The prognostic significance and potential mechanism of DBF4 zinc finger in hepatocellular carcinoma.

DBF4 zinc finger (DBF4) is a critical component involved in DNA replication and cell proliferation. It acts as a positive regulator of the cell division cycle 7 kinase. In this study, our investigation encompassed the impact of DBF4 on hepatocellular carcinoma (HCC) progression and delved into the potential mechanisms. We utilized open-access databases like TCGA and GEO to analyze the association between DBF4 and 33 different tumor types. We also conducted immunohistochemistry experiments to validate the expression of DBF4 in HCC, STAD, COAD, READ, PAAD, and LGG. Furthermore, we employed lentiviral transduction to knockdown DBF4 in HLF and SMMC cells, as well as to overexpress DBF4 in Huh7 cells. Subsequently, we evaluated the impact of DBF4 on proliferation, migration, and invasion of hepatocellular carcinoma cells. RNA sequencing and KEGG pathway enrichment analysis were also conducted to identify potential pathways, which were further validated through WB experiments. Finally, pathway inhibitor was utilized in rescue experiments to confirm whether DBF4 exerts its effects on tumor cells via the implicated pathway. Our findings revealed that DBF4 exhibited significant expression levels in nearly all examined tumors, which were further substantiated by the results of immunohistochemistry analysis. High DBF4 expression was correlated with poor overall survival (OS), disease-specific survival (DSS), progression-free interval (PFI), disease-free interval (DFI), relapse-free interval (RFI) in majority of tumor types, particularly in patients with HCC. In vitro experiments demonstrated that inhibition of DBF4 impaired the proliferative, migratory, and invasive abilities of HCC cells, whereas overexpression of DBF4 promoted these phenotypes. Sequencing results indicated that DBF4 may induce these changes through the ERBB signaling pathway. Further experimental validation revealed that DBF4 activates the ERBB signaling pathway, leading to alterations in the JNK/STAT, MAPK, and PI3K/AKT signaling pathways, thereby impacting the proliferative, migratory, and invasive abilities of tumor cells. Lastly, treatment of Huh7 cells overexpressing DBF4 with the ERBB2 inhibitor dacomitinib demonstrated the ability of ERBB2 inhibition to reverse the promoting effect of DBF4 overexpression on the proliferative, migratory, and invasive abilities of HCC cells. DBF4 plays a pivotal oncogenic role in HCC by promoting the ERBB signaling pathway and activating its downstream PI3K/AKT, JNK/STAT3, and MAPK signaling pathways. DBF4 may serve as a prognostic biomarker for patients with HCC.

Pan-immune inflammation value as a prognostic biomarker for cancer patients treated with immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) represent a paradigm shift in the development of cancer therapy. However, the improved efficacy of ICIs remains to be further investigated. We conducted a systematic review and meta-analysis to evaluate the pan-immunoinflammatory value (PIV) and PILE score used to predict response to ICI therapy. Methods: We searched selected databases for studies on pan-immune inflammation values and their association with outcomes of treatment with immune checkpoint inhibitors. We used hazard ratios (HRS) and 95% confidence intervals (CI) to summarize survival outcomes. All data analyses were performed using STATA 15.0. Results: 7 studies comprising 982 patients were included in the meta-analysis. The pooled results showed that higher PIV was significantly associated with shorter overall survival OS (HR = 1.895, 95%CI: 1.548-2.318) and progression-free survival (PFS) (HR = 1.582, 95%CI: 1.324-1.890). Subgroup analyses also confirmed the reliability of the results. Conclusions: High PIV and PILE metrics are associated with lower survival in cancer patients receiving ICIs.

Leveraging an immune cell signature to improve the survival and immunotherapy response of lung adenocarcinoma.

