Heterozygous somatic mutations affecting the spliceosome gene SF3B1 drive age-related clonal hematopoiesis, myelodysplastic syndromes (MDS) and other neoplasms. To study their role in such disorders, ...we generated knock-in mice with hematopoietic-specific expression of Sf3b1-K700E, the commonest type of SF3B1 mutation in MDS. Sf3b1
animals had impaired erythropoiesis and progressive anemia without ringed sideroblasts, as well as reduced hematopoietic stem cell numbers and host-repopulating fitness. To understand the molecular basis of these observations, we analyzed global RNA splicing in Sf3b1
hematopoietic cells. Aberrant splicing was associated with the usage of cryptic 3' splice and branchpoint sites, as described for human SF3B1 mutants. However, we found a little overlap between aberrantly spliced mRNAs in mouse versus human, suggesting that anemia may be a consequence of globally disrupted splicing. Furthermore, the murine orthologues of genes associated with ring sideroblasts in human MDS, including Abcb7 and Tmem14c, were not aberrantly spliced in Sf3b1
mice. Our findings demonstrate that, despite significant differences in affected transcripts, there is overlap in the phenotypes associated with SF3B1-K700E between human and mouse. Future studies should focus on understanding the basis of these similarities and differences as a means of deciphering the consequences of spliceosome gene mutations in MDS.
•Novel technique for growing model-based trees for ordinal responses proposed.•Mixture models estimated at nodes accounting for uncertainty in ordinal scores.•Splitting criteria featuring both ...inferential and fitting issues introduced.•Effective graphical visualization of the results and flexibility.•Application to survey data and benchmark study to assess the proposal.
The paper introduces a new technique for growing trees for ordinal responses in the model-based framework. We consider the class of cub mixtures which is particularly appropriate to model perceptions and evaluations, as it designs the response process as the combination of a personal feeling and an inherent uncertainty. In our proposal, the partitioning process is based on the local estimation of cubregression models to profile responses according to feeling and uncertainty conditional to the splitting variables. In this regard, two alternative splitting criteria are introduced featuring both inferential and fitting issues. Moreover, the chosen modelling framework allows for advantageous visualization of the classification results. The proposal is illustrated using real data from a survey conducted by the Italian National Statistical Office, with focus on perceived trust towards the European Parliament. A benchmark study is conducted to settle the proposal among the available tree methods for ordinal responses.
Recent literature on the role of patents in shaping competition between incumbents and new entrants shows mixed evidence, as patents can discourage entry into markets but may also encourage potential ...entrants by increasing profitability from research and development. The increasing use of patents as strategic weapons motivates this investigation of the impact of innovation on competition. In a case study of US pharmaceutical cardiovascular submarkets over the period 1988-1998, we use a panel probit model to study the impact of a firm's patents and rivals' patents in the firm's decision to launch new products. Our results show that the number of a firm's lagged patents encourages the firm's entry with new products, while rivals' initial stock of patents discourages entry, but more recent patents promote entry by opening new technological opportunities.
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Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted ...quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs.
This paper offers a new estimator of volatility's common component of a return. This estimator is obtained by applying a procedure based on the generalized dynamic factor model to the observations on ...squared returns. A Monte-Carlo study is conducted to evaluate the performance of the proposed estimator.
Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or ...resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.
The clinical manifestations of ADPKD are related to the growth of renal cysts. Renal volume has been recognised as the biomarker that is able to identify those patients at risk of complications ...(hypertension and haematuria) and at risk of progression to End Stage Renal Disease (ESRD). Recently, several scores have been introduced to predict the evolution of ADPKD. The Mayo Clinic Group developed a classification based on renal volume as measured by CT or MRI and corrected for age and height (Ht-TKV); this allowed predicting the evolution of the disease, but it has not been fully validated so far. In addition, it is used to identify patients labelled as “fast progressors” and eligible for Tolvaptan therapy according to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recommendations. We studied 80 patients who underwent MRI and had been classified as ADPKD typical form (class 1A-1E). A significant correlation between renal volume, hypertension, and low GFR was found (p<0.005). A progressive increase in disease severity has been found across the different Mayo classes; 41.2% were eligible for Tolvaptan therapy. The results demonstrate that the Mayo method is easy to perform and provides valid information in order to identify with rapidly progressing disease.
This correspondence presents the results of the enumeration of Costas arrays of order 27: all arrays found, except for one, are accounted for by the Golomb and Welch construction methods.
An abstract of the study by Williams et al performing a high-throughput combinatorial siRNA screen of the human kinome across a panel of 33 colorectal cancer cell lines to identify synthetic lethal ...combinations and potential targets for therapy is presented. In this study, the screen utilised inhibitors of EGFR, MEK and PI3K in combination with the siRNA library to identify synergistic gene interaction events. Genomic and proteomic data were utilised in order to identify biomarker signatures that could be used to stratify patient populations that are predicted to be sensitive to these novel combinations.
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