Potential Biomarkers For Early Detection Research Articles

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.

Detection of increased serum miR-122-5p and miR-455-3p levels before the clinical diagnosis of liver cancer in people with type 2 diabetes

People with type 2 diabetes (T2D) have increased cancer risk. Liver cancer (LC) has a high prevalence in East Asia and is one of the leading causes of cancer death globally. Diagnosis of LC at early stage carries good prognosis. We used stored serum from patients of Hong Kong Diabetes Register before cancer diagnosis to extract RNA to screen for microRNA markers for early detection of LC in T2D. After screening with Affymetrix GeneChip microarray with serum RNA from 19 incident T2D LC (T2D-LC), 20 T2D cancer free (T2D-CF) and 20 non-T2D non-cancer patients, top signals were validated in a 3-group comparison including 1888 T2D-CF, 127 T2D-LC, and 487 T2D patients with non-liver cancer patients using qPCR. We detected 2.55-fold increase in miR-122-5p and 9.21-fold increase in miR-455-3p in the T2D-LC group. Using ROC analysis, miR-122-5p and miR-455-3p jointly predicted LC with an area under the curve of 0.770. After adjustment for confounders, each unit increase of miR-455-3p increased the odds ratio for liver cancer by 1.022. Increased serum levels of miR-122-5p and miR-455-3p were independently associated with increased risk of incident LC in T2D and may serve as potential biomarkers for early detection of LC in T2D.

Association of ergothioneine with neurodegeneration and cerebrovascular disease in cognitive impairment and dementia

AbstractBackgroundErgothioneine (ET) is a dietary amino‐thione with strong antioxidant properties and therapeutic potential for neurodegenerative and vascular diseases (Halliwell et al., 2018; Smith et al., 2020). Decreased blood concentrations of ET have been found in patients with mild cognitive impairment (Cheah et al., 2016), but its status in neurodegenerative and vascular dementias are currently unclear. We thus investigated the association of plasma ET levels with (1) cognitive impairment and dementia, (2) cerebrovascular disease (CeVD), namely white matter hyperintensities (WMH), cortical infarcts and lacunes and (3) brain atrophy.MethodA cross‐sectional study was conducted in a total of 496 participants in an ongoing longitudinal study, including 88 subjects with no cognitive impairment (NCI), 201 subjects with cognitive impairment but no dementia (CIND), 207 dementia patients of whom 160 had Alzheimer’s Disease and 47 vascular dementia (VaD). All subjects underwent collection of blood samples, neuropsychological assessment, and neuroimaging. Plasma ET levels were measured with a high sensitivity liquid chromatography tandem‐mass spectrometry (LC‐MS/MS) method.ResultPlasma ET concentrations were lowest in dementia (p&lt;0.001 vs. NCI and CIND), with intermediate levels in CIND (p&lt;0.001 vs. NCI). In multivariate analyses, lower levels of ET were significantly associated with CIND (OR, 0.20; 95% CI, 0.07–0.56; p&lt;0.01) and dementia (OR, 0.06; 95% CI, 0.02–0.20; p&lt;0.001) after adjustment for demographics and risk factors. There was a positive correlation between plasma ET and MMSE scores (r=0.341, p&lt;0.001). Lower ET levels were also strongly associated with WMH (OR, 0.44; 95% CI, 0.123–0.85); p&lt;0.01) and brain atrophy markers (cortical atrophy: OR, 0.42; 95% CI, 0.20–0.92; central atrophy: OR, 0.46; 95% CI, 0.22–0.93; medial temporal atrophy: OR, 0.45; 95% CI, 0.24–0.99, p&lt;0.05 for all).ConclusionThe incremental decreases in ET levels along the clinical continuum suggest that ET may be associated with disease severity and is a potential biomarker for early detection of cognitive impairment. Deficiency of ET may contribute towards neurodegeneration‐ and CeVD‐associated cognitive impairments by exacerbating the deleterious effects of oxidative stress in these conditions.

