver disease (CLD) are at high risk of sarcopenia because of the adverse effects of chronic inflammation, endocrine dysfunction, and hyperammonemia on muscle metabolism and adequate nutrition. Our aim is to review the clinical relationship between HCC and sarcopenia, and the assessment and management of these patients. A narrative review based on a literature search using PubMed. Keywords related to HCC and sarcopenia were used to identify relevant articles, primarily those published 2018-2023. The information was synthesized to provide a narrative review focused on the most recent literature. Sarcopenia frequently co-exists with HCC and increases risk for adverse clinical outcomes such as symptom burden, quality of life (QoL), survival, and side effects of antineoplastic therapy. Tools are available to screen, assess and manage patients with HCC, and although there is no specific pharmacologic agent approved for sarcopenia in the United States, multimodal therapy is feasible in daily practice. Comprehensive management by an interdisciplinary team should include nutritional counseling, an exercise regimen and control of symptoms affecting nutrition and function. Sarcopenia has adverse effects on prognosis and tolerability of surgical and medical therapy in HCC. Patients with CLD and/or HCC would benefit from early identification, assessment, and therapeutic intervention. Management should be comprehensive, interdisciplinary, and include both pharmacologic and non-pharmacologic treatments. Further research is needed to identify individual agents that may mitigate muscle wasting and trials are needed to evaluate the benefit of multimodal therapy in HCC.

Serum RNase L levels in patients with chronic hepatitis B virus infection.

Chronic hepatitis B virus (HBV) infection still poses a major threat to global health. Oligoadenylate synthetase-ribonuclease L (RNase L) antiviral pathway is one of interferon-induced antiviral effectors. The relationship between RNase L and HBV has never been investigated and we aim to examine the serum RNase L levels in patients with different stages of chronic HBV infection. The patients were enrolled from 1985 to 2000, who had been HBsAg positive for longer than 6months, at the National Taiwan University Hospital. In total, 426 patients with chronic HBV infection were included in this study, including 135 inactive carriers, 148 cirrhosis, and 143 hepatocellular carcinoma (HCC) cases. The RNase L levels increase as the disease severity increases. Higher RNase L levels were associated with higher HBV viral load, and the HBV-RNase L relationship was replaced by the disease severity status when adding disease status into the model. Compared with inactive carriers, the risk of liver cirrhosis was 60-fold (odds ratio=60.8, 95% confidence interval=3.49-1061) with the highest quintile of RNase L levels, after the adjustment of HBV DNA. The dose-response trend was statistically significant with quintiles and one increment of RNase L level in relation to liver cirrhosis. Similar results were found when HCC was compared with inactive carriers, while there was no association when compared between liver cirrhosis and HCC. A positive relationship between serum RNase L and HBV viral titers or advanced disease status is uncovered in this study. Further investigation in this area may provide more details of an innate immune response for HBV and opportunity for novel therapeutic strategy.

Pan-Cancer Analysis and Experimental Validation of SOX4 as a Potential Diagnosis, Prognosis, and Immunotherapy Biomarker.

SOX4 plays an important role in tumorigenesis and cancer progression. The role of SOX4 in pan-cancer and its underlying molecular mechanism in liver hepatocellular carcinoma (LIHC) are not fully understood. In this study, a comprehensive analysis and experimental validation were performed to explore the function of SOX4 across tumor types. Raw data in regard to SOX4 expression in malignant tumors were downloaded from the TCGA and GTEx databases. The expression levels, prognostic values, genetic mutation, and DNA promoter methylation of SOX4 across tumor types were explored via systematic bioinformatics analysis. The ceRNA regulatory network, immune characteristics, and prognostic models were analyzed in LIHC. Finally, we conducted in vitro experiments including Western blotting, cell proliferative assay, trypan blue staining, and fluorescence microscopy to further explore the function of SOX4 in LIHC. SOX4 expression was significantly upregulated in 24 tumor types. SOX4 expression level was strongly associated with unfavorable prognoses, genetic mutations, and DNA methylation levels across different tumor types. Especially in LIHC, LINC00152/hsa-miR-139-3p/SOX4 was identified as a crucial ceRNA network. Moreover, this study also provides insight into the roles of SOX4 expression in immune cell infiltration, macrophage polarization, immune subtype, molecular subtype, and immunomodulators, as well as the tumor immune microenvironment (TIME)-related prognosis, in LIHC. The study established six favorable prognostic models to predict LIHC prognosis based on the SOX4-associated genes. Finally, lenvatinib treatment can increase the expression of SOX4 in hepatocellular carcinoma cells and lead to drug resistance. Silencing SOX4 can effectively eliminate the drug resistance caused by lenvatinib treatment and inhibit the proliferation of cancer cells. This study highlights that SOX4 may serve as a promising therapeutic target for tumor treatment.

