RUVBL1 in Clear-Cell Renal Cell Carcinoma: Unraveling Prognostic Significance and Correlation with HIF1A.

This study investigates the roles of RUVBL1 and HIF1A in ccRCC development and explores their clinical significance as prognostic biomarkers. mRNA and protein expressions were analyzed using TCGA data and an institutional tissue cohort, respectively. Correlations with clinicopathological parameters and patient outcomes were assessed. TCGA data revealed significantly elevated RUVBL1 mRNA expression in ccRCC tissues, associated with advanced histological grade, T stage, lymph node metastasis, and clinical stage. High RUVBL1 mRNA expression correlated with inferior overall survival and served as an adverse prognostic factor. Similarly, HIF1A mRNA expression was significantly higher in ccRCC tissues, correlating with worse overall survival and acting as an adverse prognostic factor for treatment outcomes. Simultaneous evaluation of RUVBL1 and HIF1A mRNA expression demonstrated enhanced prognostic capacity, surpassing the predictive power of individual markers. Immunohistochemical staining confirmed substantial upregulation of both RUVBL1 and HIF-1α proteins in ccRCC tissues. Furthermore, high expression of both RUVBL1 and HIF-1α proteins was significantly associated with shorter patient survival time. Our findings underscore the significance of RUVBL1 and HIF-1α as potential prognostic markers in ccRCC, paving the way for further research to translate these insights into clinically relevant applications.

Age-associated B cell infiltration in salivary glands represents a hallmark of Sjögren's-like disease in aging mice.

Sjögren's disease (SjD), characterized by circulating autoantibodies and exocrine gland inflammation, is typically diagnosed in women over 50 years of age. However, the contribution of age to SjD pathogenesis is unclear. C57BL/6 female mice at different ages were studied to investigate how aging influences the dynamics of salivary gland inflammation. Salivary glands were characterized for immune cell infiltration, inflammatory gene expression, and saliva production. At 8 months, gene expression of several chemokines involved in immune cell trafficking was significantly elevated. At this age, age-associated B cells (ABCs), a unique subset of B cells expressing the myeloid markers CD11b and/or CD11c, were preferentially enriched in the salivary glands compared to other organs like the spleen or liver. The salivary gland ABCs increased with age and positively correlated with increased CD4 T follicular helper cells. By 14 months, lymphocytic foci of well-organized T and B cells spontaneously developed in the salivary glands. In addition, the mice progressively developed high titers of serum autoantibodies. A subset of aged mice developed salivary gland dysfunction mimicking SjD patients. Our data demonstrates that aging is a significant confounding factor for SjD. Thus, aged female C57BL/6 mice are more appropriate and a valuable preclinical model for investigating SjD pathogenesis and novel therapeutic interventions.

Overexpression of cyclin F/CCNF as an independent prognostic factor for poor survival in clear cell renal cell carcinoma.

Cyclin F (encoded by CCNF gene) has been reported to be implicated in the pathobiology of several human cancers. However, its potential clinical significance in clear cell renal cell carcinoma (ccRCC) remains unknown. The present study aimed to evaluate the potential significance of cyclin F, assessed by immunohistochemical (IHC) staining and molecular (bioinformatics) techniques, as a prognostic marker in ccRCC in relation to clinicopathological features and outcomes. IHC staining was performed using two independent ccRCC tissue array cohorts, herein called tissue macroarray (TMA)_1 and tissue microarray (TMA)_2, composed of 108 ccRCCs and 37 histologically normal tissues adjacent to the tumor (NAT) and 192 ccRCCs and 16 normal kidney samples, respectively. The mRNA expression data were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) public datasets, followed by bioinformatics analysis of biological mechanisms underlying prognosis. The relationship between immune cell infiltration level and CCNF expression in ccRCC was investigated using the Tumor Immune Estimation Resource 2.0 (TIMER2) and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Cyclin F expression was significantly elevated in ccRCC lesions compared to both NAT and normal renal tissues. Likewise, CCNF mRNA was markedly increased in ccRCCs relative to non-cancerous tissues. In all analyzed cohorts, tumors with features of more aggressive behavior were more likely to display cyclin F/CCNF-high expression than low. Furthermore, patients with high cyclin F/CCNF expression had shorter overall survival (OS) times than those with low expression. In addition, multivariable analysis revealed that cyclin F/CCNF-high expression was an independent prognostic factor for poor OS in ccRCC. Enrichment analysis for mechanistically relevant processes showed that CCNF and its highly correlated genes initiate the signaling pathways that eventually result in uncontrolled cell proliferation. CCNF expression was also correlated with immune cell infiltration and caused poor outcomes depending on the abundance of tumor-infiltrating immune cells in ccRCC. Our findings suggest that cyclin F/CCNF expression is likely to have an essential role in ccRCC pathobiology through regulating multiple oncogenic signaling pathways and affecting the tumor immune microenvironment and may serve as prognostic biomarker and promising therapeutic target in ccRCC.

