Determination of withdrawal times in individualized opportunistic screening colonoscopies

To investigate effects of bowel preparation, experience level of colonoscopists, and colonoscopy withdrawal time (CWT) on the quality of an individual opportunistic screening colonoscopy, according to adenoma detection rate (ADR).Data were retrospectively analyzed from opportunistic screening colonoscopies (n = 16,951) at 4 hospitals of various care levels in China.The ADR positively correlated with the experience level of the colonoscopist. The individualized CWT varied, depending on the quality of bowel preparation and the number of colonoscopies performed previously by the colonoscopist. In a setting of adequate bowel preparation, the mean CWT decreased with the increased experience of the colonoscopist. With poor and inadequate bowel preparation, no colonoscopist at any level of experience could obtain a satisfactory ADR.For adequately prepared colonoscopies, minimum CWTs have been determined. Repeat colonoscopy is strongly recommended for patients with poor bowel preparation, regardless of the colonoscopist's experience.publishersversionpublishe

Krüppel-like factor 4 (KLF4) regulates the miR-183~96~182 cluster under physiologic and pathologic conditions

Cèl·lules mare embrionàries; Melanoma; MicroARNCélulas madre embrionarias; Melanoma; MicroARNEmbryonic stem cells; Melanoma; MicroRNAMicroRNAs (miRNAs) are a class of endogenous non-coding small RNAs that post-transcriptionally control the translation and stability of target mRNAs in a sequence-dependent manner. MiRNAs are essential for key cellular processes including proliferation, differentiation, cell death and metabolism, among others. Consequently, alterations of miRNA expression contribute to developmental defects and a myriad of diseases. The expression of miRNAs can be altered by several mechanisms including gene copy number alterations, aberrant DNA methylation, defects of the miRNA processing machinery or unscheduled expression of transcription factors. In this work, we sought to analyze the regulation of the miR-182 cluster, located at the 7q32 locus, which encodes three different miRNAs that are abundantly expressed in human embryonic stem cells and de-regulated in cancer. We have found that the Krüppel-like factor 4 (KLF4) directly regulates miR-182 cluster expression in human embryonic stem cells (hESCs) and in melanoma tumors, in which the miR-182 cluster is highly expressed and has a pro-metastatic role. Furthermore, higher KLF4 expression was found to be associated with metastatic progression and poor patient outcome. Loss of function experiments revealed that KLF4 is required for melanoma cell maintenance. These findings provide new insights into the regulation of the miR-182 cluster expression and new opportunities for therapeutic intervention in tumors in which the KLF4-miR-182 cluster axis is deregulated.This work was supported by NCI/NIH Grant (5R01CA155234), Instituto de Salud Carlos III (CP11/00052 and RD12/0036/0016) co-financed by the European Regional Development Fund (ERDF), and European Commission’s Framework Programme 7 through the Marie Curie Career Integration Grants

Irbesartan Ameliorates Lipid Deposition by Enhancing Autophagy via PKC/AMPK/ULK1 Axis in Free Fatty Acid Induced Hepatocytes

Irbesartan has shown significant therapeutic effects in hypertensive patients with non-alcoholic fatty liver disease (NAFLD). To determine the underlying mechanisms of its action, we established an in vitro model of NAFLD by treating human and mouse hepatocytes with free fatty acids (FFAs) and angiotensin (Ang) II. Irbesartan significantly reversed AngII/FFA-induced lipid deposition and mitochondrial dysfunction by restoring ATP production and the mitochondrial membrane potential (MMP), and decreasing the levels of reactive oxygen species (ROS) and inflammatory markers. In addition, irbesartan also increased the autophagy flux, in terms of increased numbers of autolysosomes and autophagosomes, and the upregulation and mitochondrial localization of the autophagic proteins Atg5 and LC3BII/I. Activation of protein kinase C (PKC) and inhibition of the autophagic flux exacerbated mitochondrial dysfunction in the steatotic hepatocytes. Furthermore, AngII upregulated PKC which inhibited AMPK phosphorylation via direct interaction with the AngII receptor AT1-R. Irbesartan inhibited PKC and activated AMPK and its downstream effector ULK1, thereby inducing autophagy, decreasing lipid deposition, and restoring mitochondrial function. Taken together, irbesartan triggers autophagy via the PKC/AMPK/ULK1 axis to ameliorate the pathological changes in the steatotic hepatocytes

