Potential Prognostic Biomarker Research Articles

Prognostic and Potential Therapeutic Roles of PRKDC Expression in Lung Cancer.

PRKDC is a key factor involved in the ligation step of the non-homologous end joining pathway. Its dysfunction has proven to be a biomarker for radiosensitivity of cancer cells. However, the prognostic value of PRKDC and its underlying mechanisms have not been clarified yet. In this study, we found that PRKDC overexpressed in lung adenocarcinoma (LUAD) and is significantly related to unfavorable survival, while downregulation of PRKDC is link to inflamed tumor immune signature. Our further in vitro results also showed a potent antitumor efficacy of PRKDC inhibitors alone or combined with cisplatin in human lung cancer cells. This study demonstrated that PRKDC is a potential prognostic biomarker, immunotherapy target, and promising combination candidate for chemotherapy for lung cancer, and highlighted the potential of PRKDC-targeted inhibitors for the treatment of lung cancer.

Scinderin is a potential prognostic biomarker and correlated with immunological regulation: from pan-cancer analysis to liver hepatocellular carcinoma

Scinderin is a potential prognostic biomarker and correlated with immunological regulation: from pan-cancer analysis to liver hepatocellular carcinoma

WNT5A in Cancer: A Pan-Cancer Analysis Revealing Its Diagnostic and Prognostic Biomarker Potential

WNT5A in Cancer: A Pan-Cancer Analysis Revealing Its Diagnostic and Prognostic Biomarker Potential

Comprehensive analysis of PHF5A as a potential prognostic biomarker and therapeutic target across cancers and in hepatocellular carcinoma

ObjectiveCancer is a predominant cause of death globally. PHD-finger domain protein 5 A (PHF5A) has been reported to participate in various cancers; however, there has been no pan-cancer analysis of PHF5A. This study aims to present a novel prognostic biomarker and therapeutic target for cancer treatment.MethodsThis study explored PHF5A expression and its impact on prognosis, tumor mutation burden (TMB), microsatellite instability (MSI), functional status and tumor immunity across cancers using various public databases, and validated PHF5A expression and its correlation with survival, immune evasion, angiogenesis, and treatment response in hepatocellular carcinoma (HCC) using bioinformatics tools, qRT-PCR and immunohistochemistry (IHC).ResultsPHF5A was differentially expressed between tumor and corresponding normal tissues and was correlated with prognosis in diverse cancers. Its expression was also associated with TMB, MSI, functional status, tumor microenvironment, immune infiltration, immune checkpoint genes and tumor immune dysfunction and exclusion (TIDE) score in diverse malignancies. In HCC, PHF5A was confirmed to be upregulated by qRT-PCR and IHC, and elevated PHF5A expression may promote immune evasion and angiogenesis in HCC. Additionally, multiple canonical pathways were revealed to be involved in the biological activity of PHF5A in HCC. Moreover, immunotherapy and transcatheter arterial chemoembolization (TACE) worked better in the low PHF5A expression group, while sorafenib, chemotherapy and AKT inhibitor were more effective in the high expression group.ConclusionsThis study provides a comprehensive understanding of the biological function of PHF5A in the carcinogenesis and progression of various cancers. PHF5A could serve as a tumor biomarker related to prognosis across cancers, especially HCC, and shed new light on the development of novel therapeutic targets.

Role of WAVE3 as an of actin binding protein in the pathology of triple negative breast cancer.