Background: Immune cells play a critical role in the prognosis of cancer. However, the function of different immune cell types in lung adenocarcinoma (LUAD) and the development of a prognostic signature based on immune cell types have not been comprehensively investigated. Methods: We collected and included a total of 2499 LUAD patients and performed calculations to determine the penetration level of 24 immune cells. This examination was conducted using the macro-gene-based approach provided by ImmuCellAI. We performed a meta-analysis using Lasso-Cox analysis to establish the immune cell pair score (ICPS). We conducted a survival analysis to measure differences in survival across ICPS-risk groups. Wilcox test was used to measure the difference in expression level. Spearman correlation analysis was used for the relevance assessment. Results: We collected a total of 24 immune cell types to construct cell pairs. Utilizing 17 immune cell pairs, we constructed and validated the ICPS, which plays a critical role in stratifying survival and dynamically monitoring the effectiveness of immunotherapy. Additionally, we identified several candidate drugs that target ICPS. Conclusions: The ICPS shows promise as a valuable tool for identifying suitable candidates for immunotherapy among patients. Our comprehensive assessment of immune cell interactions in LUAD contributes to a deeper understanding of infiltration patterns and functions, thereby guiding the development of more efficacious immunotherapy strategies.

Sarcopenia affects the clinical efficacy of immune checkpoint inhibitors in patients with gastrointestinal cancers.

OBJECTIVE: The impact of sarcopenia on the efficacy of immune checkpoint inhibitors (ICI) in gastrointestinal cancer (GIC) patients remains uncertain in clinical practice. Hence, this study aims to investigate the potential correlation between sarcopenia and the clinical outcomes of GIC patients treated with ICIs. METHODS: To gather pertinent studies, a systematic literature search was implemented across multiple databases, including PubMed, Embase, the Cochrane Library, and Google Scholar. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), measured with the hazard ratio (HR). And the secondary outcomes, including disease control rate (DCR), overall response rate (ORR), and adverse events (AE), were evaluated with the odd ratio (OR). RESULTS: A total of 13 articles involving 1294 patients were collected for this analysis. The pooled results revealed that GIC patients with sarcopenia had significantly poorer OS (HR = 1.697, 95% CI = 1.367-2.106, p < 0.001) and PFS (HR: 1.551, 95% CI: 1.312-1.833, p < 0.001), and lower ORR (OR = 0.594, 95% CI = 0.388-0.909, p = 0.016) and DCR (OR: 0.553, 95% CI: 0.360-0.850, p = 0.007) compared to those without sarcopenia. However, sarcopenia did not increase the incidence of treatment-related adverse events compared with non-sarcopenia (OR = 1.377, 95% CI = 0.693-2.737, p = 0.361). According to subgroup analysis, the association between sarcopenia and the therapeutic effect of ICI on patients with primary liver cancer or gastric cancer was consistent with the above findings. CONCLUSION: Sarcopenia is significantly correlated with poorer treatment response and worse long-term efficacy in GIC patients treated with ICIs. Moreover, sarcopenia does not increase the incidence of adverse events.

Prognostic value of body composition on survival outcomes in melanoma patients receiving immunotherapy.

Objective: The influence of body composition on the effectiveness of immune checkpoint inhibitors (ICIs) in patients with melanoma is still uncertain in clinical practice. Therefore, the objective of this study was to examine the potential association between body composition and clinical outcomes in patients with melanoma undergoing ICIs treatment. Methods: A systematic literature search was performed across several databases, including PubMed, Embase, Cochrane Library and Google Scholar, to gather relevant studies. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), assessed by hazard ratios (HR). Secondary outcomes, such as adverse events (AE), were evaluated using odds ratios (OR). Results: This meta-analysis comprised ten articles involving a total of 1,283 patients. Systemic analysis of all collected evidence revealed that body composition, including low skeletal muscle index (SMI) (OS: HR = 1.66, 95% CI = 1.13-2.43, p = 0.010; PFS: HR = 1.28, 95% CI = 1.06-1.55, p = 0.009), high subcutaneous adipose tissue density (SMD) (OS: HR = 1.93, 95% CI = 1.09-3.44, p = 0.025; PFS: HR = 1.31, 95% CI = 1.06-1.63, p = 0.012), and sarcopenia (OS: HR = 1.25, 95% CI = 1.03-1.51, p = 0.022; PFS: HR = 1.25, 95% CI = 1.03-1.51, p = 0.022), were significantly associated with OS and PFS in melanoma patients treated with ICIs. However, these markers did not show a significant association with treatment-related adverse events. Interestingly, no significant correlation was found between visceral fat index (VFI) (OS: HR = 0.71, 95% CI = 0.29-1.76, p = 0.462; PFS: HR = 0.98, 95% CI = 0.93-1.02, p = 0.274) and OS or PFS in melanoma patients under ICIs treatment. Conclusion: Body composition was found to be associated with decreased treatment response and lower long-term efficacy in patients with melanoma undergoing immune checkpoint inhibitor (ICI) therapy. However, it is important to note that body composition did not appear to contribute to increased incidence of adverse events in these patients.