Identification of Niche-Specific Gene Signatures between Malignant Tumor Microenvironments by Integrating Single Cell and Spatial Transcriptomics Data.

The tumor microenvironment significantly affects the transcriptomic states of tumor cells. Single-cell RNA sequencing (scRNA-seq) helps elucidate the transcriptomes of individual cancer cells and their neighboring cells. However, cell dissociation results in the loss of information on neighboring cells. To address this challenge and comprehensively assess the gene activity in tissue samples, it is imperative to integrate scRNA-seq with spatial transcriptomics. In our previous study on physically interacting cell sequencing (PIC-seq), we demonstrated that gene expression in single cells is affected by neighboring cell information. In the present study, we proposed a strategy to identify niche-specific gene signatures by harmonizing scRNA-seq and spatial transcriptomic data. This approach was applied to the paired or matched scRNA-seq and Visium platform data of five cancer types: breast cancer, gastrointestinal stromal tumor, liver hepatocellular carcinoma, uterine corpus endometrial carcinoma, and ovarian cancer. We observed distinct gene signatures specific to cellular niches and their neighboring counterparts. Intriguingly, these niche-specific genes display considerable dissimilarity to cell type markers and exhibit unique functional attributes independent of the cancer types. Collectively, these results demonstrate the potential of this integrative approach for identifying novel marker genes and their spatial relationships.

Assessment of LI-RADS efficacy in classification of hepatocellular carcinoma and benign liver nodules using DCE-MRI features and machine learning

PurposeThe current study aimed to evaluate the efficiency of dynamic contrast-enhanced (DCE) MRI visual features in classifying benign liver nodules and hepatocellular carcinoma (HCC) using a machine learning model. Methods115 LI-RADS3, 137 LI-RADS4, and 140 LI-RADS5 nodules were included (392 nodules from 245 patients), which were evaluated by follow-up imaging for LR-3 and pathology results for LR-4 and LR-5 nodules. Data was collected retrospectively from 3 T and 1.5 T MRI scanners. All the lesions were categorized into 124 benign and 268 HCC lesions. Visual features included tumor size, arterial-phase hyper-enhancement (APHE), washout, lesion segment, mass/mass-like, and capsule presence. Gini-importance method extracted the most important features to prevent over-fitting. Final dataset was split into training(70%), validation(10%), and test dataset(20%). The SVM model was used to train the classifying algorithm. For model validation, 5-fold cross-validation was utilized, and the test data set was used to assess the final accuracy. The area under the curve and receiver operating characteristic curves were used to assess the performance of the classifier model. ResultsFor test dataset, the accuracy, sensitivity, and specificity values for classifying benign and HCC lesions were 82%,84%, and 81%, respectively. APHE, washout, tumor size, and mass/mass-like features significantly differentiated benign and HCC lesions with p-value < .001. ConclusionsThe developed classification model employing DCE-MRI features showed significant performance of visual features in classifying benign and HCC lesions. Our study also highlighted the significance of mass and mass-like features in addition to LI-RADS categorization. For future work, this study suggests developing a deep-learning algorithm for automatic lesion segmentation and feature assessment to reduce lesion categorization errors.

