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1.  GPOPSIM: a simulation tool for whole-genome genetic data 
BMC Genetics  2015;16(1):10.
Background
Population-wide genotypic and phenotypic data is frequently used to predict the disease risk or genetic/phenotypic values, or to localize genetic variations responsible for complex traits. GPOPSIM is a simulation tool for pedigree, phenotypes, and genomic data, with a variety of population and genome structures and trait genetic architectures. It provides flexible parameter settings for a wide discipline of users, especially can simulate multiple genetically correlated traits with desired genetic parameters and underlying genetic architectures.
Results
The model implemented in GPOPSIM is presented, and the code has been made freely available to the community. Data simulated by GPOPSIM is a good mimic to the real data in terms of genome structure and trait underlying genetic architecture.
Conclusions
GPOPSIM would be a useful tool for the methodological and theoretical studies in the population and quantitative genetics and breeding.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0173-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-015-0173-4
PMCID: PMC4328615  PMID: 25652552
Data simulation; SNP; Pedigree; Multiple traits; Mutation-drift equilibrium; Genetic correlation
2.  Saliva and Plasma Quantitative Polymerase Chain Reaction–Based Detection and Surveillance of Human Papillomavirus–Related Head and Neck Cancer 
IMPORTANCE
Human papillomavirus type 16 (HPV-16) is a major causative factor in oropharyngeal squamous cell carcinoma (OPSCC). The detection of primary OPSCC is often delayed owing to the challenging anatomy of the oropharynx.
OBJECTIVE
To investigate the feasibility of HPV-16 DNA detection in pretreatment and posttreatment plasma and saliva and its potential role as a marker of prognosis.
DESIGN, SETTING, AND PARTICIPANTS
This is a retrospective analysis of a prospectively collected cohort. Among a cohort of patients with oropharyngeal and unknown primary squamous cell carcinoma with known HPV-16 tumor status from the Johns Hopkins Medical Institutions and Greater Baltimore Medical Center (from 1999 through 2010), 93 patients were identified with a complete set of pretreatment and posttreatment plasma or saliva samples, of which 81 patients had HPV-16–positive tumors and 12 patients had HPV-16–negative tumors. Real-time quantitative polymerase chain reaction was used to detect HPV-16 E6 and E7 DNA in saliva and plasma samples.
MAIN OUTCOMES AND MEASURES
Main outcomes included sensitivity, specificity, negative predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status, as well as the association of posttreatment HPV DNA status with clinical outcomes, including recurrence-free survival and overall survival.
RESULTS
The median follow-up time was 49 months (range, 0.9–181.0 months). The sensitivity, specificity, negative predictive value, and positive predictive value of combined saliva and plasma pretreatment HPV-16 DNA status for detecting tumor HPV-16 status were 76%, 100%, 42%, and 100%, respectively. The sensitivities of pretreatment saliva or plasma alone were 52.8%and 67.3%, respectively. In a multivariable analysis, positive posttreatment saliva HPV status was associated with higher risk of recurrence (hazard ratio [HR], 10.7; 95% CI, 2.36–48.50) (P = .002). Overall survival was reduced among those with posttreatment HPV-positive status in saliva (HR, 25.9; 95% CI, 3.23–208.00) (P = .002) and those with HPV-positive status in either saliva or plasma but not among patients with HPV-positive status in plasma alone. The combined saliva and plasma posttreatment HPV-16 DNA status was 90.7%specific and 69.5%sensitive in predicting recurrence within 3 years.
CONCLUSIONS AND RELEVANCE
Using a combination of pretreatment plasma and saliva can increase the sensitivity of pretreatment HPV-16 status as a tool for screening patients with HPV-16–positive OPSCC. In addition, analysis of HPV-16 DNA in saliva and plasma after primary treatment may allow for early detection of recurrence in patients with HPV-16–positive OPSCC.
doi:10.1001/jamaoto.2014.1338
PMCID: PMC4313904  PMID: 25078109
3.  Transcription of the Lysine-2,3-Aminomutase Gene in the kam Locus of Bacillus thuringiensis subsp. kurstaki HD73 Is Controlled by Both σ54 and σK Factors 
Journal of Bacteriology  2014;196(16):2934-2943.
