Comparative accuracy of biomarkers for the prediction of hospital-acquired acute kidney injury: a systematic review and meta-analysis.

BACKGROUND: Several biomarkers have been proposed to predict the occurrence of acute kidney injury (AKI); however, their efficacy varies between different trials. The aim of this study was to compare the predictive performance of different candidate biomarkers for AKI. METHODS: In this systematic review, we searched PubMed, Medline, Embase, and the Cochrane Library for papers published up to August 15, 2022. We selected all studies of adults (> 18 years) that reported the predictive performance of damage biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP)), inflammatory biomarker (interleukin-18 (IL-18)), and stress biomarker (tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 (TIMP-2 × IGFBP-7)) for the occurrence of AKI. We performed pairwise meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. Hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the pooled test performance, and the Grading of Recommendations, Assessment, Development and Evaluations criteria were used to appraise the quality of evidence. RESULTS: We identified 242 published relevant studies from 1,803 screened abstracts, of which 110 studies with 38,725 patients were included in this meta-analysis. Urinary NGAL/creatinine (diagnostic odds ratio [DOR] 16.2, 95% CI 10.1-25.9), urinary NGAL (DOR 13.8, 95% CI 10.2-18.8), and serum NGAL (DOR 12.6, 95% CI 9.3-17.3) had the best diagnostic accuracy for the risk of AKI. In subgroup analyses, urinary NGAL, urinary NGAL/creatinine, and serum NGAL had better diagnostic accuracy for AKI than urinary IL-18 in non-critically ill patients. However, all of the biomarkers had similar diagnostic accuracy in critically ill patients. In the setting of medical and non-sepsis patients, urinary NGAL had better predictive performance than urinary IL-18, urinary L-FABP, and urinary TIMP-2 × IGFBP-7: 0.3. In the surgical patients, urinary NGAL/creatinine and urinary KIM-1 had the best diagnostic accuracy. The HSROC values of urinary NGAL/creatinine, urinary NGAL, and serum NGAL were 91.4%, 85.2%, and 84.7%, respectively. CONCLUSIONS: Biomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine, and especially in medically treated patients. However, the predictive performance of urinary NGAL was limited in surgical patients, and urinary NGAL/creatinine seemed to be the most accurate biomarkers in these patients. All of the biomarkers had similar predictive performance in critically ill patients. Trial registration CRD42020207883 , October 06, 2020.

CircMEMO1 modulates the promoter methylation and expression of TCF21 to regulate hepatocellular carcinoma progression and sorafenib treatment sensitivity.

BACKGROUND: Cirrhosis is a recognized risk factor for developing hepatocellular carcinoma (HCC). Few studies have reported the expression profile of circRNAs in HCC samples compared to paratumour dysplastic nodule (DN) samples. METHODS: The Arraystar Human circRNA Array combined with laser capture microdissection (LCM) was used to analyse the expression profile of circRNAs in HCC samples compared to paratumour DN samples. Then, both in vitro and in vivo HCC models were used to determine the role and mechanism of key circRNA in HCC progression and treatment sensitivity. RESULTS: We found that circMEMO1 was significantly downregulated in HCC samples and that the level of circMEMO1 was closely related to the OS and disease-free survival (DFS) of HCC patients. Mechanistic analysis revealed that circMEMO1 can modulate the promoter methylation and gene expression of TCF21 to regulate HCC progression by acting as a sponge for miR-106b-5p, which targets the TET family of genes and increases the 5hmC level. More importantly, circMEMO1 can increase the sensitivity of HCC cells to sorafenib treatment. CONCLUSION: Our study determined that circMEMO1 can promote the demethylation and expression of TCF21 and can be considered a crucial epigenetic modifier in HCC progression.

TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage.