Influence of intermittent fasting on autophagy in the liver.

Studies have found that intermittent fasting (IF) can prevent diabetes, cancer, heart disease, and neuropathy, while in humans it has helped to alleviate metabolic syndrome, asthma, rheumatoid arthritis, Alzheimer's disease, and many other disorders. IF involves a series of coordinated metabolic and hormonal changes to maintain the organism's metabolic balance and cellular homeostasis. More importantly, IF can activate hepatic autophagy, which is important for maintaining cellular homeostasis and energy balance, quality control, cell and tissue remodeling, and defense against extracellular damage and pathogens. IF affects hepatic autophagy through multiple interacting pathways and molecular mechanisms, including adenosine monophosphate (AMP)-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), silent mating-type information regulatory 2 homolog-1 (SIRT1), peroxisomal proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR), as well as signaling pathways and molecular mechanisms such as glucagon and fibroblast growth factor 21 (FGF21). These pathways can stimulate the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), play a cytoprotective role, downregulate the expression of aging-related molecules, and prevent the development of steatosis-associated liver tumors. By influencing the metabolism of energy and oxygen radicals as well as cellular stress response systems, IF protects hepatocytes from genetic and environmental factors. By activating hepatic autophagy, IF has a potential role in treating a variety of liver diseases, including non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis, hepatic fibrosis, and hepatocellular carcinoma. A better understanding of the effects of IF on liver autophagy may lead to new approaches for the prevention and treatment of liver disease.

CENPL accelerates cell proliferation, cell cycle, apoptosis, and glycolysis via the MEK1/2-ERK1/2 pathway in hepatocellular carcinoma

Centromere protein L (CENPL) is involved in the mitotic process of eukaryotic cells and the development of various types of cancer. However, its role in hepatocellular carcinoma (HCC) remains unclear. This study aimed to investigate the expression and clinical significance of CENPL in HCC, and explore its involvement in regulating HCC cell proliferation, apoptosis, cell cycle, and glycolysis both in vivo and in vitro. CENPL expression was analyzed in HCC and normal liver tissues using The Cancer Genome Atlas, Gene Expression Omnibus mining, real-time quantitative polymerase chain reaction, and immunohistochemistry. Functional assays were used to assess the role of CENPL in HCC cell proliferation, apoptosis, cell cycle, and glycolysis. The potential pathways underlying the regulatory effects of CENPL, as well as the expression of mitogen-activated protein kinase (MAPK) signaling pathway-related molecules and markers of proliferation and glycolysis were investigated. CENPL was significantly upregulated in HCC tissue and associated with multiple clinicopathological features and poor patient prognosis. Univariate and multivariate analyses demonstrated that CENPL may serve as an independent prognostic factor for HCC. Upregulation of CENPL in HCC regulated tumor proliferation and glycolytic processes. Mechanistic studies revealed that differentially expressed genes between the CENPL-overexpressing and control groups were mainly concentrated in the MAPK signaling pathway. Pathway inhibition analysis indicated that CENPL activated the MEK1/2-ERK1/2 signaling pathway to promote proliferation and glycolysis in HCC cells. This study elucidated the role of CENPL in regulating cell proliferation, apoptosis, cell cycle, and glycolysis in HCC. CENPL may represent a therapeutic target and prognostic biomarker for HCC.

ABHD12 contributes to tumorigenesis and sorafenib resistance by preventing ferroptosis in hepatocellular carcinoma

Sorafenib induces ferroptosis, making it a useful treatment against advanced liver hepatocellular carcinoma (LIHC). However, sorafenib resistance is extremely common among LIHC patients. Here, we used a comprehensive approach to investigate the effects of ABHD12, which regulates tumorigenesis and sorafenib resistance in LIHC. We validated ABHD12 expression was upregulated in LIHC tissue, which correlated with worse overall survival and related to tumor size or stage. ABHD12 facilitated a pro-tumorigenic phenotype involving increased cell proliferation, migration, and clonogenicity as well as sorafenib resistance. Knockout of ABHD12 sensitized liver cancer cells to sorafenib-induced ferroptosis. Co-delivery of sorafenib and ABHD12 inhibitor into a nude mouse model enhanced therapeutic efficacy for LIHC. Our study demonstrates that ABHD12 contributes to tumor growth and sorafenib resistance in liver cancer, which indicate the promising potential of ABHD12 in diagnosis and prognosis as well as highlight the potential therapeutic applications for co-delivery of sorafenib and ABHD12 inhibitor.