Low geriatric nutritional risk index as a poor prognostic biomarker for immune checkpoint inhibitor treatment in solid cancer.

Objective: In this investigation, we focused on the geriatric nutritional risk index (GNRI), a comprehensive metric that takes into account the patient's ideal weight, actual weight, and serum albumin levels to measure malnutrition. Our primary objective was to examine the predictive value of GNRI-defined malnutrition in determining the response to immunotherapy among cancer patients. Methods: Relevant articles for this study were systematically searched in PubMed, the Cochrane Library, EMBASE, and Google Scholar up to July 2023. Our analysis evaluated overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) as clinical outcomes. Results: This analysis comprised a total of eleven articles encompassing 1,417 patients. The pooled results revealed that cancer patients with low GNRI levels exhibited shorter OS (HR: 2.64, 95% CI: 2.08-3.36, p < 0.001) and PFS (HR: 1.87, 95% CI: 1.46-2.41, p < 0.001), and lower ORR (OR: 0.46, 95% CI: 0.33-0.65, p < 0.001) and DCR (OR: 0.42, 95% CI: 0.29-0.61, p < 0.001). Sensitivity analyses confirmed that the above results were stable. Egger's and Begg's tests revealed that there was no publication bias in the above results. Conclusion: Our results imply that the GNRI is a useful predictor of immunotherapy response in cancer patients.

Construction of a Nomogram to Predict Overall Survival in Patients with Early-Onset Hepatocellular Carcinoma: A Retrospective Cohort Study.

Hepatocellular carcinoma (HCC) is a widespread and impactful cancer which has pertinent implications worldwide. Although most cases of HCC are typically diagnosed in individuals aged ≥60 years, there has been a notable rise in the occurrence of HCC among younger patients. However, there is a scarcity of precise prognostic models available for predicting outcomes in these younger patients. A retrospective analysis was conducted to investigate early-onset hepatocellular carcinoma (EO-LIHC) using data from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2018. The analysis included 1392 patients from the SEER database and our hospital. Among them, 1287 patients from the SEER database were assigned to the training cohort (n = 899) and validation cohort 1 (n = 388), while 105 patients from our hospital were assigned to validation cohort 2. A Cox regression analysis showed that age, sex, AFP, grade, stage, tumor size, surgery, and chemotherapy were independent risk factors. The nomogram developed in this study demonstrated its discriminatory ability to predict the 1-, 3-, and 5-year overall survival (OS) rates in EO-LIHC patients based on individual characteristics. Additionally, a web-based OS prediction model specifically tailored for EO-LIHC patients was created and validated. Overall, these advancements contribute to improved decision-making and personalized care for individuals with EO-LIHC.

Prognostic value of controlling nutritional status on clinical and survival outcomes in cancer patients treated with immunotherapy.

Cancer is a leading cause of death globally. Immunotherapy has shown promise in treating various types of cancer, but its effectiveness varies among patients. The Controlling Nutritional Status (CONUT) score has been linked to the prognosis of different cancers. However, its predictive value for immunotherapy outcomes is not well understood. Our research represents the pioneering meta-study to examine the prognostic value of the CONUT score on cancer patients treated with an immune checkpoint inhibitor (ICI). A comprehensive literature search was conducted using various databases including PubMed, the Cochrane Library, EMBASE, and Google Scholar. The study was conducted until July 28, 2023. This analysis encompassed a comprehensive evaluation of various clinical outcomes, namely overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). 663 patients from 8 studies were included in this study. It showed that cancer patients with high CONUT score had poorer OS (HR: 1.94, 95% CI, 1.52-2.47, p < 0.001) and PFS (HR: 2.22, 95% CI, 1.48-3.31, p < 0.001), as well as worse ORR (OR: 0.46, 95% CI, 0.25-0.85, p = 0.013) and DCR (HR: 0.29, 95% CI, 0.14-0.59, p = 0.001). The CONUT score can predict the prognosis of tumor patients treated with ICIs.

