Potential Biomarker For Prognosis Research Articles

Soluble PD-L1 and Serum Vascular Endothelial Growth Factor-B May Independently Predict Prognosis in Patients with Advanced Non-Small Cell Lung Cancer Treated with Pembrolizumab

Background: Previous preclinical data have shown that the dynamic cross-talk between abnormal tumor vasculature and immune cell factors in the tumor microenvironment may exert a critical role in the progression and treatment resistance of non-small cell lung cancer (NSCLC). In the clinical setting, a variety of blood-based angiogenesis- and immune-related factors are being increasingly investigated as potential biomarkers of prognosis or treatment response in immunotherapy-treated NSCLC. We herein aimed to evaluate the clinical relevance of the peripheral blood levels of vascular endothelial growth factor-A and -B (VEGF-A and VEGF-B, respectively), soluble programmed cell death-1 (sPD-1), and programmed cell death-ligand 1 (sPD-L1) in patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs). Methods: Consecutive patients with advanced-stage, non-oncogene-addicted NSCLC, eligible to receive ICIs at the Oncology Unit of Sotiria Athens General Hospital, were prospectively recruited. A group of sex- and age-matched healthy controls was also enrolled for the evaluation of the potential diagnostic significance of the examined biomarkers. Serum levels of all biomarkers were measured using ELISA, both before and after treatment, and were correlated with standard clinicopathological features of patients, treatment response, progression-free survival (PFS), and overall survival (OS). Results: A total of 55 patients and 16 healthy controls were included in the final analysis. The mean age of patients and controls was 66.5 years (SD = 8.0 years) and 65.4 years (SD = 9.1 years), respectively. The majority of patients (65.5%) received pembrolizumab in combination with chemotherapy, while the remaining patients received pembrolizumab monotherapy. ROC curve analysis showed that VEGFB and sPD-1 were the only markers with a significant diagnostic value. Higher pre-treatment values of sPD-L1 (HR = 1.68; p = 0.040) and sPD-1 (HR = 10.96; p = 0.037) as well as higher post-treatment values of VEGF-B (HR = 2.99; p = 0.049) were all significantly associated with a reduced OS in univariate Cox regression analysis. The adverse prognostic significance of higher pre-treatment values of sPD-L1 (HR = 2.10; p = 0.014) and higher post-treatment values of VEGFB (HR = 3.37; p = 0.032) was further confirmed in multivariate analysis. Conclusions: Our study results suggest that serum levels of sPD-L1 and VEGF-B may independently predict prognosis in ICI-treated advanced-stage NSCLC.

Association between serum levels of 12 different cytokines and short-term efficacy of chemoradiotherapy in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) has a poor prognosis, with chemoradiotherapy (CRT) being a key treatment method. This study focused on circulating cytokines as potential predictors of treatment response and prognosis in patients with ESCC.Materials and methodsSerum samples were collected from 36 ESCC patients, and 12 different cytokines were quantified using a multiplex immunofluorescence assay. We used non-parametric Wilcoxon unpaired rank tests to examine the relationship between cytokine concentrations and clinical outcomes. The duration of progression-free survival was assessed through imaging studies and telephone follow-ups. Kaplan–Meier survival plots, analyzed with the log-rank test, were utilized to depict survival trends.ResultsPre-treatment serum IL-8 levels were significantly elevated in patients with lymphoid metastases (p = 0.036). Lower initial levels of IL-8 and IL-1β were observed in patients with partial response group compared to those with stable disease (p = 0.002, p = 0.01). Elevated baseline levels of IL-8 and interferon-gamma (IFN-γ) were correlated with a poorer prognosis. Higher levels of IL-5 and IFN-γ levels following therapy were associated with worse outcomes.ConclusionsOur findings indicate that IL-8, IL-1β, IL-5, and IFN-γ may serve as potential biomarkers for treatment efficacy and prognosis in ESCC. Patients with low levels of IL-8 and IL-1β demonstrate a favorable response to CRT. Elevated serum levels of IL-8, IL-1β, IFN-γ, and IL-5 may predict poorer clinical outcomes.

