Six-Gene Signature for Differential Diagnosis and Therapeutic Decisions in Non-Small-Cell Lung Cancer-A Validation Study.

Non-small-cell lung cancer (NSCLC) poses a challenge due to its heterogeneity, necessitating precise histopathological subtyping and prognostication for optimal treatment decision-making. Molecular markers emerge as a potential solution, overcoming the limitations of conventional methods and supporting the diagnostic-therapeutic interventions. In this study, we validated the expression of six genes (MIR205HG, KRT5, KRT6A, KRT6C, SERPINB5, and DSG3), previously identified within a 53-gene signature developed by our team, utilizing gene expression microarray technology. Real-time PCR on 140 thoroughly characterized early-stage NSCLC samples revealed substantial upregulation of all six genes in squamous cell carcinoma (SCC) compared to adenocarcinoma (ADC), regardless of clinical factors. The decision boundaries of the logistic regression model demonstrated effective separation of the relative expression levels between SCC and ADC for most genes, excluding KRT6C. Logistic regression and gradient boosting decision tree classifiers, incorporating all six validated genes, exhibited notable performance (AUC: 0.8930 and 0.8909, respectively) in distinguishing NSCLC subtypes. Nevertheless, our investigation revealed that the gene expression profiles failed to yield predictive value regarding the progression of early-stage NSCLC. Our molecular diagnostic models manifest the potential for an exhaustive molecular characterization of NSCLC, subsequently informing personalized treatment decisions and elevating the standards of clinical management and prognosis for patients.

miRNA Studies in Glaucoma: A Comprehensive Review of Current Knowledge and Future Perspectives.

Glaucoma, a neurodegenerative disorder that leads to irreversible blindness, remains a challenge because of its complex nature. MicroRNAs (miRNAs) are crucial regulators of gene expression and are associated with glaucoma and other diseases. We aimed to review and discuss the advantages and disadvantages of miRNA-focused molecular studies in glaucoma through discussing their potential as biomarkers for early detection and diagnosis; offering insights into molecular pathways and mechanisms; and discussing their potential utility with respect to personalized medicine, their therapeutic potential, and non-invasive monitoring. Limitations, such as variability, small sample sizes, sample specificity, and limited accessibility to ocular tissues, are also addressed, underscoring the need for robust protocols and collaboration. Reproducibility and validation are crucial to establish the credibility of miRNA research findings, and the integration of bioinformatics tools for miRNA database creation is a valuable component of a comprehensive approach to investigate miRNA aberrations in patients with glaucoma. Overall, miRNA research in glaucoma has provided significant insights into the molecular mechanisms of the disease, offering potential biomarkers, diagnostic tools, and therapeutic targets. However, addressing challenges such as variability and limited tissue accessibility is essential, and further investigations and validation will contribute to a deeper understanding of the functional significance of miRNAs in glaucoma.

Serum Insights: Leveraging the Power of miRNA Profiling as an Early Diagnostic Tool for Non-Small Cell Lung Cancer.

Non-small cell lung cancer is the predominant form of lung cancer and is associated with a poor prognosis. MiRNAs implicated in cancer initiation and progression can be easily detected in liquid biopsy samples and have the potential to serve as non-invasive biomarkers. In this study, we employed next-generation sequencing to globally profile miRNAs in serum samples from 71 early-stage NSCLC patients and 47 non-cancerous pulmonary condition patients. Preliminary analysis of differentially expressed miRNAs revealed 28 upregulated miRNAs in NSCLC compared to the control group. Functional enrichment analyses unveiled their involvement in NSCLC signaling pathways. Subsequently, we developed a gradient-boosting decision tree classifier based on 2588 miRNAs, which demonstrated high accuracy (0.837), sensitivity (0.806), and specificity (0.859) in effectively distinguishing NSCLC from non-cancerous individuals. Shapley Additive exPlanations analysis improved the model metrics by identifying the top 15 miRNAs with the strongest discriminatory value, yielding an AUC of 0.96 ± 0.04, accuracy of 0.896, sensitivity of 0.884, and specificity of 0.903. Our study establishes the potential utility of a non-invasive serum miRNA signature as a supportive tool for early detection of NSCLC while also shedding light on dysregulated miRNAs in NSCLC biology. For enhanced credibility and understanding, further validation in an independent cohort of patients is warranted.

miRNA-Seq Tissue Diagnostic Signature: A Novel Model for NSCLC Subtyping.

