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1.  Generation and characterization of a target-selectively activated antibody against epidermal growth factor receptor with enhanced anti-tumor potency 
mAbs  2015;7(2):440-450.
Panitumumab, as a commercially available antibody, is an effective anticancer therapeutic against epidermal growth factor receptor (EGFR), although it exerts weak antibody-dependent cell-mediated cytotoxicity (ADCC) activity owing to its IgG2 nature. Here, we firstly engineered panitumumab by grafting its variable region into an IgG1 backbone. The engineered panitumumab (denoted as Pan) retained binding activity identical to the parental antibody while exhibiting stronger ADCC activity in vitro and more potent antitumor effect in vivo. To further enhance the target selectivity of Pan, we generated Pan-P by tethering an epitope-blocking peptide to Pan via a tumor-specific protease selective linker. Pan-P showed almost 40-fold weaker affinity compared with Pan, but functional activity was restored to a similar extent as Pan when Pan-P was selectively activated by urokinase-type plasminogen activator (uPA). More importantly, targeted localization of Pan-P was observed in tumor samples from colorectal cancer (CRC) patients and tumor-bearing nude mice, strongly indicating that specific activation also existed ex vivo and in vivo. Furthermore, Pan-P also exhibited effective in vivo antitumor potency similar to Pan. Taken together, our data evidence the enhanced antitumor potency and excellent target selectivity of Pan-P, suggesting its potential use for minimizing on-target toxicity in anti-EGFR therapy.
doi:10.1080/19420862.2015.1008352
PMCID: PMC4622528  PMID: 25679409
monoclonal antibody; EGFR; panitumumab; ADCC; target-selective activation; Probody™
2.  Exome sequencing in one family with gastric- and rectal cancer 
BMC Genetics  2016;17:41.
Background
Heritable factors are well known to increase the risk of cancer in families. Known susceptibility genes account for a small proportion of all colorectal cancer cases. The aim of this study was to identify the genetic background in a family suggested to segregate a dominant cancer syndrome with a high risk of rectal- and gastric cancer. We performed whole exome sequencing in three family members, 2 with rectal cancer and 1 with gastric cancer and followed it up in additional family members, other patients and controls.
Results
We identified 12 novel non-synonymous single nucleotide variants, which were shared among 5 affected members of this family. The mutations were found in 12 different genes; DZIP1L, PCOLCE2, IGSF10, SUCNR1, OR13C8, EPB41L4B, SEC16A, NOTCH1, TAS2R7, SF3A1, GAL3ST1, and TRIOBP. None of the mutations was suggested as a high penetrant mutation. It was not possible to completely rule out any of the mutations as contributing to disease, although seven were more unlikely than the others. Neither did we rule out the effect of all thousands of intronic, intergenic and synonymous variants shared between the three persons used for exome sequencing.
Conclusions
We propose this family, suggested to segregate dominant disease, could be an example of complex inheritance.
doi:10.1186/s12863-016-0351-z
PMCID: PMC4752738  PMID: 26872740
Next Generation Sequencing; Exome sequencing; Bioinformatics; Familial; Colorectal cancer; Genetics
3.  The long non-coding RNA TUG1 indicates a poor prognosis for colorectal cancer and promotes metastasis by affecting epithelial-mesenchymal transition 
Background
Long intergenic non-coding RNAs (lncRNAs) are a class of non-coding RNAs that are involved in gene expression regulation. Taurine up-regulated gene 1 (TUG1) is a cancer progression related lncRNA in some tumor oncogenesis; however, its role in colorectal cancer (CRC) remains unclear. In this study, we determined the expression patterns of TUG1 in CRC patients and explored its effect on CRC cell metastasis using cultured representative CRC cell lines.
Methods
The expression levels of TUG1 in 120 CRC patients and CRC cells were determined using quantitative real-time PCR. HDACs and epithelial-mesenchymal transition (EMT)-related gene expression were determined using western blot. CRC cell metastasis was assessed by colony formation, migration assay and invasion assay.
Results
Our data showed that the levels of TUG1 were upregulated in both CRC cell lines and primary CRC clinical samples. TUG1 upregulation was closely correlated with the survival time of CRC patients. Overexpression of TUG1 in CRC cells increased their colony formation, migration, and invasion invitro and promoted their metastatic potential in vivo, whereas knockdown of TUG1 inhibited the colony formation, migration, and invasion of CRC cells invitro. It is also worth pointing out that TUG1 activated EMT-related gene expression.
Conclusion
Our data suggest that tumor expression of lncRNA TUG1 plays a critical role in CRC metastasis. TUG1 may have potential roles as a biomarker and/or a therapeutic target in colorectal cancer.
doi:10.1186/s12967-016-0786-z
PMCID: PMC4745176  PMID: 26856330
Colorectal cancer cell lines; EMT; HDACs; Metastasis; Taurine upregulated gene 1
4.  Betel quid dependence is associated with functional connectivity changes of the anterior cingulate cortex: a resting-state fMRI study 
Objective
It is generally acknowledged that drug dependence is connected with abnormal functional organization in the individual’s brain. The present study aimed to identify the anterior cingulate cortex (ACC) abnormality with the cerebral networks involved in betel quid dependence (BQD) by resting-state functional connectivity (rsFC) using functional magnetic resonance imaging (fMRI).
