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1.  Effects of siRNA-mediated knockdown of jumonji domain containing 2A on proliferation, migration and invasion of the human breast cancer cell line MCF-7 
Jumonji domain containing 2A (JMJD2A) is a potential cancer-associated gene that may be involved in human breast cancer. The present study aimed to investigate suppressive effects on the MCF-7 human breast cancer cell line by transfection with JMJD2A-specific siRNA. Quantitative real-time PCR and western blot analysis were used to detect the expression levels of JMJD2A. Flow cytometric (FCM) analysis and WST-8 assay were used to evaluate cell proliferation. Boyden chambers were used in cell migration and invasion assays to evaluate the cell exercise capacity. Expression levels of JMJD2A mRNA and protein in the siRNA group were both downregulated successfully by transfection. FCM results showed that the percentage of cells in the G0/G1 phase in the siRNA group was significantly greater than that in the blank (P<0.05) and negative control groups (P<0.05). Additionally, the mean absorbance in the siRNA group was significantly lower (P<0.05), as observed by WST-8 assay. Moreover, a decreased number of migrated cells in the siRNA group was observed (P<0.05) using a cell migration and invasion assay. These data indicated that knockdown of JMJD2A may cause inhibition of proliferation, migration and invasion of MCF-7 cells. This study provides a new perspective in understanding the molecular mechanisms underlying the progression of breast cancer and offers a potential therapeutic target for breast cancer.
doi:10.3892/etm.2012.662
PMCID: PMC3501409  PMID: 23170139
jumonji domain containing 2A; transfection; invasion; proliferation; migration
2.  Effects of RNA interference-mediated gene silencing of JMJD2A on human breast cancer cell line MDA-MB-231 in vitro 
Previous data demonstrate that JMJD2A is a cancer-associated gene and may be involved in human breast cancer by demethylation of H3K9me3. The aim of this study was to investigate depressive effects on JMJD2A by transfection with JMJD2A-sepcific siRNA in human breast cancer cell line MDA-MB-231 and effects on cell proliferation, invasion and migration. JMJD2A-specific siRNA was chemically synthesised and transfected into human breast cancer cell line MDA-MB-231. Expression levels of JMJD2A were detected by quantitative real-time PCR and Western blot analysis. Cells proliferation was evaluated by using flow cytometric anlysis and MTT assay. The abilities of invasion and migration were evaluated by cell migration and invasion assay with Boyden chambers. The results showed that the transfection was successful and expression levels of JMJD2A mRNA and protein in siRNA group were both down-regulated. By MTT assay, the mean actual absorbance in siRNA group was significantly lower than that in blank control group (P < 0.05) and negative control group (P < 0.05). In addition, the percentage of cells in G0/G1 phase in siRNA group was significantly more than that in blank control group (P < 0.05) and negative control group (P < 0.05). Furthermore, by cell invasion and migration assay, the decreased number of migrated cells in siRNA group was observed (P < 0.05). These data imply that silencing JMJD2A gene could result in cell cycle change and proliferation inhibition, and lead to suppress tumor cell invasion and migration. It provides a new perspective in understanding the pleiotropic functions of JMJD2A and its contribution to human breast cancer.
doi:10.1186/1756-9966-30-90
PMCID: PMC3215938  PMID: 21962223
JMJD2A; transfection; proliferation; invasion; migration
3.  Active Targeting Using HER-2-affibody-conjugated Nanoparticles Enabled Sensitive and Specific Imaging of Orthotopic HER-2 Positive Ovarian Tumors 
Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, we have developed HER-2 targeted magnetic iron oxide nanoparticles (IONPs) by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, we have shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. We have determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery.
doi:10.1002/smll.201301593
PMCID: PMC3946402  PMID: 24038985
HER-2 targeted nanoparticles; HER-2 affibody; NIR-830 dye; orthotopic human ovarian tumor xenograft model
4.  Re-evaluation of ABO gene polymorphisms detected in a genome-wide association study and risk of pancreatic ductal adenocarcinoma in a Chinese population 
Chinese journal of cancer  2013;33(2):68-73.
