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Oct 2020 DOI 10.14302/issn.2379-7835.ijn-20-3418
Isolation methods that employ readily-available inexpensive supplies on the open market, which are reliable, as well as economical, such as nucleic acid amplification techniques (NAAT) based on microfluidic technology in low-resource research settings (LRRS) that meets the ASSURED guidelines are essential to develop a noninvasive diagnostic colon cancer screen in stool using micro(mi)RNA molecules. A combination of a microfluidic-based MiRNA stool test with a reliable rolling circle amplification/detection method applied to the quantification of miRNA molecules, result in an affordable sensitive and specific isothermal method for the noninvasive quantitative detection of miRNAs in LRRS. Scientists and engineers have become interested in miRNAs, and they have intensified their efforts to apply emerging simple detection tools to the important bioanalytical challenge of quantifying these small 18-26 nt long molecules. Some of the proposed approaches incorporate novel material, such as simple centrifuges and methods based on microfluidic technology, while others utilize the interesting biological properties of these molecules, such as forming branched RCA structures, allowing for the detection of these biomarker molecules at an attomolar "aM" concentration level, using low cost extraction and isothermal amplification methods in LRRS. We have been interested in studying colorectal cancer (CRC) because it is the 3rd most common malignancy worldwide, and stool can be obtained noninvasively from the patients. We have focused in this research on colon cancer (CC) because it is more common in the USA than rectal cancer (RC). The innovation of our approach lies in the exploratory use of an affordable, quantitative miRNA profiling in noninvasive stool samples in LRRS, whose extracted fragile total RNA is stabilized shortly after excretion from stool by commercially available kits, so it does not ever fragment, followed by quantitative standardized analytical tests that are neither labor intensive, nor require expensive instrumentation, in order to develop apanel of novel miRNA genes for the noninvasive diagnostic screening of early left and right sporadic colon cancers, more economically, and with higher sensitivity and specificity than any other colon cancer screening test currently available on the market. To show the clinical sensitivity and specificity of the proposed quantitative miRNA test using simple methodologies in LRRS,the miRNA results are to be correlated with FOBT, colonoscopy, and pathology data. Standardization establishes test’s performance criteria (sample selection, optimal sample running conditions, preservation and storage), in order to ensure that the assay will perform the same way in any laboratory, by any trained personnel, anywhere in low-resource laboratory settings worldwide.
Jun 2020 DOI 10.14302/issn.2379-7835.ijn-19-3123
Isolation methods that employ readily-available inexpensive supplies on the open market, which are reliable, as well as economical, such as nucleic acid amplification techniques (NAAT) based on microfluidic technology in low-resource research settings (LRRS) that meets the ASSURED guidelines are essential to develop a noninvasive diagnostic colon cancer screen in stool using micro(mi)RNA molecules. A combination of a microfluidic-based MiRNA stool test with a reliable rolling circle amplification/detection method applied to the quantification of miRNA molecules, result in an affordable sensitive and specific isothermal method for the noninvasive quantitative detection of miRNAs in LRRS. Scientists and engineers have become interested in miRNAs, and they have intensified their efforts to apply emerging simple detection tools to the important bioanalytical challenge of quantifying these small 18-26 nt long molecules. Some of the proposed approaches incorporate novel material, such as simple centrifuges and methods based on microfluidic technology, while others utilize the interesting biological properties of these molecules, such as forming branched RCA structures, allowing for the detection of these biomarker molecules at an attomolar "aM" concentration level, using low cost extraction and isothermal amplification methods in LRRS. We have been interested in studying colorectal cancer (CRC) because it is the 3rd most common malignancy worldwide, and stool can be obtained noninvasively from the patients. We have focused in this research on colon cancer (CC) because it is more common in the USA than rectal cancer (RC). The innovation of our approach lies in the exploratory use of an affordable, quantitative miRNA profiling in noninvasive stool samples in LRRS, whose extracted fragile total RNA is stabilized shortly after excretion from stool by commercially available kits, so it does not ever fragment, followed by quantitative standardized analytical tests that are neither labor intensive, nor require expensive instrumentation, in order to develop apanel of novel miRNA genes for the noninvasive diagnostic screening of early left and right sporadic colon cancers, more economically, and with higher sensitivity and specificity than any other colon cancer screening test currently available on the market. To show the clinical sensitivity and specificity of the proposed quantitative miRNA test using simple methodologies in LRRS,the miRNA results are to be correlated with FOBT, colonoscopy, and pathology data. Standardization establishes test’s performance criteria (sample selection, optimal sample running conditions, preservation and storage), in order to ensure that the assay will perform the same way in any laboratory, by any trained personnel, anywhere in low-resource laboratory settings worldwide.
