Clinicopathological and Immunohistochemical Study of Low-Grade Myofibroblastic Sarcoma of the Liver-One Case Report

Low-grade myofibroblastic sarcoma is a recently characterized tumor showing features of myofibroblastic differentiation that is part of the spectrum of malignant mesenchymal tumors.This extremely rare ...     

DNA Duplexes with Hydrophobic Modifications Inhibit Fusion between HIV-1 and Cell Membranes

Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.     

Gene Expression Profiling as an Initial Approach for Mechanistic Studies of Toxicity and Tumorigenicity of Herbal Plants and Herbal Dietary Supplements

Dietary supplements are consumed by more than 300 million people worldwide, and herbal dietary supplements represent the most rapidly growing portion of this industry. Even though adverse health effects of many herbal dietary supplements have been reported, safety assurances are not being addressed adequately. Toxicological data on the identification of genotoxic and tumorigenic ingredients in many raw herbs are also lacking. Currently, more than 30 herbal dietary supplements and active ingredients have been selected by the National Toxicology Program (NTP) for toxicity and tumorigenicity studies. Due to the complexity of the chemical components present in plant extracts, there are no established methodologies for determining the mechanisms of toxicity (particularly tumorigenicity) induced by herbs, such as Gingko biloba leaf extract (GBE) and other herbal plant extracts. Consequently, the understanding of toxicity of herbal dietary supplements remains limited.

We have proposed that application of DNA microarrays could be a highly practical initial approach for revealing biological pathways and networks associated with toxicity induced by herbal dietary supplements and the generation of hypotheses to address likely mechanisms. The changes in expression of subsets of genes of interest, such as the modulation of drug metabolizing genes, can be analyzed after treatment with an herbal dietary supplement. Although levels of gene expression do not represent fully the levels of protein activities, we propose that subsequent biochemical and genomic experiments based on these initial observations will enable elucidation of the mechanisms leading to toxicity, including tumorigenicity. This review summarizes the current practices of microarray analysis of gene expressions in animals treated with herbal dietary supplements and discusses perspectives for the proposed strategy.     

Nucleostemin deletion reveals an essential mechanism that maintains the genomic stability of stem and progenitor cells

Stem and progenitor cells maintain a robust DNA replication program during the tissue expansion phase of embryogenesis. The unique mechanism that protects them from the increased risk of replication-induced DNA damage, and hence permits self-renewal, remains unclear. To determine whether the genome integrity of stem/progenitor cells is safeguarded by mechanisms involving molecules beyond the core DNA repair machinery, we created a nucleostemin (a stem and cancer cell-enriched protein) conditional-null allele and showed that neural-specific knockout of nucleostemin predisposes embryos to spontaneous DNA damage that leads to severe brain defects in vivo. In cultured neural stem cells, depletion of nucleostemin triggers replication-dependent DNA damage and perturbs self-renewal, whereas overexpression of nucleostemin shows a protective effect against hydroxyurea-induced DNA damage. Mechanistic studies performed in mouse embryonic fibroblast cells showed that loss of nucleostemin triggers DNA damage and growth arrest independently of the p53 status or rRNA synthesis. Instead, nucleostemin is directly recruited to DNA damage sites and regulates the recruitment of the core repair protein, RAD51, to hydroxyurea-induced foci. This work establishes the primary function of nucleostemin in maintaining the genomic stability of actively dividing stem/progenitor cells by promoting the recruitment of RAD51 to stalled replication-induced DNA damage foci.     

