Predictive Prognostic Biomarker Research Articles

Clinico-Pathological Factors and AR-LBD Mutations in Early and Late Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) is not well understood because of its enormous biological heterogeneity and unreliable progression. We conducted this retrospective analysis to examine the variables predicting early and late progression to castration-resistant PCa (CRPC) for better management of this disease. This single institutional retrospective study was conducted from January 2018 to January 2022. A total of 98 consecutive men meeting with the diagnosis of CRPC as per the inclusion criteria were included in the study and were stratified in four quartiles on the basis of time to CRPC (time to castration resistance [TTCR]) development. Early CRPC (1st quartile, TTCR = 6-12 months) and late CRPC (4th quartile, TTCR = 38-120 months) were then compared on the basis of different clinical, pathological and AR-LBD sequence to find the correlation with response duration. Median time to develop castration resistance was 25 ± 26.44 months. The mean age of the patients was 66.8 ± 9.20 years and median baseline PSA was calculated 100±685.06 ng/mL respectively. Higher Gleason score (≥7-10) was found to be significantly associated with early development of CRPC (p<0.001) and lower nadir PSA was significantly indicating late CRPC progression (p<0.005). No mutations were found in androgen receptor exon-5, 6, 7 except a homozygous mutation in the 7th intronic region, which is involved in splice variants formation playing noteworthy role in CRPC development. Time for metastatic PCa to CRPC ranges from 6-120 months revealing its heterogeneous nature. Early age presentation in the clinic and high initial PSA and high grade (GS>7) at diagnosis were positively associated with early CRPC while lower nadir PSA was correlated with late CRPC progression. No remarkable genomic mutations were discovered. Therefore, more data are needed and further research is required with large no. of patients to discover the predictive prognostic biomarkers for better patients' management.

METTL3-mediated m6A Modification of hsa_circ_0131922 Attenuates the Progression of Papillary Thyroid Cancer by Regulating the p53 Pathway.

This study aimed to confirm the regulatory role and mechanism of circular RNA (circRNA) hsa_circ_0131922 in Papillary Thyroid Carcinoma (PTC) progression. Accumulating evidence suggests that N6-methyladenosine (m6A)-modified circular RNAs (circRNAs) perform pivotal functions in various malignancies. However, the specific role of the m6A modification of circRNA mediated by METTL3 in Papillary Thyroid Carcinoma (PTC) remains undocumented. In this work, we aimed to examine the molecular mechanisms of a novel m6Amodified circRNA, hsa_circ_0131922, in PTC progression. Potential circRNA was identified from GEO datasets. The RNA or protein levels of hsa_circ_0131922, METTL3, p53, and p21 were evaluated by qRT-PCR or western blot assays. The various cellular functions were checked by CCK8, wound healing, transwell, and xenograft tumor assays. MeRIP-qPCR was performed to observe the METTL3-mediated m6A modification of hsa_circ_0131922. Furthermore, the interactions between hsa_circ_0131922 and METTL3 in PTC were analyzed by bioinformatics analysis and various rescue experiments. The levels of hsa_circ_0131922 were markedly downregulated in PTC tissues and cell lines. In addition, the lower hsa_circ_0131922 levels correlated with poor prognosis in PTC patients. The hsa_circ_0131922 overexpression reduced the malignant phenotypes of PTC cells and activated the p53/p21 pathway. Bioinformatic analysis showed the m6A-modified sites of hsa_circ_0131922, and a positive correlation between hsa_circ_0131922 and METTL3. Moreover, overexpression of METTL3 increased the levels of m6A modification of hsa_circ_0131922. Mechanistically, the anti-tumor effects of hsa_circ_0131922 overexpression have been found to be partially reversed by silencing METTL3 in vivo and in vitro. The results have demonstrated m6A-modified hsa_circ_0131922 by METTL3 to attenuate the progression of PTC by regulating the p53 pathway. Therefore, hsa_circ_0131922 could be a predictive prognostic biomarker and therapeutic target for PTC.

FTO is Associated with Patient Prognosis and Immune Infiltrates in Gastric Cancer and Regulates TGF-β Expression.