Breast cancer, a prevalent global health concern, has sparked extensive research efforts, particularly focusing on triple negative breast cancer (TNBC), a subtype lacking estrogen receptor (ER), progesterone receptor, and epidermal growth factor receptor. TNBC's aggressive nature and resistance to hormone-based therapies heightens the risk of tumor progression and recurrence. Actin-binding proteins, specifically WAVE3 from the Wiskott-Aldrich syndrome protein (WASP) family, have emerged as major drivers in understanding TNBC biology. This review delves into the intricate molecular makeup of TNBC, shedding light on actin's fundamental role in cellular processes. Actin, a structural element in the cytoskeleton, regulates various cellular pathways essential for homeostasis. Its dynamic nature enables functions such as cell migration, motility, intracellular transport, cell division, and signal transduction. Actin-binding proteins, including WAVE3, play pivotal roles in these processes. WAVE3, a member of the WASP family, remains the focus of this review due to its potential involvement in TNBC progression. While actin-binding proteins are studied for their roles in healthy cellular cycles, their significance in TNBC remains underexplored. This review aims to discuss WAVE3's impact on TNBC, exploring its molecular makeup, functions, and significance in tumor progression. The intricate structure of WAVE3, featuring elements like the verprolin-cofilin-acidic domain and regulatory elements, plays a crucial role in regulating actin dynamics. Dysregulation of WAVE3 in TNBC has been linked to enhanced cell migration, invasion, extracellular matrix remodeling, epithelial-mesenchymal transition, tumor proliferation, and therapeutic resistance. Understanding the role of actin-binding proteins in cancer biology has potential clinical implications, making them potential prognostic biomarkers and promising therapeutic targets. The review emphasizes the need for further research into actin-binding proteins' clinical applications, diagnostic value, and therapeutic interventions. In conclusion, this comprehensive review explores the complex interplay between actin and actin-binding proteins, with special emphasis on WAVE3, in the context of TNBC. By unraveling the molecular intricacies, structural characteristics, and functional significance, the review paves the way for future research directions, clinical applications, and potential therapeutic strategies in the challenging landscape of TNBC.

Identification and verification of KEAP1‐related genes and targets regulated by potential ingredients in KRAS mutant colorectal cancer

AbstractAs one of the most prevalent tumors, colorectal cancer (CRC) owns complex pathogenesis and the high recurrence rate significantly influence the prognosis of patients with KRAS mutant CRC, to discovery the crosstalk among KEAP1‐NFE2L2 and oncogenic KRAS as the potential prognostic biomarkers in CRC, which might be used to develop novel and effective therapeutics. By using bioinformatics analysis, we explored and identified key genes as the predicted targets in the crosstalk among KEAP1 oncogenic signatures of KRAS mutation that were linked with development, metastasis, and poor prognosis in CRC. We further investigated the correlations between the clinical characteristics and expressions of prognostic genes among the KRAS and KEAP1‐related key hub genes in CRC, which as predicted targets to find the potential herbal ingredients in HERB database, further to verify the active herbal ingredients could regulate the key targets that related to KEAP1‐NFE2L2 in KRAS mutant CRC. The newest TCGA data reveals that the mutation of KRAS is found in 44% of CRC patients. In total, 28 genes were identified as differentially expressed genes (DEGs), and the hub genes such as CDKN2A, SPP1, FOS, BCL2L11, and HPSE were verified. Results indicated that key genes (SOX9, SPP1) significant correlation with the target prediction of the active herbal ingredients by molecular docking analysis. Furthermore, KEAP1, NFE2L2, SOX9 expression were decreased significantly with the treatment of potential ingredients. Furthermore, cyclopamine could enhance the sensitivity of HCT116 cells, downregulated the expression of SPP1, and induced activation of KEAP1‐NFE2L2 pathway, which cell death are characteristic features of apoptosis, and enhanced anticancer effect. Therefore, KEAP1‐related genes might be important oncogenic signatures in KRAS mutant CRC cells and cyclopamine was identified as a potential ingredient and regulated the predict targets of SOX9 and SPP1, may be expand the efficacy and range of novel and effective therapeutics.

Body-wide genetic deficiency of poly(ADP-ribose) polymerase 14 sensitizes mice to colitis.

