Structural elucidation of a polysaccharide from Lonicera japonica flowers, and its neuroprotective effect on cerebral ischemia-reperfusion injury in rat

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Danying Su, Shi Li, Wei Zhang, Jing Wang, Jingjing Wang, Manhua Lv
A water-soluble polysaccharide, LJPB2, was purified from Lonicera japonica flowers. The present study was aimed to illustrate its structural features and its neuroprotective effect via anti-oxidant activity on focal ischemia/reperfusion (I/R) injury in rat brain. Via chemical and spectral methods, LJPB2, a polysaccharide with molecular weight of 8.9×10³Da, was composed of arabinose, mannose, glucose, and galactose, in a molar ratio of 1.8: 1.0: 3.6: 3.7. In addition, the linkage analysis revealed that it mainly contained 1, 4, 6-linked mannose, 1, 4-linked glucose and 1, 4-linked galactose, with a highly branched structure of araban and terminal glucose. LJPB2 exhibited a strong capacity of scavenging DPPH free radical in vitro. Moreover, in vivo assay using a commonly used cerebral I/R model demonstrated that LJPB2 could significantly improve the neurological deficit scores and infract volume. In addition, LJPB2 remarkably reduced the MDA level and NO production, and elevated the SOD and GSH-Px enzyme activities in the rat brain tissues. These results certainly indicated that LJPB2 had a distinct neuroprotective effect related to its strong antioxidant capacity in the cerebral ischemia/reperfusion injury.



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Fibulin-4 reduces extracellular matrix production and suppresses chondrocyte differentiation via DKK1- mediated canonical Wnt/β-catenin signaling

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Lei Shangguan, Guangzhi Ning, Zhuojing Luo, Yue Zhou
Fibulin-4 is an extracellular matrix (ECM) protein implicated in connective tissue development and elastic fiber formation. However, little is known about the underlying function of Fibulin-4 in cartilage development. The aim of this study was to investigate the role and probable mechanism of Fibulin-4 stimulation in ECM production and chondrocyte differentiation. Fibulin-4 has been observed to be abnormally elevated and matrix metalloproteinases 13 (MMP13) level was highly expressed in human osteoarthritis (OA) chondrocytes. In the chondrogenic cell line ATDC5, Fibulin-4 stimulation profoundly inhibited the expression of ECM gene type II collagen (Col2a1), aggrecan (Acan), and type X collagen (Col10a1). Overexpression of Fibulin-4 attenuated the expression of master transcription factors Sox6, Sox9 and Runx2, but had no effect on the expression of Sox5. Additionally, Fibulin-4 stimulation activated canonical Wnt pathway by reducing the expression of Wnt inhibitor DKK1 but not Sost. Moreover, Fibulin-4 augmented the expression of Wnt/β-catenin signaling target genes like β-catenin and Wnt-3a as well as diminished GSK-3β activation, and DKK1 abolished the effect of Fibulin-4 on chondrocyte differentiation, suggesting that Fibulin-4 is an important regulator of ECM production and chondrocyte differentiation through DKK1-mediated Wnt/β-catenin signaling. Our study provides evidence of a previously unknown link between Fibulin-4 and the canonical Wnt/β-catenin pathway that may contribute to our understanding of the molecular mechanisms of OA.



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Structural insight of an antioxidative arabinogalactan protein of Aegle marmelos fruit gum and it’s interaction with β-lactoglobulin

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Kaushik Bera, Sayani Ray, Washim Raja, Bimalendu Ray
The complication of arabinogalactan protein (AGP) structure, a significant ingredient of gum polysaccharides, not merely hinders the allocation of its role, but restricts its utilization as well. Here, we describe structural details of an AGP purified from Aegle marmelos fruit gum. This AGP (310×10³g/mol), which is water-soluble, contains β-1,3-linked galactopyranosyl main chain substituted at O-6 position with side chains containing galactose and arabinose residues. Also data on sugar composition, ring size, glycosidic linkage pattern, anomeric configuration and sequence of monosaccharide units of a number of oligosaccharides produced from this AGP by chemical and enzymatic methods were acquired. Biochemical analysis reveals resemblance in antioxidative potential between this arabinogalactan protein and standard antioxidants. Moreover, mixture of AGP and β-lactoglobulin form stable water soluble complex having binding constant K=2.38×10⁶/M. As gum polysaccharides are important raw materials of food industry discovering an antioxidative gum with the ability of creating stable water soluble complex with β-lactoglobulin may have important implication.



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Structural characterization and bioavailability of ternary nanoparticles consisting of amylose, α-linoleic acid and β-lactoglobulin complexed with naringin

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Tao Feng, Ke Wang, Fangfang Liu, Ran Ye, Xiao Zhu, Haining Zhuang, Zhimin Xu
Naringin is a bioflavonoid that is rich in citrus plants and possesses enormous health benefits. However, the use of naringin as a nutraceutical is significantly limited by its low bioavailability. In this study, a novel water-soluble ternary nanoparticle material consisting of amylose, α-linoleic acid and β-lactoglobulin was developed to encapsulate naringin to improve its bioavailability. The physicochemical characteristics of the ternary nanoparticle-naringin inclusion complex were analysed by ultraviolet-visible spectroscopy (UV), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), high-resolution transmission electron microscopy (TEM), X-ray diffractometry (XRD) and particle size distribution. The results confirmed the formation of the ternary nanoparticle-naringin inclusion complex. The encapsulation efficiency (EE) and loading content (LC) of the ternary nanoparticle-naringin inclusion complex were 78.73±4.17% and 14.51±3.43%, respectively. In addition, the results of the ternary nanoparticle-naringin inclusion complex in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) demonstrated that naringin can be gradually released from the complex. In conclusion, ternary nanoparticles are considered promising carriers to effectively improve the bioavailability of naringin.



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Structural characterization and antioxidant activity of polysaccharide from Hohenbuehelia serotina

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98
Author(s): Xiaoyu Li, Lu Wang, Zhenyu Wang
Previous research found that the polysaccharides isolated from Hohenbuehelia serotina possessed various biological activities, such as antioxidant, immunomodulation and radioprotective effects. However, the structural information of H. serotina polysaccharides has not yet been reported. Therefore, based on the investigation of the antioxidative tracking, a novel polysaccharide named as NTHSP-A1 was isolated from H. serotina by ultrasonic-assistance extraction and anion-exchange and gel permeation chromatography approaches. Structural characterization revealed that NTHSP-A1 had an average molecular weight of 8.09×10³Da and composed of arabinose, mannose, glucose and galactose in a molar ratio of 4:16:28:11. The polysaccharide was semi-crystalline substance with multi-branching structure. The backbone of NTHSP-A1 was shown to contain →3,6)-α-d-Glcp-(1→, with branches substituted at C-3 of →2)-α-l-Arap-(1→, C-3 of α-d-Manp-(1→, and C-6 of →6)-β-d-Galp-(1→, respectively. This study provides a theoretical basis for the further research on the relationship between biological activity and structure of NTHSP-A1.

Graphical abstract

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In vivo cough suppressive activity of pectic polysaccharide with arabinogalactan type II side chains of Piper nigrum fruits and its synergistic effect with piperine

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Sadhana Khawas, Gabriela Nosáľová, Sujay Kumar Majee, Kanika Ghosh, Washim Raja, Veronika Sivová, Bimalendu Ray
Piper nigrum L. fruits are not only a prized spice, but also highly valued therapeutic agent that heals many ailments including asthma, cold and respiratory problems. Herein, we have investigated structural features and in vivo antitussive activity of three fractions isolated from Piper nigrum fruits. The water extract (PN-WE) upon fractionation with EtOH yielded two fractions: a soluble fraction (PN-eSf) and a precipitated (PN-ePf) one. The existence of a pectic polysaccharide with arabinogalactan type II side chains (147kDa) in PN-ePf and piperine in PN-eSf were revealed. Moreover, oligosaccharides providing fine structural details of side chains were generated from PN-ePf and then characterized. The parental water extract (PN-WE) that contained both pectic polysaccharide and piperine, after oral administration (50mgkg⁻¹ body weight) to guinea pigs, showed antitussive activity comparable to codeine phosphate (10mgkg⁻¹ body weight). The EtOH precipitated fraction (PN-ePf) containing pectic polysaccharide showed comparatively higher antitussive activity than EtOH soluble fraction (PN-eSf) that contained piperine, but their potencies are lower than the parental water extract. Significantly, the specific airway smooth muscle reactivity of all three fractions remained unchanged. Finally, pectic polysaccharide-piperine combination in parental extract synergistically enhances antitussive effect in guinea pigs.



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The functional and structural stabilization of trypsin by sucrose

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Lida Momeni, Sheida Mahmodian, Behzad Shareghi, Ali Akbar Saboury, Sadegh Farhadian
Docking and spectroscopic techniques were performed to probe the stabilizing effect of sucrose on the dynamics, structure and activity of trypsin. The thermodynamic folding properties, melting temperature (Tm), enthalpy change (ΔH°) and entropy change (ΔS°) were measured by thermal stability studies to understand the picture of trypsin folding. Sucrose acted as an enhancer for trypsin stability. Fluorescence spectroscopy revealed the static model of the quenching. The number of binding sites was 1. The Absorption, Fluorescence and circular dichroism spectral analysis illustrated that sucrose could protect the native structural conformation of enzyme and prevent the enzyme unfolding. Fluorescence spectroscopy and the molecular docking technique simulation displayed that the hydrogen bonding and Vander Waals forces played a main role in stabilizing the trypsin-sucrose complex, and the number of direct H-bonds between sucrose and trypsin was low; thus, the direct interactions had little contribution in the stabilizing effect and the indirect interactions caused by the preferential hydration were resulting from a molecular mechanism principally causing the stabilizing effects of sucrose.Upon sucrose conjugation, the kcat/Km value of the enzyme was increased. Tm of the trypsin-sucrose complex was increased due to the higher H-bond formation and the lower surface hydrophobicity after sucrose modification. Sucrose acted as enhancers for trypsin stability and activity. The result shows the ability of sucrose to protect the native structural conformation of trypsin. These results explicitly describe that stabilizing sucrose is preferentially excluded from the surface of trypsin, since water has a higher tendency toward favorable interactions with functional groups of trypsin than with sucrose.