Non-small cell lung cancer (NSCLC) encompasses distinct histopathological subtypes, namely adenocarcinoma (AC) and squamous cell lung carcinoma (SCC), which require precise differentiation for effective treatment strategies. In this study, we present a novel molecular diagnostic model that integrates tissue-specific expression profiles of microRNAs (miRNAs) obtained through next-generation sequencing (NGS) to discriminate between AC and SCC subtypes of NSCLC. This approach offers a more comprehensive and precise molecular characterization compared to conventional methods such as histopathology or immunohistochemistry. Firstly, we identified 31 miRNAs with significant differential expression between AC and SCC cases. Subsequently, we constructed a 17-miRNA signature through rigorous multistep analyses, including LASSO/elastic net regression. The signature includes both upregulated miRNAs (hsa-miR-326, hsa-miR-450a-5p, hsa-miR-1287-5p, hsa-miR-556-5p, hsa-miR-542-3p, hsa-miR-30b-5p, hsa-miR-4728-3p, hsa-miR-450a-1-3p, hsa-miR-375, hsa-miR-147b, hsa-miR-7705, and hsa-miR-653-3p) and downregulated miRNAs (hsa-miR-944, hsa-miR-205-5p, hsa-miR-205-3p, hsa-miR-149-5p, and hsa-miR-6510-3p). To assess the discriminative capability of the 17-miRNA signature, we performed receiver operating characteristic (ROC) curve analysis, which demonstrated an impressive area under the curve (AUC) value of 0.994. Our findings highlight the exceptional diagnostic performance of the miRNA signature as a stratifying biomarker for distinguishing between AC and SCC subtypes in lung cancer. The developed molecular diagnostic model holds promise for providing a more accurate and comprehensive molecular characterization of NSCLC, thereby guiding personalized treatment decisions and improving clinical management and prognosis for patients.

Applied Molecular-Based Quality Control of Biobanked Samples for Multi-Omics Approach.

Biobanks are vital for high-throughput translational research, but the rapid development of novel molecular techniques, especially in omics assays, poses challenges to traditional practices and recommendations. In our study, we used biospecimens from oncological patients in Polish clinics and collaborated with the Indivumed Group. For serum/plasma samples, we monitored hemolysis, controlled RNA extraction, assessed cDNA library quality and quantity, and verified NGS raw data. Tissue samples underwent pathologic evaluation to confirm histology and determine tumor content. Molecular quality control measures included evaluating the RNA integrity number, assessing cDNA library quality and quantity, and analyzing NGS raw data. Our study yielded the creation of distinct workflows for conducting preanalytical quality control of serum/plasma and fresh-frozen tissue samples. These workflows offer customization options to suit the capabilities of different biobanking entities. In order to ensure the appropriateness of biospecimens for advanced research applications, we introduced molecular-based quality control methods that align with the demands of high-throughput assays. The novelty of proposed workflows, rooted in innovative molecular techniques, lies in the integration of these QC methods into a comprehensive schema specifically designed for high-throughput research applications.

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives.

Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC.

Clinical Validation of GenBody COVID-19 Ag, Nasal and Nasopharyngeal Rapid Antigen Tests for Detection of SARS-CoV-2 in European Adult Population.

Accurate and rapid identification of COVID-19 is critical for effective patient treatment and disease outcomes, as well as the prevention of SARS-CoV-2 transmission. Rapid antigen tests (RATs) for identifying SARS-CoV-2 are simpler, faster and less expensive than molecular assays. Any new product to be considered a medical device is subject to evaluation and data analysis to verify the in vitro diagnostic ability to achieve its intended purpose. Clinical validation of such a test is a prerequisite before clinical application. This study was a clinical validation on adult Europeans of GenBody COVID-19 Ag, nasal and nasopharyngeal RATs. A set of 103 positive and 301 negative from nose and nasopharynx samples confirmed by RT-qPCR were examined. The tests were safe to use and showed 100% specificity in both specimens, and high sensitivity of 94.17% (95%CI 87.75% to 97.83%) and 97.09% (95%CI 91.72% to 99.4%), respectively. The parameters were significantly better for samples with higher virus loads (the highest for CT ≤ 25). The GenBody COVID-19 Ag RATs are inexpensive (compared to RT-qPCR), reliable and rapid with high sensitivity and specificity, making them suitable for diagnosis and timely isolation and treatment of COVID-19 patients, contributing to the better control of virus spread.