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract affecting millions of people. Here, we investigated the expression and functions of poly(ADP-ribose) polymerase 14 (Parp14), an important regulatory protein in immune cells, with an IBD patient cohort as well as two mouse colitis models, that is, IBD-mimicking oral dextran sulfate sodium (DSS) exposure and oral Salmonella infection. Parp14 was expressed in the human colon by cells in the lamina propria, but, in particular, by the epithelial cells with a granular staining pattern in the cytosol. The same expression pattern was evidenced in both mouse models. Parp14-deficiency caused increased rectal bleeding as well as stronger epithelial erosion, Goblet cell loss, and immune cell infiltration in DSS-exposed mice. The absence of Parp14 did not affect the mouse colon bacterial microbiota. Also, the colon leukocyte populations of Parp14-deficient mice were normal. In contrast, bulk tissue RNA-Seq demonstrated that the colon transcriptomes of Parp14-deficient mice were dominated by abnormalities in inflammation and infection responses both prior and after the DSS exposure. Overall, the data indicate that Parp14 has an important role in the maintenance of colon epithelial barrier integrity. The prognostic and predictive biomarker potential of Parp14 in IBD merits further investigation.

CRISPR screens in 3D tumourspheres identified miR-4787-3p as a transcriptional start site miRNA essential for breast tumour-initiating cell growth

Our study employs pooled CRISPR screens, integrating 2D and 3D culture models, to identify miRNAs critical in Breast Cancer (BC) tumoursphere formation. These screens combine with RNA-seq experiments allowing identification of miRNA signatures and targets essential for tumoursphere growth. miR-4787-3p exhibits significant up-regulation in BC, particularly in basal-like BCs, suggesting its association with aggressive disease. Surprisingly, despite its location within the 5’UTR of a protein coding gene, which defines DROSHA-independent transcription start site (TSS)-miRNAs, we find it dependant on both DROSHA and DICER1 for maturation. Inhibition of miR-4787-3p hinders tumoursphere formation, highlighting its potential as a therapeutic target in BC. Our study proposes elevated miR-4787-3p expression as a potential prognostic biomarker for adverse outcomes in BC. We find that protein-coding genes positively selected in the CRISPR screens are enriched of miR-4787-3p targets. Of these targets, we select ARHGAP17, FOXO3A, and PDCD4 as known tumour suppressors in cancer and experimentally validate the interaction of miR-4787-3p with their 3’UTRs. Our work illuminates the molecular mechanisms underpinning miR-4787-3p’s oncogenic role in BC. These findings advocate for clinical investigations targeting miR-4787-3p and underscore its prognostic significance, offering promising avenues for tailored therapeutic interventions and prognostic assessments in BC.

TGF-β1-Induced LINC01094 promotes epithelial-mesenchymal transition in hepatocellular carcinoma through the miR-122-5p/TGFBR2-SAMD2-SMAD3 Axis.

Hepatocellular carcinoma (HCC) is a common malignancy with a poor prognosis. It has been proven that long non-coding RNAs (lncRNAs) play an essential role in regulating HCC progression. However, the involvement of LINC01094 in regulating epithelial-mesenchymal transition (EMT) in HCC remains unclear. LINC01094 expression in HCC patients was retrieved from the Cancer Genome Atlas database. Overexpressing and downregulating LINC01094 were conducted to investigate its biological functions using Hep3B, SNU-387, and HuH-7 cells. Western blotting and morphological observation were performed to study the EMT in HCC cells. Transwell assay was adopted to determine the migration and invasion of HCC cells. The underlying mechanism of competitive endogenous RNAs (ceRNAs) was investigated using bioinformatics analysis, quantitative reverse-transcription polymerase chain reaction, and rescue experiments. Elevated LINC01094 expression was observed in HCC and associated with a poor prognosis. Knockdown of LINC01094 expression in SNU-387 and HuH-7 cells could inhibit migration, invasion, and EMT markers. Overexpression of LINC01094 indicated that LINC01094 promoted EMT via the TGF-β/SMAD signaling pathway. The bioinformatics analysis revealed that miR-122-5p was a target of LINC01094. The miRWalk database analysis showed that TGFBR2, SMAD2, and SMAD3 were downstream targets of miR-122-5p. Mechanically, LINC01094 acted as a ceRNA that facilitated HCC metastasis by sponging miR-122-5p to regulate the expression of TGFBR2, SMAD2, and SMAD3. Further, TGF-β1 could enhance the expression of LINC01094, forming a positive feedback loop. TGF-β1-induced LINC01094 expression promotes HCC cell migration and invasion by targeting the miR-122-5p/TGFBR2-SMAD2-SMAD3 axis. LINC01094 may be a potential prognostic biomarker and therapeutic target for HCC metastasis.