BACKGROUND AND AIMS: Heparin-binding epidermal growth factor (HB-EGF), a member of the epidermal growth factor family, plays a pivotal role in the progression of several malignancies, but its role and regulatory mechanisms in hepatocellular carcinoma (HCC) remain obscure. Here, we report that transmembrane protease serine 4 (TMPRSS4) significantly enhanced the expression and proteolytic cleavage of HB-EGF to promote angiogenesis and HCC progression. APPROACH AND RESULTS: A mechanistic analysis revealed that TMPRSS4 not only increased the transcriptional and translational levels of HB-EGF precursor, but also promoted its proteolytic cleavage by enhancing matrix metallopeptidase 9 expression through the EGF receptor/Akt/mammalian target of rapamycin/ hypoxia-inducible factor 1 α signaling pathway. In addition, HB-EGF promoted HCC proliferation and invasion by the EGF receptor/phosphoinositide 3-kinase/Akt signaling pathway. The level of HB-EGF in clinical samples of serum or HCC tissues from patients with HCC was positively correlated with the expression of TMPRSS4 and the microvessel density, and was identified as a prognostic factor for overall survival and recurrence-free survival, which suggests that HB-EGF can serve as a potential therapeutic target for HCC. More importantly, we provide a demonstration that treatment with the HB-EGF inhibitor cross-reacting material 197 alone or in combination with sorafenib can significantly suppress angiogenesis and HCC progression. CONCLUSIONS: HB-EGF can be regulated by TMPRSS4 to promote HCC proliferation, invasion, and angiogenesis, and the combination of the HB-EGF inhibitor cross-reacting material 197 with sorafenib might be used for individualized treatment of HCC.

Effects of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α overexpression on hepatocellular carcinoma survival: A systematic review with meta-analysis.

BACKGROUND AND AIM: The role of hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) has been implicated in the clinical prognosis of hepatocellular carcinoma (HCC), but the results remain controversial. We aim to investigate the association of HIF-1α and HIF-2α overexpression with the prognosis and clinicopathological features of HCC. METHODS: A systematic search was conducted in PubMed, Embase, Scopus, Web of Science, and Cochrane Library until June 20, 2020. Meta-analysis was conducted to generate combined HRs with 95% confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS). Odds ratios (ORs) with 95% CI were also derived by fixed or random effect model. RESULTS: Twenty-two studies involving 3238 patients were included. Combined data suggested that overexpression of HIF-1α in HCC was not only correlated with poorer OS [HR = 1.75 (95% CI: 1.53-2.00)] and DFS [HR = 1.64 (95% CI: 1.34-2.00)] but was also positively associated with vascular invasion [OR = 1.83 (95% CI: 1.36-2.48)], tumor size [OR = 1.36 (95% CI: 1.12-1.66)], and tumor number [1.74 (95% CI: 1.34-2.25)]. In contrast, HIF-2α overexpression was not associated with the prognosis and clinicopathological features of HCC. CONCLUSION: Our data provided compelling evidence of a worse prognosis of HCC in HIF-1α overexpression patients but not HIF-2α overexpression ones.

Image artifacts and noise reduction algorithm for cone-beam computed tomography with low-signal projections.

This study aims to investigate and test a new image reconstruction algorithm applying to the low-signal projections to generate high quality images by reducing the artifacts and noise in the cone-beam computed tomography (CBCT). For the low-signal and noisy projections, a multiple sampling method is first utilized in projection domain to suppress environmental noise, which guarantees the accuracy of the data for reconstruction, simultaneously. Next, a fuzzy entropy based method with block matching 3D (BM3D) filtering algorithm is employed to improve the image quality to reduce artifacts and noise in image domain. Then, simulation studies on polychromatic spectrum were performed to evaluate the performance of the proposed new algorithm. Study results demonstrated significant improvement in the signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) of the images reconstructed using the new algorithm. SNRs and CNRs of the new images were averagely 40% and 20% higher than those of the previous images reconstructed using the traditional algorithms, respectively. As a result, since the new image reconstruction algorithm effectively reduced the artifacts and noise, and produced images with better contour and grayscale distribution, it has the potential to improve image quality using the original CBCT data with the low and missing signals.

[Complex enzyme combined with ultrasound extraction technology, physicochemical properties and antioxidant activity of Hedysarum polysaccharides].