Quantitative analysis of RT-PCR test results for SARS-CoV-2 diagnostics across Poland during COVID-19 pandemic: Comparison between early stage and major pandemic waves in 2020 and 2021 with reference to SARS-CoV-2 variants.

PURPOSE: From April to September 2020, Poland was minimally affected by COVID-19 compared to other EU countries. We aimed to investigate the risks of false reverse transcription polymerase chain reaction (RT-PCR) results during the first wave (compared to later waves), that rises when cycle threshold (Ct) of positive result is close to limit of detection (LOD). MATERIALS/METHODS: We analyzed Ct values of SARS-CoV-2 positive RT-PCR results of 7726 patients in Poland from April-September 2020. SARS-CoV-2 positive RT-PCR results of 14,534 patients in the 2nd-3rd wave and 10,861 patients in the 4th-5th pandemic waves were used. Statistical analysis was based on one-way analysis of variance. To verify, 95% confidence intervals with Bonferroni correction were computed. Incidence of SARS-CoV-2 variants in Poland was analyzed using Whole Genome Sequencing from 923 (3.6%) patients. RESULTS: The mean Ct of RT-PCR positive test results analyzed ranged between 22.89 and 26.71 depending on the month of the results collection. The differences between months were significant (p â€‹< â€‹0.001). Differences in Ct were observed between age groups, with younger patients displaying higher Ct values, however, major trends over time were paralleled between age groups. CONCLUSIONS: The mean Ct of the tested RT-PCR positive test results was lower than 35 which is considered an upper borderline for reliable positive results of the assay. Therefore, most COVID-19 cases recorded in Poland from April to September 2020 were detected with minor risks of inaccuracy. Data from a single center exhibited greater consistency for both virus Ct level and SARS-CoV-2 virus variant identification.

A Signature of 14 Long Non-Coding RNAs (lncRNAs) as a Step towards Precision Diagnosis for NSCLC.

LncRNAs have arisen as new players in the world of non-coding RNA. Disrupted expression of these molecules can be tightly linked to the onset, promotion and progression of cancer. The present study estimated the usefulness of 14 lncRNAs (HAGLR, ADAMTS9-AS2, LINC00261, MCM3AP-AS1, TP53TG1, C14orf132, LINC00968, LINC00312, TP73-AS1, LOC344887, LINC00673, SOX2-OT, AFAP1-AS1, LOC730101) for early detection of non-small-cell lung cancer (NSCLC). The total RNA was isolated from paired fresh-frozen cancerous and noncancerous lung tissue from 92 NSCLC patients diagnosed with either adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC). The expression level of lncRNAs was evaluated by a quantitative real-time PCR (qPCR). Based on Ct and delta Ct values, logistic regression and gradient boosting decision tree classifiers were built. The latter is a novel, advanced machine learning algorithm with great potential in medical science. The established predictive models showed that a set of 14 lncRNAs accurately discriminates cancerous from noncancerous lung tissues (AUC value of 0.98 ± 0.01) and NSCLC subtypes (AUC value of 0.84 ± 0.09), although the expression of a few molecules was statistically insignificant (SOX2-OT, AFAP1-AS1 and LOC730101 for tumor vs. normal tissue; and TP53TG1, C14orf132, LINC00968 and LOC730101 for LUAD vs. LUSC). However for subtypes discrimination, the simplified logistic regression model based on the four variables (delta Ct AFAP1-AS1, Ct SOX2-OT, Ct LINC00261, and delta Ct LINC00673) had even stronger diagnostic potential than the original one (AUC value of 0.88 ± 0.07). Our results demonstrate that the 14 lncRNA signature can be an auxiliary tool to endorse and complement the histological diagnosis of non-small-cell lung cancer.

Plasmid Mediated mcr-1.1 Colistin-Resistance in Clinical Extraintestinal Escherichia coli Strains Isolated in Poland.