Unveiling the Intratumor Microbiome in Liver Cancer: Current Insights and Prospective Applications.

The role of the gut microbiome in the development and progression of liver cancer has long been recognized. However, the presence of microbes in tumors that were previously considered sterile has only recently been discovered. The intratumor microbiome in liver cancer likely originates from various sources, including the gut, hematogenous spread from other mucosal locations, adjacent non-cancerous tissues, and co-metastasis with the tumor cells. As a newly discovered component of the tumor microenvironment, it regulates host immune responses, promotes chronic inflammation, modulates metabolic pathways, and exerts other influences in liver cancer. These unique features offer potential new biomarkers for liver cancer prognosis and treatment response. Exploring the complex interactions between intratumor microbiome and the host to modulate or target the intratumor microbiome may provide new avenues for liver cancer treatment. This article provides a comprehensive review of our current understanding regarding the potential origins of the intratumor microbiome in liver cancer, its unique characteristics, and the underlying mechanisms by which it affects liver cancer. Furthermore, we discuss the promising clinical implications and potential challenges that remain before this knowledge can be fully integrated into clinical practice.

Lipid Metabolism Related Gene ACSL3 as a Biomarker for Predicting Immunotherapy Outcomes in Lung Adenocarcinoma.

Investigate the role of lipid metabolism in the tumor immune microenvironment (TIME) of lung adenocarcinoma (LUAD) and identify vital lipid metabolism-related genes (LMRGs) that contribute to immunotherapy outcomes. 1130 LUAD patients were acquired utilizing public databases. Multiple algorithms were used to analyze the contribution of lipid metabolism in TIME. Importantly, cell lines, clinical samples (52 patients in surgery cohort and 36 in immunotherapy cohort), animal models, RNA-seq, experiments in protein and mRNA levels were conducted for identifying and validating key biomarker in LUAD immunotherapy. A prognostic signature comprising 33 LMRGs was developed and validated as an effective predictor of prognosis and TIME, with a C-index of 0.766 (95% CI: 0.729-0.804). Additionally, we identified Acyl-CoA Synthetase Long Chain Family Member 3 (ACSL3) as a potential biomarker for immunotherapy prognosis. The expression of ACSL3 was verified in 88 clinical tissues from LUAD patients, which indicated that elevated ACSL3 expression was correlated with worse progression-free survival (PFS) (p<0.001) and overall survival (OS) (p=0.008). Subsequent experiments revealed that knockdown of ACSL3 in vivo enhanced the efficacy of immunotherapy, potentially through increasing interferon α secretion, as indicated by Bulk RNA-seq and ELISA analysis, thereby promoting the infiltration of anti-tumor immune cells. The study established a model that accurately predicts immunotherapy response, prognosis, and TIME dynamics in LUAD patients. Notably, the pivotal role of ACSL3 in driving tumor progression and immune evasion was uncovered, offering novel insights into the optimization of immunotherapy strategies for LUAD.

Increased Plasma Pyruvate Kinase M2 (PK-M2) in Heart Failure: A Novel Biomarker Related to Cardiac Function and its Clinical Implications.

The purpose of this study was to investigate whether circulating pyruvate kinase M2 (PK-M2) levels are elevated in the peripheral blood and to assess their association with diagnosis and prognosis in patients with heart failure (HF). We conducted a prospective investigation involving 222 patients with HF and 103 control subjects, measuring PK-M2 concentrations using ELISA. The primary outcome, assessed over a median follow-up of 2 years (interquartile range: 776 to 926 days), was the time to the first occurrence of either rehospitalization for worsening HF or cardiovascular death. Patients with HF had higher PK-M2 levels than controls (17.4±4.1 versus 7.8±2.3 U/mL, P <0.001), and these levels correlated with HF severity (New York Heart Association cardiac function class). Patients with reduced left ventricular ejection fraction had higher PK-M2 concentrations than those with preserved ejection fraction (18.3±4.5 versus 16.7±3.6 U/mL, P <0.01). In a subset of patients with HF (n=52), PK-M2 levels significantly decreased following standardized HF treatment (mean difference, -4.3±0.5 U/mL, P <0.001). A high PK-M2 level had a 1.913-fold higher risk of the primary outcome (P=0.033) after adjusting for multiple cardiovascular risk factors, but not with cardiovascular death. Additionally, PK-M2 added incremental prognostic value beyond clinical predictors and N-terminal pro-brain natriuretic peptide (P <0.05). Elevated PK-M2 levels are associated with primary outcomes and rehospitalization for worsening heart failure in patients with HF. These findings suggest that PK-M2 is a potential biomarker for HF diagnosis and prognosis, warranting consideration for serial patient assessment.

