The dismal prognosis of pancreatic cancer has been linked to poor tumor differentiation. However, molecular basis of pancreatic cancer differentiation and potential therapeutic value of the ...underlying molecules remain unknown. We investigated the mechanistic underexpression of Krüppel-like factor 4 (KLF4) in pancreatic cancer and defined a novel epigenetic pathway of its activation for pancreatic cancer differentiation and treatment.
Expressions of KLF4 and DNMT1 in pancreatic cancer tissues were determined by IHC and the genetic and epigenetic alterations of KLF4 in and KLF4's impact on differentiation of pancreatic cancer were examined using molecular biology techniques. The function of dietary 3,3'-diindolylmethane (DIM) on miR-152/DNMT1/KLF4 signaling in pancreatic cancer was evaluated using both cell culture and animal models.
Overexpression of DNMT1 and promoter hypermethylation contributed to decreased KLF4 expression in and associated with poor differentiation of pancreatic cancer. Manipulation of KLF4 expression significantly affected differentiation marker expressions in pancreatic cancer cells. DIM treatment significantly induced miR-152 expression, which blocked DNMT1 protein expression and its binding to KLF4 promoter region, and consequently reduced promoter DNA methylation and activated KLF4 expression in pancreatic cancer cells. In addition, DIM treatment caused significant inhibition of cell growth
and tumorigenesis in animal models of pancreatic cancer.
This is the first demonstration that dysregulated KLF4 expression associates with poor differentiation of pancreatic cancer. Epigenetic activation of miR-152/DNMT1/KLF4 signaling pathway by dietary DIM causes differentiation and significant growth inhibition of pancreatic cancer cells, highlighting its translational implications for pancreatic and other cancers.
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Cell fate determination is a necessary and tightly regulated process for producing different cell types and structures during development. Cranial neural crest cells (CNCCs) are unique to vertebrate ...embryos and emerge from the neural plate borders into multiple cell lineages that differentiate into bone, cartilage, neurons and glial cells. We have previously reported that Irf6 genetically interacts with Twist1 during CNCC-derived tissue formation. Here, we have investigated the mechanistic role of Twist1 and Irf6 at early stages of craniofacial development. Our data indicate that TWIST1 is expressed in endocytic vesicles at the apical surface and interacts with β/δ-catenins during neural tube closure, and Irf6 is involved in defining neural fold borders by restricting AP2α expression. Twist1 suppresses Irf6 and other epithelial genes in CNCCs during the epithelial-to-mesenchymal transition (EMT) process and cell migration. Conversely, a loss of Twist1 leads to a sustained expression of epithelial and cell adhesion markers in migratory CNCCs. Disruption of TWIST1 phosphorylation in vivo leads to epidermal blebbing, edema, neural tube defects and CNCC-derived structural abnormalities. Altogether, this study describes a previously uncharacterized function of mammalian Twist1 and Irf6 in the neural tube and CNCCs, and provides new target genes for Twist1 that are involved in cytoskeletal remodeling.
Metastasis and thrombosis are serious threats to cancer patients and generally associated with poor prognosis. The elusive mechanisms underlying the pathogenesis of metastasis and thrombosis have ...been subjects of extensive investigations. The presence of circulating tumor cells (CTCs) is closely related to tumor metastasis, and these cells play an important role in thrombosis in cancer patients. In this review, we describe the latest findings on the role of CTCs in tumor metastasis and cancer-related thrombosis and the regulatory role of microRNAs in CTCs and thrombosis. Additionally, we discuss anticoagulant-based strategies for the prevention of thrombosis and reduction of cancer metastasis and the potential to translate current knowledge on these strategies to the treatment of cancer.
Background
In multidisciplinary education, different perspectives from more than one discipline are used to illustrate a certain topic. The aim of this study was to evaluate the effectiveness of an ...online, multidisciplinary radiology curriculum to teach radiology to medical students in Egypt. A multidisciplinary team of radiologists, surgeons, and internists taught a series of 5 case-based radiology sessions on a web conference platform. Topics included common clinical case scenarios for various body systems. Undergraduate medical students across Egypt were enrolled in the course. A pre-test–post-test design was used to evaluate the efficacy of each session. Upon course completion, students filled out a subjective survey to assess the radiology education series.
Results
On average, 1000 students attended each session. For each session, an average of 734 students completed both the pre-test and post-test. There was a statistically significant increase in post-test scores compared to pre-test scores across all 5 sessions (
p
< 0.001) with an overall average score improvement of 63%. A subjective survey at the end of the course was completed by 1027 students. Over 96% of students found the lecture series to be a worthwhile experience that increased their imaging knowledge and interest in radiology, and that the use of a multidisciplinary approach added educational value. About 66% of students also reported that the session topics were “excellent and clinically important.” There was a marked increase in reported confidence levels in radiology competencies before and after attendance of the sessions.
Conclusions
An online radiology curriculum with a multidisciplinary approach can be implemented successfully to reach a large group of medical students and meet their educational objectives.