Antenatal hepatitis B virus sero-prevalence, risk factors, pregnancy outcomes and vertical transmission rate within 24 months after birth in a high HIV prevalence setting

BackgroundDespite the availability of an effective vaccine, chronic hepatitis B virus (HBV) infections remain a major cause of liver cirrhosis and hepatocellular carcinoma. HBV burden in pregnancy, risk factors and the timing of mother to child transmission remain poorly described especially during this era of lifelong use of Tenofovir/Lamivudine/Efavirenz as firstline for HIV treatment. We aimed to determine the burden of HBV in pregnancy and infants receiving their first dose of HBV vaccine 6 weeks after birth in a high HIV-prevalence setting.MethodsPregnant women ≥ 20 weeks’ gestational age were enrolled and followed up as mother-infant dyads from delivery, 6, 24 and 96 weeks after birth. HBV surface antigen (HBsAg) was tested (fresh plasma, immunochromatography) in pregnancy. Women testing HBsAg-seropositive were further evaluated for other four HBV-biomarkers. Maternally HBV exposed babies were tested for HBsAg from birth and HBs-antibodies from 6 months of age. Maternal-infant factors were tested in univariable and multivariable analyses for predictors of HBsAg-seropositivity.Results Six hundred HIV-uninfected and 608 HIV-infected women on Tenofovir/Lamivudine/Efavirenz-regimen with median (interquartile range) 350: (87–1477) days of therapy use were enrolled. The overall HBsAg-seroprevalence was 32/1208: 2.65%, 95% confidence interval (CI) [1.74, 3.55]; being 7/600: 1.17%, 95% CI [0.37, 1.97] and 25/608: 4.11%, 95% CI [2.52, 5.68] in HBsAg-monoinfected and HBsAg/HIV-coinfected respectively, disproportionately detected in 31/32: 96.9%, 95% CI [90.8, 100] women presumably HBV-unvaccinated in infancy.HBV exposed babies tended to be born prematurely (< 37 weeks); 15.2% versus 9.9% in the HBV-unexposed, p = 0.009.In multivariate logistic regression-models with variable elimination, HIV-infection and reported tooth extractions predicted antenatal HBsAg-seropositivity; odds ratios (CI): 3.85 (1.61–10.7) and 2.46 (1.07–5.34), respectively.None of the exposed infants were HBsAg-seropositive neither before nor after 6 weeks of age. No HBs-antibodies were detected in 23.3% of HBsAg-exposed infants at two years despite having successfully completed the HBV vaccination schedule.ConclusionLow and moderate HBV endemics were observed in HIV-uninfected and HIV-infected pregnant women, respectively. This underscores the need to routinely screen for HBV in pregnancy, especially the HIV-infected attending antenatal-care. Being HIV-infected and reported tooth extractions were independent risk factors for maternal HBsAg-seropositivity. Vertical and child horizontal transmissions were both absent, probably due to ~ the 50% frequency of antenatal anti-HBe-antibodies observed. Of concern was the absence of anti-HBs-antibodies in 23.3% of fully vaccinated/maternally HBV-exposed infants by two years. Absence of molecular diagnosis may have underestimated HBV burden.Trial registrationwww.clinicaltrials.gov, trial registration number: NCT04087239.

