The Composition of Small Extracellular Vesicles (sEVs) in the Blood Plasma of Colorectal Cancer Patients Reflects the Presence of Metabolic Syndrome and Correlates with Angiogenesis and the Effectiveness of Thermoradiation Therapy.

The majority of colorectal cancer patients (CRCPs) develop tumors on the background of "metabolically healthy obesity" or metabolic syndrome. The aim of the work was to study the levels of matrix metalloproteinases (MMPs) and heat shock proteins (HSPs) on the surface of blood plasma CD9-positive and FABP4-positive small extracellular vesicles (sEVs) from CRCPs depending on metabolic status and tumor angiogenesis, as well as to evaluate the sEVs markers as predictors of the effectiveness of thermoradiotherapy. In CRCPs, compared with patients with colorectal polyps (CPPs), the proportion of triple positive EVs and EVs with the MMP9+MMP2-TIMP1+ phenotype increased significantly among FABP4-positive EVs (adipocyte-derived EVs), which in general may indicate the overexpression of MMP9 and TIMP1 by adipocytes or adipose tissue macrophages in CRCPs. The results obtained have prospects for use as markers to clarify cancer risk in CPPs. One can assume that for CRCPs with metabolic syndrome or metabolically healthy obesity, it is the FABP4+MMP9+MMP2-TIMP1- population of circulating sEVs that is the most optimal biomarker reflecting tumor angiogenesis. Determining this population in the blood will be useful in monitoring patients after treatment for the early detection of tumor progression. CD9+MMP9+MMP2-TIMP1- and MMP9+MMP2-TIMP1+ subpopulations of circulating sEVs are the most promising predictors of the efficacy of thermoradiation therapy because their levels at baseline differ significantly in CRCPs with different tumor responses.

Human Papillomavirus in Non-Small Cell Lung Carcinoma: Assessing Virus Presence in Tumor and Normal Tissues and Its Clinical Relevance.

The significance of the role of human papillomavirus (HPV) in the development of lung cancer remains an open question. The data from the literature do not provide conclusive evidence of HPV being involved in the pathogenesis of lung cancer. The aim of this work was to detect the presence of HPV infections with a high carcinogenic risk in patients with non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: the study involved 274 patients with stage IIA-IIIB non-small cell lung cancer. We analyzed normal and tumor tissues as well as blood from each patient. DNA was extracted from patients' specimens, and HPV detection and genotyping was carried out using commercially available kits by PCR. RESULTS: HPV was detected in 12.7% of the patients (35/274 of all cases). We detected nine different types of human papillomavirus in the patients, namely, types 16, 18, 31, 35, 45, 51, 52, 56, and 59. The HPV-positive samples had a clinically insignificant viral load and were predominantly integrated. The relationship between the presence of HPV and its virological parameters and the clinical and pathological parameters of the patients was established. A metastatic-free survival analysis showed that all patients with HPV in the tumor tissue had a higher 5-year survival rate (94%) compared with the HPV-negative patients (78%). The result was not statistically significant (p = 0.08). CONCLUSIONS: data showing a 12.7% human papillomavirus representation among patients with non-small cell lung cancer were obtained. The presence/absence of a viral component in patients with lung cancer was a clinically significant parameter. HPV types 16, 18, and 56, which are the most oncogenic, were most often detected.

Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBß3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer

Objectives: A growing body of evidence suggests the important role of chemosensitive gene expression in the prognosis of patients with lung cancer. However, studies on combined gene expression assessments for personalized prescriptions of chemotherapy regimens in patients have not yet been conducted. The aim of this work was to conduct a prospective study on the appointment of personalized chemotherapy in patients with non-small-cell lung cancer. Materials and methods: The present study analyzed 85 patients with lung cancer (stage IIB-IIIB). Within this group, 48 patients received individualized chemotherapy, and 37 patients received classical chemotherapy. In the individualized chemotherapy group, the mRNA expression levels of ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 in lung tissues were measured by quantitative real-time PCR (qPCR), and an individual chemotherapy regimen was developed for each patient according to the results. Patients in the classical chemotherapy group received the vinorelbine/carboplatin regimen. Survival analyses were performed using the Kaplan−Meier method. Prognostic factors of metastasis-free survival (MFS) and overall survival (OS) of patients were identified via Cox's proportional hazards regression model. Results: MFS and OS were significantly better in the personalized chemotherapy group compared to the classic chemotherapy group (MFS, 46.22 vs. 22.9 months, p = 0.05; OS, 58.6 vs. 26.9 months, p < 0.0001). Importantly, the best metastasis-free survival rates in the group with personalized ACT were achieved in patients treated with the paclitaxel/carboplatin regimen. Based on an assessment of chemosensitivity gene expression in the tumors, the classical chemotherapy strategy also increased the risk of death (HR = 14.82; 95% CI: 3.33−65.86; p < 0.000) but not metastasis (HR = 1.95; 95% CI: 0.96−3.98; p = 0.06) compared to the group of patients with chemotherapy. Conclusions: The use of combined ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 gene expression results for personalized chemotherapy can improve treatment efficacy and reduce unnecessary toxicity.