Pancreatic cancer is a fatal malignancy with an increasing incidence in Shanghai, China. A genome-wide association study (GWAS) and other work have shown that ABO alleles are associated with pancreatic cancer risk. We conducted a population-based case-control study involving 256 patients with pathologically confirmed pancreatic ductal adenocarcinoma (PDAC) and 548 healthy controls in Shanghai, China, to assess the relationships between GWAS-identified ABO alleles and risk of PDAC. Carriers of the C allele of rs505922 had an increased cancer risk [adjusted odds ratio (OR) = 1.42, 95% confidence interval (CI): 1.02–1.98] compared to TT carriers. The T alleles of rs495828 and rs657152 were also significantly associated with an elevated cancer risk (adjusted OR = 1.58, 95% CI: 1.17–2.14; OR = 1.51, 95% CI: 1.09–2.10). The rs630014 variant was not associated with risk. We did not find any significant gene-environment interactions with cancer risk using a multifactor dimensionality reduction (MDR) method. Haplotype analysis also showed that the haplotype CTTC was associated with an increased risk of PDAC (adjusted OR = 1.46, 95% CI: 1.12–1.91) compared with haplotype TGGT. GWAS-identified ABO variants are thus also associated with risk of PDAC in the Chinese population.
doi:10.5732/cjc.013.10060
PMCID: PMC3884064  PMID: 23816557
Pancreatic ductal adenocarcinoma; ABO gene; genome-wide association study; genetic variation; haplotype
5.  Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors 
A W153L substitution in HIV-1 reverse transcriptase (RT) was recently identified by selection with a novel nucleotide-competing RT inhibitor (NcRTI) termed compound A that is a member of the benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI family of drugs. To investigate the impact of W153L, alone or in combination with the clinically relevant RT resistance substitutions K65R (change of Lys to Arg at position 65), M184I, K101E, K103N, E138K, and Y181C, on HIV-1 phenotypic susceptibility, viral replication, and RT enzymatic function, we generated recombinant RT enzymes and viruses containing each of these substitutions or various combinations of them. We found that W153L-containing viruses were impaired in viral replicative capacity and were hypersusceptible to tenofovir (TFV) while retaining susceptibility to most nonnucleoside RT inhibitors. The nucleoside 3TC retained potency against W153L-containing viruses but not when the M184I substitution was also present. W153L was also able to reverse the effects of the K65R substitution on resistance to TFV, and K65R conferred hypersusceptibility to compound A. Biochemical assays demonstrated that W153L alone or in combination with K65R, M184I, K101E, K103N, E138K, and Y181C impaired enzyme processivity and polymerization efficiency but did not diminish RNase H activity, providing mechanistic insights into the low replicative fitness associated with these substitutions. We show that the mechanism of the TFV hypersusceptibility conferred by W153L is mainly due to increased efficiency of TFV-diphosphate incorporation. These results demonstrate that compound A and/or derivatives thereof have the potential to be important antiretroviral agents that may be combined with tenofovir to achieve synergistic results.
doi:10.1128/AAC.02729-14
PMCID: PMC4136044  PMID: 24867966
6.  Phage as a Template to Grow Bone Mineral Nanocrystals 
Phage display is a biotechnique that fuses functional peptides on the outer surface of filamentous phage by inserting DNA encoding the peptides into the genes of its coat proteins. The resultant peptide-displayed phage particles have been widely used as biotemplates for the synthesis of functional hybrid nanomaterials. Here, we describe the bioengineering of M13 filamentous phage to surface-display bone mineral (hydroxyapatite (HAP))-nucleating peptides derived from dentin matrix protein-1 and using the engineered phage as a biotemplate to grow HAP nanocrystals.
doi:10.1007/978-1-62703-751-8_10
PMCID: PMC4288845  PMID: 24243246
Phage display; Hydroxyapatite (HAP); Biomineralization; Bone mineral; Dentin matrix protein-1
7.  Snail Recruits Ring1B to Mediate Transcriptional Repression and Cell Migration in Pancreatic Cancer Cells 
Cancer research  2014;74(16):4353-4363.
Transcriptional repressor Snail is a master regulator of epithelial–mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis. Cancer Res; 74(16); 4353-63. ©2014 AACR
doi:10.1158/0008-5472.CAN-14-0181
PMCID: PMC4285394  PMID: 24903147
8.  Whole-Genome Sequence of Marine Bacterium Phaeodactylibacter xiamenensis Strain KD52, Isolated from the Phycosphere of Microalga Phacodactylum tricornutum 
Genome Announcements  2014;2(6):e01289-14.
