Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients Resistant to Topotecan

Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression signatures derived from patient specimens at surgery and available subsequent responses to therapy. Gene expression was collected for 1436 patients and 10,103 genes. Based on disease progression, patients were categorized as responders/nonresponders depending on their progression free survival (PFS) state at 9, 12, 15 and 18 months after surgery. For each gene, the median expression was compared between responders and nonresponders for two treatment regimens (chemotherapy including/excluding topotecan) with Mann-Whitney U test at each of the four different PFS cutoffs. Statistical significance was accepted in the case of p < 0.05 with a fold change (FC) 1.44. Four genes (EPB41L2, HLA-DQB1, LTF and SFRP1) were consistently overexpressed across multiple PFS cutoff times in initial tumor samples of patients with disease progression following topotecan treatment. A common theme linked to topotecan resistance was altered immune modulation. Genes associated with disease progression after systemic chemotherapy emphasize the role of the initial organization of the tumor microenvironment in therapy resistance. Our results uncover biomarkers with potential utility for patient stratification

Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples.

Transcriptomic analysis of global gene expression in ovarian carcinoma can identify dysregulated genes capable to serve as molecular markers for histology subtypes and survival. The aim of our study was to validate previous candidate signatures in an independent setting and to identify single genes capable to serve as biomarkers for ovarian cancer progression. As several datasets are available in the GEO today, we were able to perform a true meta-analysis. First, 829 samples (11 datasets) were downloaded, and the predictive power of 16 previously published gene sets was assessed. Of these, eight were capable to discriminate histology subtypes, and none was capable to predict survival. To overcome the differences in previous studies, we used the 829 samples to identify new predictors. Then, we collected 64 ovarian cancer samples (median relapse-free survival 24.5 months) and performed TaqMan Real Time Polimerase Chain Reaction (RT-PCR) analysis for the best 40 genes associated with histology subtypes and survival. Over 90% of subtype-associated genes were confirmed. Overall survival was effectively predicted by hormone receptors (PGR and ESR2) and by TSPAN8. Relapse-free survival was predicted by MAPT and SNCG. In summary, we successfully validated several gene sets in a meta-analysis in large datasets of ovarian samples. Additionally, several individual genes identified were validated in a clinical cohort

Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples

Transcriptomic analysis of global gene expression in ovarian carcinoma can identify dysregulated genes capable to serve as molecular markers for histology subtypes and survival. The aim of this study was to validate previous candidate signatures in an independent setting and to identify single genes capable to serve as biomarkers for ovarian cancer progression. As several datasets are available in the GEO today, we were able to perform a true meta-analysis. First, 829 samples (11 datasets) were downloaded, and the predictive power of 16 previously published gene sets was assessed. Of these, 8 were capable to discriminate histology subtypes and none was capable to predict survival. To overcome the differences in previous studies, we used the 829 samples to identify new predictors. Then we collected 64 ovarian cancer samples (median relapse-free survival 24.5 months) and performed TaqMan RT-PCR analysis for the best 40 genes associated with histology subtypes and survival. Over 90% of subtype-associated genes were confirmed. Overall survival was effectively predicted by hormone receptors (PGR and ESR2) and by TSPAN8. Relapse-free survival was predicted by MAPT and SNCG. In summary, we successfully validated several gene sets in a meta-analysis in large datasets of ovarian samples. Additionally, several individual genes identified were validated in a clinical cohort

A nemszinaptikus nikotinikus acetilkolin és NMDA receptorok szerepe élettani körülmények között és pathológiás állapotokban = Role of nonsynaptic nicotinic acetylcholine receptors and NMDA receptors in physiological and pathophysiological conditions