Objectives: The growing incidence of multidrug-resistant (MDR) bacteria is an inexorable and fatal challenge in modern medicine. Colistin is a cationic polypeptide considered a "last-resort" antimicrobial for treating infections caused by MDR Gram-negative bacterial pathogens. Plasmid-borne mcr colistin resistance emerged recently, and could potentially lead to essentially untreatable infections, particularly in hospital and veterinary (livestock farming) settings. In this study, we sought to establish the molecular basis of colistin-resistance in six extraintestinal Escherichia coli strains. Methods: Molecular investigation of colistin-resistance was performed in six extraintestinal E. coli strains isolated from patients hospitalized in Medical University Hospital, Bialystok, Poland. Complete structures of bacterial chromosomes and plasmids were recovered with use of both short- and long-read sequencing technologies and Unicycler hybrid assembly. Moreover, an electrotransformation assay was performed in order to confirm IncX4 plasmid influence on colistin-resistance phenotype in clinical E. coli strains. Results: Here we report on the emergence of six mcr-1.1-producing extraintestinal E. coli isolates with a number of virulence factors. Mobile pEtN transferase-encoding gene, mcr-1.1, has been proved to be encoded within a type IV secretion system (T4SS)-containing 33.3 kbp IncX4 plasmid pMUB-MCR, next to the PAP2-like membrane-associated lipid phosphatase gene. Conclusion: IncX4 mcr-containing plasmids are reported as increasingly disseminated among E. coli isolates, making it an "epidemic" plasmid, responsible for (i) dissemination of colistin-resistance determinants between different E. coli clones, and (ii) circulation between environmental, industrial, and clinical settings. Great effort needs to be taken to avoid further dissemination of plasmid-mediated colistin resistance among clinically relevant Gram-negative bacterial pathogens.

The first SARS-CoV-2 genetic variants of concern (VOC) in Poland: The concept of a comprehensive approach to monitoring and surveillance of emerging variants.

PURPOSE: We analyzed the SARS-CoV-2 genome using our integrated genome analysis system and present the concept of a comprehensive approach to monitoring and surveillance of emerging variants. MATERIAL/METHODS: A total of 69 SARS-CoV-2 positive samples (with Ct value â€‹≤ â€‹28) were tested. Samples included in this study were selected from 7 areas of eastern Poland. All samples were sequenced on an Illumina MiSeq platform using a 300-cycle MiSeq Reagent Kit v2. BWA was used for reads mapping on the reference SARS-CoV-2 sequence. SAMTools were used for post-processing of reads to genome assembly. Pango lineage and Nexstrain were used to identify variants and amino acid mutations. Statistical analysis was performed with R 4.0.2. RESULTS: This study shows the first confirmed case of SARS-CoV-2 in Poland with the lineage B.1.351 (known as 501Y.V2 South African variant), as well as another 18 cases with epidemiologically relevant lineage B.1.1.7, known as British variant. Supplementary analysis of SARS-CoV-2 sequences deposited in GISAID shows that the share of a new variant can change rapidly within one month. In addition, we show a complete, integrated concept of a networked system for analyzing the variability of the SARS-CoV-2 genome, which, used in the present study, generated data and a variant report within 6 days. CONCLUSION: The analyzed viral genomes showed considerable variability with simultaneous clear distinction of local clusters of genomes showing high similarity. Implementing real-time monitoring of new SARS-CoV-2 variants in Poland is urgently needed, and our developed system is available to be implemented on a large scale.

[Corrigendum] Pituitary sex hormones enhance the pro­metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase­1.

After the publication of the article, the authors realize that they overlooked stating that the author Magda Kucia was the recipient of an OPUS grant (grant no. UMO­2016/21/B/NZ4/00201). Therefore, the Acknowledgements section of the paper should have read as follows (the added text is highlighted in bold): "This study was supported by NIH grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment, and NCN Harmonia grant UMO­2014/14/M/NZ3/00475 to M.Z.R., and OPUS grant UMO­2016/21/B/NZ4/00201 to M.K." The authors regret their oversight in failing to include this information in the Acknowledgements section of their paper. [the original article was published in International Journal of Oncology 50: 317-328, 2017; DOI: 10.3892/ijo.2016.3787].