Feb 2020 DOI 10.14302/issn.2577-2279.ijha-20-3180
Background Colon cancer is one of the leading causes of cancer death world-wide. There is a steady increase in incidence over the past four decades in developing countries. This has been partly attributed to increasingly low intake of vegetables among other causes. Aims Therefore this study aims to evaluate the protective effect of aqueous extract of Ocimumgratissimum (OG) leaves (a staple vegetable) on experimental model of colon carcinogenesis induced with 1, 2 Dimethylhydrazine (DMH). This is compared with celecoxib (a cyclooxygenase-2 inhibitor) which is used in the chemoprevention of colon cancer. Methods Sixty adult male Wistar rats were randomly divided into six groups: A to F, n=10. Group A was the normal control, Group B was given only DMH weekly for 16 weeks,Groups C, D and E were given graded doses of OG for two weeks prior to cancer induction by DMH. After which both OG and DMH were given for 16weeks. Group F received celecoxib daily for two weeks prior to cancer induction. Colonic wall was analysed grossly, histologically and biochemically. The induced lesions were staged investigated and staged using Duke’s Staging method. Results The result showed tumour incidence in groups B and C while no evidence of primary colonic tumour was observed in groups A, D, E and F. There was a dose dependent increase in the goblet cell count in the groups treated with OG with group E being statistically higher than group F. There was a significant reduction in collagen staining intensity (F = 129.74, p < 0.0001) for the colonic wall in group B when compared to other groups. There was a decreased nucleo-cytoplasmic ratio in groups C, D, E and F when compared to group B. There was a significant increase in the concentration of nitric oxide and prostaglandin E2in group B when compared to other groups D, E and F. Conclusion In conclusion, this research showed a protective effect of Ocimumgratissimum leaves on 1, 2-dimethylhydrazine-induced colon cancer which further corroborated its ethno-medicinal use.
Feb 2019 DOI 10.14302/issn.2471-7061.jcrc-18-2526
There is currently no validated micro(mi)RNA diagnostic stool test to screen for colon cancer (CC) on the market because of the complexity of fecal density, vulnerability of stool to daily changes, and the presence of three sources of miRNAs in stool (cell-free from fecal homogenates, exsosomal miRNAs from fecal exosomes, and fecal colonocytes). To address these complexities, we have first carried out a microarray miRNA experiment, using Affymetrix GeneChip miRNA 2.0 Arrays, on immunocaptured and enriched stool colonocytes of 15 subjects (three healthy controls and twelve colon cancer patients [three TNM stage 0-1 (e.g., polyps◻ ³ 1 cm, villous or tubvillous, or with high grade dysplasia), three stage 2, three stage 3, and three stage 4 in triplicates to select a smaller panel of 14 preferentially expressed mature miRNAs associated with colon cancer (12 Up-Regulated, miR-19a, miR-20a, miR-21, miR-31, miR-34a, miR-96, miR-106a, miR-133a, miR-135b, miR-206, miR-224 and miR-302; and 2 Down-Regulated, miR-143 and miR-145). In a subsequent validation study carried out on total small RNA extracted by immunocapture, followed by RT that employed TaqMan® miRNA Reverse Transcription (RT) Kit and a Custom TaqMan RT Primer Pool, absolute quantification of miRNAs, in copies/µl, was measured using a chip-based Absolute QuantStudio 3D Digital PCR analysis. To ensure that we have chosen human and not bacterial small total RNA, we have carried out coextraction protocols with E. coli K1 strain RS18, compare Agilent electrophoretic patterns, and also sequenced random samples throughout this research using mRNA/miRNA sequencing. Our initial quantitative dPCR miRNA data presented herein showe that the quantitative changes in the expression of a few mature miRNA genes in stool, which are associated with right and left colon cancer, would provide for a more convenient, sensitive and specific diagnostic screening markers thatare more useful than those test markers currently available on the market, such as the low-sensitivity (<15%) fecal occult blood test (FOBT); result in better compliance; and is more economical than the invasive and expensive colonoscopy exam in colon cancer, which can be cured if that cancer is detected at the early TNM stages, and that becomes incurable and deadly if not diagnosed before metastasis. Initial test performance characteristics of the miRNA approach showed that the test has a high numerical predictive value in colon cancer. Moreover, underpinning of the miRNA markers as a function of total RNA showed that the test can numerically differentiate between control subjects and colon cancer patients, particularly at the early stages of that curable cancer. We propose to extend our initial research results to a larger prospective and randomized five-years nested case-control study, to validate the expression of the above 14 miRNAs, in stool of 180 individuals in an epidemiologically designed study, using (30 controls and 150 colon cancer patients (thirty precancerous polyps (stage 0-1), forty five stage 2, and seventy-five colon cancer stages 3 or 4). chosen randomly by an