Abstract only
A wide variety of common craniofacial birth defects and pediatric cancers arise from errors in the development of cranial neural crest cells (CNCC) that give rise to craniofacial ...skeletal and peripheral nervous systems. Identification of the genetic and environmental factors that regulate cell fate of CNCCs is crucial for uncovering the causes behind craniofacial disorders. Our lab has identified a dual‐transcription factor pathway that regulates CNCCs during EMT and migration. Initially, we identified a causative mutation in a TWIST1 binding site within an
Interferon Regulatory Factor 6
(
IRF6
) enhancer in a multi‐generational family affected with syndromic cleft lip and palate called Van der Woude syndrome. Our subsequent animal work has shown that
Twist1
and
Irf6
genetically interact during early craniofacial development, and that the compound heterozygotes exhibit craniofacial abnormalities. We recently demonstrated that
Irf6
is required for neural tube and CNCC development and that it interacts with
Twist1
during EMT and migration of CNCCs. We also showed that TWIST1 is highly phosphorylated in CNCCs and its phosphorylation is crucial for regulating
Irf6
and potentially
miR10
family members in CNCC‐derived craniofacial tissues. Our recent
in‐vivo
and neural tube explants using dual fluorescent cell tracing system showed that
Twist1
conditional knockout (CKO) in CNCCs significantly reduced cell delamination and disrupted EMT. The detached
Twist1
CKO in CNCCs retained their epithelial signatures and migrated as clusters of epithelial‐like cells over significantly shorter distances. Finally,
Twist1
phospho‐incompetent mice for two serine residues were recently generated to determine their impact on TWIST1 activity. Our preliminary results showed that
Twist1
S68A/S68A
phospho‐mutant mice have craniofacial bone defects and forebrain hemorrhage.
Support or Funding Information
UTHealth start‐up funds and a small grant from the
Rolanette and Berdon Lawrence Bone Disease Program of Texas
Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the ...heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.
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•Most small cell lung cancer (SCLC) tumors share a small PLCG2-high subpopulation•This PLCG2-high SCLC subpopulation is linked to metastasis and poor prognosis•SCLC is enriched in profibrotic and immunosuppressive monocytes/macrophages•The presence of myeloid cells is associated with the PLCG2-high SCLC subpopulation
Chan et al. use single-cell transcriptome sequencing and imaging techniques to study the heterogeneity and tumor microenvironment of clinical small cell lung cancer specimens. This analysis identifies a PLCG2-high-expressing subpopulation linked to metastasis and poor prognosis, and an enrichment of a monocyte/macrophage population with a profibrotic, immunosuppressive phenotype.
Aggressive neuroendocrine lung cancers, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), represent an understudied tumor subset that accounts for approximately 40,000 ...new lung cancer cases per year in the United States. No targeted therapy exists for these tumors. We determined that achaetescute homolog 1 (ASCL1), a transcription factor required for proper development of pulmonary neuroendocrine cells, is essential for the survival of a majority of lung cancers (both SCLC and NSCLC) with neuroendocrine features. By combining whole-genome microarray expression analysis performed on lung cancer cell lines with ChlP-Seq data designed to identify conserved transcriptional targets of ASCL1, we discovered an ASCL1 target 72-gene expression signature that (i) identifies neuroendocrine differentiation in NSCLC cell lines, (ii) is predictive of poor prognosis in resected NSCLC specimens from three datasets, and (iii) represents novel "druggable" targets. Among these druggable targets is B-cell CLL/lymphoma 2, which when pharmacologically inhibited stops ASCL1-dependent tumor growth in vitro and in vivo and represents a proof-of-principle ASCL1 downstream target gene. Analysis of downstream targets of ASCL1 represents an important advance in the development of targeted therapy for the neuroendocrine class of lung cancers, providing a significant step forward in the understanding and therapeutic targeting of the molecular vulnerabilities of neuroendocrine lung cancer.
Crohn's disease (CD) involves activation of mast cells (MC) and NF-кB in parallel with the PPAR-α/NLRP3 inflammasome/IL-1β pathway in the inflamed colon. Whether polyphenols from maqui (
) represent ...a natural alternative treatment for CD is unclear. Therefore, we used an animal model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD-like colitis to investigate protective effects of maqui extract through monitoring NLRP3 inflammasome and MC activation in colon tissue.
Maqui extract was administered via orogastric route to mice after (post-Treatment group) or prior (pre-Treatment group) to TNBS-induction. Colon pathology was characterized by histoarchitectural imaging, disease activity index (DAI), and assessing NF-кB, p-NF-кB, PPAR-α/NLRP3 expression and IL-1β levels.
Compared to mice treated with TNBS alone administration of anthocyanin-rich maqui extract improved the DAI, colon histoarchitecture and reduced both colon wet-weight and transmural inflammation. Induction with TNBS significantly increased colonic NLPR3 inflammasome activation, while co-treatment with maqui extract (either post- or pre-Treatment) significantly downregulated NLRP3, ASC and caspase-1 levels, which manifested as reduced colonic IL-1β levels. Supplemented maqui extract marginally diminished NF-кB activity in epithelial cells but reached statistical significance in immune cells (as judged by decreased NF-кB phosphorylation). PPAR-α signaling was largely unaffected by Maqui whereas MC infiltration into the colon mucosa and submucosa decreased and their level of degranulation was suppressed.
These outcomes show the post- and pre- Treatment effect of a polyphenolic extract rich in anthocyanins from maqui the acute phase of TNBS- induced CD-like colitis is linked to suppression of the NLRP3 inflammasome and reduced MC responses. These data indicate that maqui extract represents a potential nutraceutical for the treatment of inflammatory bowel disease (IBD).
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