Dual Targeting of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase and Histone Deacetylase as a Therapy for Colorectal Cancer

AbstractStatins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) inhibitors decreasing serum cholesterol and have shown promise in cancer prevention. In this study, we demonstrated the oncogenic role of HMGR in colorectal cancer (CRC) by disclosing increased HMGR activity in CRC patients and its enhancement of anti-apoptosis and stemness. Our previous studies showed that statins containing carboxylic acid chains possessed activity against histone deacetylases (HDACs), and strengthened their anti-HDAC activity through designing HMGR-HDAC dual inhibitors, JMF compounds. These compounds exerted anti-cancer effect in CRC cells as well as in AOM-DSS and ApcMin/+ CRC mouse models. JMF mostly regulated the genes related to apoptosis and inflammation through genome-wide ChIP-on-chip analysis, and Ingenuity Pathways Analysis (IPA) predicted their respective regulation by NR3C1 and NF-κB. Furthermore, JMF inhibited metastasis, angiogenesis and cancer stemness, and potentiated the effect of oxaliplatin in CRC mouse models. Dual HMGR-HDAC inhibitor could be a potential treatment for CRC

Targeting canine bladder transitional cell carcinoma with a human bladder cancer-specific ligand

<p>Abstract</p> <p>Objective</p> <p>To determine if a human bladder cancer-specific peptide named PLZ4 can target canine bladder cancer cells.</p> <p>Experimental Design</p> <p>The binding of PLZ4 to five established canine invasive transitional cell carcinoma (TCC) cell lines and to normal canine bladder urothelial cells was determined using the whole cell binding assay and an affinitofluorescence assay. The WST-8 assay was performed to determine whether PLZ4 affected cell viability. <it>In vivo </it>tumor-specific homing/targeting property and biodistribution of PLZ4 was performed in a mouse xenograft model via tail vein injection and was confirmed with <it>ex vivo </it>imaging.</p> <p>Results</p> <p>PLZ4 exhibited high affinity and specific dose-dependent binding to canine bladder TCC cell lines, but not to normal canine urothelial cells. No significant changes in cell viability or proliferation were observed upon incubation with PLZ4. The <it>in vivo </it>and <it>ex vivo </it>optical imaging study showed that, when linked with the near-infrared fluorescent dye Cy5.5, PLZ4 substantially accumulated at the canine bladder cancer foci in the mouse xenograft model as compared to the control.</p> <p>Conclusions and Clinical Relevance</p> <p>PLZ4 can specifically bind to canine bladder cancer cells. This suggests that the preclinical studies of PLZ4 as a potential diagnostic and therapeutic agent can be performed in dogs with naturally occurring bladder cancer, and that PLZ4 can possibly be developed in the management of canine bladder cancer.</p

Metal contact and carrier transport in single crystalline CH3NH3PbBr3 perovskite

Organic-inorganic perovskites have arrived at the forefront of solar technology due to their impressive carrier lifetimes and superior optoelectronic properties. By having the cm-sized perovskite single crystal and employing device patterning techniques, and the transfer length method (TLM), we are able to get the insight into the metal contact and carrier transport behaviors, which is necessary for maximizing device performance and efficiency. In addition to the metal work function, we found that the image force and interface charge pinning effects also affect the metal contact, and the studied single crystal CH3NH3PbBr3 features Schottky barriers of 0.17 eV, 0.38 eV, and 0.47 eV for Au, Pt, and Ti electrodes, respectively. Furthermore, the surface charges lead to the thermally activated transport from 207 K to 300 K near the perovskite surface. In contrast, from 120 K to 207 K, the material exhibited three-dimensional (3D) variable range hopping (VRH) carrier transport behavior. Understanding these fundamental contact and transport properties of perovskite will enable future electronic and optoelectronic applications

Impact of Ancestral Differences and Reassessment of the Classification of Previously Reported Pathogenic Variants in Patients With Brugada Syndrome in the Genomic Era: A SADS-TW BrS Registry

Brugada syndrome (BrS) is a heritable disease that results in sudden cardiac death. In the exome/genomic era, certain reported pathogenic variants in some genetic diseases have been reclassified as benign owing to their high frequency in some ancestries. In the present study, we comprehensively reassessed all previously reported pathogenic variants of BrS. We collected all pathogenic variants of BrS reported in the Human Gene Mutation Database and ClinVar throughout April 2017. We compared the minor allele frequency (MAF) of each variant among different ancestries by searching public whole-genome and exome databases. After considering the maximum credible allele frequency, variants with a MAF ≥ 0.001 were considered to be of questionable pathogenicity. We also investigated the percentage of SCN5A variants with a MAF ≥ 0.001 in 124 BrS patients from the Han Chinese population. We collected a total of 440 BrS variants, of which 18 had a MAF ≥ 0.001. There was a greater percentage of non-SCN5A variants with a MAF ≥ 0.001 than of SCN5A variants (21.8 versus 1.6%, p &lt; 0.0001). There were fewer frameshift and nonsense mutations than missense mutations (0.9 versus 5.6%, p = 0.032). Of the 18 variants, 14 (77.8%) were present only in the reference Asian population. In our cohort, we identified two SCN5A variants (p.A226V and p.V1340I) with MAFs ≥ 0.001 (0.45%). In conclusion, ancestral differences are important when considering the pathogenicity of BrS variants, especially in the case of missense variants and non-SCN5A variants, which may be pathogenic in some ancestries but only disease-predisposing in others

Effect of Temperature Gradient Direction in the Catalyst Nanoparticle on CNTs Growth Mode

To improve the understanding on CNT growth modes, the various processes, including thermal CVD, MP-CVD and ECR-CVD, have been used to deposit CNTs on nanoporous SBA-15 and Si wafer substrates with C2H2 and H2 as reaction gases. The experiments to vary process parameter of ΔT, defined as the vector quantities of temperature at catalyst top minus it at catalyst bottom, were carried out to demonstrate its effect on the CNT growth mode. The TEM and TGA analyses were used to characterize their growth modes and carbon yields of the processes. The results show that ΔT can be used to monitor the temperature gradient direction across the catalyst nanoparticle during the growth stage of CNTs. The results also indicate that the tip-growth CNTs, base-growth CNTs and onion-like carbon are generally fabricated under conditions of ΔT > 0, <0 and ~0, respectively. Our proposed growth mechanisms can be successfully adopted to explain why the base- and tip-growth CNTs are common in thermal CVD and plasma-enhanced CVD processes, respectively. Furthermore, our experiments have also successfully demonstrated the possibility to vary ΔT to obtain the desired growth mode of CNTs by thermal or plasma-enhanced CVD systems for different applications