Introduction: Cardiac complications are a major cause of perioperative morbidity and mortality in patients undergoing colorectal cancer surgery. A quick and reliable system for predicting postoperative cardiac morbidity is needed to predict cardiac events in order to improve outcome in surgery. The aim of this study was to investigate the role of the biochemical marker NT-proBNP in the prediction of postoperative all-cause mortality, cardiac-related mortality and cardiovascular events in patients undergoing colorectal cancer resections. Methods: 100 consecutive patients undergoing colorectal cancer surgery were prospectively recruited. Blood samples were taken preoperatively, 24h, 48h and 5-7 postoperative days to measure NT-proBNP levels. The predictive power of NT-proBNP levels was assessed using Receiver Operating Characteristics (ROC) curves. Results: Cardiac-related morbidity and mortality was 9%. Of eleven deaths, 5 were cardiac-related. Preoperative NT-proBNP was a good predictor of death with ROC area under curve (AUC) of 0.83 (95% C.I. 0.673, 0.993) a strong predictor of cardiac death with AUC of 0.914 (95% C.I. 0.823, 1.000) and a good predictor of cardiac complications with AUC of 0.875 (95% C.I. 0.757, 0.993). NT-proBNP levels 24 hours and 48 hours postoperatively were also strongly predictive of postoperative cardiac morbidity and mortality. Conclusion: Pre- and postoperative NT-proBNP have a role in predicting postoperative death and cardiac complications. This may have significant implications in the planning of postoperative care for high-risk patients. Show less

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. Show less

We examined special roles of the Central Nervous System (CNS) in an attempt to resolve the puzzle that chronic diseases cannot be cured in medicine. By exploring a skill-learning model, we found that the CNS is able to remember certain information reflecting biochemical and cellular (B&C) processes in the body. From the skill-using ability, we found that the CNS is able to control basic B&C processes that drive and power the skill. From the ability to adjust forces and moving direction of body parts, we infer that the CNS is able to adjust B&C processes that control physical acts. From this controlling capability, we inferred that the CNS must also store certain information on the baseline B&C processes, is able to up-regulate or down-regulate the B&C processes, and make comparisons in performing its regulatory functions. We found that chronic diseases are the results of deviated baseline B&C processes, the CNS plays a role in maintaining deviated baseline B&C processes, and protects the body state of a fully developed disease. The three CNS roles can explain that cancer progresses with increasing malignancy, cancer quickly returns after a surgery, cancer cells repopulate after chemotherapy and radiotherapy, cancer patients develop drug resistance inevitably, immune cells rebound after suppression, etc. We further showed that long-term exercises generally can correct part of the departures in B&C processes and thus help to reverse chronic diseases. Finally, we propose strategies for resetting the CNS’ state memory as an essential condition for curing chronic diseases and cancer. Show less