Methods
With fMRI data measured from 33 resting-state BQD individuals and 32 non-addicted and age-, sex-, education-matched healthy controls, we inquired into the BQD-related changes in FC between the regions of ACC with the whole brain involved in BQD individuals using a region of interest vised method, and to identify the relation of the alteration with the severity of BQD and duration.
Results
Compared to controls, the BQD group showed increased connectivity from ACC to the regions of the reward network (brainstem including midbrain regions such as the ventral tegmental area and pons, caudate, thalamus) and cerebellum. Decreased connectivity was observed in the BQD group in regions from ACC to the default mode network (medial prefrontal cortex and precuneus) and para Hippocampal/hypothalamus. Specifically, the BQD scale was positively correlated with increased FC of right ACC to left thalamus and left ACC to pons; the durations were negatively correlated with FC of right ACC to left precuneus.
Conclusion
These disturbances in rsFC from ACC to the reward network and DMN revealed by fMRI may have a key function in providing insights into the neurological pathophysiology underlying BQD-associated executive dysfunction and disinhibition. These findings may contribute to our better understanding of the mechanisms underlying BQD.
doi:10.1186/s12967-016-0784-1
PMCID: PMC4736480  PMID: 26837944
Betel quid; Drug dependence; Resting-state fMRI; Resting-state functional connectivity
5.  CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer 
Thompson, Deborah J | O'Mara, Tracy A | Glubb, Dylan M | Painter, Jodie N | Cheng, Timothy | Folkerd, Elizabeth | Doody, Deborah | Dennis, Joe | Webb, Penelope M | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Michailidou, Kyriaki | Tyrer, Jonathan P | Maranian, Mel J | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif B | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Zhao, Hui | Depreeuw, Jeroen | Schrauwen, Stefanie | Amant, Frederic | Goode, Ellen L | Fridley, Brooke L | Dowdy, Sean C | Winham, Stacey J | Salvesen, Helga B | Trovik, Jone | Njolstad, Tormund S | Werner, Henrica M J | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Carvajal-Carmona, Luis | Tham, Emma | Liu, Tao | Mints, Miriam | Scott, Rodney J | McEvoy, Mark | Attia, John | Holliday, Elizabeth G | Montgomery, Grant W | Martin, Nicholas G | Nyholt, Dale R | Henders, Anjali K | Hopper, John L | Traficante, Nadia | Ruebner, Matthias | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Lambrechts, Diether | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Bolla, Manjeet K | Wang, Qin | Bojesen, Stig E | Shah, Mitul | Luben, Robert | Khaw, Kay-Tee | Pharoah, Paul D P | Dunning, Alison M | Tomlinson, Ian | Dowsett, Mitch | Easton, Douglas F | Spurdle, Amanda B
Endocrine-Related Cancer  2016;23(2):77-91.
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
doi:10.1530/ERC-15-0386
PMCID: PMC4697192  PMID: 26574572
endometrial cancer; CYP19A1; estradiol
6.  Invariant community structure of soil bacteria in subtropical coniferous and broadleaved forests 
Scientific Reports  2016;6:19071.
Soil bacteria may be influenced by vegetation and play important roles in global carbon efflux and nutrient cycling under global changes. Coniferous and broadleaved forests are two phyletically distinct vegetation types. Soil microbial communities in these forests have been extensively investigated but few studies have presented comparable data regarding the characteristics of bacterial communities in subtropical forests. We investigated soil bacterial biomass and community composition in three pairs of coniferous and broadleaved forests across a subtropical climatic gradient. We found that bacterial biomass differed between the coniferous and broadleaved forests across the subtropical climate gradient; however, this difference disappeared at some individual sites. In contrast, the same 90 bacterial genera were found in both forest types, and their relative abundances didn’t differ between the forest types, with the exception of one genus that was more abundant in broadleaved forests. Soil nitrogen or moisture was associated with bacterial groups in the coniferous and broadleaved forests, respectively. Thus, we inferred that these forests can respond differently to future changes in nitrogen deposition or precipitation. This study highlights soil bacterial invariant community composition in contrasting subtropical forests and provides a new perspective on the potential response and feedback of forests to global changes.
doi:10.1038/srep19071
PMCID: PMC4709558  PMID: 26754326
8.  Dysfunction of Liver Receptor Homolog-1 in Decidua: Possible Relevance to the Pathogenesis of Preeclampsia 
PLoS ONE  2015;10(12):e0145968.