Ubiquitin B, Ubiquitin C, and ß-Catenin as Promising Diagnostic and Prognostic Tools in Prostate Cancer.

Prostate cancer (PC) is a major global public health concern, imposing a significant burden on men and ranking as the second most prevalent malignancy. This study delves into the intricate world of ubiquitination processes and expression regulation, with a specific focus on understanding the roles of ubiquitin B (UBB), ubiquitin C (UBC), and ß-Catenin in PC development. We thoroughly analyze the expression profiles of UBB, UBC, and ß-Catenin, investigating their interactions and associations with clinical and histopathological data. These findings offer valuable insights into their potential as robust prognostic markers and their significance for patient survival. Our research uncovers the upregulation of UBB and UBC expression in PC tissues, and an even more pronounced expression in lymph node metastases, highlighting their pivotal roles in PC progression. Moreover, we identify a compelling correlation between high UBB and UBC levels and diminished overall survival in PC patients, emphasizing their clinical relevance. Additionally, we observe a significant reduction in membranous ß-Catenin expression in PC tissues. Importantly, abnormal ß-Catenin expression is strongly associated with shorter survival in PC patients and serves as a significant, independent prognostic factor for patient outcomes. Kaplan-Meier survival analysis indicates that patients with tumors characterized by simultaneous UBB and aberrant ß-Catenin expression exhibit the poorest overall survival. These collective insights underline the clinical importance of evaluating UBB, UBC, and ß-Catenin as combined prognostic markers in PC.

Macrophage migration inhibitory factor (MIF) predicts survival in patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common subtypes of renal cancer, with 30% of patients presenting with systemic disease at diagnosis. This aggressiveness is a consequence of the activation of epithelial-mesenchymal transition (EMT) caused by many different inducers or regulators, signaling cascades, epigenetic regulation, and the tumor environment. Alterations in EMT-related genes and transcription factors are associated with poor prognosis in ccRCC. EMT-related factors suppress E-cadherin expression and are associated with tumor progression, local invasion, and metastasis. The aim of this study was to investigate the expression levels and prognostic significance of macrophage migration inhibitory factor (MIF), ß-catenin, and E-cadherin in ccRCC patients. We examined these proteins immunohistochemically in tumor areas and adjacent normal tissues resected from patients with ccRCC. Analysis of the cancer genome atlas (TCGA) cohort was performed to verify our results. Kaplan-Meier analysis showed that median overall survival (OS) was significantly shorter in patients with tumors exhibiting high MIFn and MIFm-c levels compared to those with low MIFn and MIFm-c levels (p = 0.03 and p = 0.007, respectively). In the TCGA cohort, there was a significant correlation between MIF expression and OS (p < 0.0001). In conclusion, this study provides further evidence for the biological and prognostic value of MIF in the context of EMT as a potential early prognostic marker for advanced-stage ccRCC.

Age-associated B cell infiltration in salivary glands represents a hallmark of Sjögren's-like disease in aging mice.

Sjögren's disease (SjD), characterized by circulating autoantibodies and exocrine gland inflammation, is typically diagnosed in women over 50 years of age. However, the contribution of age to SjD pathogenesis is unclear. C57BL/6 female mice at different ages were studied to investigate how aging influences the dynamics of salivary gland inflammation. Salivary glands were characterized for immune cell infiltration, inflammatory gene expression, oxidative stress, and saliva production. At 8 months, gene expression of several chemokines involved in immune cell trafficking was significantly elevated. At this age, Age-associated B cells (ABCs), a unique subset of B cells expressing the myeloid markers CD11b and/or CD11c, were preferentially enriched in the salivary glands compared to other organs like the spleen or liver. The salivary gland ABCs increased with age and positively correlated with increased CD4 T follicular helper cells. By 14 months, lymphocytic foci of well-organized T and B cells spontaneously developed in the salivary glands. In addition, the mice progressively developed high titers of serum autoantibodies. A subset of aged mice developed salivary gland dysfunction mimicking SjD patients. Our data demonstrates that aging is a significant confounding factor for SjD. Thus, aged female C57BL/6 mice are more appropriate and a valuable preclinical model for investigating SjD pathogenesis and novel therapeutic interventions.