Tumor-associated endothelial cell prognostic risk model and tumor immune environment modulation in liver cancer based on single-cell and bulk RNA sequencing: Experimental verification.

BACKGROUND: To build a prognostic and immunotherapeutic response prediction model for liver cancer based on marker genes of tumor-associated endothelial cell (TEC). METHOD: Single cell sequencing data from Gene Expression Omnibus (GEO) liver cancer patients were utilized to identify TEC subpopulations. Models were built from transcriptomic and clinical data of TCGA liver cancer patients. The GSE76427 and ICGC databases were used as independent validation sets. Time-dependent receiver operating characteristic (ROC) curves and Kaplan-Meier curves were used to verify the ability of the model to predict survival. XCELL, TIMER, QUANTISEQ, CIBERSORT, CIBERSORT-ABS, and ssGSEA were applied to evaluate tumor immune cell infiltration. The TIDE score was used to predict the effect of immunotherapy. Immune blockade checkpoint gene, tumor mutational load and GSVA enrichment analyses were further explored. The expression levels of candidate genes were measured and validated by real-time PCR between liver cancer tissues and adjacent nontumor liver tissues. RESULTS: Eighty-seven genes were identified as marker genes for TECs. IGFBP3, RHOC, S100A16, FSCN1, and CLEC3B were included in the constructed prognostic model. Time-dependent ROC curve values were higher than 0.700 in both the model and validation groups. The low risk group exhibited high immune cell infiltration and function than the higher risk group. The TIDE score indicated that the low-risk group benefited more from immunotherapy than the high-risk group. The risk score and multiple immune blockade checkpoint genes and immune-related pathways were strongly correlated. CONCLUSION: Novel signatures of TEC marker genes showed a powerful ability to predict prognosis and immunotherapy response in patients with liver cancer.

Prognostic nutritional index as a prognostic biomarker for gastrointestinal cancer patients treated with immune checkpoint inhibitors.

Objective: Our study represents the first meta-analysis conducted to evaluate the prognostic utility of the baseline prognostic nutritional index (PNI) in patients with gastrointestinal cancer (GIC) who received immune checkpoint inhibitor (ICI) therapy. Methods: We searched PubMed, the Cochrane Library, EMBASE, and Google Scholar until April 23, 2023, to obtain relevant articles for this study. Our analysis examined several clinical outcomes, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: In this analysis, a total of 17 articles with 2883 patients were included. Our pooled results indicated that patients with high PNI levels had longer OS (HR: 0.530, 95% CI: 0.456-0.616, p < 0.001) and PFS (HR: 0.740, 95% CI: 0.649-0.844, p < 0.001), as well as higher ORR (OR: 1.622, 95% CI: 1.251-2.103, p < 0.004) and DCR (OR: 1.846, 95% CI: 1.428-2.388, p < 0.001). Subgroup analysis showed that PNI cutoff values of 40 to 45 showed greater predictive potential. Subgroup analysis also confirmed that the above findings still hold true in patients with esophageal cancer, gastric cancer, and hepatocellular carcinomas. Conclusion: The PNI were reliable predictors of outcomes in GIC patients treated with ICIs.

Investigating causal associations among gut microbiota, metabolites, and liver diseases: a Mendelian randomization study.

