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1.  Molecular diagnosis and comprehensive treatment of multiple endocrine neoplasia type 2 in Southeastern Chinese 
Background
Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited endocrine malignancy syndrome. Early and normative surgery is the only curative method for MEN 2-related medullary thyroid carcinoma (MTC). In patients with adrenal pheochromocytoma, cortical-sparing adrenalectomy (CSA) can be utilized to preserve adrenocortical function.
Methods
We present twenty-six of 33 MEN2 patients underwent prophylactic thyroidectomy with varying neck dissection and eight of 24 MEN2A patients with PHEO underwent adrenal-sparing surgery. Direct sequencing of entire RET exons was performed in all participants.
Results
The RET mutations (p.C634Y [n = 10], p.C634R [n = 9], p.C634F [n = 2], p.C618Y [n = 8], p.C618R [n = 3], and p.M918T [n = 1]) were confirmed in 20 symptomatic patients and identified in 13 at-risk relatives (RET carriers). Twenty-six of 33 MEN2 patients underwent thyroidectomies with neck dissections; the mean age at the time of the first thyroid surgery and the tumor diameter of the 6 RET carriers was decreased compared with 20 symptomatic patients (P < 0.001 and P = 0.007, respectively), while the disease-free survival was increased (80% vs.10%, P = 0.0001). Seven RET carriers who were declined surgery. One of 20 symptomatic patients with MTC bone metastases after surgery received vandetanib therapy for 20 months and responded well. Additionally, 8 of 24 MEN2A patients who initially had unilateral pheochromocytomas underwent CSA, 1 developed contralateral pheochromo cytomas 10 years later, then also accepted and also agreed to a CSA. None of the patients required steroid replacement therapy.
Conclusions
Based on our results, integrated RET screening and the pre-operative calcitonin level is an excellent strategy to ensure earlier diagnosis and standard thyroidectomy. CSA can be utilized to preserve adrenocortical function in patients with pheochromocytomas.
doi:10.1186/s13053-015-0026-1
PMCID: PMC4307225  PMID: 25628771
Multiple endocrine neoplasia type 2; Mutation screening; RET; Prophylactic thyroidectomy; Cortical-sparing adrenalectomy
2.  Intensity modulated radiotherapy for locally advanced and metastatic pancreatic cancer: a mono-institutional retrospective analysis 
Background
To evaluate the role of intensity modulated radiotherapy (IMRT) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC), and the prognostic factors in the setting of multidisciplinary approach strategies.
Methods
63 patients with LAPC and MPC receiving IMRT in our institution were retrospectively identified. Information on patient baseline, treatment characteristics and overall survival (OS) time were collected. Data of pain relief and toxicity were evaluated. Univariate and multivariate analyses were conducted to investigate the prognostic factors.
Results
All patients received IMRT with a median dose of 46.0 Gy. The median OS for LAPC and MPC patients were 15.7 months and 8.0 months, respectively (p = 0.029). Symptomatic improvements were observed in the 44 patients with abdominal/back pain after radiotherapy (RT) or concurrent chemoradiotherapy (CCRT), particularly in those with severe pain. Only 13.9% and 14.8% cases presented Grade ≥ 3 hematologic toxicities in RT and CCRT group, while no cases developed Grade ≥ 3 non-hematologic toxicities in both groups. Multivariate analysis indicated that tumors located in pancreas body/tail (HR 0.28, p = 0.008), pretreatment CA19-9 < 1000 U/mL (HR 0.36, p = 0.029) and concurrent chemotherapy (HR 0.37, p = 0.016) were independent favorable predictors for OS.
Conclusions
CCRT further improved OS for LAPC and MPC with acceptable toxicities, and use of RT markedly alleviated pain. Tumors located in pancreas body/tail, pretreatment CA19-9 level of < 1000 U/mL and CCRT were associated with better OS. However, regional intra-arterial chemotherapy did not show any survival benefit in our study.
doi:10.1186/s13014-014-0312-5
PMCID: PMC4296685  PMID: 25575617
Locally advanced pancreatic cancer; Metastatic pancreatic cancer; Concurrent chemoradiotherapy; Intensity modulated radiotherapy; Regional intra-arterial chemotherapy
3.  Nicotiana Small RNA Sequences Support a Host Genome Origin of Cucumber Mosaic Virus Satellite RNA 
PLoS Genetics  2015;11(1):e1004906.
Satellite RNAs (satRNAs) are small noncoding subviral RNA pathogens in plants that depend on helper viruses for replication and spread. Despite many decades of research, the origin of satRNAs remains unknown. In this study we show that a β-glucuronidase (GUS) transgene fused with a Cucumber mosaic virus (CMV) Y satellite RNA (Y-Sat) sequence (35S-GUS:Sat) was transcriptionally repressed in N. tabacum in comparison to a 35S-GUS transgene that did not contain the Y-Sat sequence. This repression was not due to DNA methylation at the 35S promoter, but was associated with specific DNA methylation at the Y-Sat sequence. Both northern blot hybridization and small RNA deep sequencing detected 24-nt siRNAs in wild-type Nicotiana plants with sequence homology to Y-Sat, suggesting that the N. tabacum genome contains Y-Sat-like sequences that give rise to 24-nt sRNAs capable of guiding RNA-directed DNA methylation (RdDM) to the Y-Sat sequence in the 35S-GUS:Sat transgene. Consistent with this, Southern blot hybridization detected multiple DNA bands in Nicotiana plants that had sequence homology to Y-Sat, suggesting that Y-Sat-like sequences exist in the Nicotiana genome as repetitive DNA, a DNA feature associated with 24-nt sRNAs. Our results point to a host genome origin for CMV satRNAs, and suggest novel approach of using small RNA sequences for finding the origin of other satRNAs.