Plasma extracellular vesicle long RNA profiles in the diagnosis and prediction of treatment response for breast cancer

A large number RNAs are enriched and stable in extracellular vesicles (EVs), and they can reflect their tissue origins and are suitable as liquid biopsy markers for cancer diagnosis and treatment efficacy prediction. In this study, we used extracellular vesicle long RNA (exLR) sequencing to characterize the plasma-derived exLRs from 112 breast cancer patients, 19 benign patients and 41 healthy participants. The different exLRs profiling was found between the breast cancer and non-cancer groups. Thus, we constructed a breast cancer diagnostic signature which showed high accuracy with an area under the curve (AUC) of 0.960 in the training cohort and 0.900 in the validation cohort. The signature was able to identify early stage BC (I/II) with an AUC of 0.940. Integrating the signature with breast imaging could increase the diagnosis accuracy for breast cancer patients. Moreover, we enrolled 58 patients who received neoadjuvant treatment and identified an exLR (exMSMO1), which could distinguish pathological complete response (pCR) patients from non-pCR with an AUC of 0.790. Silencing MSMO1 could significantly enhance the sensitivity of MDA-MB-231 cells to paclitaxel and doxorubicin through modulating mTORC1 signaling pathway. This study demonstrated the value of exLR profiling to provide potential biomarkers for early detection and treatment efficacy prediction of breast cancer.

Plasma-Derived Extracellular Vesicles Reveal Galectin-3 Binding Protein as Potential Biomarker for Early Detection of Glioma.

Gliomas are the most common type of the malignant brain tumor, which arise from glial cells. They make up about 40% of all primary brain tumors and around 70% of all primary malignant brain tumors. They can occur anywhere in the central nervous system (CNS) and have a poor prognosis. The average survival of glioma patients is approximately 6–15 months with poor aspects of life. In this edge, identification of proteins secreted by cancer cells is of special interest because it may provide a better understanding of tumor progression and provide early diagnosis of the diseases. Extracellular vesicles (EVs) were isolated from pooled plasma of healthy controls (n=03) and patients with different grades of glioma (Grade I or II or III, n=03 each). Nanoparticle tracking analysis, western blot, and flow cytometry were performed to determine the size, morphology, the concentration of glioma-derived vesicles and EV marker, CD63. Further, iTRAQ-based LC-MS/MS analysis of EV protein was performed to determine the differential protein abundance in extracellular vesicles across different glioma grades. We further verified galectin-3 binding protein (LGALS3BP) by ELISA in individual blood plasma and plasma-derived vesicles from control and glioma patients (n=40 each). Analysis by Max Quant identified 123 proteins from the pooled patient exosomes, out of which 34, 21, and 14 proteins were found to be differentially abundant by more than 1.3-fold in the different grades of glioma grade I, pilocytic astrocytoma; grade II, diffuse astrocytoma; grade III, anaplastic astrocytoma, respectively, in comparison with the control samples. A total of seven proteins—namely, CRP, SAA2, SERPINA3, SAA1, C4A, LV211, and KV112—showed differential abundance in all the three grades. LGALS3BP was seen to be upregulated across the different grades, and ELISA analysis from individual blood plasma and plasma-derived extracellular vesicles confirmed the increased expression of LGALS3BP in glioma patients (p<0.001). The present study provides LGALS3BP as a potential biomarker for early detection of glioma and improve survival outcome of the patient. The present study further provides the information of progression and monitoring the tumor grades (grade 1, grade II, grade III).

Knocking down Sterol regulatory element binding protein 2 (SREBF2) inhibits the Serine Protease 8 (PRSS8) /sodium channel epithelial 1alpha subunit (SCNN1A) axis to reduce the cell proliferation, migration and epithelial-mesenchymal transformation of ovarian cancer