CircATF6 inhibits hepatocellular carcinoma progression by suppressing calreticulin-mediated Wnt/β-catenin signaling pathway

Circular RNAs (circRNAs) are covalently closed, single-stranded RNAs that play critical roles in various biological processes and diseases, including cancers. However, the functions and mechanisms of circRNAs in hepatocellular carcinoma (HCC) need further clarification. Here, we identified and confirmed that circATF6 is downregulated in HCC tissues and negatively associated with the overall survival of HCC patients. Ectopic overexpression of circATF6 inhibits malignant phenotypes of HCC cells in vitro and in vivo, while knockdown of circATF6 had opposite effects. Mechanistically, we found that circATF6 bound to calreticulin (CALR) protein and acted as a scaffold to enhance the interaction of CALR with calpain2 (CAPN2), which promoted the degradation of CALR by its enzymatic activity. Moreover, we found that circATF6 inhibited HCC cells by suppressing CALR-mediated wnt/β-catenin signaling pathway. Taken together, our findings suggest that circATF6 is a potential prognostic biomarker and therapeutic target for HCC.

Proteomic insights into extracellular vesicles in ALS for therapeutic potential of Ropinirole and biomarker discovery

BackgroundExtracellular vesicles (EVs) hold the potential for elucidating the pathogenesis of amyotrophic lateral sclerosis (ALS) and serve as biomarkers. Notably, the comparative and longitudinal alterations in the protein profiles of EVs in serum (sEVs) and cerebrospinal fluid (CSF; cEVs) of sporadic ALS (SALS) patients remain uncharted. Ropinirole hydrochloride (ROPI; dopamine D2 receptor [D2R] agonist), a new anti-ALS drug candidate identified through induced pluripotent stem cell (iPSC)-based drug discovery, has been suggested to inhibit ALS disease progression in the Ropinirole Hydrochloride Remedy for Amyotrophic Lateral Sclerosis (ROPALS) trial, but its mechanism of action is not well understood. Therefore, we tried to reveal longitudinal changes with disease progression and the effects of ROPI on protein profiles of EVs.MethodsWe collected serum and CSF at fixed intervals from ten controls and from 20 SALS patients participating in the ROPALS trial. Comprehensive proteomic analysis of EVs, extracted from these samples, was conducted using liquid chromatography/mass spectrometer (LC/MS). Furthermore, we generated iPSC-derived astrocytes (iPasts) and performed RNA sequencing on astrocytes with or without ROPI treatment.ResultsThe findings revealed notable disparities yet high congruity in sEVs and cEVs protein profiles concerning disease status, time and ROPI administration. In SALS, both sEVs and cEVs presented elevated levels of inflammation-related proteins but reduced levels associated with unfolded protein response (UPR). These results mirrored the longitudinal changes after disease onset and correlated with the revised ALS Functional Rating Scale (ALSFRS-R) at sampling time, suggesting a link to the onset and progression of SALS. ROPI appeared to counteract these changes, attenuating inflammation-related protein levels and boosting those tied to UPR in SALS, proposing an anti-ALS impact on EV protein profiles. Reverse translational research using iPasts indicated that these changes may partly reflect the DRD2-dependent neuroinflammatory inhibitory effects of ROPI. We have also identified biomarkers that predict diagnosis and disease progression by machine learning-driven biomarker search.ConclusionsDespite the limited sample size, this study pioneers in reporting time-series proteomic alterations in serum and CSF EVs from SALS patients, offering comprehensive insights into SALS pathogenesis, ROPI-induced changes, and potential prognostic and diagnostic biomarkers.

MiR-584-5p is a New Potential Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma.