Author Summary
Satellite RNAs (satRNAs) are small RNA pathogens in plants that depend on associated viruses for replication and spread. While much is known about the replication and pathogenicity of satRNAs, their origin remains a mystery. We report evidence for a host genome origin of the Cucumber mosaic virus (CMV) satRNA. We show that only the CMV Y-satRNA (Y-Sat) sequence region of a fusion transgene was methylated in Nicotiana tabacum, indicating that the Y-Sat sequence is subject to 24-nt small RNA (sRNA)-directed DNA methylation. 24-nt sRNAs as well as multiple genomic DNA fragments, with sequence homology to Y-Sat, were detected in Nicotiana plants, suggesting that the Nicotiana genome contains Y-Sat-like repetitive DNA sequences, a genomic feature associated with 24-nt sRNAs. Our results suggest that CMV satRNAs have originated from repetitive DNA in the Nicotiana plant genome, and highlight the possibility that small RNA sequences can be used to identify the origin of other satRNAs.
doi:10.1371/journal.pgen.1004906
PMCID: PMC4287446  PMID: 25568943
4.  Crystal structure of N′-(2,6-di­methyl­phen­yl)benzene­carboximidamide tetra­hydro­furan monosolvate 
The asymmetric unit of the title compound, C15H16N2·C4H8O, contains two amidine mol­ecules (A and B) with slightly different conformations and two tetra­hydro­furan (THF) solvent mol­ecules. In the amidine mol­ecules, the di­methyl­phenyl ring and the NH2 group lie to the same side of the N=C bond and the dihedral angles between the aromatic rings are 54.25 (7) (mol­ecule A) and 58.88 (6) ° (mol­ecule B). In the crystal, N—H⋯N hydrogen bonds link the amidine mol­ecules into [100] C(4) chains of alternating A and B mol­ecules. Both amidine mol­ecules form an N—H⋯O hydrogen bond to an adjacent THF solvent mol­ecule.
doi:10.1107/S2056989014026255
PMCID: PMC4331870
crystal structure; benzene­carboximidamide; tetra­hydro­furan solvate; hydrogen bonding
5.  Intercropping Enhances Productivity and Maintains the Most Soil Fertility Properties Relative to Sole Cropping 
PLoS ONE  2014;9(12):e113984.
Yield and nutrient acquisition advantages are frequently found in intercropping systems. However, there are few published reports on soil fertility in intercropping relative to monocultures. A field experiment was therefore established in 2009 in Gansu province, northwest China. The treatments comprised maize/faba bean, maize/soybean, maize/chickpea and maize/turnip intercropping, and their correspoding monocropping. In 2011 (the 3rd year) and 2012 (the 4th year) the yields and some soil chemical properties and enzyme activities were examined after all crop species were harvested or at later growth stages. Both grain yields and nutrient acquisition were significantly greater in all four intercropping systems than corresponding monocropping over two years. Generally, soil organic matter (OM) did not differ significantly from monocropping but did increase in maize/chickpea in 2012 and maize/turnip in both years. Soil total N (TN) did not differ between intercropping and monocropping in either year with the sole exception of maize/faba bean intercropping receiving 80 kg P ha−1 in 2011. Intercropping significantly reduced soil Olsen-P only in 2012, soil exchangeable K in both years, soil cation exchangeable capacity (CEC) in 2012, and soil pH in 2012. In the majority of cases soil enzyme activities did not differ across all the cropping systems at different P application rates compared to monocrops, with the exception of soil acid phosphatase activity which was higher in maize/legume intercropping than in the corresponding monocrops at 40 kg ha−1 P in 2011. P fertilization can alleviate the decline in soil Olsen-P and in soil CEC to some extent. In summary, intercropping enhanced productivity and maintained the majority of soil fertility properties for at least three to four years, especially at suitable P application rates. The results indicate that maize-based intercropping may be an efficient cropping system for sustainable agriculture with carefully managed fertilizer inputs.
doi:10.1371/journal.pone.0113984
PMCID: PMC4259307  PMID: 25486249
6.  Utilisation of adsorption and desorption for simultaneously improving protein crystallisation success rate and crystal quality 
Scientific Reports  2014;4:7308.
High-quality protein crystals of suitable size are an important prerequisite for applying X-ray crystallography to determine the 3-dimensional structure of proteins. However, it is often difficult to obtain protein crystals of appropriate size and quality because nucleation and growth processes can be unsuccessful. Here, we show that by adsorbing proteins onto porous polystyrene-divinylbenzene microspheres (SDB) floating on the surface of the crystallisation solution, a localised high supersaturation region at the surface of the microspheres and a low supersaturation region below the microspheres can coexist in a single solution. The crystals will easily nucleate in the region of high supersaturation, but when they grow to a certain size, they will sediment to the region of low supersaturation and continue to grow. In this way, the probability of crystallisation and crystal quality can be simultaneously increased in a single solution without changing other crystallisation parameters.