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Refolding and unfolding of CT-DNA by newly designed Pd(II) complexes. Their synthesis, characterization and antitumor effects

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Mahin Dustkami, Hassan Mansouri-Torshizi
New antitumor Pd(II) compounds derived from oxygen donor ligands salicylate (SA) (1) and sulfosalicylate (SSA) (2) dianions and nitrogen donor heterocyclic ligand 2,2′-bipyridine (bpy) were synthesized and characterized by elemental analysis, UV–Vis, FT-IR, ¹H NMR and conductivity measurements. The complexes evaluated for their cytotoxicity effects towards cancer cell line of K562 using MTT assay. They are more cytotoxic than cisplatin. The dependence of their interaction modes with CT-DNA on concentration of the compounds has been discovered in this work. CT-DNA binding studies of these complexes have been investigated by UV–Vis absorption, ethidium bromide (EB) displacement, fluorescence, circular dichroism and gel electrophoresis techniques. The apparent binding constants (Kapp) has been obtained 3.9 and 10.9×10⁴M⁻¹ at lower concentration range and 1.03 and 1.59×10⁴M⁻¹ at higher concentration range for complexes (1) and (2), respectively. These complexes effectively interact with CT-DNA in the order of (2)>(1). Fluorescence studies exhibited that the complexes quench CT-DNA-EB by simultaneous static and dynamic quenching processes. The calculated binding (Kapp, kq, KSV, n) and thermodynamic (ΔG°, ΔH°, ΔS°) parameters revealed that hydrophobic, van der Waals forces and hydrogen binding holds the Pd(II) complexes in the CT-DNA grooves. Gel electrophoresis supports the spectroscopic experiments.



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Characterization of the selective alkylation site in hemoglobin A by dihydroartemisinin with tandem mass spectrometry

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Khomsan Tiensomjitr, Samran Prabpai, Palangpon Kongsaeree
The reaction between the antimalarial drug dihydroartemisinin (DHA) and hemoglobin A (HbA) was investigated in vitro. A fluorescein-tagged artemisinin analog reacted with HbA and fluorescent HbA-drug adducts could be visualized on SDS-PAGE to confirm stable covalent reaction adducts and necessity of the endoperoxide moiety and Fe(II). Mass spectrometric analyses revealed that DHA favourably alkylated protein part rather than heme and the modification site was identified to be at Tyr35 of the beta globin chain.

Graphical abstract

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IFC: Editorial Board

Publication date: May 2017
Source:International Journal of Biological Macromolecules, Volume 98





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Antitumor and antimetastatic activities of rhamnogalacturonan-II-type polysaccharide isolated from mature leaves of green tea via activation of macrophages and natural killer cells

Publication date: June 2017
Source:International Journal of Biological Macromolecules, Volume 99
Author(s): Hye-Ryung Park, Dahyun Hwang, Hyung-Joo Suh, Kwang-Won Yu, Tae Young Kim, Kwang-Soon Shin
To investigate the antitumor and antimetastatic polysaccharide from the mature leaves of green tea, GTE-II was purified using size exclusion chromatography. GTE-II consisted of 15 different sugars including rarely observed sugars such as 2-O-methyl-fucose, 2-O-methyl-xylose, apiose, aceric acid, 3-deoxy-d-manno-2-octulosonic acid, and 3-deoxy-d-lyxo-2-heptulosaric acid, which were characteristics of pectic polysaccharide rhamnogalacturonan-II. Treatment of peritoneal macrophages with GTE-II not only increased interleukin (IL)-6 and IL-12 production, but also had significantly increased tumoricidal activity against Yac-1 tumor cells than those obtained from untreated mice. In an assay of natural killer (NK) cell activity, intravenous administration of GTE-II significantly stimulated NK cytotoxicity against Yac-1 tumor cells. Furthermore, the depletion of NK cells by injection of rabbit anti-asialo GM1 serum eliminated the inhibitory effect of GTE-II on B16BL6 melanoma cells. These data suggest that GTE-II inhibits tumor metastasis, and its antitumor effect is associated with activation of macrophages and NK cells.



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Editorial Board

Publication date: May 2017
Source:Cellular Signalling, Volume 33





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Issue Information

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Loss of BRCA1 in the cells of origin of ovarian cancer induces glycolysis: A window of opportunity for ovarian cancer chemoprevention.

Mutations in the breast cancer susceptibility gene 1 (BRCA1) are associated with an increased risk of developing epithelial ovarian cancer. However, beyond the role of BRCA1 in DNA repair, little is known about other mechanisms by which BRCA1 impairment promotes carcinogenesis. Given that altered metabolism is now recognized as important in the initiation and progression of cancer, we asked whether loss of BRCA1 changes metabolism in the cells of origin of ovarian cancer. The findings show that silencing BRCA1 in ovarian surface epithelial and fallopian tube cells increased glycolysis. Furthermore, when these cells were transfected with plasmids carrying deleterious BRCA1 mutations (5382insC or the P1749R), there was an increase in hexokinase-2 (HK2), a key glycolytic enzyme. This effect was mediated by MYC and the signal transducer and activator of transcription 3 (STAT3). To target the metabolic phenotype induced by loss of BRCA1, a drug repurposing approach was used and aspirin was identified as an agent that counteracted the increase in HK2 and the increase in glycolysis induced by BRCA1 impairment. Evidence from this study indicates that the tumor suppressor functions of BRCA1 extend beyond DNA repair to include metabolic endpoints and identifies aspirin as an ovarian cancer chemopreventive agent capable of reversing the metabolic derangements caused by loss of BRCA1.

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Cancer stem-like cell related protein CD166 degrades through E3 ubiquitin ligase CHIP in head and neck cancer

Publication date: Available online 6 March 2017
Source:Experimental Cell Research
Author(s): Meng Xiao, Ming Yan, Jianjun Zhang, Qin Xu, Shengcai Qi, Xu Wang, Wantao Chen
Our previous studies have identified that CD166 works as a cancer stem-like cell (CSC) marker in epithelial cancers with a large repertoire of cellular functions. However, the post-translational regulatory mechanisms underlying CD166 turnover remain elusive. Several independent studies have reported that E3 ubiquitin ligase CHIP revealed significant biological effects through ubiquitin proteasome pathway on some kinds of malignant tumors. With analyzing the effects of CHIP expressions on stem-like cell populations, we found that CHIP represses CSC characteristics mainly targeting the CSC related protein CD166 in head and neck cancer (HNC). To investigate the role and relationship between CD166 and CHIP, HNC tissues and cell lines were used in this study. A significant negative correlation was observed between the expression levels of CHIP and CD166 in HNC patient samples. We also found that CHIP directly regulates the stability of CD166 protein through the ubiquitin proteasome system, which was also identified participating in the regulation of CSC behaviors in HNCs. Our findings demonstrate that CHIP-CD166-proteasome axis participates in regulating CSC properties in HNCs, suggesting that the regulation of CD166 by CHIP could provide new options for diagnosing and treating in the patients with HNCs.



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Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro

Publication date: Available online 6 March 2017
Source:Experimental Cell Research
Author(s): Weifeng Li, Wenbing Zhi, Fang Liu, Zehong He, Xiuei Wang, Xiaofeng Niu
Pathogenesis of atherosclerosis is characterized by the proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammatory lesions. The aim of this study is to elucidate the effect of atractylenolide I (AO-I) on smooth muscle cell inflammation, proliferation and migration induced by oxidized modified low density lipoprotein (Ox-LDL). Here, We found that atractylenolide I inhibited Ox-LDL-induced VSMCs proliferation and migration in a dose-dependent manner, and decreased the production of inflammatory cytokines and the expression of monocyte chemoattractant protein-1 (MCP-1) in VSMCs. The study also identified that AO-I prominently inhibited p38-MAPK and NF-κB activation. More importantly, the specific heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin (ZnPP) IX partially abolished the beneficial effects of atractylenolide I on Ox-LDL-induced VSMCs. Furthermore, atractylenolide I blocked the foam cell formation in macrophages induced by Ox-LDL. In summary, inhibitory roles of AO-I in VSMCs proliferation and migration, lipid peroxidation and subsequent inflammatory responses might contribute to the anti-atherosclerotic property of AO-I.

Graphical abstract

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Evolution and diversity of cadherins and catenins

Publication date: Available online 6 March 2017
Source:Experimental Cell Research
Author(s): Ismail Sahin Gul, Paco Hulpiau, Yvan Saeys, Frans van Roy
Cadherin genes encode a superfamily of conserved transmembrane proteins that share an adhesive ectodomain composed of tandem cadherin repeats. More than 100 human cadherin superfamily members have been identified, which can be classified into three families: major cadherins, protocadherins and cadherin-related proteins. These superfamily members are involved in diverse fundamental cellular processes including cell-cell adhesion, morphogenesis, cell recognition and signaling. Epithelial cadherin (E-cadherin) is the founding cadherin family member. Its cytoplasmic tail interacts with the armadillo catenins, p120 and β-catenin. Further, α-catenin links the cadherin/armadillo catenin complex to the actin filament network. Even genomes of ancestral metazoan species such as cnidarians and placozoans encode a limited number of distinct cadherins and catenins, emphasizing the conservation and functional importance of these gene families. Moreover, a large expansion of the cadherin and catenin families coincides with the emergence of vertebrates and reflects a major functional diversification in higher metazoans. Here, we revisit and review the functions, phylogenetic classifications and co-evolution of the cadherin and catenin protein families.



