The alcohol dehydrogenase isoenzyme (ADH IV) as a candidate tumour marker of esophageal cancer.

Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are present in esophageal cancer cells. Moreover the total activity of ADH as well as the activity of class IV ADH isoenzyme is significantly higher in cancer tissue than in healthy mucosa. The activity of these enzymes in cancer cells is reflected in the sera and could thus be helpful for diagnostics of esophageal cancer. The aim of this study was to investigate a potential significance of ADH isoenzymes and ALDH as tumour markers of esophageal cancer. We defined diagnostic sensitivity, specificity, predictive value for positive and negative results, and receiver-operating characteristics (ROC) curve for tested enzymes. Serum samples were taken for routine biochemical investigation from 180 patients with esophageal cancer before treatment. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline as a substrate and ALDH activity by a fluorometric method with 6-methoxy-2-naphtaldehyde as a substrate. For the measurement of the activity of class I and II isoenzymes we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was measured by a photometric method with formaldehyde and class IV with m-nitrobenzaldehyde as a substrate. There was a significant increase in the activity of class IV of ADH isoenzyme (7.65 mU/l vs 5.88 mU/l) and total ADH activity (1198 mU/l vs 848 mU/l) in the sera of esophageal cancer patients compared to the control. The diagnostic sensitivity for ADH IV was 72%, the specificity 76%, the positive and negative predictive values were 80% and 72% respectively. The area under the ROC curve for ADH IV was 0.65. The results suggest a potential significance of ADH IV as a marker of esophageal cancer.

Download Full-text

Retinoic acid formation from retinol in the human gastric mucosa: role of class IV alcohol dehydrogenase and its relevance to morphological changes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00502.2004 ◽

2005 ◽

Vol 289 (3) ◽

pp. G429-G433 ◽

Cited By ~ 16

Author(s):

Michinaga Matsumoto ◽

Hirokazu Yokoyama ◽

Hidekazu Suzuki ◽

Haruko Shiraishi-Yokoyama ◽

Toshifumi Hibi

Keyword(s):

Retinoic Acid ◽

Gastric Mucosa ◽

Alcohol Dehydrogenase ◽

Intestinal Metaplasia ◽

Morphological Changes ◽

Acid Formation ◽

Human Gastric Mucosa ◽

Sydney System ◽

Adh Activity ◽

Class Iv

Alcohol dehydrogenase (ADH) participates in the formation of retinoic acid from retinol in various organs including the gastric mucosa. However, its clinical significance still remains to be clarified. In this study, we identified the ADH isoforms responsible for the retinoic acid formation among various ADH isoforms and examined associations among the ADH activities, the retinoic acid formation level, and morphological changes in the human gastric mucosa. Human gastric samples were endoscopically obtained from 67 male subjects. Morphological changes were assessed by the Sydney system and activities of class I, III, and IV ADH isoforms were determined in each specimen. In 26 cases, levels of all- trans retinoic acid (ATRA) formation from all- trans retinol were examined. Among activities of the three ADH isoforms, class IV ADH activity was solely associated with the ATRA formation level. This association was found even when subjects' age and Helicobacter pylori infection status were adjusted. As the degrees of inflammation, atrophy, and intestinal metaplasia increased, the class IV ADH activity as well as the potential for the ATRA formation decreased. Class IV ADH is a major enzyme in the retinoic acid supply in the human gastric mucosa, and the reduction of its activity was associated with decreasing retinoic acid supply and progression of inflammation, atrophy, and intestinal metaplasia in the gastric mucosa. In that retinoic acid is a key molecule for maintaining normal morphology, the reduction of class IV ADH activity may be involved in the pathogenesis of these morphological changes in the human gastric mucosa.

Download Full-text

Diagnostic Ability of Peguero-Lo Presti Electrocardiographic Left Ventricular Hypertrophy Criterion in Severe Aortic Stenosis

Journal of Clinical Medicine ◽

10.3390/jcm10132864 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2864

Author(s):

Aleksandra Gamrat ◽

Katarzyna Trojanowicz ◽

Michał A. Surdacki ◽

Aleksandra Budkiewicz ◽

Adrianna Wąsińska ◽

...

