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1.  Pharmacokinetics and pharmacodynamics of levofloxacin injection in healthy Chinese volunteers and dosing regimen optimization 
Cao, G | Zhang, J | Wu, X | Yu, J | Chen, Y | Ye, X | Zhu, D | Zhang, Y | Guo, B | Shi, Y
What is known and objective
The pharmacokinetics (PK) and pharmacodynamics (PD) of levofloxacin were investigated following administration of levofloxacin injection in healthy Chinese volunteers for optimizing dosing regimen.
Methods
The PK study included single-dose (750 mg/150 mL) and multiple-dose (750 mg/150 mL once daily for 7 days) phases. The concentration of levofloxacin in blood and urine was determined using HPLC method. Both non-compartmental and compartmental analyses were performed to estimate PK parameters. Taking fCmax/MIC ≥5 and fAUC24 h/MIC ≥30 as a target, the cumulative fraction of response (CFR) of levofloxacin 750 mg for treatment of community-acquired pneumonia (CAP) was calculated using Monte Carlo simulation. The probability of target attainment (PTA) of levofloxacin at various minimal inhibitory concentrations (MICs) was also evaluated.
Results and discussion
The results of PK study showed that the Cmax and AUC0–∞ of levofloxacin were 14·94 μg/mL and 80·14 μg h/mL following single-dose infusion of levofloxacin. The half-life and average cumulative urine excretion ratio within 72 h post-dosing were 7·75 h and 86·95%, respectively. The mean Css,max, Css,min and AUC0–τ of levofloxacin at steady state following multiple doses were 13·31 μg/mL, 0·031 μg/mL and 103·7 μg h/mL, respectively. The accumulation coefficient was 1·22. PK/PD analysis revealed that the CFR value of levofloxacin 750-mg regimen against Streptococcus pneumoniae was 96·2% and 95·4%, respectively, in terms of fCmax/MIC and fAUC/MIC targets.
What is new and conclusion
The regimen of 750-mg levofloxacin once daily provides a satisfactory PK/PD profile against the main pathogenic bacteria of CAP, which implies promising clinical and bacteriological efficacy for patients with CAP. A large-scale clinical study is warranted to confirm these results.
doi:10.1111/jcpt.12074
PMCID: PMC4285945  PMID: 23701411
healthy volunteer; levofloxacin; Monte Carlo simulation; pharmacodynamics; pharmacokinetics
2.  HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts 
Cell Death and Differentiation  2013;20(12):1675-1687.
Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs); however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named ‘hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients. We show that these T-UCRs are predominantly nuclear and that the hypoxia-inducible factor (HIF) is at least partly responsible for the induction of several members of this group. One specific HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host protein-coding gene, O-linked N-acetylglucosamine transferase, which is overexpressed in epithelial cancer types. Consistent with the hypothesis that T-UCRs have important function in tumor formation, HINCUT-1 supports cell proliferation specifically under hypoxic conditions and may be critical for optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data gives a first glimpse of a novel functional hypoxic network comprising protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.
doi:10.1038/cdd.2013.119
PMCID: PMC3824588  PMID: 24037088
ultraconserved genes; colorectal cancer; glioblastoma; hypoxia; OGT
3.  Comparisons of vaginal and abdominal radical trachelectomy for early-stage cervical cancer: preliminary results of a multi-center research in China 
British Journal of Cancer  2013;109(11):2778-2782.
Background:
There are limited data comparing the prognosis and fertility outcomes of the patients with early cervical cancer treated by trans-vaginal radical trachelectomy (VRT) or abdominal radical trachelectomy (ART).The objective of this study was to compare the surgical and pathologic characteristics, the prognosis and fertility outcomes of the patients treated by VRT or ART.
Methods:
Matched-case study based on a prospectively maintained database of patients underwent radical trachelectomy in 10 centres of China was designed to compare the prognosis and fertility outcomes of the patients treated by VRT or ART.
Results:
Totally 150 cases, 77 in the VRT and 73 in the ART group, were included. VRT and ART provide similar surgical and pathological outcomes except larger specimens obtained by ART. In the ART group, no patient developed recurrent diseases, but, in the VRT group, 7 (9.8%) patients developed recurrent diseases and 2 (1.6%) patients died of the tumours (P=0.035). The rate of pregnancy in the VRT group was significantly higher than those of ART (39.5% vs 8.8% P=0.003). The patients with tumour size >2 cm showed significant higher recurrent rate (11.6% vs 2.4%, P<0.05) and lower pregnant rate (12.5% vs 32.1%, P=0.094) compared with the patients with tumour size <2 cm.