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In situ and in silico kinetic analyses of the Programmed Cell Death 1, Programmed Cell Death-Ligands, and B7-1 interaction network [Molecular Biophysics]

Programmed cell death-1 (PD-1) is an inhibitory receptor with an essential role in maintaining peripheral tolerance, and among the most promising immunotherapeutic targets for treating cancer, autoimmunity, and infectious diseases. A complete understanding of the consequences of PD-1 engagement by its ligands, PD-L1 and PD-L2, and of PD-L1 binding to B7-1, requires quantitative analysis of their interactions at the cell surface. We present here the first complete in situ kinetic analysis of the PD-1/PD-1 ligands/B7-1 system. Consistent with previous solution measurements, we observed higher in situ affinities for human (h) than murine (m) PD-1 interactions, stronger binding of hPD-1 to hPD-L2 than hPD-L1, and comparable binding of mPD-1 to both ligands. However, in contrast to the relatively weak solution affinities, the in situ affinities of PD-1 are as high as those of the TCR for agonist pMHC and of LFA-1 for ICAM-1, but significantly lower than that of the B7-1-CTLA-4 interaction, suggesting a distinct basis for PD-1 versus CTLA-4 mediated inhibition. Notably, the in situ interactions of PD-1 are much stronger than that of B7-1 with PD-L1. Overall, the in situ affinity ranking greatly depends on the on-rate instead of the off-rate. In silico simulations predict that PD-1-PD-L1 interactions dominate at interfaces between activated T cells and mature dendritic cells, and that these interactions will be highly sensitive to the dynamics of PD-L1 and PD-L2 expression. Our results provide a kinetic framework for better understanding inhibitory PD-1 activity in health and disease.

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Outcomes in elderly patients admitted to the intensive care unit with solid tumors

As the population ages and cancer therapies improve, there is an increased call for elderly cancer patients to be admitted to the intensive care unit (ICU). This study aimed to assess short-term survival and p...

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Health-related quality of life of children on treatment for acute lymphoblastic leukemia: A systematic review

Abstract

Children with acute lymphoblastic leukemia (ALL) undergo intense anticancer treatment. We systematically reviewed 22 studies evaluating 2,073 ALL patients’ health-related quality of life (HRQL) and its clinical/demographic correlates during treatment. Overall HRQL was significantly reduced on treatment. Despite HRQL improvements over time, longitudinal studies reported a proportion of children continued to experience reduced HRQL after treatment completion. We found inconsistent associations between clinical/demographic factors and HRQL outcomes. Tentative evidence emerged for worse HRQL being associated with intensive phases of chemotherapy, corticosteroid therapy, experiencing greater toxicity, older age, and female sex. Longitudinal studies are needed to identify children at-risk of reduced HRQL.

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Household income and risk-of-poverty of parents of long-term childhood cancer survivors

Abstract

Background

Taking care of children diagnosed with cancer affects parents’ professional life and may place the family at risk-of-poverty. We aimed to (i) compare the household income and risk-of-poverty of parents of childhood cancer survivors (CCS) to parents of the general population, and (ii) identify sociodemographic and cancer-related factors associated with risk-of-poverty.

Methods

As part of the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to parents of CCS aged 5–15 years, who survived ≥5 years after diagnosis. Information on parents of the general population came from the Swiss Household Panel (parents with ≥1 child aged 5–15 years). Risk-of-poverty was defined as having a monthly household income of <4,500 Swiss Francs (CHF) for single parents and <6,000 CHF for parent-couples. We used logistic regression to identify factors associated with risk-of-poverty.

Results

We included parents of 383 CCS and 769 control parent households. Parent-couples of CCS had a lower household income (P_trend < 0.001) and were at higher risk-of-poverty (30.4% vs. 19.3%, P = 0.001) compared to control parent-couples. Household income and risk-of-poverty of single parents of CCS was similar to control single parents. Parents of CCS were at higher risk-of-poverty if they had only standard education (OR_mother = 3.77 [where OR is odds ratio], confidence interval [CI]: 1.61–8.82; OR_father = 8.59, CI: 4.16–17.72) and were from the German language region (OR = 1.99, CI: 1.13–3.50). We found no cancer-related risk factors.

Conclusion

Parents of long-term CCS reported lower household income and higher risk-of-poverty than control parents. Support strategies may be developed to mitigate parents’ risk-of-poverty in the long term, particularly among parents with lower education.

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A population genetics perspective on the determinants of intra-tumor heterogeneity

Publication date: Available online 6 March 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Zheng Hu, Ruping Sun, Christina Curtis
Cancer results from the acquisition of somatic alterations in a microevolutionary process that typically occurs over many years, much of which is occult. Understanding the evolutionary dynamics that are operative at different stages of progression in individual tumors might inform the earlier detection, diagnosis, and treatment of cancer. Although these processes cannot be directly observed, the resultant spatiotemporal patterns of genetic variation amongst tumor cells encode their evolutionary histories. Such intra-tumor heterogeneity is pervasive not only at the genomic level, but also at the transcriptomic, phenotypic, and cellular levels. Given the implications for precision medicine, the accurate quantification of heterogeneity within and between tumors has become a major focus of current research. In this review, we provide a population genetics perspective on the determinants of intra-tumor heterogeneity and approaches to quantify genetic diversity. We summarize evidence for different modes of evolution based on recent cancer genome sequencing studies and discuss emerging evolutionary strategies to therapeutically exploit tumor heterogeneity. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.



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Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma [Review]

Dopamine is a catecholamine that acts both as a neurotransmitter and as a hormone, exerting its functions via dopamine (DA) receptors that are present in a broad variety of organs and cells throughout the body. In the circulation, DA is primarily stored in and transported by blood platelets. Recently, the important contribution of DA in the regulation of angiogenesis has been recognized. In vitro and in vivo studies have shown that DA inhibits angiogenesis through activation of the DA receptor type 2. Overproduction of catecholamines is the biochemical hallmark of pheochromocytoma (PCC) and paraganglioma (PGL). The increased production of DA has been shown to be an independent predictor of malignancy in these tumors. The precise relationship underlying the association between DA production and PCC and PGL behavior needs further clarification. Herein, we review the biochemical and physiologic aspects of DA with a focus on its relations with VEGF and hypoxia inducible factor related angiogenesis pathways, with special emphasis on DA producing PCC and PGL.—Osinga, T. E., Links, T. P., Dullaart, R. P. F., Pacak, K., van der Horst-Schrivers, A. N. A., Kerstens, M. N., Kema, I. P. Emerging role of dopamine in neovascularization of pheochromocytoma and paraganglioma.

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Key Proteins and Pathways that Regulate Lifespan [Cell Biology]

Here, we review three sets of key proteins and their corresponding downstream pathways that have been linked to extending lifespan and promoting health span in a wide range of organisms. In particular, we review the biology of the sirtuin family of proteins, the Insulin/Insulin-like Growth Factor (IGF) signaling (IIS) pathway, and the mechanistic Target of Rapamycin (mTOR). Using insights derived from simple model organisms, mice and humans we discuss how these proteins and pathways may potentially alter the rate of aging. We further describe how knowledge of these pathways may lead to the rational design of small molecules that modulate aging and hence alter the propensity for a host of age-related diseases.

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Non-Enzymatic Molecular Damage as a Prototypic Driver of Aging [Molecular Bases of Disease]

The chemical potentialities of metabolites far exceed metabolic requirements. The required potentialities are realized mostly through enzymatic catalysis. The rest are realized spontaneously through organic reactions that (i) occur wherever appropriate reactants come together, (ii) are so typical that many have proper names (e.g. Michael addition, Amadori rearrangement, Pictet-Spengler reaction), and (iii) often have damaging consequences. There are many more causes of non-enzymatic damage to metabolites than reactive oxygen species and free radical processes (the "usual suspects"). Endogenous damae accumulation in non-renewable macromolecules and spontaneously polymerized material is sufficient to account for aging and differentiates aging from wear-and-tear of inanimate objects by deriving it from metabolism, the essential attribute of life.

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Zinc starvation induces autophagy in yeast [Cell Biology]

Zinc is an essential nutrient for all forms of life. Within cells, most zinc is bound to protein. Because zinc serves as a catalytic or structural cofactor for many proteins, cells must maintain zinc homeostasis under severely zinc-deficient conditions. In yeast, the transcription factor Zap1 controls the expression of genes required for uptake and mobilization of zinc, but to date the fate of existing zinc-binding proteins under zinc starvation remains poorly understood. Autophagy is an evolutionarily conserved cellular degradation/recycling process in which cytoplasmic proteins and organelles are sequestered for degradation in the vacuole/lysosome. In this study, we investigated how autophagy functions under zinc starvation. Zinc depletion induced non-selective autophagy, which is important for zinc-limited growth. Induction of autophagy by zinc starvation was not directly related to transcriptional activation of Zap1. Instead, TORC1 inactivation directed zinc starvation-induced autophagy. Abundant zinc proteins, such as Adh1, Fba1, and ribosomal protein Rpl37, were degraded in an autophagy-dependent manner. But the targets of autophagy were not restricted to zinc-binding proteins. When cellular zinc is severely depleted, this non-selective autophagy plays a role in releasing zinc from the degraded proteins and recycling zinc for other essential purposes.