This study aimed to examine the associations of FTO expression with prognosis, tumor microenvironment (TME), immune cell infiltration, immune checkpoint genes, and relevant signaling pathways in GC. Furthermore, the relationship between FTO and TGF-β was studied in GC. The mRNA expression and clinical survival data of GC samples were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD). TIMER2, TNM plot, and GEPIA database were used to analyze FTO expression. The associations of FTO with prognosis and clinicopathologic features were assessed using the Kaplan-Meier plotter and UALCAN database, respectively. The R software was employed to analyze its related signaling pathways and the associations with TME, immune cell infiltration, and immune checkpoint genes. GEPIA and ENCORI were used to examine the association of FTO with TGF-β expression. The SRAMP website was utilized to predict m6A modification of TGF-β. IHC, Western blot, and qPCR were used to analyze the expression levels of FTO and TGF-β in clinical gastric cancer tissue samples or gastric cancer cell lines. In addition, a m6A RNA methylation assay kit was used to determine m6A levels in gastric cancer cells. FTO mRNA and protein levels were significantly elevated in GC compared to normal gastric tissues. Kaplan-Meier survival analysis suggested that upregulated FTO was associated with a worse prognosis in GC. Upregulated FTO was markedly correlated with differentiation degree, lymph node metastasis, and clinical TNM stage. GO and KEGG pathway analyses revealed that FTO-associated molecules were enriched in neuroactive ligand-receptor interaction, calcium signaling, PI3k-Akt signaling, cAMP signaling pathways, and TGF-β signaling pathways, among others. The TME score was remarkably higher in the high-FTO group than in the low-FTO group. Furthermore, FTO expression had positive correlations with different types of immune cells and immune checkpoint genes. Moreover, FTO may regulate TGF-β in an m6A RNA modification manner in GC. FTO may become an independent predictive prognostic biomarker correlating with TME, immune cell infiltration, and immune checkpoint genes in gastric cancer and might influence GC progression by regulating TGF-β expression.

Identification of P3H1 as a Predictive Prognostic Biomarker for Bladder Urothelial Carcinoma Based on the Cancer Genome Atlas Database.

The extracellular matrix in the tumor microenvironment are closely related to the development of tumors. This study's primary aim is to study the association between prolyl 3-hydroxylase 1 (P3H1) which mainly expresses collagen in extracellular matrix and the progression and prognosis of bladder cancer (BC). The clinical and transcriptome data were acquired from the cancer genome atlas database. BLCAsubtyping is used to evaluate tissue subtypes of BC. The COX proportional hazards can be used to evaluate the survival process's influencing factors. Immunohistochemistry was used to identify differences in the expression of P3H1 in cancer and paired adjacent tissues. GSEA was used to investigate the underlying biological processes. Finally, ssGSEA, TIMER and pRRophetic were used to study the relationship between P3H1 and immune cell infiltration and drug sensitivity. The expression of P3H1 was substantially higher in highly invasive BC samples than in low invasive BC. P3H1 was an independent predictor of overall survival (HR = 1.12, p = 0.03). P3H1 expression was significantly higher in tumor tissues than adjacent normal tissues in clinical tissue samples, and was significantly higher in highly stage cancer than low stage cancer samples. Samples with high P3H1 expression had a higher level of immune cell infiltration and immune function, as well as a significant correlation with macrophage and dendritic cell infiltration and TGF-beta, Th1 cells, and macrophage regulation (cor >0.3, p <0.05). P3H1 high expression samples were substantially more sensitive to docetaxel, cisplatin, vinblastine, camptothecin, paclitaxel, and other medicines than P3H1 low expression samples. P3H1 is a possible oncogene and an independent predictor of poor prognosis in BC; it also has enhanced sensitivity to docetaxel, cisplatin, vinblastine, camptothecin, paclitaxel, and other medications.

Tumor immune microenvironment and clinical outcomes in stage IV urothelial cancer: YODO study