Underrecognition and Suboptimal Quality of Care for Nonalcoholic Fatty Liver Disease Cirrhosis in Primary Care Patients with Diabetes Mellitus

BackgroundNonalcoholic fatty liver disease (NAFLD) is a leading cause of cirrhosis but is underrecognized in primary care. Cirrhosis management requires complex monitoring, and the quality of care (QoC) for NAFLD cirrhosis patients in primary care may be inadequate. MethodsIn this retrospective-prospective cohort study of primary care patients with diabetes mellitus, we identified patients with NAFLD cirrhosis by 1) evidence of cirrhosis from abdominal imaging identified by natural language processing, or 2) existence of International Classification of Diseases code for cirrhosis. A finding of either was followed by manual chart review for confirmation of both cirrhosis and NAFLD. We then determined if cirrhosis care measures were up-to-date, including hepatitis A and B vaccination, Model for End-Stage Liver Disease score components, esophagogastroduodenoscopy, and hepatocellular carcinoma screening. We created a composite score quantifying overall QoC (scale 0-8), with high QoC defined as ≥6 points. ResultsAmong 3,028 primary care patients with diabetes mellitus, we identified 51 (1.7%) with NAFLD cirrhosis. Although 78% had ≥3 average primary care visits/year, only 24% completed hepatocellular carcinoma screening at least annually in at least 75% of years since diagnosis. The average QoC composite score was 4.9 (SD 2.4), and less than one-third had high QoC. ConclusionsNAFLD cirrhosis is prevalent but underdiagnosed in primary care, and receipt of comprehensive QoC was suboptimal. Given the rising incidence of NAFLD cirrhosis, primary care providers need improved awareness and mechanisms to ensure high QoC for this population.

Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.

ANTIVIRAL RESPONSE OF DRUGS USED AGAINST HBV PATIENTS OF KHYBER PAKHTUNKHWA, PAKISTAN

Hepatitis B virus is an ample cause of end-stage liver diseases and hepatocellular carcinoma. Effective treatment in high-risk countries such as Pakistan can help delay or prevent these consequences.The existing study aims to evaluate the response rates of antiviral drugs tenofovir and entecavir (6-48 months) based on different clinical parameters. Sera collected from HBV patients (43) subjected to DNA extraction, followed by real-time PCR detection. Furthermore, ICT was performed to detect HBs-Ag and ELISA for HBe-Ag. Response rate after 6 months of tenofovir treatments showed 100% normal creatinine and ultrasound and ALT (50%) and while in the case of entecavir, each ALT and ultrasound normalization (66.7%), showed creatinine (100%). The fatty liver was reported 50% and 33.3% after tenofovir and entecavir treatment, respectively. The response after 12 months of treatment with tenofovir showed normalization of ALT and ultrasound (84.6%), bilirubin and creatinine normalization (92.3%), and fatty liver (15.4%). Whereas bilirubin and creatinine levels showed (100%) normal, ALT and ultrasound normalization (80%) with 20% of patients having congenital left lobe of the liver after entecavir. Patients profiles after 24 months of tenofovir treatment showed normal ALT and ultrasound (85.7%), bilirubin (100%), and renal impairment observed in patients (14.3%). The 24 months entecavir treatment showed significant improvement in various clinical parameters normalization with 100% such as ALT, bilirubin, and creatinine in all patients. The efficacy of entecavir showed a significant response as compared to Tenofovir. Furthermore, nucleoside/nucleotide analogues enhanced its efficacy with longer treatment duration.

Analysis and experimental validation of the innate immune gene PSMD1 in liver hepatocellular carcinoma and pan-cancer