Phaeodactylibacter xiamenensis KD52 is a novel bacterium isolated from a culture of the alga Phaeodactylum tricornutum in Xiamen, Fujian Province, China. Here, we present the first draft genome sequence of this strain, which will provide an opportunity to further understand the functional genes related to signing for nutrition from the host algae and the molecular mechanisms underlying its beneficial properties.
doi:10.1128/genomeA.01289-14
PMCID: PMC4263839  PMID: 25502677
9.  Draft Genome Sequence of the Anti-Algal Marine Actinomycete Streptomyces sp. JS01 
Genome Announcements  2014;2(6):e01261-14.
Streptomyces sp. JS01 is the producer of an anti-algal compound that shows inhibitory activity against a harmful algal species Phaeocystis globosa and can also produce a red pigment. Its genome sequence will allow for the characterization of the anti-algal compound and the molecular mechanisms underlying its beneficial properties.
doi:10.1128/genomeA.01261-14
PMCID: PMC4256195  PMID: 25477414
10.  Effects of Acupuncture Knife on Inflammatory Factors and Pain in Third Lumbar Vertebrae Transverse Process Syndrome Model Rats 
The aim of this paper was to explore the long-term effects and pain relief mechanism of acupuncture knife on third lumbar vertebrae (L3) transverse process syndrome. Forty SD rats were randomized into control, model, electroacupuncture (EA), and acupuncture knife (AK) group. Except control rats, other rats were subjected to an operation to emulate L3 transverse process syndrome. Fourteen days after the operation, EA and AK rats were given electroacupuncture and acupuncture knife treatments, respectively. Fifty-six days after the operation, enzyme-linked immunosorbent assay was used to measure substance P (SP), 5-hydroxytryptamine (5-HT), interleukin-1β (IL-1β), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF-β) in peripheral blood. The tail flick test was used to observe pain threshold. We found that rats with the simulation operation had significantly higher levels of SP, 5-HT, IL-1, IL-10, TNF-α, and TGF-β, while the AK rats had lower levels. In addition, the pain threshold of AK rats was similar to that of control rats. AK pretreatment could alleviate pain through modulating inflammatory response.
doi:10.1155/2014/892406
PMCID: PMC4269310  PMID: 25544854
12.  Effects of polymorphisms in translesion DNA synthesis genes on lung cancer risk and prognosis in Chinese men 
Cancer epidemiology  2013;37(6):10.1016/j.canep.2013.08.003.
Purpose
Translesion DNA synthesis (TLS) plays an important role in promoting replication through DNA lesions. Genetic polymorphisms in TLS genes may have potential roles in lung cancer development in humans.
Methods
We evaluated the association between genetic variants in six TLS genes and the risk and survival of lung cancer in a case-control study in China. Included in the study are 224 lung cancer patients and 448 healthy controls.
Results
Carriers of the CG genotype of POLκ rs5744724 had significantly reduced risk of lung cancer (odds ratio (OR) = 0.60, 95% confidence interval (CI): 0.42-0.87), comparing with those carrying the CC genotype, and the AA genotype of PCNA rs25406 was also associated with significantly decreased cancer risk compared with the major homozygote alleles (OR= 0.47, 95% CI: 0.25-0.86). Haplotype analysis showed that subjects with the POLκ C-G (rs5744533-rs5744724) haplotype had decreased risk of lung cancer (OR = 0.69, 95% CI: 0.49-0.98), comparing with those carrying the C-C haplotype. Besides, the heterozygotes of REV1 rs3087386 and rs3792136 were independent prognostic factors for lung cancer survival with hazard ratios (HR) 1.54 (95% CI: 1.12-2.12) and 1.44 (95% CI: 1.06-1.97) respectively.
Conclusions
Our findings suggested that genetic variants in POLκ and PCNA genes may play roles in the susceptibility of lung cancer, and REV1 gene may have roles in lung cancer survival in Chinese men.
doi:10.1016/j.canep.2013.08.003
PMCID: PMC3875838  PMID: 24012694
lung cancer; TLS pathway; genetic mutation; susceptibility; survival; men
13.  Piericidin A Aggravates Tau Pathology in P301S Transgenic Mice 
PLoS ONE  2014;9(12):e113557.
