Potential Biomarkers For Early Detection Research Articles

Evaluation of lncRNA FOXD2-AS1 Expression as a Diagnostic Biomarker in Colorectal Cancer.

Colorectal cancer (CRC) is still considered one of the prevalent cancers worldwide. Investigation of potential biomarkers for early detection of CRC is essential for the effective management of patients using therapeutic strategies. Considering that, this study was aimed to examine the changes in lncRNA FOXD2-AS1 expression through colorectal tumorigenesis. Fifty CRC tumor tissues and fifty adjacent normal tissue samples were prepared and involved in the current study. Total RNA was extracted from the samples and then reverse transcribed to complementary DNA. Next, the expression levels of lncRNA FOXD2-AS1 were evaluated using real-time PCR in CRC samples compared to normal ones. Also, receiver operating characteristic curve analysis was used to evaluate the diagnostic value of FOXD2-AS1 for CRC. The obtained results showed that the expression level of FOXD2-AS1 gene was significantly (p<0.0001) up-regulated in tumor tissues compared to normal marginal tissues. Also, a significant correlation was observed between higher the expression of FOXD2-AS1and the differentiation of tumor cells. Furthermore, ROC curve analysis estimated an AUC value of 0.59 for FOXD2-AS1, suggesting its potential as a diagnostic target. Taken together, the current study implied that tissue-specific upregulation of lncRNA FOXD2-AS1 might be appropriate diagnostic biomarkers for CRC. Nonetheless, more studies are needed to validate these results and further illustrate FOXD2-AS1 function through colorectal tumorigenesis.

Circulating Cell Free DNA as Predictive Biomarker in Cervical Cancer Patients Treated with Radical Chemo-Radiation

<h3>Purpose/Objective(s)</h3> Liquid biopsy is a new technique for cancer detection. Evaluation of circulating cell-free DNA (ccfDNA) through liquid biopsy is a minimally invasive and cost-effective method that may serve as a potential biomarker for early detection, treatment monitoring, status of residual disease, and distant tumor metastasis in cervical cancer patients. We evaluated plasma ccfDNA levels in patients of cervical cancer undergoing chemo-radiation and correlated their levels with treatment response and short-term clinical outcome. <h3>Materials/Methods</h3> This prospective, single arm, open–label, observational pilot study included patients of cervical cancer, being radically treated with three-dimensional conformal radiotherapy or intensity modulated radiotherapy to a dose of 46Gy/23 fractions over 4.5weeks followed by high dose rate (HDR) brachytherapy to deliver EQD2 of >80Gy. Concurrent weekly cisplatin 40mg/m² was administered weekly throughout the course of external radiotherapy. Peripheral blood samples were collected in EDTA tubes before starting treatment and at 6months after completion of treatment. On the same day, tubes were centrifuged at 800g for 10 minutes. The supernatant was transferred to 10ml tubes and centrifuged at 1600g for 10 minutes to remove debris. Plasma supernatants were transferred in 1mL aliquots and stored at -80°C. Total genomic DNA of plasma aliquots were extracted using the commercially available Circulating Nucleic Acid Kits. Categorical variables were tested using the chi-square test. Univariate analysis was done to analyze the factors affecting ccfDNA levels and if found significant, multivariate analysis was used. <h3>Results</h3> Of 22 patients of histologically confirmed cervical cancer, 11 (50%) were of stage II disease followed by 7 (31.8%) with stage III disease. The median age was 53.5 years (range 39-70 years). The baseline mean ccfDNA levels was 69.68±58.335 ng/μL which was significantly reduced post-treatment to 0.452±0.199 ng/μL (p<0.001). The stage of the disease significantly affected the baseline ccfDNA levels (p=0.029). Positive pelvic and para-aortic lymph nodes showed a trend towards higher baseline ccfDNA levels (p=0.068 and 0.38 respectively). Patients with progressive disease had a trend towards higher post-treatment ccfDNA levels (p=0.19). <h3>Conclusion</h3> Our study revealed the role of ccfDNA as a potential biomarker in cervical cancer, which, however requires further longitudinal studies for confirmation.