doi:10.1038/srep07308
PMCID: PMC4255177  PMID: 25471817
7.  Correlation research on ADMA plasma levels and left ventricular function of peritoneal dialysis patients 
Asymmetric dimethylarginine (ADMA) has been involved in the development mechanism of cardiovascular disease (CVD) in patients with chronic kidney disease. The aim of this study is to investigate the relationship between the plasma ADMA levels and echocardiography, and understand the relationship between ADMA and left ventricular function. All of the patients were divided into three groups, including End-stage renal disease patients on CAPD, Conservative treatment in patients with ESRD and Control group. All the cases in the outpatient clinic or hospital at the next morning were collected fasting venous blood 2 ml. All cases were detected by American GE company Vivid7 Colour Doppler Ultrasonic Echocardiograph to detected left ventricular end-diastolic dimension (LVEDD), Left atrial diameter (LAD), Left ventricular posterior wall thickness in diastole (LVPWT), Interventricular septum thickness in diastole (IVST), left ventricular ejection fraction (LVEF). There were significant differences among all of the three groups for the GFR, urine albumin, SGA, Hb, iPTH and ALB levels. There was statistically significant difference for serum ADMA levels among three groups (F = 34.047, P = 0.000). CAPD patient plasma ADMA levels were negatively correlated with LVEF, and positively correlated with LVMI, LVM, LVEDD, LAD. Conservative treatment group had higher proportion of average artery, left ventricular hypertrophy and left ventricular mass index. The peritoneal dialysis fluid ADMA levels of CAPD patients with peritoneal were positively correlated with LVEF (r = 0.367, P = 0.046), negatively correlated with LVMI. In conclusion, ADMA may be involved in change of left ventricular structure, function, and remodeling process through a complex network.
PMCID: PMC4276226  PMID: 25550968
Asymmetric dimethylarginine; cardiovascular disease; left ventricular function; peritoneal dialysis
8.  Smart Soup, a Traditional Chinese Medicine Formula, Ameliorates Amyloid Pathology and Related Cognitive Deficits 
PLoS ONE  2014;9(11):e111215.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes substantial public health care burdens. Intensive efforts have been made to find effective and safe disease-modifying treatment and symptomatic intervention alternatives against AD. Smart Soup (SS), a Chinese medicine formula composed of Rhizoma Acori Tatarinowii (AT), Poria cum Radix Pini (PRP) and Radix Polygalae (RP), is a typical prescription against memory deficits. Here, we assessed the efficacy of SS against AD. Oral administration of SS ameliorated the cognitive impairment of AD transgenic mice, with reduced Aβ levels, retarded Aβ amyloidosis and reduced Aβ-induced gliosis and neuronal loss in the brains of AD mice. Consistently, SS treatment reduced amyloid-related locomotor dysfunctions and premature death of AD transgenic Drosophila. Mechanistic studies showed that RP reduced Aβ generation, whereas AT and PRP exerted neuroprotective effects against Aβ. Taken together, our study indicates that SS could be effective against AD, providing a practical therapeutic strategy against the disease.
doi:10.1371/journal.pone.0111215
PMCID: PMC4227681  PMID: 25386946
9.  Assessment of immune cells and function of the residual spleen after subtotal splenectomy due to splenomegaly in cirrhotic patients 
BMC Immunology  2014;15(1):42.
Background
The spleen is thought to be central in regulating the immune system, a metabolic asset involved in endocrine function. Overwhelming postsplenectomy infection leads to a mortality rate of up to 50%. However, there is still controversy on performing subtotal splenectomy as treatment of splenomegaly due to portal hypertension in cirrhotic patients. In the present study, immunocytes and the indexes of splenic size, hemodynamics, hematology and immunology in the residual spleen were analyzed to support subtotal splenectomy due to splenomegaly.
Results
In residual spleen, T lymphocytes mainly were focal aggregation in the periarterial lymphatic sheath. While B lymphocytes densely distributed in splenic corpuscle. In red pulp, macrophages were equally distributed in the xsplenic cord and adhered to the wall of splenic sinus with high density. The number of unit area T and B lymphocytes of splenic corpuscle and marginal zone as well as macrophages of red pulp were obviously increased in the residual spleen, while the number of macrophages didn’t be changed among the three groups in white pulp. While there were some beneficial changes (i.e., Counts of platelet and leucocyte as well as serum proportion of CD3+ T cells, CD4+ T cells, CD8+ T cells were increased markedly; serum levels of M-CSF and GM-CSF were decreased significantly; The proportion of granulocyte, erythrocyte, megakaryocyte in bone marrow were changed obviously; But serum IgA, IgM, IgG, Tuftsin level, there was no significant difference; splenic artery flow volume, portal venous diameter and portal venous flow volume, a significant difference was observed in residual spleen) in the clinical indices.
Conclusion
After subtotal splenectomy with splenomegaly due to portal hypertension in cirrhotic patients, the number of unit area T and B lymphocytes, and MØ in red pulp of residual spleen increased significantly. However, whether increase of T, B lymphocytes and MØs in residual splenic tissue can enhance the immune function of the spleen, still need further research to confirm.
doi:10.1186/s12865-014-0042-3
PMCID: PMC4193139  PMID: 25293512
Residual spleen; Splenomegaly; Portal hypertension; T, B lymphocytes; Macrophage; Immune
11.  Intensity of stromal changes is associated with tumor relapse in clinically advanced prostate cancer after castration therapy 
Asian Journal of Andrology  2014;16(5):710-714.