Preeclampsia (PE) is a multisystem disorder unique to Homo sapiens that is known to cause maternal and perinatal mortality and morbidity. Between 5–7% of all pregnancies are affected by PE and it is responsible for approximately 50,000 maternal deaths annually. The pathogenesis of PE remains poorly understood. However, the results of this study indicated that insufficient decidualization plays a significant role. NR5A1 and NR5A2 are orphan members of the Ftz-F1 subfamily of nuclear receptors and are involved in mammal follicular development, female reproduction, steroidogenesis, and decidualization. The expression of NR5A1 and NR5A2 in the human decidua and their functions during decidualization were investigated using in vitro cultured cells by real-time PCR, immunohistochemistry, western blotting, and siRNA techniques. The results demonstrated that the levels of NR5A2 mRNA and protein in the decidual tissues of women with PE were lower than those of normal pregnant women. However, the levels of NR5A1 mRNA and protein did not significantly differ between groups. The expression of NR5A2 was upregulated after in vitro decidualization, but the expression of NR5A1 remained low and showed no difference compared with that of the control cells. Knocking down of NR5A2 in human endometrial stromal cells (hESC) resulted in a significant reduction in their expression of decidualization markers (IGFBP1 and PRL) and signaling pathway molecules (WNT4 and BMP2) (P < 0.05). From these data, we concluded that NR5A2 is pivotal for the decidualization of decidual tissues and cultured human endometrial stromal cells. Disorders of the endometrium in decidual tissues may be associated with the abnormal decidualization thought to cause PE.
doi:10.1371/journal.pone.0145968
PMCID: PMC4696807  PMID: 26717016
9.  A spiking neuron network model for the delayed motion direction discrimination task 
BMC Neuroscience  2015;16(Suppl 1):P281.
doi:10.1186/1471-2202-16-S1-P281
PMCID: PMC4699159
10.  Controllable Fabrication and Optical Properties of Uniform Gadolinium Oxysulfate Hollow Spheres 
Scientific Reports  2015;5:17934.
Uniform gadolinium oxysulfate (Gd2O2SO4) hollow spheres were successfully fabricated by calcination of corresponding Gd-organic precursor obtained via a facile hydrothermal process. The Gd2O2SO4 hollow spheres have a mean diameter of approximately 550 nm and shell thickness in the range of 30–70 nm. The sizes and morphologies of as-prepared Gd2O2SO4 hollow spheres could be deliberately controlled by adjusting the experimental parameters. Eu-doped Gd2O2SO4 hollow spheres have also been prepared for the property modification and practical applications. The structure, morphology, and properties of as-prepared products were characterized by XRD, TEM, HRTEM, SEM and fluorescence spectrophotometer. Excited with ultraviolet (UV) pump laser, successful downconversion (DC) could be achieved for Eu-doped Gd2O2SO4 hollow spheres.
doi:10.1038/srep17934
PMCID: PMC4680860  PMID: 26671661
11.  Neurochemical abnormalities in anterior cingulate cortex on betel quid dependence: a 2D 1H MRS investigation 
The effects of betel quid dependence (BQD) on biochemical changes remain largely unknown. Individuals with impaired cognitive control of behavior often reveal altered neurochemicals in Magnetic Resonance Spectroscopy Imaging (MRSI) and those changes are usually earlier than structural alteration. Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy control participants (n = 32) in an 2D 1H-MRS study to observe brain biochemical alterations in the anterior cingulated cortex (ACC) associated with the severity of BQD and duration of BQD. In the bilateral ACC, our study found NAA/Cr were lower in BQD individuals compared to the healthy controls, Cho/Cr and Glx/Cr were higher in individuals with BQD compared to the healthy group, but increase was noted for mI/Cr in BQD individuals only in the left ACC. NAA/Cr ratios of the right ACC negatively correlated with BQDS and duration, NAA/Cr ratios of the left ACC negatively correlated with duration, Glx/Cr ratios of the right ACC positively correlated with BQDS. The findings of the study support previous analyses of a role for ACC area in the mediation of BQ addiction and mechanistically explain past observations of reduced ACC grey matter in BQD patients. These data jointly point to state related abnormalities of BQ effect and provide a novel strategy of therapeutic intervention designed to normalize Glu transmission and function during treating BQ addiction.
PMCID: PMC4731676  PMID: 26885276
Betel quid; substance dependence; magnetic resonance spectroscopy; anterior cingulated cortex; N-acetylaspartate; myo-inositol; creatine; choline; glutamate
12.  Preventive effects of phenylethanol glycosides from Cistanche tubulosa on bovine serum albumin-induced hepatic fibrosis in rats 
Background
Cistanche tubulosa is a traditional Chinese herbal medicine that is widely used for regulating immunity. Phenyl ethanol glycosides (CPhGs) from this plant are the primarily efficacious materials. This aim of this study was to evaluate the preventive and therapeutic effects of CPhGs on BSA-induced hepatic fibrosis in rats and related molecular mechanisms involving hepatic stellate cells. Biejiarangan (BJRG), another traditional Chinese herbal medicine, was used as a positive control.