Lysine 2,3-aminomutase (KAM; EC 5.4.3.2) catalyzes the interconversion of l-lysine and l-β-lysine. The transcription and regulation of the kam locus, including lysine-2,3-aminomutase-encoding genes, in Bacillus thuringiensis were analyzed in this study. Reverse transcription-PCR (RT-PCR) analysis revealed that this locus forms two operons: yodT (yodT-yodS-yodR-yodQ-yodP-kamR) and kamA (kamA-yokU-yozE). The transcriptional start sites (TSSs) of the kamA gene were determined using 5′ rapid amplification of cDNA ends (RACE). A typical −12/−24 σ54 binding site was identified in the promoter PkamA, which is located upstream of the kamA gene TSS. A β-galactosidase assay showed that PkamA, which directs the transcription of the kamA operon, is controlled by the σ54 factor and is activated through the σ54-dependent transcriptional regulator KamR. The kamA operon is also controlled by σK and regulated by the GerE protein in the late stage of sporulation. kamR and kamA mutants were prepared by homologous recombination to examine the role of the kam locus. The results showed that the sporulation rate in B. thuringiensis HD(ΔkamR) was slightly decreased compared to that in HD73, whereas that in HD(ΔkamA) was similar to that in HD73. This means that other genes regulated by KamR are important for sporulation.
doi:10.1128/JB.01675-14
PMCID: PMC4135644  PMID: 24914178
4.  Circadian Factor BMAL1 in Histaminergic Neurons Regulates Sleep Architecture 
Current Biology  2014;24(23):2838-2844.
Summary
Circadian clocks allow anticipation of daily environmental changes [1]. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body [1]. Although some peripheral clocks have established roles [1], it is unclear what local brain clocks do [2, 3]. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset [4–6]; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness [7–11]. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3 [12]) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN.
Highlights
•The first role for a putative local clock in sleep regulation is identified•Local expression of BMAL1 directs rhythmic synthesis of histamine•Local BMAL1 regulates balance of sleep-wake activity within the circadian cycle•Local BMAL1 specifies sufficient spontaneous and recovery sleep during the circadian day
The suprachiasmatic nucleus houses the master circadian clock, but local clocks are also found in many cells. It is unclear what local brain clocks do. Yu et al. reveal that a local clock in histaminergic neurons determines fluctuations of the “wakefulness transmitter” histamine, thus balancing sleep and wake within the animal’s circadian behavior.
doi:10.1016/j.cub.2014.10.019
PMCID: PMC4252164  PMID: 25454592
6.  A Safety and Feasibility Study of an Allogeneic Colon Cancer Cell Vaccine Administered with a Granulocyte–Macrophage Colony Stimulating Factor–Producing Bystander Cell Line in Patients with Metastatic Colorectal Cancer 
Annals of surgical oncology  2014;21(12):3931-3937.
Background
Despite recent advances in earlier detection and improvements in chemotherapy, the 5-year survival rate of patients with metastatic colorectal carcinoma remains poor. Immunotherapy is a potentially effective therapeutic approach to the treatment of colorectal carcinoma. Preclinical studies have supported the antitumor activity of immunization with a granulocyte–macrophage colony-stimulating factor (GM-CSF) producing murine colon tumor cell vaccine.
Methods
A novel colorectal cancer vaccine composed of irradiated, allogeneic human colon cancer cells and GM-CSF-producing bystander cells was developed and tested in combination with a single intravenous low dose of cyclophosphamide in a phase 1 study of patients with metastatic colorectal cancer.
Results
A total of nine patients were enrolled onto and treated in this study. Six patients had a history of colorectal adenocarcinoma hepatic metastases and underwent curative metastasectomy, while three other patients had unresectable stage IV disease. This study demonstrates the safety and feasibility of this vaccine administered in patients with metastatic colorectal cancer. At last follow-up, the six patients who underwent curative metastasectomy survived longer than 36 months, and four of these six patients were without disease recurrence. Immunologic correlate results suggest that the GM-CSF-producing colon cancer vaccine enhances the production of anti-MUC1 antibodies.
Conclusions
This vaccine is feasible and safe. Future investigation of the efficacy and antitumor immunity of this vaccine is warranted.
doi:10.1245/s10434-014-3844-x
PMCID: PMC4192092  PMID: 24943235
7.  Upregulated periostin promotes angiogenesis in keloids through activation of the ERK 1/2 and focal adhesion kinase pathways, as well as the upregulated expression of VEGF and angiopoietin-1 
Molecular Medicine Reports  2014;11(2):857-864.
Periostin, a secreted extracellular matrix protein, is highly expressed in wound healing and in various types of human cancer and is involved in angiogenesis. Keloids, considered dermal benign tumors, are granulomatous lesions characterized by capillary proliferation. However, the underlying regulatory mechanism of angiogenesis in keloids remains to be elucidated. The present study aimed to examine the effect of periostin on angiogenesis in keloids. The expression of periostin was upregulated and the vessel density was higher in human keloids compared with normal tissue, observed following staining with CD31 and CD105. Periostin demonstrated a markedly positive correlation with blood vessel density, which was assessed using CD31 staining (r=0.711; P<0.01) and a weak correlation was observed using CD105 staining (r=0.251; P<0.01). Conditioned medium from keloid fibroblasts (KFs) promoted the migration and tube formation of human umbilical vein endothelial cells (HUVECs) compared with normal fibroblasts and this effect may have been abrogated by the short hairpin RNA knockdown of periostin. Treatment with recombinant human periostin promoted the migration and tube formation of HUVECs by activating the extracellular signal-regulated kinase 1/2 and focal adhesion kinase signaling pathway. In addition, periostin increased the secretion of vascular endothelial growth factor and angiopoietin-1 in the KFs. In conclusion, these data suggested that upregulation in the level of periostin may promote angiogenesis directly and indirectly in keloids and may be a key factor in keloid development. Periostin may, therefore, be a promising therapeutic target in the treatment of keloids and other angioproliferative diseases.
