Dead or alive? Pitfall of survival analysis with TCGA datasets.
Ontology highlight
ABSTRACT:
SUBMITTER: Idogawa M
PROVIDER: S-EPMC8726696 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The standard Gompertz equation for human survival fits very poorly the survival data of the very old (age 85 and above), who appear to survive better than predicted. An alternative Gompertz model based on the number of individuals who have died, rather than the number that are alive, at each age, tracks the data more accurately. The alternative model is based on the same differential equation as in the usual Gompertz model. The standard model describes the accelerated exponential decay of the number alive, whereas the alternative, heretofore unutilized model describes the decelerated exponential growth of the number dead. The alternative model is complementary to the standard and, together, the two Gompertz formulations allow accurate prediction of survival of the older as well as the younger mature members of the population.
| S-EPMC2585644 | biostudies-other
Project description:The Eph receptor tyrosine kinase member EphB6 is a pseudokinase, and similar to other pseudoenzymes has not attracted an equivalent amount of interest as its enzymatically-active counterparts. However, a greater appreciation for the role pseudoenzymes perform in expanding the repertoire of signals generated by signal transduction systems has fostered more interest in the field. EphB6 acts as a molecular switch that is capable of modulating the signal transduction output of Eph receptor clusters. Although the biological effects of EphB6 activity are well defined, the molecular mechanisms of EphB6 function remain enigmatic. In this review, we use a comparative approach to postulate how EphB6 acts as a scaffold to recruit adaptor proteins to an Eph receptor cluster and how this function is regulated. We suggest that the evolutionary repurposing of EphB6 into a kinase-independent molecular switch in mammals has involved repurposing the kinase activation loop into an SH3 domain-binding site. In addition, we suggest that EphB6 employs the same SAM domain linker and juxtamembrane domain allosteric regulatory mechanisms that are used in kinase-positive Eph receptors to regulate its scaffold function. As a result, although kinase-dead, EphB6 remains a strategically active component of Eph receptor signaling.
| S-EPMC8347583 | biostudies-literature
Project description:Reactivation of the multi-subunit ribonucleoprotein telomerase is the primary telomere maintenance mechanism in cancer, but it is rate-limited by the enzymatic component, telomerase reverse transcriptase (TERT). While regulatory in nature, TERT alternative splice variant/isoform regulation and functions are not fully elucidated and are further complicated by their highly diverse expression and nature. Our primary objective was to characterize TERT isoform expression across 7887 neoplastic and 2099 normal tissue samples using The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression Project (GTEx), respectively. We confirmed the global overexpression and splicing shift towards full-length TERT in neoplastic tissue. Stratifying by tissue type we found uncharacteristic TERT expression in normal brain tissue subtypes. Stratifying by tumor-specific subtypes, we detailed TERT expression differences potentially regulated by subtype-specific molecular characteristics. Focusing on β-deletion splicing regulation, we found the NOVA1 trans-acting factor to mediate alternative splicing in a cancer-dependent manner. Of relevance to future tissue-specific studies, we clustered cancer cell lines with tumors from related origin based on TERT isoform expression patterns. Taken together, our work has reinforced the need for tissue and tumour-specific TERT investigations, provided avenues to do so, and brought to light the current technical limitations of bioinformatic analyses of TERT isoform expression.
| S-EPMC8070023 | biostudies-literature
Project description:Oncogenic RAS proteins, which are mutated in approximately 24% of all human cancers, have earned a well-deserved reputation as being "undruggable." However, several studies have challenged that reputation. With the first small molecules that directly target one oncogenic RAS mutant (G12C) undergoing clinical evaluation, there have been substantial advances in finding anti-RAS therapeutic strategies. Furthermore, new insights have come from the growing appreciation that neither all RAS proteins (HRAS, NRAS, and KRAS4A/KRAS4B) nor all oncogenic RAS mutations (such as at residues Gly12, Gly13, and Gln61) have the same impact on RAS signaling and function. The role of the nonmutated, wild-type RAS proteins in the context of mutant RAS is increasingly considered to be targetable, with reports of strategies that directly disrupt either the RAS interaction with activating guanine nucleotide exchange factors (GEFs) or receptor tyrosine kinase-mediated and GEF-dependent RAS activation (such as by targeting the scaffolding phosphatase SHP2). Last, the development of agents that target downstream effectors of RAS signaling has advanced substantially. In this review, we highlight some important trends in the targeting of RAS proteins in cancer.