Supplemental Material for Cognitive Intraindividual Variability as a Potential Biomarker for Early Detection of Cognitive and Functional Decline

Supplemental Material for Cognitive Intraindividual Variability as a Potential Biomarker for Early Detection of Cognitive and Functional Decline

Abstract PO020: Identification of lipid species: potential biomarkers for early detection of hepatocellular carcinoma

Abstract Purpose of Study To investigate alterations in lipid metabolism during carcinogenesis from pretumor tissue towards hepatocellular carcinoma (HCC) and to identify lipid species biomarkers for early detection of HCC. Methods Liver tissue samples were collected from HCC patients. The samples were used to investigate the differences in lipid compositions between tumor and its surrounding hepatic tissue (SHT). A sample of the liver tumor and a sample of SHT were collected from each patient. A total of 32 samples were included in this study. Lipid profiling was performed using an automated electrospray ionization–tandem mass spectrometry with continuous infusion at 30 μl/min. The signal detection limit is 0.0005 mol. Concentrations of 1881 lipid species in tissue samples were analyzed. These lipid species include 348 species in 13 polar lipid groups, 44 species in triacylglycerol (TAG) group and 1489 species containing specific fatty acyl (FA). Lipid species with signal detected above or equal to the detection limit and coefficient of variation below 0.3 were retained for statistical analysis. Concentration differences in lipid species between HCC and SHT were compared using paired t-test or Wilcox signed rank. Differences in lipid compositions between HCC and SHT were assessed. Results Our study shows that significant difference (p &amp;lt; 0.05) of lipid species between SHT and HCC was found in 61 species including 50 species from polar lipid groups and 11 species from TAG group. Most of these species are phosphatidylcholine, ether-linked phosphatidylcholine and TAG species accounted for 36.07%, 13.11% and 18.03% respectively. In addition, significant changes in total ether-linked phosphatidylethanolamine (ePE) and total phosphatidylinositol (PI) were observed. Furthermore, there were significant decreases in FA 18:2 and FA18:3, but significant increase in FA 18:0 in HCC compared with that in SHT. Conclusions Our study suggests that total ePE, total PI, FA 18:0, FA 18:2 and FA 18:3 may serve as biomarkers for the early detection of HCC. Additional study is needed to understand the detailed mechanism of lipid alteration. Our study provides novel insights in the progress of pretumor tissue towards HCC. Citation Format: Kit Yee Leung, KayLee Freitas, Yu Kuang. Identification of lipid species: potential biomarkers for early detection of hepatocellular carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO020.

Modulation of EphA7 and pEphA7 Protein Expression: Potential Biomarkers for Early Detection of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading drivers of cancer-related mortality in the world. As a result, researchers are constantly looking for ways to optimize the screening and diagnosis of the said malignancy. To establish the mice model of hepatocellular carcinoma with the administration of a suitable dose of diethylnitrosamine (DEN) and examine the utility of EphA7 and pEphA7 as ideal diagnostic markers in HCC. Swiss Albino (BALB/c) mice of around 10-12 weeks old were exposed to a known hepatocarcinogen-diethylnitrosamine at a dose of 20 mg/kg body weight at weekly intervals for a period of 4, 8, 12, & 16 weeks. Blood was collected from mice of different experimental groups, and age-matched control and serum were separated from whole blood samples. The liver homogenate was prepared after completion of treatment, and the resulting supernatant was used for enzyme assays. A range of liver biomarker enzyme assays such as Gamma-glutamyl transpeptidase (GGT), Acetylcholine esterase (AChE), GPx activity and GSH level, Heme oxygenase-1 (HO-1), GPC3 and alpha-fetoprotein (AFP) level along with the expression of Caspase-3, EphA7 and pEphA7 were evaluated. An elevation in body weight and relative liver weight across the treatment period (4, 8, 12, 16 weeks) was observed in DEN-treated mice. Significant differences in GGT levels between control and DEN treated mice were noted in the present study (P < 0.005). In the 16th week of the treatment period, a significant difference in AchE level was noted between the treated and control group (P < 0.001). However, there was no statistically significant difference in the levels of SGOT and SGPT levels between the control and DEN treated groups (P > 0.001). Lower GSH and GPx levels were demonstrated in the treated mice as compared to control over all the treatment period. Loss of Caspase-3 expression and significant differences in expression of HO-1 activity in treated vs. non-treated group of mice were observed. Significant differences in EphA7 and pEphA7 protein expression levels were noted in the DEN-treated vs. control groups across all the treatment periods (4 weeks: P < 0.05; 8 weeks: P < 0.05; 12 weeks: P < 0.005; 16 weeks: P < 0.05). The present study indicated that EphA7 and phosphoEphA7 over-expression might contribute to the malignancy transition, invasion development, and metastasis of HCC. As a result, along with the known markers such as AFP and others, EphA7 and pEphA7 could be a very putative biomarkers of HCC, particularly at a very early stage of cancer development.