doi:10.3892/mmr.2014.2827
PMCID: PMC4262479  PMID: 25369801
periostin; fibroblast; keloid; endothelial cells; angiogenesis
8.  Traditional Chinese medicine for stable angina pectoris via TCM pattern differentiation and TCM mechanism: study protocol of a randomized controlled trial 
Trials  2014;15(1):422.
Background
Stable angina pectoris is experienced as trans-sternal or retro-sternal pressure or pain that may radiate to the left arm, neck or back. Although available evidence relating to its effectiveness and mechanism are weak, traditional Chinese medicine is used as an alternative therapy for stable angina pectoris. We report a protocol of a randomized controlled trial using traditional Chinese medicine to investigate the effectiveness, mechanism and safety for patients with stable angina pectoris.
Methods/Design
This is a north-east Chinese, multi-center, multi-blinded, placebo-controlled and superiority randomized trail. A total of 240 patients with stable angina pectoris will be randomly assigned to three groups: two treatment groups and a control group. The treatment groups will receive Chinese herbal medicine consisting of Yi-Qi-Jian-Pi and Qu-Tan-Hua-Zhuo granule and Yi-Qi-Jian-Pi and Qu-Tan-Hua-Yu granule, respectively, and conventional medicine. The control group will receive placebo medicine in addition to conventional medicine. All 3 groups will undergo a 12-week treatment and 2-week follow-up. Four visits in sum will be scheduled for each subject: 1 visit each in week 0, week 4, week 12 and week 14. The primary outcomes include: the frequency of angina pectoris attack; the dosage of nitroglycerin; body limited dimension of Seattle Angina Questionnaire. The secondary outcomes include: except for the body limited dimension of SAQ, traditional Chinese medicine pattern questionnaire and so on. Therapeutic mechanism outcomes, safety outcomes and endpoint outcomes will be also assessed.
Discussion
The primary aim of this trial is to develop a standard protocol to utilize high-quality EBM evidence for assessing the effectiveness and safety of SAP via TCM pattern differentiation as well as exploring the efficacy mechanism and regulation with the molecular biology and systems biology.
Trial registration
Clinical Trials Registration: ChiCTR-TRC-13003608, registered 18 June 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-422) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-422
PMCID: PMC4233055  PMID: 25359307
9.  Rational Design of Small-Molecule Stabilizers of Spermine Synthase Dimer by Virtual Screening and Free Energy-Based Approach 
PLoS ONE  2014;9(10):e110884.
Snyder-Robinson Syndrome (SRS) is a rare mental retardation disorder which is caused by the malfunctioning of an enzyme, the spermine synthase (SMS), which functions as a homo-dimer. The malfunctioning of SMS in SRS patients is associated with several identified missense mutations that occur away from the active site. This investigation deals with a particular SRS-causing mutation, the G56S mutation, which was shown computationally and experimentally to destabilize the SMS homo-dimer and thus to abolish SMS enzymatic activity. As a proof-of-concept, we explore the possibility to restore the enzymatic activity of the malfunctioning SMS mutant G56S by stabilizing the dimer through small molecule binding at the mutant homo-dimer interface. For this purpose, we designed an in silico protocol that couples virtual screening and a free binding energy-based approach to identify potential small-molecule binders on the destabilized G56S dimer, with the goal to stabilize it and thus to increase SMS G56S mutant activity. The protocol resulted in extensive list of plausible stabilizers, among which we selected and tested 51 compounds experimentally for their capability to increase SMS G56S mutant enzymatic activity. In silico analysis of the experimentally identified stabilizers suggested five distinctive chemical scaffolds. This investigation suggests that druggable pockets exist in the vicinity of the mutation sites at protein-protein interfaces which can be used to alter the disease-causing effects by small molecule binding. The identified chemical scaffolds are drug-like and can serve as original starting points for development of lead molecules to further rescue the disease-causing effects of the Snyder-Robinson syndrome for which no efficient treatment exists up to now.
doi:10.1371/journal.pone.0110884
PMCID: PMC4207787  PMID: 25340632
10.  Genome-Wide Expression Analysis in Fibroblast Cell Lines from Probands with Pallister Killian Syndrome 
PLoS ONE  2014;9(10):e108853.