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Structure/activity Relationship of Thapsigargin Inhibition on the Purified Golgi/secretory Pathway Ca2+/Mn2+ Transport ATPase (SPCA1a) [Membrane Biology]

The Golgi/secretory pathway Ca2+/Mn2+ transport ATPase (SPCA1a) is implicated in breast cancer and Hailey-Hailey disease. Here, we purified recombinant human SPCA1a from Saccharomyces cerevisiae and measured Ca2+ dependent ATPase activity following reconstitution in proteoliposomes. The purified SPCA1a displays a higher apparent Ca2+ affinity and lower maximal turnover rate than the purified sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1a). The lipids cholesteryl hemisuccinate, linole-/oleamide and phosphatidyl ethanolamine inhibit, whereas phosphatidic acid and sphingomyelin enhance SPCA1a activity. Moreover, SPCA1a is blocked by μM concentrations of commonly used SERCA1a inhibitors thapsigargin (Tg), cyclopiazonic acid (CPA) and 2,5-di-tert-butyl hydroquinone (BHQ). Since tissue-specific targeting of SERCA2b by Tg analogues is considered for prostate cancer therapy, the inhibition of SPCA1a by Tg might represent an off-target risk. We assessed the structure-activity relationship (SAR) of Tg for SPCA1a by in silico modeling, site-directed mutagenesis, and by measuring the potency of a series of Tg analogues. These indicate that Tg and the analogues are bound via the Tg scaffold, but with lower affinity to the same homologous cavity as on the membrane surface of SERCA1a. The lower Tg affinity may depend on a more flexible binding cavity in SPCA1a, with low contributions of the Tg O-3, O-8 and O-10 chains to the binding energy. Conversely, the protein interaction of the Tg O-2 side chain with SPCA1a appears comparable with that of SERCA1a. These differences define a SAR of Tg for SPCA1a distinct from that of SERCA1a, indicating that Tg analogues with a higher specificity for SPCA1a can probably be developed.

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The hydrogen peroxide hypersensitivity of OxyR2 in Vibrio vulnificus depends on conformational constraints [Microbiology]

Most Gram-negative bacteria respond to excessive levels of H2O2 using the peroxide-sensing transcriptional regulator OxyR, which can induce the expression of antioxidant genes to restore normality. Vibrio vulnificus has two distinct OxyRs (OxyR1 and OxyR2), which are sensitive to different levels of H2O2 and induce expression of two different peroxidases, Prx1 and Prx2. While OxyR1 has both high sequence similarity and comparable H2O2 sensitivity to other OxyR proteins, OxyR2 exhibits limited sequence similarity and is more sensitive to H2O2. To investigate the basis for this difference, we determined crystal structures and carried out biochemical analyses of OxyR2. The determined structure of OxyR2 revealed a flipped conformation of the peptide bond before Glu204, a position occupied by glycine in other OxyR proteins. Activity assays showed that the sensitivity to H2O2 was reduced to the level of other OxyR proteins by the E204G mutation. We solved the structure of the OxyR2-E204G mutant with the same packing environment. The structure of the mutant revealed a dual conformation of the peptide bond before Gly204, indicating the structural flexibility of the region. This structural duality extended to the backbone atoms of Gly204 and the imidazole ring of His205, which interact with H2O2 and invariant water molecules near the peroxidatic cysteine, respectively. Structural comparison suggests that Glu204 in OxyR2 provides rigidity to the region that is important in H2O2 sensing, compared to the E204G structure or other OxyR proteins. Our findings provide a structural basis for the higher sensitivity of OxyR2 to H2O2 and also suggest a molecular mechanism for bacterial regulation of expression of antioxidant genes at divergent concentrations of cellular H2O2.

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The Agouti-Related Peptide Binds Heparan Sulfate Through Segments Critical For Its Orexigenic Effects [Neurobiology]

Syndecans potently modulate agouti-related peptide (AgRP) signaling in the central melanocortin system. Through heparan sulfate moieties, syndecans are thought to anchor AgRP near its receptor, enhancing its orexigenic effects. Original work proposed that AgRP's N-terminal domain facilitates this interaction. However, this is not compatible with evidence that this domain is post-translationally cleaved. Addressing this long-standing incongruity, we used calorimetry and magnetic resonance to probe interactions of AgRP peptides with glycosaminoglycans including heparan sulfate. We show that mature, cleaved, C-terminal AgRP, not the N-terminal domain, binds heparan sulfate. NMR shows that the binding site consists of regions distinct from the melanocortin receptor-binding site. Using a library of designed AgRP variants, we find that the strength of the syndecan interaction perfectly tracks orexigenic action. Our data provides compelling evidence that AgRP is a heparan sulfate binding protein, and localizes critical regions in the AgRP structure required for this interaction.

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Inhibition of Coactivator-associated Arginine Methyltransferase 1 Modulates Dendritic Arborization and Spine Maturation of Cultured Hippocampal Neurons [Neurobiology]

An improved understanding of the molecular mechanisms in synapse formation provides insight into both learning and memory and the etiology of neurodegenerative disorders. Coactivator-associated arginine methyltransferase 1 (CARM1) is a protein methyltransferase that negatively regulates synaptic gene expression and inhibits neuronal differentiation. Despite its regulatory function in neurons, little is known about CARM1's cellular location and its role in dendritic maturation and synapse formation. Here, we examined the effects of CARM1 inhibition on dendritic spine and synapse morphology in the rat hippocampus. CARM1 was localized in hippocampal post-synapses, with immunocytochemistry and electron microscopy revealing co-localization of CARM1 with post-synaptic density (PSD)-95 protein, a post-synaptic marker. Specific siRNA-mediated suppression of CARM1 expression resulted in precocious dendritic maturation, with increased spine width and density at sites along dendrites and induction of mushroom-type spines. These changes were accompanied by a striking increase in the cluster size and number of key synaptic proteins, including N-methyl-D-aspartate receptor subunit 2B (NR2B) and PSD-95. Similarly, pharmacological inhibition of CARM1 activity with the CARM1-specific inhibitor AMI-1 significantly increased spine width and mushroom-type spines and also increased the cluster size and number of NR2B and cluster size of PSD-95. These results suggest that CARM1 is a post-synaptic protein that plays roles in dendritic maturation and synaptic formation and that spatio-temporal regulation of CARM1 activity modulates neuronal connectivity and improves synaptic dysfunction.

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First Video Case Report of Chronic Retrograde Jejunojejunal Intussusception after Subtotal Gastrectomy with Braun’s Anastomosis

Intussusception, which is seen rarely in adults, is defined as the pulling or invagination of a part of the intestine into another segment of the intestine. In this case report we present chronic retrograde jejunojejunal intussusception following gastric surgery with Braun’s anastomosis in adult with video presentation. A 66-year-old woman, who had undergone gastric surgery 39 years ago and cholecystectomy 20 years ago, was admitted to our clinic with the complaints about weight loss, abdominal pain, nausea, and vomiting. Upper gastrointestinal endoscopy (UGISE) was applied, and patient was treated with surgery. This case report indicates that intussusception should be considered in the presence of clinical complaints following gastric surgery, as well as importance of endoscopy in diagnosis.

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On the Viscoelastic Parameters of Gussasphalt Mixture Based on Modified Burgers Model: Deviation and Experimental Verification

Viscoelasticity is an important characteristic of gussasphalt mixtures. The aim of this study is to find the correct viscoelastic material parameters of the novel gussasphalt applied in the 4th Yangtze River Bridge based on the modified Burgers model. This study firstly derives the explicit Prony series form of the shear relaxation modulus of viscoelastic material from Laplace transformation, to fulfill the parameter inputting requirements of commonly used finite element software suites. Secondly, a kind of uniaxial penetration creep experiment on the gussasphalt mixtures is conducted. By fitting the creep compliance, the viscoelastic parameters characterized by the modified Burgers model are obtained. And thirdly, based on the viscoelastic test data of asphalt mixtures, the Prony series formula derived in this study is verified through the finite element simulation. The comparison results of the relative errors between the finite element simulation and the theoretical calculation confirm the reliability of the Prony series formulas deduced in this research. And finally, a stress-correcting method is proposed, which can significantly improve the accuracy of model parameters identification and reduce the relative error between the finite element simulation and the experimental data.

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Broadband Circular Polarizer Based on Plasmon Hybridizations

This paper presents a broadband circular polarizer with a ring/disk cavity structure, which is a broadband application of plasmon hybridizations. The proposed design can convert a linearly polarized wave to a circularly polarized wave from 12.66 GHz to 17.43 GHz within a bandwidth of 30%. The broadband polarization conversion characterization results from the different plasmon hybridization modes induced in the ring/disk cavity. The proposed broadband circular polarizer is demonstrated by both full-wave simulation and measurement.

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Minerals, Toxic Heavy Metals, and Antioxidant Properties of Honeys from Bangladesh

The study reports on major and trace elements as well as antioxidant properties of honey samples from Bangladesh. Four major cationic elements, seven trace elements, and three heavy metals were determined in the 12 honey samples using atomic absorption spectrophotometer. Nutritional values in these honey samples were further investigated according to their antioxidant properties. The content of major elements was in the range of 62.75–616.58, 579.48–2219.43, 69.42–632.25, and 0.13–1.20 mg/kg for sodium, potassium, magnesium, and calcium, respectively. The trace elements varied in the range of 0.41–28, 0.12–3.54, 1.54–2.85, 0.29–0.59, 0.02–0.35, and 0.01–0.06 mg/kg for iron, zinc, copper, nickel, cobalt, and cadmium, respectively. Among the heavy metals, only lead (0.17–2.19 mg/kg) was detected. The results of antioxidant analysis based on phenolics, flavonoids, ascorbic acid, reducing sugar, and proteins (as nonphenolic antioxidants) revealed that multifloral raw honey samples contain significantly higher levels of reducing agents than monofloral and commercial brand honeys. The study provides a useful insight on the minerals, heavy metals, and antioxidant properties of honey samples commonly consumed in Bangladesh and found to be rich source of antioxidants and minerals. Some samples might pose some risk to the health due to lead contamination.