Objective
The P301S mutation in exon 10 of the tau gene causes a hereditary tauopathy. While mitochondrial complex I inhibition has been linked to sporadic tauopathies. Piericidin A is a prototypical member of the group of the piericidins, a class of biologically active natural complex I inhibitors, isolated from streptomyces spp. with global distribution in marine and agricultural habitats. The aim of this study was to determine whether there is a pathogenic interaction of the environmental toxin piericidin A and the P301S mutation.
Methods
Transgenic mice expressing human tau with the P301S-mutation (P301S+/+) and wild-type mice at 12 weeks of age were treated subcutaneously with vehicle (N = 10 P301S+/+, N = 7 wild-type) or piericidin A (N = 9 P301S+/+, N = 9 wild-type mice) at a dose of 0.5 mg/kg/d for a period of 28 days via osmotic minipumps. Tau pathology was measured by stereological counts of cells immunoreative with antibodies against phosphorylated tau (AD2, AT8, AT180, and AT100) and corresponding Western blot analysis.
Results
Piericidin A significantly increased the number of phospho-tau immunoreactive cells in the cerebral cortex in P301S+/+ mice, but only to a variable and mild extent in wild-type mice. Furthermore, piericidin A led to increased levels of pathologically phosphorylated tau only in P301S+/+ mice. While we observed no apparent cell loss in the frontal cortex, the synaptic density was reduced by piericidin A treatment in P301S+/+ mice.
Discussion
This study shows that exposure to piericidin A aggravates the course of genetically determined tau pathology, providing experimental support for the concept of gene-environment interaction in the etiology of tauopathies.
doi:10.1371/journal.pone.0113557
PMCID: PMC4249965  PMID: 25437199
14.  Draft Genome Sequence of the Algicidal Bacterium Mangrovimonas yunxiaonensis Strain LY01 
Genome Announcements  2014;2(6):e01234-14.
Mangrovimonas yunxiaonensis LY01, a novel bacterium isolated from mangrove sediment, showed high algicidal effects on harmful algal blooms of Alexandrium tamarense. Here, we present the first draft genome sequence of this strain to further understanding of the functional genes related to algicidal activity.
doi:10.1128/genomeA.01234-14
PMCID: PMC4246170  PMID: 25428978
15.  Mitochondrial Complex 1 Inhibition Increases 4-Repeat Isoform Tau by SRSF2 Upregulation 
PLoS ONE  2014;9(11):e113070.
Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by intracellular aggregation of the microtubule-associated protein tau. The tau protein exists in 6 predominant isoforms. Depending on alternative splicing of exon 10, three of these isoforms have four microtubule-binding repeat domains (4R), whilst the others only have three (3R). In PSP there is an excess of the 4R tau isoforms, which are thought to contribute significantly to the pathological process. The cause of this 4R increase is so far unknown. Several lines of evidence link mitochondrial complex I inhibition to the pathogenesis of PSP. We demonstrate here for the first time that annonacin and MPP+, two prototypical mitochondrial complex I inhibitors, increase the 4R isoforms of tau in human neurons. We show that the splicing factor SRSF2 is necessary to increase 4R tau with complex I inhibition. We also found SRSF2, as well as another tau splicing factor, TRA2B, to be increased in brains of PSP patients. Thereby, we provide new evidence that mitochondrial complex I inhibition may contribute as an upstream event to the pathogenesis of PSP and suggest that splicing factors may represent an attractive therapeutic target to intervene in the disease process.
doi:10.1371/journal.pone.0113070
PMCID: PMC4234644  PMID: 25402454
16.  Effect of anterior cervical discectomy and fusion on adjacent segments in rabbits 
This study is to investigate the effect of anterior cervical discectomy with internal fixation and fusion at different levels on adjacent segments in rabbits. Sixty New Zealand rabbits were randomly divided into four groups, one control group and three model groups, with 15 in each group. Each group underwent anterior cervical internal fixation and fusion at C3-4, C4-5, and C5-6 levels respectively. X-ray film was examined three, six and nine months after fusion to observe the changes in intervertebral space and endplate of adjacent segment. Immunohistochemistry was utilized to evaluate the effects of different fusion methods on adjacent segments of spine. As time went by, in model groups, the majority of cartilage endplates were calcified, as examined by X-ray. Immunohistochemical results of the intervertebral disc showed that the expression levels of collagen type II in nucleus pulposus were decreased significantly, while the expression levels collagen type I in annular fibrosus were increased. And collagen type I tends to replace collagen type II gradually in nucleus pulposus as time goes by. The change in collagen between upper and lower adjacent segments at C3-4 and C4-5 showed no statistical significance after fixation and fusion (p > 0.05). But for C5-6, the change showed statistical significance (p < 0.05). Cervical internal fixation and fusion can induce intervertebral disc degeneration of adjacent segment in rabbits, and cervical internal fixation and fusion operated at different levels may result in different effects on adjacent segments of cervical intervertebral disc.