Predicting Alzheimer's disease subtypes and understanding their molecular characteristics in living patients with transcriptomic trajectory profiling.

Deciphering the diverse molecular mechanisms in living Alzheimer's disease (AD) patients is a big challenge but is pivotal for disease prognosis and precision medicine development. Utilizing an optimal transport approach, we conducted graph-based mapping of transcriptomic profiles to transfer AD subtype labels from ROSMAP monocyte samples to ADNI and ANMerge peripheral blood mononuclear cells. Subsequently, differential expression followed by comparative pathway and diffusion pseudotime analysis were applied to each cohort to infer the progression trajectories. Survival analysis with real follow-up time was used to obtain potential biomarkers for AD prognosis. AD subtype labels were accurately transferred onto the blood samples of ADNI and ANMerge living patients. Pathways and associated genes in neutrophil degranulation-like immune process, immune acute phase response, and IL-6 signaling were significantly associated with AD progression. The work enhanced our understanding of AD progression in different subtypes, offering insights into potential biomarkers and personalized interventions for improved patient care. We applied an innovative optimal transport-based approach to map transcriptomic data from different Alzheimer's disease (AD) cohort studies and transfer known AD subtype labels from ROSMAP monocyte samples to peripheral blood mononuclear cell (PBMC) samples within ADNI and ANMerge cohorts. Through comprehensive trajectory and comparative analysis, we investigated the molecular mechanisms underlying different disease progression trajectories in AD. We validated the accuracy of our AD subtype label transfer and identified prognostic genetic markers associated with disease progression, facilitating personalized treatment strategies. By identifying and predicting distinctive AD subtypes and their associated pathways, our study contributes to a deeper understanding of AD heterogeneity.

Therapeutic implications and comprehensive insights into cellular senescence and aging in the tumor microenvironment of sarcoma

Sarcoma (SARC), a diverse group of stromal tumors arising from mesenchymal tissues, is often associated with a poor prognosis. Emerging evidence indicates that senescent cells within the tumor microenvironment (TME) significantly contribute to cancer progression and metastasis. Although the influence of senescence on SARC has been partially acknowledged, it has yet to be fully elucidated. In this study, we revealed that senescence level and age were associated with TME, immune treatment indicators, and prognosis in SARC. Utilizing the weighted gene co-expression network analysis and least absolute shrinkage and selection operator algorithm, we identified senescence-related genes and developed a senescence predictor. Three genes, RAD54, PIK3IP1, and TRIP13, were selected to construct a multiple linear regression model. Validation cohorts, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction confirmed that the predictor derived from these three genes possessed prognostic and pathological relevance. Our senescence predictor provides comprehensive insights into the molecular mechanisms of SARC and identifies potential biomarkers for prognosis, paving the way for effective treatments. The results of this study hold promise for developing therapeutic strategies tailored to the unique characteristics of SARC.

Increased circulatory Krebs cycle metabolites in sepsis is associated with increased interleukin-6 release and worse survival.