ABSTRACT The pathogenesis of ovarian cancer (OC) is complex. Serine Protease 8 (PRSS8) is a potential biomarker for early detection of OC. Multiple databases were used to predict the expression of PRSS8, Sterol regulatory element binding protein (SREBP) and sodium channel epithelial 1alpha subunit (SCNN1A) in OC patients and to detect the relationship among the three. The expressions of PRSS8, SREBF2, SCNN1A and related factors of the pathway were detected by RT-qPCR and Western blot. The cell transfection was used to overexpress or inhibit the expression of PRSS8 and SREBF2, so as to explore its mechanism. MTT assay and Colony formation assay were used to detect cell proliferation. The Transwell and Wound Healing assays were utilized to measure cell invasion and migration. We have further confirmed cell-level studies in animals. We found that PRSS8 expression was up-regulated in OC patients and cell lines. Knocking down PRSS8 reduced the proliferation, migration and epithelial-mesenchymal transition (EMT) of OC cells, which was realized by SREBF2 transcriptional regulation. Knocking down SREBF2 reduced PRSS8 and then inhibited the expression of SCNN1A, thus affecting the proliferation, migration and EMT of OC cells. These results also applied to animals experiments. In conclusion, SREBF2 activates the PRSS8/SCNN1A axis to accelerate cell proliferation, migration and EMT of OC.

Association of Plasma Branched-Chain and Aromatic Amino Acids with Reduction in Kidney Function Evaluated in Apparently Healthy Adults.

The published literature on the association of circulatory branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) with reduced kidney function is inconsistent or conflicting. Clarification of it might help to better understand the underlying pathophysiology and to determine potential biomarkers for early detection and evaluation of kidney function decline. Our main purpose was to explore and clarify the potential relationships of individual BCAAs and AAAs with estimated glomerular filtration rate (eGFR) decline. We included the data from 2804 healthy subjects and categorized them into three groups based on eGFR tertiles. The associations between individual amino acids and eGFR were explored by covariate-adjusted logistic regression models. There was a progressive increase in the concentrations of BCAAs and AAAs from the upper to the lower tertiles. We revealed significant positive associations of isoleucine, leucine, and phenylalanine with lower tertiles of eGFR in the adjusted models (p < 0.01–0.001). The findings hold a promising potential of using plasma isoleucine, leucine, and phenylalanine levels for evaluation of kidney function decline. Future longitudinal studies should investigate the causal association between altered levels of these amino acids and impaired kidney function and also the utility of the former as potential biomarkers for evaluating the risk and early detection of the latter.

Lung cancer-associated T cell repertoire as potential biomarker for early detection of stage I lung cancer

BackgroundEarly detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer. MethodsIndividuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs). ResultsA total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96). ConclusionThis work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.

High leukotriene B4 serum levels increase risk of painful diabetic neuropathy among type 2 diabetes mellitus patients

BackgroundPainful diabetic neuropathy is one of the most common complications of type 2 diabetes mellitus, with approximately 30–50% of people will experience diabetic neuropathy. Chronic hyperglycemia will cause an inflammatory process that will trigger an immune response included leukotrienes. Leukotriene B4 is associated with hemoglobin glycation levels. This study aimed to determine high serum leukotriene B4 levels and other factors as a risk factor for painful diabetic neuropathy in type 2 diabetes mellitus patient.ResultsForty-two subjects with 22 cases (median age 56.5 ± 4.9 years) and 20 controls (median age 56.5 ± 5.2 years) group were collected. In bivariate analysis, significant factor for high risk PDN was high leukotriene B4 serum level (OR 5.10; 95% CI 1.34–19.4, p 0.014). Meanwhile, insignificant factors were anti-diabetic drugs (OR 2.139; 0.62–7.37; p = 0.226), and duration of diabetes mellitus (OR 2.282; 0.56–9.25; p = 0.315). Independent risk factor was serum leukotriene B4 levels (OR 5.10; 95% CI 1.336–19.470; p = 0.017).ConclusionsIn this study, high leukotriene B4 serum levels increase the risk of painful diabetic neuropathy among type 2 diabetes mellitus. The leukotriene B4 may consider as a potential biomarker for early detection in high risk for PDN and early treatment.

Quantitative Analysis of Methylated Adenosine Modifications Revealed Increased Levels of N 6-Methyladenosine (m6A) and N 6,2'-O-Dimethyladenosine (m6Am) in Serum From Colorectal Cancer and Gastric Cancer Patients.