Systematic biobanking, novel imaging techniques, and advanced molecular analysis for precise tumor diagnosis and therapy: The Polish MOBIT project.

Personalized and precision medicine is gaining recognition due to the limitations by standard diagnosis and treatment; many areas of medicine, from cancer to psychiatry, are moving towards tailored and individualized treatment for patients based on their clinical characteristics and genetic signatures as well as novel imaging techniques. Advances in whole genome sequencing have led to identification of genes involved in a variety of diseases. Moreover, biomarkers indicating severity of disease or susceptibility to treatment are increasingly being characterized. The continued identification of new genes and biomarkers specific to disease subtypes and individual patients is essential and inevitable for translation into personalized medicine, in estimating both, disease risk and response to therapy. Taking into consideration the mostly unsolved necessity of tailored therapy in oncology the innovative project MOBIT (molecular biomarkers for individualized therapy) was designed. The aims of the project are: (i) establishing integrative management of precise tumor diagnosis and therapy including systematic biobanking, novel imaging techniques, and advanced molecular analysis by collecting comprehensive tumor tissues, liquid biopsies (whole blood, serum, plasma), and urine specimens (supernatant; sediment) as well as (ii) developing personalized lung cancer diagnostics based on tumor heterogeneity and integrated genomics, transcriptomics, metabolomics, and radiomics PET/MRI analysis. It will consist of 5 work packages. In this paper the rationale of the Polish MOBIT project as well as its design is presented. (iii) The project is to draw interest in and to invite national and international, private and public, preclinical and clinical initiatives to establish individualized and precise procedures for integrating novel targeted therapies and advanced imaging techniques.

Gene Expression Signature Differentiates Histology But Not Progression Status of Early-Stage NSCLC.

Advances in molecular analyses based on high-throughput technologies can contribute to a more accurate classification of non-small cell lung cancer (NSCLC), as well as a better prediction of both the disease course and the efficacy of targeted therapies. Here we set out to analyze whether global gene expression profiling performed in a group of early-stage NSCLC patients can contribute to classifying tumor subtypes and predicting the disease prognosis. Gene expression profiling was performed with the use of the microarray technology in a training set of 108 NSCLC samples. Subsequently, the recorded findings were validated further in an independent cohort of 44 samples. We demonstrated that the specific gene patterns differed significantly between lung adenocarcinoma (AC) and squamous cell lung carcinoma (SCC) samples. Furthermore, we developed and validated a novel 53-gene signature distinguishing SCC from AC with 93% accuracy. Evaluation of the classifier performance in the validation set showed that our predictor classified the AC patients with 100% sensitivity and 88% specificity. We revealed that gene expression patterns observed in the early stages of NSCLC may help elucidate the histological distinctions of tumors through identification of different gene-mediated biological processes involved in the pathogenesis of histologically distinct tumors. However, we showed here that the gene expression profiles did not provide additional value in predicting the progression status of the early-stage NSCLC. Nevertheless, the gene expression signature analysis enabled us to perform a reliable subclassification of NSCLC tumors, and it can therefore become a useful diagnostic tool for a more accurate selection of patients for targeted therapies.

Profiling of selected angiogenesis-related genes in serous ovarian cancer patients.

PURPOSE: Since angiogenesis plays an important role in the pathogenesis of ovarian cancer the aim of the study was to compare the expression of the most relevant angiogenesis-related genes in serous ovarian cancer samples. Genes were divided into 5 subgroups according to their angiogenic potential: growth factors and their receptors; cytokines/chemokines; adhesion molecules and other matrix related proteins; transcriptions factors and signaling molecules; morphogenic factors, and angiogenesis inhibitors. MATERIALS/METHODS: Twenty-nine patients were involved in the study: 20 with serous ovarian cancer and 9 healthy controls. All neoplasms were confirmed by histopathological examination. Healthy ovarian control samples were obtained from women diagnosed with fibroids and had previously scheduled operations. Real-time PCR gene arrays were used to examine the expression of 84 human angiogenesis-related genes and expression of selected proteins was assessed with ELISA. RESULTS: Significantly higher expressions of 46 genes were found in the ovarian cancer group compared to the healthy control group. By the use of ELISA we confirmed the expression of three proteins i.e.: angiopoietin-2, angiopoietin-like protein 3, and angiopoietin receptor 2. Only angiopoietin-2 and angiopoietin receptor 2 showed significant differences between ovarian cancer and healthy controls. CONCLUSIONS: Changes in the expression of selected genes associated with angiogenesis may add new information to the pathogenesis of ovarian cancer. Although the angiopoietin-2 signaling pathway may play an important role in neovascularization in ovarian cancer, the role of angiopoietin-like protein 3 is yet to be established.