Pallister Killian syndrome (OMIM: # 601803) is a rare multisystem disorder typically caused by tissue limited mosaic tetrasomy of chromosome 12p (isochromosome 12p). The clinical manifestations of Pallister Killian syndrome are variable with the most common findings including craniofacial dysmorphia, hypotonia, cognitive impairment, hearing loss, skin pigmentary differences and epilepsy. Isochromosome 12p is identified primarily in skin fibroblast cultures and in chorionic villus and amniotic fluid cell samples and may be identified in blood lymphocytes during the neonatal and early childhood period. We performed genomic expression profiling correlated with interphase fluorescent in situ hybridization and single nucleotide polymorphism array quantification of degree of mosaicism in fibroblasts from 17 Caucasian probands with Pallister Killian syndrome and 9 healthy age, gender and ethnicity matched controls. We identified a characteristic profile of 354 (180 up- and 174 down-regulated) differentially expressed genes in Pallister Killian syndrome probands and supportive evidence for a Pallister Killian syndrome critical region on 12p13.31. The differentially expressed genes were enriched for developmentally important genes such as homeobox genes. Among the differentially expressed genes, we identified several genes whose misexpression may be associated with the clinical phenotype of Pallister Killian syndrome such as downregulation of ZFPM2, GATA6 and SOX9, and overexpression of IGFBP2.
doi:10.1371/journal.pone.0108853
PMCID: PMC4199614  PMID: 25329894
11.  Long term prognosis and risk factors among HPV-associated oropharyngeal squamous cell carcinoma patients 
Cancer  2013;119(19):3462-3471.
Background
A subset of HPV-associated oropharyngeal squamous cell carcinoma (HPV-OSCC) patients experience poor clinical outcomes. We explored prognostic risk factors on overall survival (OS) and recurrence free survival (RFS).
Methods
Patients with incident HPV-OSCC treated at the Johns Hopkins Hospital between 1997– 2008 with available tissue for HPV testing and demographic and clinicopathologic information (N=176) were included. Tissue was tested for HPV by in situ hybridization (ISH) and/or p16 immunohistochemistry (IHC). Demographic and clinicopathologic information was extracted from medical records.
Results
90% (157/176) of the OSCC cases were HPV-associated. In the HPV-OSCC patients, we observed a 3- and 5-year OS rate of 93% (95% CI: 88%–98%) and 89% (95% CI: 81%–97%), respectively. Lower survival was observed with older patient age (HR 2.33 per 10-year increase, CI: 1.05–5.16, p=0.038), advanced clinical T-stage (HR 5.78, 95% CI: 1.60–20.8, p=0.007), and current tobacco use (HR 4.38, 95% CI: 1.07–18.0, p=0.04). Disease recurrence was associated with advanced clinical T stage (HR 8.32, 95% CI: 3.06–23, p<0.0001), current/former alcohol use (HR 13, 95% CI: 1.33–120, p=0.03), and unmarried status (HR 3.28, 95% CI: 1.20–9.00, p=0.02).. Patients who remained recurrence-free for 5 years had an 8.6% chance of recurrence by 10 years (one-sided 95% CI upper bound is 19%, p=0.088).
Conclusions
Prognostic risk factors are identified for HPV-OSCC patients. Observed recurrence rates between 5 and 10 years following definitive therapy needs to be validated in additional studies to determine whether extended cancer surveillance is warranted in this cancer population.
doi:10.1002/cncr.28250
PMCID: PMC3788050  PMID: 23861037
HPV; head and neck cancer; oropharyngeal cancer; gender; risk factors
12.  Sensory Guillain-Barré syndrome: A case report 
A 58-year-old female exhibited the onset of symmetrical sensory abnormalities of the face and extremities. The neurological examination revealed normal muscle strength with abated or absent tendon reflexes. The patient experienced symmetrical glove- and stocking-type pinprick sensations in the distal extremities and a loss of temperature sensation, but had normal proprioception and vibration senses and joint topesthesia. The lumbar puncture showed protein cell separation at the fifth week after the onset of symptoms. At the same time-point, the electrophysiological examination showed demyelination changes involving the trigeminal nerve and the somatic motor nerve. Needle electromyography revealed normal results. The clinical symptoms ceased progression at the fourth week after symptom onset, and began to improve from the sixth. This case was considered to be sensory Guillain-Barré syndrome, which was characterized by its cranial nerve involvement.
doi:10.3892/etm.2014.1995
PMCID: PMC4217785  PMID: 25371720
sensory Guillain-Barré syndrome; electrophysiology; cranial nerve
13.  Human leukocyte antigen-haploidentical donor-derived cytokine-induced killer cells are safe and prolong the survival of patients with advanced non-small cell lung cancer 
Oncology Letters  2014;8(6):2727-2733.