Recent studies have proposed that Krebs cycle metabolites may serve as potential biomarkers for prognosis in sepsis. However, whether these metabolites are associated with disease severity and can be applied to improve the effectiveness of current prognosis assessment in sepsis remains unclear and is explored in this study. This prospective multicenter cohort study was conducted in medical intensive care units (ICUs). From December 2019 to September 2022, consecutive patients admitted to medical ICUs for sepsis were screened and recruited. Plasma samples were obtained for measurements of cytokines and Krebs cycle metabolites, including citrate/isocitrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate and malate. In total, 97 patients admitted for sepsis were enrolled in the study. The 28-day mortality rate was 17.5%, and non-survivors exhibited significantly increased plasma lactate levels and Sequential Organ Failure Assessment (SOFA) scores. Plasma levels of Krebs cycle metabolites were significantly correlated with both plasma lactate and interleukin-6 levels. Except for citrate/isocitrate, all Krebs cycle metabolites were significantly elevated in patients with acute kidney injury. Multivariate Cox proportional hazard models, adjusted for plasma lactate levels and SOFA scores, revealed that plasma levels of alpha-ketoglutarate (adjusted hazard ratio [HR]: 2.404, P = 0.002), fumarate (adjusted HR: 1.904, P = 0.001) and malate (adjusted HR: 1.327, P = 0.019) were associated with increased risk of 28-day mortality. Study findings indicate that Krebs cycle metabolites, particularly alpha-ketoglutarate, fumarate, and malate, when applied with SOFA score, might enhance prognostic assessment in patients with sepsis.

ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in human epidermal growth factor receptor 2-positive breast cancer.

Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20 kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. We demonstrated that metastatic BC cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ BC.

HIF-1α and VEGF Immunophenotypes as Potential Biomarkers in the Prognosis and Evaluation of Treatment Efficacy of Atherosclerosis: A Systematic Review of the Literature.

Hypoxia-inducible factor 1 alpha (HIF-1α) and its related vascular endothelial growth factor (VEGF) may play a significant role in atherosclerosis and their targeting is a strategic approach that may affect multiple pathways influencing disease progression. This study aimed to perform a systematic review to reveal current evidence on the role of HIF-1α and VEGF immunophenotypes with other prognostic markers as potential biomarkers of atherosclerosis prognosis and treatment efficacy. We performed a systematic review of the current literature to explore the role of HIF-1α and VEGF protein expression along with the relation to the prognosis and therapeutic strategies of atherosclerosis. We used the terms {"Atherosclerosis" [OR] "Atheroma" [OR] "atheromatous plaque" [OR] "plaque atherosclerotic"} [AND] {"HIF-1α"} [AND] {"VEGF"} from 2009 up to May 2024 and the Medline/Embase/PubMed database. We used methodological approaches to assess unbiased data [ROBIS (Risk of Bias in Systematic) tool]. We used study eligibility criteria, and data were collected and evaluated from original articles by two independent teams, judged by an independent reviewer, and reported by PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) 2020. We included 34 original studies investigating 650 human specimens, 21 different cell lines, and 9 animal models. Increased HIF-1α in vascular smooth muscle cells, macrophages, or endothelial cells, under hypoxia, chronic loss of nitric oxide (NO), or reduced micro ribonucleic acid (miRNA)-17 and miR-20, is associated with the upregulation of pro-inflammatory molecules, such as interleukin-1 beta (IL-1β) or tumor necrosis factor-alpha (TNF-α), increased migration inhibitory factor of macrophages, glycolytic flux, lipid accumulation, necroptosis via miR-383, and adverse effects in atherosclerosis and plaque vulnerability. However, increased HIF-1α in lymphocytes is associated with decreased interferon-gamma (IFN-γ) and a favorable prognosis. Increased VEGF in a coronary artery, activated macrophages, or chronic exposure to methamphetamine is associated with elevated levels of serum inflammatory cells (interleukin-18; IL18), p38 mitogen-activated protein kinase (MAPK) phosphorylation, lipopolysaccharide-induced tumor necrosis factor-alpha factor (LITAF), and signal transducer and activator of transcription 6 isoform B (STAT6B) overexpression, leading to atherosclerosis progression and plaque break. However, VEGF overexpression in serum is marginally associated with an elevated risk for atherosclerosis. In contrast, stable overexpression of VEGF in macrophages correlates with reduced hyperplasia after arterial injury, reduced foam cell formation, and attenuation of atherosclerosis progression. HIF-1α/VEGF immunophenotypes reflect atherosclerosis treatment efficacy using, among others, HIF-inhibitors, statins, polyphenols, miR-497-5p, methylation modification, adenosine receptor antagonists, natural products, or glycosides. We present an overview of HIF-1α/VEGF expression in chronic inflammatory-related atherosclerosis disease. Exploring pathogenetic mechanisms and therapeutic options, we included several studies using variable methods to evaluate HIF-1α/VEGF immunophenotypes with controversial and innovative results. Data limitations may include the use of different survival methods. Our data support HIF-1α/VEGF immunophenotypes as potential biomarkers of atherosclerosis prognosis and treatment efficacy.