Keyword(s):

Left Ventricular Hypertrophy ◽

Aortic Stenosis ◽

Roc Curve ◽

Ventricular Hypertrophy ◽

Severe Aortic Stenosis ◽

Positive Likelihood Ratio ◽

Left Ventricular ◽

The Novel ◽

Operating Characteristics ◽

Diagnostic Ability

Traditional electrocardiographic (ECG) criteria for left ventricular hypertrophy (LVH), introduced in the pre-echocardiographic era of diagnosis, have a relatively low sensitivity (usually not exceeding 25–40%) in detecting LVH. A novel Peguero-Lo Presti ECG-LVH criterion was recently shown to exhibit a higher sensitivity than the traditional ECG-LVH criteria in hypertension. Our aim was to test the diagnostic ability of the novel Peguero-Lo Presti ECG-LVH criterion in severe aortic stenosis. We retrospectively analyzed 12-lead ECG tracings and echocardiographic records from the index hospitalization of 50 patients with isolated severe aortic stenosis (mean age: 77 ± 10 years; 30 women and 20 men). Exclusion criteria included QRS > 120 ms, bundle branch blocks or left anterior fascicular block, a history of myocardial infarction, more than mild aortic or mitral regurgitation, and significant LV dysfunction by echocardiography. We compared the agreement of the novel Peguero-Lo Presti criterion and traditional ECG-LVH criteria with echocardiographic LVH (LV mass index > 95 g/m2 in women and >115 g/m2 in men). Echocardiographic LVH was found in 32 out of 50 study patients. The sensitivity of the Peguero-Lo Presti criterion in detecting LVH was improved (55% vs. 9–34%) at lower specificity (72% vs. 78–100%) in comparison to 8 single traditional ECG-LVH criteria. Additionally, the positive predictive value (77% vs. 72%), positive likelihood ratio (2.0 vs. 1.5), and odds ratio (3.2 vs. 2.4) were higher for the Peguero-Lo Presti criterion versus the presence of any of these 8 traditional ECG-LVH criteria. Cohen’s Kappa, a measure of concordance between ECG and echocardiography with regard to LVH, was 0.24 for the Peguero-Lo Presti criterion, −0.01–0.13 for single traditional criteria, and 0.20 for any traditional criterion. However, by the receiver operating characteristics (ROC) curve analysis, the overall ability to discriminate between patients with and without LVH was insignificantly lower for the Peguero-Lo Presti versus Cornell voltage as a continuous variable (area under the ROC curve: 0.65 (95% CI, 0.48–0.81) vs. 0.71 (0.55–0.86), p = 0.5). In conclusion, our preliminary results suggest a slightly better, albeit still low, agreement of the novel Peguero-Lo Presti ECG criterion compared to the traditional ECG-LVH criteria with echocardiographic LVH in severe aortic stenosis.

Download Full-text

GENETIC AND BIOCHEMICAL BASIS OF ENZYME ACTIVITY VARIATION IN NATURAL POPULATIONS. I. ALCOHOL DEHYDROGENASE IN DROSOPHILA MELANOGASTER

Genetics ◽

10.1093/genetics/89.2.371 ◽

1978 ◽

Vol 89 (2) ◽

pp. 371-388

Author(s):

John F McDonald ◽

Francisco J Ayala

Keyword(s):

Gene Regulation ◽

Drosophila Melanogaster ◽

Alcohol Dehydrogenase ◽

Natural Populations ◽

Difficult Problem ◽

Regulatory Genes ◽

Biochemical Basis ◽

Evolutionary Consequence ◽

The Third ◽

Adh Activity

ABSTRACT Recent studies by various authors suggest that variation in gene regulation may be common in nature, and might be of great evolutionary consequence; but the ascertainment of variation in gene regulation has proven to be a difficult problem. In this study, we explore this problem by measuring alcohol dehydrogenase (ADH) activity in Drosophila melanogaster strains homozygous for various combinations of given second and third chromosomes sampled from a natural population. The structural locus (Adh) coding for ADH is on the second chromosome. The results show that: (1) there are genes, other than Adh, that affect the levels of ADH activity; (2) at least some of these "regulatory" genes are located on the third chromosome, and thus are not adjacent to the Adh locus; (3) variation exists in natural populations for such regulatory genes; (4) the effect of these regulatory genes varies as they interact with different second chromosomes; (5) third chromosomes with high-activity genes are either partially or completely dominant over chromosomes with low-activity genes; (6) the effects of the regulatory genes are pervasive throughout development; and (7) the third chromosome genes regulate the levels of ADH activity by affecting the number of ADH molecules in the flies. The results are consistent with the view that the evolution of regulatory genes may play an important role in adaptation.

