New Insight into the Anti-liver Fibrosis Effect of Multitargeted Tyrosine Kinase Inhibitors: From Molecular Target to Clinical Trials

Tyrosine kinases (TKs) is a family of tyrosine protein kinases with important functions in the regulation of a broad variety of physiological cell processes. Overactivity of TK disturbs cellular homeostasis and has been linked to the development of certain diseases, including various fibrotic diseases. In regard to liver fibrosis, several TKs, such as vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) kinases, have been identified as central mediators in collagen production and potential targets for anti-liver fibrosis therapies. Given the essential role of TKs during liver fibrogenesis, multitargeted inhibitors of aberrant TK activity, including sorafenib, erlotinib, imatinib, sunitinib, nilotinib, brivanib and vatalanib, have been shown to have potential for treating liver fibrosis. Beneficial effects are observed by researchers of this field using these multitargeted TK inhibitors in preclinical animal models and in patients with liver fibrosis. The present review will briefly summarize the anti-liver fibrosis effects of multitargeted TK inhibitors and molecular mechanisms

Heritable and Lineage-Specific Gene Knockdown in Zebrafish Embryo

BACKGROUND: Reduced expression of developmentally important genes and tumor suppressors due to haploinsufficiency or epigenetic suppression has been shown to contribute to the pathogenesis of various malignancies. However, methodology that allows spatio-temporally knockdown of gene expression in various model organisms such as zebrafish has not been well established, which largely limits the potential of zebrafish as a vertebrate model of human malignant disorders. PRINCIPAL FINDING: Here, we report that multiple copies of small hairpin RNA (shRNA) are expressed from a single transcript that mimics the natural microRNA-30e precursor (mir-shRNA). The mir-shRNA, when microinjected into zebrafish embryos, induced an efficient knockdown of two developmentally essential genes chordin and alpha-catenin in a dose-controllable fashion. Furthermore, we designed a novel cassette vector to simultaneously express an intronic mir-shRNA and a chimeric red fluorescent protein driven by lineage-specific promoter, which efficiently reduced the expression of a chromosomally integrated reporter gene and an endogenously expressed gata-1 gene in the developing erythroid progenitors and hemangioblasts, respectively. SIGNIFICANCE: This methodology provides an invaluable tool to knockdown developmental important genes in a tissue-specific manner or to establish animal models, in which the gene dosage is critically important in the pathogenesis of human disorders. The strategy should be also applicable to other model organisms

Biomechanical characterization of the periodontal ligament: Orthodontic tooth movement

To quantify the biomechanical properties of the bovine periodontal ligament (PDL) in postmortem sections and to apply these properties to study orthodontic tooth intrusion using finite element analysis (FEA). We hypothesized that PDL’s property inherited heterogeneous (anatomical dependency) and nonlinear stress-strain behavior that could aid FEA to delineate force vectors with various rectangular archwires

Three-dimensional printing technique assisted cognitive fusion in targeted prostate biopsy

AbstractObjectiveTo explore the effect of 3-dimensional (3D) printing-assisted cognitive fusion on improvement of the positive rate in prostate biopsy.MethodsFrom August to December 2014, 16 patients with suspected prostatic lesions detected by multiparametric magnetic resonance imaging (MRI) were included. Targeted prostate biopsy was performed with the use of prostate 3D reconstruction modeling, computer-simulated biopsy, 3D printing, and cognitive fusion biopsy. All patients had received 3.0 T multiparametric MRI before biopsy. The DICOM MRI files were imported to medical imaging processing software for 3D reconstruction modeling to generate a printable .stl file for 3D printing with use of transparent resin as raw material. We further performed a targeted 2- to 3-core biopsy at suspected lesions spotted on MRI.ResultsFor the 16 patients in the present study, 3D modeling with cognitive fusion-based targeted biopsy was successfully performed. For a single patient, 1–2 lesions (average: 1.1 lesions) were discovered, followed by 2–6 cores (average: 2.4 cores) added as targeted biopsy. Systematic biopsies accounted for 192 cores in total, with a positive rate of 22.4%; targeted biopsies accounted for 39 cores in total, with a positive rate of 46.2%. Among these cases, 10 patients (62.5%) were diagnosed with prostate adenocarcinoma, in which seven were discovered by both systematic and targeted biopsy, one was diagnosed by systematic biopsy only, and two were diagnosed by targeted biopsy only. For systematic biopsy, Gleason score ranged from 6 to 8 (average: 7), while that for targeted biopsy ranged from 6 to 9 (average: 7.67). Among the seven patients that were diagnosed by both systematic and targeted biopsy, three (42.8%) were reported with a higher Gleason score in targeted therapy than in systematic biopsy.Conclusion3D printing-assisted cognitive fusion technique markedly promoted positive rate in prostate biopsy, and reduced missed detection in high-risk prostate cancer

Bicontrol of Pythium aphanidermatum and Damping-off Disease of Papaya Seedlings (Carica papaya cv. Tainung No.2) by Different Smoke-water

Two key trends of sustainable agriculture are reducing the amount of inputs such as pesticides, fungicides, or fertilizer and finding ways to reduce or reuse agricultural waste. Leafy plant waste can be burned to produced smoke-water extracts that have effective antimicrobial and germination properties. Damping-off disease caused by Pythium spp. leads to significant losses at the papaya seedling stage and is usually managed with fungicides. Five smoke-water extracts derived from burning different plant residues—namely, rice straw smoke-water (R-SW), wheat straw smoke-water (W-SW), pangola grass smoke-water (P-SW), cornstalk smoke-water (C-SW), and bamboo leave smoke-water (B-SW)—were prepared. These were mixed into the V8 media used for culture of Pythium aphanidermatum. In vitro treatment with 5% P-SW, C-SW, or B-SW reduced mycelial growth rate significantly, whereas 5% B-SW inhibited mycelial growth completely. All 1% smoke-water preparations reduced zoospore production significantly, but the inhibition rate of 3% R-SW, 3% W-SW, 1% P-SW, 1% C-SW, and 1% B-SW reached 100%. For in vivo experiments, P. aphanidermatum was inoculated in 1 kg of potting soil and mixed with B-SW in concentrations of 1% to 5%. The papaya seedlings treated with 2% to 5% B-SW maintained the growth parameter without damping-off symptoms

Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation

Introduction: Cognitive impairment is a common complication and comorbidity of diabetes. However, the underlying mechanisms of diabetes-associated cognitive dysfunction are currently unclear. M1 microglia secretes pro-inflammatory factors and can be marked by CD16, iNOS, Iba1 and TNF-ɑ. The decline of M2 microglia in the diabetic rats indicates that high glucose promotes the differentiation of microglia into the M1 type to trigger neuroinflammatory responses. Moreover, there is a lack of strong evidence for treatments of diabetes-associated cognitive impairment in addition to controlling blood glucose.Methods: Diabetic rats were established by intraperitoneal injection of one dose of streptozotocin (60 mg/kg). Polarization transitions of microglia were induced by high glucose treatment in BV2 cells. Levetiracetam was orally administered to rats 72 h after streptozotocin injection for 12 weeks.Results: In STZ-induced diabetic rats, the results demonstrated that levetiracetam improved rat cognitive function (Morris water maze test) and hippocampus morphology (Hematoxylin-eosin staining), and the effect was more evident in the high-dose levetiracetam group. Microglia activation in the hippocampus was inhibited by levetiracetam treatment for 12 weeks. Serum levels of TNF-α, IL-1β, and IL-6 were reduced in the LEV-L and LEV-H groups, and IL-1β level was obviously reduced in the LEV-H group. In vitro, we found that levetiracetam 50 µM attenuated high-glucose induced microglial polarization by increasing IL-10 level and decreasing IL-1β and TNF-α levels. Moreover, levetiracetam 50 µM increased and decreased the proportion of CD206+/Iba1+ and iNOS+/Iba1+cells, respectively. Western blot analysis illustrated that LEV 50 µM downregulated the expression of MyD88 and TRAF6, and phosphorylation of TAK1, JNK, p38, and NF-κB p65. The effect of levetiracetam on the anti-polarization and expression of p-JNK and p-NF-κB p65 were partly reversed by anisomycin (p38 and JNK activators).Discussion: Together, our data suggest that levetiracetam attenuates streptozotocin-induced cognitive impairment by suppressing microglia activation. The in vitro findings also indicate that the levetiracetam inhibited the polarization of microglia via the JNK/MAPK/NF-κB signaling pathway

Investigation of Tumor Suppressing Function of CACNA2D3 in Esophageal Squamous Cell Carcinoma.

Background: Deletion of 3p is one of the most frequent genetic alterations in esophageal squamous cell carcinoma (ESCC), suggesting the existence of one or more tumor suppressor genes (TSGs) within these regions. In this study, one TSG, CACNA2D3 at 3p21.1, was characterized. Methods: Expression of CACNA2D3 in ESCCs was tested by quantitative real-time PCR and tissue microarray. The mechanism of CACNA2D3 downregulation was investigated by methylation-specific polymerase chain reaction (MS-PCR). The tumor suppressive function of CACNA2D3 was characterized by both in vitro and in vivo tumorigenic assays, cell migration and invasion assays. Results: CACNA2D3 was frequently downregulated in ESCCs (24/48, 50%), which was significantly associated with promoter methylation and allele loss (P<0.05). Tissue microarray result showed that downregulation of CACNA2D3 was detected in (127/224, 56.7%) ESCCs, which was significantly associated with lymph node metastasis (P = 0.01), TNM staging (P = 0.003) and poor outcome of ESCC patients (P<0.05). Functional studies demonstrated that CACNA2D3 could inhibit tumorigenicity, cell motility and induce apoptosis. Mechanism study found that CACNA2D3 could arrest cell cycle at G1/S checkpoint by increasing expressions of p21 and p53 and decreasing expression of CDK2. In addition, CACNA2D3 could upregulate intracellular free cytosolic Ca2+ and subsequently induce apoptosis. Conclusion: CACNA2D3 is a novel TSG responsible to the 3p21 deletion event and plays a critical suppressing role in the development and progression of ESCC. © 2013 Li et al.link_to_OA_fulltex

A study of the types and manifestations of physicians' unintended behaviors in the DRG payment system

IntroductionIn recent years, China has implemented the Diagnosis Related Groups (DRG) payment system as part of its healthcare insurance reimbursement policy. Numerous studies have focused on the effectiveness of DRG payment system in controlling unreasonable growth in medical expenses. However, there has been no systematic report on the types of unintended behaviors exhibited by doctors under the DRG payment system.MethodsThe study first utilized interrupted time series analysis to analyze medical records and insurance data from eight hospitals. It investigated the data changes in MDC and ADRG groups before and after the implementation of the DRG payment system. Subsequently, a semi-structured interview method was employed to conduct qualitative research on the unintended behaviors of physicians, aiming to gain a more accurate understanding of specific changes in physician behavior after the implementation of the DRG payment system.ResultsThis study discovered that doctors engage in unintended behaviors within the framework of the DRG payment system.DiscussionIn the early implementation of the DRG payment system in China, the contradictions between the flawed DRG payment methods and supporting systems and the actual diagnostic and treatment work manifested in the form of unintended doctor behaviors. Most of these unintended behaviors can be considered reasonable feedback from doctors to cope with the existing system flaws. They are conducive to identifying the deficiencies in China's DRG payment system and suggesting directions for improvement