BackgroundBladder cancer is the 10th most common cancer globally, with a growing incidence in Japan. Evaluation of molecular, genetic, and cellular biomarkers that predict treatment response and prognosis in patients with metastatic urothelial carcinoma (mUC) may help optimize sequential treatment strategies with chemotherapy and immune checkpoint inhibitors (ICIs).MethodsThis multicenter, retrospective cohort study, evaluated programmed death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and cancer-immune phenotype as predictive prognostic biomarkers following first-/second-line treatment in Japanese adult patients with mUC. The primary endpoint was prevalence of PD-L1 expression. Secondary endpoints were TMB, overall survival (OS), and progression-free survival (PFS) from initiation of first-line treatment, and exploratory endpoints were cancer-immune phenotype, OS, PFS, and treatment response according to potential biomarker status.ResultsOf the 143 patients included (mean age 71.7 years), PD-L1 expression was high in 29.4% of patients. Non-synonymous TMB was high in 33.6% and low in 66.4%. Cancer-immune phenotype was immune-desert in 62.9%, immune-excluded in 30.8%, and inflamed in 6.3%. Median OS and PFS following first-line treatment were 18.2 and 7.4 months, respectively. Overall response to second-line treatment was slightly better with high versus low/negative PD-L1 expression. PD-L1 expression and TMB were non-significant predictors of OS or PFS, whereas immune-excluded phenotype was associated with better OS in comparison with immune-desert phenotype.ConclusionPD-L1 expression and TMB were non-significant predictors of prognosis after first-line treatment in Japanese patients with mUC, but cancer-immune phenotype may be an important prognostic factor in chemotherapy-ICI sequential treatment strategies.Clinical trial registration number UMIN000037727.

Characterization and clinical verification of immune-related genes in hepatocellular carcinoma to aid prognosis evaluation and immunotherapy

BackgroundImmune-related genes (IRGs) have been confirmed to play an important role in tumorigenesis and tumor microenvironment formation in hepatocellular carcinoma (HCC). We investigated how IRGs regulates the HCC immunophenotype and thus affects the prognosis and response to immunotherapy.MethodsWe investigated RNA expression of IRGs and developed an immune-related genes-based prognostic index (IRGPI) in HCC samples. Then, the influence of the IRGPI on the immune microenvironment was comprehensively analysed.ResultsAccording to IRGPI, HCC patients are divided into two immune subtypes. A high IRGPI was characterized by an increased tumor mutation burden (TMB) and a poor prognosis. More CD8 + tumor infiltrating cells and expression of PD-L1 were observed in low IRGPI subtypes. Two immunotherapy cohorts confirmed patients with low IRGPI demonstrated significant therapeutic benefits. Multiplex immunofluorescence staining determined that there were more CD8 + T cells infiltrating into tumor microenvironment in IRGPI-low groups, and the survival time of these patients was longer.ConclusionsThis study demonstrated that the IRGPI serve as a predictive prognostic biomarker and potential indicator for immunotherapy.

CHRM4/AKT/MYCN upregulates interferon alpha-17 in the tumor microenvironment to promote neuroendocrine differentiation of prostate cancer

Current treatment options for prostate cancer focus on targeting androgen receptor (AR) signaling. Inhibiting effects of AR may activate neuroendocrine differentiation and lineage plasticity pathways, thereby promoting the development of neuroendocrine prostate cancer (NEPC). Understanding the regulatory mechanisms of AR has important clinical implications for this most aggressive type of prostate cancer. Here, we demonstrated the tumor-suppressive role of the AR and found that activated AR could directly bind to the regulatory sequence of muscarinic acetylcholine receptor 4 (CHRM4) and downregulate its expression. CHRM4 was highly expressed in prostate cancer cells after androgen-deprivation therapy (ADT). CHRM4 overexpression may drive neuroendocrine differentiation of prostate cancer cells and is associated with immunosuppressive cytokine responses in the tumor microenvironment (TME) of prostate cancer. Mechanistically, CHRM4-driven AKT/MYCN signaling upregulated the interferon alpha 17 (IFNA17) cytokine in the prostate cancer TME after ADT. IFNA17 mediates a feedback mechanism in the TME by activating the CHRM4/AKT/MYCN signaling-driven immune checkpoint pathway and neuroendocrine differentiation of prostate cancer cells. We explored the therapeutic efficacy of targeting CHRM4 as a potential treatment for NEPC and evaluated IFNA17 secretion in the TME as a possible predictive prognostic biomarker for NEPC.

Predictive prognostic biomarkers in patients with COVID‑19 infection.