PMCID: PMC4276202  PMID: 25550944
Cervical vertebra; adjacent segment; internal fixation and fusion; intervertebral disc
17.  Crystal structure of dimethyl 3,3′-[(3-nitro­phen­yl)methyl­ene]bis­(1H-indole-2-carboxyl­ate) ethanol monosolvate 
In the title compound, the planes of the two indole ring systems are approximately perpendicular to each other, with a dihedral angle of 89.3 (5)°.
In the title compound, C27H21N3O6·C2H5OH, the indole ring systems are approximately perpendicular to each other, with a dihedral angle of 89.3 (5)°; the plane of the benzene ring is oriented with respect to the indole ring systems at 49.9 (5) and 73.4 (3)°. In the crystal, mol­ecules are linked by N—H⋯O and O—H⋯O hydrogen bonds and weak C—H⋯π inter­actions into a three-dimensional supra­molecular architecture. A void of 33.0 (7) Å3 is observed in the crystal structure. The solvent ethanol molecule acts as a donor, forming an O—H⋯O hydrogen bond, reinforcing the framework structure.
doi:10.1107/S1600536814022296
PMCID: PMC4257280  PMID: 25484748
indole; crystal structure; MRI contrast agent
18.  Mucous Membrane Pemphigoid 
Dental clinics of North America  2013;57(4):611-630.
doi:10.1016/j.cden.2013.07.003
PMCID: PMC3928007  PMID: 24034069
cicatricial pemphigoid; mucous membrane; subepithelial autoimmune disease; oral; ocular
19.  Selective propagation of functional mtDNA during oogenesis restricts the transmission of a deleterious mitochondrial variant 
Nature genetics  2014;46(4):389-392.
Though mitochondrial DNA is prone to mutation and few mtDNA repair mechanisms exist1, crippling mitochondrial mutations are exceedingly rare2. Recent studies demonstrated strong purifying selection in the mouse female germline3,4. However, the mechanisms underlying the positive selection of healthy mitochondria remain to be elucidated. We visualized mtDNA replication during Drosophila oogenesis. We found that mtDNA replication commenced prior to oocyte determination during the late germarium stage, and was dependent on mitochondrial fitness. We isolated a temperature-sensitive lethal mtDNA mutation, mt:CoIT300I, which displayed reduced mtDNA replication in the germarium at the restrictive temperature. Additionally, the frequency of mt:CoIT300I in heteroplasmic flies was decreased both through oogenesis and over multiple generations at the restrictive temperature. Furthermore, we determined that selection against mt:CoIT300I overlaps with the timing of selective replication of mtDNA in the germarium. These findings establish a previously uncharacterized developmental mechanism for selective amplification of healthy mtDNA, which may be evolutionarily conserved to limit transmission of deleterious mutations.
doi:10.1038/ng.2920
PMCID: PMC3976679  PMID: 24614072
20.  Crystal structure of dimethyl 3,3′-[(4-chloro­phen­yl)methyl­ene]bis­(1H-indole-2-carboxyl­ate) 
In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds, forming inversion dimers, which are linked by a further N—H⋯O hydrogen bond, forming chains along [100]. There are intra- and inter­molecular C—H⋯π inter­actions present, the latter linking the chains to form a three-dimensional supra­molecular structure.
In the title compound, C27H21ClN2O4, the mean planes of the two indole ring systems (r.m.s. deviations = 0.021 and 0.024 Å) are approximately perpendicular to one another, with a dihedral angle of 79.54 (12)°. The benzene ring is twisted with respect to the mean planes of the two indole ring systems at angles of 80.14 (15) and 86.30 (15)°. In the crystal, mol­ecules are linked by N—H⋯O hydrogen bonds, forming inversion dimers with an R 2 2(18) ring motif. The dimers are linked by a further N—H⋯O hydrogen bond, forming chains along [100]. There are intra- and inter­molecular C—H⋯π inter­actions present, the latter linking the chains to form a three-dimensional supra­molecular structure.
