Doddrossen2242
Importantly, rigosertib treatment delays tumor growth and prolongs survival in a xenograft model of RMS. In conclusion, rigosertib, through its impact on the mitotic spindle, represents a potential therapeutic for RMS.Mesothelioma is a universally lethal cancer lacking effective therapy. The spindle poison vinorelbine exhibits clinical activity in the relapsed setting, and in preclinical models requires BRCA1 to initiate apoptosis. However, the mechanisms underlying this regulation and the clinical implications have not been explored. Here, we show that BRCA1 silencing abrogated vinorelbine-induced cell-cycle arrest, recruitment of BUBR1 to kinetochores, and apoptosis. BRCA1 silencing led to codepletion of MAD2L1 at the mRNA and protein levels consistent with its status as a transcriptional target of BRCA1 Silencing of MAD2L1 phenocopied BRCA1 and was sufficient to confer resistance to vinorelbine. This was recapitulated in cell lines selected for resistance to vinorelbine, which acquired loss of both BRCA1 and MAD2L1 expression. Following ex vivo vinorelbine in 20 primary tumor explants, apoptotic response rate was 59% in BRCA1/MAD2L1-positive explants compared with 0% in BRCA1/MAD2L1-negative explants. In 48 patients, BRCA1 and/or MAD2L1 loss of expression was not prognostic; however, in a subset of patients treated with vinorelbine, survival was shorter for patients lacking BRCA1/MAD2L1 expression compared with double-positive patients (5.9 vs. 36.7 months, P = 0.03). Our data implicate BRCA1/MAD2L1 loss as a putative predictive marker of resistance to vinorelbine in mesothelioma and warrant prospective clinical evaluation.Acute myeloid leukemia (AML) is characterized by impaired myeloid lineage differentiation, uncontrolled proliferation, and inhibition of proapoptotic pathways. In spite of a relatively homogeneous clinical disease presentation, risk of long-term survival in AML varies from 20% to 80% depending on molecular disease characteristics. In recognition of the molecular heterogeneity of AML, the European Leukemia Net (ELN) and WHO classification systems now incorporate cytogenetics and increasing numbers of gene mutations into AML prognostication. Pevonedistat supplier Several of the genomic AML subsets are characterized by unique transcription factor alterations that are highlighted in this review. There are many mechanisms of transcriptional deregulation in leukemia. We broadly classify transcription factors based on mechanisms of transcriptional deregulation including direct involvement of transcription factors in recurrent translocations, loss-of-function mutations, and intracellular relocalization. Transcription factors, due to their pleiotropic effects, have been attractive but elusive targets. Indirect targeting approaches include inhibition of upstream kinases such as TAK1 for suppression of NFκB signaling and downstream effectors such as FGF signaling in HOXA-upregulated leukemia. Other strategies include targeting scaffolding proteins like BrD4 in the case of MYC or coactivators such as menin to suppress HOX expression; disrupting critical protein interactions in the case of β-cateninTCF/LEF, and preventing transcription factor binding to DNA as in the case of PU.1 or FOXM1. We comprehensively describe the mechanism of deregulation of transcription factors in genomic subsets of AML, consequent pathway addictions, and potential therapeutic strategies.
Notwithstanding the widespread implementation of flow diverters (FDs) in the treatment of intracranial aneurysms, the exact mechanism of action of these devices remains elusive. We aimed to advance the understanding of cellular responses to FD implantation using a 3D tissue-engineered in vitro aneurysm model.
Aneurysm-like blood vessel mimics (aBVMs) were constructed by electrospinning polycaprolactone nanofibers onto desired aneurysm-like geometries. aBVMs were seeded with human aortic smooth muscle cells (SMCs) followed by human aortic endothelial cells (ECs). FDs were then deployed in the parent vessel of aBVMs covering the aneurysm neck and were cultivated for 7, 14, or 28 days (n=3 for each time point). The EC and SMC coverage in the neck was measured semi-quantitatively.
At day 7, the device segment in contact with the parent vessel was partially endothelialized. Also, the majority of device struts, but not pores, at the parent vessel and neck interface were partially covered with ECs and SMCs, while device struts in the middle of the neck lacked cell coverage. At 14 days, histology verified a neointimal-like lining had formed, partially covering both the struts and pores in the center of the neck. At 28 days, the majority of the neck was covered with a translucent neointimal-like layer. A higher degree of cellular coverage was seen on the struts and pores at the neck at 28 days compared with both 7 and 14 days.
aBVMs can be a valuable alternative tool for evaluating the healing mechanisms of endovascular aneurysm devices.
aBVMs can be a valuable alternative tool for evaluating the healing mechanisms of endovascular aneurysm devices.
Morphological differences between ruptured and unruptured cerebral aneurysms represent a focus of neuroimaging researchfor understanding the mechanisms of aneurysmal rupture. We evaluated the performance of Radiomics derived morphological features, recently proposed for rupture status classification, against automatically measured shape and size features previously established in the literature.
353 aneurysms (123 ruptured) from three-dimensional rotational catheter angiography (3DRA) datasets were analyzed. Based on a literature review, 13 Radiomics and 13 established morphological descriptors were automatically extracted per aneurysm, and evaluated for rupture status prediction using univariate and multivariate statistical analysis, yielding an area under the curve (AUC) metric of the receiver operating characteristic.
Validation of overlapping descriptors for size/volume using both methods were highly correlated (p<0.0001,
=0.99). Univariate analysis selected AspectRatio (p<0.0001, AUC=0.75mpared with established descriptors. Future research is needed to extend the current Radiomics feature set to better capture aneurysm shape information.
Although recently introduced Radiomics analysis for aneurysm shape and size evaluation has the advantage of being an efficient operator independent methodology, it currently offers inferior rupture status discriminant performance compared with established descriptors. Future research is needed to extend the current Radiomics feature set to better capture aneurysm shape information.