MicroRNA-584-5p (miR-584-5p) plays an important role in certain types of cancer. However, its precise role in head and neck squamous cell carcinoma (HNSC) remains unknown. Our aim was to investigate how miR-584-5p influences HNSC. The Cancer Genome Atlas (TCGA) provided samples for the study. We use statistical methods to evaluate the diagnostic value, the prognostic value, and the correlation with the clinical features of miR-584-5p. We analyze the target genes and the regulatory network of miR- 584-5p. Quantitative reverse transcriptase PCR (qRT-PCR) confirmed the expression of miR- 584-5p in HNSC cell lines. MiR-584-5p expression of miR-584-5p varied significantly among different types of cancer. A notable correlation was observed between elevated miR-584-5p expression and gender (p < 0.001) and histological grade (p < 0.001). Furthermore, high levels of miR-584-5p were found to be associated with a decrease in overall survival (HR: 1.44; 95% CI: 1.10-1.88; p = 0.007), progression-free survival (HR: 1.35; 95% CI: 1.02-1.79; p = 0.035) and disease-specific survival (HR: 1.54; 95% CI: 1.09-2.18; p = 0.016) in the context of HNSC. miR-584-5p demonstrated independent prognostic significance in HNSC and potentially contributes to disease progression through multiple pathways, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In particular, HNSC cell lines exhibited a substantial upregulation of miR-584-5p compared to normal epithelial cells. It is possible that miR-584-5p could serve as a promising patent for a therapeutic target and prognostic biomarker for people with HNSC.

Treatment, Prognostic Markers, and Survival in Thymic Neuroendocrine Tumors, with Special Reference to Temozolomide-Based Chemotherapy

Background: Thymic neuroendocrine tumors (Th-NETs) are rare and aggressive, with a scarcity of research on predicting patient prognosis. Our study aimed to assess the impact of prognostic markers and temozolomide (TMZ)-based chemotherapy on survival in Th-NETs. Methods: We retrospectively reviewed the medical records of patients diagnosed with Th-NETs between 2013 and 2023 at our institution. We collected clinicopathological data, including tumor pathological grading, staging, serum concentrations of neuron-specific enolase (NSE) and pro-gastrin-releasing peptide, levels of inflammatory factors, and expression of oxygen 6-methylguanine-DNA methyltransferase (MGMT). Treatment details (such as surgery and chemotherapy) and survival outcomes were also documented. Results: A total of 32 patients were included in our study after excluding those without complete available information. The median progression-free survival (PFS) was 12.5 months (95%CI, 8–16 months) for 19 patients who received TMZ-based chemotherapy. Twenty-one patients underwent surgery as the primary treatment, demonstrating a median disease-free survival (DFS) of 51.0 months. The inflammatory factor neutrophil-to-lymphocyte ratio (NLR) was an independent prognostic indicator of DFS in postoperative patients and PFS in TMZ-treated patients. The overall 3-, 5-, and 10-year survival rates were 86.6%, 69.5%, and 33.8%, respectively. Ki67 level exceeding 10% (p = 0.048) and absence of surgical resection (p = 0.003) were significantly associated with worse overall survival (OS). Conclusion: Surgical treatment was currently the primary method for treating Th-NETs, and postoperative adjuvant therapy was an essential consideration for specific patient cohorts. Despite widespread positive MGMT expression, TMZ-based chemotherapy showed promise. Some potential prognostic biomarkers such as NLR and NSE need more attention.

Identification and validation of calcium extrusion-related genes prognostic signature in colon adenocarcinoma.