Objective: There is some evidence for an association between gut microbiota and nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and viral hepatitis, but no studies have explored their causal relationship. Methods: Instrumental variables of the gut microbiota (N = 13266) and gut microbiota-derived metabolites (N = 7824) were acquired, and a Mendelian randomization study was performed to explore their influence on NAFLD (1483 European cases and 17,781 European controls), ALD (2513 European cases and 332,951 European controls), and viral hepatitis risk (1971 European cases and 340,528 European controls). The main method for examining causality is inverse variance weighting (IVW). Results: IVW results confirmed that Anaerotruncus (p = 0.0249), Intestinimonas (p = 0.0237), Lachnoclostridium (p = 0.0245), Lachnospiraceae NC2004 group (p = 0.0083), Olsenella (p = 0.0163), and Peptococcus (p = 0.0472) were protective factors for NAFLD, and Ruminococcus 1 (p = 0.0120) was detrimental for NAFLD. The higher abundance of three genera, Lachnospira (p = 0.0388), Desulfovibrio (p = 0.0252), and Ruminococcus torques group (p = 0.0364), was correlated with a lower risk of ALD, while Ruminococcaceae UCG 002 level was associated with a higher risk of ALD (p = 0.0371). The Alistipes (p = 0.0069) and Ruminococcaceae NK4A214 group (p = 0.0195) were related to a higher risk of viral hepatitis. Besides, alanine (p = 0.0076) and phenyllactate (p = 0.0100) were found to be negatively correlated with NAFLD, while stachydrine (Op = 0.0244) was found to be positively associated with NAFLD. The phenylacetate (p = 0.0353) and ursodeoxycholate (p = 0.0144) had a protective effect on ALD, while the threonate (p = 0.0370) exerted a detrimental influence on ALD. The IVW estimates of alanine (p = 0.0408) and cholate (p = 0.0293) showed their suggestive harmful effects against viral hepatitis, while threonate (p = 0.0401) displayed its suggestive protective effect against viral hepatitis. Conclusion: In conclusion, our research supported causal links between the gut microbiome and its metabolites and NAFLD, ALD, and viral hepatitis.

Construction of a T-cell exhaustion-related gene signature for predicting prognosis and immune response in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with a rising prevalence worldwide. Immunotherapy has been shown to improve treatment outcomes for HCC. We aimed to construct a T-cell exhaustion-related gene prognostic model (TEXPM) for HCC and to elucidate the immunologic characteristics and advantages of immunotherapy in T-cell exhaustion-Related Gene-defined HCC groups. METHODS: Single-cell RNA sequencing data were used in conjunction with TCGA Differentially expressed genes (DEGs) to screen for T-cell exhaustion-Related Genes (TEXGs) for subsequent evaluation. Using univariate Cox regression analysis and LASSO regression analysis, five genes (FTL, GZMA, CD14, NPC2, and IER3) were subsequently selected for the construction of a TEXPM. Then, we evaluated the immunologic characteristics and advantages of immunotherapy in groups identified by TEXPM. RESULTS: The TEXPM was formed with FTL, GZMA, CD14, NPC2, and IER3. The results of the training and validation team studies were consistent, with the low TEXPM group surviving longer than the high TEXPM group (P < 0.001). Multivariate Cox regression analysis demonstrated that TEXPM (HR: 2.347, 95%CI: 1.844-2.987; HR: 2.172, 95% CI: 1.689-2.793) was an independent prognostic variable for HCC patients. The low-TEXPM group was linked to active immunity, less aggressive phenotypes, strong infiltration of CD8+ T cells, CD4 + T cells, and M1 macrophages, and a better response to ICI treatment. A high TEXPM group, on the other hand, was associated with suppressive immunity, more aggressive phenotypes, a significant infiltration of B cells, M0 macrophages, and M2 macrophages, and a reduced response to ICI treatment. FTL is an independent prognostic variable in HCC patients and the knockdown of FTL can affect the biological behavior of hepatocellular carcinoma cells. CONCLUSIONS: TEXPM is a promising prognostic biomarker connected to the immune system. Differentiating immunological and molecular features and predicting patient outcomes may be facilitated by TEXPM grouping. Furthermore, the expression of FTL was found to be an independent prognostic factor for HCC. Knockdown of FTL significantly inhibited proliferation, migration, and invasive activity in liver cancer cells.

Effects of hormones on intestinal stem cells.