Prognostic significance of Notch ligands in patients with non-small cell lung cancer.

The Notch signaling pathway is deregulated in numerous solid types of cancer including non-small cell lung cancer (NSCLC). However, the profile of Notch ligand expression remains unclear. Therefore, the present study aimed to determine the profile of Notch ligands in NSCLC patients and to investigate whether quantitative assessment of Notch ligand expression may have prognostic significance in NSCLC patients. The study was performed in 61 pairs of tumor and matched unaffected lung tissue specimens obtained from patients with various stages of NSCLC, which were analyzed by reverse transcription-polymerase chain reaction. The marked expression levels of certain analyzed genes were detected in NSCLC samples and in noncancerous lung samples. Of the five Notch ligands, jagged 1 (Jag1), jagged 2, delta-like protein 1 and delta-like protein 4 were expressed in the majority of tissues, but their expression levels were reduced in NSCLC when compared with noncancerous lung tissue (P<0.001). Delta-like protein 3 expression was consistently low and was observed only in 21/61 tumor tissue samples. Taken together, Notch ligands are expressed in NSCLC. However, the expression level is reduced when compared to noncancerous tissue. Furthermore, the present study revealed that quantitative assessment of Jag1 expression in NSCLC may improve prognostication of patient survival.

Pituitary sex hormones enhance the pro­metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase­1.

We report that human lung cancer cell lines express functional receptors for pituitary sex hormones (SexHs) and respond to stimulation by follicle­stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL). Expression of these receptors has also been confirmed in patient lung cancer samples at the mRNA level. Stimulation of human lung cancer cell lines with FSH, LH, or PRL stimulated migration and chemotaxis, and some cell lines responded by enhanced proliferation. Moreover, priming of human lung cancer cells by exposing them to pituitary SexHs resulted in enhanced seeding efficiency of injected human lung cancer cells into bone marrow, liver, and lungs in an immunodeficient mouse model. The chemotaxis of lung cancer cell lines corresponded with the activity of heme oxygenase­1 (HO­1), as stimulation of these cells by FSH, LH, and PRL downregulated its expression in a p38 MAPK­dependent manner. Moreover, while downregulation of HO­1 by the small­molecule inhibitor tin protoporphyrin (SnPP) promoted migration, upregulation of HO­1 by the small­molecule activator cobalt protoporphyrin (CoPP) showed the opposite effect. Based on this finding, we propose that pituitary SexHs play a significant role in the pathogenesis of lung cancer, particularly when the blood level of FSH increases due to gonadal dysfunction with advanced age. Finally, we propose that upregulation of HO­1 expression by a small­molecule activator may be effective in controlling SexH­induced cell migration in lung cancer.

Lipid mediators involved in the oxidative stress and antioxidant defence of human lung cancer cells.

BACKGROUND: The oxidative modifications of bioactive macromolecules have important roles in carcinogenesis. Of particular interest are lipid peroxidation products, which are involved in the activation of Nrf2 and endocannabinoids that affect cancer progression. METHODS: In lung cancer tissues (squamous cell lung carcinoma - SCC and adenocarcinoma - AC), the glutathione peroxidase and catalase activity and glutathione level, together with the expression of Nrf2 and its activators/inhibitors were estimated. The oxidative modifications of DNA (8-hydroxy-2'-deoxyguanosine and N7-methylguanine), endocannabinoids (anandamide and 2- arachidonylglyceriol), their receptors (CB1/2, TRV1, GPR55), phospholipid fatty acids (arachidonic, linoleic and docosahexaenoic), and reactive aldehydes (4-hydroxynonenal, 4-oxononenal and malondialdehyde) were determined. RESULTS: Tumour tissues showed lower antioxidant capacity than healthy tissues, which was accompanied by lower levels of fatty acids and higher levels of reactive aldehydes. Disturbances in antioxidant capacity and enhanced DNA oxidative modifications were observed in 88% of AC patients and 81% of SCC patients. The 4-hydroxynonenal-Histidine adducts were detected in the necrotic and stromal cells in all tumours. These findings were associated with the enhanced Nrf2 activity, especially in AC. The strong difference between the cancer subtypes was evident in the levels of endocannabinoids, with an increase in 89% of SCC and a decrease in 85% of AC patients being observed. Additionally, the increase in the expression of CB1/2 receptors was observed only in 82% of AC, while the expression of VR1 and GPR55 was enhanced in 79% of SCC and 82% of AC patients. CONCLUSIONS: This study shows significant differences in the redox status, Nrf2 pathway and endocannabinoid system between SCC and AC tissues. Understanding the relation between the various lipid mediators and antioxidants in different lung cancer subtypes may be beginning for further research on the effective anticancer therapy.