Effect of Systemic Prednisone Treatment on Changes of Inflammation Markers in Chronic Rhinosinusitis.

(1) Objective: We aimed to evaluate the effect of treatment with prednisone on nasal and systemic periostin and eotaxin expression, IgE in plasma and eosinophils in tissue. (2) Methods: We compared the values of nasal and systemic periostin, eotaxin, IgE and eosinophils in tissue in patients treated with only nasal steroids before FESS, group 1, with those treated with an oral steroid-prednisone, group 2. (3) Results: A statistically significant decrease in the level of periostin, eotaxin and IgE in plasma was achieved in patients treated with prednisone one week before and after surgery (in sequence: p < 0.0476, p < 0.0006, p < 0.0031). In patients treated with steroids, we also observed a lower level of periostin in the epithelium (p < 0.044), eotaxin in the stroma (p limit value < 0.075) and eosinophils (p < 0.031) in the tissues collected during the operation. (4) Conclusions: Systemic steroid treatment with prednisone distinctly decreases periostin, eotaxin and IgE expression in plasma. We also observed a lower level of periostin in the epithelium, eotaxin in the stroma and eosinophils in the tissues. We need more attempts to find inflammatory markers associated with chronic rhinosinusitis. Identifying drugs that decrease inflammatory parameters would allow for more targeted therapy.

The Prognostic Role of ACO2 in Renal Cell Carcinoma.

BACKGROUND/AIM: Renal cell carcinoma (RCC) continues to pose a challenge due to our limited understanding of its underlying pathophysiology. Aconitase 2 (ACO2) is a mitochondrial Fe-S cluster enzyme that catalyzes the stereospecific isomerization of citrate to isocitrate in the second step of the Krebs cycle. We investigated the relationship between ACO2 protein expression and the clinical course of RCC. MATERIALS AND METHODS: Tumor samples were evaluated in a commercial tissue microarray for ACO2 expression using the H-score. The tissue microarrays contained a total of 96 cores from primary tumors, matched metastases, and matched adjacent tissues derived from 32 patients with RCC. The mean follow-up was 82.74 months. Correlation analysis of clinicopathological data and survival was performed. Expression levels of ACO2 mRNA were compared using publicly available data. RESULTS: All the tissue samples showed cytoplasmic ACO2 expression, with median H-scores of 139.7, 130.3 and 166.7 in primary tumor, metastatic tissue, and matched control tissue, respectively. A significantly higher ACO2 expression was found in normal tissues compared to primary and metastatic RCC. The analysis demonstrated a significantly positive correlation between ACO2 expression in primary tumors and their metastases. The results also showed a significant correlation between the expression of ACO2 and worse overall survival among patients with RCC. CONCLUSION: ACO2 may be used as a prognostic factor in RCC. Significant alterations in ACO2 expression are thought to occur in the early stages of RCC carcinogenesis. Considering the physiological role of ACO2, its dysregulation may constitute an adaptive trait of RCC for escaping the equilibrium phase of immunoediting.

Low Expression of MATR3 Is Associated with Poor Survival in Clear Cell Renal Cell Carcinoma.

Matrin 3 (MATR3) is one of the most abundant inner nuclear matrix proteins involved in multiple nuclear processes. However, to date, the biological role and prognostic relevance of MATR3 in human cancers still need to be explored. Therefore, the present study aimed to examine the expression levels and prognostic significance of MATR3 in clear cell renal cell carcinoma (ccRCC) patients. We assessed MATR3 immunohistochemical staining and RNA-seq data from publicly available data sets, and the results were analyzed with reference to clinicopathological characteristics and the overall survival of patients. Furthermore, the protein-protein interaction (PPI) network for MATR3 and its neighbors was constructed, functionally annotated, and screened for survival-related genes. MATR3 protein and mRNA levels were lower in tumor tissues compared to control tissues. Lower MATR3 protein (HR 2.36, 95%CI 1.41-3.97; p = 0.001) and mRNA (HR 2.01, 95%CI 1.46-2.75; p < 0.0001) expression levels were found to be a significant independent adverse prognostic factor for the patient's overall survival (OS). Moreover, of the candidate genes, the MRPL23 gene was identified as being the most predictive of OS, and combined MRPL23/MATR3 expression status predicted patient survival better than looking at each marker individually (HR 3.15, 95%CI 2.05-4.83; p < 0.0001). In conclusion, the results from the present investigation warrant further research into the biological and prognostic value of MATR3 and MRPL23 in ccRCC patients.