A Criterion of Colorectal Cancer Diagnosis Using Exosome Fluorescence-Lifetime Imaging.

This study was aimed to investigate the applicability of the exosome fluorescence-lifetime imaging microscopy (FLIM) for colorectal cancer (CRC) diagnosis. Differential ultra-centrifugation was used to extract exosomes from the blood plasma of 11 patients with colon polyps (CPs) and 13 patients with CRC at the T2-4, N0-3, and M0-1 stages. Analysis was performed using a two-photon FLIM device. In total, 165 and 195 FLIM images were recorded for the CP and CCR patient groups, respectively. Two classes of exosomes differentiated by autofluorescence average lifetime tm were discovered in the samples. The first class of exosomes with tm = (0.21 ± 0.06) ns was mostly found in samples from CRC patients. The second class with tm = (0.43 ± 0.19) ns was mostly found in samples from CP patients. The relative number of "CRC-associated" exosomes Nch in the FLIM dataset was shown to be very small for the CP patient group and large for the CRC patient group. This difference was statistically significant. Therefore, the suggested CRS diagnostics criterion can be as follows. If Nch > 0.5, the probability of CRC is high. If Nch < 0.3, the probability of CRC is low.

Interaction Features of Sodium Oleate and Oxyethylated Phosphoric Acid Esters with the Apatite Surface.

Apatite ores are the most important phosphate materials used for the agricultural and livestock chemical production. With the global demand for phosphorous compounds, apatite and other phosphorus-bearing ores are being depleted. The main method of apatite ore enrichment at the moment is the flotation process, the efficiency of which depends on complex heterogeneous processes occurring at the boundary of three phases ("liquid-gas", "solid-liquid", and "solid-gas"). Significant influence on the process have the flotation modes and composition of the reagent mixture, which provide a synergistic effect. The purpose of this work was to investigate the reasons for the synergism of surfactants used in apatite ore flotation with fatty acid-based collectors. The object of the study is a monomineral fraction of apatite, separated from the apatite-nepheline ore of Khibiny deposits. In the course of the work, it was found that the mixture of sodium oleate and phospholane PE65 has a synergistic effect on the mineral surface of apatite during foam flotation. The ratio of reagents was determined at which the maximum synergistic effect was observed.

Thermodynamic Characteristics of the Hydrogen Sulfide Sorption Process by Ferromanganese Materials.

The work analyzes hydrogen sulfide sorption from model gas mixtures containing H2S from 1.25 × 10-3 to 1.28 × 10-4 mol/L under static conditions at temperatures 253 and 298 K on the raw manganese ore of the Ulu-Telyak deposit (Bashkortostan, Russia), manganese(IV) oxide, and manganese(IV) and iron(III) oxide mixtures. The thermodynamic models for calculating the equilibrium constants and Gibbs energy changes were analyzed. The sorption isotherms were described by the Langmuir, Freundlich, Temkin, and Dubinin-Radushkevich models. The value of enthalpy of hydrogen sorption on the ore was -68.98 ± 3.45 kJ/mol and those on model mixtures Mn4 + Fe2O3 and MnO4 were ±12.20 kJ/mol and -103.826 ± 5.19 kJ/mol, respectively, and the entropies of the hydrogen sulfide sorption process on three manganese materials at 253 K were calculated. The limiting capacity values of manganese materials at 253 and 298 K were obtained. The morphological analysis of the ore samples, Mn4 + Fe2O3, and MnO4, before and after hydrogen sulfide sorption, was carried out at 253 K. The obtained thermodynamic parameters determine the advantage of using the raw manganese ore over pure oxides, which characterizes its effective practical application in the desulfurization process.

Exosomal Protease Cargo as Prognostic Biomarker in Colorectal Cancer.

OBJECTIVE: The aim of the study was to develop a model for predicting cancer risk in colorectal polyps' patients (CPPs), as well as to reveal additional prognosis factors for Stage III colorectal cancer based on differences in subpopulations of tetraspanins, tetraspanin-associated and tetraspanin-non-associated proteases in blood plasma exosomes of CPPs and colorectal cancer patients (CRCPs). METHODS: The subpopulations of CD151- and Tspan8-positive exosomes, the subpopulations of metalloproteinase at the surface of СD9-positive exosomes and the level of 20S proteasomes in plasma exosomes in 15 CPPs (tubulovillous adenomas) and 60 CRCPs were evaluated using flow cytometry and Western blotting. Logistic regression analysis was performed to predict cancer risk of CPPs. RESULTS: The levels of 20S proteasomes in exosomes, MMP9+, MMP9+/MMP2+/EMMPRIN+ in CD9-positive blood plasma exosomes are associated with the risk of malignant transformation of colorectal tubulovillous adenomas.  In patients with Stage III CRC, the levels of 20S proteasomes (less than 2 units) and MMP9+ subpopulations (more than 61%) in plasma exosomes are unfavorable prognostic factors for overall survival. The levels of 20S proteasomes and ADAM10+/ADAM17- subpopulations in CD9-positive blood plasma exosomes are the most significant values for predicting relapse-free survival. CONCLUSION: Protease cargo in CD9-positive blood plasma exosomes is prognostic biomarker for colorectal polyps and colorectal cancer.