In this study, complex enzymes combined with ultrasonic extraction technology（MC） were used, to select optimal extraction combinations by single factor and orthogonal test, with Hedysarum polysaccharides yield and content as the comprehensive indexes. The components, physicochemical properties and antioxidant activity of Hedysarum polysaccharides from complex enzyme combined with ultrasonic extraction（HPS-MC）and the Hedysarum polysaccharides from hot water extraction（HPS-R）were analyzed. The results showed that：complex enzymes had significant effect on the yield and content of Hedysarum polysaccharides, and the ultrasonic power could significantly improve the content of Hedysarum polysaccharides. The optimum technological parameters were as follows: complex enzyme ratio 1:1, ultrasonic power 105 W, ultrasonic time 60 min, and enzymatic hydrolysis pH 5, achieving （14.01±0.64）% and （92.45±1.47）% respectively for the yield and content of Polysaccharides. As compared with HPS-R, the molecular weight, absolute viscosity and protein content of HPS-MC were decreased, while the content of uronic acid was increased. In the antioxidant system, the concentration of polysaccharide was within the range of 1-7 g·L⁻¹; the antioxidant activity of HPS-MC was higher than that of HPS-R, and HPS-MC (80%) with the lowest molecular weight showed a significant dose effect relationship with the increase of the experimental concentration. In conclusion, MC is a simple, convenient, economical and environmentally friendly extraction technology, and the Hedysarum polysaccharides extracted by this method have obvious antioxidant activity.

Prolonged QT interval is linked to all-cause and cardiac mortality in chronic peritoneal dialysis patients.

AIM: Prolonged QT interval is related to changes of electrolytes in haemodialysis (HD) and is associated with all-cause mortality in HD patients. It is unknown if prolonged QT interval is associated with all-cause mortality in peritoneal dialysis (PD) patients as the electrolytes were relatively stable in PD. We therefore investigated the association of prolonged QT interval and all-cause mortality in chronic PD patients. METHODS: The QT intervals were measured in 2003 and all patients were followed to December 2012. A prolonged QT interval was defined as a QT interval > 450 ms. The association of prolonged QT interval with all-cause and cardiac-specific mortality was analyzed using Cox regression and Kaplan-Meier analysis. RESULTS: Of 306 patients, 196 (64%) patients had prolonged QT interval. The incidence density rate was 9.7 per 100 persons-years for all-cause mortality and 5.6 for cardiac specific mortality in patients with prolonged QT interval. Prolonged QT interval was associated with all-cause mortality with a hazard ratio (HR) of 1.59 (95% confidence interval (CI): 1.06-2.39, P = 0.03] and cardiac mortality (HR: 1.66, 95% CI: 1.00-2.78, P = 0.05) with adjustments for age, gender, diabetes, and vintage of dialysis. Longer QT interval (>500 ms, 450-500 ms, and < 450 ms) was significantly associated with a worse overall survival (P = 0.03, log-rank test) and cardiac mortality free survival (P = 0.05, log-rank test). CONCLUSIONS: Prolonged QT interval was associated with all-cause and cardiac mortality in patients on peritoneal dialysis. The association is independent of patient's age and diabetes.

Nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study: Design and methods.

AIM: Acute kidney injury (AKI) carries an increasing incidence rate worldwide and increases the risk of developing end-stage renal disease (ESRD) as well as the medical expenses during the post-AKI course. The Taiwan Consortium for Acute Kidney Injury and Renal Diseases (CAKs) has thus launched a nationwide epidemiology and prognosis of dialysis-requiring acute kidney injury (NEP-AKI-D) study, which prospectively enrols critically ill patients with AKI. Through thoroughly evaluating the risk and prognostic factors of AKI, we hope to lower the incidence of AKI and ESRD from the perspective of AKI-ESRD interaction. METHODS: The CAKs includes 30 hospitals which distribute widely through the four geographical regions (north, middle, south, and east) of Taiwan, and have a 1:1 ratio of medical centres to regional hospitals in each region. The NEP-AKI-D study enrols intensive care unit-based AKI patients who receive dialysis in the four seasonal sampled months (October 2014, along with January, April, and July 2015) in the included hospitals. The collected data include demographic information, pertaining laboratory results, dialysis settings and patient outcomes. The data are uploaded in a centre website and will be audited by on-site principal investigators, computer logic gates, and the CAKs staffs. The outcomes of interest are in-hospital mortality, dialysis-dependency and readmission rate within 90 days after discharge. CONCLUSION: The NEP-AKI-D study enrols a large number of representative AKI patients throughout Taiwan. The results of the current study are expected to provide more insight into the risk and prognostic factors of AKI and further attenuated further chronic kidney disease transition.