The present study aimed to identify useful biomarkers to predict deterioration in patients with coronavirus disease 2019 (COVID‑19). A total of 201 COVID‑19 patients were classified according to their disease severity into non‑severe (n=125) and severe (n=76) groups, and the behavior of laboratory biomarkers was examined according to the prognosis. Neutrophil count, aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase (LDH), C‑reactive protein (CRP), sialylated carbohydrate antigen KL‑6 (KL‑6), procalcitonin (PCT), presepsin (PSP) and D‑dimer levels were significantly higher, and lymphocyte count and platelet count were significantly lower in the non‑severe group compared with the severe group. In the non‑severe group, ROC analysis demonstrated that only four biomarkers, CRP, PSP, AST and LDH were useful for differentiating the prognosis between improvement and deterioration subgroups. No strong correlation was revealed for any of the markers. Multivariate analysis identified CRP as a significant prognostic factor in non‑severe cases (odds ratio, 41.45; 95% confidence interval, 4.91‑349.24; P<0.001). However, there were no blood biomarkers that could predict the outcome of patients in the severe group. Overall, several blood markers changed significantly according to disease severity in the course of COVID‑19 infection. Among them, CRP, PSP, LDH and AST were the most reliable markers for predicting the patient's prognosis in non‑severe COVID‑19 cases.

Untargeted metabolomics identified kynurenine as a predictive prognostic biomarker in acute myocardial infarction.

The occurrence of cardiovascular adverse events in the first year after ST-acute myocardial infarction (STEMI) remains high; therefore, identification of patients with poor prognosis is essential for early intervention. This study aimed to evaluate the prognostic value of metabolomics-based biomarkers in STEMI patients and explore their functional mechanisms. Metabolite profiling was performed using nuclear magnetic resonance. The plasma concentration of Kynurenine (Kyn) was measured using ultraperformance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Major adverse cardiac and cerebral events were assessed for 1 year. A functional metabolomics strategy was proposed for investigating the role of Kyn in both vitro and vivo models. The adjusted hazard ratios in STEMI patients for Kyn in the 4th quartile 7.12(5.71-10.82) was significantly higher than that in the 3rd quartile 3.03(2.62-3.74), 2nd quartile 1.86(1.70-2.03), and 1st quartile 1.20(0.93-1.39).The incidence of MACCE was significantly different among Kyn quartiles and the highest incidence of MACCE was observed in the 4th quartile when compared with the 1st quartile (9.84% vs.2.85%, P<0.001).Immunofluorescence staining indicated that indoleamine-pyrrole 2,3-dioxygenase (IDO1) was located in the CD68 positive staining area of thrombi from STEMI patients and Kyn was induced in the early phase after myocardial infarction. Kyn could trigger inflammation and oxidative stress of macrophage cells by activation of the Sirt3-acSOD2/IL-1β signaling pathway in vitro. Plasma Kyn levels were positively associated with the occurrence of STEMI. Kyn could induce macrophage cells inflammation and oxidative stress by activating the Sirt3-acSOD2/IL-1β pathway following myocardial ischemia injury. Kyn could be a robust biomarker for STEMI prognosis and reduction of Kyn could be beneficial in STEMI patients.

High expression of PTGES3 is an independent predictive poor prognostic biomarker and correlates with immune infiltrates in lung adenocarcinoma

BackgroundImmune-infiltration was positively relationship with overall survival in lung adenocarcinoma (LUAD). Nevertheless, the potential clinical value of PTGES3, especially in terms of prognosis and tumor immune-infiltration in LUAD had not been fully elucidated. MethodsOriginal data available from TCGA and GEO databases and integrated via R3.6.3. Kaplan-Meier and Cox regression methods were used to examine the effect of PTGES3 expression in overall survival, and nomogram was performed to illustrate the correlation between the PTGES3 expression and the risk of LUAD. The associate between PTGES3 and cancer immune characteristics were analyzed via the TISIDB databases. Western blot and RT-qPCR were used to analyze PTGES3 expression in the clinical lung adenocarcinoma tissue samples or non-small cell lung cancer cell lines. ResultsPTGES3 mRNA and protein expression were significantly elevated in LUAD compared with normal lung tissues. Up-regulated PTGES3 was significantly associated with pathologic stage and TM stage. Kaplan-Meier survival analysis and subgroup analysis showed that up-regulated PTGES3 was associated with a worse overall survival of LUAD (HR = 1.71 (1.27–2.31), p < 0.001). Multivariate Cox analysis showed that high PTGES3 expression was an independent factor affecting overall survival (HR = 1.64 (1.14–2.37), p < 0.001). GO and KEGG analysis revealed that the cell cycle, regulation of DNA replication, and regulation of innate immune response were enriched. A positive correlation between PTGES3 expression and immune infiltrating levels of Th2 cells was found. ConclusionPTGES3 may play an important role in the cell cycle and as an independent predictive prognostic biomarker correlates with immune infiltrates in lung adenocarcinoma.

