Single Nucleotide Polymorphisms in Genes for Non-Coding RNAs as Diagnostic and Prognostic Markers in Patients with Metastatic Colorectal Cancer // Единични нуклеотидни полиморфизми в гените за некодиращи РНК-и като диагностични и прогностични маркери при болни с колоректален карцином в метастатичен стадий

Single nucleotide polymorphisms (SNPs) are a common genetic variation affecting individual susceptibility to certain cancers. This is why SNPs are considered a biomarker for predicting the risk of CRC. In our study, we compared the alleles, frequencies, and genotypic distribution of five selected SNPs (rs7372209, rs2910164, rs2682818, rs353293 and rs322931) in the mRNA genes among a Bulgarian group of healthy individuals with other healthy cohorts. The analysis of our results showed a similar frequency distribution of the studied polymorphisms in Bulgarian individuals with that of European cohorts. We found an association with the risk of CRC for three of the studied polymorphisms in the Bulgarian cohort of patients with metastatic CRC (rs2910164 in the miRNA-146a gene, rs2682818 in the miR-618 gene and rs353293 in the promoter region of the miRNA-143 gene cluster -145). Statistically significant associations with overall patient survival were found for two of the polymorphisms studied (TT genotype for rs7372209-miR-26a-1 and AA genotype for rs353293 in the promoter region of the miRNA-143/145 gene cluster). Plasma levels in patients and healthy controls of siRNAs in whose genes the polymorphisms studied in the study were also assessed during the study. Four showed different expressions between healthy controls and selected patients with high specificity and sensitivity - miRNA-26a-1, miR-146a, miRNA-618 and miRNA-181b.Единичните нуклеотидни полиморфизми (SNPs) са често срещана генетична вариация, засягаща индивидуалната чувствителност към определени онкологични заболявания. Това е причината SNPs да се разглеждат като биомаркер за прогнозиране на риска от КРК. В хода на нашето проучване сравнихме алелните и честоти и генотипното разпределение на пет подбрани SNPs (rs7372209, rs2910164, rs2682818, rs353293 и rs322931) в гените за миРНК-ите сред българска група здрави индивиди с други здрави кохорти. Анализът на нашите резултати показа сходно честотно разпределение на изследваните полиморфизми в българските индивиди с това при европейските кохорти. Установихме асоциация с риска от развитие на КРК за три от изследваните полиморфизми в българската кохорта пациенти с метастатичен КРК (rs2910164 в гена за miRNA-146a, rs2682818 в гена за miR-618 и rs353293 в промоторния район на генния клъстер за miRNA-143 и miRNA-145). За два от изследваните полиморфизми беше установена статистически значима асоциация с общата преживяемост на пациентите (генотип TT за rs7372209-miR-26a-1 и генотип АА за rs353293 в промоторния район на генния клъстер за miRNA-143/145). В хода на изследването беше оценено и нивото в плазмата при пациенти и здрави контроли на миРНК-ите в чийто гени са локализирани изследваните в проучването полиморфизми. Четири от тях показаха различна експресия между здравите контроли и селектираните болни с висока специфичност и чувствителност - miRNA-26а-1, miR-146a, miRNA-618 и miRNA-181b

Osteomyelitis

Introduction: Osteomyelitis is an infection and inflammation of the bone or the bone marrow, caused by an infecting organism. Although bone is normally resistant to bacterial colonization, events such as trauma, surgery, the presence of foreign bodies, or the placement of prostheses may disrupt bony integrity and lead to the onset of bone infection. Osteomyelitis can also result from hematogenous spread after bacteremia. Other risk factors are conditions that impair the immune system; circulatory problems as poorly controlled diabetes, peripheral arterial disease, often related to smoking, sickle cell disease; problems requiring intravenous lines or catheters as dialysis machine tubing, urinary catheters, long-term intravenous tubing; illicit drugs.  Early and specific treatment is important in osteomyelitis, and identification of the microorganisms causing the disease is essential for antibiotic therapy. Staphylococcus aureus is the most frequently isolated microorganism in these patients. Methicillin-resistant S. aureus (MRSA) is usually considered a nosocomial pathogen, but it is increasingly acquired in the communityMaterials and Methods: We present a case that begins as acute osteomyelitis but evolves into chronic condition. The disease occurred after inflammation caused by fracture of the femur.  Microbiological and pathological examination is necessary to confirm the diagnosis of osteomyelitis and to proceed to targeted and long-lasting antibiotic therapy, which usually includes combination of antimicrobial agents.Results: If left untreated, the infection can become chronic and cause loss of blood supply to the affected bone. When this happens, it can lead to the eventual necrosis of the bone tissue. It requires surgical removal.Conclusion: This case report offers a basic review of the classification, etiology, epidemiology, pathogenesis, and treatment of osteomyelitis

Key Apoptosis Signaling Pathways In Malignant Diseases

Apoptosis is a process of controlled cell death in multicellular organisms. Despite complex control mechanisms, apoptosis can escape the regulatory processes, leading to cell proliferation and oncogenesis.Several important signaling pathways affect controlled cell death, including the AKT signaling path-way and p53-mediated apoptosis pathways, as well as two major cellular pathways—external and internal, which are best studied.The use of targeted therapies that interfere with specific molecules involved in the regulation of apoptosis is a possible new approach to cancer treatment