The aim of the present study was to evaluate the safety and efficacy of administering cytokine-induced killer cells (termed allogeneic CIKs), obtained from the blood of the offspring of patients, for the treatment of non-small cell lung cancer. Symptoms, signs and laboratory assessment results for 303 cancer patients were collected prior to and following treatment with autologous or allogeneic CIKs. In addition, 54 patients with advanced non-small cell lung cancer (NSCLC) were enrolled and divided into allogeneic CIK and optimal support groups (n=27 per group) according to gender, age, Karnofsky performance status score, TNM stage and histological type. In addition, overall survival (OS) was compared between the two groups. A total of 303 patients were treated with CIKs for 647 cycles, with 308 and 339 cycles in the autologous and allogeneic CIK groups, respectively. The mean number of CIKs in the autologous and allogeneic groups was 2.11±0.32×1010 and 2.29±0.36×1010, respectively, with no marked differences identified between the two groups (t=1.147; P>0.05). The predominant adverse events included insomnia, fever, nausea, vomiting and mild abdominal pain, which were found, respectively, in nine (6.8%), eight (6.0%), two (1.5%) and one (0.8%) patients receiving autologous CIKs and 11 (6.5%), 10 (5.9%), one (0.6%) and one (0.6%) patients receiving allogeneic CIKs, with no marked differences identified between the two groups (P>0.05). Adverse events were not associated with cell count, frequency or duration of treatment. Following CIK treatment, the outcomes of routine blood tests, and liver and kidney function tests, as well as immune function and electrocardiogram examinations remained unchanged (P>0.05). The median OS was 11.0 months (95% confidence interval (CI), 8.6–13.4 months) and 8.0 months (95% CI, 5.3–10.7 months) for NSCLC patients receiving allogeneic CIKs and optimal support, respectively; a statistically significant difference was identified (χ2=5.618; P=0.018). The present study demonstrated that CIKs from human leukocyte antigen haploidentical donors are safe and prolong the survival of NSCLC patients.
doi:10.3892/ol.2014.2558
PMCID: PMC4214449  PMID: 25364456
cytokine-induced killer cells; immunotherapy; adoptive; allogeneic; malignant tumor; carcinoma; non-small cell lung
14.  A Y328C missense mutation in spermine synthase causes a mild form of Snyder–Robinson syndrome 
Human Molecular Genetics  2013;22(18):3789-3797.
Snyder–Robinson syndrome (SRS, OMIM: 309583) is an X-linked intellectual disability (XLID) syndrome, characterized by a collection of clinical features including facial asymmetry, marfanoid habitus, hypertonia, osteoporosis and unsteady gait. It is caused by a significant decrease or loss of spermine synthase (SMS) activity. Here, we report a new missense mutation, p.Y328C (c.1084A>G), in SMS in a family with XLID. The affected males available for evaluation had mild ID, speech and global delay, an asthenic build, short stature with long fingers and mild kyphosis. The spermine/spermidine ratio in lymphoblasts was 0.53, significantly reduced compared with normal (1.87 average). Activity analysis of SMS in the index patient failed to detect any activity above background. In silico modeling demonstrated that the Y328C mutation has a significant effect on SMS stability, resulting in decreased folding free energy and larger structural fluctuations compared with those of wild-type SMS. The loss of activity was attributed to the increase in conformational dynamics in the mutant which affects the active site geometry, rather than preventing dimer formation. Taken together, the biochemical and in silico studies confirm the p.Y328C mutation in SMS is responsible for the patients having a mild form of SRS and reveal yet another molecular mechanism resulting in a non-functional SMS causing SRS.
doi:10.1093/hmg/ddt229
PMCID: PMC3749864  PMID: 23696453
15.  miR-107 regulates cisplatin chemosensitivity of A549 non small cell lung cancer cell line by targeting cyclin dependent kinase 8 
Previous studies demonstrated that the acquired drug resistance of non-small cell lung cancer (NSCLC) was related to deregulation of miRNAs. However, the effects of miR-107 and the mechanism through which miR-107 affects the cisplatin chemoresistance in NSCLC have not been reported. TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-107 and cyclin dependent kinase 8 (CDK8) protein. The viabilities of treated cells were analyzed using MTT assay. We found that the expression level of miR-107 in A549 cells was significantly lower than that in normal human bronchial epithelial cells (0.45 ± 0.26 vs. 1.00 ± 0.29, P = 0.032). The MTT assay showed that the A549 cells transfected with miR-107 mimics were significantly more sensitive to the therapy of cisplatin than control cells. A549 cells transfected with miR-107 mimics showed a decreased CDK8 protein expression. Downregulation of CDK8 expression by siRNAs, A549 cells became more sensitive to the therapy of cisplatin. In addition, the enhanced growth-inhibitory effect by the miR-107 mimic transfection was enhanced after the addition of CDK8 siRNA. In conclusion, the present study provides the first evidence that miR-107 plays a key role in cisplatin resistance by targeting the CDK8 protein in NSCLC cell lines, suggesting that miR-107 can be used to predict a patient’s response to chemotherapy as well as serve as a novel potential maker for NSCLC therapy.