Reactive stromal changes in prostate cancer (PCa) are likely involved in the emergence of castration-resistant PCa (CRPC). This study was designed to investigate stromal changes in patients with clinically advanced PCa and analyze their prognostic significance. Prostate needle biopsies obtained from 148 patients before castration therapy were analyzed by Masson trichrome staining and immunohistochemical analysis of vimentin and desmin. Reactive stroma grading was inversely correlated with Gleason score. Stroma grade (Masson stain 82.8% vs 45.6%, P < 0.001) and vimentin expression (P = 0.005) were significantly higher, and desmin expression (P = 0.004) significantly lower, in reactive stroma of tumors with a Gleason score of 6–7 than in adjacent peritumoral tissue. Kaplan-Meier analysis showed a significant association between reactive stroma grade in tumors and the occurrence of CRPC in patients with a Gleason score of 6–7 (P = 0.009). Furthermore, patients with higher vimentin or lower desmin expression had a shorter disease-free period. In multivariate analysis, only vimentin expression was a significant predictor of tumor relapse (hazard ratio 1.78, 95% confidence interval 1.12–10.26, P = 0.012). These findings indicate that the intensity of reactive stroma is associated with castration responsiveness, especially in patients with a lower Gleason score where the abundant stroma component is most frequently found. High expression of vimentin in tumor stroma was independently associated with poor outcomes in patients with Gleason scores of 6–7, and may serve as a new prognostic marker in daily practice.
doi:10.4103/1008-682X.129131
PMCID: PMC4215666  PMID: 24875819
cancer-associated fibroblasts; castration resistance; prostate cancer; reactive stroma; vimentin
12.  NLRP3 and downstream cytokine expression elevated in the monocytes of patients with coronary artery disease 
Archives of Medical Science : AMS  2014;10(4):791-800.
Introduction
Pattern recognition receptor (PRR)-mediated signaling pathways have recently been elucidated to bridge the innate immune system and atherosclerosis. NLRP3 is among the family members of NOD-like receptors (NLRs), a type of PRRs. At present, most studies about the NLRP3 inflammasome focus on animal models and immune cells. Limited information is available regarding the role of NLRP3 in patients with coronary artery disease (CAD).
Material and methods
In this study, we observed the expression of NLRP3 and downstream cytokines in patients with CAD by ELISA, real-time qPCR and Western blot.
Results
We found that NLRP3 and downstream cytokines were coupled with increasing severity of CAD and a dynamic variation exists in patients with acute myocardial infarction. We also found that NLRP3 was correlated with Gensini score, indicating that NLRP3 might be relevant not only for the severity of CAD but also for the severity of coronary atherosclerosis.
Conclusions
This study provides a new theoretical basis for innate immune participation in atherosclerosis development and highlights the potential of the NLRP3 inflammasome as a target for prevention and treatment of CAD.
doi:10.5114/aoms.2014.44871
PMCID: PMC4175781  PMID: 25276166
NLRP3 inflammasome; interleukin 1β; interleukin 18; coronary artery disease; atherosclerosis
13.  Phenotypic Modulation of Corpus Cavernosum Smooth Muscle Cells in a Rat Model of Cavernous Neurectomy 
PLoS ONE  2014;9(8):e105186.
Background
Patients undergoing radical prostatectomy (RP) are at high risk for erectile dysfunction (ED) due to potential cavernous nerve (CN) damage during surgery. Penile hypoxia after RP is thought to significantly contribute to ED pathogenesis.
Aim
We previously showed that corpora cavernosum smooth muscle cells (CCSMCs) undergo phenotypic modulation under hypoxic conditions in vitro. Here, we studied such changes in an in vivo post-RP ED model by investigating CCSMCs in bilateral cavernous neurectomy (BCN) rats.
Methods
Sprague-Dawley rats underwent sham (n = 12) or BCN (n = 12) surgery. After 12 weeks, they were injected with apomorphine to determine erectile function. The penile tissues were harvested and assessed for fibrosis using Masson trichrome staining and for molecular markers of phenotypic modulation using immunohistochemistry and western blotting. CCSMC morphological structure was evaluated by hematoxylin-eosin (H&E) staining and transmission electron microscopy (TEM).
Results
Erectile function was significantly lower in BCN rats than in sham rats. BCN increased hypoxia-inducible factor-1α and collagen protein expression in corpora cavernous tissue. H&E staining and TEM showed that CCSMCs in BCN rats underwent hypertrophy and showed rough endoplasmic reticulum formation. The expression of CCSMC phenotypic markers, such as smooth muscle α-actin, smooth muscle myosin heavy chain, and desmin, was markedly lower, whereas vimentin protein expression was significantly higher in BCN rats than in control rats.
Conclusions
CCSMCs undergo phenotype modulation in rats with cavernous neurectomy. The results have unveiled physiological transformations that occur at the cellular and molecular levels and have helped characterize CN injury–induced ED.
doi:10.1371/journal.pone.0105186
PMCID: PMC4134279  PMID: 25127037
14.  Isolation and complete nucleotide sequence of a Batai virus strain in Inner Mongolia, China 
Virology Journal  2014;11:138.
Background
Batai virus (BATV) is a member of the Orthobunyavirus genus of the family Bunyaviridae, and a vector-borne pathogen. Genomic variations of BATV exist in different regions of the world, due to genetic reassortment. Whole-genome sequencing of any isolate is necessary for a phylogenetic analysis. In 1998, a BATV strain was isolated from an Anopheles philippines mosquito in Yunnan Province, China. This strain has not been found to infect any other host. We investigated BATV infection in cattle in Inner Mongolia, China and performed deep sequencing of the genome of the BATV isolate.