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Electrostatic Switch Function in the Mechanism of Protein Kinase A I Activation: Results of the Molecular Dynamics Simulation

We used molecular dynamics to find the average path of the A-domain conformational transition in protein kinase A Iα. We obtained thirteen productive trajectories and processed them sequentially using factor and cross-correlation analyses. The conformational transition is presented as partly deterministic sequence of six events. Event B represents transition of the phosphate binding cassette. Main participants of this event form electrostatic switch cAMP(O6)–A202(N-H)–G199(C=O). Through this switch, cAMP transmits information about its binding to hydrophobic switch L203–Y229 and thus triggers conformational transition of A-domain. Events C and D consist in N3A-motif displacement towards phosphate binding cassette and B/C-helix rotation. Event E involves an increase in interaction energy between Y229 and β-subdomain. Taken together, events B, E, and D correspond to the hinge movement towards β-barrel. Transition of B/C-helix turn (a.a. 229–234) from α-form to π-form accounts for event F. Event G implies that π-helical turn is replaced by kink. Emerging in the resulting conformation, electrostatic interaction R241–E200 facilitates kink formation. The obtained data on the mechanism of cAMP-dependent activation of PKA Iα may contribute to new approaches to designing pharmaceuticals based on cAMP analogs.

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Evidence of Presynaptic Localization and Function of the c-Jun N-Terminal Kinase

The c-Jun N-terminal kinase (JNK) is part of a stress signalling pathway strongly activated by NMDA-stimulation and involved in synaptic plasticity. Many studies have been focused on the post-synaptic mechanism of JNK action, and less is known about JNK presynaptic localization and its physiological role at this site. Here we examined whether JNK is present at the presynaptic site and its activity after presynaptic NMDA receptors stimulation. By using N-SIM Structured Super Resolution Microscopy as well as biochemical approaches, we demonstrated that presynaptic fractions contained significant amount of JNK protein and its activated form. By means of modelling design, we found that JNK, via the JBD domain, acts as a physiological effector on T-SNARE proteins; then using biochemical approaches we demonstrated the interaction between Syntaxin-1-JNK, Syntaxin-2-JNK, and Snap25-JNK. In addition, taking advance of the specific JNK inhibitor peptide, D-JNKI1, we defined JNK action on the SNARE complex formation. Finally, electrophysiological recordings confirmed the role of JNK in the presynaptic modulation of vesicle release. These data suggest that JNK-dependent phosphorylation of T-SNARE proteins may have an important functional role in synaptic plasticity.

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Synthetic Peptides as Potential Antigens for Cutaneous Leishmaniosis Diagnosis

This work’s goal was to research new candidate antigens for cutaneous leishmaniosis (CL). In order to reach the goal, we used random peptide phage display libraries screened using antibodies from Leishmania braziliensis patients. After selection, three peptides (P1, P2, and P3) were synthesized using Fmoc chemistry. The peptides individually or a mixture of them (MIX) was subsequently emulsified in complete and incomplete Freund’s adjuvant and injected subcutaneously in golden hamsters. Sera from the hamsters administered with P1 presented antibodies that recognized proteins between 76 and 150 kDa from L. braziliensis. Sera from hamsters which had peptides P2 and P3, as well as the MIX, administered presented antibodies that recognized proteins between 52 and 76 kDa of L. braziliensis. The research on the similarity of the peptides’ sequences in protein databases showed that they match a 63 kDa glycoprotein. The three peptides and the MIX were recognized by the sera from CL patients by immunoassay approach (ELISA). The peptides’ MIX showed the best performance (79% sensitivity) followed by the P1 (72% sensitivity), and the AS presented 91% sensitivity. These results show a new route for discovering molecules for diagnosis or for immunoprotection against leishmaniosis.

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A New CMOS Controllable Impedance Multiplier with Large Multiplication Factor

This paper presents a new compact controllable impedance multiplier using CMOS technology. The design is based on the use of the translinear principle using MOSFETs in subthreshold region. The value of the impedance will be controlled using the bias currents only. The impedance can be scaled up and down as required. The functionality of the proposed design was confirmed by simulation using BSIM3V3 MOS model in Tanner Tspice 0.18 μm TSMC CMOS process technology. Simulation results indicate that the proposed design is functioning properly with a tunable multiplication factor from 0.1- to 100-fold. Applications of the proposed multiplier in the design of low pass and high pass filters are also included.

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Estimation of Container Traffic at Seaports by Using Several Soft Computing Methods: A Case of Turkish Seaports

Container traffic forecasting is important for the operations and the design steps of a seaport facility. In this study, performances of the novel soft computing models were compared for the container traffic forecasting of principal Turkish seaports (Istanbul, Izmir, and Mersin seaports) with excessive container traffic. Four forecasting models were implemented based on Artificial Neural Network with Artificial Bee Colony and Levenberg-Marquardt Algorithms (ANN-ABC and ANN-LM), Multiple Nonlinear Regression with Genetic Algorithm (MNR-GA), and Least Square Support Vector Machine (LSSVM). Forecasts were carried out by using the past records of the gross domestic product, exports, and population of the Turkey as indicators of socioeconomic and demographic status. Performances of the forecasting models were evaluated with several performance metrics. Considering the testing period, the LSSVM, ANN-ABC, and ANN-LM models performed better than the MNR-GA model considering overall fitting and prediction performances of the extreme values in the testing data. The LSSVM model was found to be more reliable compared to the ANN models. Forecasting part of the study suggested that container traffic of the seaports will be increased up to 60%, 67%, and 95% at the 2023 for the Izmir, Mersin, and Istanbul seaports considering official growth scenarios of Turkey.

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Development and Assessment of the Sand Dust Prediction Model by Utilizing Microwave-Based Satellite Soil Moisture and Reanalysis Datasets in East Asian Desert Areas

For several decades, satellite-based microwave sensors have provided valuable soil moisture monitoring in various surface conditions. We have first developed a modeled aerosol optical depth (AOD) dataset by utilizing Soil Moisture and Ocean Salinity (SMOS), Advanced Microwave Scanning Radiometer 2 (AMSR2), and the Global Land Data Assimilation System (GLDAS) soil moisture datasets in order to estimate dust outbreaks over desert areas of East Asia. Moderate Resolution Imaging Spectroradiometer- (MODIS-) based AOD products were used as reference datasets to validate the modeled AOD (MA). The SMOS-based MA (SMOS-MA) dataset showed good correspondence with observed AOD (-value: 0.56) compared to AMSR2- and GLDAS-based MA datasets, and it overestimated AOD compared to observed AOD. The AMSR2-based MA dataset was found to underestimate AOD, and it showed a relatively low -value (0.35) with respect to observed AOD. Furthermore, SMOS-MA products were able to simulate the short-term AOD trends, having a high -value (0.65). The results of this study may allow us to acknowledge the utilization of microwave-based soil moisture datasets for investigation of near-real time dust outbreak predictions and short-term dust outbreak trend analysis.

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Statistical Methods for Predicting Malaria Incidences Using Data from Sudan

Malaria is the leading cause of illness and death in Sudan. The entire population is at risk of malaria epidemics with a very high burden on government and population. The usefulness of forecasting methods in predicting the number of future incidences is needed to motivate the development of a system that can predict future incidences. The objective of this paper is to develop applicable and understood time series models and to find out what method can provide better performance to predict future incidences level. We used monthly incidence data collected from five states in Sudan with unstable malaria transmission. We test four methods of the forecast: () autoregressive integrated moving average (ARIMA); () exponential smoothing; () transformation model; and () moving average. The result showed that transformation method performed significantly better than the other methods for Gadaref, Gazira, North Kordofan, and Northern, while the moving average model performed significantly better for Khartoum. Future research should combine a number of different and dissimilar methods of time series to improve forecast accuracy with the ultimate aim of developing a simple and useful model for producing reasonably reliable forecasts of the malaria incidence in the study area.

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Protection of Human Umbilical Vein Endothelial Cells against Oxidative Stress by MicroRNA-210

Oxidative stress induces endothelial cell apoptosis and promotes atherosclerosis development. MicroRNA-210 (miR-210) is linked with apoptosis in different cell types. This study aimed to investigate the role of miR-210 in human umbilical vein endothelial cells (HUVECs) under oxidative stress and to determine the underlying mechanism. HUVECs were treated with different concentrations of hydrogen peroxide (H2O2), and cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ATP assay. To evaluate the role of miR-210 in H2O2-mediated apoptosis, gain-and-loss-of-function approaches were used, and the effects on apoptosis and reactive oxygen species (ROS) level were assayed using flow cytometry. Moreover, miR-210 expression was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and expression of the following apoptosis-related genes was assessed by qRT-PCR and Western blot at the RNA and protein level, respectively: caspase-8-associated protein 2 (CASP8AP2), caspase-8, and caspase-3. The results showed that H2O2 induced apoptosis in HUVECs in a dose-dependent manner and increased miR-210 expression. Overexpression of miR-210 inhibited apoptosis and reduced ROS level in HUVECs treated with H2O2. Furthermore, miR-210 downregulated CASP8AP2 and related downstream caspases at protein level. Thus, under oxidative stress, miR-210 has a prosurvival and antiapoptotic effect on HUVECs by reducing ROS generation and downregulating the CASP8AP2 pathway.