Disruptions in calcium homeostasis are associated with a wide range of diseases, and play a pivotal role in the development of cancer. However, the construction of prognostic models using calcium extrusion-related genes in colon adenocarcinoma (COAD) has not been well studied. We aimed to identify whether calcium extrusion-related genes serve as a potential prognostic biomarker in the COAD progression. We constructed a prognostic model based on the expression of calcium extrusion-related genes (SLC8A1, SLC8A2, SLC8A3, SLC8B1, SLC24A2, SLC24A3 and SLC24A4) in COAD. Subsequently, we evaluated the associations between the risk score calculated by calcium extrusion-related genes and mutation signature, immune cell infiltration, and immune checkpoint molecules. Then we calculated the immune score, stromal score, tumor purity and estimate score using the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm. The response to immunotherapy was assessed using tumor immune dysfunction and exclusion (TIDE). Finally, colorectal cancer cells migration, growth and colony formation assays were performed in RKO cells with the overexpression or knockdown SLC8A3, SLC24A2, SLC24A3, or SLC24A4. We found that patients with high risk score of calcium extrusion-related genes tend to have a poorer prognosis than those in the low-risk group. Additionally, patients in high-risk group had higher rates of KRAS mutations and lower MUC16 mutations, implying a strong correlation between KRAS and MUC16 mutations and calcium homeostasis in COAD. Moreover, the high-risk group showed a higher infiltration of regulatory T cells (Tregs) in the tumor microenvironment. Finally, our study identified two previously unreported model genes (SLC8A3 and SLC24A4) that contribute to the growth and migration of colorectal cancer RKO cells. Altogether, we developed a prognostic risk model for predicting the prognosis of COAD patients based on the expression profiles of calcium extrusion-related genes, Furthermore, we validated two previously unreported tumor suppressor genes (SLC8A3 and SLC24A4) involved in colorectal cancer progression.

EV-miRNAs from breast cancer patients of plasma as potential prognostic biomarkers of disease recurrence

BackgroundExtracellular vesicles (EVs), ubiquitously released by blood cells, facilitate intercellular communication. In cancer, tumor-derived EVs profoundly affect the microenvironment, promoting tumor progression and raising the risk of recurrence. These EVs contain miRNAs (EV-miRNAs), promising cancer biomarkers. Characterizing plasma EVs and identifying EV-miRNAs associated with breast cancer recurrence are crucial aspects of cancer research since they allow us to discover new biomarkers that are effective for understanding tumor biology and for being used for early detection, disease monitoring, or approaches to personalized medicine. This study aimed to characterize plasma EVs in breast cancer (BC) patients and identify EV-miRNAs associated with BC recurrence. MethodsThis retrospective observational study included 24 BC patients divided into recurrence (n= 11) and non-recurrence (n= 13) groups. Plasma EVs were isolated and characterized. Total RNA from EVs was analyzed for miRNA expression using NanoString's nCounter® miRNA Expression Assays panel. MicroRNA target prediction used mirDIP, and pathway interactions were assessed via Reactome. ResultsA stronger presence of circulating EVs was found to be linked with a less favorable prognosis (p = 0.0062). We discovered a distinct signature of EV-miRNAs, notably including miR-19a-3p and miR-130b-3p, which are significantly associated with breast cancer recurrence. Furthermore, miR-19a-3p and miR-130b-3p were implicated in the regulation of PTEN and MDM4, potentially contributing to breast cancer progression.A notable association emerged, indicating a high concentration of circulating EVs predicts poor prognosis (p = 0.0062). Our study found a distinct EV-miRNA signature involving miR-19a-3p and miR-130b-3p, strongly associated with disease recurrence. We also presented compelling evidence for their regulatory roles in PTEN and MDM4 genes, contributing to BC development. ConclusionThis study revealed that increased plasma EV concentration is associated with BC recurrence. The prognostic significance of EVs is closely tied to the unique expression profiles of miR-19a-3p and miR-130b-3p. These findings underscore the potential of EV-associated miRNAs as valuable indicators for BC recurrence, opening new avenues for diagnosis and treatment exploration.