Implication of COPB2 Expression on Cutaneous Squamous Cell Carcinoma Pathogenesis.

Simple SummaryThe present study aimed to evaluate the effect of COPB2 expression on cutaneous squamous cell carcinoma (cSCC) pathogenesis. cSCC, a common category of skin cancer, is marked by a reasonably favorable prognosis. However, there has been a steady rise in the annual incidence of cases; in particular, a subset of cases showed aggressive progression. However, the underlying molecular mechanism of cSCC pathogenesis is largely unknown. In the present study, we found that COPB2 may act as a potential oncogene and modulator of the tumor immune microenvironment in cSCC pathogenesis. Therefore, COPB2 can serve as a novel predictive prognostic biomarker and immunotherapeutic target in cSCC patients.The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients.

Untargeted Metabolomics Identified Kynurenine as a Predictive Prognostic Biomarker in Acute Myocardial Infarction

Untargeted Metabolomics Identified Kynurenine as a Predictive Prognostic Biomarker in Acute Myocardial Infarction

Red Blood Cell Mechanical Fragility as a Potential Predictor of Long-Term Hemolysis from Ventricular Assist Devices

Introduction: Recent improvement in design and performance of Left Ventricular Assist Devices facilitate their use for destination therapy. The shear stresses in such devices can damage patients’ red blood cells (RBC), leading to increased hemolysis, which has been associated with pump thrombosis and patient mortality. Here we report an investigation assessing RBC mechanical fragility as a potential metric of blood damage and its potential utility in monitoring LVAD performance. Methods: Twenty subjects were recruited from the Center for Circulatory Support at the University of Michigan. Thirteen were implanted with the HeartWare HVAD (Medtronic, Inc.) and 7 with HeartMate 3® LVAD (HM3; Abbott Labs). Blood samples were obtained before surgery and at 1 hour, 24 hours, 1 week and 4 weeks after. Hemolysis biomarkers, total lactate dehydrogenase (LDH) and LDH isoenzymes, bilirubin, haptoglobin, and serum hemoglobin were determined through standard clinical tests. Mechanical fragility, as a metric of sub-hemolytic RBC damage, was determined using electromagnetically driven bead milling in a tube with a cylindrical bead, combined with non-invasive spectrophotometric analysis of induced hemolysis upon selected durations of the stress application. Certain variations of the stressing regime were employed for comparison. Results: RBC mechanical fragility, as assessed through some of the stress application regimes, was correlated with certain hemolysis metrics like bilirubin, LDH, and LDH1. Specifically, a subset of pre-surgery RBC mechanical fragility markers were strongly correlated with bilirubin levels measured 1 day, 1 week, and 1 month (though not immediately) after the surgery. While such correlation with unconjugated bilirubin declined in significance over time, the correlation to conjugated bilirubin reached significance at 1 month. Mechanical fragility values determined in albumin-supplemented medium at 1-day post-surgery, showed strong correlation to total LDH and LDH1 at 1-month post-surgery (p &lt; 0.01, R2 up to 0.45), with the correlation with LDH1 stronger than with total LDH. Conclusions: These data demonstrate the potential for some RBC mechanical fragility metrics as predictive prognostic biomarkers for hemolysis induced by implantable circulatory support systems. With appropriate tailoring of testing parameters to best suit the application, mechanical fragility assays could help facilitate the transition to greater utilization of ventricular assist devices.

Prognostic Role of Long Noncoding RNAs in Oral Squamous Cell Carcinoma: A Meta-Analysis.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of tumor progression, and lncRNA expression levels could serve as a potential molecular biomarker for the prognosis and diagnosis of some cancers. However, the prognostic value of lncRNAs in oral squamous cell carcinoma (OSCC) remains unclear. Thus, a meta-analysis was conducted to explore the potential prognostic value of lncRNAs in OSCC. We systematically searched PubMed, EBSCO, Web of Science, and Elsevier from 2005 to 2021 to identify all published studies that reported the association between lncRNAs and prognosis in OSCC. Then, we used meta-analytic methods to identify the actual effect size of lncRNAs on cancer prognosis. The hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated to assess the strength of the association. The reliability of those results was then examined using measures of heterogeneity and testing for selective reporting biases. According to the inclusion and exclusion criteria, a total of 17 studies were eligible in our meta-analysis, involving 1384 Asian patients. The results identified a statistically significant association of high lncRNA expression with poor overall survival [adjusted pooled hazard ratio (AHR) = 1.52; 95% confidence interval (CI): [1.26–1.84], p ≤ 0.001]. The present meta-analysis demonstrated that lncRNA expression might be used as a predictive prognostic biomarker for Asian patients with OSCC.