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Capsular Polysaccharide of Mycoplasma ovipneumoniae Induces Sheep Airway Epithelial Cell Apoptosis via ROS-Dependent JNK/P38 MAPK Pathways

In an attempt to better understand the pathogen-host interaction between invading Mycoplasma ovipneumoniae (M. ovipneumoniae) and sheep airway epithelial cells, biological effects and possible molecular mechanism of capsular polysaccharide of M. ovipneumoniae (CPS) in the induction of cell apoptosis were explored using sheep bronchial epithelial cells cultured in air-liquid interface (ALI). The CPS of M. ovipneumoniae was first isolated and purified. Results showed that CPS had a cytotoxic effect by disrupting the integrity of mitochondrial membrane, accompanied with an increase of reactive oxygen species and decrease of mitochondrial membrane potential (). Of importance, the CPS exhibited an ability to induce caspase-dependent cell apoptosis via both intrinsic and extrinsic apoptotic pathways. Mechanistically, the CPS induced extrinsic cell apoptosis by upregulating FAS/FASL signaling proteins and cleaved-caspase-8 and promoted a ROS-dependent intrinsic cell apoptosis by activating a JNK and p38 signaling but not ERK1/2 signaling of mitogen-activated protein kinases (MAPK) pathways. These findings provide the first evidence that CPS of M. ovipneumoniae induces a caspase-dependent apoptosis via both intrinsic and extrinsic apoptotic pathways in sheep bronchial epithelial cells, which may be mainly attributed by a ROS-dependent JNK and p38 MAPK signaling pathways.

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Health promotion and psychological interventions for adolescent and young adult cancer survivors: a systematic literature review

Publication date: Available online 6 March 2017
Source:Cancer Treatment Reviews
Author(s): Natalie Katrina Bradford, Raymond Javan Chan
BackgroundThe effects of cancer and treatment have severe and long lasting negative impacts on quality of life. Adolescents and Young Adults (AYA) have high survival rates but may not reach their full life potential because of these consequences. This review aims to identify, appraise and synthesise the effects of health promotion and psychological interventions for AYA after cancer treatment.MethodsThe review was undertaken using the preferred reporting items for systematic reviews and meta-analyses guidelines. Included studies were identified though a range of electronic databases through to May 2016. Studies were critically appraised using the Cochrane Risk of Bias tool.ResultsSeventeen studies, comprising a total of 2314 participants aged 13-39 years were included in this review. Participants in 15 studies were survivors of childhood cancer, with only two studies specifically recruiting survivors of cancer diagnosed during young adulthood. Ten studies were randomised controlled trials (RCTs); the remaining seven were before and after studies. The quality of studies was variable across all appraised domains; risk of bias was evident in regards to recruitment, measures of exposure and outcomes, confounding factors, attrition and lost-to follow-up. Studies evaluated a range of health promotion and psychological interventions to improve health related and process outcomes. Eleven studies reported modest positive outcomes, with psychological and physical activity interventions achieving greater success compared to general health promotion interventions.ConclusionThis review highlights the lack of high-quality studies for optimising the health and well-being of AYA cancer survivors. No conclusive evidence favouring specific interventions were identified, although recommendations for future studies are made. Interventions delivered face-to-face and those that facilitate peer-to-peer support hold promise. Harnessing social media and technology to deliver interventions is likely to increase and these modes of delivery require further investigations.



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Choosing wisely - preclinical test models in the era of precision medicine

Publication date: Available online 6 March 2017
Source:Cancer Treatment Reviews
Author(s): Konrad Klinghammer, Wolfgang Walther, Jens Hoffmann
Through the introduction of a steadily growing variety of preclinical test models drug development and biomarker research has advanced. Next to classical used 2D cell line cultures, tissue-slice cultures, 3D organoid cell cultures, genetically engineered mouse models, cell line derived mouse models and patient derived xenografts may be selected for a specific question. All models harbor advantages and disadvantages. This review focuses on the available preclinical test models, novel developments such as humanized mice and discusses for which question a particular model should be employed.



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Editorial Board

Publication date: March 2017
Source:Cancer Treatment Reviews, Volume 54





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How a Bottom-Up Multi-Stakeholder Initiative Helped Transform the Renal Replacement Therapy Landscape in Spain

Abstract

Healthcare reforms aim to change certain parts of the health system to improve quality of care, access, or financial sustainability. Traditionally, healthcare reform is understood as an action undertaken by a government at a national or local level. However, bottom-up changes can also lead to improvements in the health system. This paper describes the efforts of a coordinated multi-stakeholder advocacy group in Spain to promote a more cost-effective and patient-centred treatment for people receiving renal replacement therapy and assesses the outcomes of their advocacy for health system financing and patient satisfaction. It concludes that bottom-up initiatives do indeed have the power to change health policy and that policy makers should pay attention to their arguments.

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Prevention of liver tumor formation in woodchucks with established hepatocellular carcinoma by treatment with cationic liposome-DNA complexes

Approximately 250 million people worldwide are chronically infected with hepatitis B virus (HBV) and more than half of the hepatocellular carcinoma (HCC) cases are attributed to this infection. As HCC has a hi...

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The C-reactive protein/albumin ratio, a validated prognostic score, predicts outcome of surgical renal cell carcinoma patients

The preoperative C-reactive protein/Albumin (CRP/Alb) ratio has been shown to be valuable in predicting the prognosis of patients with certain cancers. The aim of our study is to explore its prognostic value i...

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A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors

The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has ...

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Response-Derived Input Function Estimation for Dynamic Contrast-Enhanced MRI Demonstrated by Anti-DLL4 Treatment in a Murine U87 Xenograft Model

Abstract

Purpose

Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is an accepted method to evaluate tumor perfusion and permeability and anti-vascular cancer therapies. However, there is no consensus on the vascular input function estimation method, which is critical to kinetic modeling and K ^trans estimation. This work proposes a response-derived input function (RDIF) estimated from the response of the tumor, modeled as a linear, time-invariant (LTI) system.

Procedures

In an LTI system, an unknown input can be estimated from the system response. If applied to DCE MRI, this method would eliminate need of distal image-derived inputs, model inputs, or reference regions. The RDIF method first determines each tumor pixel’s best-fit input function, and then combines the individual fits into a single input function for the entire tumor. The method was tested with simulations and a xenograft study with anti-vascular drug treatment.

Results

Simulations showed successful estimation of input function expected values and good performance in the presence of noise. In vivo, significant reductions in K ^trans and AUC occurred 2 days following anti-delta-like ligand 4 treatment. The in vivo study results yielded K ^trans consistent with published data in xenograft models.

Conclusion

The RDIF method for DCE analysis offers an alternative, easy-to-implement method for estimating the input function in tumors. The method assumes that during the DCE experiment, the changes observed by MRI result solely from vascular perfusion and permeability kinetics, and that information can be used to model the input function. Importantly, the method is demonstrated in a murine xenograft study to yield K ^trans results consistent with literature values and suitable for compound studies.

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Coronary Artery Disease in HIV-Infected Patients: Downside of Living Longer

Abstract

Purpose of Review

Introduction of combination antiretroviral therapy (ART) has increased the life expectancy of patients with HIV infection, allowing them to live longer with this chronic medical condition and consequently experiencing conditions such as cardiovascular diseases (CVDs). Several studies have investigated the increased risk of CVD in people living with HIV (PLWH). However, less is known about the exact mechanisms involved in this increased risk. Also, specific guidelines for management of CVD in PLWH have not been developed yet. In this article, we review the recent literature on the mechanisms involved in pathogenesis of CVD in PLWH, with an emphasis on coronary artery disease (CAD).

Recent Findings

Although initial studies suspected the increased prevalence of traditional CVD risk factors and side effects of ART to be involved in the increased CVD risk in PLWH, recent studies have uncovered the important role of chronic persistent inflammation in this increased risk. In addition, biomarkers of inflammation have been associated with both CVD events and subclinical CAD in this population. Lastly, recent studies and ongoing clinical trials have been investigating medical interventions that aim to reduce inflammation and cardiovascular events.

Summary

Different mechanisms of inflammation have been examined in PLWH, including subclinical viremia, microbial translocation, and coinfection with other pathogens such as cytomegalovirus. Although inflammatory biomarkers have been consistently associated with CVD and subclinical CVD outcomes, their prognostic value is unknown. Recent and ongoing trials are exploring the benefits of anti-inflammatory drugs, statins, and antimicrobial translocation drugs on both inflammation and CVD risk among PLWH.