Promoter methylation analysis of DKK2 may be a potential biomarker for early detection of cervical cancer.

Dickkopf 2 (DKK2) plays an important role in multiple cancers. Its potential value in the clinical diagnosis of cervical cancer has remained unclear. To investigate the expression and promoter methylation levels of DKK2 in cervical cancer and their clinicopathological associations. We used the Gene Expression Omnibus, Oncomine, Cancer Genome Atlas, and University of ALabama at Birmingham CANcer data analysis databases, reverse transcription-PCR, and methylation-specific PCR analysis to predict and examine the expression of DKK2 mRNA and DKK2 methylation levels in cell lines and cervical cancer tissues from 79 patients with cervical cancer and 63 with cervical precancerous lesions including 25 with low-grade squamous intraepithelial lesions (LSIL) and 38 patients with high-grade squamous intraepithelial lesions (HSIL). DKK2 mRNA expression was downregulated in all cancer cell lines and cervical cancer tissues, whereas hypermethylation of DKK2 was higher in cervical cancer tissue samples. DKK2 methylation in cervical cancer was significantly higher than that in HSIL (χ2 = 8.346, P = 0.004), whereas DKK2 methylation in HSIL was significantly higher than that in normal cervical samples (χ2 = 7.934, P = 0.005) and in LSIL samples (χ2 = 4.375, P = 0.037). DKK2 silencing caused by its promoter hypermethylation was confirmed by treatment with the methyltransferase inhibitor 5-Aza-dC in cell lines. Patients with lymph node metastasis exhibited increased promoter methylation frequency (χ2 = 5.239, P = 0.022) and low DKK2 mRNA expression (χ2 = 3.958, P = 0.047) compared with patients with no lymph node metastasis. Patients with high-risk human papillomavirus infection exhibited increased promoter methylation frequency (χ2 = 6.279, P = 0.015). DKK2 epigenetic changes of DKK2 may play a key role in the development of cervical cancer, suggesting that DKK2 hypermethylation could be used as a triage test for screening, early diagnosis, or risk prediction of cervical cancer.

Identification of potential biomarkers for early detection of nephrotic changes in type 2 diabetic patients

Introduction: Diabetes mellitus (DM) is one of the most common endocrine disorders affecting almost 6% of the world’s population. This chronic metabolic disorder affects the metabolism of carbohydrates, protein, fat, water, and electrolytes, leading to structural changes in tissues of many organ systems in the body, especially those of the vascular system. Nephropathy is a major cause of morbidity and mortality in patients with diabetes mellitus. Persistent albuminuria is the hallmark of diabetic nephropathy. Materials and methods: This is a prospective study carried out in the Department of Biochemistry at Index Medical College, Hospital and Research center, among the people attending the OP/IP departments, based on random selection. Informed consent was taken from the patients. Institutional Ethical Clearance Certificate was obtained. Type 2 diabetic patients with age group of 40 years and above are included in the study. Patients were considered to be diabetic based on WHO criteria for diagnosis of diabetes mellitus. Results In Table 3, the mean fasting blood glucose level in Group A was 131.71 ±12.04 mg/dl, in Group B was 148.29±13.06 mg/dl and in Group C was 161.92±15.11 mg/dl.