| S-EPMC7393681 | biostudies-literature
Project description:Small molecular dyes are commonly used for bacterial imaging, but they still meet a bottleneck of biological toxicity and fluorescence photobleaching. Carbon dots have shown high potential for bio-imaging due to their low cost and negligible toxicity and anti-photobleaching. However, there is still large space to enhance the quantum yield of the carbon quantum dots and to clarify their mechanisms of bacterial imaging. Using carbon dots for dyeing alive bacteria is difficult because of the thick density and complicated structure of bacterial cell walls. In this work, both dead or alive bacterial cell imaging can be achieved using the primary amine functionalized carbon dots based on their small size, excellent quantum yield and primary amine functional groups. Four types of carbon quantum dots were prepared and estimated for the bacterial imaging. It was found that the spermine as one of precursors can obviously enhance the quantum yield of carbon dots, which showed a high quantum yield of 66.46% and high fluorescence bleaching-resistance (70% can be maintained upon 3-h-irradiation). Furthermore, a mild modifying method was employed to bound ethylenediamine on the surface of the spermine-carbon dots, which is favorable for staining not only the dead bacterial cells but also the alive ones. Investigations of physical structure and chemical groups indicated the existence of primary amine groups on the surface of spermine-carbon quantum dots (which own a much higher quantum yield) which can stain alive bacterial cells visibly. The imaging mechanism was studied in detail, which provides a preliminary reference for exploring efficient and environment-friendly carbon dots for bacterial imaging.
| S-EPMC9920602 | biostudies-literature
Project description:A rapid decline of Abies koreana has been reported in most of the natural alpine habitats in Korea. It is generally accepted that this phenomenon is due to climate change even though no clear conclusions have been drawn. Most research has focused on abiotic environmental factors, but studies on the relationships between A. koreana and soil fungal microbiomes are scarce. In this study, the rhizoplane and rhizosphere fungal communities in the alive and dead Korean fir trees from its three major natural habitats including Mt. Deogyu, Mt. Halla, and Mt. Jiri in Korea were investigated to identify specific soil fungal groups closely associated with A. koreana. Soil fungal diversity in each study site was significantly different from another based on the beta diversity calculations. Heat tree analysis at the genus level showed that Clavulina, Beauveria, and Tomentella were most abundant in the healthy trees probably by forming ectomycorrhizae with Korean fir growth and controlling pests and diseases. However, Calocera, Dacrymyces, Gyoerffyella, Hydnotrya, Microdochium, Hyaloscypha, Mycosymbioces, and Podospora were abundant in the dead trees. Our findings suggested that Clavulina, Beauveria, and Tomentella are the major players that could be considered in future reforestation programs to establish ectomycorrhizal networks and promote growth. These genera may have played a significant role in the survival and growth of A. koreana in its natural habitats. In particular, the genus Gyoerffyella may account for the death of the seedlings. Our work presented exploratory research on the specific fungal taxa associated with the status of A. koreana.
| S-EPMC10896143 | biostudies-literature
Project description:Several large-scale human cancer genomics projects such as TCGA offered huge genomic and clinical data for researchers to obtain meaningful genomics alterations which intervene in the development and metastasis of the tumor. A web-based TCGA data analysis platform called TCGA4U was developed in this study. TCGA4U provides a visualization solution for this study to illustrate the relationship of these genomics alternations with clinical data. A whole genome screening of the survival related gene expression patterns in breast cancer was studied. The gene list that impacts the breast cancer patient survival was divided into two patterns. Gene list of each of these patterns was separately analyzed on DAVID. The result showed that mitochondrial ribosomes play a more crucial role in the cancer development. We also reported that breast cancer patients with low HSPA2 expression level had shorter overall survival time. This is widely different to findings of HSPA2 expression pattern in other cancer types. TCGA4U provided a new perspective for the TCGA datasets. We believe it can inspire more biomedical researchers to study and explain the genomic alterations in cancer development and discover more targeted therapies to help more cancer patients.