STING Agonist-Induced Skin Inflammation Is Exacerbated with Prior Systemic Innate Immune Activation.

Activation of the Stimulator of Interferon Genes (STING) protein has paradoxical outcomes in skin disease. STING activation exacerbates psoriatic skin disease and delays wound healing in diabetic mice, yet it also facilitates wound healing in normal mice. To address the role of localized STING activation in the skin, mice were injected subcutaneously with a STING agonist, diamidobenzimidazole STING Agonist-1 (diAbZi). The effect of a prior inflammatory stimulus on STING activation was addressed by pre-treating mice intraperitoneally with poly (I:C). The skin at the injection site was evaluated for local inflammation, histopathology, immune cell infiltration, and gene expression. Serum cytokine levels were measured to assess systemic inflammatory responses. Localized diABZI injection induced severe skin inflammation with erythema, scaling, and induration. However, the lesions were self-limiting and resolved within 6 weeks. At the peak of inflammation, the skin showed epidermal thickening, hyperkeratosis, and dermal fibrosis. Neutrophils, CD3 T cells, and F4/80 macrophages were present in the dermis and subcutaneous layers. Gene expression was consistent with increased local interferon and cytokine signaling. Interestingly, the poly (I:C)-pre-treated mice showed higher serum cytokine responses and developed worse inflammation with delayed wound resolution. Our study demonstrates that prior systemic inflammation amplifies STING-mediated inflammatory responses and skin disease.

TOLLIP Protein Expression Predicts Unfavorable Outcome in Renal Cell Carcinoma.

Resistance to systemic therapy is one of the hallmarks of renal cell carcinoma (RCC). Recently, TOLLIP has emerged as a possible driver of autophagy and chemoresistance. We explored the relationship between primary and metastatic RCC tumor characteristics, patient survival, and TOLLIP expression. The tissue microarrays cohort contained 95 cores of the primary tumor, matched metastases, and matched adjacent tissues derived from 32 RCC patients. TOLLIP expression in tumor samples was evaluated using the H-score. All examined samples showed cytoplasmic TOLLIP expression, with a median value of 100 in primary tumors, 107.5 in metastases, and 220 in the control group. The expression was significantly higher in the normal adjacent tissues compared to primary or metastatic RCC (p < 0.05). We found a positive correlation between expressions of TOLLIP in the primary tumor and its metastases (p < 0.05; k = 0.48). TOLLIP expression significantly correlates with a lower overall survival rate (p = 0.047). TOLLIP functions as a ubiquitin-LC3 adaptor in the intracellular pathway associated with autophagy. Relative TOLLIP overexpression may augment autophagy-related signaling, limiting susceptibility to therapy. The blockade of TOLLIP physiological function seems to be a promising approach to overcoming resistance to systemic therapy.

High expression of RUVBL1 and HNRNPU is associated with poor overall survival in stage I and II non-small cell lung cancer patients.

The present study aimed to investigate expression levels and prognostic significance of RUVBL1 and HNRNPU in stage I and II non-small-cell lung cancer (NSCLC) patients. Therefore, we evaluated immunohistochemical staining of RUVBL1 and HNRNPU, as well as RNA-seq data from public sources, and the results were evaluated concerning overall survival (OS) and clinicopathological features. We found that RUVBL1 and HNRNPU proteins and mRNA levels were higher in tumor tissues as compared to adjacent/normal tissues. RUVBL1 (p = 0.013) and HNRNPU (p = 0.021) high protein levels were independent prognostic factors for poor OS. Also, the multivariate analysis in the TCGA dataset revealed that high RUVBL1 (p = 0.064) and HNRNPU (p = 0.181) mRNA levels were not significantly associated with prognosis. However, the co-expression status of these markers (R + H +) was independently associated with poor OS both in the TCGA dataset (p = 0.027) and in our cohort (p = 0.001). In conclusion, combined and individual expression of RUVBL1 and HNRNPU proteins, as well as R + H + mRNA status, may serve as potential prognostic biomarkers for NSCLC. This study adds to the previous observations that RUVBL1 and HNRNPU might be novel and promising therapeutic targets and markers for prognostic evaluation.