Removal of nitrogen from secondary effluent of a petrochemical industrial park by a hybrid biofilm-carrier reactor with one-stage ANAMMOX.

A laboratory study was undertaken to explore the capability of one-stage ANAMMOX in a hybrid biofilm-carrier reactor (HBCR) fed with petrochemical wastewater. Under favorable operating conditions in continuous-flow operations (at the dissolved oxygen level of 0.5-1.0 mg L(-1)), the average total nitrogen (TN) removal efficiency reached 62-67% and approximately 90% of TN can be removed by ANAMMOX. In batch operations of the hybrid biofilm-carrier reactor (without adding carbon substrate), the specific TN removal rate of the reactor in which both Kaldnes and nonwoven carriers were kept was two-fold higher than that of the reactor in which only nonwoven carriers were kept. This indicated that the microbial activity of thinner biofilms (Kaldnes carriers) was remarkably higher than that of thicker biofilms (nonwoven carriers). Finally, based on the 16S rRNA clone library, a cluster of ANAMMOX Candidatus Kuenenia stuttgartiensis was identified.

Diacylglycerol lipase alpha promotes hepatocellular carcinoma progression and induces lenvatinib resistance by enhancing YAP activity.

As an important hydrolytic enzyme that yields 2-AG and free fatty acids, diacylglycerol lipase alpha (DAGLA) is involved in exacerbating malignant phenotypes and cancer progression, but the role of the DAGLA/2-AG axis in HCC progression remains unclear. Here, we found that the upregulation of components of the DAGLA/2-AG axis in HCC samples is correlated with tumour stage and patient prognosis. In vitro and in vivo experiments demonstrated that the DAGLA/2-AG axis promoted HCC progression by regulating cell proliferation, invasion and metastasis. Mechanistically, the DAGLA/2AG axis significantly inhibited LATS1 and YAP phosphorylation, promoted YAP nuclear translocation and activity, and ultimately led to TEAD2 upregulation and increased PHLDA2 expression, which could be enhanced by DAGLA/2AG-induced activation of the PI3K/AKT pathway. More importantly, DAGLA induced resistance to lenvatinib therapy during HCC treatment. Our study demonstrates that inhibiting the DAGLA/2-AG axis could be a novel therapeutic strategy to inhibit HCC progression and enhance the therapeutic effects of TKIs, which warrant further clinical studies.

The association of fatty liver and risk of hepatocellular carcinoma in HBV or HCV infected individuals: a systematic review and meta-analysis.

BACKGROUND: Fatty liver (FL) is reportedly a risk factor for hepatocellular carcinoma (HCC) in individuals affected with Hepatitis C (HCV) or B (HBV) virus. However, the results are contradictory, necessitating a meta-analysis. RESEARCH DESIGN AND METHODS: Sixteen relevant studies involving 88,618 individuals were retrieved from the Cochrane Library, PubMed, MEDLINE, Embase, and Scopus databases from their inception to 10 December 2022. The hazard ratios (HR) and 95% confidence intervals (CI) were analyzed. RESULTS: Liver biopsy-proven FL may be a significant risk factor for HCC in individuals affected with HBV (univariate analyses: HR = 3.13, 95% CI = 1.69-5.79; multivariate analyses: HR = 3.42, 95% CI = 0.83-14.09) as well as HCV (univariate analyses: HR = 1.64, 95% CI = 0.93-2.90; multivariate analyses: HR = 1.75, 95% CI = 1.02-3.00). However, the presence of FL confirmed using reasonable methods other than liver biopsy may not indicate a risk for HCC in HBV-infected individuals (univariate analyses: HR = 0.90, 95% CI = 0.44-1.81; multivariate analyses: HR = 0.69, 95% CI = 0.45-1.08). CONCLUSIONS: Biopsy-proven FL may be a significant risk factor for HCC in HCV/HBV-infected individuals. Thus, such individuals should receive suitable interventions to prevent HCC formation or at least attenuate the risk of HCC.

Risk prediction of nephropathy by integrating clinical and genetic information among adult patients with type 2 diabetes.

