The diagnosis of new variants and monitoring their potential effects on diagnosis, therapeutics, and vaccines by genomic sequencing is essential to manage global public crises. In the current study, ...spike-genome next-generation sequencing was generated from 492 SARS-CoV-2 isolates to evaluate the mutations in Turkey from April 2021 to February 2022. The variant analysis was performed using (Coronavirus Antiviral and Resistance Database (CoV-RDB) by Stanford University). We revealed that the lineages Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), Eta (B.1.525), variant of interest (VOI), lota (B.1.526), Zeta (P.2), Omicron (B.1.1.529), and Omicron BA.1 (B.1.1.529.1) were in the circulation in Turkey during the given period. The most common lineages were B.1.1.7, B.1.617.2, B.1.1.529, and B.1.1.529.1 SARS-CoV-2 variant circulation in Turkey seems highly heterogenetic; however, quite similar to the global epidemiologic analysis. The existence of globally circulating variants in the same chronological order in Turkey can be a guide for precautions, treatment, and vaccine options to be taken in the future.
Despite the availability of various treatment protocols, response to therapy in patients with Acute Myeloid Leukemia (AML) remains largely unpredictable. Transcriptomic profiling studies have thus ...far revealed the presence of molecular subtypes of AML that are not accounted for by standard clinical parameters or by routinely used biomarkers. Such molecular subtypes of AML are predicted to vary in response to chemotherapy or targeted therapy. The Renin-Angiotensin System (RAS) is an important group of proteins that play a critical role in regulating blood pressure, vascular resistance and fluid/electrolyte balance. RAS pathway genes are also known to be present locally in tissues such as the bone marrow, where they play an important role in leukemic hematopoiesis. In this study, we asked if the RAS genes could be utilized to predict drug responses in patients with AML. We show that the combined in silico analysis of up to five RAS genes can reliably predict sensitivity to Doxorubicin as well as Etoposide in AML. The same genes could also predict sensitivity to Doxorubicin when tested in vitro. Additionally, gene set enrichment analysis revealed enrichment of TNF-alpha and type-I IFN response genes among sensitive, and TGF-beta and fibronectin related genes in resistant cancer cells. However, this does not seem to reflect an epithelial to mesenchymal transition per se. We also identified that RAS genes can stratify patients with AML into subtypes with distinct prognosis. Together, our results demonstrate that genes present in RAS are biomarkers for drug sensitivity and the prognostication of AML.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. In order to better prognosticate ...patients with PDAC, we identified 20 genes by utilizing publically available high-throughput transcriptomic data from GEO, TCGA and ICGC which are associated with overall survival and event-free survival. A score generated based on the expression matrix of these genes was validated in two independent cohorts. We find that this "Pancreatic cancer prognostic score 20 -PPS20" is independent of the confounding factors in multivariate analyses, is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological sub-groups but can predict response to targeted therapy as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This research paper presents a novel approach to identifying biomarkers that can be used to prognosticate patients with triple-negative breast cancer (TNBC) eligible for neoadjuvant therapy. The ...study utilized survival and RNA sequencing data from a cohort of TNBC patients and identified 276 genes whose expression was related to survival in such patients. The gene expression data were then used to classify patients into two major groups based on the presence or absence of Wingless/Integrated-pathway (Wnt-pathway) and mesenchymal (Mes) markers (Wnt/Mes). Patients with a low expression of Wnt/Mes-related genes had a favorable outcome, with no deaths observed during follow-up, while patients with a high expression of Wnt/Mes genes had a higher mortality rate of 50% within 19 months. The identified gene list could be validated and potentially used to shape treatment options for TNBC patients eligible for neoadjuvant therapy providing valuable insights into the development of more effective treatments for TNBC. Our data also showed significant variation in gene expression profiles before and after chemotherapy, with most tumors switching to a more mesenchymal/stem cell-like profile. To verify this observation, we performed an in silico analysis to classify breast cancer tumors in Prediction Analysis of Microarray 50 (PAM50) molecular classes before treatment and after treatment using gene expression data. Our findings demonstrate that following drug intervention and metastasis, certain tumors undergo a transition to alternative subtypes, resulting in diminished therapeutic efficacy. This underscores the necessity for reevaluation of patients who have experienced relapse or metastasis post-chemotherapy, with a focus on molecular subtyping. Tailoring treatment strategies based on these refined subtypes is imperative to optimize therapeutic outcomes for affected individuals.