CBX2 promotes cervical cancer cell proliferation and resistance to DNA-damaging treatment via maintaining cancer stemness.

Cervical cancer is the fourth most common malignancy and the fourth leading cause of cancer-related death among women. Advanced stages and resistance to treatment in cervical cancer induce cancer-related deaths. Although epigenetics has been known to plays a vital role in tumor progression and resistance, the function of epigenetic regulators in cervical cancer is an area of investigation. In this study, we focused on an epigenetic regulator, polycomb repressor complex 1 (PRC1) in cervical cancer. Through bioinformatics analysis and immunochemistry, we subsequently identified CBX2, the deregulated subunit of PRC1, which is up-regulated in cervical cancer and associated with poor prognosis and unfavorable clinicopathological characteristics. We provided functional evidence demonstrating that CBX2 promoted cervical cancer cell proliferation. Furthermore, CBX2 exhibited an anti-apoptotic effect, which induced resistance to cisplatin and ionizing radiation in cervical cancer cells. Moreover, CBX2 was involved in maintaining cancer stemness. These findings suggest CBX2 plays an important role in cervical cancer progression and resistance to treatment, and may serve as a potential biomarker for prognosis and resistance as well as a potential therapeutic target.

ICOSL deficiency promotes M1 polarization to alleviate liver fibrosis in Schistosomiasis Mice

The expression of inducible co-stimulator ligand (ICOSL) on macrophage (Mφ) implies their ability to interact with inducible co-stimulator (ICOS)-expressing T cells, thereby modulating immune responses within the liver microenvironment. This study aimed to elucidate the mechanism underlying ICOS/ICOSL signaling in the regulation of Mφ polarization during Schistosomiasis-induced liver fibrosis. To investigate this, ICOSL-knock out (KO) and wildtype (WT) C57BL/6 mice were infected with Schistosoma japonicum (S. japonicum) to examine the dynamic changes in Mφ phenotype and observe the pathology alterations in the liver. There was significantly decreased expression of ICOSL both in monocytes of cirrhosis patients and the liver tissue of mice infected with S. japonicum. Furthermore, ICOSL-KO mice exhibited reduced liver granuloma formation and fibrosis during S. japonicum infection. Simultaneously, Mφ in ICOSL-KO mice polarized towards M1-type and induced apoptosis of hepatic stellate cells (HSCs). Overall, the blockade of ICOSL signaling could promote M1 polarization, induce HSCs apoptosis, and ameliorate hepatic fibrosis, suggesting that ICOSL may serve as a potential biomarker for prognosis and therapeutic target for schistosomiasis-induced hepatic fibrosis.

The 7-Methylguanosine (m7G) methylation METTL1 acts as a potential biomarker of clear cell renal cell carcinoma progression.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. 7-Methylguanosine (m7G), one of the most prevalent RNA modifications, has been reported to play an important role in ccRCC progression; however, the specific regulators of m7G modification that are involved in this function remain unclear. This study aimed to explore the correlation between regulators of m7G methylation and ccRCC progression using unsupervised machine learning methods. Transcriptome and clinical data of ccRCC were retrieved from The Cancer Genome Atlas (TCGA) database to identify differentially expressed m7G-related genes associated with the overall survival of patients with ccRCC. To construct and validate a prognostic risk model, TCGA dataset samples were divided into training and test sets. A multiple-gene risk signature was constructed using least absolute shrinkage and selection operator Cox regression analysis, and its prognostic significance was assessed using Cox regression and survival analyses. Finally, immunohistochemistry was performed to verify the prognostic significance of this signature. In total, 537 patients with ccRCC were included in this study. We found that 26 m7G RNA methylation regulators that were significantly differentially expressed. Univariate and multifactorial Cox regression analyses revealed that METTL1 expression was associated with ccRCC progression. METTL1 associated with m7G may serve as a potential biomarker for ccRCC prognosis and diagnosis. Moreover, it may affect the prognosis of ccRCC by regulating the tumor immune microenvironment, providing a potential therapeutic target for immunotherapy. These results provide a new perspective on the role of M7G-related RNAs in ccRCC pathogenesis.