AIMS: Diabetic nephropathy (DN) is a major healthcare challenge. We developed and internally and externally validated a risk prediction model of DN by integrating clinical factors and SNPs from genes of multiple CKD-related pathways in the Han Chinese population. MATERIALS AND METHODS: A total of 1526 patients with type 2 diabetes were randomly allocated into derivation (n = 1019) or validation (n = 507) sets. External validation was performed with 3899 participants from the Taiwan Biobank. We selected 66 SNPs identified from literature review for building our weighted genetic risk score (wGRS). The steps for prediction model development integrating clinical and genetic information were based on the Framingham Heart Study. RESULTS: The AUROC (95% CI) for this DN prediction model with combined clinical factors and wGRS was 0.81 (0.78, 0.84) in the derivation set. Furthermore, by directly using the information of these 66 SNPs, our final prediction model had AUROC values of 0.85 (0.82, 0.87), 0.89 (0.86, 0.91), and 0.77 (0.74, 0.80) in the derivation, internal validation, and external validation sets, respectively. Under the combined model, the results with a cutoff point of 30% showed 70.91% sensitivity, 67.84% specificity, 51.54% positive predictive value, and 82.86% negative predictive value. CONCLUSIONS: We developed and internally and externally validated a model with clinical factors and SNPs from genes of multiple CKD-related pathways to predict DN in Taiwan. This model can be used in clinical risk management practice as a screening tool to identify persons who are genetically predisposed to DN for early intervention and prevention.

The somatic mutational landscape and role of the ARID1A gene in hepatocellular carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. Clarification of the somatic mutational landscape of important genes could reveal new therapeutic targets and facilitate individualized therapeutic approaches for HCC patients. The mutation and expression changes in the ARID1A gene in HCC remain controversial. Methods: First, cBioPortal was used to visualize genetic alterations and DNA copy number alterations (CNAs) in ARID1A. The relationships between ARID1A mutation status and HCC patient clinicopathological features and overall survival (OS) were also determined. Then, a meta-analysis was performed to evaluate the effect of ARID1A mutation or expression on the prognosis of HCC patients. Finally, the role of ARID1A in HCC progression was verified by in vitro experiments. Results: ARID1A mutation was detected in 9.35% (33/353) of sequenced HCC cases, and ARID1A mutation decreased ARID1A mRNA expression. Patients with ARID1A alterations presented worse OS than those without ARID1A alterations. Meta-analysis and human HCC tissue microarray (TMA) analysis revealed that HCC patients with low ARID1A expression had worse OS and relapse-free survival (RFS), and low ARID1A expression was negatively correlated with tumour size. Then, ARID1A gain-of-function and loss-of-function experiments demonstrated the tumour suppressor role of ARID1A in HCC in vitro. In terms of the mechanism, we found that ARID1A could inhibit HCC progression by regulating retinoblastoma-like 1 (RBL1) expression via the JNK/FOXO3 pathway. Conclusions: ARID1A can be considered a potential prognostic biomarker and candidate therapeutic target for HCC.

Oncogenic miR-93-5p/Gal-9 axis drives CD8 (+) T-cell inactivation and is a therapeutic target for hepatocellular carcinoma immunotherapy.

Evading immune destruction is an emerging hallmark of cancer and a potential key step in tumorigenesis. Immune checkpoint blocker (ICB)-based combination therapies revolutionize the landscape of systemic therapy for HCC. However, the molecular underpinnings governing immune evasion and responses remain unclear. Our study aims to find new regulatory molecules that drive HCC immune escape and tumorigenesis and find new promising immunotherapeutic approaches for HCC. In our study, laser capture microdissection (LCM) and miRNA sequencing combined with in vitro and in vivo experiments identified miR-93-5p as a crucial initiating oncogene during liver progenitor cell (LPC) malignant transformation and immune escape. Mechanistically, miR-93-5p could directly target canonical tumour suppressors such as APC to promote LPC malignant transformation and hepatocarcinogenesis. More importantly, miR-93-5p could induce deviant GAL-9 augmentation to inactivate infiltrated CD8(+) T cells and induce immune evasion by targeting several epigenetic regulators, such as AEBP2, and then regulating H3K4me3/H3K27me3 bivalency. Experiments in C57BL/6 mice demonstrated that blockade of Gal-9 abrogated miR-93-5p-induced HCC progression and improved their prognosis. Clinically, we identified a unique subtype of HCC closely associated with high GAL-9 expression and anti-PD1 treatment resistance. Our study highlights the pivotal role of the miR-93-5p/Gal-9 axis in driving HCC immune escape and tumorigenesis. Blocking GAL-9 is an effective and promising immunotherapeutic approach for HCC.