Monocyte-to-lymphocyte ratio is associated with 28-day mortality in patients with acute respiratory distress syndrome: a retrospective study

BackgroundSystemic inflammation relates to the initiation and progression of acute respiratory distress syndrome (ARDS). Neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW)/albumin ratio have been reported to be predictive prognostic biomarkers in ARDS patients. However, the role of monocyte-to-lymphocyte ratio (MLR) as a prognostic inflammatory biomarker in a variety of diseases is rarely mentioned in ARDS. In this study, we explored the relationship between MLR and disease severity in ARDS patients and compared it with other indicators associated with 28-day mortality in patients with ARDS.MethodsWe retrospectively included 268 patients who fulfilled the Berlin definition of ARDS and were admitted to a single institute from 2016 to 2020. Clinical characteristics and experimental test data were collected from medical records within 24 h after the ARDS diagnosis. MLR, NLR, and RDW/albumin ratio levels were calculated. The primary clinical outcome was 28-day mortality. Logistic regression analysis was used to illustrate the relationship between indicators and 28-day mortality. Receiver operating characteristic (ROC) curve was used to evaluate the area under the curve (AUC), and propensity score matching (PSM) was employed to validate our findings.ResultsThe median MLR values were higher for non-survivors than for survivors before and after matching (P<0.001, P=0.001, respectively). MLR values were significantly associated with 28-day mortality (OR 2.956; 95% CI 1.873–4.665; P<0.001). MLR and NLR indicators were combined for predictive efficacy analysis, and its AUC reached 0.750. There was a significant increase in 28-day mortality depending on the increasing MLR level: low MLR group 38 (20.4%), high MLR group 47 (57.3%) (P<0.001).ConclusionsHigher MLR values were associated with 28-day mortality in patients with ARDS. Further investigation is required to verify this relationship with prospectively collected data.

Expression of PAWR predicts prognosis of ovarian cancer

BackgroundOvarian cancer greatly threatens the general health of women worldwide. Implementation of predictive prognostic biomarkers aids in ovarian cancer management.MethodsUsing online databases, the general expression profile, target-disease associations, and interaction network of PAWR were explored. To identify the role of PAWR in ovarian cancer, gene correlation analysis, survival analysis, and combined analysis of drug responsiveness and PAWR expression were performed. The predictive prognostic value of PAWR was further validated in clinical samples.ResultsPAWR was widely expressed in normal and cancer tissues, with decreased expression in ovarian cancer tissues compared with normal tissues. PAWR was associated with various cancers including ovarian cancer. PAWR formed a regulatory network with a group of proteins and correlated with several genes, which were both implicated in ovarian cancer and drug responsiveness. High PAWR expression denoted better survival in ovarian cancer patients (OS: HR = 0.84, P = 0.0077; PFS, HR = 0.86, P = 0.049). Expression of PAWR could predict platinum responsiveness in ovarian cancer and there was a positive correlation between PAWR gene effect and paclitaxel sensitivity. In 12 paired clinical samples, the cancerous tissues exhibited significantly lower PAWR expression than matched normal fallopian tubes. The predictive prognostic value of PAWR was maintained in a cohort of 50 ovarian cancer patients.ConclusionsHigh PAWR expression indicated better survival and higher drug responsiveness in ovarian cancer patients. PAWR could be exploited as a predictive prognostic biomarker in ovarian cancer.

SPAG6 promotes cell proliferation and inhibits apoptosis through the PTEN/PI3K/AKT pathway in Burkitt lymphoma.