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Organic Semiconducting Nanoparticles as Efficient Photoacoustic Agents for Lightening Early Thrombus and Monitoring Thrombolysis in Living Mice

ACS Nano

DOI: 10.1021/acsnano.7b00594

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Chemical Composition, Antiprotozoal and Cytotoxic Activities of Indole Alkaloids and Benzofuran Neolignan of Aristolochia cordigera

Planta Med
DOI: 10.1055/s-0043-104776

This is a comparative study on the intraspecific chemical variability of Aristolochia cordigera species, collected in two different regions of Brazil, Biome Cerrado (semiarid) and Biome Amazônia (coastal). The use of GC-MS and statistical methods led to the identification of 56 compounds. A higher percentage of palmitone and germacrene-D in the hexanes extracts of the leaves of plants from these respective biomes was observed. Phytochemical studies on the extracts led to the isolation and identification of 19 known compounds, including lignans, neolignans, aristolochic acids, indole-β-carboline, and indole alkaloids. In addition, two new indole alkaloids, 3,4-dihydro-hyrtiosulawesine and 6-O-(β-glucopyranosyl)hyrtiosulawesine, were isolated and a new neolignan, cis-eupomatenoid-7, was obtained in a mixture with its known isomer eupomatenoid-7. Their structures were determined by spectroscopic methods, mainly by 1D- and 2D-NMR. The occurrence of indole alkaloids is being described for the first time in the Aristolochiaceae family. Moreover, the in vitro susceptibility of intracellular amastigote and promastigote forms of Leishmania amazonensis to the alkaloids and eupomatenoid-7 were evaluated. This neolignan exhibited low activity against promastigotes (IC50 = 46 µM), while the alkaloids did not show inhibitory activity. The new alkaloid 6-O-(β-glucopyranosyl)hyrtiosulawesine exhibited activity in the low micromolar range against Plasmodium falciparum, with an IC50 value of 5 µM and a selectivity index higher than 50.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Chamomile Flower, Myrrh, and Coffee Charcoal, Components of a Traditional Herbal Medicinal Product, Diminish Proinflammatory Activation in Human Macrophages

Planta Med
DOI: 10.1055/s-0043-104391

A traditional herbal medicinal product, containing myrrh, chamomile flower, and coffee charcoal, has been used in Germany for the relief of gastrointestinal complaints for decades. Clinical studies suggest its use in the maintenance therapy of inflammatory bowel disease. However, the pharmacological mechanisms underlying the clinical effects are not yet fully understood.The present study aims to elucidate immunopharmacological activities of myrrh, chamomile flower, and coffee charcoal by studying the influence of each plant extract on gene expression and protein release of activated human macrophages.The plant extracts effect on gene and protein expression of activated human monocyte-derived macrophages was investigated by microarray gene expression analysis and assessment of the release of pro- and anti-inflammatory mediators (TNFα, chemokine CXCL13, and interleukin-10) using an ELISA test system.The extracts of myrrh, chamomile flower, and coffee charcoal influenced gene expression of activated human macrophages within the cytokine/chemokine signaling pathway. Particularly, chemokine gene expression was suppressed. Subsequently, the production of CXCL13 and, to a minor extent, cytokine TNFα was inhibited by all herbal extracts. Chamomile flower and coffee charcoal extracts enhanced interleukin-10 release from activated macrophages. The observed effects on protein release were comparable to the effect of budesonide, which decreased TNFα and CXCL13 and enhanced interleukin-10 release.The components of the herbal medicinal product influence the activity of activated human macrophages on both gene and protein level. The induced alterations within chemokine/cytokine signaling could contribute to a positive effect on the immunological homeostasis, which is disturbed in patients with chronic intestinal inflammation.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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New Curcumin-Loaded Chitosan Nanocapsules: In Vivo Evaluation

Planta Med
DOI: 10.1055/s-0043-104633

The medicinal applications of curcumin, the major component of Curcuma longa, are limited by its poor solubility and low oral bioavailability. In order to overcome this limitation, a method to produce nanocapsules of chitosan loaded with curcumin was developed. Three different molecular weight and deacetylation degree chitosan polymers were used in the formulation in order to prepare curcumin-loaded nanocapsules (mass ratio 1 : 1.4). The best results were achieved using chitosan-Bi with a molecular weight of 710 000 Da. A bimodal distribution was observed in samples; moreover, chitosan-Bi produced the lowest particle size (197 nm). The entrapment efficacy of all chitosan nanocapsules produced reached values between 75 and 92 %. Their rate of drug release at different pH levels (2.0 and 7.4) showed a fast onset of curcumin release. Swiss mice were used to determine oral and total bioavailability of the new curcumin-loaded nanocapsules. Remarkably, the bioavailability of curcumin nanoformulated increased 9-fold compared with no formulated curcumin. These nanocapsules have the ability to cross the blood-brain barrier, and its production is an easy to scale-up procedure using nontoxic materials.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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HLA-G: At the Interface of Maternal–Fetal Tolerance

Publication date: Available online 6 March 2017
Source:Trends in Immunology
Author(s): Leonardo M.R. Ferreira, Torsten B. Meissner, Tamara Tilburgs, Jack L. Strominger
During pregnancy, semiallogeneic fetal extravillous trophoblasts (EVT) invade the uterine mucosa without being rejected by the maternal immune system. Several mechanisms were initially proposed by Peter Medawar half a century ago to explain this apparent violation of the laws of transplantation. Then, three decades ago, an unusual human leukocyte antigen (HLA) molecule was identified: HLA-G. Uniquely expressed in EVT, HLA-G has since become the center of the present understanding of fetus-induced immune tolerance. Despite slow progress in the field, the last few years have seen an explosion in our knowledge of HLA-G biology. Here, we critically review new insights into the mechanisms controlling the expression and function of HLA-G at the maternal–fetal interface, and discuss their relevance for fetal tolerance.



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Expanding the B Cell-Centric View of Systemic Lupus Erythematosus

Publication date: Available online 6 March 2017
Source:Trends in Immunology
Author(s): Peter A. Morawski, Silvia Bolland
Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by a breakdown of self-tolerance in B cells and the production of antibodies against nuclear self-antigens. Increasing evidence supports the notion that additional cellular contributors beyond B cells are important for lupus pathogenesis. In this review we consider recent advances regarding both the pathogenic and the regulatory role of lymphocytes in SLE beyond the production of IgG autoantibodies. We also discuss various inflammatory effector cell types involved in cytokine production, removal of self-antigens, and responses to autoreactive IgE antibodies. We aim to integrate these ideas to expand the current understanding of the cellular components that contribute to disease progression and ultimately help in the design of novel, targeted therapeutics.



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Reducing Exposure to Mouse Allergen Among Children and Adolescents

Exposure to indoor allergens contributes significantly to asthma morbidity, with children raised in inner-city areas particularly affected by such exposures. Most inner-city homes have evidence of mouse infestation, with a linear dose-response relationship between mouse allergen exposure and asthma morbidity among mouse-sensitized children and adolescents. Furthermore, a threshold exposure level of greater than 0.5 μg of the major mouse allergen (Mus m1) per gram of house dust has been identified as clinically relevant. Preschool children with asthma living in inner-city Baltimore, Maryland, who were sensitized to mouse allergen and exposed to greater than 0.5 μg/g of Mus m1 experienced 50% more symptom days, 80% more days of β-agonist use, and increased risks of emergency department visits and hospitalizations compared with children with lower levels of exposure.

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Effects of Integrated Pest Management on Asthma in Children and Adolescents

This randomized clinical trial compares the effects of an integrated pest management intervention vs pest management education alone on asthma symptoms among mouse-sensitized and exposed children and adolescents with asthma living in Baltimore, Maryland, and Boston, Massachusetts.

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Solvent removal precipitation based in situ forming implant for controlled drug delivery in periodontitis

Publication date: 10 April 2017
Source:Journal of Controlled Release, Volume 251
Author(s): Siddhesh Juvekar, Harsha Kathpalia

Graphical abstract

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A hyaluronic acid-based hydrogel enabling CD44-mediated chondrocyte binding and gapmer oligonucleotide release for modulation of gene expression in osteoarthritis

Publication date: Available online 6 March 2017
Source:Journal of Controlled Release
Author(s): Yunpeng Cai, Elena López-Ruiz, Jesper Wengel, Laura B. Creemers, Kenneth A. Howard
Hyaluronic acid (HA) is an attractive biomaterial for osteoarthritis (OA) treatment due to inherent functional and compatibility properties as an endogenous knee joint component. In this work, we describe a HA-based hydrogel with the dual functionality of increased CD44-dependent chondrocyte binding and controlled release of gapmer antisense oligonucleotides for unassisted cellular entry and subsequent gene silencing activity. A Schiff base-mediated gelation method was used to produce a panel of hydrogels varying in the aldehyde-modified HA (900kDa) to chitosan ratios (3:7, 5:5 and 7:3) for identifying designs displaying optimal engagement of OA patient-derived CD44-expressing chondrocytes. Correlation was found between cell binding and CD44 expression, with maximal binding exhibited at a HA/chitosan ratio of 7:3, that was 181% higher than CD44-negative MCF-7 cell control cells. Transfection agent-free uptake into OA chondrocytes of fluorescent 13-mer DNA oligonucleotides with a flanked locked nucleic acid (LNA) gapmer design, in contrast to naked siRNA, was demonstrated by confocal and flow cytometric analysis. A sustained and complete release over 5days was found with the 7:3 hydrogel, in contrast, the 5:5 and 3:7 hydrogel released 60% and 43% of loaded gapmers, respectively over the same period. A COX-2-specific gapmer designed with maximal chondrocyte gene silencing (~70% silencing efficiency at 500nM compared with a mismatch gapmer sequence) resulted in effective COX-2 silencing over 14days in hydrogels seeded with OA chondrocytes, with significant difference exhibited between day 3 and 10. This work introduces a novel HA-based CD44-mediated cellular binding and gapmer controlled release platform to modulate cellular gene expression.