Findings
Ninety-five blood samples were collected from cattle in Inner Mongolia, China in 2012. The BATV infection rate was 2.1%. Previously, BATV strain NM/12 was isolated from two cattle in Inner Mongolia, China, and the whole genomic sequence of the strain has been available. We determined the complete genomic nucleotide sequences of the small (S), medium (M), and large (L) genome segments using bovine blood obtained in 2012, and the nucleotide homologies of these segments with those from GenBank were 88.7%-97%, 84%-95.4%, and 72.6%-95.8%, respectively. The deduced amino acid identities were 87.2-99.7%, 64.2-96.8%, and 81.1-98.6%. Phylogenetic analyses based on full-length genomic sequences indicated that the M and L segments, and a portion of the S segment, of NM/12 are most closely related to the BATV strains isolated in Asia. The S and M segments of NM/12 were independent of phylogenetic lineages. The L segment was the most closely related to Chittoor/IG-20217 (isolated in India), and distantly related to isolated strains in Italy. Nucleotide substitution rates in the nucleotide sequences that code for the nucleocapsid, envelope glycoprotein, and polymerase protein of NM/12 strain were 2.56%, 4.69%, and 4.21%, respectively, relative to the original strain of MM2222.
Conclusion
A novel BATV NM/12 strain from bovine serum collected in Inner Mongolia was isolated from cattle in China for the first time. Our findings elucidate the evolutionary status of the BATV NM/12 strain among different orthobunyavirus strains and may provide some clues to prevent the emergence of BATV infection in cattle and humans.
doi:10.1186/1743-422X-11-138
PMCID: PMC4127039  PMID: 25100223
Batai virus; Orthobunyavirus; Bunyaviridae; Reassortment
15.  Accurate Inference of Local Phased Ancestry of Modern Admixed Populations 
Scientific Reports  2014;4:5800.
Population stratification is a growing concern in genetic-association studies. Averaged ancestry at the genome level (global ancestry) is insufficient for detecting the population substructures and correcting population stratifications in association studies. Local and phase stratification are needed for human genetic studies, but current technologies cannot be applied on the entire genome data due to various technical caveats. Here we developed a novel approach (aMAP, ancestry of Modern Admixed Populations) for inferring local phased ancestry. It took about 3 seconds on a desktop computer to finish a local ancestry analysis for each human genome with 1.4-million SNPs. This method also exhibits the scalability to larger datasets with respect to the number of SNPs, the number of samples, and the size of reference panels. It can detect the lack of the proxy of reference panels. The accuracy was 99.4%. The aMAP software has a capacity for analyzing 6-way admixed individuals. As the biomedical community continues to expand its efforts to increase the representation of diverse populations, and as the number of large whole-genome sequence datasets continues to grow rapidly, there is an increasing demand on rapid and accurate local ancestry analysis in genetics, pharmacogenomics, population genetics, and clinical diagnosis.
doi:10.1038/srep05800
PMCID: PMC4107375  PMID: 25052506
16.  Highly Oxygenated Limonoids and Lignans from Phyllanthus flexuosus 
Abstract
Two new highly oxygenated limonoids, flexuosoids A (1) and B (2), and three new arylnaphthalene lignan glycosides, phyllanthusmins D–F (3–5), were isolated from the roots of Phyllanthus flexuosus, in addition to three known lignans, phyllanthusmin C, arabelline, and (+)-diasyringaresinol. Their structures were elucidated on the basis of detailed spectroscopic analysis and chemical methods. Compounds 1 and 2, two new decaoxygenated limonoids with a C-19/29 lactol bridge and heptaoxygenated substituents at C-1, C-2, C-3, C-7, C-11, C-17, and C-30, represent the second example of limonoids in the Euphorbiaceae family. Most of the isolates were tested for their antifeedant, anti-herpes simplex virus 1, and cytotoxic activities. The new limonoids 1 and 2 showed promising antifeedant activity against the beet army worm (Spodoptera exigua) with EC50 values of 25.1 and 17.3 μg/cm2, respectively. In addition, both of them displayed moderate cytotoxicity against the ECA109 human esophagus cancer cell line, along with the known lignan glycoside, phyllanthusmin C, with the IC50 values of 11.5 (1), 8.5 (2), and 7.8 (phyllanthusmin C) μM, respectively.