The maintenance of intestinal renewal and repair mainly depends on intestinal stem cells (ISCs), which can also contribute to the growth of intestinal tumours. Hormones, which are vital signalling agents in the body, have various effects on the growth and replacement of intestinal stem cells. This review summarises recent progress in the identification of hormones associated with intestinal stem cells. Several hormones, including thyroid hormone, glucagon-like peptide-2, androgens, insulin, leptin, growth hormone, corticotropin-releasing hormone and progastrin, promote the development of intestinal stem cells. However, somatostatin and melatonin are two hormones that prevent the proliferation of intestinal stem cells. Therefore, new therapeutic targets for the diagnosis and treatment of intestinal illnesses can be identified by examining the impact of hormones on intestinal stem cells.

The Use of Antibiotics During Immune Checkpoint Inhibitor Treatment Is Associated with Lower Survival in Advanced Esophagogastric Cancer.

OBJECTIVE: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to explore the impact of antibiotic use on outcomes in ICI-treated EGC patients. METHODS: Patients with advanced EGC treated with ICIs at our center were identified between 2017 and 2021. The impact of antibiotic use on overall survival (OS) and progression-free survival (PFS) was assessed by a log-rank test. Eligible articles were retrieved using PubMed, the Cochrane Library, EMBASE, and Google Scholar by December 17, 2022. Clinical outcomes were OS, PFS, and disease control rate (DCR). RESULTS: In our cohort, 85 EGC patients were recruited. The results showed that antibiotic use significantly shortens OS (HR: 1.91, 95% CI: 1.11-3.28, P = 0.020) and PFS (HR: 2.13, 95% CI: 1.21-3.74, P = 0.009) and reduces DCR (OR: 0.27, 95% CI: 0.10-0.720, P = 0.013) in EGC patients treated with ICIs. The meta-analysis results revealed that antibiotic use was significantly associated with worse OS (HR = 2.454, 95% CI: 1.608-3.748, P < 0.001), PFS (HR = 2.539, 95% CI: 1.455-4.432, P = 0.001), and lower DCR (OR = 0.246, 95% CI: 0.105-0.577, P = 0.001). No publication bias existed, and sensitivity analysis confirmed stable results. CONCLUSION: In patients with advanced EGC undergoing ICI, the use of antibiotics, such as cephalosporins, was associated with inferior survival rates.

Blood biomarkers predict outcomes in patients with hepatocellular carcinoma treated with immune checkpoint Inhibitors: A pooled analysis of 44 retrospective sudies.

OBJECTIVE: We conducted the first meta-analysis to identify the predictive significance of baseline blood biomarkers (such as neutrophil to lymphocyte ratio (NLR), early alpha-fetoprotein (AFP) response, albumin-bilirubin (ALBI), AFP, platelet to lymphocyte ratio (PLR), C-reactive protein (CRP), protein induced by vitamin K absence II (PIVKA-II), and lymphocyte to monocyte ratio (LMR)) in hepatocellular carcinoma (HCC) patients treated with immune checkpoint inhibitors (ICIs). METHODS: Eligible articles were retrieved using PubMed, the Cochrane Library, EMBASE, and Google Scholar by November 24, 2022. Clinical outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and hyperprogressive disease (HPD). RESULTS: A total of 44 articles with 5322 patients were included in this meta-analysis. The pooled results demonstrated that patients with high NLR levels had significantly poorer OS (HR: 1.951, P < 0.001) and PFS (HR: 1.632, P < 0.001), lower ORR (OR: 0.484, P < 0.001) and DCR (OR: 0.494, P = 0.027), and higher HPD (OR: 8.190, P < 0.001). The patients with high AFP levels had shorter OS (HR: 1.689, P < 0.001) and PFS (HR: 1.380, P < 0.001), and lower DCR (OR: 0.440, P < 0.001) than those with low AFP levels, however, there was no difference in ORR (OR: 0.963, P = 0.933). We also found that early AFP response was correlated with better OS (HR: 0.422, P < 0.001) and PFS (HR: 0.385, P < 0.001), higher ORR (OR: 7.297, P < 0.001) and DCR (OR: 13.360, P < 0.001) compared to non-responders. Besides, a high ALBI grade was significantly related to shorter OS (HR: 2.440, P = 0.009) and PFS (HR: 1.373, P = 0.022), lower ORR (OR: 0.618, P = 0.032) and DCR (OR: 0.672, P = 0.049) than those with an ALBI grade 1. CONCLUSION: The NLR, early AFP response, and ALBI were useful predictors of outcomes in HCC patients treated with ICIs.