Differential Methylation Profile in Fragile X Syndrome-Prone Offspring Mice after in Utero Exposure to Lactobacillus Reuteri

Environmental factors such as diet, gut microbiota, and infections have proven to have a significant role in epigenetic modifications. It is known that epigenetic modifications may cause behavioral and neuronal changes observed in neurodevelopmental disabilities, including fragile X syndrome (FXS) and autism (ASD). Probiotics are live microorganisms that provide health benefits when consumed, and in some cases are shown to decrease the chance of developing neurological disorders. Here, we examined the epigenetic outcomes in offspring mice after feeding of a probiotic organism, Lactobacillus reuteri (L. reuteri), to pregnant mother animals. In this study, we tested a cohort of Western diet-fed descendant mice exhibiting a high frequency of behavioral features and lower FMRP protein expression similar to what is observed in FXS in humans (described in a companion manuscript in this same GENES special topic issue). By investigating 17,735 CpG sites spanning the whole mouse genome, we characterized the epigenetic profile in two cohorts of mice descended from mothers treated and non-treated with L. reuteri to determine the effect of prenatal probiotic exposure on the prevention of FXS-like symptoms. We found several genes involved in different neurological pathways being differentially methylated (p ≤ 0.05) between the cohorts. Among the key functions, synaptogenesis, neurogenesis, synaptic modulation, synaptic transmission, reelin signaling pathway, promotion of specification and maturation of neurons, and long-term potentiation were observed. The results of this study are relevant as they could lead to a better understanding of the pathways involved in these disorders, to novel therapeutics approaches, and to the identification of potential biomarkers for early detection of these conditions.

Abstract 3386: Detection of TGFbR2 frameshift mutation

Abstract TGFβR2 a10→a9 frameshift mutation is an early occurring cancer driver mutation and mutant TGFβR2 cell free DNA (cfDNA) is therefore a potential biomarker for early detection of cancer (E.G. Lynch Syndrome) as well as for monitoring response to cancer treatment. The frameshift mutation is associated with micro satellite instability (MSI) and is found in 80% of MSI-colorectal cancers (MSI-CRC) and in over 90% of hereditary nonpolyposis colorectal cancer. Here we show that cell free mutant (a9) TGFβR2 DNA is present in liquid biopsies from MSI-CRC patients and that the a9 micro satellite of mutant TGFβR2 can be selectively detected by using specially designed PCR primers modelled after the a9 microsatellite. PCR and primers defining a fragment of TGFβR2 comprising the a10/a9 microsatellite was used to amplify cfDNA extracted from MSI-CRC and microsatellite stable-CRC (MSS-CRC) patients. The resulting PCR products were analysed and confirmed by DNA sequencing after gel electrophoresis. In addition, primers modelled after the shorter a9 microsatellite was designed and tested using synthetic DNA of both TGFβR2 variants. Despite the naturally established mismatch between the a10 sequence and primers modelled after the a9 sequence, conventionally designed primers could not differentiate enough for specific annealing to the a9 sequence. A further mismatch with the a10 sequence was introduced at the 3’ end of the primer, which, in combination with the already established mismatch, denied the primer tail-end annellation with the a10 sequence that is necessary for polymerase amplification of this sequence. Experiments to optimise PCR conditions and buffer solution were conducted prior to analysing the cfDNA extracted from the patient samples. It was found that TGFβR2 DNA was present in cfDNA from all (10/10) CRC patients tested and that TGFβR2 a10→a9 frameshift was present in all (5/5) MSI-CRC patients and none (0/5) of MSS-CRC patients tested, shown by sequencing. PCR using the selected a9 modelled primer yielded a PCR product that was clearly detectable on the electrophoresis gel only for cfDNA from the MSI-CRC patients (5/5). The results show that TGFβR2 a10→a9 frameshift DNA is present in cfDNA of liquid biopsies from MSI-CRC patients which establishes cell free TFGβR2 frameshift DNA as a potential biomarker for early detection of hereditary CRC (Lynch Syndrome) as well as for monitoring cancer progression and remission of sporadic MSI-CRC. Citation Format: Henrik K. Eriksen, Jon A. Eriksen. Detection of TGFbR2 frameshift mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3386.