Graphical Abstract
Two new highly oxygenated limonoids, flexuosoids A (1) and B (2), and three new arylnaphthalene lignan glycosides, phyllanthusmins D–F (3–5), were isolated from the roots of Phyllanthus flexuosus, along with three known lignans. Flexuosoids A (1) and B (2) showed promising antifeedant activity against the beet army worm (Spodoptera exigua) with EC50 values of 25.1 and 17.3 μg/cm2, respectively. In addition, both of them and the known lignan glycoside, phyllanthusmin C, displayed moderate cytotoxicity against the ECA109 human esophagus cancer cell line, with the IC50 values of 11.5, 8.5, and 7.8 μM, respectively.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0026-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-014-0026-2
PMCID: PMC4111870  PMID: 25089242
Phyllanthus flexuosus; Euphorbiaceae; Limonoids; Lignan glycosides; Antifeedant; Antiviral; Cytotoxicity
17.  Highly Oxygenated Limonoids and Lignans from Phyllanthus flexuosus 
Abstract
Two new highly oxygenated limonoids, flexuosoids A (1) and B (2), and three new arylnaphthalene lignan glycosides, phyllanthusmins D–F (3–5), were isolated from the roots of Phyllanthus flexuosus, in addition to three known lignans, phyllanthusmin C, arabelline, and (+)-diasyringaresinol. Their structures were elucidated on the basis of detailed spectroscopic analysis and chemical methods. Compounds 1 and 2, two new decaoxygenated limonoids with a C-19/29 lactol bridge and heptaoxygenated substituents at C-1, C-2, C-3, C-7, C-11, C-17, and C-30, represent the second example of limonoids in the Euphorbiaceae family. Most of the isolates were tested for their antifeedant, anti-herpes simplex virus 1, and cytotoxic activities. The new limonoids 1 and 2 showed promising antifeedant activity against the beet army worm (Spodoptera exigua) with EC50 values of 25.1 and 17.3 μg/cm2, respectively. In addition, both of them displayed moderate cytotoxicity against the ECA109 human esophagus cancer cell line, along with the known lignan glycoside, phyllanthusmin C, with the IC50 values of 11.5 (1), 8.5 (2), and 7.8 (phyllanthusmin C) μM, respectively.
Graphical Abstract
Two new highly oxygenated limonoids, flexuosoids A (1) and B (2), and three new arylnaphthalene lignan glycosides, phyllanthusmins D–F (3–5), were isolated from the roots of Phyllanthus flexuosus, along with three known lignans. Flexuosoids A (1) and B (2) showed promising antifeedant activity against the beet army worm (Spodoptera exigua) with EC50 values of 25.1 and 17.3 μg/cm2, respectively. In addition, both of them and the known lignan glycoside, phyllanthusmin C, displayed moderate cytotoxicity against the ECA109 human esophagus cancer cell line, with the IC50 values of 11.5, 8.5, and 7.8 μM, respectively.
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0026-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s13659-014-0026-2
PMCID: PMC4111870  PMID: 25089242
Phyllanthus flexuosus; Euphorbiaceae; Limonoids; Lignan glycosides; Antifeedant; Antiviral; Cytotoxicity
18.  Mapping risk of plague in Qinghai-Tibetan Plateau, China 
BMC Infectious Diseases  2014;14:382.
Background
Qinghai-Tibetan Plateau of China is known to be the plague endemic region where marmot (Marmota himalayana) is the primary host. Human plague cases are relatively low incidence but high mortality, which presents unique surveillance and public health challenges, because early detection through surveillance may not always be feasible and infrequent clinical cases may be misdiagnosed.
Methods
Based on plague surveillance data and environmental variables, Maxent was applied to model the presence probability of plague host. 75% occurrence points were randomly selected for training model, and the rest 25% points were used for model test and validation. Maxent model performance was measured as test gain and test AUC. The optimal probability cut-off value was chosen by maximizing training sensitivity and specificity simultaneously.
Results
We used field surveillance data in an ecological niche modeling (ENM) framework to depict spatial distribution of natural foci of plague in Qinghai-Tibetan Plateau. Most human-inhabited areas at risk of exposure to enzootic plague are distributed in the east and south of the Plateau. Elevation, temperature of land surface and normalized difference vegetation index play a large part in determining the distribution of the enzootic plague.
Conclusions
This study provided a more detailed view of spatial pattern of enzootic plague and human-inhabited areas at risk of plague. The maps could help public health authorities decide where to perform plague surveillance and take preventive measures in Qinghai-Tibetan Plateau.
doi:10.1186/1471-2334-14-382
PMCID: PMC4227279  PMID: 25011940
19.  Arabidopsis phospholipase Dβ1 modulates defense responses to bacterial and fungal pathogens 
The New phytologist  2013;199(1):228-240.
Summary
Pathogen infection of higher plants often induces a rapid production of phosphatic acid (PA) and changes in lipid profiles, but the enzymatic basis and the function of the lipid change in pathogen-plant interactions are not well understood.Infection of PLDβ1-deficient plants by Pseudomonas syringae pv. DC3000 resulted in less bacterial growth than in wild-type plants, and the effect was more profound in virulent Pst DC3000 than avirulent Pst DC3000 (avrRpt2) infection. The expression levels of salicylic acid (SA)-inducible genes were higher, but those inducible by jasmonic acid (JA) were lower in PLDβ1 mutants than in wild-type plants.However, PLDβ1-deficient plants were more susceptible than wild-type plants to the fungus Botrytis cinerea. The PLDβ1-deficient plants had lower levels of PA, JA and JA-related defense gene expression after B. cinerea inoculation.PLDβ1 plays a positive role in pathogen-induced JA production and plant resistance to necrotrophic fungal pathogen B. cinerea, but a negative role in the SA-dependent signaling pathway and plant tolerance to the infection of biotrophic Pst DC3000. PLDβ1 is responsible for the major part of PA increased in response to necrotrophic B. cinerea and virulent Pst DC3000 infection, but contributes less to the avirulent Pst DC3000 (avrRpt2)-induced PA production.
