An Inhibitor of Arachidonate 5-Lipoxygenase, Nordy, Induces Differentiation and Inhibits Self-Renewal of Glioma Stem-Like Cells

Recent progress in cancer biology indicates that eradication of cancer stem cells (CSCs) is essential for more effective cancer therapy. Unfortunately, cancer stem cells such as glioma stem-like cells (GSLCs) are often resistant to either radio- or chemotherapy. Therefore, screening and development for novel therapeutic modalities against CSCs has been an important emerging field in cancer research. In this study, we report that a synthetic dl-nordihydroguaiaretic acid compound (dl-NDGA or “Nordy”), inhibited self-renewal and induced differentiation of GSLCs in vitro and in vivo. We found that Nordy inhibited an enzyme known to be involved in leukemia stem cell and leukemia progression, Alox-5, and attenuated the growth of GSLCs in vitro. Nordy reduced the GSLC pool through a decrease in the CD133⁺ population and abrogated clonogenicity. Nordy appeared to exert its effect via astrocytic differentiation by up-regulation of GFAP and down-regulation of stemness related genes, rather than by inducing apoptosis of GSLCs. The growth inhibition of xenografted glioma by Nordy was more long-lasting compared with that of the akylating agent BCNU, which exhibited significant relapse on drug discontinuation resulting from an enrichment of GSLCs. Meanwhile, transient exposure to Nordy reduced tumorigenecity of GSLCs and induced differentiation of the xenografts. Taken together, we have identified Alox-5 as a novel target in GSLCs and its inhibition with Nordy exhibits therapeutic implications through inducing GSLC differentiation.     

Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP^R155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ inflammatory macrophages that infiltrate the muscles of VCP^R155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP^R155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80⁽⁺⁾Ly6C⁽⁺⁾IL-1β⁽⁺⁾ macrophage infiltrates in the muscle, and significantly ameliorated muscle strength. Together, these results suggest that (i) NLRP3 inflammasome and local IL-1β⁽⁺⁾F4/80⁽⁺⁾Ly6C⁽⁺⁾ inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.     

Polymorphism of HLA-DRB1, -DQB1 and -DPB1 genes in Bai ethnic group in southwestern China

In this work, polymorphism of human leukocyte antigen (HLA)-DRB1, -DQB1 and -DPB1 genes was detected using polymerase chain reaction-sequence-based typing method in 128 healthy unrelated volunteers from the Bai ethnic group of Yunnan province of southwest China. Among all the 28 alleles detected for the DRB1 gene, the most common allele was DRB1*120201 with a frequency of 16.41%, followed by DRB1*090102, DRB1*080302, DRB1*1404, DRB1*150101, DRB1*140101 and DRB1*160201, with frequencies of 10.16%, 9.77%, 9.38%, 8.98%, 8.59% and 8.21%, respectively. Among 19 DQB1 alleles detected, the most frequent allele was DQB1*030101/0309 (35.94%), followed by DQB1*050201 (11.33%), DQB1*060101/060103 (10.54%) and DQB1*0401 (10.16%). For the DPB1 locus, the most common alleles were DPB1*0501 (42.19%), DPB1*1301 (13.28%), DPB1*020102 (10.93%) and DPB1*040101 (9.77%). The comparison of HLA class II allele frequencies of Bais with those of other Chinese populations suggested that the Bai ethnic group belonged to the southern group of Chinese.     

Scaffold development using selective laser sintering of polyetheretherketone-hydroxyapatite biocomposite blends

In tissue engineering (TE), temporary three-dimensional scaffolds are essential to guide cell proliferation and to maintain native phenotypes in regenerating biologic tissues or organs. To create the scaffolds, rapid prototyping (RP) techniques are emerging as fabrication techniques of choice as they are capable of overcoming many of the limitations encountered with conventional manual-based fabrication processes. In this research, RP fabrication of solvent free porous polymeric and composite scaffolds was investigated. Biomaterials such as polyetheretherketone (PEEK) and hydroxyapatite (HA) were experimentally processed on a commercial selective laser sintering (SLS) RP system. The SLS technique is highly advantageous as it provides good user control over the microstructures of created scaffolds by adjusting the SLS process parameters. Different weight percentage (wt%) compositions of physically mixed PEEK/HA powder blends were sintered to assess their suitability for SLS processing. Microstructural assessments of the scaffolds were conducted using electron microscopy. The results ascertained the potential of SLS-fabricated TE scaffolds.     