Screening of Biomarkers and Toxicity Mechanisms of Rifampicin-Induced Liver Injury Based on Targeted Bile Acid Metabolomics.

Rifampicin (RIF) is a critical first-line drug for tuberculosis. However, long-term or high-dose treatment with RIF can induce severe liver injury; the underlying mechanism of this effect has not yet been clarified. This study was performed to screen reliable and sensitive biomarkers in serum bile acids (BAs) using targeted BA metabolomics and evaluate the toxicity mechanisms underlying RIF-induced liver injury through the farnesoid x receptor (Fxr)-multidrug resistance-associated proteins (Mrps) signaling pathway. Thirty-two Institute of Cancer Research mice were randomly divided into four groups, and normal saline, isoniazid 75 mg/kg + RIF 177 mg/kg (RIF-L), RIF-L, or RIF 442.5 mg/kg (RIF-H) was orally administered by gavage for 21 days. After treatment, changes in serum biochemical parameters, hepatic pathological conditions, BA levels, Fxr expression, and BA transporter levels were measured. RIF caused notable liver injury and increased serum cholic acid (CA) levels. Decline in the serum secondary BAs (deoxycholic acid, lithocholic acid, taurodeoxycholic acid, and tauroursodeoxycholic acid) levels led to liver injury in mice. Serum BAs were subjected to metabolomic assessment using partial least squares discriminant and receiver operating characteristic curve analyses. CA, DCA, LCA, TDCA, and TUDCA are potential biomarkers for early detection of RIF-induced liver injury. Furthermore, RIF-H reduced hepatic BA levels and elevated serum BA levels by suppressing the expression of Fxr and Mrp2 messenger ribonucleic acid (mRNA) while inducing that of Mrp3 and Mrp4 mRNAs. These findings provide evidence for screening additional biomarkers based on targeted BA metabolomics and provide further insights into the pathogenesis of RIF-induced liver injury.

Differences in the gut microbiome and reduced fecal butyrate in elders with low skeletal muscle mass

Despite animal studies revealing a causal link between the gut microbiota and skeletal muscle mass, the role of the gut microbiome and its metabolites in humans having low muscle mass remains unclear. Eighty-eight subjects older than 65 years were measured for sarcopenia-related parameters, including body composition, grip strength, gait speed and flexibility. Participants were divided into normal muscle mass group (NM, n=52) and low muscle mass group (LM, n=36) and fresh fecal samples were collected for metagenome and short chain fatty acids (SCFAs) analysis. The richness and evenness of gut microbiota diversity were significantly decreased in the subjects with low muscle mass, including observed ASVs, Shannon and Chao 1 index. A significant difference of gut microbiota profile was noted between NM group and LM group. The Firmicutes/Bacteroidetes ratio was significantly reduced in the LM group. A significant decrease in the abundance of a SCFA-producer, Marvinbryantia spp., whereas a remarkable enrichment of a flavonoid degrader, Flavonifractor spp., was observed in the LM elders. Comparing with the NM group, the fecal butyrate significantly diminished in the LM group and correlated with skeletal muscle mass index. This is the first study that demonstrates the reduced fecal butyrate in elders with low muscle mass and highlights the associated gut microbiome changes. The identified gut microbial features and fecal butyrate level may serve as potential biomarkers for early detection of sarcopenic patients.

Fatty acids of erythrocyte membranes and blood serum as biomarkers for early detection of colorectal cancer