doi:10.1107/S1600536814020686
PMCID: PMC4257187  PMID: 25484668
crystal structure; indole; bis-indolymethane; MRI contrast agent; N—H⋯O hydrogen bonds; C—H⋯π inter­actions
21.  Influence of Per3 genotypes on circadian rhythmicity in flight cadets after militarized management 
Objective: The purpose of this study was to explore the effect of PERIOD3 (PER3) genotypes on circadian rhythmicity in flight cadets after militarized management. Methods: We performed a preliminary study in 146 newly enrolled male flight cadets. Venous blood samples were collected, and genotyping of PER3 (4/5) was determined by using PCR. The morningness-eveningness questionnaire (MEQ) survey was given to flight cadets upon enrollment and after militarized management for 24 months respectively. Comparison of frequency distribution of PER3 genotypes between cases and controls (120 well-matched civilians) was performed using the X2 test. We also compared the circadian rhythmicity upon enrollment and 24 months after enrollment in flight cadets, and analyzed the connection of changes in circadian clock with PER3 genotypes. Results: The frequency distribution of PER3 genotypes in flight cadets was not significantly different from that in controls subjects. MEQ survey results showed chronotype within flight cadet group varied widely at the two time-points: the moderately morning type (50%) and the neither type (41.1%) upon enrollment; the neither type (76.7%) and the moderately morning type (21.2%) 24 months after enrollment. The circadian rhythm of individuals with the PER3 (5/5) genotype showed no significant difference before and after 24 months of militarized management, whereas notable changes were found in individuals with the PER3 (4/4) genotype (n=116, X2=37.26, P < 0.001). Conclusion: In conclusion, we provide some evidence that circadian rhythm of flight cadets with the PER3 (5) allele are less likely to be affected compared to those with the PER3 (4) allele.
PMCID: PMC4230062  PMID: 25400784
Circadian rhythmicity; PER3 gene; flight cadet; militarized management
22.  Mesothelioma of the tunica vaginalis testis with prominent adenomatoid features: a case report 
Malignant mesotheliomas of the testis arise from the tunica vaginalis, formed from the evagination of the abdominal peritoneum into the scrotum. It is an extremely rare tumor representing 0.3% to 5% of all malignant mesotheliomas. We presented an interesting case of 68-year-old male with swelling and slightly painful in the right scrotum. Histologically, the lesion were composed of small tubular, microcystic, gland lined by flattened epithelioid cells and vague signet ring cells set in a myxofibrous stroma, which is resemblance to adenomatoid tumor. But the tumor cells showed significant atypical cytologic morphology and invaded into spermatic cord tissue, which indicated the diagnosis of malignant tumor. Immunohistochemistry study showed positive expression of CK, CK5/6, CK7, Calretinin, D2-40 and Vimentin which indicated the diagnosis of malignant mesothelioma. This case of mesothelioma should be classified as epithelial in type. To our knowledge, the mesothelioma of the tunica vaginalis testis with adenomatoid tumor-like microscopic features is very rare.
PMCID: PMC4230092  PMID: 25400801
Mesothelioma; tunica vaginalis testis; histology; adenomatoid
23.  Mitochondrial ferritin, a new target for inhibiting neuronal tumor cell proliferation 
Mitochondrial ferritin (FtMt) has a significant effect on the regulation of cytosolic and mitochondrial iron levels. However, because of the deficiency of iron regulatory elements (IRE) in FtMt’s gene sequence, the exact function of FtMt remains unclear. In the present study, we found that FtMt dramatically inhibited SH-SY5Y cell proliferation and tumor growth in nude mice. Interestingly, excess FtMt did not adversely affect the development of drosophila. Additionally, we found that the expression of FtMt in human normal brain tissue was significantly higher than that of neuroblastoma, but not higher than that of neurospongioma. However, the expression of transferrin receptor 1 is completely opposite. We therefore hypothesized that increased expression of FtMt may negatively affect the vitality of neuronal tumor cells. Therefore, we further investigated the underlying mechanisms of FtMt’s inhibitory effects on neuronal tumor cell proliferation. As expected, FtMt overexpression disturbed the iron homeostasis of tumor cells and significantly downregulated the expression of proliferating cell nuclear antigen. Moreover, FtMt affected cell cycle, causing G1/S arrest by modifying the expression of cyclinD1, cyclinE, Cdk2, Cdk4 and p21. Remarkably, FtMt strongly upregulated the expression of the tumor suppressors, p53 and N-myc downstream-regulated gene-1 (NDRG1), but dramatically decreased C-myc, N-myc and p-Rb levels. This study demonstrates for the first time a new role and mechanism for FtMt in the regulation of cell cycle. We thus propose FtMt as a new candidate target for inhibiting neuronal tumor cell proliferation. Appropriate regulation of FtMt expression may prevent tumor cell growth. Our study may provide a new strategy for neuronal cancer therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00018-014-1730-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00018-014-1730-0
PMCID: PMC4323545  PMID: 25213357
Neuroblastoma; Cyclin; Cell cycle; Cyclin-dependent protein kinase; Iron metabolism
24.  Targeted Iron-Oxide Nanoparticle for Photodynamic Therapy and Imaging of Head and Neck Cancer 
ACS nano  2014;8(7):6620-6632.