This work intends to examine the diagnostic, prognostic, and biological roles of PSMD1 (proteasome 26S subunit, non-ATPase 1) in liver hepatocellular carcinoma (LIHC) and other malignancies, using bioinformatics techniques. PSMD1 is an innate immune gene that has been identified as a biomarker for several cancers. By analyzing TCGA data, we determined that PSMD1 has excellent diagnostic and prognostic value in LIHC. We also examined its correlation with stage-matching clinical features, particularly T staging and stage staging. Independent prognostic analysis, nomogram, and Decision Curve Analysis (DCA) analysis confirmed the predictive ability of PSMD1 on patient clinical outcomes. Our focus was on exploring the biological process, immune infiltration, and genetic variation in which PSMD1 is involved in LIHC. We found a close relationship between PSMD1 and the tumor microenvironment (TME), as well as various immune cell infiltration, immune function, and immune checkpoints. Furthermore, our results suggested that liver cancer patients with low PSMD1 expression were more actively responsive to immunotherapy according to TIDE predictions. Additionally, we observed significant differences in patient survival based on the different immune molecular types of tumors and their correlation with PSMD1 expression. The close relationship between PSMD1 and copy number variation (CNV), tumor mutational burden (TMB), and methylation was also confirmed, showing a significant impact on patient survival. Moreover, the pan-cancer analysis revealed that PSMD1 is closely related to the diagnosis and prognosis of various cancers, as well as immune infiltration across different cancer types. In summary, PSMD1 has the potential to be a useful diagnostic and prognostic biomarker for LIHC and other types of cancers. It is closely associated with indicators such as immune infiltration, CNV, TMB, and methylation. The identification of PSMD1 may offer a potential intervention target for LIHC and various cancers.

Cuproptosis-related gene SLC31A1: prognosis values and potential biological functions in cancer

Cuproptosis is a unique type of cell death that may influence tumour formation by targeting lipoylated tricarboxylic acid cycle proteins. Solute carrier family 31 member 1 (SLC31A1), an important copper transporter, influences dietary copper absorption in the cell membrane. However, various SLC31A1 properties in pan-cancer profiles remain unknown. This study investigated the role of SLC31A1 in human malignancies and analysed its prognostic value. Raw data were obtained from The Cancer Genome Atlas database and processed using numerous internet databases, including UALCAN, GEPIA, cBioPortal, TIMER2.0, and Human Protein Atlas. SLC31A1 expression was found to be elevated in cervical, endometrial, and breast cancers compared to that in normal tissues, but reduced in clear cell renal cell carcinoma, liver hepatocellular carcinoma, and lung adenocarcinoma. Furthermore, SLC31A1 expression was strongly associated with overall survival and disease-free survival in several cancers. SLC31A1 gene mutations and methylations were identified in 33 cancers. SLC31A1 expression was positively correlated with immune cells in immune infiltration data. Single-cell sequencing revealed that SLC31A1 may play key roles in DNA repair, DNA damage, and proliferation. These findings may lead to better understanding of SLC31A1 in pan-cancer profiles and suggest that SLC31A1 could be a viable predictive biomarker, particularly in gynaecological cancers.

Risk assessment of cancer patients based on HLA-I alleles, neobinders and expression of cytokines

Advancements in cancer immunotherapy have shown significant outcomes in treating cancers. To design effective immunotherapy, it's important to understand immune response of a patient based on its genomic profile. However, analyses to do that requires proficiency in the bioinformatic methods. Swiftly growing sequencing technologies and statistical methods create a blockage for the scientists who want to find the biomarkers for different cancers but don't have detailed knowledge of coding or tool. Here, we are providing a web-based resource that gives scientists with no bioinformatics expertise, the ability to obtain the prognostic biomarkers for different cancer types at different levels. We computed prognostic biomarkers from 8346 cancer patients for twenty cancer types. These biomarkers were computed based on i) presence of 352 Human leukocyte antigen class-I, ii) 660959 tumor-specific HLA1 neobinders, and iii) expression profile of 153 cytokines. It was observed that survival risk of cancer patients depends on presence of certain type of HLA-I alleles; for example, liver hepatocellular carcinoma patients with HLA-A*03:01 are at lower risk. Our analysis indicates that neobinders of HLA-I alleles have high correlation with overall survival of certain type of cancer patients. For example, HLA-B*07:02 binders have 0.49 correlation with survival of lung squamous cell carcinoma and −0.77 with kidney chromophobe patients. Additionally, we computed prognostic biomarkers based on cytokine expressions. Higher expression of few cytokines is survival favorable like IL-2 for bladder urothelial carcinoma, whereas IL-5R is survival unfavorable for kidney chromophobe patients. Freely accessible to public, CancerHLA-I maintains raw and analysed data (https://webs.iiitd.edu.in/raghava/cancerhla1/).