Download Full-text

Estimating the area under a receiver operating characteristic curve using partially ordered sets

The International Journal of Biostatistics ◽

10.1515/ijb-2019-0127 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Ehsan Zamanzade ◽

Xinlei Wang

Keyword(s):

Roc Curve ◽

Characteristic Curve ◽

Partially Ordered Sets ◽

Sampling Technique ◽

Real Data ◽

Cost Effective ◽

Ordered Sets ◽

Operating Characteristics ◽

Partially Ordered ◽

Receiver Operating

AbstractRanked set sampling (RSS), known as a cost-effective sampling technique, requires that the ranker gives a complete ranking of the units in each set. Frey (2012) proposed a modification of RSS based on partially ordered sets, referred to as RSS-t in this paper, to allow the ranker to declare ties as much as he/she wishes. We consider the problem of estimating the area under a receiver operating characteristics (ROC) curve using RSS-t samples. The area under the ROC curve (AUC) is commonly used as a measure for the effectiveness of diagnostic markers. We develop six nonparametric estimators of the AUC with/without utilizing tie information based on different approaches. We then compare the estimators using a Monte Carlo simulation and an empirical study with real data from the National Health and Nutrition Examination Survey. The results show that utilizing tie information increases the efficiency of estimating the AUC. Suggestions about when to choose which estimator are also made available to practitioners.

Download Full-text

PER2 Circadian Oscillation Sensitizes Esophageal Cancer Cells to Chemotherapy

Biology ◽

10.3390/biology10040266 ◽

2021 ◽

Vol 10 (4) ◽

pp. 266

Author(s):

Juan Alfonso Redondo ◽

Romain Bibes ◽

Alizée Vercauteren Drubbel ◽

Benjamin Dassy ◽

Xavier Bisteau ◽

...

Keyword(s):

Esophageal Cancer ◽

Circadian Rhythm ◽

Survival Rate ◽

Circadian Clock ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Human Cancer ◽

Response To Therapy ◽

Circadian Oscillation ◽

Resistance To Therapy

Esophageal squamous cell carcinoma (eSCC) accounts for more than 85% cases of esophageal cancer worldwide and the 5-year survival rate associated with metastatic eSCC is poor. This low survival rate is the consequence of a complex mechanism of resistance to therapy and tumor relapse. To effectively reduce the mortality rate of this disease, we need to better understand the molecular mechanisms underlying the development of resistance to therapy and translate that knowledge into novel approaches for cancer treatment. The circadian clock orchestrates several physiological processes through the establishment and synchronization of circadian rhythms. Since cancer cells need to fuel rapid proliferation and increased metabolic demands, the escape from circadian rhythm is relevant in tumorigenesis. Although clock related genes may be globally repressed in human eSCC samples, PER2 expression still oscillates in some human eSCC cell lines. However, the consequences of this circadian rhythm are still unclear. In the present study, we confirm that PER2 oscillations still occur in human cancer cells in vitro in spite of a deregulated circadian clock gene expression. Profiling of eSCC cells by RNAseq reveals that when PER2 expression is low, several transcripts related to apoptosis are upregulated. Consistently, treating eSCC cells with cisplatin when PER2 expression is low enhances DNA damage and leads to a higher apoptosis rate. Interestingly, this process is conserved in a mouse model of chemically-induced eSCC ex vivo. These results therefore suggest that response to therapy might be enhanced in esophageal cancers using chronotherapy.