Methods
In in vivo experiments, 75 SD rats were randomly divided into 6 groups: normal (distilled water-treated), model (BSA-treated), positive drug (BSA-treated + BJRG 600 mg/kg/day), and BSA-treated + CPhGs (125, 250, and 500 mg/kg/day) groups. The liver and spleen indices, serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), type III procollagen (PCIII), type IV collagen (IV-C), hydroxyproline (Hyp), and transforming growth factor β1 (TGF-β1) were measured in rat livers. Histopathological grades for liver fibrosis were assessed for each group using H&E and Masson’s trichrome staining. The expression of TGF-β1, collagen I (Col-I) and collagen III (Col-III) were determined by an immunohistochemical staining method. These effects were further evaluated in vitro by determining expression levels of NF-κB p65 and Col-I by quantitative real-time PCR analyses. Col-I protein expression was also examined by western blotting.
Results
All dose groups (125, 250, and 500 mg/kg/day) of CPhGs significantly reduced the liver and spleen index, decreased ALT, AST, HA, LN, PCIII, IV-C serum levels, TGF-β1 content (P < 0.01, P < 0.01, and P < 0.01), and Hyp content. CPhGs also markedly alleviated the swelling of liver cells and effectively prevented hepatocyte necrosis and inflammatory cell infiltration. Immunohistochemical results showed that CPhGs significantly reduced the expression of TGF-β1 (P < 0.01, P < 0.01, and P < 0.01), Col- I, and Col-III. The in vitro effects of CPhGs (100, 75, 50, and 25 ug/ml) on HSC-T6 showed that CPhGs significantly reduced mRNA expression of NF-κB p65 and Col-I, and CPhGs also downregulated Col-I protein expression.
Conclusions
CPhGs have a significant anti-hepatic fibrosis effect, and may be used as hepatoprotective agents for treatment of hepatic fibrosis.
doi:10.1186/s40199-015-0135-4
PMCID: PMC4673721  PMID: 26646297
Hepatic fibrosis; Cistanche tubulosas; Phenylethanol glycoside; Chemokine BSA; Prevention and therapy
13.  Intravenous high mobility group box 1 upregulates the expression of HIF-1α in the myocardium via a protein kinase B-dependent pathway in rats following acute myocardial ischemia 
Molecular Medicine Reports  2015;13(2):1211-1219.
The effects of intravenous high mobility group box 1 (HMGB1) on myocardial ischemia/reperfusion (I/R) injury remains to be elucidated. The purpose of the present study was to investigate the effects of intravenous HMGB1 on the expression of hypoxia inducible factor-1α (HIF-1α) in the myocardium of rats following acute myocardial ischemia, and to examine the effects of intravenous HMGB1 on myocardial I/R injury. Male Wistar rats were divided into the following groups: Sham operation group (n=10), a group exposed to ischemia for 30 min and reperfusion for 4 h (I/R group) as a control (n=10), an HMGB group, in which 100 ng/kg HMGB was administered intravenously 30 min prior to ischemia (n=10), an LY group, in whic LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), was administered intravenously (0.3 mg/kg) 40 min prior to ischemia (n=10), and the HMGB1+LY group, in which HMGB1 (100 ng/kg) and LY294002 (0.3 mg/kg) were administered intravenously 30 min and 40 min prior to ischemia, respectively (n=10). The serum levels of cardiac troponin I (cTnI) and tumor necrosis factor-α (TNF-α), and myocardial infarct size were measured. The expression levels of phosphorylated Akt and HIF-1α were investigated using western blot analyses. The results showed that pre-treatment with HMGB1 significantly decreased serum levels of cTnI, and TNF-α, and reduced myocardial infarct size following 4 h reperfusion (all P<0.05). HMGB1 also increased the expression levels of HIF-1α and p-Akt induced by I/R (P<0.05). LY294002 was found to eliminate the effects of intravenous HMGB1 on myocardial I/R injury (P<0.05). These results suggest that intravenous pre-treatment with HMGB1 may exert its cardioprotective effects via the upregulation of the myocardial expression of HIF-1α, which may be regulated by the PI3K/Akt signaling pathway, in rats following acute myocardial I/R.
doi:10.3892/mmr.2015.4648
PMCID: PMC4732844  PMID: 26648172
high mobility group box 1; acute myocardial ischemia; ischemia reperfusion injury; hypoxia inducible factor-1α; rats
14.  Plasmon-gating photoluminescence in graphene/GeSi quantum dots hybrid structures 
Scientific Reports  2015;5:17688.
The ability to control light-matter interaction is central to several potential applications in lasing, sensing, and communication. Graphene plasmons provide a way of strongly enhancing the interaction and realizing ultrathin optoelectronic devices. Here, we find that photoluminescence (PL) intensities of the graphene/GeSi quantum dots hybrid structures are saturated and quenched under positive and negative voltages at the excitation of 325 nm, respectively. A mechanism called plasmon-gating effect is proposed to reveal the PL dependence of the hybrid structures on the external electric field. On the contrary, the PL intensities at the excitation of 405 and 795 nm of the hybrid structures are quenched due to the charge transfer by tuning the Fermi level of graphene or the blocking of the excitons recombination by excitons separation effect. The results also provide an evidence for the charge transfer mechanism. The plasmon gating effect on the PL provides a new way to control the optical properties of graphene/QD hybrid structures.
doi:10.1038/srep17688
PMCID: PMC4668550  PMID: 26631498
15.  Systematic Optimization of Long Gradient Chromatography Mass Spectrometry for Deep Analysis of Brain Proteome 
Journal of Proteome Research  2014;14(2):829-838.
