Identifying circulating miRNA biomarkers for early diagnosis and monitoring of lung cancer

Liquid biopsy refers to the sampling, screening, and detecting potential biomarkers in unique liquid samples for clinical use. Lung cancer is one of the most highly frequent cancer subtypes, which is hard to be early diagnosed and monitored by radiological and histopathological evaluation that are the most general and accurate methods. Circulating miRNA is a potential clinical examination index for tumor detection and monitoring tumorigenesis progression using liquid biopsy. However, recognizing and validating the unique clinical values of each candidate circulating miRNA is expensive and time consuming. In this study, we presented a novel computational approach for identifying significant circulating miRNAs that may be applied to early screening, diagnosis, and constant monitoring of lung cancer progression. This approach incorporated several machine learning algorithms and was applied on the expression profiles of circulating miRNAs on lung cancer patients and control samples. In brief, a powerful feature selection method, minimum redundancy maximum relevance, was adopted to evaluate the importance of all features, resulting in a feature list. Then, incremental feature selection incorporating random forest followed to extract key circulating miRNAs. At the same time, an efficient classifier with MCC 0.740 was built. Top five circulating miRNAs, including miR-92a, miR-140-5p, miR-331-3p, miR-223, miR-374a, were analyzed and confirmed that they participated in the pathogenesis of lung cancer, indicating their significant prognosis power in lung cancer.     

Genome-wide miRNA signatures of human longevity

Little is known about the functions of miRNAs in human longevity. Here, we present the first genome-wide miRNA study in long-lived individuals (LLI) who are considered a model for healthy aging. Using a microarray with 863 miRNAs, we compared the expression profiles obtained from blood samples of 15 centenarians and nonagenarians (mean age 96.4 years) with those of 55 younger individuals (mean age 45.9 years). Eighty miRNAs showed aging-associated expression changes, with 16 miRNAs being up-regulated and 64 down-regulated in the LLI relative to the younger probands. Seven of the eight selected aging-related biomarkers were technically validated using quantitative RT-PCR, confirming the microarray data. Three of the eight miRNAs were further investigated in independent samples of 15 LLI and 17 younger participants (mean age 101.5 and 36.9 years, respectively). Our screening confirmed previously published miRNAs of human aging, thus reflecting the utility of the applied approach. The hierarchical clustering analysis of the miRNA microarray expression data revealed a distinct separation between the LLI and the younger controls (P-value < 10(-5) ). The down-regulated miRNAs appeared as a cluster and were more often reported in the context of diseases than the up-regulated miRNAs. Moreover, many of the differentially regulated miRNAs are known to exhibit contrasting expression patterns in major age-related diseases. Further in silico analyses showed enrichment of potential targets of the down-regulated miRNAs in p53 and other cancer pathways. Altogether, synchronized miRNA-p53 activities could be involved in the prevention of tumorigenesis and the maintenance of genomic integrity during aging.     

Sulfasalazine-induced colitis complicating idiopathic ulcerative colitis.

A diagnosis of idiopathic ulcerative colitis was made in a previously healthy 9-year-old boy. Symptoms persisted despite therapy with sulfasalazine, 50 mg/kg daily, but they eventually responded to treatment with parenteral nutrition and prednisone, 40 mg daily. Metronidazole was also given to eradicate persistent Dientamoeba fragilis from the stools. The symptoms resolved over 3 weeks, and the daily dose of prednisone was tapered. On two subsequent occasions a challenge with sulfasalazine caused an immediate recurrence of loose, blood-streaked stools and of nonspecific histologic features of ulcerative colitis, which resolved when the sulfasalazine was discontinued.     

Proctocolectomy without ileostomy for ulcerative colitis.

An operation has been developed that permits total removal of all disease-prone mucosa in ulcerative colitis but avoids the need for a permanent ileostomy. The colon and upper half of the rectum are excised and the remaining inflamed mucosa is stripped from the rectal stump down to the dentate line of the anal canal. A pouch is fashioned from a triplicated loop of terminal ileum. This is drawn down through the denuded rectum and an anastomosis created, via the per-anal approach, between the ileum just distal to the pouch and the mid-anal canal. A temporary ileostomy is made. Out of eight patients so treated, five were available for assessment, and four of them were highly satisfied with the result in improved health and function. The remaining three were awaiting closure of their ileostomies.     

Fullerene nanoparticles for the treatment of ulcerative colitis

Ulcerative colitis (UC) is a long-term, recurrent inflammatory bowel disease for which no effective cure is yet available in the clinical setting. Repairing the barrier dysfunction of the colon and reducing intestinal inflammation are considered key objectives to cure UC. Here we demonstrate a novel therapeutic strategy based on a C₆₀ fullerene suspension (C₆₀FS) to treat dinitrobenzene sulfonic acid-induced UC in an animal model. C₆₀FS can repair the barrier dysfunction of UC and effectively promote the healing of ulcers; it also manifests better treatment effects compared with mesalazine enema. C₆₀FS can reduce the numbers of basophils in the blood of UC rats and mast cells in the colorectal tissue, thereby effectively alleviating inflammation. The expression of H1R, H4R, and VEGFR2 receptors in colorectal tissues is inhibited by C₆₀FS, and the levels of histamine and prostaglandin in the rat blood are reduced. This work presents a reliable strategy based on fullerene to cure UC and provides a novel guide for UC treatment.

     

miRNA expression profiling for identification of potential breast cancer biomarkers

To identify micro RNA (miRNA) biomarker candidates for early detection of breast cancer and detection of minimal residual breast cancer, we performed miRNA expression profiling in pooled RNA samples from breast tumors, and from bone marrow mononuclear cells, peripheral blood mononuclear cells and plasma from healthy controls. We found substantially higher levels of five miRNAs in the breast tumors compared to the normal samples. However, validation of these miRNA levels, and seven other candidates selected from the literature, in individual samples from healthy controls and patients with non-metastatic breast cancer did not suggest further examination of their biomarker potential.     

miRNA expression profiling for identification of potential breast cancer biomarkers

To identify micro RNA (miRNA) biomarker candidates for early detection of breast cancer and detection of minimal residual breast cancer, we performed miRNA expression profiling in pooled RNA samples from breast tumors, and from bone marrow mononuclear cells, peripheral blood mononuclear cells and plasma from healthy controls. We found substantially higher levels of five miRNAs in the breast tumors compared to the normal samples. However, validation of these miRNA levels, and seven other candidates selected from the literature, in individual samples from healthy controls and patients with non-metastatic breast cancer did not suggest further examination of their biomarker potential.     

Distinguishing ulcerative colitis from autoimmunity

Lymphoid hyperplasia, autoimmunity, and compromised intestinal intraepithelial lymphocyte development in colitis-free gnotobiotic IL-2-deficient miceContractor, N.V. et al. (1998)J. Immunol. 160, 385–394     

Smoking and ulcerative colitis.

In a case-control study of smoking and ulcerative colitis patients with the disease were much less likely to smoke than community controls matched for age and sex. The difference was substantial, with an estimated relative risk of 3.8 for non-smoking on current habits, was even larger (6.2) when habits at onset of the disease were examined, and was mainly accounted for by 42 of 55 patients who had given up smoking a mean of eight years before onset. The association could not be explained by confounding by social class. These findings suggest that smoking directly or indirectly confers protection against ulcerative colitis.