PMCID: PMC4230114  PMID: 25400821
Non small cell lung cancer; miR-107; CDK8; cisplatin; chemosensitivity
16.  Mitochondrial respiratory chain disease discrimination by retrospective cohort analysis of blood metabolites 
Molecular genetics and metabolism  2013;110(0):10.1016/j.ymgme.2013.07.011.
Diagnosing primary mitochondrial respiratory chain (RC) dysfunction has long relied on invasive tissue biopsies, since no blood-based biomarker has been shown to have sufficiently high sensitivity and specificity across the myriad of individual clinical presentations. We sought to determine whether cohort-level evaluation of commonly obtained blood analytes might reveal consistent patterns to discriminate a heterogenous group of primary mitochondrial RC disease subjects both from control individuals and from subjects with pyruvate dehydrogenase deficiency.
METHODS
Following IRB approval, 62 biochemical analyte concentrations or ratios were retrospectively analyzed in three well-defined and intentionally heterogeneous subject cohorts reflective of clinical practice: [1] Primary mitochondrial disease (n=19); [2] Pyruvate dehydrogenase deficiency (n=4); and [3] Controls (n=27). Blood analyte categories included comprehensive chemistry profile, creatine kinase, lipoprotein profile, lactate, pyruvate, and plasma amino acid profile. Non-parametric analyses were used to compare the median of each analyte level between cohorts.
RESULTS
Disease cohorts differed significantly in their median levels of triglycerides, lactate, pyruvate, and multiple individual plasma amino acids. Primary mitochondrial disease was significantly discriminated at the cohort level from pyruvate dehydrogenase deficiency by greater pyruvate and alanine elevation in pyruvate dehydrogenase deficiency, as well as significantly increased branched chain amino acid (BCAA) levels and increased ratios of individual BCAAs to glutamate in mitochondrial disease. In addition, significant elevation of median blood triglyceride level was seen in the primary mitochondrial disease cohort.
CONCLUSIONS
Blood metabolite profile analysis can discriminate heterogeneous cohorts of primary mitochondrial disease both from controls and from pyruvate dehydrogenase deficiency. Elevated BCAA levels, either absolutely or when considered relative to the level of glutamate, are common metabolic sequelae of primary mitochondrial RC disease. Prospective study is needed to validate observed plasma metabolite alterations as a potential biomarker of disease both in larger cohorts and at the individual subject level.
doi:10.1016/j.ymgme.2013.07.011
PMCID: PMC3812452  PMID: 23920046
primary human mitochondrial disease; pyruvate dehydrogenase deficiency; metabolites; branched chain amino acids
17.  Prognostic Value of FGFR Gene Amplification in Patients with Different Types of Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(8):e105524.
Background
Fibroblast growth factor receptor (FGFR) gene amplification has been reported in different types of cancer. We performed an up-to-date meta-analysis to further characterize the prognostic value of FGFR gene amplification in patients with cancer.
Methods
A search of several databases, including MEDLINE (PubMed), EMBASE, Web of Science, and China National Knowledge Infrastructure, was conducted to identify studies examining the association between FGFR gene amplification and cancer. A total of 24 studies met the inclusion criteria, and overall incidence rates, hazard risk (HR), overall survival, disease-free survival, and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included studies.
Results
In the meta-analysis of 24 studies, the prevalence of FGFR gene amplification was FGFR1: 0.11 (95% CI: 0.08–0.13) and FGFR2: 0.04 (95% CI: 0.02–0.06). Overall survival was significantly worse among patients with FGFR gene amplification: FGFR1 [HR 1.57 (95% CI: 1.23–1.99); p = 0.0002] and FGFR2 [HR 2.27 (95% CI: 1.73–3.00); p<0.00001].
Conclusions
Current evidence supports the conclusion that the outcomes of patients with FGFR gene amplified cancers is worse than for those with non-FGFR gene amplified cancers.
doi:10.1371/journal.pone.0105524
PMCID: PMC4149366  PMID: 25171497
18.  The Effects of the Reverse Current Caused by the Series Compensation on the Current Differential Protection 
The Scientific World Journal  2014;2014:473913.