Photodynamic therapy (PDT) is a highly specific anticancer treatment modality for various cancers, particularly for recurrent cancers that no longer respond to conventional anticancer therapies. PDT has been under development for decades, but light-associated toxicity limits its clinical applications. To reduce the toxicity of PDT, we recently developed a targeted nanoparticle (NP) platform that combines a second-generation PDT drug, Pc 4, with a cancer targeting ligand, and iron oxide (IO) NPs. Carboxyl functionalized IO NPs were first conjugated with a fibronectin-mimetic peptide (Fmp), which binds integrin β1. Then the PDT drug Pc 4 was successfully encapsulated into the ligand-conjugated IO NPs to generate Fmp-IO-Pc 4. Our study indicated that both nontargeted IO-Pc 4 and targeted Fmp-IO-Pc 4 NPs accumulated in xenograft tumors with higher concentrations than nonformulated Pc 4. As expected, both IO-Pc 4 and Fmp-IO-Pc 4 reduced the size of HNSCC xenograft tumors more effectively than free Pc 4. Using a 10-fold lower dose of Pc 4 than that reported in the literature, the targeted Fmp-IO-Pc 4 NPs demonstrated significantly greater inhibition of tumor growth than nontargeted IO-Pc 4 NPs. These results suggest that the delivery of a PDT agent Pc 4 by IO NPs can enhance treatment efficacy and reduce PDT drug dose. The targeted IO-Pc 4 NPs have great potential to serve as both a magnetic resonance imaging (MRI) agent and PDT drug in the clinic.
doi:10.1021/nn501652j
PMCID: PMC4155749  PMID: 24923902
iron-oxide nanoparticle; Fmp-IO-Pc 4; photodynamic therapy; head and neck cancer; magnetic resonance imaging; integrin β1
25.  Variants in CCK and CCKAR genes to susceptibility to biliary tract cancers and stones: a population-based study in Shanghai, China 
Journal of gastroenterology and hepatology  2013;28(9):10.1111/jgh.12278.
Background and Aim
Altered motility of the gallbladder is associated with an increased risk of gallstones and can result in biliary tract cancers. Cholecystokinin (CCK) is an important modulator of gallbladder motility which functions by activating CCK type-A receptor (CCKAR). The aim of this study was to determine whether genetic variants in CCK and CCKAR are associated with the risk of biliary tract cancers and stones.
Methods
We investigated the associations between 9 single nucleotide polymorphisms (SNPs) in CCK and CCKAR in a population-based case-control study, including 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in Shanghai, China.
Results
We found that women with the CCKAR rs1800855 AA genotype had an increased risk of gallbladder cancer (odd ratio (OR) =2.37, 95% confidence interval (CI): 1.36–4.14) compared to subjects with the TT genotype, and remained significant after Bonferroni correction (P=0.0056). Additionally, female carriers of the CCKAR haplotype C-T-C-T (rs2071011-rs915889-rs3822222-rs1800855) had a reduced risk of gallbladder cancer (OR=0.61, 95%CI: 0.43–0.86) compared to those with the G-C-C-A haplotype, the association also remained significant after Bonferroni correction.
Conclusions
These findings suggest that variants in the CCKAR gene may influence the risk of gallbladder cancer in women. Additional studies are needed to confirm our findings.
doi:10.1111/jgh.12278
PMCID: PMC3820582  PMID: 23701593
biliary tract cancer; gallstone; CCK and CCKAR; variant; haplotype; susceptibility

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