垃圾填埋场临时作业道路的构筑

以宁波市鄞州区生活垃圾卫生填埋场为例，探讨了在高含水率垃圾堆体上使用钢板路基箱和船型卸料平台构筑临时作业道路或卸料平台，可提高填埋场填埋作业质量，降低运营成本。     

Pre‐ischemia melatonin treatment alleviated acute neuronal injury after ischemic stroke by inhibiting endoplasmic reticulum stress‐dependent autophagy via PERK and IRE1 signalings

Melatonin has demonstrated a potential protective effect in central nervous system. Thus, it is interesting to determine whether pre‐ischemia melatonin administration could protect against cerebral ischemia/reperfusion (IR)‐related injury and the underlying molecular mechanisms. In this study, we revealed that IR injury significantly activated endoplasmic reticulum (ER) stress and autophagy in a middle cerebral artery occlusion mouse model. Pre‐ischemia melatonin treatment was able to attenuate IR‐induced ER stress and autophagy. In addition, with tandem RFP‐GFP‐LC3 adeno‐associated virus, we demonstrated pre‐ischemic melatonin significantly alleviated IR‐induced autophagic flux. Furthermore, we showed that IR induced neuronal apoptosis through ER stress related signalings. Moreover, IR‐induced autophagy was significantly blocked by ER stress inhibitor (4‐PBA), as well as ER‐related signaling inhibitors (PERK inhibitor, GSK; IRE1 inhibitor, 3,5‐dibromosalicylaldehyde). Finally, we revealed that melatonin significantly alleviated cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency, which were remarkably abolished by tunicamycin (ER stress activator) and rapamycin (autophagy activator), respectively. In summary, our study provides strong evidence that pre‐ischemia melatonin administration significantly protects against cerebral IR injury through inhibiting ER stress‐dependent autophagy. Our findings shed light on the novel preventive and therapeutic strategy of daily administration of melatonin, especially among the population with high risk of cerebral ischemic stroke.     

Discovery of Hydroxyamidine Derivatives as Highly Potent,Selective Indoleamine-2,3-dioxygenase 1 Inhibitors

In this study, a series of novel hydroxyamidine derivatives were identified as potent and selective IDO1 inhibitors by structure-based drug design. Among them, compounds 13–15 and 18 exhibited favorable enzymatic and cellular activities. Compound 18 showed improved bioavailability in mouse, rat, and dog (F% = 44%, 58.8%, 102.1%, respectively). With reasonable in vivo pharmacokinetic properties, compound 18 was further evaluated in a transgenic MC38 xenograft mouse model. The combination of compound 18 with PD-1 monoclonal antibody showed a synergistic antitumor effect. These data indicated that compound 18 as a potential cancer immunotherapy agent should warrant further investigation.     

Performance of Echocardiographic Parameters in Sequential Monitoring of Left Ventricular Function in an Animal Model of Acute Heart Failure

Introduction: Numerous newer parameters have been established for sensitive and reproducible evaluation of left ventricular (LV) dysfunction. We assessed the performance of these parameters in sequential monitoring of LV function in an animal model of controllable drug‐induced LV dysfunction. Methods: To establish predictable aggravating LV dysfunction, seven male beagle dogs were anesthetized and received intermittent injection of esmolol and propofol of gradually increasing dosage. Parameters reflecting LV function were measured after each drug infusion. These included LV ejection fraction (LVEF) measured by both two‐dimensional (2D) and three‐dimensional (3D) echocardiography, Tei index, ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e′) and 2D strain‐derived parameters. Changes in these parameters over time were compared with the baseline value. Results: Changes in 2D and 3D LVEF were observed after infusion with propofol (5 mg/kg) and esmolol (3.5 mg/kg). Doppler‐derived parameters including E/e′ and the Tei index failed to detect LV dysfunction prior to 2D LVEF. Significant changes in 2D strains and strain rates (SRs) could be induced by relatively small anesthetic dosages (～4 mg propofol/kg and 2.5 mg esmolol/kg). Strain‐derived parameters were generally highly reproducible and longitudinal strain had the best intraobserver and interobserver reproducibility. Conclusions: The 2D strain parameters provide accurate identification of subclinical impairment of LV function earlier than all other echocardiographic indices. (Echocardiography 2010;27:1274‐1281)