The major cockroach allergen Bla g 4 binds tyramine and octopamine

Bla g 4 is a male cockroach specific protein and is one of the major allergens produced by Blattella germanica (German cockroach). This protein belongs to the lipocalin family that comprises a set of proteins that characteristically bind small hydrophobic molecules and play a role in a number of processes such as: retinoid and pheromone transport, prostaglandin synthesis and mammalian immune response. Using NMR and isothermal titration calorimetry we demonstrated that Bla g 4 binds tyramine and octopamine in solution. In addition, crystal structure analysis of the complex revealed details of tyramine binding. As tyramine and octopamine play important roles in invertebrates, and are counterparts to vertebrate adrenergic transmitters, we speculate that these molecules are physiological ligands for Bla g 4. The nature of binding these ligands to Bla g 4 sheds light on the possible biological function of the protein. In addition, we performed a large-scale analysis of Bla g 4 and Per a 4 (an allergen from American cockroach) homologs to get insights into the function of these proteins. This analysis together with a structural comparison of Blag 4 and Per a 4 suggests that these proteins may play different roles and most likely bind different ligands.     

Infliximab‐related weight gain in inflammatory bowel disease: associations and financial impacts

Association between tumour necrosis alpha inhibitors and weight gain has been reported. We examined weight change in our cohort of inflammatory bowel disease patients treated with infliximab (IFX) for over 12 months, its associations and financial implications. Two‐thirds of patients gained weight during the course of therapy. The mean change in weight after 12 months of IFX therapy was 3.3 (±6.5) kg.     

舌下腺癌在多形性腺瘤中1例

发生于舌下腺的癌在多形性腺瘤中极为罕见。本文报道 1例发生于舌下腺的腺样囊性癌在多形性腺瘤的病例。     

Relationships between depression/somatization and self-reports of pain and disability

AIMS: To examine the relationship between depression and somatization and pain during muscle and joint palpation as well as limitations related to mandibular functioning (LRMF) in patients with temporomandibular disorders. METHODS: The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) data for Axes I and II for 196 consecutive patients (56 men and 140 women) with a history of facial pain were obtained. The mean age of the predominantly Chinese patient population (83.2%) was 33.4 years (range 18 to 55 years). A computerized diagnostic system was used to collect the RDC/TMD history data. The Symptom Check List (SCL-90) depression and somatization scales were generated on-line and archived. The mean muscle pain (MP), joint pain (JP), and LRMF scores were computed with depression and somatization as main effects. Data were subjected to analysis of variance (Scheffé test) and Pearson's correlation at a significance level of .05. RESULTS: Depression scores ranged from 4.03 to 8.16 (MP), from 0.67 to 1.03 (JP), and from 0.30 to 0.38 (LRMF); somatization scores ranged from 2.64 to 7.75 (MP), from 0.58 to 1.00 (JP), and from 0.30 to 0.41 (LRMF). Interaction effects between depression and somatization were not significant. Patients with severe depression had significantly higher MP scores than normal patients or patients with moderate depression. Patients with moderate and severe somatization had significantly higher MP scores than normal patients. LRMF scores of patients with severe somatization were significantly greater than those who were normal or suffered from moderate somatization. No significant difference in JP scores was observed for depression and somatization scales. Correlations between depression/somatization and MP, JP, and LRMF scores were significant and positive but weak; coefficients ranged from 0.15 to 0.41. CONCLUSION: The results suggest that depression and somatization are related to the self-report of MP. In addition, severe somatization may be associated with an increase in jaw disability.