Conclusion:
Patients treated by ART obtained better oncology results, but their fertility outcomes were unfavourable compared with VRT. Tumour size <2 cm should be emphasised as an indication for radical trachelectomy for improving the outcome of fertility and prognosis.
doi:10.1038/bjc.2013.656
PMCID: PMC3844910  PMID: 24169350
radical trachelectomy; cervical cancer; fertility; prognosis
4.  The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis 
Cell Death and Differentiation  2013;20(11):1485-1497.
Oncogenic stimuli trigger the DNA damage response (DDR) and induction of the alternative reading frame (ARF) tumor suppressor, both of which can activate the p53 pathway and provide intrinsic barriers to tumor progression. However, the respective timeframes and signal thresholds for ARF induction and DDR activation during tumorigenesis remain elusive. Here, these issues were addressed by analyses of mouse models of urinary bladder, colon, pancreatic and skin premalignant and malignant lesions. Consistently, ARF expression occurred at a later stage of tumor progression than activation of the DDR or p16INK4A, a tumor-suppressor gene overlapping with ARF. Analogous results were obtained in several human clinical settings, including early and progressive lesions of the urinary bladder, head and neck, skin and pancreas. Mechanistic analyses of epithelial and fibroblast cell models exposed to various oncogenes showed that the delayed upregulation of ARF reflected a requirement for a higher, transcriptionally based threshold of oncogenic stress, elicited by at least two oncogenic ‘hits', compared with lower activation threshold for DDR. We propose that relative to DDR activation, ARF provides a complementary and delayed barrier to tumor development, responding to more robust stimuli of escalating oncogenic overload.
doi:10.1038/cdd.2013.76
PMCID: PMC3792440  PMID: 23852374
ARF; carcinogenesis; DDR; E2F1; p16INK4A
5.  Inhibition of phosphodiesterase 5 reduces bone mass by suppression of canonical Wnt signaling 
Cell Death & Disease  2014;5(11):e1544-.
Inhibitors of phosphodiesterase 5 (PDE5) are widely used to treat erectile dysfunction and pulmonary hypertension in clinics. PDE5, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) are important components of the non-canonical Wnt signaling. This study aimed to investigate the effect of PDE5 inhibition on canonical Wnt signaling and osteoblastogenesis, using both in vitro cell culture and in vivo animal models. In the in vitro experiments, PDE5 inhibition resulted in activation of cGMP-dependent protein kinase 2 and consequent inhibition of glycogen synthase kinase 3β phosphorylation, destabilization of cytosolic β-catenin and the ultimate suppression of canonical Wnt signaling and reduced osteoblastic differentiation in HEK293T and C3H10T1/2 cells. In animal experiments, systemic inhibition of PDE5 suppressed the activity of canonical Wnt signaling and osteoblastogenesis in bone marrow-derived stromal cells, resulting in the reduction of bone mass in wild-type adult C57B/6 mice, significantly attenuated secreted Frizzled-related protein-1 (SFRP1) deletion-induced activation of canonical Wnt signaling and excessive bone growth in adult SFRP1−/− mice. Together, these results uncover a hitherto uncharacterized role of PDE5/cGMP/PKG signaling in bone homeostasis and provide the evidence that long-term treatment with PDE5 inhibitors at a high dosage may potentially cause bone catabolism.
doi:10.1038/cddis.2014.510
PMCID: PMC4260761  PMID: 25429621
6.  Ovariectomy and genes encoding core circadian regulatory proteins in murine bone 
Summary
This study investigated the influence of ovarian hormone deficiency on core circadian regulatory protein (CCRP) in the context of bone loss. Our data suggest that ovarian hormone deficiency disrupts diurnal rhythmicity and CCRP expression in bone. Further studies should determine if chronobiology provides a novel therapeutic target for osteoporosis intervention.