The main purpose of the present study was to elucidate the role of sperm-associated antigen 6 (SPAG6) in the occurrence and development of Burkitt lymphoma (BL) and explore the underlying molecular mechanisms. A correlation was observed between the expression of SPAG6 and the prognosis of patients with lymphoma using The Cancer Genome Atlas (TCGA) database analysis. It was demonstrated that the levels of SPAG6 in BL cells were higher compared with that in IM-9 cells by reverse transcription-PCR and western blot assays. Moreover, silencing of SPAG6 significantly decreased proliferation and increased apoptosis of Daudi and Raji cells, whereas SPAG6 overexpression exerted the opposite effects on CA46 and NAMALWA cells. When investigating the possible mechanism, it was first observed that the level of phosphatase and tensin homolog (PTEN) protein was significantly increased, while that of phosphorylated (p-)AKT protein was markedly reduced in the SPAG6-knockdown group compared with the blank control group in Daudi and Raji cells by western blot analysis. It was further ascertained whether the phosphoinositide 3-kinase (PI3K)/PTEN/protein kinase B (AKT) pathway mediates the effects of SPAG6 on cell proliferation and apoptosis, and the results demonstrated that silencing of SPAG6 suppressed the viability of Daudi and Raji cells, whereas PTEN knockdown using siRNA or SF1670 (a specific PTEN inhibitor) reversed the inhibitory effect on cell proliferation and the promoting effect on cell apoptosis induced by SPAG6 depletion in vitro as well as in vivo. These data revealed that SPAG6 may promote the proliferation and inhibit the apoptosis of BL cells via the PTEN/PI3K/AKT pathway. The results of the present study suggest that SPAG6 may play a key role in the progression of BL and may be of value as a predictive prognostic biomarker in patients with BL.

Abstract 6467: Tumor mutation burden combined with tumor markers as predictive prognostic biomarkers for neoadjuvant chemotherapy in patients with gastric cancer

Abstract Background: The ypTNM stage and tumor regression grading (TRG) is widely used to predict the efficacy of neoadjuvant chemotherapy (NAC). However, the potential prognostic role of molecular markers is unknown. There is growing evidence assessing the predictive impact of tumor mutational burden (TMB) on the clinical efficiency of immunotherapy, but few investigation has pursued the predictive value of TMB on the efficiency of neoadjuvant chemotherapy. In this study, the prognostic role of TMB and tumor markers for NAC in patients with GC were explored. Methods: Patients with Stage II/III gastric adenocarcinoma (n = 30) were enrolled in this study between Jan 2016 and Jun 2017 in Peking University Cancer Hospital. All patients were subjected to NAC before resection. Whole exome sequencing (WES) were implemented on the biopsy samples collected from the 30 patients before NAC .Tumor mutation burden (TMB) of total somatic substitutions and indels per megabase after fıltering known driver mutations were calculated. The five postoperative serum tumor markers: AFP,CEA,CA199,CA724 and CA242 were quantitatively measured before and after operation. Results: Of all the 30 patients with GC receiving neoadjuvant chemotherapy before resection, 12 patients (40.0%) with higher TMB (≥5 mutations per Mb) showed significantly better prognosis compared to the other 18 patients (P=0.019, HR=6.042). And all these 12 patients survived at follow-up. In patients with TMB&amp;lt;5, those who with tumor marker positive (TM+) postoperatively were at more risk of recurrence than patients with negative TM (TM-) in postoperative plasma. Compared to the patients with TMB≥5, the subgroup of both TMB&amp;lt;5 &amp; TM- (P = 0.0631, HR= 6.449) and TMB&amp;lt;5 &amp; TM+ (P &amp;lt;0.0001, HR=1303) had poorer survival. The results showed that TMB combined with TM (Log-rank test, P&amp;lt;0.0001) provide better predictive validity on prognostic value compared with ypTNM alone (Log-rank test, P=0.1534). In addition, whole exome sequencing data from 478 STAD patients (Stomach Adenocarcinoma (TCGA, Provisional)) obtained from TCGA were used to detect somatic mutations. The results also indicated that mutation count was the most relevant clinical attribute of overall survival (Kruskal Wallis Test, q-value&amp;lt;10−10). It is further suggested that TMB is related to prognosis. Conclusions: In patients with GC, higher TMB levels (TMB≥5) of biopsy tissue before NAC showed greater response rates for neoadjuvant chemotherapy and longer survival. TMB&amp;lt;5 together with TM+ was a strong and accessible biomarker of poor OS. This is the first report of TMB can be used as a predictive biomarker before NAC, and TMB combined with tumor markers (TM) were significantly associated with prognosis in patients with Gastric Cancer. Additional larger cohort study aimed at understanding relationship between response to therapy and TMB are further required. Citation Format: Yongning Jia, Honglin Zhu, Fei Pang, Fei Shan, Shuangxi Li, Lei Dong, Tonghui Ma, Ziyu Li. Tumor mutation burden combined with tumor markers as predictive prognostic biomarkers for neoadjuvant chemotherapy in patients with gastric cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6467.