The development of high-resolution liquid chromatography (LC) is essential for improving the sensitivity and throughput of mass spectrometry (MS)-based proteomics. Here we present systematic optimization of a long gradient LC–MS/MS platform to enhance protein identification from a complex mixture. The platform employed an in-house fabricated, reverse-phase long column (100 μm × 150 cm, 5 μm C18 beads) coupled to Q Exactive MS. The column was capable of achieving a peak capacity of ∼700 in a 720 min gradient of 10–45% acetonitrile. The optimal loading level was ∼6 μg of peptides, although the column allowed loading as many as 20 μg. Gas-phase fractionation of peptide ions further increased the number of peptide identification by ∼10%. Moreover, the combination of basic pH LC prefractionation with the long gradient LC–MS/MS platform enabled the identification of 96 127 peptides and 10 544 proteins at 1% protein false discovery rate in a post-mortem brain sample of Alzheimer’s disease. Because deep RNA sequencing of the same specimen suggested that ∼16 000 genes were expressed, the current analysis covered more than 60% of the expressed proteome. Further improvement strategies of the LC/LC–MS/MS platform were also discussed.
doi:10.1021/pr500882h
PMCID: PMC4324436  PMID: 25455107
long LC column; mass spectrometry; AD proteome
16.  Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1 
Cheng, Timothy HT | Thompson, Deborah | Painter, Jodie | O’Mara, Tracy | Gorman, Maggie | Martin, Lynn | Palles, Claire | Jones, Angela | Buchanan, Daniel D. | Ko Win, Aung | Hopper, John | Jenkins, Mark | Lindor, Noralane M. | Newcomb, Polly A. | Gallinger, Steve | Conti, David | Schumacher, Fred | Casey, Graham | Giles, Graham G | Pharoah, Paul | Peto, Julian | Cox, Angela | Swerdlow, Anthony | Couch, Fergus | Cunningham, Julie M | Goode, Ellen L | Winham, Stacey J | Lambrechts, Diether | Fasching, Peter | Burwinkel, Barbara | Brenner, Hermann | Brauch, Hiltrud | Chang-Claude, Jenny | Salvesen, Helga B. | Kristensen, Vessela | Darabi, Hatef | Li, Jingmei | Liu, Tao | Lindblom, Annika | Hall, Per | de Polanco, Magdalena Echeverry | Sans, Monica | Carracedo, Angel | Castellvi-Bel, Sergi | Rojas-Martinez, Augusto | Aguiar Jnr, Samuel | Teixeira, Manuel R. | Dunning, Alison M | Dennis, Joe | Otton, Geoffrey | Proietto, Tony | Holliday, Elizabeth | Attia, John | Ashton, Katie | Scott, Rodney J | McEvoy, Mark | Dowdy, Sean C | Fridley, Brooke L | Werner, Henrica MJ | Trovik, Jone | Njolstad, Tormund S | Tham, Emma | Mints, Miriam | Runnebaum, Ingo | Hillemanns, Peter | Dörk, Thilo | Amant, Frederic | Schrauwen, Stefanie | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif | Czene, Kamila | Meindl, Alfons | Bolla, Manjeet K | Michailidou, Kyriaki | Tyrer, Jonathan P | Wang, Qin | Ahmed, Shahana | Healey, Catherine S | Shah, Mitul | Annibali, Daniela | Depreeuw, Jeroen | Al-Tassan, Nada A. | Harris, Rebecca | Meyer, Brian F. | Whiffin, Nicola | Hosking, Fay J | Kinnersley, Ben | Farrington, Susan M. | Timofeeva, Maria | Tenesa, Albert | Campbell, Harry | Haile, Robert W. | Hodgson, Shirley | Carvajal-Carmona, Luis | Cheadle, Jeremy P. | Easton, Douglas | Dunlop, Malcolm | Houlston, Richard | Spurdle, Amanda | Tomlinson, Ian
Scientific Reports  2015;5:17369.
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers.
doi:10.1038/srep17369
PMCID: PMC4664893  PMID: 26621817
17.  Nine susceptibility loci for hepatitis B virus-related hepatocellular carcinoma identified by a pilot two-stage genome-wide association study 
Oncology Letters  2015;11(1):624-632.