A szélütés (stroke) utáni neurodegeneráció a jelenlegi morbiditási és mortalitási mutatók egyik legfontosabb tényezője. Az iszkémiás stroke kezelésében számos ígéretes gyógyszerjelölt molekula vallott kudarcot a klinikai vizsgálatokban. Ennek valószínűleg az az oka, hogy hiányosak ismereteink az iszkémiás kórképek kialakulásának mechanizmusaira vonatkozólag. A legtöbb központi idegrendszerre ható gyógyszert szinaptikusan elhelyezkedő receptorokra vagy transzporterekre fejlesztik annak érdekében, hogy igazán hatékony gyógyszereket tudjunk fejleszteni, figyelembe kell venni, hogy az extraszinaptikus receptorok és transzporterek száma jóval meghaladja a szinaptikusakét, illetve hogy nagyon sok központi idegrendszeri megbetegedés alapja a nemszinaptikus rendszer malfunkciója. Például, a szinaptikus NMDA receptorok aktivációja neuroprotektív hatást fejt ki, míg az extraszinaptikus NMDA receptor aktiváció excitotoxikus hatású. Konkrét javaslataink a gyógyszerfejlesztést illetően: Az NR2B alegységet tartalmazó NMDA receptorok szelektív gátlói (mint például a fluoxetine), és a nátriumcsatorna gátlók egyes típusai; mint neuroprotektív szerek. A nikotinikus agonisták pozitív modulátorai, amelyek a kognitív problémák kezelésében, ill. a dohányzásról való leszokás segítésében lehetnek hasznosak. | Neurodegeneration after a stroke is one of the major causes of present-day morbidity and mortality. There is a long list of neuroprotective compounds that have failed to be clinically useful in the treatment of ischaemic stroke. This is likely due, at least in part, to our inadequate knowledge regarding the core mechanisms of ischaemic diseases. Most “novel” drugs that target the CNS are designed to act on neurotransmitter receptors or transporters that are localised within synapses. To develop the most effective drugs, it is important to remember that there are extrasynaptic receptors and transporters that may outnumber those located within synapses and that, when malfunctioning, may be responsible for several symptoms of CNS disorders. For example, activation of synaptic NMDA receptors is neuroprotective, whereas stimulation of extrasynaptic NMDA receptors causes excitotoxicity. We suggest that future drug development research consider the following: Compounds that are able to selectively inhibit non-synaptic NR2B Glu receptors (such as Fluoxetine), and specific subtypes of sodium channel inhibitors as neuroprotective compounds. Positive modulators of nicotinic acetylcholine receptors. They would be potential drugs in the treatment of memory problems and in smoking cessation

Nationwide experiences with trough levels, durability, and disease activity among inflammatory bowel disease patients following COVID-19 vaccination.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has complicated the management of inflammatory bowel diseases (IBD).This study aimed to assess the efficacy of different anti-SARS-CoV-2 vaccines under different treatments in IBD patients and identify predictive factors associated with lower serological response, including anti-tumor necrosis factor (anti-TNF) drug levels.A prospective, double-center study of IBD patients was conducted following messenger ribonucleotide acid (mRNA) and non-mRNA anti-SARS-CoV-2 vaccination.Healthy control (HC) patients were enrolled to reduce bias. Baseline and control samples were obtained 14 days after the second dose to assess the impact of conventional and biological treatments. Clinical and biochemical activity, serological response level, and anti-TNF drug levels were measured.This study included 199 IBD (mean age, 40.9 ± 12.72 years) and 77 HC participants (mean age, 50.3 ± 12.36 years). Most patients (76.9%) and all HCs received mRNA vaccines. Half of the IBD patients were on biological treatment (anti-TNF 68.7%). Biological and thiopurine combined immunomodulation and biological treatment were associated with lower serological response (p < 0.001), and mRNA vaccination promoted better antibody levels (p < 0.001). Higher adalimumab levels caused lower serological response (p = 0.006). W8 persistence of anti-SARS-CoV-2 level was equal in IBD and HC groups. Vaccination did not aggravate clinical disease activity (p = 0.65).Anti-SARS-CoV-2 vaccination is considerably efficacious in IBD patients, with mRNA vaccines promoting better antibody levels. The negative impact of combined biological treatment, especially with high adalimumab drug levels, on serological response to vaccination should be considered. Although midterm durability of vaccination is encouraging, more data are needed to expand the existing understanding on this issue