| S-EPMC4630377 | biostudies-literature
Project description:ObjectiveTo determine the reliability of the Social Security Death Master File (DMF) after the November 2011 changes limiting the inclusion of state records.Data sourcesSecondary data from the DMF, New York State (NYS) and New Jersey (NJ) Vital Statistics (VS), and institutional data warehouse.Study designRetrospective study. Two cohorts: discharge date before November 1, 2011, (pre-2011) or after (post-2011). Death in-hospital used as gold standard. NYS VS used for out-of-hospital death. Sensitivity, specificity, Cohen's Kappa, and 1-year survival calculated.Data collection methodsPatients matched to DMF using Social Security Number, or date of birth and Soundex algorithm. Patients matched to NY and NJ VS using probabilistic linking.Principal findings97 069 patients January 2007-March 2016: 39 075 pre-2011; 57 994 post-2011. 3777 (3.9 percent) died in-hospital. DMF sensitivity for in-hospital death 88.9 percent (? = 0.93) pre-2011 vs 14.8 percent (? = 0.25) post-2011. DMF sensitivity for NY deaths 74.6 percent (? = 0.71) pre-2011 vs 26.6 percent (? = 0.33) post-2011. DMF sensitivity for NJ deaths 62.6 percent (? = 0.64) pre-2011 vs 10.8 percent (? = 0.15) post-2011. DMF sensitivity for out-of-hospital death 71.4 percent pre-2011 (? = 0.58) vs 28.9 percent post-2011 (? = 0.34). Post-2011, 1-year survival using DMF data was overestimated at 95.8 percent, vs 86.1 percent using NYS VS.ConclusionsThe DMF is no longer a reliable source of death data. Researchers using the DMF may underestimate mortality.
| S-EPMC6338290 | biostudies-literature
Project description:Based on the profound biological insights of the last years into the molecular pathogenesis of mantle cell lymphoma and the clinical introduction of new targeted drugs, with high efficacy and a good safety profile, the therapeutic scenario for this tumor has been shown to be thoroughly favourable. No longer characterized by a uniformly dismal prognosis, mantle cell lymphoma has been revealed as a spectrum of different diseases, ranging from very indolent cases to highly aggressive and refractory ones. Thus, there is an urgent need to adapt therapy to accommodate the diverse presentations of the disease. High-dose chemotherapy, followed by autologous stem cell transplantation is the current standard of care for younger patients, generally providing high responses and long survival rates, but hampered by acute and long-term toxicity. In addition, some patients may be overtreated, while others could benefit from targeted approaches, based on the new, molecular-directed compounds. Such a personalized treatment based on the specific characteristics of individual patients may be guided by validated prognostic tools, such as the Mantle Cell Lymphoma International Prognostic Index and the Ki-67 Proliferative Index, as well as by early predictors of treatment response, like minimal residual disease analysis. Moreover, mutation screening of distinctive genomic alterations may provide new, predictive biomarkers, with an additional impact on clinical practice. Only after tailoring treatment according to the clinical and biological heterogeneity of the disease the role of transplantation and modern therapeutic options will be redefined in mantle cell lymphoma.
| S-EPMC4938333 | biostudies-literature
Project description:The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the driver mutations, genetic backgrounds, and key pathways activated across cancer types. Analysis of TCGA datasets have mostly focused on somatic mutations and translocations, with less emphasis placed on gene amplifications. Here we describe a bioinformatics screening strategy to identify putative cancer driver genes amplified across TCGA datasets. We carried out GISTIC2 analysis of TCGA datasets spanning 16 cancer subtypes and identified 486 genes that were amplified in two or more datasets. The list was narrowed to 75 cancer-associated genes with potential "druggable" properties. The majority of the genes were localized to 14 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 42 putative cancer driver genes linked to diverse oncogenic processes. Oncogenic activity was further validated by siRNA/shRNA knockdown and by referencing the Project Achilles datasets. The amplified genes represented a number of gene families, including epigenetic regulators, cell cycle-associated genes, DNA damage response/repair genes, metabolic regulators, and genes linked to the Wnt, Notch, Hedgehog, JAK/STAT, NF-KB and MAPK signaling pathways. Among the 42 putative driver genes were known driver genes, such as EGFR, ERBB2 and PIK3CA. Wild-type KRAS was amplified in several cancer types, and KRAS-amplified cancer cell lines were most sensitive to KRAS shRNA, suggesting that KRAS amplification was an independent oncogenic event. A number of MAP kinase adapters were co-amplified with their receptor tyrosine kinases, such as the FGFR adapter FRS2 and the EGFR family adapters GRB2 and GRB7. The ubiquitin-like ligase DCUN1D1 and the histone methyltransferase NSD3 were also identified as novel putative cancer driver genes. We discuss the patient tailoring implications for existing cancer drug targets and we further discuss potential novel opportunities for drug discovery efforts.
| S-EPMC4038530 | biostudies-literature