Intracellular Adhesion Molecule-1 K469E Gene Polymorphism and Risk of Diabetic Microvascular Complications: A Meta-Analysis

Background

A number of studies evaluated the association of intracellular adhesion molecule-1 (ICAM-1) K469E (rs5498, A/G) gene polymorphism with diabetic microvascular complications (DMI) including diabetic nephropathy (DN) and diabetic retinopathy (DR) in different populations. However, the results of individual studies remain conflicting.

Methods

A comprehensive search was conducted to identify all eligible studies of the above-mentioned associations. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were assessed using the fixed or random effect model.

Results

Seven studies involving 3411 subjects were included. Overall, the meta-analysis showed a significant association of the A allele with increased risk of DMI susceptibility in a recessive model (OR = 1.37, 95% CI 1.04–1.80, P = 0.02). In the subgroup analysis stratified by ethnicity, significant association was found in Asians but not in Caucasians (OR = 1.78, 95% CI 1.13–2.81, P = 0.01; OR = 1.10, 95% CI 0.79–1.54, P = 0.58, respectively). Moreover, it showed a significant association between the A allele and risk of DN in a recessive model (OR = 1.25, 95% CI 1.02–1.55, P = 0.04).

Conclusions

This meta-analysis suggested that the K469E polymorphism in ICAM-1 gene might affect individual susceptibility to DMI and showed a discrepancy in different ethnicities. Further investigations are needed to validate the association.     

Silica Desiccant Packets for Storage and Transport of Streptococcus pneumoniae and Other Clinically Relevant Species

Bacterial isolates are often transported between laboratories for research and diagnostic purposes. Silica desiccant packets (SDPs), which are inexpensive and do not require freezing, were evaluated for storage and recovery of bacterial isolates. Conditions such as inoculum size, swab type and temperature of storage were investigated using ten Streptococcus pneumoniae isolates. The optimized protocol was then tested using 49 additional S. pneumoniae isolates representing 40 serogroups. Overall, S. pneumoniae growth was considered satisfactory (>100 colony forming units) for 98/109 (89.9%) and 20/20 (100%) swabs after 14 days at room temperature or 28 days at 4° C, respectively. Storage in SDPs did not impact on the ability of S. pneumoniae isolates to be subsequently serotyped. When the survival of nine other clinically relevant bacterial species was tested, seven were viable after 28 days at room temperature, the exceptions being Neisseria gonorrhoeae and Haemophilus influenzae. SDPs are suitable for transport and short-term storage of bacterial species including S. pneumoniae.     

Structure–activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template

In an effort to design inhibitors of human glutaminyl cyclase (QC), we have synthesized a library of N-aryl N-(5-methyl-1H-imidazol-1-yl)propyl thioureas and investigated the contribution of the aryl region of these compounds to their structure–activity relationships as cyclase inhibitors. Our design was guided by the proposed binding mode of the preferred substrate for the cyclase. In this series, compound 52 was identified as the most potent QC inhibitor with an IC₅₀ value of 58 nM, which was two-fold more potent than the previously reported lead 2. Compound 52 is a most promising candidate for future evaluation to monitor its ability to reduce the formation of pGlu-Aβ and Aβ plaques in cells and transgenic animals.     

Efficacy of Sorafenib Monotherapy versus Sorafenib-Based Loco-Regional Treatments in Advanced Hepatocellular Carcinoma

Background

Although sorafenib is accepted as the standard of care in advanced hepatocellular carcinoma (HCC), its therapeutic benefit is marginal. Here, we aimed to compare the efficacy and safety of sorafenib monotherapy (S-M) and sorafenib-based loco-regional treatments (S-LRTs) in advanced HCC.

Methods

From 2007 to 2012, 290 patients with advanced HCC (Barcelona Clinic Liver Cancer stage C) with S-M (n = 226) or S-LRTs (n = 64) were reviewed retrospectively. Survival outcomes and treatment-related toxicities between two groups were analyzed.

Results

Variables related to tumor burden and liver function were similar between the groups (all P > 0.05). Within the entire population, the S-LRTs group had both longer median overall survival (OS) (8.5 vs 5.5 months, P = 0.001) and progression-free survival (PFS) (5.3 vs 3.0 months, P = 0.002) than the S-M group. Furthermore, the S-LRTs group had longer Os than the S-M group in a subgroup with neither extrahepatic spread (EHS) nor regional nodal involvement (RNI) (18.0 vs 7.8 months, P = 0.019) and in a subgroup with EHS and/or RNI (8.3 vs 4.8 months, P = 0.028). In addition, the S-LRTs group had longer PFS than the S-M group in the subgroup with neither EHS nor RNI (9.6 vs 3.2 months, P = 0.027).

Treatment

Related toxicity was similar between two groups.

Conclusion

Combined use of sorafenib and LRTs may provide better treatment outcomes without significantly increasing treatment-related toxicities, even in patients with EHS and/or RNI. Therefore, addition of active LRTs might be considered, if feasible.     

cDNA cloning and mRNA expression of heat shock protein 90 gene in the haemocytes of Zhikong scallop Chlamys farreri

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone contributing to the folding, maintenance of structural integrity and proper regulation of a subset of cytosolic proteins. The full-length cDNA of Zhikong scallop Chlamys farreri HSP90 (designated CfHSP90) was cloned by EST and rapid RACE techniques. It was of 2710 bp, including an open reading frame (ORF) of 2181 bp encoding a polypeptide of 726 amino acids with all the five HSP90 family signatures. BLAST analysis revealed that the CfHSP90 gene shared high similarity with other known HSP90 genes. Fluorescent real-time quantitative RT-PCR was used to examine the expression pattern of CfHSP90 mRNA in haemocytes of scallops exposed to Cd²⁺, Pb²⁺ and Cu²⁺ for 10 and 20 days, respectively. All the three heavy metals could induce CfHSP90 expression. There was a clear dose-dependent expression pattern of CfHSP90 after heavy metals exposure for 10 days or 20 days. Different concentrations of the same metal resulted in different effects on CfHSP90 expression. The results indicated that CfHSP90 responded to various heavy metal stresses with a dose-dependent expression pattern as well as exposure time effect, and could be used as a molecular biomarker in a heavy metal polluted environment.     