Characterization of the intestinal fungal microbiome in patients with hepatocellular carcinoma.

OBJECTIVE: Gut mycobiota plays a crucial role in benign liver diseases; however, its correlation with hepatocellular carcinoma (HCC) remains elusive. This study aimed to elucidate fungal differences in patients with HCC-associated cirrhosis compared to cirrhotic patients without HCC and healthy controls. METHODS: The 72 fecal samples from 34 HCC patients, 20 cirrhotic patients, and 18 healthy controls were collected and analyzed using ITS2 rDNA sequencing. RESULTS: Our results revealed the presence of intestinal fungal dysbiosis with significant enrichment of opportunistic pathogenic fungi such as Malassezia, Malassezia sp., Candida, and C. albicans in HCC patients compared with healthy controls and cirrhosis patients. Alpha-diversity analysis demonstrated that patients with HCC and cirrhosis showed decreased fungal diversity compared to healthy controls. Beta diversity analysis indicated that the three groups exhibited significant segregated clustering. Besides, C. albicans was found to be significantly more abundant in the HCC patients with TNM stage III-IV than those with stage I-II, in contrast to the commensal organism S. cerevisiae. We also confirmed that the HCC patients were successfully classified with an area under the curve value of 0.906 based on the fecal fungal signature. Finally, our animal experiments confirm that aberrant colonization of the intestine by C. albicans and M. furfur can promote the development of HCC. CONCLUSIONS: This study indicates that dysbiosis of the gut mycobiome might be involved in HCC development. TRIAL REGISTRATION: ChiCTR, ChiCTR2100054537. Registered 19 December 2021, http://www.chictr.org.cn/edit.aspx?pid=144550&htm=4.

The prognostic value of the advanced lung cancer inflammation index in patients with gastrointestinal malignancy.

BACKGROUND: Systemic inflammation is crucial for the development and progression of cancers. The advanced lung cancer inflammation index (ALI) is considered to be a better indicator of systemic inflammation than current biomarkers. However, the prognostic value of the ALI in gastrointestinal neoplasms remains unclear. We performed the first meta-analysis to explore the association between ALI and gastrointestinal oncologic outcomes to help physicians better evaluate the prognosis of those patients. METHODS: Eligible articles were retrieved using PubMed, the Cochrane Library, EMBASE, and Google Scholar by December 29, 2022. Clinical outcomes were overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS). RESULTS: A total of 18 articles with 6898 patients were included in this meta-analysis. The pooled results demonstrated that a low ALI was correlated with poor OS (HR = 1.914, 95% CI: 1.514-2.419, P < 0.001), DFS (HR = 1.631, 95% CI: 1.197-2.224, P = 0.002), and PFS (HR = 1.679, 95% CI: 1.073-2.628, P = 0.023) of patients with gastrointestinal cancers. Subgroup analysis revealed that a low ALI was associated with shorter OS (HR = 2.279, 95% CI: 1.769-2.935, P < 0.001) and DFS (HR = 1.631, 95% CI: 1.197-2.224, P = 0.002), and PFS (HR = 1.911, 95% CI: 1.517-2.408, P = 0.002) of patients with colorectal cancer. However, the ALI was not related to CSS in the patients with gastrointestinal malignancy (HR = 1.121, 95% CI: 0.694-1.812, P = 0.640). Sensitivity analysis supported the stability and dependability of the above results. CONCLUSION: The pre-treatment ALI was a useful predictor of prognosis in patients with gastrointestinal cancers.

GNB1 promotes hepatocellular carcinoma progression by targeting BAG2 to activate P38/MAPK signaling.