Colorectal cancer and gastric cancer are the most prevalent gastrointestinal malignancies worldwide, and early detection of these cancers is crucial to reduce their incidence and mortality. RNA methylation plays an important regulatory role in a variety of physiological activities, and it has drawn great attention in recent years. Methylated adenosine (A) modifications such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), 2′-O-methyladenosine (Am), N6,2′-O-dimethyladenosine (m6Am), and N6,N6-dimethyladenosine (m62A) are typical epigenetic markers of RNA, and they are closely correlated to various diseases including cancer. Serum is a valuable source of biofluid for biomarker discovery, and determination of these adenosine modifications in human serum is desirable since they are emerging biomarkers for detection of diseases. In this work, a targeted quantitative analysis method using hydrophilic interaction liquid chromatography–tandem mass spectrometry (HILIC-MS/MS) was developed and utilized to analyze these methylated adenosine modifications in serum samples. The concentration differences between the healthy volunteers and cancer patients were evaluated by Mann–Whitney test, and receiver operator characteristic (ROC) curve analysis was performed to access the potential of these nucleosides as biomarkers. We demonstrated the presence of the m6Am in human serum for the first time, and we successfully quantified the concentrations of A, m6A, m1A, and m6Am in serum samples from 99 healthy controls, 51 colorectal cancer patients, and 27 gastric cancer patients. We found that the levels of m6A and m6Am in serum were both increased in colorectal cancer or gastric cancer patients, compared to that in healthy controls. These results indicate that m6A and m6Am in serum may act as potential biomarkers for early detection and prognosis of colorectal cancer and gastric cancer. In addition, the present work will stimulate investigations on the effects of adenosine methylation on the initiation and progression of colorectal cancer and gastric cancer.

RNA binding protein CUGBP1 mediates the liver metastasis of colorectal cancer by regulating the ErbB signal pathway.

BackgroundThe CUGBP1 (CELF1) is differentially expressed in liver metastasis and no liver metastasis colorectal cancers (CRC) tissues and the function of CUGBP1 in CRC is still unclear.MethodsFive cases of colorectal adenocarcinoma and 6 cases of liver metastatic CRC lesions were collected and subjected to cDNA microarray and bioinformatical analyses. The quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to confirm the result. Cell function assays were used to study the function of CUGBP1, and the western blot was used to discover the change of the downstream molecules.ResultsCUGBP1 was significantly elevated in liver metastatic CRC lesions. Besides, the CUGBP1 can promote proliferation, colony formation, invasion, metastasis abilities as well as increase the apoptosis rates of CRC cells. ERBB2 was positively related to the CUGBP1. Western blot results found that silence of CUGBP1 decreased the protein level of p-AKT and p-ERK without influence the expression level of total protein of AKT and ERK.ConclusionsCUGBP1 can promote liver metastasis of CRC by promoting the phosphorylation of AKT and ERK through the ErbB signaling pathway. CUGBP1 is a potential biomarker for early detection of CRC and maybe a novel therapeutic target of CRC treatment, especially in liver metastasis.

Identification of Early Diagnostic and Prognostic Biomarkers via WGCNA in Stomach Adenocarcinoma.

Stomach adenocarcinoma (STAD) is a leading cause of cancer deaths, and the outcome of the patients remains dismal for the lack of effective biomarkers of early detection. Recent studies have elucidated the landscape of genomic alterations of gastric cancer and reveal some biomarkers of advanced-stage gastric cancer, however, information about early-stage biomarkers is limited. Here, we adopt Weighted Gene Co-expression Network Analysis (WGCNA) to screen potential biomarkers for early-stage STAD using RNA-Seq and clinical data from TCGA database. We find six gene clusters (or modules) are significantly correlated with the stage-I STADs. Among these, five hub genes, i.e., MS4A1, THBS2, VCAN, PDGFRB, and KCNA3 are identified and significantly de-regulated in the stage-I STADs compared with the normal stomach gland tissues, which suggests they can serve as potential early diagnostic biomarkers. Moreover, we show that high expression of VCAN and PDGFRB is associated with poor prognosis of STAD. VCAN encodes a large chondroitin sulfate proteoglycan that is the main component of the extracellular matrix, and PDGFRB encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor (PDGF) family. Consistently, Gene Ontology (GO) analysis of differentially expressed genes in the STADs indicates terms associated with extracellular matrix and receptor ligand activity are significantly enriched. Protein-protein network interaction analysis (PPI) and Gene Set Enrichment Analysis (GSEA) further support the core role of VCAN and PDGFRB in the tumorigenesis. Collectively, our study identifies the potential biomarkers for early detection and prognosis of STAD.

