TEAD transcription factors pair with YAP and TAZ to orchestrate various transcriptional programs of cell proliferation and cell death suppression that promote cancer development.The structure of TEAD ...complexed with YAP/TAZ reveals several possible avenues for pharmacological modulation, making TEAD an attractive therapeutic target.Small molecules that bind to TEAD that abrogate activity are currently being tested in clinical trials.TEAD inhibitors may be effective monotherapies for a subset of cancers driven by the YAP/TAZ–TEAD transcriptional complex.The administration of TEAD inhibitors in combination with other targeted therapies is being investigated to overcome drug resistance.
The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)–TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.
Coronavirus disease 2019 (COVID-19) is sweeping the globe. Despite multiple case-series, actionable knowledge to tailor decision-making proactively is missing.
Can a statistical model accurately ...predict infection with COVID-19?
We developed a prospective registry of all patients tested for COVID-19 in Cleveland Clinic to create individualized risk prediction models. We focus here on the likelihood of a positive nasal or oropharyngeal COVID-19 test. A least absolute shrinkage and selection operator logistic regression algorithm was constructed that removed variables that were not contributing to the model's cross-validated concordance index. After external validation in a temporally and geographically distinct cohort, the statistical prediction model was illustrated as a nomogram and deployed in an online risk calculator.
In the development cohort, 11,672 patients fulfilled study criteria, including 818 patients (7.0%) who tested positive for COVID-19; in the validation cohort, 2295 patients fulfilled criteria, including 290 patients who tested positive for COVID-19. Male, African American, older patients, and those with known COVID-19 exposure were at higher risk of being positive for COVID-19. Risk was reduced in those who had pneumococcal polysaccharide or influenza vaccine or who were on melatonin, paroxetine, or carvedilol. Our model had favorable discrimination (c-statistic = 0.863 in the development cohort and 0.840 in the validation cohort) and calibration. We present sensitivity, specificity, negative predictive value, and positive predictive value at different prediction cutoff points. The calculator is freely available at https://riskcalc.org/COVID19.
Prediction of a COVID-19 positive test is possible and could help direct health-care resources. We demonstrate relevance of age, race, sex, and socioeconomic characteristics in COVID-19 susceptibility and suggest a potential modifying role of certain common vaccinations and drugs that have been identified in drug-repurposing studies.
The identification of protein-protein interaction disruptors (PPIDs) that disrupt the YAP/TAZ-TEAD interaction has gained considerable momentum. Several studies have shown that YAP/TAZ are no longer ...oncogenic when their interaction with the TEAD family of transcription factors is disrupted. The transcriptional co-regulator YAP (its homolog TAZ) interact with the surface pockets of TEADs. Peptidomimetic modalities like cystine-dense peptides and YAP cyclic and linear peptides exploit surface pockets (interface 2 and interface 3) on TEADs and function as PPIDs. The TEAD surface might pose a challenge for generating an effective small molecule PPID. Interestingly, TEADs also have a central pocket that is distinct from the surface pockets, and which small molecules leverage exclusively to disrupt the YAP/TAZ-TEAD interaction (allosteric PPIDs). Although small molecules that occupy the central pocket belong to diverse classes, they display certain common features. They are flexible, which allows them to adopt a palmitate-like conformation, and they have a predominant hydrophobic portion that contacts several hydrophobic residues and a small hydrophilic portion that faces the central pocket opening. Despite such progress, more selective PPIDs that also display favorable pharmacokinetic properties and show tolerable toxicity profiles are required to evaluate the feasibility of using these PPIDs for cancer therapy.
Sox10: a pan-schwannian and melanocytic marker Nonaka, Daisuke; Chiriboga, Luis; Rubin, Brian P
The American journal of surgical pathology,
09/2008, Letnik:
32, Številka:
9
Journal Article
Recenzirano
S100 protein is a sensitive marker for melanomas and peripheral nerve sheath tumors. It is, however, expressed by other mesenchymal and epithelial tumors. Despite its low specificity, S100 protein is ...valuable for the diagnosis of desmoplastic melanomas and peripheral nerve sheath tumors, for which no specific marker is available. Sox10 is a neural crest transcription factor crucial for specification, maturation, and maintenance of Schwann cells and melanocytes. Anti-Sox10 antibody was applied to a variety of neural crest-derived tumors, mesenchymal and epithelial neoplasms, and normal tissues. Sox10 nuclear expression was found in 76 of 78 melanomas (97%) and 38 of 77 malignant peripheral nerve sheath tumors (49%) whereas S100 protein was expressed in 71 melanomas (91%) and 23 malignant peripheral nerve sheath tumors (30%). Sox10 was diffusely expressed in schwannomas and neurofibromas. Sox10 reaction was seen only in sustentacular cells of pheochromocytomas/paragangliomas, and occasionally carcinoid tumors from various organs, but it was not seen in the tumor cells. In normal tissues, Sox10 was expressed in Schwann cells, melanocytes, and myoepithelial cells of salivary, bronchial, and mammary glands. Sox10 reaction was not identified in any other mesenchymal and epithelial tumors except for myoepitheliomas and diffuse astrocytomas. Sox10 was expressed by metastatic melanomas and nodal capsular nevus in sentinel lymph nodes, but not by other lymph node components such as dendritic cells. Our results indicate that Sox10 will serve as a more sensitive and specific marker for the diagnosis of melanocytic and schwannian tumors than S100 protein.
Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants ...remains limited.
Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes.
In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 26.9 and 513/696 73.7, respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2.
Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.
Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the ...boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.
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•Enhancers active in the cell of origin are co-amplified with oncogenes•Circular extrachromosomal amplicons are associated with enhancer rewiring•Endogenous and new enhancers on amplicons contribute to cell proliferation•Skewed co-amplification that selects enhancers is found across several tumor types
Extrachromosomal oncogene amplification is a common occurrence across a broad range of cancers, yet the chromatin landscape of these high-level amplifications is poorly understood. Using a combination of approaches to explore their chromatin topology and enhancer landscape, Morton et al. observed that these oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.
Genome sequencing enhances our understanding of the biological world by providing blueprints for the evolutionary and functional diversity that shapes the biosphere. However, microbial genomes that ...are currently available are of limited phylogenetic breadth, owing to our historical inability to cultivate most microorganisms in the laboratory. We apply single-cell genomics to target and sequence 201 uncultivated archaeal and bacterial cells from nine diverse habitats belonging to 29 major mostly uncharted branches of the tree of life, so-called 'microbial dark matter'. With this additional genomic information, we are able to resolve many intra- and inter-phylum-level relationships and to propose two new superphyla. We uncover unexpected metabolic features that extend our understanding of biology and challenge established boundaries between the three domains of life. These include a novel amino acid use for the opal stop codon, an archaeal-type purine synthesis in Bacteria and complete sigma factors in Archaea similar to those in Bacteria. The single-cell genomes also served to phylogenetically anchor up to 20% of metagenomic reads in some habitats, facilitating organism-level interpretation of ecosystem function. This study greatly expands the genomic representation of the tree of life and provides a systematic step towards a better understanding of biological evolution on our planet.
Activating mutations in KIT/PDGFRA receptor tyrosine kinases drive gastrointestinal stromal tumors (GIST). KIT/PDGFRA inhibitors, such as imatinib do not evoke an effective cytocidal response, ...leaving room for quiescence and development of multiple secondary resistance mutations. As the majority of the secondary resistance clones activate PI3K and MAPK pathways, we investigated whether combined targeting of KIT/PI3K/MAPK (KPM) pathways overcomes drug resistance and quiescence in GIST cells. We monitored the proliferation of imatinib–sensitive and–resistant GIST cell lines after treating them with various combinations of drugs to inhibit KPM pathways. Cytocidal response was evaluated through proliferation, apoptosis and colony outgrowth assays. Combined inhibition of KPM signaling pathways using a KPM inhibitor cocktail decreased the survival of drug-resistant GIST cells and dramatically reduced their proliferation. Downstream pathway analysis showed that the residual PI3K/MAPK signaling observed after KIT inhibitor treatment plays a role in mediating quiescence and drug resistance. The KPM inhibitor cocktail with sunitinib or regorafenib effectively induced apoptosis and prevented colony outgrowth after long-term drug removal, suggesting that it can be used as an effective strategy against quiescence and drug resistance in metastatic GIST.
Gastrointestinal stromal tumour Rubin, Brian P, MD; Heinrich, Michael C, Prof; Corless, Christopher L, Prof
The Lancet (British edition),
05/2007, Letnik:
369, Številka:
9574
Journal Article
Recenzirano
Summary Gastrointestinal stromal tumours are the most common mesenchymal neoplasm of the gastrointestinal tract and are highly resistant to conventional chemotherapy and radiotherapy. Such tumours ...usually have activating mutations in either KIT (75–80%) or PDGFRA (5–10%), two closely related receptor tyrosine kinases. These mutations lead to ligand-independent activation and signal transduction mediated by constitutively activated KIT or PDGFRA. Targeting these activated proteins with imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic gastrointestinal stromal tumours and is now being tested as an adjuvant or neoadjuvant. However, resistance to imatinib is a growing problem and other targeted therapeutics such as sunitinib are available. The important interplay between the molecular genetics of gastrontestinal stromal tumour and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumours.
More than 90% of chondroblastomas contain a heterozygous mutation replacing lysine-36 with methionine-36 (K36M) in the histone H3 variant H3.3. Here we show that H3K36 methylation is reduced globally ...in human chondroblastomas and in chondrocytes harboring the same genetic mutation, due to inhibition of at least two H3K36 methyltransferases, MMSET and SETD2, by the H3.3K36M mutant proteins. Genes with altered expression as well as H3K36 di- and trimethylation in H3.3K36M cells are enriched in cancer pathways. In addition, H3.3K36M chondrocytes exhibit several hallmarks of cancer cells, including increased ability to form colonies, resistance to apoptosis, and defects in differentiation. Thus, H3.3K36M proteins reprogram the H3K36 methylation landscape and contribute to tumorigenesis, in part through altering the expression of cancer-associated genes.
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