The aim of the study was to identify fatty acids (FA) of erythrocyte membranes and blood serum, which can serve as potential biomarkers for early detection of colorectal cancer.Material and methods. the study involved 65 patients with stage I-II CRC (mean age 63,3 ± 9,6 years (30 men, 35 women) and 35 people in the comparison group, matched by age and sex. the composition of fatty acids of erythrocyte membranes and blood serum was studied using a gc/ms system based on three agilent 7000B quadrupoles (USA). methods of the MATLAB software (R2019a, MathWorks) and the R programming language were used for statistical processing: t-test, unsupervised principal component analysis (PCA), Fold change, Volcano plot, machine learning method (Random Forest), Roc analysis, Heatmaps.Results. patients with stage I-II CRC showed a decrease in the level of saturated, individual monounsaturated fatty acids and a highly significant increase in the most of the polyunsaturated fatty acids with a predominance of omega-3. For most of the fatty acid levels, significant differences in erythrocyte membranes and serum between the groups were found. the levels of erythrocyte myristic, pentadecanoic, 7-palmitoleic, saturated/polyunsaturated Fa ratios (the content of which was significantly lower at stages I-II CRC than those in the control) and the levels of α-linolenic, eicosapentaenoic, docosapentaenoic, docosahexaenoic, the amount of omega-3 Fa, EPA + DHA, docodienic, dihomo-γ-linolenic, docatetraenoic fatty acids (the content of which was significantly higher in colorectal cancer than those in healthy subjects) were the most discriminating parameters in distinguishing patients with I-II stage CRC and healthy individuals. in the blood serum, the level of biomarkers had the following fatty acids: arachidonic, myristic, docosahexaenoic, the amount of omega 3 puFa, the ratio of omega 6/omega 3 puFa, pentadecanoic, docosapentaenoic, and docodiene. a model that included a list of fatty acids, such as С14:0, С15:0, С16:1;7, С18:3 n-3, C20:2 n-6, C20:3 n-6, C20:5 n-3, C22:4 n-6, C22:5 n-3, C22:6 n-3, sum of omega-3, omega-3 (EPA + DHA), and saturated / polyunsaturated fatty acids ratio provided auc 0,916 with a specificity of 0,90 and sensitivity of 0,95 in distinguishing patients with stage I-II CRC from healthy individuals.Conclusion. the study of the levels and ratios of fatty acids in erythrocyte membranes and blood serum should be considered a promising trend in the search for biomarkers for the early diagnosis of colorectal cancer.

Investigating the Molecular and Phenotypic Differences in Pancreatic Neuroendocrine Tumor (PanNET) Cells with Functional Loss of Either ATRX or DAXX

Telomeres are hexameric DNA repeats at the ends of linear chromosomes that protect genomic integrity. Telomeres shorten after each cell division until a critically shortened length is reached, whereby the cell enters a state of cellular senescence. Cancer cells must overcome this replicative barrier by either upregulating the enzyme telomerase or by using the Alternative Lengthening of Telomeres (ALT) pathway, which uses homology‐directed repair to maintain telomere lengths. ALT is present in ~10% of cancers, yet the exact underlying mechanisms are still being elucidated. However, two known drivers of ALT are loss of function mutations in either ATRX or DAXX, genes that encode a chromatin remodeling complex. Mutations in these genes were initially identified and linked to ALT in pancreatic neuroendocrine tumors (PanNETs), which are the second most common malignancy of the pancreas. This study evaluated the molecular and phenotypic differences between parental PanNET cells (BON1 and QGP1) and isogenic clones with either ATRX or DAXX knocked out via CRISPR‐Cas9 gene editing. The matched parental and isogenic clones were assessed for cell proliferation (MTS assay), clonogenic survival (colony formation assay), and invasion potential (Matrigel invasion assay). Preliminary results for QGP1 cells indicate that the ATRXKO clones show decreased proliferation and colony formation, as well as alterations in invasion potential compared to the parental cell line, thereby suggesting that functional loss of ATRX alters these phenotypic properties. Future studies will help to contribute to the ongoing efforts to understand the underlying mechanisms of ALT and work towards the overall goal of identifying potential biomarkers for early detection, prognosis, and targeted therapies for ALT‐positive cancers.