doi:10.1111/nph.12256
PMCID: PMC4066384  PMID: 23577648
Botrytis cinerea; Pseudomonas syringae; Arabidopsis thaliana; phospholipase Dβ1; pathogeneses; phosphatidic acid; lysophospholipids; lipid signaling
20.  Role of miR-146a in human chondrocyte apoptosis in response to mechanical pressure injury in vitro 
MicroRNA (miR)-146a is known to be overexpressed in osteoarthritis (OA). However, the role of miR-146a in OA has not yet been fully elucidated. In the present study, we applied mechanical pressure of 10 MPa to human chondrocytes for 60 min in order to investigate the expression of miR-146a and apoptosis following the mechanical pressure injury. Normal human chondrocytes were transfected with an miR-146a mimic or an inhibitor to regulate miR-146a expression. Potential target genes of miR-146a were predicted using bioinformatics. Moreover, luciferase reporter assay confirmed that Smad4 was a direct target of miR-146a. The expression levels of miR-146a, Smad4 and vascular endothelial growth factor (VEGF) were quantified by quantitative reverse transcription PCR and/or western blot analysis. The effects of miR-146a on apoptosis were detected by Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) flow cytometry. The results indicated that mechanical pressure affected chondrocyte viability and induced the early apoptosis of chondrocytes. Mechanical pressure injury increased the expression levels of miR-146a and VEGF and decreased the levels of Smad4 in the chondrocytes. In the human chondrocytes, the upregulation of miR-146a induced apoptosis, upregulated VEGF expression and downregulated Smad4 expression. In addition, the knockdown of miR-146a reduced cell apoptosis, upregulated Smad4 expression and downregulated VEGF expression. Smad4 was identified as a direct target of miR-146a by harboring a miR-146a binding sequence in the 3′-untranslated region (3′-UTR) of its mRNA. Furthermore, the upregulation of VEGF induced by miR-146a was mediated by Smad4 in the chondrocytes subjected to mechanical pressure injury. These results demonstrated that miR-146a was overexpressed in our chondrocyte model of experimentally induced human mechanical injury, accompanied by the upregulation of VEGF and the downregulation of Smad4 in vitro. Moreover, our data suggest that miR-146a is involved in human chondrocyte apoptosis in response to mechanical injury, and may contribute to the mechanical injury of chondrocytes, as well as to the pathogenesis of OA by increasing the levels of VEGF and damaging the transforming growth factor (TGF)-β signaling pathway through the targeted inhibition of Smad4 in cartilage.
doi:10.3892/ijmm.2014.1808
PMCID: PMC4094584  PMID: 24939082
apoptosis; osteoarthritis; mechanical injury; chondrocyte; miR-146a
21.  Clinicopathological and prognostic significance of microRNA-107 in human non small cell lung cancer 
Background: MicroRNAs (miRNAs) are small, non-coding RNAs which can function as oncogenes or tumor suppressor genes in human cancers. Researchers have found that the expression level of miR-107 was decreased in human non-small cell lung cancer (NSCLC) tissues and cell lines, however, its clinicopathological and prognostic significance in NSCLC has not been investigated. Methods: Quantitative real-time PCR (qRT-PCR) was used to analyze the expression of miR-107 in 137 pairs of fresh NSCLC and matched adjacent normal tissue specimens. The chi-square test and Fishers exact tests were used to examine the associations between miR-107 expression and the clinicopathological characters. The overall survival (OS) and progression-free survival (PFS) were analyzed by log-rank test, and survival curves were plotted according to Kaplan-Meier. Results: The expression level of miR-107 was significantly lower in tumor tissues than that in corresponding noncancerous tissues (0.4676±0.2078 vs. 1.000±0.3953, P<0.001). Low expression of miR-107 was found to significantly correlate with TNM stage (p=0.001), regional lymph node involvement (p=0.04), and tumor differentiation (p=0.003). Kaplan-Meier analysis with the log-rank test indicated that low miR-107 expression had a significant impact on OS (35.2% vs. 69.3%; P=0.008) and PFS (30.0% vs. 56.2%; P=0.029). In a multivariate Cox model, we found that miR-107 expression was an independent poor prognostic factor for both 5-year OS (HR=2.57, 95% CI: 1.88-10.28; P=0.007) and 5-year PFS (HR=3.08, 95% CI: 2.01-8.92; P=0.003). Conclusion: The expression of miR-107 was decreased in NSCLC. Low expression of miR-107 was significantly associated with tumor progression and decreased survival in patients with NSCLC, indicating that miR-107 may serve as a novel prognostic marker in NSCLC.
PMCID: PMC4129086  PMID: 25120851
MicroRNA-107; non-small cell lung cancer; prognosis
22.  Generation of neural progenitor cells by chemical cocktails and hypoxia 
Cell Research  2014;24(6):665-679.
Neural progenitor cells (NPCs) can be induced from somatic cells by defined factors. Here we report that NPCs can be generated from mouse embryonic fibroblasts by a chemical cocktail, namely VCR (V, VPA, an inhibitor of HDACs; C, CHIR99021, an inhibitor of GSK-3 kinases and R, Repsox, an inhibitor of TGF-β pathways), under a physiological hypoxic condition. These chemical-induced NPCs (ciNPCs) resemble mouse brain-derived NPCs regarding their proliferative and self-renewing abilities, gene expression profiles, and multipotency for different neuroectodermal lineages in vitro and in vivo. Further experiments reveal that alternative cocktails with inhibitors of histone deacetylation, glycogen synthase kinase, and TGF-β pathways show similar efficacies for ciNPC induction. Moreover, ciNPCs can also be induced from mouse tail-tip fibroblasts and human urinary cells with the same chemical cocktail VCR. Thus our study demonstrates that lineage-specific conversion of somatic cells to NPCs could be achieved by chemical cocktails without introducing exogenous factors.
doi:10.1038/cr.2014.32
PMCID: PMC4042166  PMID: 24638034
lineage conversion; neural progenitor cells; chemical cocktails; hypoxia
23.  First Total Syntheses and Antimicrobial Evaluation of Penicimonoterpene, a Marine-Derived Monoterpenoid, and Its Various Derivatives 
Marine Drugs  2014;12(6):3352-3370.