Exosomes in Oral Diseases: Mechanisms and Therapeutic Applications.

Exosomes, small extracellular vesicles secreted by various cells, play crucial roles in the pathogenesis and treatment of oral diseases. Recent studies have highlighted their involvement in orthodontics, periodontitis, oral squamous cell carcinoma (OSCC), and hand, foot, and mouth disease (HFMD). Exosomes have a positive effect on the inflammatory environment of the oral cavity, remodeling and regeneration of oral tissues, and offer promising therapeutic options for bone and periodontal tissue restoration. In OSCC tumor-derived exosomes promote cancer progression through cell proliferation, migration, invasion, and angiogenesis, and serve as potential biomarkers for early diagnosis and prognosis. Additionally, engineered exosomes constructed specifically based on exosome properties hold great promise for targeted drug delivery and regenerative therapies such as bone regeneration in orthodontics and periodontal healing. With continued research, exosomes hold great potential for improving diagnosis and treatment in oral diseases, advancing personalized and regenerative therapies.

Investigating the association of VHL gene variants with disease risk and clinicopathological outcomes in ccRCC patients from West Bengal, India.

Clear cell renal cell carcinoma (ccRCC) is a prevalent and aggressive malignancy, with the von Hippel-Lindau (VHL) gene playing a critical role in its pathogenesis. However, the association between VHL gene variants and sporadic ccRCC risk remains unexplored in the Indian population. This study aimed to investigate the somatic and germline variants of the VHL gene in sporadic ccRCC patients from West Bengal, India, and their association with disease risk and clinicopathological parameters. A total of 210 ccRCC patients and 255 ethnicity-matched healthy controls were enrolled. Genomic DNA from blood and tissue samples was analyzed using PCR-based Sanger sequencing. The association of VHL variants with ccRCC risk was assessed using Chi-square tests. The impact of genetic variants on patient clinicopathological features and overall survival was evaluated using Kaplan-Meier survival analysis and Cox proportional hazards models. We identified twenty-three single nucleotide variants (SNVs) in the VHL gene, including 3 novel variants, OR250433 T > G, OR125589 C > T and OQ627404 G > C. The intronic variant rs61758376 G > C and 3'UTR variant rs1642742 A > G were significantly associated with an increased risk of ccRCC (OR = 1.676, P = 0.0074; OR = 1.735, P = 0.0171, respectively). The rs1642742 GG genotype was also significantly associated with larger tumor size (P < 0.05) and advanced tumor stage (pT4). Kaplan-Meier analysis indicated poorer overall survival for patients with the rs1642742 GG genotype (log-rank P = 0.029). Our study is the first to document the association of VHL gene variants with sporadic ccRCC risk and clinical outcomes in the Indian population. The identified variants, particularly rs61758376 and rs1642742, could serve as potential biomarkers for ccRCC susceptibility and prognosis.