The series capacitor compensation is one of the key technologies in the EHV and UHV long distance power transmission lines. This paper analyzes the operation characteristics of the main protection combined with the engineering practice when the transmission line overcompensation due to the series compensation system is modified and analyzes the influence of the transition resistance and the system operation mode on the current differential protection. According to the simulation results, it presents countermeasure on improving the sensitivity of differential current protection.
doi:10.1155/2014/473913
PMCID: PMC4163404  PMID: 25247206
19.  Association between Thrombomodulin Polymorphisms and Coronary Artery Disease Risk: A Meta-Analysis 
Background
The associations between the thrombomodulin (TM) polymorphisms and coronary artery disease (CAD) risk remain controversial. The aim of this study was to evaluate the association of TM polymorphisms with CAD susceptibility using a meta-analysis approach.
Material/Methods
All eligible studies were identified through a search of PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) before February 2014. The associations between the TM polymorphisms and CAD risk was assessed by odds ratios (ORs) and 95% confidence intervals (CIs).
Results
A total of 14 case-control studies, including 5493 cases and 8297 controls, were eventually collected. There was a significant association between TM -33G/A polymorphism and CAD risk (OR=1.61; 95% CI, 1.35–1.92; I2=15%). The TM Ala455Val polymorphism was also associated with a significantly increased CAD risk (OR=1.14; 95% CI, 1.05–1.24; I2=0%). These results remained statistically significant when the adjusted ORs were combined.
Conclusions
Our results suggest that TM-33G/A and Ala455Val polymorphisms are risk factors for CAD.
doi:10.12659/MSM.890717
PMCID: PMC4138070  PMID: 25108690
Coronary Artery Disease; Genetics; Meta-Analysis; Thrombomodulin
20.  Association of Simple Anthropometric Indices and Body Fat with Early Atherosclerosis and Lipid Profiles in Chinese Adults 
PLoS ONE  2014;9(8):e104361.
Objective
The discriminatory capability of different adiposity indices for atherosclerosis and lipid abnormalities remains uncertain. This study aimed to identify the best adiposity index for predicting early atherosclerosis and abnormal lipid profiles among anthropometric parameters and body fat measures in middle-aged and elderly Chinese.
Method
A total of 2,063 women and 814 men (57.6±5.2 y) were recruited for this community-based cross-sectional study. Body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were assessed. Body fat mass and its percentage values for the whole body and trunk were measured by bioelectrical impedance analysis (BIA). The intima-media thicknesses (IMTs) of the common carotid arteries (CCA), internal carotid arteries (ICA) and bifurcation (BIF) were determined via B-mode ultrasound. The fasting lipid profiles were assessed.
Results
With per SD increase of adiposity indices, the magnitude of the changes of IMT values and lipid profiles was more substantial for WC, WHR and WHtR in both genders. A multivariate logistic regression analysis indicated that WC, WHR and WHtR were more sensitive in predicting the presence of intima-media thickening at the three segments as well as the lipids disturbances in women and men. In general, BIA-derived measures have no added predictive value for IMT-thickening as opposed to those three traditional abdominal measures.
Conclusion
Our findings suggest that abdominal anthropometric measures including WC, WHR and WHtR are sensitive for discriminating carotid atherosclerosis and lipids abnormalities. WC is the best index because of its simplicity in routine use.
doi:10.1371/journal.pone.0104361
PMCID: PMC4121270  PMID: 25090639
21.  Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity 
Developing an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 108 infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD50) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax.
doi:10.1128/CVI.00560-13
PMCID: PMC3910935  PMID: 24307239
22.  A sodium-mediated structural switch that controls the sensitivity of Kir channels to PIP2 
Nature chemical biology  2008;4(10):624-631.
Inwardly rectifying potassium (Kir) channels are gated by the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2). Among them, Kir3 channel gating requires additional molecules, such as the βγ subunits of G proteins or intracellular sodium. Using an interactive computational-experimental approach, we show that sodium sensitivity of Kir channels involves the side-chains of an aspartate and a histidine located across from each other in a critical loop in the cytosolic domain, as well as the backbone carbonyls of two additional residues and a water molecule. The location of the coordination site in the vicinity of a conserved arginine shown to affect channel-PIP2 interactions suggests that sodium triggers a structural switch that frees the critical arginine. Mutations of the aspartate and the histidine that affect sodium sensitivity also enhance the channel’s sensitivity to PIP2. Furthermore, based on the molecular characteristics of the coordination site, we identify and confirm experimentally a novel sodium-sensitive phenotype in Kir5.1.
doi:10.1038/nchembio.112
PMCID: PMC4100997  PMID: 18794864
23.  In Vivo Angiogenesis Screening and Mechanism of Action of Novel Tanshinone Derivatives Produced by One-Pot Combinatorial Modification of Natural Tanshinone Mixture from Salvia Miltiorrhiza 
PLoS ONE  2014;9(7):e100416.
Background
Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.
Methodology/Principal Findings
In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1–10) and one oxazole-tanshinone (Compound 11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.