Tumor Cell-Induced Platelet Aggregation as an Emerging Therapeutic Target for Cancer Therapy.

Tumor cells have the ability to induce platelet activation and aggregation. This has been documented to be involved in tumor progression in several types of cancers, such as lung, colon, breast, pancreatic, ovarian, and brain. During the process, platelets protect circulating tumor cells from the deleterious effects of shear forces, shield tumor cells from the immune system, and provide growth factors, facilitating metastatic spread and tumor growth at the original site as well as at the site of metastasis. Herein, we present a wider view on the induction of platelet aggregation by specific factors primarily developed by cancer, including coagulation factors, adhesion receptors, growth factors, cysteine proteases, matrix metalloproteinases, glycoproteins, soluble mediators, and selectins. These factors may be presented on the surface of tumor cells as well as in their microenvironment, and some may trigger more than just one simple receptor-ligand mechanism. For a better understanding, we briefly discuss the physiological role of the factors in the platelet activation process, and subsequently, we provide scientific evidence and discuss their potential role in the progression of specific cancers. Targeting tumor cell-induced platelet aggregation (TCIPA) by antiplatelet drugs may open ways to develop new treatment modalities. On the one hand, it may affect patients' prognosis by enhancing known therapies in advanced-stage tumors. On the other hand, the use of drugs that are mostly easily accessible and widely used in general practice may be an opportunity to propose an unparalleled antitumor prophylaxis. In this review, we present the recent discoveries of mechanisms by which cancer cells activate platelets, and discuss new platelet-targeted therapeutic strategies.

Prognostic significance of MATR3 in stage I and II non-small cell lung cancer patients.

PURPOSE: Matrin 3 (MATR3) is a nuclear matrix protein involved in mRNA stabilization, nuclear retention of hyper-edited RNAs, and RNA splicing. The role of MATR3 in cancer is still unclear. The present study aimed to investigate expression levels and prognostic significance of MATR3 in stage I and II non-small cell lung cancer (NSCLC) patients. METHODS: We examined MATR3 protein immunohistochemically in tumoral and non-tumoral tissue sections from n = 67 NSCLC patients treated at hospital, and MATR3 mRNA from The Cancer Genome Atlas (TCGA) cohort with respect to valid prognostic and predictive features, as well as treatment outcome. RESULTS: Significantly higher immunohistochemical levels of MATR3 protein were found in tumor-adjacent tissue compared to cancer (p = 0.049). A decrease in MATR3 protein expression was found to be a significant independent adverse prognostic factor for patients overall survival (p = 0.007). By contrast, we observed higher MATR3 mRNA levels in tumoral tissue compared to control lung tissues (p < 0.001). Based on the TCGA dataset, we reported that high MATR3 mRNA level was significantly associated with worse OS of NSCLC patients (p < 0.001); however, it was not an independent prognostic marker (p = 0.156). The discrepancies in prognostic significance of MATR3 gene mRNA and protein levels imply a need for further investigation. CONCLUSION: In conclusion, the present study warrants further investigation into the biological and prognostic value of MATR3 as a potential prognostic marker in early-stage NSCLC patients.

SPDL1 Is an Independent Predictor of Patient Outcome in Colorectal Cancer.