Single Nucleotide Polymorphisms in microRNA Genes and Colorectal Cancer Risk and Prognosis

There is growing interest in single nucleotide polymorphisms (SNPs) in the genes of microRNAs (miRNAs), which could be associated with susceptibility to colorectal cancer (CRC) and therefore for prognosis of the disease and/or treatment response. Moreover, these miRNAs-SNPs could serve as new, low-invasive biomarkers for early detection of CRC. In the present article, we performed a thorough review of different SNPs, which were investigated for a correlation with the CRC risk, prognosis, and treatment response. We also analyzed the results from different meta-analyses and the possible reasons for reported contradictory findings, especially when different research groups investigated the same SNP in a gene for a particular miRNA. This illustrates the need for more case-control studies involving participants with different ethnic backgrounds. According to our review, three miRNAs-SNPs—miR-146a rs2910164, miR-27a rs895819 and miR-608 rs4919510—appear as promising prognostic, diagnostic and predictive biomarkers for CRC, respectively

Circulating Histones to Detect and Monitor the Progression of Cancer

Liquid biopsies have emerged as a minimally invasive cancer detection and monitoring method, which could identify cancer-related alterations in nucleosome or histone levels and modifications in blood, saliva, and urine. Histones, the core component of the nucleosome, are essential for chromatin compaction and gene expression modulation. Increasing evidence suggests that circulating histones and histone complexes, originating from cell death or immune cell activation, could act as promising biomarkers for cancer detection and management. In this review, we provide an overview of circulating histones as a powerful liquid biopsy approach and methods for their detection. We highlight current knowledge on circulating histones in hematologic malignancies and solid cancer, with a focus on their role in cancer dissemination, monitoring, and tumorigenesis. Last, we describe recently developed strategies to identify cancer tissue-of-origin in blood plasma based on nucleosome positioning, inferred from nucleosomal DNA fragmentation footprint, which is independent of the genetic landscape

New Circulating Circular RNAs with Diagnostic and Prognostic Potential in Advanced Colorectal Cancer

Circular RNAs (circRNAs) are a group of special endogenous long non-coding RNAs which are highly stable in the circulation, and, thus, more suitable as new biomarkers of colorectal cancer (CRC). The aim of our study was to explore the plasma expression levels of four circRNAs: has_circ_0001445, hsa_circ_0003028, hsa_circ_0007915 and hsa_circ_0008717 in patients with CRC and to evaluate their associations with clinicopathological characteristics and the clinical outcome of the patients. CircRNAs were extracted from patients’ plasma obtained prior to chemotherapy. Their expression levels were measured by qPCR and calculated applying the 2−ΔΔCt method. The levels of all four circRNAs were significantly increased in the plasma of CRC patients. At the optimal cut-off values hsa_circ_0001445 and hsa_circ_0007915 in plasma could significantly distinguish between patients with or without metastatic CRC with 92.56% sensitivity and 42.86% specificity, and with 86.07% sensitivity and 57.14% specificity, respectively. The mean overall survival (OS) of patients with high/intermediate expression of hsa_circ_0001445 was 30 months, significantly higher in comparison with the mean OS of the patients with low expression—20 months (log-rank test, p = 0.034). In multivariate Cox regression analysis, the low levels of hsa_circ_0001445 were also associated with shorter survival (HR = 1.59, 95% CI: 1.02–2.47, p = 0.040). A prognostic significance of hsa_circ_0001445 for patients with metastatic CRC was established

RIPK3 expression as a potential predictive and prognostic marker in metastatic colon cancer

Background: Colorectal cancer is one of the primary causes of cancer-related deaths and 5-fluorouracil (5-FU) therapy remains the cornerstone of treatment in these patients. Resistance to 5-FU represents a major obstacle; therefore, finding new predictive and prognostic markers is crucial for improvement of patient outcomes. Recently a new type of programmed cell death was discovered—necroptosis, which depends on receptor interacting protein 3 (RIPK3). Preclinical data showed that necroptotic cell death is an important effector mechanism of 5-FU-mediated anticancer activity. Purpose: To investigate the predictive and prognostic performance of RIPK3 expression in primary tumors. Methods: Colon cancer patients (n=74) with metastatic stage were included in this retrospective study and all were treated with first-line 5-FU based chemotherapy. Immunohistochemical staining was performed. Results: The progression free survival for the low expression group of RIPK3 was 5.6 months (95% CI, 4.4-6.8) vs 8.4 months (95% CI, 6.4-10.3) of the group with high expression (p=0.02). Moreover, patients with high expression of RIPK3 were associated with lower risk of disease progression HR 0.61 (95% CI, 0.38-0.97; p=0.044). Patients with high expression levels of RIPK3 also had significantly longer mean overall survival (OS) of 29.3 months (95% CI, 20.8-37.8) as compared with those with low expression: 18.5 months (95% CI, 15.06-21.9) (p= 0.036). In addition, univariate analysis showed that high level of RIPK3 expression was associated with a longer OS HR 0.59 (95% CI, 0.35-0.98; p=0.044). Conclusions: This study suggests that expression of RIPK3 in primary tumors of metastatic colon cancer patients should be further investigated for its potential as a promising predictive and prognostic marker