Introduction
CCRP synchronize metabolic activities and display an oscillatory expression profile in murine bone. In vitro studies using bone marrow mesenchymal stromal/stem cells have demonstrated that the CCRP is present and can be regulated within osteoblast progenitors. In vivo studies have shown that the CCRP regulates bone mass via leptin/neuroendocrine pathways. The current study used an ovariectomized murine model to test the hypothesis that ovarian hormone deficiency is associated with either an attenuation and/or temporal phase shift of the CCRP oscillatory expression in bone and that these changes are correlated with the onset of osteoporosis.
Methods
Sham-operated controls and ovariectomized female C57BL/6 mice were euthanized at 4-h intervals 2 weeks post-operatively.
Results
Ovariectomy attenuated the oscillatory expression of CCRP mRNAs in the femur and vertebra relative to the controls and reduced the wheel-running activity profile.
Conclusion
Ovarian hormone deficiency modulates the expression profile of the CCRP with potential impact on bone marrow mesenchymal stem cell lineage commitment.
doi:10.1007/s00198-010-1325-z
PMCID: PMC4215737  PMID: 20593165
Diurnal; Estrogen; Mesenchymal stem cell; Osteoporosis
7.  Epigenomic alterations define lethal CIMP-positive ependymomas of infancy 
Nature  2014;506(7489):445-450.
Ependymomas are common childhood brain tumours that occur throughout the nervous system, but are most common in the paediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival. Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants. Although devoid of recurrent single nucleotide variants and focal copy number aberrations, poor-prognosis hindbrain ependymomas exhibit a CpG island methylator phenotype. Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27. CpG island methylator phenotype-positive hindbrain ependymomas are responsive to clinical drugs that target either DNA or H3K27 methylation both in vitro and in vivo. We conclude that epigenetic modifiers are the first rational therapeutic candidates for this deadly malignancy, which is epigenetically deregulated but genetically bland.
doi:10.1038/nature13108
PMCID: PMC4174313  PMID: 24553142
8.  Alterations of Directional Connectivity among Resting-State Networks in Alzheimer Disease 
BACKGROUND AND PURPOSE
AD has been documented as a kind of disconnection syndrome by functional neuroimaging studies. The primary focus of this study was to examine, with the use of resting-state fMRI, whether AD would impact connectivity among RSNs.
MATERIALS AND METHODS
Fourteen patients with AD and 16 NC were recruited and scanned by using resting-state fMRI. Group ICA and the BN learning approach were used, respectively, to separate the RSNs and construct the network-to-network connectivity patterns for each group. The convergence index for the special network DMN was measured.
RESULTS
Three of the 4 connections were significantly lower in AD compared with NC. Although numerically the AD group had more connections, none was statistically different from that in the NC group except for 1 increased connection from the DMN to the DAN. The convergence index for the DMN node was lower in AD than in NC.
CONCLUSIONS
Connections among cognitive networks in AD were more vulnerable to impairment than sensory networks. The DMN decreased its integration function for other RSNs but may also play a role in compensating for the disrupted connections in AD.
doi:10.3174/ajnr.A3197
PMCID: PMC4097966  PMID: 22790250
9.  IL-1 receptor antagonist gene as a predictive biomarker of progression of knee osteoarthritis in a population cohort 
Objective
Within the interleukin-1 (IL-1) cytokine family, IL-1 receptor antagonist (IL1RN) gene variants have been associated with radiological severity of knee osteoarthritis (OA) in cross-sectional studies. The present study tested the relation between IL1RN gene variants and progression of knee OA assessed radiographically by change in Kellgren-Lawrence (KL) score over time.
Design
1153 Caucasian adults (age range 44-89) from the Johnson County Osteoarthritis Project were evaluated for unequivocal radiographic evidence of knee OA at baseline, defined as KL score ≥ 2, and were re-examined after 4-11 years for radiographic changes typical of OA progression. IL1RN gene variants were tested for association with OA progression and for potential interaction with body mass index (BMI). Other IL-1 gene variations were tested for association with OA progression as a secondary objective.
Results
Of 154 subjects with OA at baseline, 88 showed progression at follow-up. Seven IL1RN single nucleotide polymorphisms (SNPs) and one IL-1 receptor SNP were associated with progression. Four IL1RN haplotypes, each occurring in >5% of this population, showed different relationships with progression, including one (rs315931/rs4251961/rs2637988/rs3181052/rs1794066/rs419598/rs380092/ rs579543/rs315952/rs9005/rs315943/rs1374281; ACAGATACTGCC) associated with increased progression (OR 1.91 (95%CI 1.16-3.15), p = 0.012). Haplotypes associated with progression by KL score were also associated with categorical change in joint space narrowing. BMI was associated with OA progression in subjects carrying a specific IL1RN haplotype, but not in subjects without that haplotype.