Spindle Apparatus Coiled-Coil Protein 1 (SPDL1) is a relatively recently identified coiled-coil domain containing protein and an important determinant of DNA fidelity by ensuring faithful mitosis. Hence, SPDL1 is suspected to underlie genomic (in-)stability in human cancers, yet its exact roles in these diseases remain largely underexplored. Given that genomic instability (GIN) is a crucial feature in colorectal cancer (CRC), we primarily asked whether the expression of this protein may account for differences in clinicopathological features and survival rates of CRC patients. Protein expression was evaluated by immunohistochemistry in the institutional tissue microarray (TMA), and gene expression by the analysis of publicly available datasets. To place the prognostic relevance in a predicted biological context, gene co-expression set around SPDL1 identified by public data mining was annotated and assessed for enrichment in gene ontology (GO) categories, BRITE hierarchies, and Reactome pathways. The comparison with adjacent normal tissue revealed a high expression of SPDL1 protein in a subset of tumor cases (48.84%), and these had better prognosis than the SPDL1-low expression counterpart even after adjustment for multiple confounders. SPDL1-high expression within tumors was associated with a median 56-month survival advantage, but not with any clinicopathological characteristics of our cohort. In the TCGA cohort, SPDL1 was overexpressed in tumor tissue and positively associated with improved survival, chromosome instability phenotype, and various GIN markers. In addition to the genes critically involved in the cell cycle and mitosis, a gene set co-expressed with SPDL1 contained checkpoint members of both chromosome segregation and DNA replication, as well as those associated with defective DNA repair, and retrograde vesicle-mediated transport. In conclusion, SPDL1 is an independent predictor of CRC patient survival in a possible connection with chromosomal instability.

Prognostic Significance of TLR2, SMAD3 and Localization-dependent SATB1 in Stage I and II Non-Small-Cell Lung Cancer Patients.

This study aimed to explore the prognostic value of SATB1, SMAD3, and TLR2 expression in non-small-cell lung carcinoma patients with clinical stages I-II. To investigate, we evaluated immunohistochemical staining to each of these markers using tissue sections from 69 patients from our cohort and gene expression data for The Cancer Genome Atlas (TCGA) cohort. We found that, in our cohort, high expression levels of nuclear SATB1n and SMAD3 were independent prognostic markers for better overall survival (OS) in NSCLC patients. Interestingly, expression of cytoplasmic SATB1c exhibited a significant but inverse association with survival rate, and it was an independent predictor of unfavorable prognosis. Likewise, TLR2 was a negative outcome biomarker for NSCLC even when adjusting for covariates. Importantly, stratification of NSCLCs with respect to combined expression of the three biomarkers allowed us to identify subgroups of patients with the greatest difference in duration of survival. Specifically, expression profile of SATB1n-high/SMAD3high/TLR2low was associated with the best OS, and it was superior to each single protein alone in predicting patient prognosis. Furthermore, based on the TCGA dataset, we found that overexpression of SATB1 mRNA was significantly associated with better OS, whereas high mRNA levels of SMAD3 and TLR2 with poor OS. In conclusion, the present study identified a set of proteins that may play a significant role in predicting prognosis of NSCLC patients with clinical stages I-II.

Prognostic Impact and Functional Annotations of KIF11 and KIF14 Expression in Patients with Colorectal Cancer.

Genomic instability (GIN) has an important contribution to the pathology of colorectal cancer (CRC). Therefore, we selected mitosis and cytokinesis kinesins, KIF11 and KIF14, as factors of potential clinical and functional value in CRC, as their aberrant expression has been suspected to underlie GIN. We examined the expression and the prognostic and biological significance of KIF11 and KIF14 in CRC via in-house immunohistochemistry on tissue microarrays, public mRNA expression datasets, as well as bioinformatics tools. We found that KIF11 and KIF14 expression, at both the protein and mRNA level, was markedly altered in cancer tissues compared to respective controls, which was reflected in the clinical outcome of CRC patients. Specifically, we provide the first evidence that KIF11 protein and mRNA, KIF14 mRNA, as well as both proteins together, can significantly discriminate between CRC patients with better and worse overall survival independently of other relevant clinical risk factors. The negative prognostic factors for OS were high KIF11 protein, high KIF11 protein + low KIF14 protein, low KIF11 mRNA and low KIF14 mRNA. Functional enrichment analysis revealed that the gene sets related to the cell cycle, DNA replication, DNA repair and recombination, among others, were positively associated with KIF11 or KIF14 expression in CRC tissues. In TCGA cohort, the positive correlations between several measures related to GIN and the expression of KIFs were also demonstrated. In conclusion, our results suggest that CRC patients can be stratified into distinct risk categories by biological and molecular determinants, such as KIF11 and KIF14 expression and, mechanistically, this is likely attributable to their role in maintaining genome integrity.

Prognostic Significance of KIF11 and KIF14 Expression in Pancreatic Adenocarcinoma.