Analysis of survival outcomes following robotic hepatectomy for malignant liver diseases

BackgroundDespite increased adoption of the robotic platform for complex hepatobiliary resections for malignant disease, little is known about long-term survival outcomes. This is the first study to evaluate the postoperative outcomes, and short- and long-term survival rates after a robotic hepatectomy for five major malignant disease processes. MethodsA prospectively collected database of patients who underwent a robotic hepatectomy for malignant disease was reviewed. Pathologies included colorectal liver metastases (CLM), hepatocellular carcinoma (HCC), Klatskin tumor, intrahepatic cholangiocarcinoma (IHCC), and gallbladder cancer (GC). Data are presented as median (mean ​± ​standard deviation) for illustrative purposes. ResultsOf the 210 consecutive patients who underwent robotic hepatectomy for malignant disease, 75 (35 ​%) had CLM, 69 (33 ​%) had HCC, 27 (13 ​%) had Klatskin tumor, 20 (10 ​%) had IHCC, and 19 (9 ​%) had GC. Patients were 66 (65 ​± ​12.4) years old with a BMI of 29 (29 ​± ​6.5) kg/m2. R0 resection was achieved in 91 ​%, and 65 ​% underwent a major hepatectomy. Postoperative major complication rate was 6 ​%, length of stay was four (5 ​± ​4.3) days, and 30-day readmission rate was 17 ​%. Survival at 1, 3, and 5-years were 93 ​%/75 ​%/72 ​% for CLM, 84 ​%/71 ​%/64 ​% for HCC, 73 ​%/55 ​%/55 ​% for Klatskin tumor, 80 ​%/69 ​%/69 ​% for IHCC, 79 ​%/65 ​%/65 ​% for GC. ConclusionThis study suggests a favorable 5-year overall survival benefit with use of the robotic platform in hepatic resection for colorectal metastases, hepatocellular carcinoma, intrahepatic cholangiocarcinoma, Klatskin tumor, and gallbladder cancer. The robotic platform facilitates fine dissection in complex hepatobiliary operations, with a high rate of R0 resections and excellent perioperative clinical outcomes.

Immunological function and prognostic value of lymphoid-specific helicase in liver hepatocellular carcinoma.

Lymphoid-specific helicase (HELLS), a SNF2-like chromatin-remodeling enzyme, plays a key role in tumor progression via its DNA methylation function. However, the effects of HELLS on immune infiltration and prognosis in liver hepatocellular carcinoma (LIHC) remain uncertain. The Tumor Immune Estimation Resource (TIMER) database was employed to explore the pan-cancer mRNA expression of HELLS and its correlation with immunity. GEPIA2 was used to verify the correlation between HELLS expression and survival. The role of HELLS in cancer was explored via gene set enrichment analysis (Gene Ontology and Kyoto Encyclopedia of Genes and Genomes) and the construction of gene-gene and protein-protein interaction networks (PPI). Additionally, correlations between DNA methylation, HELLS expression, and immune-related genes were explored in LIHC. HELLS expression in LIHC clinical samples was determined using qRT-PCR and western blotting. The effects of downregulated HELLS expression in hepatocellular carcinoma cells was explored via transfection experiments in vitro. High HELLS mRNA expression was identified in several cancers and was significantly associated with poorer prognosis in LIHC. Furthermore, HELLS expression was positively correlated with tumor-infiltrating lymphocytes and immune checkpoint genes in LIHC. Bioinformatics analysis suggested that DNA methylation of HELLS may be associated with the immune response. Results from the TCGA-LIHC dataset, clinical samples, and functional analysis indicated that HELLS contributed to tumor progression in LIHC. The study findings demonstrate that HELLS is an important factor in promoting LIHC malignancy and might serve as a potential biomarker for LIHC.