Urinary malate dehydrogenase 2 is a new biomarker for early detection of non-small-cell lung cancer.

Reliable and noninvasive biomarkers for the early diagnosis of non‐small‐cell lung cancer (NSCLC) are an unmet need. This study aimed to screen and validate potential urinary biomarkers for the early diagnosis of NSCLC. Using protein mass spectrometry, urinary MDH2 was found to be abundant both in patients with lung cancer and lung cancer model mice compared with controls. Urine samples obtained as retrospective and prospective cohorts including 1091 NSCLC patients and 736 healthy controls were measured using ELISA. Patients with stage I NSCLC had higher urinary MDH2 compared with healthy controls. The area under the receiver‐operating characteristic curve (AUC) for the urinary MDH2 was 0.7679 and 0.7234 in retrospective and prospective cohorts to distinguish stage I cases from controls. Urinary MDH2 levels correlated with gender and smoking history. MDH2 expression levels were elevated in lung cancer tissues. MDH2 knockdown using shRNA inhibited the proliferation of lung cancer cells. Our study demonstrated that urinary MDH2 concentration was higher in early‐stage NSCLC patients compared with that in controls and that MDH2 could serve as a potential biomarker for early detection of NSCLC.

Volutrauma Increases Exhaled Pentanal in Rats: A Potential Breath Biomarker for Ventilator-Induced Lung Injury.

Mechanical ventilation injures lungs, but there are currently no reliable methods for detecting early injury. We therefore evaluated whether exhaled pentanal, a lipid peroxidation product, might be a useful breath biomarker for stretch-induced lung injury in rats. A total of 150 male Sprague-Dawley rats were investigated in 2 substudies. The first randomly assigned 75 rats to 7 hours of mechanical ventilation at tidal volumes of 6, 8, 12, 16, and 20 mL·kg-1. The second included 75 rats. A reference group was ventilated at a tidal volume of 6 mL·kg-1 for 10 hours 4 interventional groups were ventilated at a tidal volume of 6 mL·kg-1 for 1 hour, and then for 0.5, 1, 2, or 3 hours at a tidal volume of 16 mL.kg-1 before returning to a tidal volume of 6 mL·kg-1 for additional 6 hours. Exhaled pentanal was monitored by multicapillary column-ion mobility spectrometry. The first substudy included cytokine and leukocyte measurements in blood and bronchoalveolar fluid, histological assessment of the proportion of alveolar space, and measurements of myeloperoxidase activity in lung tissue. The second substudy included measurements of pentanal in arterial blood plasma, cytokine and leukocyte concentrations in bronchoalveolar fluid, and cleaved caspase 3 in lung tissue. Exhaled pentanal concentrations increased by only 0.5 ppb·h-1 (95% confidence interval [CI], 0.3-0.6) when rats were ventilated at 6 mL·kg-1. In contrast, exhaled pentanal concentrations increased substantially and roughly linearly at higher tidal volumes, up to 3.1 ppb·h-1 (95% CI, 2.3-3.8) at tidal volumes of 20 mL·kg-1. Exhaled pentanal increased at average rates between 1.0 ppb·h-1 (95% CI, 0.3-1.7) and 2.5 ppb·h-1 (95% CI, 1.4-3.6) after the onset of 16 mL·kg-1 tidal volumes and decreased rapidly by a median of 2 ppb (interquartile range [IQR], 0.9-3.2), corresponding to a 38% (IQR, 31-43) reduction when tidal volume returned to 6 mL·kg-1. Tidal volume, inspiratory pressure, and mechanical power were positively associated with pentanal exhalation. Exhaled and plasma pentanal were uncorrelated. Alveolar space decreased and inflammatory markers in bronchoalveolar lavage fluid increased in animals ventilated at high tidal volumes. Short, intermittent ventilation at high tidal volumes for up to 3 hours increased neither inflammatory markers in bronchoalveolar fluid nor the proportion of cleaved caspase 3 in lung tissue. Exhaled pentanal is a potential biomarker for early detection of ventilator-induced lung injury in rats.