Single-cell Atlas reveals core function of CPVL/MSR1 expressing macrophages in the prognosis of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with the worst prognosis among all subtypes. The impact of distinct cell subpopulations within the tumor microenvironment (TME) on TNBC patient prognosis has yet to be clarified. Utilizing single-cell RNA sequencing (scRNA-seq) integrated with bulk RNA sequencing (bulk RNA-seq), we applied Cox regression models to compute hazard ratios, and cross-validated prognostic scoring using a GLMNET-based Cox model. Cell communication analysis was used to elucidate the potential mechanisms of CPVL and MSR1. Ultimately, RNA interference-mediated gene knockdown was utilized to validate the impact of specific genes on the polarization of tumor-associated macrophages (TAMs). Our findings revealed that the function of immune cells is more pivotal in prognosis, with TAMs showing the strongest correlation with TNBC patient outcomes, compared with other immune cells. Additionally, we identified CPVL and MSR1 as critical prognostic genes within TAMs, with CPVL expression positively correlated with favorable outcomes and MSR1 expression associated with poorer prognosis. Mechanistically, CPVL may contribute to favorable prognosis by inhibiting the SPP1-CD44 ligand-receptor and promoting CXCL9-CXCR3, C3-C3AR1 ligand-receptor, through which TAMs interact with other cells such as monocytes, neutrophils, and T cells. Moreover, cytokines including IL-18, IFNγR1, CCL20, and CCL2, along with complement-related gene like TREM2 and complement component CFD, may participate in the process of CPVL or MSR1 regulating macrophage polarization. Furthermore, RT-PCR experiments confirmed that CPVL is positively associated with M1-like TAM polarization, while MSR1 is linked to M2-like TAM polarization. Finally, the prognostic significance of these two genes is also validated in HER2-positive breast cancer subtypes. CPVL and MSR1 are potential biomarkers for macrophage-mediated TNBC prognosis, suggesting the therapeutic potential of macrophage targeting in TNBC.

Pan-Cancer Insights: A Study of Microbial Metabolite Receptors in Malignancy Dynamics.

The role of the gut microbiome in cancer biology has become an increasingly prominent area of research, particularly regarding the role of microbial metabolites and their receptors (MMRs). These metabolites, through the various gut-organ axes, have been proven to influence several pathogenetic mechanisms. This study conducted a comprehensive pan-cancer analysis of MMR transcriptomic profiles across twenty-three cancer types, exploring the mechanisms through which they can influence cancer development and progression. Utilizing both cancer cell lines from CCLE (Cancer Cell Line Encyclopedia) and human tumor samples from TCGA (The Cancer Gene Atlas), we analyzed 107 MMRs interacting with microbial metabolites such as short-chain fatty acids, bile acids, indole derivatives, and others while studying their interactions with key known cancer genes. Our results revealed that certain MMRs, such as GPR84 and serotonin receptors, are consistently upregulated in various malignancies, while others, like ADRA1A, are frequently downregulated, suggesting diverse roles in cancer pathophysiology. Furthermore, we identified significant correlations between MMR expression and cancer hallmark genes and pathways, including immune evasion, proliferation, and metastasis. These findings suggest that the interactions between microbial metabolites and MMRs may serve as potential biomarkers for cancer diagnosis, prognosis, and therapy, highlighting their therapeutic potential. This study underscores the significance of the microbiota-cancer axis and provides novel insights into microbiome-based strategies for cancer treatment.

CKAP4 in hepatocellular carcinoma: competitive RETREG1/FAM134B binding, reticulophagy regulation, and cancer progression

ABSTRACT RETREG1/FAM134B is known for its role as a reticulophagy receptor. Our previous study established that RETREG1 is upregulated in hepatocellular carcinoma (HCC) and contributes to disease progression by activating the AKT signaling pathway. However, the specific mechanisms underlying the elevated expression of RETREG1 in HCC remain unclear. This study unveils the interaction of RETREG1 with CKAP4 and TRIM21. We demonstrated that TRIM21 ubiquitinates RETREG1 at K247 and K252, facilitating its proteasomal degradation. Conversely, CKAP4 shields RETREG1 from degradation by competitively binding to it, revealing a novel post-translational modification mechanism for RETREG1. By modulating RETREG1 expression, CKAP4, and TRIM21 intricately regulate reticulophagy. Additionally, we observed that stress-induced TRIM21 upregulation mitigates the function of RETREG1 to restore ER stress equilibrium. The oncogenic potential of CKAP4 in HCC was demonstrated using various animal models. Clinical sample analyses suggested that CKAP4 is a potential biomarker for HCC prognosis and diagnosis. Abbreviation: AKT: thymoma viral proto-oncogene; aa: amino acid; bp: base pair; CHX: cycloheximide; co-IP: co-Immunoprecipitation; CQ: chloroquine; CKAP4: cytoskeleton-associated protein 4; DKK1: dickkopf WNT signaling pathway inhibitor 1; DUBs: deubiquitinating enzymes; EBSS: Earle’s balanced salt solution; EGFP: enhanced green fluorescent protein; ER: endoplasmic reticulum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HCC: hepatocellular carcinoma; HFD: high-fat diet; HiTV: hyperdynamic tail vein injection; IF: immunofluorescence; IHC: immunohistochemistry; IP-MS: immunoprecipitation-mass spectrometry; LIR: LC3-interacting region; mAbs: monoclonal antibodies; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mCherry: monomeric cherry; oe: overexpression; PDX: patient-derived tumor xenograft; reticulophagy: endoplasmic reticulum selective autophagy; RETREG1: reticulophagy regulator 1; RHD: reticulon-homology domain; Tg: thapsigargin; Tm: tunicamycin; TRIM21: tripartite motif-containing 21; UB: ubiquitin; WT: wild-type.