Effects of different omeprazole dosing on gastric pH in non-variceal upper gastrointestinal bleeding: A randomized prospective study.

OBJECTIVE: We aimed to identify the best method of omeprazole (OME) application with respect to intragastric pH, cytochrome P450 2C19 (CYP2C19) genotype and phenotype. METHODS: The patients with non-variceal upper gastrointestinal bleeding (NVUGIB) were prospectively enrolled. After the achievement of endoscopic hemostasis, the patients were randomized to 40-mg intravenous (i.v.) OME bolus injection every 12 h or 8-mg/h continuous i.v. infusion for 72 h after an 80-mg i.v. OME bolus administration. The intragastric pH was recorded for 72 h. The CYP2C19 variant alleles (*2, *3, *17) were analyzed and the serum concentrations of OME and 5-hydroxyomeprazole (5-OH OME) were determined. RESULTS: Altogether 41 Caucasians (18 in the OME infusion [OI] group and 23 in the OME bolus [OB] group) were analyzed. The median percentage of time with an intragastric pH > 4.0 was higher in the infusion group than in the OB group over 48 h (100% vs 96.6%, P = 0.009) and 72 h (100% vs 87.6%, P = 0.006), and that at an intragastric pH >6.0 was higher in the OI group than the OB group over 72 h (97.9% vs 63.5%, P = 0.04). Helicobacter pylori infection was correlated with the fastest increase in intragastric pH, especially in the OI group. In both groups, CYP2C19 genotypes (*1/*1, *1/*17, *17/*17) had no essential effect on intragastric pH. CONCLUSIONS: In patients with NVUGIB, OME i.v. bolus followed by continuous infusion is more effective than OME i.v. bolus every 12 h in maintaining higher intragastric pH, regardless of CYP2C19 genetic polymorphisms. H. pylori infection accelerates the initial elevation of intragastric pH.

Are anti-Müllerian hormone and its receptor polymorphism associated with the hormonal condition of undescended testes?

PURPOSE: Numerous genetic and endocrine factors are involved in the process of testicular descent, but only a few genetic causes have been reported in human. The aim of this study was to investigate the density and distribution of single nucleotide polymorphisms (SNPs) anti-Müllerian hormone (AMH) and AMHRII receptors in cryptorchid patients and determine potential hormone imbalance connected with undescended testes by assessing the levels of AMH, Insulin-like factor 3 (INSL3) and inhibin B. MATERIALS AND METHODS: The serum hormone levels (AMH, INSL3 and inhibin B) were compared in the two groups - cryptorchidism (n=105) and control group (n=58). The frequency of AMHRII -482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5-6 C>T, and AMH Ile49Ser polymorphisms among cryptorchid boys were compared with the control group. RESULTS: None of the hormones levels were different between the cryptorchid and the control groups. All cases of IVS 5-6 C>T homozygote and heterozygote mutation were accompanied by an IVS 10+77 A>G and 482 A>G homozygote and heterozygote mutation. Interestingly, in most cases of all four polymorphisms, homozygote recessive genotype was associated with cases of cryptorchidism. However, the groups of patients were too small to draw definite conclusions. CONCLUSION: The AMHRII -482 A>G, AMHRII IVS 10+77 A>G, AMHRII IVS 5-6 C>T and AMH Ile49Ser genotypes should be determined in a much larger group of boys with cryptorchidism.