Early Metabolomic and Immunologic Biomarkers as Prognostic Indicators for COVID-19

This prospective study in Hong Kong aimed at identifying prognostic metabolomic and immunologic biomarkers for Coronavirus Disease 2019 (COVID-19). We examined 327 patients, mean age 55 (19–89) years, in whom 33.6% were infected with Omicron and 66.4% were infected with earlier variants. The effect size of disease severity on metabolome outweighed others including age, gender, peak C-reactive protein (CRP), vitamin D and peak viral levels. Sixty-five metabolites demonstrated strong associations and the majority (54, 83.1%) were downregulated in severe disease (z score: −3.30 to −8.61). Ten cytokines/chemokines demonstrated strong associations (p &lt; 0.001), and all were upregulated in severe disease. Multiple pairs of metabolomic/immunologic biomarkers showed significant correlations. Fourteen metabolites had the area under the receiver operating characteristic curve (AUC) &gt; 0.8, suggesting a high predictive value. Three metabolites carried high sensitivity for severe disease: triglycerides in medium high-density lipoprotein (MHDL) (sensitivity: 0.94), free cholesterol-to-total lipids ratio in very small very-low-density lipoprotein (VLDL) (0.93), cholesteryl esters-to-total lipids ratio in chylomicrons and extremely large VLDL (0.92);whereas metabolites with the highest specificity were creatinine (specificity: 0.94), phospholipids in large VLDL (0.94) and triglycerides-to-total lipids ratio in large VLDL (0.93). Five cytokines/chemokines, namely, interleukin (IL)-6, IL-18, IL-10, macrophage inflammatory protein (MIP)-1b and tumour necrosis factor (TNF)-a, had AUC &gt; 0.8. In conclusion, we demonstrated a tight interaction and prognostic potential of metabolomic and immunologic biomarkers enabling an outcome-based patient stratification.

Early Metabolomic and Immunologic Biomarkers as Prognostic Indicators for COVID-19

This prospective study in Hong Kong aimed at identifying prognostic metabolomic and immunologic biomarkers for Coronavirus Disease 2019 (COVID-19). We examined 327 patients, mean age 55 (19–89) years, in whom 33.6% were infected with Omicron and 66.4% were infected with earlier variants. The effect size of disease severity on metabolome outweighed others including age, gender, peak C-reactive protein (CRP), vitamin D and peak viral levels. Sixty-five metabolites demonstrated strong associations and the majority (54, 83.1%) were downregulated in severe disease (z score: −3.30 to −8.61). Ten cytokines/chemokines demonstrated strong associations (p &lt; 0.001), and all were upregulated in severe disease. Multiple pairs of metabolomic/immunologic biomarkers showed significant correlations. Fourteen metabolites had the area under the receiver operating characteristic curve (AUC) &gt; 0.8, suggesting a high predictive value. Three metabolites carried high sensitivity for severe disease: triglycerides in medium high-density lipoprotein (MHDL) (sensitivity: 0.94), free cholesterol-to-total lipids ratio in very small very-low-density lipoprotein (VLDL) (0.93), cholesteryl esters-to-total lipids ratio in chylomicrons and extremely large VLDL (0.92);whereas metabolites with the highest specificity were creatinine (specificity: 0.94), phospholipids in large VLDL (0.94) and triglycerides-to-total lipids ratio in large VLDL (0.93). Five cytokines/chemokines, namely, interleukin (IL)-6, IL-18, IL-10, macrophage inflammatory protein (MIP)-1b and tumour necrosis factor (TNF)-a, had AUC &gt; 0.8. In conclusion, we demonstrated a tight interaction and prognostic potential of metabolomic and immunologic biomarkers enabling an outcome-based patient stratification.

Osteopontin: A Key Multifaceted Regulator in Tumor Progression and Immunomodulation