A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response.

Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive. Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells' pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes' expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation. Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines. Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.

Tenofovir versus entecavir on the prognosis of hepatitis B virus-related hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Tenofovir (TDF) and entecavir (ETV) are first-line treatments for patients with chronic hepatitis B virus (HBV) infection. However, the effect of TDF versus ETV on the prognosis of HBV-related hepatocellular carcinoma (HCC) has not been fully clarified yet. RESEARCH DESIGN AND METHODS: PubMed, Embase and Web of science were searched up to March, 2021. Meta-analyses were performed for overall survival (OS), disease-free survival (DFS) and recurrence-free survival (RFS) to assess the effect of TDF versus ETV on the prognosis of HBV-related HCC. RESULTS: A total of 10 studies comprising 4706 Asian patients were included. The pooled results revealed that TDF was associated with better OS (adjusted HR = 0.50, 95% CI: 0.40-0.62; I2 = 36.0%, p = 0.167) and better RFS/DFS (adjusted HR = 0.70, 95% CI: 0.55-0.89, I2 = 71.9%, p = 0.002) than ETV in treatment of HBV-related HCC. Subgroup analysis revealed that OS benefit from TDF was generally consistent, except for patients who underwent non-surgical treatment for HCC. Subgroup analysis also indicated that TDF reduces the risk of late recurrence (HR = 0.41, 95% CI: 0.18-0.0.93; I2 = 63.0%, p = 0.067) rather than early recurrence (HR = 0.99, 95% CI: 0.64-1.52; I2 = 61.3%, p = 0.076). CONCLUSIONS: Compared with ETV, TDF has the advantage of improving OS and reducing late recurrence of patients with HBV-related HCC patients who underwent resection.

Identification of the most effective subgroup of advanced hepatocellular carcinoma from immune checkpoint blocker treatment: a meta-analysis.

Aims: This work was designed to identify the subgroup of advanced hepatocellular carcinoma (HCC) patients for whom treatments containing immune checkpoint blockers (ICBs) were most effective. Materials & methods: A meta-analysis was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs. Results: A total of 2228 patients from four randomized control trials were included. Treatments containing ICBs had better overall survival, progression-free survival and higher objective response rate over treatment without ICBs. Subgroup analysis revealed that treatments containing ICBs were highly effective in improving the overall survival of males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients. Conclusion: Treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Immune checkpoint blockers (ICBs) have significantly improved the prognosis of advanced cancers. However, some patients still cannot benefit from ICBs. The use of ICBs in the treatment of advanced hepatocellular carcinoma (HCC) started late. The subgroup of advanced HCC patients that will benefit most from treatments containing ICBs is still largely unknown. Therefore, a meta-analysis (meta-analysis is a statistical method used to compare or synthesize research results on the same scientific problem) was performed to explore the subgroup population with the greatest benefit of treatments containing ICBs (ICBs alone or in combination with anti-VEGF agents). The results show that treatments containing ICBs are more effective for males, patients with macrovascular invasion and/or extrahepatic spread and viral-related HCC patients.

Real-time PCR analysis of the intestinal microbiotas in peritoneal dialysis patients.