Conclusion
A significantly greater likelihood of radiological progression of knee OA was associated with a commonly occurring IL1RN haplotype that could be tagged by three IL1RN SNPs (rs419598, rs9005, rs315943). Interactions were also observed between IL1RN gene variants and BMI relative to OA progression. This suggests that IL1RN gene markers may be useful in stratifying patients for medical management and drug development.
doi:10.1016/j.joca.2013.04.003
PMCID: PMC3725144  PMID: 23602982
osteoarthritis; progression; Interleukin-1; genetics; population stratification; predictive biomarker
10.  Fluid intake, genetic variants of UDP-glucuronosyltransferases, and bladder cancer risk 
British Journal of Cancer  2013;108(11):2372-2380.
Background:
Results of studies of fluid consumption and its association with bladder cancer have been inconsistent. Few studies have considered modification effects from genetic variants that may interact with the type of consumed fluids. UDP-glucuronosyltransferases (UGTs), which are membrane-bound conjugating enzymes, catalyse the transformation of hydrophobic substrates to more water-soluble glucuronides to facilitate renal or biliary excretion. Whether genetic variants in UGTs could modulate the association between fluid intake and bladder cancer has not been studied.
Methods:
We conducted a case–control study with 1007 patients with histopathologically confirmed bladder cancer and 1299 healthy matched controls. Fluid intake and epidemiologic data were collected via in-person interview. Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI).
Results:
After adjustment for potential confounders, high quantity of total fluid intake (⩾2789 vs <1696 ml per day) conferred a 41% increased risk of bladder cancer (OR=1.41; 95% CI=1.10–1.81). Specific fluids such as regular soft drinks and decaffeinated coffee were also associated with increased risks, whereas tea, wine, and liquor were associated with decreased risks. Among 83 single-nucleotide polymorphisms in the UGT gene family, 18 were significantly associated with bladder cancer risk. The most significant one was rs7571337, with the variant genotype conferring a 29% reduction in risk (OR=0.71; 95% CI=0.56–0.90).
Conclusions:
Total and specific fluid intakes are associated with bladder cancer risk in the study population and that genetic variants of UGT genes could modulate the effects. These results facilitate identification of high-risk individuals and have important implications in bladder cancer prevention.
doi:10.1038/bjc.2013.190
PMCID: PMC3681021  PMID: 23632476
bladder cancer; fluid intake; UDP-glucuronosyltransferase; genetic polymorphism
11.  TALEN-mediated genetic tailoring as a tool to analyze the function of acquired mutations in multiple myeloma cells 
Blood Cancer Journal  2014;4(5):e210-.
Multiple myeloma (MM) is a clonal plasma cell malignancy that is initiated by a number of mutations and the process of disease progression is characterized by further acquisition of mutations. The identification and functional characterization of these myelomagenic mutations is necessary to better understand the underlying pathogenic mechanisms in this disease. Recent advancements in next-generation sequencing have made the identification of most of these mutations a reality. However, the functional characterization of these mutations has been hampered by the lack of proper and efficient tools to dissect these mutations. Here we explored the possible utility of transcription activator-like effector nuclease (TALEN) genome engineering technology to tailoring the genome of MM cells. To test this possibility, we targeted the HPRT1 gene and found that TALENs are a very robust and efficient genome-editing tool in MM cells. Using cotransfected green fluorescent protein as an enrichment marker, single-cell subclones with desirable TALEN modifications in the HPRT1 gene were obtained in as little as 3–4 weeks of time. We believe that TALENs will greatly facilitate the functional study of somatic mutations in MM as well as other cancers.
doi:10.1038/bcj.2014.32
PMCID: PMC4042302  PMID: 24813078
12.  Scattering Coefficients of Mice Organs Categorized Pathologically by Spectral Domain Optical Coherence Tomography 
BioMed Research International  2014;2014:471082.