A wrapper-based feature selection approach to investigate potential biomarkers for early detection of breast cancer

Breast cancer (BC) biomarkers can radically improve the early detection in patients and, as a result, reduce mortality rate, whether for detecting individuals at increased risk of developing cancer or in the screening process. Finding a successful biomarker for breast cancer would be a fast and low-cost first solution to predicting BC, and it could potentially lead to a decline in the global BC mortality rate. However, biomarker exploration translates into the role of feature ranking and selection in machine learning terminology. This study explores the influence of using a particular biomarker or combinations of different biomarkers as predictors for breast cancer. Three different classification algorithms were integrated with a sequential backward selection model: support vector machine (SVM), random forests (RF), and Decision Trees (DTs). The result shows that the optimal set of biomarkers comprises Glucose, Resistin, homo, BMI, and Age using the SVM model. The sensitivity and specificity were 0.94 and 0.90, respectively and the 95% confidence interval for the AUC was [0.89, 0.98]. The result indicates that Glucose, Resistin, homo, BMI, and Age combined can serve as a crucial BC biomarker in BC screening and detection.

PKC is an indispensable factor in promoting environmental toxin chromium-mediated transformation and drug resistance

Hexavalent chromium [Cr(VI)] pollution is a serious environmental problem, due to not only its toxicity but also carcinogenesis. Although studies reveal several features of Cr(VI)-induced carcinogenesis, the underlying mechanisms of how Cr(VI) orchestrates multiple mitogenic pathways to promote tumor initiation and progression remain not fully understood. Src/Ras and other growth-related pathways are shown to be key players in Cr(VI)-initiated tumor prone actions. The role of protein kinase C (PKC, an important signal transducer) in Cr(VI)-mediated carcinogenesis has not been thoroughly investigated. In this study, using human bronchial/lung epithelial cells and keratinocytes, we demonstrate that PKC activity is increased by transient or chronic Cr(VI) exposure, which plays no role in the activation of Src/Ras signaling and ROS upregulation by this metal toxin. PKC in chronic Cr(VI)-treated cells stabilizes Bcl-2 to mitigate doxorubicin (an anti-cancer drug)-mediated apoptosis. After the suppression of this kinase by GO6976 (a PKC inhibitor), the cells chronically exposed to Cr(VI) partially regain the sensitivity to doxorubicin. However, when co-suppressed PKC and Ras, the chronic Cr(VI)-treated cells become fully responsive to doxorubicin and are unable to be transformed. Taken together, our study provides a new insight into the mechanisms, in which PKC is an indispensable player and cooperates with other mitogenic pathways to achieve Cr(VI)-induced carcinogenesis as well as to establish drug resistance. The data also suggest that active PKC can serve as a potential biomarker for early detection of health damages by Cr(VI) and therapeutic target for developing new treatments for diseases caused by Cr(VI).

Characterization of alpha-1-acid glycoprotein as a potential biomarker for breast cancer

ABSTRACT Breast cancer is a malignant tumor that poses a serious threat to the health of women worldwide. The early diagnosis of patients with cancer or those at high risk remains difficult, which makes treatment challenging. Therefore, the study of diagnostic biomarkers for early detection of cancer is very important. AGP biomarkers are expected to be potential biomarkers for early detection of breast cancer. This study aimed to explore the potential of alpha-1-acid glycoprotein (AGP) as a biomarker for the diagnosis of breast cancer. The results revealed that the expression of AGP was high in breast cancer cells and tissues and was higher at stage IV than at stages III and II. Knockdown of ORM1, which encodes AGP, in MCF-7 cells suppressed the production of the inflammatory factors interleukin (IL)-1β, IL-8, and tumor necrosis factor-α. These results suggest that AGP can serve as a therapeutic target and/or diagnostic marker for breast cancer. Overall, we found that AGP can serve as a biomarker for breast cancer and inhibit secretion of related pro-inflammatory facto by blocking ORM1 expression.

A0241 - Urine cellular DNA point mutation and methylation as potential biomarkers for early detection of urothelial carcinoma

A0241 - Urine cellular DNA point mutation and methylation as potential biomarkers for early detection of urothelial carcinoma

The Utility of Serum Vasorin Levels as a Novel Potential Biomarker for Early Detection of Colon Cancer.

