We hypothesize that time perception and executive functions are interrelated and share neuroanatomical basis, and that fluctuations in levels of cognitive effort play a role in mediating that ...relation. The main goal of this study was to identify brain structures activated both by increases in cognitive activity and during time perception tasks.
We performed a multimodal meta-analysis to identify common brain regions in the findings of (a) an SDM meta-analysis of neuroimaging studies assessing the brain response to increasing levels of cognitive difficulty, and (b) an ALE meta-analysis on neuroimaging of time perception (Ortuño, Guillén-Grima, López-García, Gómez, & Pla, 2011. Schizophr. Res., 125(2–3), 129–35).
Consistent with results of previous, separate meta-analyses, the current study supports the hypothesis that there exists a group of brain regions engaged both in time perception tasks and during tasks requiring cognitive effort. Thus, brain regions associated with working memory and executive functions were found to be engaged during time estimation tasks, and regions associated with time perception were found to be engaged by an increase in the difficulty of non-temporal tasks. The implication is that temporal perception and cognitive processes demanding cognitive control become interlinked when there is an increase in the level of cognitive effort demanded.
•There are brain regions engaged in both time perception and cognitive effort.•Temporal perception and processes demanding cognitive control are interlinked.•Increased demand for cognitive effort engages temporal networks.
Differentiated cells can be converted into pluripotent stem cells by expressing the transcription factors OCT4, SOX2, KLF4, and MYC (OSKM) in a process known as reprogramming. Here, using single-cell ...RNA sequencing of pancreas undergoing reprogramming, we identify markers along the trajectory from acinar cell identity to pluripotency. These markers allow direct in situ visualization of cells undergoing dedifferentiation and acquiring features of early and advanced intermediate reprogramming. We also find that a fraction of cells do not dedifferentiate upon OSKM expression and are characterized by stress markers of the REG3 and AP-1 families. Importantly, most markers of intermediate reprogramming in the pancreas are also observed in stomach, colon, and cultured fibroblasts expressing OSKM. Among them is LY6A, a protein characteristic of progenitor cells and generally upregulated during tissue repair. Our roadmap defines intermediate reprogramming states that could be functionally relevant for tissue regeneration and rejuvenation.
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•scRNA-seq captures pancreatic acinar cells during the process of OSKM reprogramming•Non-reprogrammed fates co-exist with intermediate-reprogrammed states•Markers of intermediate reprogramming are shared across tissues and fibroblasts•Cells at intermediate states of reprogramming can be visualized within tissues
In this work, Serrano and colleagues identify markers along the trajectory of OSKM reprogramming in the pancreas. Several tissues and cultured fibroblasts present the same markers, suggesting that reprogramming follows a common path in vivo and in vitro. These markers allow to visualize cells at different states of reprogramming within tissues.
Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding ...the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine‐specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas‐specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial–mesenchymal transition genes. We also identify a subset of non‐classical PDAC samples that exhibit the HNF1A/KDM6A‐deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor‐suppressive role of KDM6A deficiency with a cell‐specific molecular mechanism that underlies PDAC subtype definition.
Synopsis
Whether defective transcriptional control of cell differentiation contributes to the development of pancreatic ductal adenocarcinoma (PDAC) remains poorly understood. Here, cooperation of transcription factor HNF1A with lysine‐specific demethylase 6A (KDM6A/UTX) is found to activate an epithelial program in pancreatic acinar cells and to impair KrasG12D ‐driven tumorigenesis.
HNF1A recruits KDM6A to target genes that specify acinar cell epithelial identity.
HNF1A and KDM6A regulate a common transcriptional program that is defective in non‐classical human PDAC.
Hnf1a loss in mice cooperates with KrasG12D mutation and recapitulates Kdm6a‐deficient PDAC.
Cooperation between a transcription factor and an epigenetic modifier reveals how defective transcriptional control can contribute to development of pancreatic ductal adenocarcinoma.
Chromatin remodeling factors contribute to establish aberrant gene expression programs in cancer cells and therefore represent valuable targets for therapeutic intervention. BPTF (Bromodomain PhD ...Transcription Factor), a core subunit of the nucleosome remodeling factor (NURF), modulates c-MYC oncogenic activity in pancreatic cancer. Here, we analyze the role of BPTF in c-MYC-driven B-cell lymphomagenesis using the Eμ-Myc transgenic mouse model of aggressive B-cell lymphoma. We find that BPTF is required for normal B-cell differentiation without evidence of haploinsufficiency. In contrast, deletion of one Bptf allele is sufficient to delay lymphomagenesis in Eμ-Myc mice. Tumors arising in a Bptf heterozygous background display decreased c-MYC levels and pathway activity, together with increased activation of the NF-κB pathway, a molecular signature characteristic of human diffuse large B-cell lymphoma (DLBCL). In human B-cell lymphoma samples, we find a strong correlation between BPTF and c-MYC mRNA and protein levels, together with an anti-correlation between BPTF and NF-κB pathway activity. Our results indicate that BPTF is a relevant therapeutic target in B-cell lymphomas and that, upon its inhibition, cells acquire distinct oncogenic dependencies.
Pancreatic acinar cells rely on PTF1 and other transcription factors to deploy their transcriptional program. We identify NFIC as a NR5A2 interactor and regulator of acinar differentiation. NFIC ...binding sites are enriched in NR5A2 ChIP-Sequencing peaks. Nfic knockout mice have a smaller, histologically normal, pancreas with reduced acinar gene expression. NFIC binds and regulates the promoters of acinar genes and those involved in RNA/protein metabolism, and Nfic knockout pancreata show defective ribosomal RNA maturation. NFIC dampens the endoplasmic reticulum stress program through binding to gene promoters and is required for resolution of Tunicamycin-mediated stress. NFIC is down-regulated during caerulein pancreatitis and is required for recovery after damage. Normal human pancreata with low levels of NFIC transcripts display reduced expression of genes down-regulated in Nfic knockout mice. NFIC expression is down-regulated in mouse and human pancreatic ductal adenocarcinoma. Consistently, Nfic knockout mice develop a higher number of mutant Kras-driven pre-neoplastic lesions.
VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate ...chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer.
Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed.
26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×10
viral particles (vp)/patient (Part I), and 3.3×10
vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×10
vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×10
vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×10
vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration.
Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma.
NCT02045602.
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