Long interspersed nuclear element-1 methylation status in the circulating DNA from blood of patients with malignant and chronic inflammatory lung diseases.

Along with other malignant diseases, lung cancer arises from the precancerous lung tissue state. Aberrant DNA methylation (hypermethylation of certain genes and hypomethylation of retrotransposons) is known as one of the driving forces of malignant cell transformation. Epigenetic changes were shown to be detectable in DNA, circulating in the blood (cirDNA) of cancer patients, indicating the possibility to use them as cancer markers. The current study is the first to compare the Long interspersed nuclear element-1 (LINE-1) methylation level in the blood from lung cancer patients before treatment versus different control groups as healthy subjects, patients with bronchitis and patients with chronic obstructive pulmonary disease (COPD). The concentration of LINE-1 methylated fragments, region 1 (LINE-1 methylated, LINE-1-met) was estimated by quantitative methyl-specific PCR. The total concentration of the circulating LINE-1 copies was measured by qPCR specific for LINE-1 region 2, which was selected due to its CpG methylation-independent sequence (LINE-1-Ind). Both LINE-1 methylation level and LINE-1 methylation index (LINE-1-met/LINE-1-Ind ratio) was decreased in lung cancer patients compared with the joint control group (healthy subjects + patients with bronchitis + COPD patients) (Mann-Whitney U-test, P = 0.016). We also found that the tendency of LINE-1 methylation index decreases in the cirDNA from lung cancer patients versus COPD patients (Mann-Whitney U-test, P = 0.07). Our data indicate that the quantitative analysis of the LINE-1 methylation level in the cirDNA is valuable for discrimination of lung cancer patients from patients with chronic inflammatory lung diseases.

Nanoparticles in Gastric Cancer Management.

Gastric cancer is the second most common cause of cancer-related deaths in the world. The surgical management of the tumor is the best therapeutic option for gastric cancer patients. A combination of a heterogeneous distribution of genetic and environmental factors appears to be required to explain patients' poor prognosis. A search for targeted and molecular-based approaches is affected by the optimal gastric cancer drug management. The modern multidisciplinary approach to treating the pathology used worldwide prolongs the overall patient survival and decreases the rate of recurrence. An understanding of the mechanisms that underlie therapies will provide new insights into gastric cancer treatment. The improvement in medicine will probably be associated with a study of tumor biology, followed by a personalized and molecular-based approach development in anticancer drugs administration. The modern perspective in gastric cancer detection and treatment is the application of nanoparticles. Nanoparticles affecting the intensity of biological processes in cancer cells can be used to treat cancers to increase the effectiveness of anti-tumor therapy. Their cytotoxicity involves a wide range of pathological events. Their targets are the extracellular matrix degradation, epithelial-mesenchymal transition, tumor angiogenesis, tumor microenvironment modulation. These are accompanied by lipid peroxidation, apoptosis, and autophagic flux. Preliminary studies on the efficacy of the use of nanoparticles in cultured gastric cancers open new opportunities for anti-tumor treatment to overcome the toxicity of therapeutic agents and decrease the rate of resistance to anticancer drugs and therapies.

Molecular Mechanism of Resistance to Chemotherapy in Gastric Cancers, the Role of Autophagy.

Gastric cancer (GC) is biologically and genetically heterogeneous with complex carcinogenesis at the molecular level. Despite the application of multiple approaches in the GC treatment, its 5-year survival is poor. A major limitation of anti-cancer drugs application is intrinsic or acquired resistance, especially to chemotherapeutical agents. It is known that the effectiveness of chemotherapy remains debatable and varies according to the molecular type of GC. Chemotherapy has an established role in the management of GC. Perioperative chemotherapy or postoperative chemotherapy is applied for localized ones. Most of the advanced GC patients have a poor response to treatment and unfavorable outcomes with standard therapies. Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of MAPK, AKT/mTOR, and Wnt/ß-catenin signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. We have summarized the mechanisms of resistance development to cisplatin, 5-fluorouracil, and multidrug resistance in the GC management. The complexity of molecular targets and components of signaling cascades altered in the resistance development results in the absence of significant benefits in GC treatment, and its efficacy remains low. The universal process responsible for the failure in the multimodal approach in GC treatment is autophagy. Its dual role in oncogenesis is the most unexplored issue. We have discussed the possible mechanism of autophagy regulation upon the action of endogenous factors and drugs. The experimental data obtained in the cultured GC cells need further verification. To overcome the cancer resistance and to prevent autophagy as the main reason of ineffective treatment, it is suggested the concept of the direct influence of autophagy molecular markers followed by the standard chemotherapy. Dozen of studies have focused on finding the rationale for the benefits of such complex therapy. The perspectives in the molecular-based management of GC are associated with the development of molecular markers predicting the protective autophagy initiation and search for novel targets of effective anticancer therapy.