Graphical abstract

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A systemic evaluation of drug in acrylic pressure sensitive adhesive patch in vitro and in vivo: The roles of intermolecular interaction and adhesive mobility variation in drug controlled release

Publication date: Available online 6 March 2017
Source:Journal of Controlled Release
Author(s): Chao Liu, Peng Quan, Shanshan Li, Yongshan Zhao, Liang Fang
Though acrylic pressure sensitive adhesives (PSAs) are widely used in transdermal drug delivery system, molecular details of drug-PSA interactions, PSA molecular mobility variations and their influences on drug skin permeation are unclear. In this study, three classes of acrylic PSAs containing hydroxyl (AAOH), carboxyl (AACOOH) and non-functional group (AAnone) were synthesized. Their abilities of controlling drug release were evaluated using propranolol (PRO) and zaltoprofen (ZAL) in vitro and in vivo. Interaction details were identified by FT-IR, solid-state NMR and molecular modeling. Thermodynamic activity of drug and strength of drug-PSA interaction were characterized using miscibility study. PSA mobility was characterized using thermal analysis and rheology study. Thus, ionic interaction reduced the thermodynamic activity of PRO and mobility of AACOOH, which made PRO-AACOOH obtain a significant lower bioavailability (11.8±0.7%) than these of PRO-AAnone (40.7±2.5%) and PRO-AAOH (42.3±2.9%). Though thermodynamic activity of ZAL in AACOOH was lower than that in AAOH due to the hydrogen bonding, bioavailability of ZAL-AAOH (19.0±4.1%) exhibited no significant difference with ZAL-AACOOH (15.4±2.8%), mainly because AAOH mobility was decreased by ZAL. In conclusion, the strength, types and involved functional groups of drug-PSA interactions were identified. On this basis, it was found that different control patterns of drug release were not only caused by the thermodynamic or kinetic hindrance effects of drug-PSA interactions, but also influenced by the interactions introduced PSA mobility variations, which was an innovative mechanism of controlled release in transdermal patch. These conclusions extended our understanding about the mechanism of controlled drug release of drug-in-adhesive patch. In addition, they contributed to the design of TDDS and custom acrylic PSAs.

Graphical abstract

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Deep cuts to environmental research in Trump’s budget proposal

US agencies doing climate research see concerning budget proposal that would eliminate funding for government science on air, energy and water within EPA, and slash satellite and coastal research at NOAA

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Deep cuts to environmental research in Trump’s budget proposal

US agencies doing climate research see concerning budget proposal that would eliminate funding for government science on air, energy and water within EPA, and slash satellite and coastal research at NOAA

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Control of Ice Formation

ACS Nano

DOI: 10.1021/acsnano.6b07348

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Using Torsion for Controllable Reconfiguration of Binary Nanoparticle Networks

ACS Nano

DOI: 10.1021/acsnano.7b00037

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Clomiphene citrate-induced visual hallucinations: a case report

Polycystic ovary syndrome is a common cause of chronic anovulation and infertility in otherwise healthy fertile couples. Clomiphene citrate is used as a first-line ovulation induction therapy in patients with ...

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Human immunoglobulin heavy gamma chain polymorphisms: molecular confirmation of proteomic assessment [Research]

Immunoglobulin G (IgG) proteins are known for the huge diversity of the variable domains of their heavy and light chains, aimed at protecting each individual against foreign antigens. The IgG also harbor specific polymorphism concentrated in the CH2 and CH3-CHS constant regions located on the Fc fragment of their heavy chains. But this individual particularity relies only on a few amino acids among which some could make accurate sequence determination a challenge for mass spectrometry-based techniques. The purpose of the study was to bring a molecular validation of proteomic results by the sequencing of encoding DNA fragments. It was performed using ten individual samples (DNA and sera) selected on the basis of their Gm (gamma marker) allotype polymorphism in order to cover the main immunoglobulin heavy gamma (IGHG) gene diversity. Gm allotypes, reflecting part of this diversity, were determined by a serological method. On its side, the IGH locus comprises four functional IGHG genes totalizing 34 alleles and encoding the four IgG subclasses. The genomic study focused on the nucleotide polymorphism of the CH2 and CH3-CHS exons and of the intron. Despite strong sequence identity, four pairs of specific gene amplification primers could be designed. Additional primers were identified to perform the subsequent sequencing. The nucleotide sequences obtained were first assigned to a specific IGHG gene, and then IGHG alleles were deduced using a home-made decision tree reading of the nucleotide sequences. IGHG amino acid (AA) alleles were determined by mass spectrometry. Identical results were found at 95% between alleles identified by proteomics and those deduced from genomics. These results validate the proteomic approach which could be used for diagnostic purposes, namely for a mother-and-child differential IGHG detection in a context of suspicion of congenital infection.

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Early deaths from childhood cancer up to 4 times more common than previously reported

Treatments for childhood cancers have improved to the point that 5-year survival rates are over 80 percent. However, one group has failed to benefit from these improvements, namely children who die so soon after diagnosis that they are not able to...

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Available drug may protect ovaries and fertility from damage by chemotherapies

A drug already used to slow tumor growth may also prevent infertility caused by standard chemotherapies, according to a study published online in the Proceedings of the National Academy of Sciences. Led by researchers from NYU Langone Medical Center, the...

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Brain’s inability to see that something is safe causes OCD

People with obsessive compulsive disorder aren’t more afraid of things than other people, they struggle to learn that mildly risky things are generally safe

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Being a Trans Mathematician: A Q&A with Autumn Kent

"Being trans is beautiful."

-- Read more on ScientificAmerican.com

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Palbociclib inhibits proliferation of human adrenocortical tumor cells

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Brain’s inability to see that something is safe causes OCD

People with obsessive compulsive disorder aren’t more afraid of things than other people, they struggle to learn that mildly risky things are generally safe

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New title will be launched on J-STAGE.Studies in Art Education

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New title will be launched on J-STAGE.The Japanese Journal of Criminal Psychology

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New title will be launched on J-STAGE.The Bulletin of St.Margaret's

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.35 No.1

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The new issue is now available.Nihon Kessho Gakkaishi

Vol.59 No.1

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The new issue is now available.The Journal of the Japanese Society of Clinical Cytology

Vol.56 No.1

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The new issue is now available.Nihon Ika Daigaku Igakkai Zasshi

Vol.13 No.1

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.37 No.Supplement

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.36 No.3

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The new issue is now available.Journal of Textile Engineering

Vol.62 No.5

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.35 No.3

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The new issue is now available.Journal of Textile Engineering

Vol.62 No.6

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The new issue is now available.JOURNAL OF JAPAN SOCIETY FOR HEAD AND NECK SURGERY

Vol.26 No.3

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.36 No.2

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The new issue is now available.The Journal of Educational Research

Vol.11

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.36 No.1

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The new issue is now available.The Journal of Educational Sociology

Vol.97

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The new issue is now available.Fundamental Toxicological Sciences

Vol.4 No.2

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The new issue is now available.Dental Journal of Iwate Medical University

Vol.35 No.2

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Human immunoglobulin heavy gamma chain polymorphisms: molecular confirmation of proteomic assessment [Research]

Immunoglobulin G (IgG) proteins are known for the huge diversity of the variable domains of their heavy and light chains, aimed at protecting each individual against foreign antigens. The IgG also harbor specific polymorphism concentrated in the CH2 and CH3-CHS constant regions located on the Fc fragment of their heavy chains. But this individual particularity relies only on a few amino acids among which some could make accurate sequence determination a challenge for mass spectrometry-based techniques. The purpose of the study was to bring a molecular validation of proteomic results by the sequencing of encoding DNA fragments. It was performed using ten individual samples (DNA and sera) selected on the basis of their Gm (gamma marker) allotype polymorphism in order to cover the main immunoglobulin heavy gamma (IGHG) gene diversity. Gm allotypes, reflecting part of this diversity, were determined by a serological method. On its side, the IGH locus comprises four functional IGHG genes totalizing 34 alleles and encoding the four IgG subclasses. The genomic study focused on the nucleotide polymorphism of the CH2 and CH3-CHS exons and of the intron. Despite strong sequence identity, four pairs of specific gene amplification primers could be designed. Additional primers were identified to perform the subsequent sequencing. The nucleotide sequences obtained were first assigned to a specific IGHG gene, and then IGHG alleles were deduced using a home-made decision tree reading of the nucleotide sequences. IGHG amino acid (AA) alleles were determined by mass spectrometry. Identical results were found at 95% between alleles identified by proteomics and those deduced from genomics. These results validate the proteomic approach which could be used for diagnostic purposes, namely for a mother-and-child differential IGHG detection in a context of suspicion of congenital infection.

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Development of a replication-deficient adenoviral vector-based vaccine candidate for the interception of HPV16- and HPV18-induced infections and disease

Abstract

High-risk Human papilloma virus (HPV) types are the causative agents of cervical cancer and several other anogenital malignancies. The viral proteins expressed in the (pre)malignant cells are considered ideal targets for immunological intervention. Many approaches have been evaluated for this purpose, mostly aiming at the induction of HPV16 E7- and/or E6-specific cellular immunogenicity. As clinical success has so far been limited, novel approaches are required. We describe the development and pre-clinical testing of a vaccine candidate consisting of replication-deficient adenovirus type 26 and 35 based vectors for the interception of HPV16- and HPV18-related disease. We developed HPV16- and HPV18-specific antigens consisting of fusion proteins of E2, E6 and E7. The vaccine will be suitable for every disease stage, from incident and persistent infections where E2 is predominantly expressed up to late stages where E6 and E7 expression are upregulated. Importantly E6 and E7 are present as re-ordered fragments to abrogate the transforming activity of these two proteins. Loss of transforming activity was demonstrated in different in vitro models. Robust T-cell immunogenicity was induced upon immunization of mice with the vaccine candidate. Finally, the developed vaccine vectors showed considerable therapeutic efficacy in the TC-1 mouse model. The absence of transforming activity of the antigens and the favorable immunogenicity profile of the adenovirus based vectors along with the fact that these vectors can be readily produced on a large scale makes this approach attractive for clinical evaluation. This article is protected by copyright. All rights reserved.

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