The first total synthesis of marine-derived penicimonoterpene (±)-1 has been achieved in four steps from 6-methylhept-5-en-2-one using a Reformatsky reaction as the key step to construct the basic carbon skeleton. A total of 24 new derivatives of 1 have also been designed and synthesized. Their structures were characterized by analysis of their 1H NMR, 13C NMR and HRESIMS data. Some of them showed significant antibacterial activity against Aeromonas hydrophila, Escherichia coli, Micrococcus luteus, Staphylococcus aureus, Vibrio anguillarum, V. harveyi and/or V. parahaemolyticus, and some showed activity against plant-pathogenic fungi (Alternaria brassicae, Colletotrichum gloeosporioides and/or Fusarium graminearum). Some of the derivatives exhibited antimicrobial MIC values ranging from 0.25 to 4 μg/mL, which were stronger than those of the positive control. Notably, Compounds 3b and 10 showed extremely high selectively against plant-pathogenic fungus F. graminearum (MIC 0.25 μg/mL) and pathogenic bacteria E. coli (MIC 1 μg/mL), implying their potential as antimicrobial agents. SAR analysis of 1 and its derivatives indicated that modification of the carbon-carbon double bond at C-6/7, of groups on the allylic methylene unit and of the carbonyl group at C-1, effectively enhanced the antimicrobial activity.
doi:10.3390/md12063352
PMCID: PMC4071580  PMID: 24897384
(±)-penicimonoterpene; total synthesis; antimicrobial activity; structure-activity relationship
24.  Association between nocturnal hypoxia and liver injury in the setting of nonalcoholic fatty liver disease 
Purpose
Obstructive sleep apnea (OSA) is suggested as a potential risk factor of nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism is still far from clear. The aim of this observational study was to investigate the influence of OSA-related hypoxia on severity of liver injury in patients with NAFLD.
Methods
Consecutive patients with ultrasound-diagnosed NAFLD who underwent standard polysomnography were enrolled. Fasting blood samples were obtained from all patients for biological profile measurements, and demographic data were collected. Subjects were divided into control, moderate, and severe groups.
Results
A total of 85 subjects with 73 males and 12 females were included (mean age, 44.67 ± 1.28 years; mean body mass index, 27.28 ± 0.33 kg/m2). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), ALT/AST, gamma glutamyltransferase, total cholesterol, low density lipoprotein-cholesterol, fasting glucose, and high-sensitivity C-reactive protein significantly increased with the aggravation of OSA. In multivariate analysis, oxygen desaturation index was the major contributing factor for elevated ALT (β = 0.435, p = 0.000), average O2 saturation was the major independent predictor of elevated AST (β = −0.269, p = 0.020).
Conclusions
OSA-related hypoxia was independently associated with the biochemical evidence of liver injury in the presence of NAFLD.
doi:10.1007/s11325-014-1008-7
PMCID: PMC4330463  PMID: 24870112
Obstructive sleep apnea; Hypoxia; Fatty liver; Liver injury
25.  Prognostic significance of SUVmax and serum carbohydrate antigen 19-9 in pancreatic cancer 
AIM: To investigate the prognostic significance of pretreatment standardized maximum uptake value (SUVmax) and serum carbohydrate antigen (CA)19-9 in pancreatic cancer.
METHODS: From January 2007 to October 2011, 80 consecutive patients with pancreatic cancer who received positron emission/computed tomography before any treatment were enrolled in this study. The pretreatment SUVmax and CA19-9 level of the primary pancreatic tumor were obtained and compared with clinicopathological and prognostic factors. Student’s t test for unpaired data was used to analyze the differences between two groups. Univariate analysis and Cox proportional hazards regression were used to examine the independent effects of each significant variable. Survival was analyzed by the Kaplan-Meier method.
RESULTS: There was a significant correlation between both the SUVmax and serum CA19-9 of pancreatic cancer and R0 surgical resection (P = 0.043 and P = 0.007). Lymph node metastasis was associated with SUVmax (P = 0.017), but not serum CA19-9 (P = 0.172). On the contrary, the tumor stage was significantly related to serum CA19-9 (P = 0.035), but not SUVmax (P = 0.110). The univariate analysis showed that survival time was significantly related to tumor stage (P < 0.001), lymph node metastasis (P = 0.043), R0 surgical resection (P < 0.001), serum CA19-9 (P = 0.001), SUVmax (P < 0.001) and SUVmax plus CA19-9 (P = 0.002). Multivariate analysis clearly showed that only tumor stage (hazard ratio = 0.452; P = 0.020) was an independent prognostic factor for overall survival in pancreatic cancer. Higher SUVmax or CA19-9 showed worse prognosis. We found that high serum CA19-9 plus SUVmax was the most significant variable.
CONCLUSION: Higher pretreatment SUVmax and serum CA19-9 indicates poor prognosis. SUVmax plus serum CA19-9 is the most significant variable in predicting survival.
doi:10.3748/wjg.v20.i19.5875
PMCID: PMC4024797  PMID: 24914348
Pancreatic cancer; Maximum standardized uptake value; Carbohydrate antigen 19-9; Prognostic factors

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