N-Glycosylation-Defective Splice Variants of Neuropilin-1 Promote Metastasis by Activating Endosomal Signals

Neuropilin-1 (NRP1) is an essential transmembrane receptor with a variety of cellular functions. Here, we identify two human NRP1 splice variants resulting from the skipping of exon 4 and 5, respectively, in colorectal cancer (CRC). Both NRP1 variants exhibit increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes. This increased endocytic trafficking of the two NRP1 variants, upon HGF stimulation, is due to loss of N-glycosylation at the Asn150 or Asn261 site, respectively. Moreover, these NRP1 variants enhance interactions with the Met and β1-integrin receptors, resulting in Met/β1-integrin co-internalization and co-accumulation on endosomes. This provides persistent signals to activate the FAK/p130Cas pathway, thereby promoting CRC cell migration, invasion and metastasis. Blocking endocytosis or endosomal Met/β1-integrin/FAK signaling profoundly inhibits the oncogenic effects of both NRP1 variants. These findings reveal an important role for these NRP1 splice variants in the regulation of endocytic trafficking for cancer cell dissemination

Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation

10.1073/pnas.1111628109Proceedings of the National Academy of Sciences1093841-84

Quantifying spin Hall topological Hall effect in ultrathin Tm 3 Fe 5 O 12 / Pt bilayers

Recent reports have shown that thulium iron garnet (TmIG) based bilayers are promising material platforms for realizing small, room-temperature skyrmions. For potential applications, it is impera- tive to accurately evaluate electrical read-out signals of skyrmions. In this context, the topological Hall effect has been considered as a characteristic signature of skyrmion formation. Unlike previous studies that have modeled the anomalous Hall effect in ultrathin TmIG/Pt bilayers, we isolate its contribution to the electrical read-out signal by directly measuring the magnetic hysteresis loops using a sensitive Sagnac magneto-optical Kerr effect technique. Our combined optical and electrical measurements reveal that the spin-Hall topological Hall resistivity is considerably larger than previ- ously estimated values. Our finding further indicates that skyrmions can exist at room-temperature and near-zero applied magnetic fields.This research was primarily supported by the National Science Foundation through the Center for Dynamics and Control of Materials: an NSF MRSEC under Coopera- tive Agreement No. DMR-1720595, and the Center for Emergent Materials, an NSF MRSEC under Grant No. DMR-2011876. Additional support was provided by the Welch Foundation F-1662. Facilities provided by MR- SEC DMR-1720595 and by NSF MRI DMR-2019130 are gratefully acknowledged. Partial funding for L. J. Chang while visiting UT-Austin was provided by a Portugal-UT collaboration grant. The collaboration between S,F. Lee and X. Li is facilitated by the AFOSR grant FA2386-21- 1-4067.Center for Dynamics and Control of Material

The Spectrum of NF1 Mutations in Korean Patients with Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations in the NF1 gene which consists of 57 exons and encodes a GTPase activating protein (GAP), neurofibromin. To date, more than 640 different NF1 mutations have been identified and registered in the Human Gene Mutation Database (HGMD). In order to assess the NF1 mutational spectrum in Korean NF1 patients, we screened 23 unrelated Korean NF1 patients for mutations in the coding region and splice sites of the NF1 gene. We have identified 21 distinct NF1 mutations in 22 patients. The mutations included 10 single base substitutions (3 missense and 7 nonsense), 10 splice site mutations, and 1 single base deletion. Eight mutations have been previously identified and thirteen mutations were novel. The mutations are evenly distributed across exon 3 through intron 47 of the NF1 gene and no mutational hot spots were found. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. A genotype-phenotype correlation analysis suggests that there is no clear relationship between specific NF1 mutations and clinical features of the disease