Available biomarkers for pancreatic adenocarcinoma (PAC) are inadequate to guide individual patient prognosis or therapy. Therefore, herein we aimed to verify the hypothesis that differences in the expression of KIF11 and KIF14, i.e., molecular motor proteins being primarily implicated in cell division events could account for the differences in the clinical outcome of PAC patients. In-house immunohistochemistry was used to evaluate the protein expressions of KIF11 and KIF14 in PAC, whereas RNA-seq datasets providing transcript expression data were obtained from public sources. IHC and mRNA results were correlated with clinicopathological features and overall survival (OS). Furthermore, the genes co-expressed with KIF11 or KIF14 were predicted and functionally annotated. In our series, malignant ducts displayed more intense but less abundant KIF11 staining than normal-appearing ducts. The former was also true for KIF14, whereas the prevalence of positive staining was similar in tumor and normal adjacent tissues. Based on categorical immunoreactive scores, we found KIF11 and KIF14 to be frequently downregulated or upregulated in PAC cases, respectively, and those with elevated levels of either protein, or both together, were associated with better prognosis. Specifically, we provide the first evidence that KIF11 or KIF14 proteins can robustly discriminate between patients with better and worse OS, independently of other relevant clinical risk factors. In turn, mRNA levels of KIF11 and KIF14 were markedly elevated in tumor tissues compared to normal tissues, and this coincided with adverse prognosis, even after adjusting for multiple confounders. Tumors with low predicted KIF11 or KIF14 expression were seen to have enrichment for circadian clock, whereas those with high levels were enriched for the genomic instability-related gene set. KIF11 and KIF14 were strongly correlated with one another, and CEP55, ASPM, and GAMT were identified as the main hub genes. Importantly, the combined expression of these five genes emerged as the most powerful independent prognostic indicator associated with poor survival outcome compared to classical clinicopathological factors and any marker alone. In conclusion, our study identifies novel prognostic biomarkers for PAC, which await validation.

Expression of Genomic Instability-Related Molecules: Cyclin F, RRM2 and SPDL1 and Their Prognostic Significance in Pancreatic Adenocarcinoma.

In the present study, we aimed to assess the selected components of cell cycle machinery, checkpoint, DNA repair, and synthesis, namely RRM2, cyclin F, and SPDL1 in pancreatic adenocarcinomas (PAC) by in-house immunohistochemistry (IHC) and bioinformatic analysis of public datasets, in terms of expression, correlation with clinicopathological parameters, and patient survival. Sixty eight patients with pancreatic ductal adenocarcinoma (PDAC) were included in our cohort study, and IHC was performed on tissue macroarrays. RNA-Seq-based transcriptome data for 177 PACs were retrieved from the Cancer Genome Atlas (TCGA). We found cyclin F, RRM2, and SPDL1 to be overexpressed at both protein and mRNA levels in tumor tissues compared to respective controls. Based on TCGA dataset, we have demonstrated that CCNF, RRM2, and SPDL1 are potent independent prognostic markers for poor overall survival, both by themselves and even more in combination with each other. Furthermore, high CCNF mRNA expression was associated with features of cancer progression. By contrast, overexpression of cyclin F or SPDL1 proteins denoted a good prognosis in PDAC patients; however, in the case of the former protein, the results did not reach statistical significance. Specifically, high levels of SPDL1 protein emerged as the most powerful independent prognostic factor associated with a better outcome. If validated, the CCNF/RRM2/SPDL1 three-gene panel developed in this study, as well as SPDL1 protein, may provide significant clinical implications for the prognosis prediction of PAC patients.

The clinical, prognostic and therapeutic significance of liver cancer stem cells and their markers.

Hepatocellular carcinoma (HCC) is the fourth most common cause of death among cancers. The poor prognosis of HCC might be caused by a population of cancer stem cells (CSC). CSC have similar characteristics to normal stem cells and are responsible for cancer recurrence, chemoresistance, radioresistance and metastasis. Liver cancer stem cells (LCSC) are identified via specific surface markers, such as CD44, CD90, CD133, and EpCAM (CD326). Recent studies suggested a complex interaction between mentioned LCSC markers and clinical features of HCC. A high expression of CSC is correlated with a negative prognostic factor after surgical resection of HCC and is connected with more aggressive tumor behavior. Moreover, LCSC might be responsible for increasing resistance to sorafenib, a kinase inhibitor drug. A reduction in the LCSC population may be crucial to successful advanced HCC therapy.