Differences in tissue density cause a variety of scattering coefficients. To quantify optical coherence tomography (OCT) images for diagnosis, the tissue's scattering coefficient is estimated by curve fitting the OCT signals to a confocal single backscattering mode. The results from a group of 30 mice show that the scattering coefficients of bone, skin, liver, brain, testis, and spleen can be categorized into three groups: a scattering coefficient between 1.947 and 2.134 mm−1: bone and skin; a scattering coefficient between 1.303 and 1.461 mm−1: liver and brain; a scattering coefficient between 0.523 and 0.634 mm−1: testis and spleen. The results indicate that the scattering coefficient is tissue specific and could be used in tissue diagnosis.
doi:10.1155/2014/471082
PMCID: PMC4005150  PMID: 24822213
13.  CD123 targeting oncolytic adenoviruses suppress acute myeloid leukemia cell proliferation in vitro and in vivo 
Li, G | Li, X | Wu, H | Yang, X | Zhang, Y | Chen, L | Wu, X | Cui, L | Wu, L | Luo, J | Liu, X Y
Blood Cancer Journal  2014;4(3):e194-.
We report here a novel strategy to redirect oncolytic adenoviruses to CD123 by carry a soluble coxsackie-adenovirus receptor (sCAR)-IL3 expression cassette in the viral genome to form Ad.IL3, which sustainably infected acute myeloid leukemia (AML) cells through CD123. Ad.IL3 was further engineered to harbor gene encoding manganese superoxide dismutase (MnSOD) or mannose-binding plant lectin Pinellia pedatisecta agglutinin (PPA), forming Ad.IL3-MnSOD and Ad.IL3-PPA. As compared with Ad.IL3 or Ad.sp-E1A control, Ad.IL3-MnSOD and Ad.IL3-PPA significantly suppressed in vitro proliferation of HL60 and KG-1 cells. Elevated apoptosis was detected in HL60 and KG-1 cells treated with either Ad.IL3-MnSOD or Ad.IL3-PPA. The caspase-9–caspase-7 pathway was determined to be activated by Ad.IL3-MnSOD as well as by Ad.IL3-PPA in HL60 cells. In an HL60/Luc xenograft nonobese diabetic/severe-combined immunodeficiency mice model, Ad.IL3-MnSOD and Ad.IL3-PPA suppressed cancer cell growth as compared with Ad.IL3. A significant difference of cancer cell burden was detected between Ad.IL3 and Ad.IL3-PPA groups at day 9 after treatment. Furthermore, Ad.IL3-MnSOD significantly prolonged mouse survival as compared with Ad.sp-E1A. These findings demonstrated that Ad.IL3-gene could serve as a novel agent for AML therapy. Harboring sCAR-ligand expression cassette in the viral genome may provide a universal method to redirect oncolytic adenoviruses to various membrane receptors on cancer cells resisting serotype 5 adenovirus infection.
doi:10.1038/bcj.2014.15
PMCID: PMC3972701  PMID: 24658372
14.  Feedback loops blockade potentiates apoptosis induction and antitumor activity of a novel AKT inhibitor DC120 in human liver cancer 
Cell Death & Disease  2014;5(3):e1114-.
The serine/threonine kinase AKT is generally accepted as a promising anticancer therapeutic target. However, the relief of feedback inhibition and enhancement of other survival pathways often attenuate the anticancer effects of AKT inhibitors. These compensatory mechanisms are very complicated and remain poorly understood. In the present study, we found a novel 2-pyrimidyl-5-amidothiazole compound, DC120, as an ATP competitive AKT kinase inhibitor that suppressed proliferation and induced apoptosis in liver cancer cells both in vitro and in vivo. DC120 blocked the phosphorylation of downstream molecules in the AKT signal pathway in dose- and time-dependent manners both in vitro and in vivo. However, unexpectedly, DC120 activated mammalian target of rapamycin complex 1 (mTORC1) pathway that was suggested by increased phosphorylation of 70KD ribosomal protein S6 kinase (P70S6K) and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). The activated mTORC1 signal was because of increase of intracellular Ca2+ via Ca2+/calmodulin (CaM)/ signaling to human vacuolar protein sorting 34 (hVps34) upon AKT inhibition. Meanwhile, DC120 attenuated the inhibitory effect of AKT on CRAF by decreasing phosphorylation of CRAF at Ser259 and thus activated the mitogen-activated protein kinase (MAPK) pathway. The activation of the mTORC1 and MAPK pathways by DC120 was not mutually dependent, and the combination of DC120 with mTORC1 inhibitor and/or MEK inhibitor induced significant apoptosis and growth inhibition both in vitro and in vivo. Taken together, the combination of AKT, mTORC1 and/or MEK inhibitors would be a promising therapeutic strategy for liver cancer treatment.