G-proteins are intracellular partners of G-protein-coupled receptors. As a member of the G-protein family, GNB1 has been shown to play a pro-cancer role in lung cancer and breast cancer. However, the biological function and detailed mechanisms of GNB1 in hepatocellular carcinoma progression are unclear. In this study, we investigated the effects of GNB1 and its possible mechanism of action in hepatocellular carcinoma (HCC). The clinical significance of GNB1 was evaluated in a large cohort of HCC patients, showing that GNB1 was overexpressed in HCC compared to adjacent normal liver tissues, and increased GNB1 expression was associated with poor prognosis. We also demonstrated that GNB1 enhances cell proliferation, colony formation, and cell migration and invasion in vitro and promotes the epithelial-to-mesenchymal transition process in HCC cells. Tumor xenograft model assay confirmed the oncogenic role of GNB1 in tumorigenicity in nude mice. Activation of P38 signaling was found in the GNB1 overexpressed HCC cells. Further intervention of P38 confirmed it as an important signaling pathway for the oncogenic role of GNB1 in HCC. Moreover, co-immunoprecipitation followed by liquid chromatograph-mass spectrometry identified that GNB1 exerted oncogenic functions via the interaction of BAG2 and activated P38 signaling pathway. Together, our results reveal that GNB1 plays a pivotal oncogenic role in HCC by promoting the P38 pathway via cooperating with BAG2. GNB1 may serve as a prognostic biomarker for patients with HCC.

Effects of PPIs use on clinical outcomes of urothelial cancer patients receiving immune checkpoint inhibitor therapy.

Objective: Immune checkpoint inhibitors (ICIs) have recently demonstrated promising performance in improving the prognosis of urological cancer patients. The goal of this meta-analysis was to determine the impact of PPI use on the clinical outcomes of urological cancer patients receiving ICI therapy. Methods: Before 6 May 2022, the eligible literature was searched using PubMed, EMBASE, Cochrane Library, and Google Scholar. The clinical outcomes were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: A total of six articles met the inclusion criteria, and of the 1980 patients with advanced or metastatic urothelial cancers (UC) included. The meta-analysis displayed that PPI use could increase the risk of progression by 50.7% (HR: 1.507, 95% CI: 1.327-1.711, p < 0.001) and death by 58.7% (HR: 1.587, 95% CI: 1.367-1.842, p < 0.001), and reduce the ORR (OR: 0.503, 95% CI: 0.360-0.703, p < 0.001) in UC patients receiving ICIs. No significant heterogeneity and publication bias existed. Sensitivity analysis proved that the results were stable and reliable. Conclusion: The meta-analysis indicated that concomitant PPI use was significantly associated with low clinical benefit in UC patients.

The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors.

Objective: Recently, immune checkpoint inhibitor (ICI) treatment has shown encouraging performance in improving the prognosis of hepatocellular carcinoma (HCC) patients. The gut microbiome plays a vital role in altering the efficacy of ICIs, which may be impacted by antibiotics. The aim of the meta-analysis is to estimate the influence of antibiotic use on the survival of HCC patients treated with ICIs. Methods: The literature review was conducted using databases like PubMed, EMBASE, Cochrane Library, CNKI, WANFANG DATA, VIP, Google Scholar, and ClinicalTrials.gov before May 15, 2022. The primary endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results: A total of six retrospective studies met the inclusion criteria. 1056 patients were included in the study, of which 352 (33.33%) received antibiotic treatment. The meta-analysis results revealed antibiotic use did not affect the OS (HR: 1.41, 95% CI: 0.96-2.08, P = 0.088) and PFS (HR: 1.21, 95% CI: 0.73-2.00, P = 0.459) in HCC patients treated with ICIs. Besides, the use of antibiotics did not reduce the ORR (OR: 1.06, 95% CI: 0.69-1.64, P = 0.784) and DCR (OR: 0.42, 95% CI: 0.09-2.06, P = 0.286) in HCC patients treated with ICIs. Conclusion: Current evidence reveals that antibiotic use does alter the therapeutic efficacy of ICIs in HCC patients. Systematic Review Registration: https://www.crd.york.ac.uk/, identifier CRD42022311948.