epidemiological method from 900 control and CC subjects to allow for an adequate time to collect the required 900 stool samples, as well as allowing for statistically valid analysis, standardized test conditions, and to provide a mean for determining the true sensitivity and specificity of a miRNA-screening approach in noninvasive human stool. Power-analysis has indicated that a total of 180 individuals, which will take us 5 years to enroll in testing, is an appropriate number of subjects to standardize and validate our proposed miRNA screening test. We may find out at the end of the proposed validation study in stool that fewer miRNAs, or even one miRNA, may suffice to serve as an efficient and a quantitative marker for the non-invasive diagnostic screening of colon cancer in human stool. The above approach when combined with bioinformatics analysis, to correlate miRNA seed data with our previously published messenger (m)RNA target data in stool, allows for a thorough mechanistic understanding of how miRNA genes regulate mRNA expression, and would offer a better comprehensive diagnostic screening test for the non-invasive early detection stage (0-1) of colon cancer. In order to show the clinical sensitivity and specificity of the proposed miRNA test, the absolute miRNA PCR values, in copies/µl, will be correlated with FOBT, colonoscopy, and pathology data. Standardization will establish test’s performance characteristics (sample selection, optimal sample running conditions, preservation and storage) to ensure that the assay will perform the same way in any laboratory, by any trained personnel, anywhere in the World. Ultimately, a smaller number of selected validated miRNAs (<10) showing increased and reduced expression could suffice to give quantitative miRNAs colon cancer expression values, useful for the early diagnostic screening of that curable cancer.
Jul 2016 DOI 10.14302/issn.2574-4526.jddd-16-1203
Background: Iron deficiency is a common reason for referral to a gastroenterologist. Objective: To identify predictors of colorectal cancer in patients referred to a gastroenterologist for iron deficiency. Methods: This was a retrospective review of consecutive patients referred to one of two gastroenterologists for assessment of iron deficiency. The office files and electronic health records were reviewed for all patients. Clinical data, such as hemoglobin level, and clinical symptoms were recorded. The final diagnosis was that of the attending gastroenterologist. Variables associated with a diagnosis of colorectal cancer by univariate analysis were entered into a multivariate logistic regression model to identify variables independently associated with the diagnosis of colorectal cancer. Results: Two hundred and seventy eight patients were included in this study. One hundred and fifty-eight (56.8%) were female. Mean age was 60.7 years (± 16.7 years). The most common causes of iron deficiency were: menorrhagia 16.2%, colorectal cancer 14%, use of aspirin or non-steroidal agents 11.2% and regular blood donation 7.2%. In 11.5% of patients, no cause was found. In univariate analysis, lower hemoglobin, greater age, shorter duration of iron deficiency, weight loss, symptoms from anemia and NSAID use were associated with colorectal cancer. In multivariate analysis, only older age (OR=1.06; 95% CI 1.04-1.09) and symptoms from anemia (OR=2.19; 95% CI 1.20-4.0) were independently associated with colorectal cancer. Conclusions: Colorectal cancer was found in 14% of patients referred to a gastroenterologist because of iron deficiency. Older age, and symptomatic anemia may help predict a diagnosis of colorectal cancer.
May 2015 DOI 10.14302/issn.2471-7061.jcrc-14-574
Colon cancer has a five-year survival of 64.7%, and about 50,000 people are expected to die from colon cancer this year. Patients with metastatic colorectal cancer have a significantly worse prognosis, a 12.9% five-year survival. This emphasizes the need for strategies to inhibit the growth and metastases of colorectal cancer. Prostate apoptosis response protein 4 (Par-4) is a pro-apoptotic protein that has been shown to mediate apoptosis in response to stimuli, such as chemotherapeutics and radiation. Recombinant Par-4 protein has been shown to reduce the occurrence of Lewis lung carcinoma metastases in-vivo; however, the mechanism by which Par-4 can inhibit metastasis has not been elucidated. In this study, human colon cancer cell lines - SW480 and SW620 - were transfected with Par-4 plasmid or anti-Par-4 shRNA, and the effect on metastasis was examined. Par-4 overexpression inhibited cell migration and invasion, while Par-4 knockdown promoted it. Moreover, the morphology of SW620 cells was altered when Par-4 levels were increased. The change was characteristic of a mesenchymal-to-epithelial transition (MET) in these cells. MET can be induced by upregulation of E-cadherin expression, and RT-PCR and Western blot analyses showed that E-cadherin mRNA and protein levels, respectively, were increased in the Par-4 overexpressing cells concomitant with a decrease in vimentin. The results of this study demonstrate the potential of Par-4 in colon cancer therapy, not only in primary tumors but also in metastatic cells.