Download Full-text

EMT Participates in the Regulation of Exosomes Secretion and Function in Esophageal Cancer Cells

Technology in Cancer Research & Treatment ◽

10.1177/15330338211033077 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110330

Author(s):

Chuangui Chen ◽

Zhao Ma ◽

Hongjing Jiang

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Promoting Effect ◽

Migration Ability ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

And Migration ◽

And Function ◽

Esophageal Cancer Cells

Epithelial-mesenchymal transition (EMT) is a key step in tumor invasion and distant metastasis. Abundant evidence has documented that exosomes can mediate EMT of tumor cells and endow them with the ability of invasion and migration. However, there are few studies focusing on whether EMT can reverse the secretion of exosomes. In this study, 2 esophageal cancer cells (FLO-1 and SK-GT-4) were selected to compare the migration ability and EMT activation, and to further analyze the secretion ability of exosomes of the 2 cell lines. According to the results, inhibited activation of EMT in FLO-1 cells with relatively high migration ability could effectively reduce the secretion of exosomes. Besides, in SK-GT-4 cells, EMT activation induced by TGF-β could promote the secretion of exosomes. FLO-1 cell derived exosomes exhibited a paracrine effect of promoting the migration of SK-GT-4 cells, and the use of EMT inhibitors could weaken this ability. Furthermore, inhibition of EMT could change the relative content of some miRNAs in exosomes, with a particularly significant downregulation in the expression of miR-196-5p, miR-21-5p and miR-194-5p. Significantly, artificial transfection of the 3 miRNAs into exosomes by electroporation resulted in the recovery of migration-promoting effect of exosomes. Subsequent experiments further revealed that the effect of EMT on these miRNAs could be explained by the intracellular transcription level or the specific sorting mechanism of exosomes. To sum up, our study undoubtedly reveals that EMT has a regulatory effect on exosomes in the quantity and contents in esophageal cancer cells. Significantly, findings in our study provide experimental evidence for the interaction of EMT with the secretion and sorting pathway of exosomes, and also give a new direction for the further study of tumor metastasis.

Download Full-text

Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Scientific Reports ◽

10.1038/s41598-021-81465-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ryoichi Katsube ◽

Kazuhiro Noma ◽

Toshiaki Ohara ◽

Noriyuki Nishiwaki ◽

Teruki Kobayashi ◽

...

Keyword(s):

Esophageal Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Near Infrared ◽

Fibroblast Activation Protein ◽

Therapeutic Resistance ◽

Fibroblast Activation ◽

Human Esophageal Cancer

AbstractCancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

Download Full-text

Right choice of a method for determination of cut-off values: A statistical tool for a diagnostic test

Asian Journal of Medical Sciences ◽

10.3126/ajms.v5i3.9296 ◽

2014 ◽

Vol 5 (3) ◽

pp. 30-34 ◽

Cited By ~ 19

Author(s):

Balkishan Sharma ◽

Ravikant Jain

Keyword(s):

Logistic Regression ◽

Discriminant Analysis ◽

Diagnostic Test ◽

Roc Curve ◽

Traditional Method ◽

Statistical Technique ◽

Curve Analysis ◽

Operating Characteristics ◽

Roc Curve Analysis

Objective: The clinical diagnostic tests are generally used to identify the presence of a disease. The cutoff value of a diagnostic test should be chosen to maximize the advantage that accrues from testing a population of human and others. When a diagnostic test is to be used in a clinical condition, there may be an opportunity to improve the test by changing the cutoff value. To enhance the accuracy of diagnosis is to develop new tests by using a proper statistical technique with optimum sensitivity and specificity. Method: Mean±2SD method, Logistic Regression Analysis, Receivers Operating Characteristics (ROC) curve analysis and Discriminant Analysis (DA) have been discussed with their respective applications. Results: The study highlighted some important methods to determine the cutoff points for a diagnostic test. The traditional method is to identify the cut-off values is Mean±2SD method. Logistic Regression Analysis, Receivers Operating Characteristics (ROC) curve analysis and Discriminant Analysis (DA) have been proved to be beneficial statistical tools for determination of cut-off points.Conclusion: There may be an opportunity to improve the test by changing the cut-off value with the help of a correctly identified statistical technique in a clinical condition when a diagnostic test is to be used. The traditional method is to identify the cut-off values is Mean ± 2SD method. It was evidenced in certain conditions that logistic regression is found to be a good predictor and the validity of the same can be confirmed by identifying the area under the ROC curve. Abbreviations: ROC-Receiver operating characteristics and DA-Discriminant Analysis. Asian Journal of Medical Science, Volume-5(3) 2014: 30-34 http://dx.doi.org/10.3126/ajms.v5i3.9296

Download Full-text