Conclusions/Significance
Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great potential of adopting a newly modified one-pot approach to enhance the chemical diversity and biological activities of constituents from natural products regardless of their abundances.
doi:10.1371/journal.pone.0100416
PMCID: PMC4081027  PMID: 24992590
24.  A rational free energy-based approach to understanding and targeting disease-causing missense mutations 
Background and significance
Intellectual disability is a condition characterized by significant limitations in cognitive abilities and social/behavioral adaptive skills and is an important reason for pediatric, neurologic, and genetic referrals. Approximately 10% of protein-encoding genes on the X chromosome are implicated in intellectual disability, and the corresponding intellectual disability is termed X-linked ID (XLID). Although few mutations and a small number of families have been identified and XLID is rare, collectively the impact of XLID is significant because patients usually are unable to fully participate in society.
Objective
To reveal the molecular mechanisms of various intellectual disabilities and to suggest small molecules which by binding to the malfunctioning protein can reduce unwanted effects.
Methods
Using various in silico methods we reveal the molecular mechanism of XLID in cases involving proteins with known 3D structure. The 3D structures were used to predict the effect of disease-causing missense mutations on the folding free energy, conformational dynamics, hydrogen bond network and, if appropriate, protein-protein binding free energy.
Results
It is shown that the vast majority of XLID mutation sites are outside the active pocket and are accessible from the water phase, thus providing the opportunity to alter their effect by binding appropriate small molecules in the vicinity of the mutation site.
Conclusions
This observation is used to demonstrate, computationally and experimentally, that a particular condition, Snyder-Robinson syndrome caused by the G56S spermine synthase mutation, might be ameliorated by small molecule binding.
doi:10.1136/amiajnl-2012-001505
PMCID: PMC3721167  PMID: 23408511
In Silico Modeling; Experimenatal Measurements; Mental Disorders; Missense Mutation; Small Molecule Screening
25.  Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5 
eLife  2014;3:e02687.
Rabex-5 and Rabaptin-5 function together to activate Rab5 and further promote early endosomal fusion in endocytosis. The Rabex-5 GEF activity is autoinhibited by the Rabex-5 CC domain (Rabex-5CC) and activated by the Rabaptin-5 C2-1 domain (Rabaptin-5C21) with yet unknown mechanism. We report here the crystal structures of Rabex-5 in complex with the dimeric Rabaptin-5C21 (Rabaptin-5C212) and in complex with Rabaptin-5C212 and Rab5, along with biophysical and biochemical analyses. We show that Rabex-5CC assumes an amphipathic α-helix which binds weakly to the substrate-binding site of the GEF domain, leading to weak autoinhibition of the GEF activity. Binding of Rabaptin-5C21 to Rabex-5 displaces Rabex-5CC to yield a largely exposed substrate-binding site, leading to release of the GEF activity. In the ternary complex the substrate-binding site of Rabex-5 is completely exposed to bind and activate Rab5. Our results reveal the molecular mechanism for the regulation of the Rabex-5 GEF activity.
DOI: http://dx.doi.org/10.7554/eLife.02687.001
eLife digest
Cells need to allow various molecules to pass through the plasma membrane on their surface. Some molecules have to enter the cell, whereas others have to leave. Cells rely on a process called endocytosis to move large molecules into the cell. This involves part of the membrane engulfing the molecule to form a ‘bubble’ around it. This bubble, which is called an endosome, then moves the molecule to final destination inside the cell.
A protein called Rab5 controls how a new endosome is produced. However, before this can happen, various other molecules—including two proteins called Rabex-5 and Rabaptin-5—must activate the Rab5 protein. Exactly how these three proteins interact with each other was unknown.
Zhang et al. used X-ray crystallography to examine the structures of the complexes formed when Rabex-5 and Rabaptin-5 bind to each other, both when Rab5 is present, and also when it is absent. Biochemical and biophysical experiments confirmed that the Rabex-5/Rabaptin-5 complex is able to activate Rab5.
Zhang et al. also found that Rabex-5, on its own, folds so that the site that normally binds to Rab5 instead binds to a different part of Rabex-5, thus preventing endocytosis. However, when Rabaptin-5 forms a complex with Rabex-5, the Rab5 binding site is freed up.
The Rabex-5/Rabaptin-5 complex can switch between a V shape and a linear structure. Binding to Rab5 stabilizes the linear form of the complex, which then helps activate Rab5, and subsequently the activated Rab5 can interact with other downstream molecules, triggering endocytosis.
DOI: http://dx.doi.org/10.7554/eLife.02687.002
doi:10.7554/eLife.02687
PMCID: PMC4102244  PMID: 24957337
crystal structure; Rab5; rabex-5; Rabaptin-5; GEF activity; molecular mechanism; E. coli; human

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