The tumor microenvironment (TME) is composed of various cellular components such as tumor cells, stromal cells including fibroblasts, adipocytes, mast cells, lymphatic vascular cells and infiltrating immune cells, macrophages, dendritic cells and lymphocytes. The intricate interplay between these cells influences tumor growth, metastasis and therapy failure. Significant advancements in breast cancer therapy have resulted in a substantial decrease in mortality. However, existing cancer treatments frequently result in toxicity and nonspecific side effects. Therefore, improving targeted drug delivery and increasing the efficacy of drugs is crucial for enhancing treatment outcome and reducing the burden of toxicity. In this review, we have provided an overview of how tumor and stroma-derived osteopontin (OPN) plays a key role in regulating the oncogenic potential of various cancers including breast. Next, we dissected the signaling network by which OPN regulates tumor progression through interaction with selective integrins and CD44 receptors. This review addresses the latest advancements in the roles of splice variants of OPN in cancer progression and OPN-mediated tumor‒stromal interaction, EMT, CSC enhancement, immunomodulation, metastasis, chemoresistance and metabolic reprogramming, and further suggests that OPN might be a potential therapeutic target and prognostic biomarker for the evolving landscape of cancer management.

LCP1 correlates with immune infiltration: a prognostic marker for triple-negative breast cancer

ObjectiveTriple-Negative Breast Cancer (TNBC) is known for its aggressiveness and treatment challenges due to the absence of ER, PR, and HER2 receptors. Our work emphasizes the prognostic value of LCP1 (Lymphocyte cytosolic protein 1), which plays a crucial role in cell processes and immune cell activity, to predict outcomes and guide treatments in TNBC.MethodsWe explored LCP1 as a potential biomarker in TNBC and investigated the mRNA and protein expression levels of LCP1. We investigated different databases, including GTEX, TCGA, GEO, cBioPortal and Kaplan-Meier Plotter. Immunohistochemistry on TNBC and benign tumor samples was performed to examine LCP1's relationship with patient clinical characteristics and macrophage markers. We also assessed survival rates, immune cell infiltration, and drug sensitivity related to LCP1 using various bioinformatics tools.ResultsThe results indicated that LCP1 expression was higher in TNBC tissues compared to adjacent normal tissues. However, high expression of LCP1 was significantly associated with favorable survival outcomes in patients with TNBC. Enrichment analysis revealed that genes co-expressed with LCP1 were significantly enriched in various immune processes. LCP1 showed a positive correlation with the infiltration of resting dendritic cells, M1 macrophages, and memory CD4 T cells, and a negative correlation with M2 macrophages. Further analysis suggested a link between high levels of LCP1 and increased survival outcomes in cancer patients receiving immunotherapy.ConclusionLCP1 may serve as a potential diagnostic and prognostic biomarker for TNBC, which was closely associated with immune cell infiltration, particularly M1 and M2 macrophages. Our findings may provide valuable insights into immunotherapeutic strategies for TNBC patients.

SEC61 translocon gamma subunit is correlated with glycolytic activity, epithelial mesenchymal transition and the immune suppressive phenotype of lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains a predominant cause of cancer-related mortality globally, underscoring the urgency for targeted therapeutic strategies. The specific role and impact of the SEC61 translocon gamma subunit (SEC61G) in LUAD progression and metastasis remain largely unexplored. In this study, we use a multifaceted approach, combining bioinformatics analysis with experimental validation, to elucidate the pivotal role of SEC61G and its associated molecular mechanisms in LUAD. Our integrated analyses reveal a significant positive correlation between SEC61G expression and the glycolytic activity of LUAD, as evidenced by increased fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT scans. Further investigations show the potential influence of SEC61G on metabolic reprogramming, which contributes to the immunosuppressive tumor microenvironment (TME). Remarkably, we identify a negative association between SEC61G expression levels and the infiltration of critical immune cell populations within the TME, along with correlations with immune checkpoint gene expression and tumor heterogeneity scores in LUAD. Functional studies demonstrate that SEC61G knockdown markedly inhibits the migration of A549 and H2030 LUAD cells. This inhibitory effect is accompanied by a significant downregulation of key regulators of tumor progression, including hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A, and genes involved in the epithelial-mesenchymal transition pathway. In conclusion, our comprehensive analyses position SEC61G as a potential prognostic biomarker intricately linked to glycolytic metabolism, the EMT pathway, and the establishment of an immune-suppressive phenotype in LUAD. These findings underscore the potential of SEC61G as a therapeutic target and predictive marker for immunotherapeutic responses in LUAD patients.