doi:10.1038/cddis.2014.43
PMCID: PMC3973233  PMID: 24625973
AKT inhibitor; apoptosis; MAPK pathway; mTOR complexes; PI3K/AKT pathway
15.  TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer 
Xu, W | Wang, S | Chen, Q | Zhang, Y | Ni, P | Wu, X | Zhang, J | Qiang, F | Li, A | Røe, O D | Xu, S | Wang, M | Zhang, R | Zhou, J
Cell Death & Disease  2014;5(2):e1055-.
Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.
doi:10.1038/cddis.2014.27
PMCID: PMC3944244  PMID: 24525731
cisplatin; gastric cancer; drug resistance; XRCC1; TXNL1
16.  Single-photon property characterization of 1.3 μm emissions from InAs/GaAs quantum dots using silicon avalanche photodiodes 
Scientific Reports  2014;4:3633.
We developed a new approach to test the single-photon emissions of semiconductor quantum dots (QDs) in the optical communication band. A diamond-anvil cell pressure device was used for blue-shifting the 1.3 μm emissions of InAs/GaAs QDs to 0.9 μm for detection by silicon avalanche photodiodes. The obtained g(2)(0) values from the second-order autocorrelation function measurements of several QD emissions at 6.58 GPa were less than 0.3, indicating that this approach provides a convenient and efficient method of characterizing 1.3 μm single-photon source based on semiconductor materials.
doi:10.1038/srep03633
PMCID: PMC3887382  PMID: 24407193
17.  Nox4 and redox signaling mediate TGF-β-induced endothelial cell apoptosis and phenotypic switch 
Cell Death & Disease  2014;5(1):e1010-.
Transforming growth factor-β (TGF-β) triggers apoptosis in endothelial cells, while the mechanisms underlying this action are not entirely understood. Using genetic and pharmacological tools, we demonstrated that TGF-β induced a moderate apoptotic response in human cultured endothelial cells, which was dependent upon upregulation of the Nox4 NADPH oxidase and production of reactive oxygen species (ROS). In contrast, we showed that ectopic expression of Nox4 via viral vectors (vNox4) produced an antiapoptotic effect. TGF-β caused ROS-dependent p38 activation, whereas inhibition of p38 blunted TGF-β-induced apoptosis. However, vNox4, but not TGF-β, activated Akt, and inhibition of Akt attenuated the antiapoptotic effect of vNox4. Akt activation induced by vNox4 was accompanied by inactivation of the protein tyrosine phosphatase-1B (PTP1B) function and enhanced vascular endothelial growth factor receptor (VEGFR)-2 phosphorylation. Moreover, we showed that TGF-β enhanced Notch signaling and increased expression of the arterial marker EphrinB2 in a redox-dependent manner. In summary, our results suggest that Nox4 and ROS have pivotal roles in mediating TGF-β-induced endothelial apoptosis and phenotype specification. Redox mechanisms may influence endothelial cell functions by modulating p38, PTP1B/VEGFR/Akt and Notch signaling pathways.
doi:10.1038/cddis.2013.551
PMCID: PMC4040700  PMID: 24457954
transforming growth factor-β; apoptosis; endothelial cell; Nox4; p38; arterial–venous specification
18.  A NANOS3 mutation linked to protein degradation causes premature ovarian insufficiency 
Wu, X | Wang, B | Dong, Z | Zhou, S | Liu, Z | Shi, G | Cao, Y | Xu, Y
Cell Death & Disease  2013;4(10):e825-.