Previous studies have indicated that complex interactions among viral, environmental and genetic factors lead to hepatocellular carcinoma (HCC). To identify susceptibility alleles for hepatitis B virus (HBV)-related HCC, the present study conducted a pilot two-phase genome-wide association study (GWAS) in 660 Han Chinese individuals. In phase 1, a total of 500,447 single-nucleotide polymorphisms (SNPs) were genotyped in 50 HCC cases and 50 controls using Affymetrix GeneChip 500k Array Set. In phase 2, 1,152 SNPs were selected from phase 1 and genotyped in 282 cases and 278 controls using the Illumina GoldenGate platform. The prior probability of HCC in control subjects was assigned at 0.01, and false-positive report probability (FPRP) was utilized to evaluate the statistical significance. In phase 1, one SNP (rs2212522) showed a significant association with HCC (Pallele=5.23×10−8; ORallele=4.96; 95% CI, 2.72–9.03). In phase 2, among 27 SNPs with unadjusted Pallele<0.05, 9 SNPs were associated with HCC based on FPRP criteria (FPRP <0.20). The strongest statistical evidence for an association signal was with rs2120243 (combined ORallele=1.76; 95% CI, 1.39–2.22; P=2.00×10−6), which maps within the fourth intron of VEPH1. The second strongest statistical evidence for an association was identified for rs1350171 (combined ORallele=1.66; 95% CI, 1.33–2.07; P=6.48×10−6), which maps to the region downstream of the FZD4 gene. The other potential susceptibility genes included PCDH9, PRMT6, LHX1, KIF2B and L3MBTL4. In conclusion, this pilot two-phase GWAS provides the evidence for the existence of common susceptibility loci for HCC. These genes involved various signaling pathways, including those associated with transforming growth factor β, insulin/phosphoinositide 3 kinase, Wnt and epidermal growth factor receptor. These associations must be replicated and validated in larger studies.
doi:10.3892/ol.2015.3958
PMCID: PMC4727098  PMID: 26870257
single-nucleotide polymorphisms; hepatitis B virus; hepatocellular carcinoma
18.  Pre-operative TNM staging of primary colorectal cancer by 18F-FDG PET-CT or PET: a meta-analysis including 2283 patients 
The aim of the present study was to perform a meta-analysis to assess the diagnostic value of fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT/PET in the pre-operative evaluation of TNM staging in patients with primary colorectal cancer (CRC). The Medline, Embase and Web of Knowledge were searched for studies assessing the diagnostic value of 18F-FDG PET-CT/PET in the pre-operative evaluation of TNM staging in CRC patients. We pooled the sensitivity, specificity, positive and negative Likelihood ratio (LR+ and LR-) and Diagnostic Odds Ratio (DOR) and constructed summary receiver operating characteristic curves. A total of 28 studies including 2283 CRC patients were analyzed. The pre-operative tumor detecting rate of PET-CT was 95.35%, which was superior to CT (P < 0.05). The pooled sensitivity and specificity of pre-operative T staging by PET-CT/PET was 0.73 (95% CI: 0.65-0.81) and 0.99 (95% CI: 0.98-0.99), which the AUC and Q* were 0.96 and 0.91, respectively. Concerning pre-operative N staging, the pooled sensitivity and specificity of PET-CT/PET were 0.62 and 0.70, which the AUC and Q* were 0.76 and 0.70, respectively. As for M staging, the pooled sensitivity and specificity of PET-CT/PET were 0.91 (95% CI: 0.80-0.96) and 0.95 (95% CI: 0.91-0.98), which the AUC and Q* were 0.96 and 0.91, respectively. 18F-FDG PET-CT/PET had good performance in the pre-operative tumor detecting rate, T staging and M staging in patients with primary CRC, which might alter the therapeutic strategy. However, the diagnostic value of 18F-FDG PET-CT/PET in pre-operative N staging in CRC patients was not ideal.
PMCID: PMC4723987  PMID: 26885142
Colorectal cancer; 18F-FDG-PET; PET-CT; TNM staging; meta-analysis
19.  A systematic review for the antidepressant effects of sleep deprivation with repetitive transcranial magnetic stimulation 
BMC Psychiatry  2015;15:282.
Background
Sleep deprivation (SD) and repetitive transcranial magnetic stimulation (rTMS) have been commonly used to treat depression. Recent studies suggest that co-therapy with rTMS and SD may produce better therapeutic effects than either therapy alone. Therefore, this study was to review the current findings to determine if rTMS can augment the therapeutic effects of SD on depression.
Methods
Embase, JSTOR, Medline, PubMed, ScienceDirect, and the Cochrane Central Register of Controlled Trials were searched for clinical studies published between January 1985 and March 2015 using the search term “rTMS/repetitive transcranial magnetic stimulation AND sleep deprivation AND depress*”. Only randomized and sham-controlled trials (RCTs) involving the combined use of rTMS and SD in depression patients were included in this systematic review. The scores of the Hamilton Rating Scale for Depression were extracted as primary outcome measures.