Plant regeneration of Chorispora bungeana via somatic embryogenesis

Summary A method was developed for in vitro regeneration of plants via somatic embryogenesis in Chorispora bungeana, an alpine plant with freeze-tolerance, using cell suspensions initiated from leaf-derived callus. Primary calli were induced from leaves of C. bungeana grown on Murashige and Skoog (MS) media supplemented with 4.0 mg l⁻¹ gibberellic acid (GA₃), 0.2 mgl⁻¹ α-naphthaleneacetic acid (NAA) and 0.2 mgl⁻¹ 2,4-dichlorophenoxyacetic acid (2,4-D). Suspension culture was initiated by incubating the callus particulates in liquid MS medium supplemented with 1.0 mgl⁻¹ kinetin (KT) and 0.2 mgl⁻¹ NAA. Individual early cotyledonary-stage somatic embryos isolated from cell suspension developed into whole plants on medium containing high levels of sucrose (60 and 90 gl⁻¹), whereas lower sucrose concentrations (0 and 30 gl⁻¹) were inhibitory to main root development. On the MS medium with 90 gl⁻¹ sucrose, one regenerated plant exhibited hetero-morphologic leaves, while other plants grown on different media showed a transformation from stem to root.     

Apoptotic and anti-proliferative effects of 17β-estradiol and 17β-estradiol-like compounds in the Hep3B cell line

Since there is evidence for estrogen and estrogen-like compounds to have beneficial effect on the pathogenesis of hepatocellular carcinoma (HCC), this study was designed to investigative the apoptotic and anti-proliferative effects of these compounds on the human hepatoma Hep3B cell line. The Hep3B cells were treated with 17β-estradiol (E2), diethylstilbestrol (DES), tamoxifen, and genistein. After treatments of these compounds at the concentration of 10^-6 or 10^-8 M, the Hep3B cells were demonstrated to have significant DNA fragmentation, nucleus condensation, cytochrome-c leaking from the mitochondria and caspase-3 activation by DAPI and Western blotting. The cells were also observed to have declined proliferative potential by MTT assay, arrested cell cycle by flow-cytometry measurements. However, the cytochrome-c leaking from the mitochondria induced by E2 and E2-like compounds was blocked totally by ICI 182,780 treatment. These finding suggest that estrogen and the estrogen-like compounds may induce anti-proliferative and apoptotic effects in Hep3B cells, and the E2 and the E2-like compounds mediated apoptotic effect was estrogen receptor dependent. Among the drugs tested, E2, E2 agonists (DES and genistein) and partial antagonist (tamoxifen), all showed the stronger anti-tumor potential. The last two authors, Wei-Wen Kuo and Chih-Yang Huang, share equal contribution.     

Xenopus GDF6, a new antagonist of noggin and a partner of BMPs.

In Xenopus, ectodermal cell fates are determined by antagonistic interaction between the BMP subfamily of TGF-(beta) ligands and the organizer-specific secreted factors (e.g. noggin, chordin and follistatin). Inhibition of BMP function by these factors can convert cells from an epidermal to a neural cell fate. In this study, we report that GDF6, a new member of the Xenopus TGF-(beta) family, can function in antagonistic interaction with neural inducers. GDF6 induces epidermis and inhibits neural tissue in dissociated cells, and this activity is blocked by the presence of noggin. We demonstrate that GDF6 binds directly to the neural inducer noggin. Furthermore, we find that GDF6 and BMP2 can form heterodimers and the process seems to require cotranslation of the proteins in the same cells. In normal embryos, GDF6 and BMP2 are coexpressed in several places, including the edge of the neural plate at early neurula stages, suggesting that GDF6 may synergize with BMPs to regulate patterning of the ectoderm. Our data show for the first time that noggin can bind directly to and inhibit another TGF-(beta) family member: GDF6. In addition, BMP and GDF6 heterodimers may play an important role in vivo to regulate cell fate determination and patterning.     

Chromosomal localization of the loci responsible for dystrophic cardiac calcinosis in DBA/2 mice.

Dystrophic cardiac calcinosis (DCC) occurs in certain inbred strains of mice, including DBA/2 and C3H/He, and is generally found as an incidental lesion in adult animals at necropsy. Preliminary genetic studies into the cause of DCC have been performed in DBA/2 mice and suggest that DCC is inherited as an autosomal recessive trait involving three or four unlinked genes. To investigate the genetics of DCC further, we produced myocardial cell death by freeze-thaw injury to induce DCC. Experiments were conducted with three F1 hybrids made using three inbred strains of mice (DBA/2J and C3H/HeJ, DCC-susceptible strains; C57BL/6J, DCC-resistant strain) to compare the genetic factors in the development of DCC. We found that DBA/2 and C3H/He mice share the same gene pattern(s) that is responsible for DCC. We determined by backcross linkage analysis in DBA/2 and C57BL/6 mice that at least one recessive locus is responsible for DCC. A haplotype analysis of the backcross data demonstrated that the recessive locus, designated dyscalc1, is located on Chromosome 7, 20.5 cM distal to the centromere. The likely candidate genes for dyscalc1 are discussed. Further understanding of the structure and function of these mutant genes will be beneficial in explaining the molecular pathogenesis of DCC.