Primary ovarian insufficiency (POI), or premature ovarian failure, is defined as the cessation of ovarian function before the age of 40. An insufficient ovarian follicle pool derived from primordial germ cells (PGCs) is an important cause of POI. Although the Nanos gene family is known to be required for PGC development and maintenance in diverse model organisms, the relevance of this information to human biology is not yet clear. In this study, we screened the coding regions of the NANOS1, NANOS2 and NANOS3 genes in 100 Chinese POI patients and identified four variants in the coding regions of these three genes, including one synonymous variant in NANOS3, one missense variant in each of NANOS1 and NANOS2 and one potentially relevant mutation (c.457C>T; p.Arg153Trp, heterozygous) in NANOS3. We demonstrated that the p.Arg153Trp substitution decreases the stability of NANOS3, potentially resulting in a hypomorph. Furthermore, an investigation of the relationship between the number of PGCs and the dosage of NANOS3 in mouse models showed that the population of PGCs is controlled by the level of NANOS3 protein. Taken together, our results provide new insight into the properties of the NANOS3 protein and establish that NANOS3 mutation is one possible cause of POI.
doi:10.1038/cddis.2013.368
PMCID: PMC3824677  PMID: 24091668
POI; PGCs; NANOS3; human genetics; mouse model
19.  OCT4 promotes tumorigenesis and inhibits apoptosis of cervical cancer cells by miR-125b/BAK1 pathway 
Cell Death & Disease  2013;4(8):e760-.
Octamer-binding transcription factor 4 (OCT4) is a key regulatory gene that maintains the pluripotency and self-renewal properties of embryonic stem cells. Although there is emerging evidence that it can function as oncogene in several cancers, the role in mediating cervical cancer remains unexplored. Here we found that OCT4 protein expression showed a pattern of gradual increase from normal cervix to cervical carcinoma in situ and then to invasive cervical cancer. Overexpression of OCT4 in two types of cervical cancer cells promotes the carcinogenesis, and inhibits cancer cell apoptosis. OCT4 induces upregulation of miR-125b through directly binding to the promoter of miR-125b-1 confirmed by chromatin immunoprecipitation analysis. MiRNA-125b overexpression suppressed apoptosis and expression of BAK1 protein. In contrast, miR-125b sponge impaired the anti-apoptotic effect of OCT4, along with the upregulated expression of BAK1. Significantly, Luciferase assay showed that the activity of the wild-type BAK1 3′-untranslated region reporter was suppressed and this suppression was diminished when the miR-125b response element was mutated or deleted. In addition, we observed negative correlation between levels of BAK1 and OCT4, and positive between OCT4 and miR-125b in primary cervical cancers. These findings suggest an undescribed regulatory pathway in cervical cancer, by which OCT4 directly induces expression of miR-125b, which inhibits its direct target BAK1, leading to suppression of cervical cancer cell apoptosis.
doi:10.1038/cddis.2013.272
PMCID: PMC3763434  PMID: 23928699
OCT4; cervical cancer; apoptosis; miR-125b-1; BAK1
20.  A robust general phase retrieval method for medical applications 
From medical imaging perspective the robustness of a phase retrieval method is of critical importance. In this presentation we compare the robustness of two general phase retrieval methods, namely the transport of intensity equation inversion (TIE-inversion) method and the attenuation partition based (AP-based) method. We showed that the TIE-inversion method, regardless if being assisted with the Tikhonov regularization, failed to retrieve the phase maps in two experimental studies. The failure exposes this method’s weakness as being unstable against the noise. In contrast, the sample phase maps are retrieved successfully by using the AP-based method. The stark performance differences of the two methods are rooted in their different techniques dealing with the singularity problem. This comparison shows that the robust AP-based phase retrieval method will be superior to the TIE-inversion method for medical imaging applications where radiation doses are stringently limited.
doi:10.1088/1748-0221/8/05/C05007
PMCID: PMC3721370  PMID: 23894250
Medical-image reconstruction methods and algorithms; computer-aided so; X-ray radiography and digital radiography (DR)
21.  Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies 
Heredity  2012;109(1):34-40.
Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the ‘standard vegetable' type (subgroup SV) and the ‘non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r2) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0–2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈5 cM) five times longer than the shortest (≈1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform.
doi:10.1038/hdy.2012.8
PMCID: PMC3375410  PMID: 22378357
asparagus bean; association mapping; cowpea; domestication history; linkage disequilibrium; population structure
22.  Quantitative analysis of rectal cancer by spectral domain optical coherence tomography 
Physics in medicine and biology  2012;57(16):5235-5244.