Magyar Tanítóképző 51 (1938) 1

Magyar Tanítóképző A Tanítóképző-intézeti Tanárok Országos Egyesületének folyóirata 51. évfolyam, 1. szám Budapest, 1938. januá

New Transcriptomic Biomarkers of 5-Fluorouracil Resistance

The overall response rate to fluoropyrimidine monotherapy in colorectal cancer (CRC) is limited. Transcriptomic datasets of CRC patients treated with 5-fluorouracil (5FU) could assist in the identification of clinically useful biomarkers. In this research, we aimed to analyze transcriptomic cohorts of 5FU-treated cell lines to uncover new predictive biomarker candidates and to validate the strongest hits in 5FU-treated human colorectal cancer samples with available clinical response data. We utilized an in vitro dataset of cancer cell lines treated with 5FU and used the reported area under the dose–response curve values to determine the therapeutic response to 5FU treatment. Mann–Whitney and ROC analyses were performed to identify significant genes. The strongest genes were combined into a single signature using a random forest classifier. The compound 5-fluorouracil was tested in 592 cell lines (294 nonresponders and 298 responders). The validation cohort consisted of 157 patient samples with 5FU monotherapy from three datasets. The three strongest associations with treatment outcome were observed in SHISA4 (AUC = 0.745, p-value = 5.5 × 10−25), SLC38A6 (AUC = 0.725, p-value = 3.1 × 10−21), and LAPTM4A (AUC = 0.723, p-value = 6.4 × 10−21). A random forest model utilizing the top genes reached an AUC value of 0.74 for predicting therapeutic sensitivity. The model correctly identified 83% of the nonresponder and 73% of the responder patients. The cell line cohort is available and the entire human colorectal cohort have been added to the ROCPlot analysis platform. Here, by using in vitro and in vivo data, we present a framework enabling the ranking of future biomarker candidates of 5FU resistance. A future option is to conduct an independent validation of the established predictors of resistance

miRNA Expression Signatures of Therapy Response in Squamous Cell Carcinomas

Introduction: Squamous cell carcinomas (SCC) are a major subgroup of malignant tumors with a platinum-based first-line systematic chemotherapy. miRNAs play a role in various diseases and modulate therapy response as well. The aim of this study was to identify predictive miRNAs in platinum-treated SCCs. Methods: miRNA expression data of platinum-treated head and neck (HNSC), cervical (CESC) and lung (LUSC) cancer were collected from the TCGA repositories. Treatment response was defined based on presence or absence of disease progression at 18 months. Responder and nonresponder cohorts were compared using Mann&ndash;Whitney and Receiver Operating Characteristic tests. Logistic regression was developed to establish a predictive miRNA signature. Significance was set at FDR &lt; 5%. Results: The integrated database includes 266 SCC patient samples with platinum-based therapy and available follow-up. We uncovered 16, 103, and 9 miRNAs correlated to chemotherapy response in the CESC, HNSC, and LUSC cohorts, respectively. Eight miRNAs overlapped between the CESC and HNSC subgroups, and three miRNAs overlapped between the LUSC and HNSC subgroups. We established a logistic regression model in HNSC and CESC which included six miRNAs: hsa-miR-5586 (Exp (B): 2.94, p = 0.001), hsa-miR-632 (Exp (B): 10.75, p = 0.002), hsa-miR-2355 (Exp (B): 0.48, p = 0.004), hsa-miR-642a (Exp (B): 2.22, p = 0.01), hsa-miR-101-2 (Exp (B): 0.39, p = 0.013) and hsa-miR-6728 (Exp (B): 0.21, p = 0.016). The model using these miRNAs was able to predict chemotherapy resistance with an AUC of 0.897. Conclusions: We performed an analysis of RNA-seq data of squamous cell carcinomas samples and identified significant miRNAs correlated to the response against platinum-based therapy in cervical, head and neck, and lung tumors