Genome-wide association study analysis of single nucleotide variants in L. infantum associated with IL-6 inflammatory response in visceral leishmaniasis.

Elevated levels of IL-6 in plasma are associated with the severity of visceral leishmaniasis (VL). The clinical manifestations of VL vary among patients, influenced by host factors and the virulence of the Leishmania infantum parasite. Considering that severe VL may result from an exaggerated inflammatory response, this study investigated whether IL-6 could serve as a biomarker to identify pro-inflammatory virulence factors. We conducted a genome-wide association study (GWAS) analysis on L. infantum isolates from patients with VL, whose IL-6 concentrations were measured. The analysis revealed that the relationship between IL-6 levels and clinical outcomes (survival vs mortality) had an area under the curve (AUC) of 0.67 (95% CI 0.52–0.81). A cut-off of 391.7 pg mL−1 for IL-6 was established to conduct a logistic regression analysis. We identified 10 029 single nucleotide variants (SNVs) across 62 genomes, resulting in 6,948 SNVs after filtering, of which 6,341 are located in protein-coding regions. The association analysis with PLINK identified 722 variants, of which 35 showed significant associations, with odds ratios ≥3.3, primarily in coding regions. These findings demonstrate that IL-6 levels tended to be associated with the fatal outcome of VL and highlight 35 novel genetic variants that could serve as potential biomarkers for prognosis. Further research into the biological role of these variants may lead to new therapeutic targets and improve the clinical management of VL, especially in identifying high-risk patients.

Serum pentraxin-3 as a potential biomarker for diagnosis and prognosis in primary liver cancer: An observational study.

This study aimed to examine serum pentraxin 3 levels in patients with primary liver cancer and to assess its potential as a diagnostic and prognostic biomarker. Serum samples were obtained from 180 patients with primary liver cancer and 180 healthy control subjects. The concentration of PTX3 in these samples was measured using an ELISA kit. The study also investigated the correlation between PTX3 levels and the clinicopathological characteristics of patients with primary liver cancer. The effectiveness of serum PTX3 in diagnosing primary liver cancer was evaluated using receiver operating characteristic (ROC) curves and their corresponding areas under the curve (AUC). The prognostic significance of serum PTX3 in patients with primary liver cancer was assessed using Kaplan-Meier survival curves. Serum PTX3 levels were elevated in patients with primary liver cancer compared to those in healthy control subjects. These levels were significantly correlated with drinking history, TNM stage, BCLC stage, tumor size, tumor number, and vascular invasion. However, no significant correlations were observed between PTX3 levels and other factors, such as age, sex, BMI, liver cirrhosis, histological grade, and histological type. With a cut-off value of 5.1 ng/mL, PTX3 effectively differentiated patients with primary liver cancer from healthy control subjects, achieving an AUC of 0.734, a sensitivity of 73.24%, and a specificity of 84.78%. Patients with higher serum PTX3 levels had lower overall survival rates and recurrence-free survival rates than those with lower PTX3 levels. Serum PTX3 levels are elevated in patients with primary liver cancer and high serum PTX3 levels are associated with poor prognosis. This suggests that serum PTX3 has the potential to be a novel biomarker for both the diagnosis and prognosis of primary liver cancer. These findings may improve patient outcomes by enabling early detection and continuous monitoring.