To quantify OCT images of rectal tissue for clinic diagnosis, the scattering coefficient of the tissue is extracted by curve fitting the OCT signals to a confocal single model. A total of 1000 measurements (half and half of normal and malignant tissues) were obtained from 16 recta. The normal rectal tissue has a larger scattering coefficient ranging from 1.09 to 5.41 mm–1 with a mean value of 2.29 mm–1 (std: ± 0.32), while the malignant group shows lower scattering property and the values ranging from 0.25 to 2.69 mm–1 with a mean value of 1.41 mm–1 (std: ± 0.18). The peri-cancer of recta has also been investigated to distinguish the difference between normal and malignant rectal tissue. The results demonstrate that the quantitative analysis of the rectal tissue can be used as a promising diagnostic criterion of early rectal cancer, which has great value for clinical medical applications.
doi:10.1088/0031-9155/57/16/5235
PMCID: PMC3691818  PMID: 22850124
24.  Safety and efficacy of intravitreal injection of recombinant erythropoietin for protection of photoreceptor cells in a rat model of retinal detachment 
Xie, Z | Chen, F | Wu, X | Zhuang, C | Zhu, J | Wang, J | Ji, H | Wang, Y | Hua, X
Eye  2011;26(1):144-152.
Purpose
To elucidate the safety and efficacy of exogenous erythropoietin (EPO) for the protection of photoreceptor cells in a rat model of retinal detachment (RD).
Methods
Recombinant rat EPO (400 ng) was injected into the vitreous cavity of normal rats to observe the eye manifestations. Retinal function was assessed by flash electroretinograms. Histopathological examination of retinal tissue was performed at 14 days and 2 months after injection, respectively. To investigate the inhibitory effect of EPO on photoreceptor cell apoptosis in RD rats, 100, 200, or 400 ng EPO was injected into the vitreous cavity immediately after RD model establishment. Apoptosis of photoreceptor cells was determined at 3 days after injection. Caspase-3 activation was measured by western blot analysis and immunofluorescence, respectively, and the level of Bcl-XL expression was analyzed by western blot.
Results
Intravitreal injection of EPO 400 ng into normal rats had no significant impact on retinal function, morphology, or structure. Apoptosis of retinal photoreceptor cells apparently increased after RD and was significantly reduced following EPO treatment. The thickness of the outer nuclear layer in the RD+400 ng group was significantly thicker than that in other experimental RD groups both at 14 days and at 2 months after RD (P<0.05). Western blot and immunofluorescence analyses showed decreased caspase-3 activation and increased Bcl-XL expression following EPO treatment.
Conclusion
Intravitreal injection of EPO 400 ng is safe, and EPO may suppress caspase-3 activation and enhance Bcl-XL expression, resulting in inhibition of apoptosis and protection of photoreceptor cells.
doi:10.1038/eye.2011.254
PMCID: PMC3259587  PMID: 22020175
erythropoietin; retinal detachment/experimental; flash electroretinogram; apoptosis
25.  RESISTANCE TO ANNEXIN A5 ANTICOAGULANT ACTIVITY IN WOMEN WITH HISTORIES FOR OBSTETRIC ANTIPHOSPHOLIPID SYNDROME 
American journal of obstetrics and gynecology  2011;205(5):485.e17-485.e23.
Objectives
To investigate whether resistance to annexin A5 anticoagulant activity (AnxA5) occurs in women with histories for obstetric complications of antiphospholipid syndrome (Obs-APS) and whether this correlates with antibody recognition of domain 1 of β2- glycoprotein.
Study Design
136 women with antiphospholipid antibodies, including 70 with histories for Obs-APS, and 30 controls, were investigated.
Results
Women with Obs-APS showed resistance to AnxA5 activity (median (range) 216% (130-282%) vs. controls 247% (217-283%), p<0.0001) and elevated levels of anti-domain I IgG (OD: median (range) 0.056 (0.021-0.489) vs. 0.042 (0.020-0.323); p=0.002). Those in the lowest tertile of AnxA5 anticoagulant ratios had an OR for Obs-APS APS of 58.0 (95% CI 3.3-1021.5). There was an inverse correlation between levels of annexin A5 anticoagulant activity and anti-domain I IgG.
Conclusions
Resistance to AnxA5 anticoagulant activity is associated with antibody recognition of domain I of β2GPI and identifies a subset of women with histories for Obs-APS.
doi:10.1016/j.ajog.2011.06.019
PMCID: PMC3205287  PMID: 21784397
annexin V; obstetric; Antiphospholipid antibodies; Antiphospholipid syndrome; Annexin A5; β2-glycoprotein I; Pregnancy loss

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