Bifidobacterium and Lactobacillus can beneficially affect the host by producing acetic acid and lactic acid, which lower pH and thereby inhibit the growth of pathogens or allow the probiotic bacteria to compete with pathogens for epithelial adhesion sites and nutrients. The transmural migration of enteric organisms into the peritoneal cavity can cause peritonitis in peritoneal dialysis (PD) patients. We hypothesized that the composition of the intestinal microbiota with regard to Lactobacillus species and Bifidobacterium species differed between PD patients and healthy controls. The aim of the study was to investigate these differences by real-time PCR analysis of fecal samples. From 1 August 2009 to 31 March 2010, a total of 29 nondiabetic PD patients and 41 healthy controls from China Medical University Hospital were recruited after giving their informed consent. Fecal samples were collected from the PD patients and their age-matched counterparts in the morning using a standardized procedure. DNA extracted from these samples was analyzed by real-time PCR. All bifidobacteria, Bifidobacterium catenulatum, B. longum, B. bifidum, Lactobacillus plantarum, L. paracasei, and Klebsiella pneumoniae were less frequently detected in the patient samples. Dysbiosis (microbial imbalance) may impair intestinal barrier function and increase host vulnerability to pathogen invasion. Further studies are necessary to confirm our findings before clinical trials with probiotic supplementation in PD patients.

Somatic mutation and expression of BAP1 in hepatocellular carcinoma: an indicator for ferroptosis and immune checkpoint inhibitor therapies.

BRCA1-Associated Protein 1 (BAP1) is a deubiquitylase that is found associated with multiprotein complexes that regulate key cellular pathways, and subsequent researches have revealed that BAP1 acts independently as a tumor suppressor. Somatic BAP1 mutations occur in various malignancies, but malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. Whether somatic mutation or expression alteration of BAP1 in hepatocellular carcinoma (HCC) influence carcinogenesis or immunogenicity is still unknown. In this study, we analyzed RNA expression, immune infiltration, survival and mutation data of HCC from The Cancer Genome Atlas databases. The association between BAP1 and clinicopathological features was further investigated by immunohistochemistry on tissue microarray. We found that the prognosis of patients with high BAP1 expression was significantly worse than that of patients with low BAP1 expression, and multivariate analyses revealed that BAP1 expression was an independent prognostic factor for poor prognosis. HCC with high BAP1 expression was associated with low ESTIMATE Score, recruitment of more tumor-infiltrating macrophage, and elevated levels of tumor mutation burden, microsatellite instability, neoantigen count, as well as programmed death-ligand1 in HCC. In addition, BAP1 mutated HCC showed reduced ability to promote ferroptosis and high BAP1 expression was correlated with ferroptosis. In conclusion, high BAP1 expression reflects immunosuppression and ferroptosis in HCC. BAP1 is a promising prognostic marker for survival of HCC and may act as a complementary indicator for patients to receive ferroptosis-promoting therapy or immunotherapy.

Peripheral cytokine levels as novel predictors of survival in cancer patients treated with immune checkpoint inhibitors: A systematic review and meta-analysis.

Background: Early identification of patients who will benefit from immune checkpoint inhibitors (ICIs) has recently become a hot issue in cancer immunotherapy. Peripheral cytokines are key regulators in the immune system that can induce the expression of immune checkpoint molecules; however, the association between peripheral cytokines and the efficiency of ICIs remains unclear. Methods: A systematic review was conducted in several public databases from inception through 3 February 2022 to identify studies investigating the association between peripheral cytokines (i.e., IL-1ß, IL-2, IL-2RA, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF-α, IFN-γ, and TGF-ß) and ICI treatment. Survival data, including overall survival (OS) and/or progression-free survival (PFS), were extracted, and meta-analyses were performed. Results: Twenty-four studies were included in this analysis. The pooled results demonstrated that the pretreatment peripheral levels of IL-6 (univariate analysis: HR = 2.53, 95% CI = 2.21-2.89, p < 0.00001; multivariate analysis: HR = 2.21, 95% CI = 1.67-2.93, p < 0.00001) and IL-8 (univariate analysis: HR = 2.17, 95% CI = 1.98-2.38, p < 0.00001; multivariate analysis: HR = 1.88, 95% CI= 1.70-2.07, p < 0.00001) were significantly associated with worse OS of cancer patients receiving ICI treatment in both univariate and multivariate analysis. However, high heterogeneity was found for IL-6, which might be attributed to region, cancer type, treatment method, sample source, and detection method. Conclusion: The peripheral level of IL-8 may be used as a prognostic marker to identify patients with inferior response to ICIs. More high-quality prospective studies are warranted to assess the predictive value of peripheral cytokines for ICI treatment.