ObjectiveThe objective of this study was to investigate the utility of vasorin, a newly discovered transmembrane protein, as a novel biomarker in the early detection of colon cancer.MethodsA total of 80 patients aged 55-70 years, diagnosed with colon cancer and followed up in our clinics, and 50 healthy volunteer blood donors were included in the study. Participants' demographics such as age, gender, and vasorin levels were recorded and compared between the patient and control groups. In addition, primary tumor status (pT) values N and T stages of the tumors were studied in the patient group. All patients included in the study were pathologically confirmed by colonoscopy plus biopsy and postoperative histopathologic examination.ResultsThe mean age was found as 64.59±3.70 (min-max: 55-70) years old in the patient group and 63.56±3.07 (min-max: 57-70) years. There was no statistically significant difference between both groups regarding demographics (p>0.05). Serum Vasorin levels were higher in patients with colon cancer than in the control group (p<0.001). Serum Vasorin levels were higher among patients with advanced disease and related to the clinical stage of the locally advanced tumor. ConclusionOur findings revealed that serum vasorin levels are upregulated in patients with colon cancer. Raised vasorin levels may be a non-invasive biomarker beneficial for early detection and prediction of colon cancer prognosis. In addition, vasorin levels further rose as the disease advanced to higher TNM (tumor (T), nodes (N), and metastases (M)) stages. Further comprehensive studies are needed to draw more evident conclusions and generalize our results.

Serum C18:1-Cer as a Potential Biomarker for Early Detection of Gestational Diabetes.

We hypothesized that sphingolipids may be early biomarkers of gestational diabetes mellitus (GDM). Here, 520 women with normal fasting plasma glucose levels were recruited in the first trimester and tested with a 75 g oral glucose tolerance test in the 24th–28th week of pregnancy. Serum sphingolipids concentrations were measured in the first and the second trimester by ultra-high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC/MS/MS) in 53 patients who were diagnosed with GDM, as well as 82 pregnant women with normal glucose tolerance (NGT) and 32 non-pregnant women. In the first trimester, pregnant women showed higher concentrations of C16:0, C18:1, C22:0, C24:1, and C24:0-Cer and lower levels of sphinganine (SPA) and sphingosine-1-phosphate (S1P) compared to non-pregnant women. During pregnancy, we observed significant changes in C16:0, C18:0, C18:1, and C24:1-Cer levels in the GDM group and C18:1 and C24:0-Cer in NGT. The GDM (pre-conversion) and NGT groups in the first trimester differed solely in the levels of C18:1-Cer (AUC = 0.702 p = 0.008), also considering glycemia. Thus, C18:1-Cer revealed its potential as a GDM biomarker. Sphingolipids are known to be a modulator of insulin resistance, and our results indicate that ceramide measurements in early pregnancy may help with GDM screening.

Decreased Choroidal Blood Perfusion Induces Myopia in Guinea Pigs.

PurposeThe development of myopia in guinea pigs can be inhibited by attenuating scleral hypoxia by increasing choroidal blood perfusion (ChBP). In this study, we reduced ChBP through surgical and pharmacological methods to determine the effect on myopia development. We also determined whether ChBP was reduced by quinpirole, a drug that enhances form-deprivation myopia (FDM).MethodsChBP was reduced in the right eyes of guinea pigs via transection of the temporal ciliary arteries or daily injections of phenylephrine into the inferior peribulbar space for one week during normal ocular growth. Other guinea pigs were subjected to two weeks of monocular FDM—with facemasks, along with daily injections of quinpirole, a dopamine D2 receptor agonist, to enhance the FDM. Changes in refraction, axial length, ChBP, and choroidal thickness (ChT) were measured in both treated and fellow eyes of the treatment and control groups. Scleral hypoxia labeling with pimonidazole adducts and α-smooth muscle actin (α-SMA) protein were also measured.ResultsSurgical and pharmacological reduction of ChBP induced myopia development in the treated eyes. These treatments rendered the scleral hypoxia and increased scleral α-SMA expression. Furthermore, quinpirole injections, which increased the magnitude of myopia, augmented the FDM-associated reductions in ChBP and ChT and increased the levels of scleral hypoxia and α-SMA protein.ConclusionsDecreased ChBP in guinea pigs leads to scleral hypoxia and scleral myofibroblast transdifferentiation with increased α-SMA expression, ultimately resulting in myopia development. In future clinical trials, ChBP reduction can serve as a potential biomarker for early detection of myopia development.