Results
Three RCTs with 72 patients that met the inclusion criteria were included for the systematic review. One of the trials reported skewed data and was described alone. The other two studies, which involved 30 patients in the experimental group (SD + active rTMS) and 22 patients in the control group (SD + sham rTMS), reported normally distributed data. The primary outcome measures showed different results among the three publications: two of which showed great difference between the experimental and the control subjects, and the other one showed non-significant antidepressant effect of rTMS on SD. In addition, two of the included studies reported secondary outcome measures with Clinical Global Impression Rating Scale and a self-reported well-being scale which presented good improvement for the depressive patients in the experiment group when compared with the control. The follow-up assessments in two studies indicated maintained results with the immediate measurements.
Conclusions
From this study, an overview of the publications concerning the combined use of rTMS and SD is presented, which provides a direction for future research of therapies for depression. More studies are needed to confirm whether there is an augmentative antidepressant effect of rTMS on SD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-015-0674-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12888-015-0674-8
PMCID: PMC4647580  PMID: 26573324
Depression; Sleep deprivation; Repetitive transcranial magnetic stimulation (rTMS); Systematic review
20.  Site-Selective C(sp3)–H Functionalization of Di-, Tri-, and Tetrapeptides at the N-Terminus 
Journal of the American Chemical Society  2014;136(48):16940-16946.
Although the syntheses of novel and diverse peptides rely mainly on traditional coupling using unnatural amino acids, postsynthetic modification of peptides could provide a complementary method for the preparation of nonproteinogenic peptides. Site selectivity of postsynthetic modification of peptides is usually achieved by targeting reactive moieties, such as the thiol group of cysteine or the C-2 position of tryptophan. Herein, we report the development of site-selective functionalizations of inert C(sp3)–H bonds of N-terminal amino acids in di-, tri-, and tetrapeptides without installing a directing group. The native amino acid moiety within the peptide is used as a ligand to accelerate the C–H activation reaction. In the long run, this newly uncovered reactivity could provide guidance for developing site-selective C(sp3)–H activation toward postsynthetic modification of a broader range of peptides.
doi:10.1021/ja510233h
PMCID: PMC4277765  PMID: 25384178
21.  Versatile characterization of glycosylation modification in CTLA4-Ig fusion proteins by liquid chromatography-mass spectrometry 
mAbs  2014;6(6):1474-1485.
CTLA4-Ig is a highly glycosylated therapeutic fusion protein that contains multiple N- and O-glycosylation sites. Glycosylation plays a vital role in protein solubility, stability, serum half-life, activity, and immunogenicity. For a CTLA4-Ig biosimilar development program, comparative analytical data, especially the glycosylation data, can influence decisions about the type and amount of animal and clinical data needed to establish biosimilarity. Because of the limited clinical experience with biosimilars before approval, a comprehensive level of knowledge about the biosimilar candidates is needed to achieve subsequent development. Liquid chromatography-mass spectrometry (LC–MS) is a versatile technique for characterizing N- and O-glycosylation modification of recombinant therapeutic proteins, including 3 levels: intact protein analysis, peptide mapping analysis, and released glycans analysis. In this report, an in-depth characterization of glycosylation of a candidate biosimilar was carried out using a systematic approach: N- and O-linked glycans were identified and electron-transfer dissociation was then used to pinpoint the 4 occupied O-glycosylation sites for the first time. As the results show, the approach provides a set of routine tools that combine accurate intact mass measurement, peptide mapping, and released glycan profiling. This approach can be used to comprehensively research a candidate biosimilar Fc-fusion protein and provides a basis for future studies addressing the similarity of CTLA4-Ig biosimilars.
doi:10.4161/mabs.36313
PMCID: PMC4622558  PMID: 25484062
characterization; CTLA4-Ig fusion protein; glycan; glycosylation modification; intact protein; mass spectrometry; peptide mapping; similarity
22.  Anti-tumor activity of the TRPM8 inhibitor BCTC in prostate cancer DU145 cells 
Oncology Letters  2015;11(1):182-188.
The present study investigated the anti-tumor activity of N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC), a potent and specific inhibitor of transient receptor potential cation channel subfamily M member 8 (TRPM8) in prostate cancer (PCa) DU145 cells. TRPM8 expression in DU145 and normal prostate PNT1A cells was detected by reverse transcription polymerase chain reaction and western blot analysis. The effect of BCTC on DU145 cells was analyzed by flow cytometry analysis, and MTT, scratch motility and Transwell invasion assays. The molecular mechanism through which BCTC acts was investigated by western blot analysis. TRPM8 expression was increased in DU145 cells compared with PNT1A cells at the mRNA and protein levels. The present study provided evidence that inhibition of TRPM8 by BCTC reduced the viability of DU145 cells, but not PNT1A cells. In addition, BCTC inhibited cell cycle progression, migration and invasion in DU145 cells. Cell cycle-associated proteins, including phosphorylated protein kinase B, cyclin D1, cyclin dependent kinase (CDK) 2 and CDK6 were downregulated by BCTC, while phosphorylated glycogen synthase kinase 3β was upregulated. However, investigations in the present study revealed that BCTC failed to trigger apoptosis in DU145 cells. In addition, in BCTC-treated DU145 cells, phosphorylated extracellular signal-regulated kinase 1/2 was downregulated substantially while phosphorylated p38 (p-p38) and phosphorylated c-Jun N-terminal kinases (p-JNK) were upregulated. The anti-proliferative activity of BCTC on DU145 cells was attenuated by p38 and JNK-specific inhibitors, suggesting that MAPK pathways are involved. Overall, the TRPM8 specific antagonist BCTC demonstrated excellent anti-tumor activity in PCa DU145 cells, and therefore has the potential to become a targeted therapeutic strategy against PCa.