The prognosis of malignant pleural mesothelioma (MPM) is poor, with a limited survival time. In this study, we aimed to examine expression levels of genes selected from relevant literature and to ...utilize in silico methods to determine genes whose expression could reflect the prognosis of patients with MPM by
validation experiments.
The study group consisted of 54 MPM patients treated with chemotherapy. Expression of 6 genes - midkine (MDK), syndecan-1 (SDC1), hyaluronan synthase-2 (HAS2), sestrin-1 (SESN1), laminin subunit alpha-4 (LAMA4), and fibulin-3 (FBLN3) - was examined by qPCR in tumor tissues. Sestrin-1 and LAMA4 were identified using an in house R-based script: Unsupervised Survival Analysis Tool. Midkine, SDC1, HAS2, and FBLN3 were selected from current literature. We used two housekeeping genes, i.e. glucose-6-phosphate dehydrogenase and TATA-box binding protein, as controls.
Of the patients, 43 (79.6%) had epithelioid mesothelioma. The median survival for all patients was 10 (±1.2 SE) months (95% CI: 7.7-12.3). In multivariate analyses, MDK (
= 0.007), HAS2 (
= 0.008) and SESN1 (
= 0.014) expression levels were related to survival time in the whole group. In epithelioid type MPM patients, MDK (
= 0.014), FBLN3 (
= 0.029), HAS2 (
= 0.014) and SESN1 (
= 0.045) expression was related to survival time in multivariate analyses.
High HAS2 and SESN1 expressions and low MDK are potential biomarkers of good prognosis in MPM. High HAS2 and SESN1 expression and low MDK and FBLN3 can also be utilized as biomarkers of good prognosis for epithelioid MPM. Those results should be further investigated in sera, plasma, and pleural effusions.
Abstract
Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug ...resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine ...to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better ( p = 0.0001 ) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone ( p = 0.007 ). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.
The study's objective was to assess whether the performance of the DIAGNOVITAL SARS-CoV-2 Mutation Detection Assays is affected by Omicron mutations. In silico evaluation of 67,717 Variant of ...Concern, Variant of Interest sequences and 6,612 sequences of the Omicron variants involving BA1., BA2., BA3 sub-lineages downloaded from the GISAID database by 17 December 2021, were performed. The sequences were aligned according to the reference genome MN908947.3 using MAFFT multiple sequence alignment software version 7. Our findings showed that among 6,612 Omicron, 41 Spike gene mutations with a frequency of ≥70% were identified. Some of the Omicron mutations (R408S, N440K, G446S, Q493S, Q498R) could affect the diagnostic performance of K417N, L452R, and E484K assays against the Omicron sub-lineages. However, L452R and K417N mutation tests allow differentiation of the Delta and Omicron variants mutation profile. The COVID-19 pandemic lasted longer than expected, and the rapid modification of diagnostic kits seems necessary to combat the pandemic.
This study determined SARS-CoV-2 variations by phylogenetic and virtual phenotyping analyses.
Strains isolated from 143 COVID-19 cases in Turkey in April 2021 were assessed. Illumina ...NexteraXT library preparation kits were processed for next-generation sequencing. Phylogenetic (neighbor-joining method) and virtual phenotyping analyses (Coronavirus Antiviral and Resistance Database CoV-RDB by Stanford University) were used for variant analysis.
B.1.1.7–1/2 (n = 103, 72%), B.1.351 (n = 5, 3%) and B.1.525 (n = 1, 1%) were identified among 109 SARS-CoV-2 variations by phylogenetic analysis and B.1.1.7 (n = 95, 66%), B.1.351 (n = 5, 4%), B.1.617 (n = 4, 3%), B.1.525 (n = 2, 1.4%), B.1.526-1 (n = 1, 0.6%) and missense mutations (n = 15, 10%) were reported by CoV-RDB. The two methods were 85% compatible and B.1.1.7 (alpha) was the most frequent SARS-CoV-2 variation in Turkey in April 2021.
The Stanford CoV-RDB analysis method appears useful for SARS-CoV-2 lineage surveillance.
PDF