Quantifying spin Hall topological Hall effect in ultrathin Tm 3 Fe 5 O 12 / Pt bilayers

Recent reports have shown that thulium iron garnet (TmIG) based bilayers are promising material platforms for realizing small, room-temperature skyrmions. For potential applications, it is imperative to accurately evaluate electrical readout signals of skyrmions. In this context, the topological Hall effect has been considered as a characteristic signature of skyrmion formation. Unlike previous studies that have modeled the anomalous Hall effect in ultrathin TmIG/Pt bilayers, we isolate its contribution to the electrical readout signal by directly measuring the magnetic hysteresis loops using a sensitive Sagnac magneto-optical Kerr effect technique. Our combined optical and electrical measurements reveal that the spin Hall topological Hall resistivity is considerably larger than previously estimated values. Our finding further indicates that skyrmions can exist at room-temperature and near-zero applied magnetic fields.This research was primarily supported by the National Science Foundation through the Center for Dynamics and Control of Materials: an NSF MRSEC under Coopera- tive Agreement No. DMR-1720595, and the Center for Emergent Materials, an NSF MRSEC under Grant No. DMR-2011876. Additional support was provided by the Welch Foundation F-1662. Facilities provided by MR- SEC DMR-1720595 and by NSF MRI DMR-2019130 are gratefully acknowledged. Partial funding for L. J. Chang while visiting UT-Austin was provided by a Portugal-UT collaboration grant. The collaboration between S,F. Lee and X. Li is facilitated by the AFOSR grant FA2386-21- 1-4067.Center for Dynamics and Control of Material

Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1α

The Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) is a transcriptional co-activator that plays a central role in adapted metabolic responses. PGC-1α is dynamically methylated and unmethylated at the residue K779 by the methyltransferase SET7/9 and the Lysine Specific Demethylase 1A (LSD1), respectively. Interactions of methylated PGC-1α[K779me] with the Spt-Ada-Gcn5-acetyltransferase (SAGA) complex, the Mediator members MED1 and MED17, and the NOP2/Sun RNA methytransferase 7 (NSUN7) reinforce transcription, and are concomitant with the m(5)C mark on enhancer RNAs (eRNAs). Consistently, loss of Set7/9 and NSun7 in liver cell model systems resulted in depletion of the PGC-1α target genes Pfkl, Sirt5, Idh3b, and Hmox2, which was accompanied by a decrease in the eRNAs levels associated with these loci. Enrichment of m(5)C within eRNA species coincides with metabolic stress of fasting in vivo. Collectively, these findings illustrate the complex epigenetic circuitry imposed by PGC-1α at the eRNA level to fine-tune energy metabolism

The FOXK1-CCDC43 Axis Promotes the Invasion and Metastasis of Colorectal Cancer Cells

Background/Aims: The CCDC43 gene is conserved in human, rhesus monkey, mouse and zebrafish. Bioinformatics studies have demonstrated the abnormal expression of CCDC43 gene in colorectal cancer (CRC). However, the role and molecular mechanism of CCDC43 in CRC remain unknown. Methods: The functional role of CCDC43 and FOXK1 in epithelial-mesenchymal transition (EMT) was determined using immunohistochemistry, flow cytometry, western blot, EdU incorporation, luciferase, chromatin Immunoprecipitation (ChIP) and cell invasion assays. Results: The CCDC43 gene was overexpressed in human CRC. High expression of CCDC43 protein was associated with tumor progression and poor prognosis in patients with CRC. Moreover, the induction of EMT by CCDC43 occurred through TGF-β signaling. Furthermore, a positive correlation between the expression patterns of CCDC43 and FOXK1 was observed in CRC cells. Promoter assays demonstrated that FOXK1 directly bound and activated the human CCDC43 gene promoter. In addition, CCDC43 was necessary for FOXK1- mediated EMT and metastasis in vitro and vivo. Taken together, this work identified that CCDC43 promoted EMT and was a direct transcriptional target of FOXK1 in CRC cells. Conclusion: FOXK1-CCDC43 axis might be helpful to develop the drugs for the treatment of CRC