CORRELATION BETWEEN VISUAL FUNCTIONS AND OPTICAL COHERENCE TOMOGRAPHY, FUNDUS AUTO FLUORESCENCE AND FUNDUS FLUORESCEIN ANGIOGRAPHY FINDINGS IN TREATMENT-NAIVE DIABETIC MACULAR EDEMA

Background: Diabetic macular edema (DME) is a sightthreatening consequence of diabetic retinopathy. So, identifyingreliable methods for DME prognosis is actually very helpful. Multimodal retinal imaging tools provide us with these predictive prognostic biomarkers Aim of the Work: To correlate between visual functions (visual acuity and color vision) with macular features of OCT, FAF and FFA in patients with untreated (treatment naive) DME as a guide for visualprognosis of these patients. Patients and Methods: Fifty eyes of35 diabetic patients with untreated clinically significant macular edema (CSME)underwent best corrected visual acuity (BCVA) determination (logMAR), fluoresce in angiography(FFA;FAZ size, macular leakage pattern, areas of capillary dropout)optical coherence tomography (OCT; central point foveal thickness [CPFT], volume, outer and inner retinal layers integrity[ONL,INL],hyper-reflective foci[HRF], subfoveal choroidal thickness[SFCT]); fundus auto fluorescence (Hyper FAF; absent or increased (FAF, single or multiple spots). Linear correlation and three-way analysis of covariance were used for statistics. Results: In OCT, we found that CPFT & ORL integrity is significantly well correlated to visual function (BCVA, color vision).However, CSFT was only correlated to visual acuity but not color vision. Regarding FFA parameters, especially (FAZ size, areas of capillary drop out), we found that these parameters are correlated significantly to visual acuity but not color vision. On the other hand,we found that the presence of hyper FAF spots was not related significantly to visual acuity but related to a significant level to color vision. However, a number of spots were not correlated to visual acuity or color vision. There was significant correlation between retinal thickness in OCT and type of leakage in FFA. Also, large cystoid spaces and FAF spots in the fovea were significantly correlated together. Conclusions: Integration between different retinal imaging tools in DME helps to find alternative and less invasive way in diagnosis.FAF is new, simple non-invasive imaging mode to assess RPE function with evolving application in DME.

Serum Circular FoxO3a Serves as a Novel Prognostic Biomarker in Squamous Cervical Cancer.

PurposeCircular RNAs (circRNAs) are novel type of noncoding RNAs that play important roles and serve as noninvasive biomarkers in various cancers. In the present study, we focused on circFoxO3a and aimed to investigate its prognostic value as a novel serum biomarker for squamous cervical cancer (SCC).Patients and MethodsOur study included 103 SCC patients from Obstetrics and Gynecology Hospital of Fudan University. Expression levels of circFoxO3a in the serum of patients with SCC were examined by reverse transcription‑quantitative PCR (RT‑qPCR). The correlation between serum circFoxO3a expression and clinicopathologic factors was analyzed. The Kaplan–Meier method and multivariate Cox regression analysis were applied to evaluate the independent prognostic factors for SCC. A prognostic predictive nomogram was constructed using R software.ResultsLevels of serum circFoxO3a were decreased in SCC patients compared with controls. Low expression of circFoxO3a was correlated with deeper stromal invasion and positive lymph node metastasis. Moreover, SCC patients with lower expression of serum circFoxO3a showed poorer prognosis, including both overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox analysis indicated low serum circFoxO3a levels to be an unfavorable prognostic factor for both OS and RFS, independent of positive lymph node metastasis. Notably, the predictive nomogram we established further confirmed that serum circFoxO3a is a useful tool for predicting survival in SCC.ConclusionAltogether, our findings demonstrated that serum circFoxO3a could serve as a potential novel noninvasive predictive prognostic biomarker and therapeutic target for SCC.