doi:10.3892/ol.2015.3854
PMCID: PMC4727066  PMID: 26870186
BCTC; inhibitor; prostate cancer; TRPM8; targeted therapy
23.  Disease Burden from Hepatitis B Virus Infection in Guangdong Province, China 
Objective: To estimate the disease burden and financial burden attributed to hepatitis B virus (HBV) infection in Guangdong Province. Methods: Based on the data of incidence, mortality and healthcare cost of HBV-related diseases and other socio-economic data in Guangdong Province, we estimated deaths, disability-adjusted life-years (DALYs) and economic cost for the three HBV-related diseases—hepatitis B, liver cirrhosis and liver cancer—in Guangdong following the procedures developed for the global burden of disease study. Then disease burden and economic cost attributed to HBV infection was estimated. Results: HBV infection was estimated to have caused 33,600 (95% confidence interval (CI): 29,300–37,800) premature deaths and the loss of 583,200 (95% CI: 495,200–671,100) DALYs in Guangdong in 2005. The greatest loss of deaths and DALYs were from liver cancer. The 45–59 years age group had the greatest burden attributable to HBV infection. The estimated total annual cost of HBV-related diseases in Guangdong was RMB 10.8 (95% CI: 8.7–13.0) billion,the direct and indirect cost were RMB 2.6 (95% CI: 2.1–3.2) and 8.2 (95% CI: 6.6–9.8) billion. Conclusions: HBV infection is a great medical challenge as well as a significant economic burden to Guangdong Province. The results suggest that substantial health benefits could be gained by extending effective public health and clinical interventions to reduce HBV infection in Guangdong Province.
doi:10.3390/ijerph121114055
PMCID: PMC4661632  PMID: 26540065
hepatitis B virus; DALYs; burden of disease
24.  Comprehensive Quantitative Analysis of Ovarian and Breast Cancer Tumor Peptidomes 
Journal of Proteome Research  2014;14(1):422-433.
Aberrant degradation of proteins is associated with many pathological states, including cancers. Mass spectrometric analysis of tumor peptidomes, the intracellular and intercellular products of protein degradation, has the potential to provide biological insights on proteolytic processing in cancer. However, attempts to use the information on these smaller protein degradation products from tumors for biomarker discovery and cancer biology studies have been fairly limited to date, largely due to the lack of effective approaches for robust peptidomics identification and quantification and the prevalence of confounding factors and biases associated with sample handling and processing. Herein, we have developed an effective and robust analytical platform for comprehensive analyses of tissue peptidomes, which is suitable for high-throughput quantitative studies. The reproducibility and coverage of the platform, as well as the suitability of clinical ovarian tumor and patient-derived breast tumor xenograft samples with postexcision delay of up to 60 min before freezing for peptidomics analysis, have been demonstrated. Moreover, our data also show that the peptidomics profiles can effectively separate breast cancer subtypes, reflecting tumor-associated protease activities. Peptidomics complements results obtainable from conventional bottom-up proteomics and provides insights not readily obtainable from such approaches.
doi:10.1021/pr500840w
PMCID: PMC4286152  PMID: 25350482
protein degradation; peptidomics; proteases; tumor; ovarian cancer; breast cancer; ischemia
25.  sRNATarBase 3.0: an updated database for sRNA-target interactions in bacteria 
Nucleic Acids Research  2015;44(Database issue):D248-D253.
Bacterial sRNAs are a class of small regulatory RNAs of about 40–500 nt in length; they play multiple biological roles through binding to their target mRNAs or proteins. Therefore, elucidating sRNA targets is very important. However, only targets of a few sRNAs have been described. To facilitate sRNA functional studies such as developing sRNA target prediction models, we updated the sRNATarBase database, which was initially developed in 2010. The new version (recently moved to http://ccb1.bmi.ac.cn/srnatarbase/) contains 771 sRNA-target entries manually collected from 213 papers, and 23 290 and 11 750 predicted targets from sRNATarget and sTarPicker, respectively. Among the 771 entries, 475 and 17 were involved in validated sRNA–mRNA and sRNA–protein interactions, respectively, while 279 had no reported interactions. We also presented detailed information for 316 binding regions of sRNA-target mRNA interactions and related mutation experiments, as well as new features, including NCBI sequence viewer, sRNA regulatory network, target prediction-based GO and pathway annotations, and error report system. The new version provides a comprehensive annotation of validated sRNA-target interactions, and will be a useful resource for bacterial sRNA studies.
doi:10.1093/nar/gkv1127
PMCID: PMC4702819  PMID: 26503244

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