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1.  Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A 
Nature communications  2015;6:8048.
Autophagy is a cellular catabolic process critical for cell viability and homeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity toward ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A-B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells (PDACs), whose growth depends on high basal autophagy, possess stronger basal phosphatase activity toward ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A-B55α stimulation fuel ULK1-dependent autophagy.
doi:10.1038/ncomms9048
PMCID: PMC4552084  PMID: 26310906
2.  The efficacy of postoperative radiotherapy in localized primary soft tissue sarcoma treated with conservative surgery 
Background
To evaluate the efficacy of postoperative radiotherapy (RT) on local failure-free survival (LFFS), distant metastasis-free survival (DMFS) and overall survival (OS) in patients with localized primary soft tissue sarcoma (STS) and to identify prognostic factors.
Methods and materials
Between January 2000 and July 2010, 220 consecutive patients with localized primary STS, who received conservative surgery with or without postoperative RT, were enrolled in the study. Survival curves were constructed by the Kaplan-Meier method and log-rank test was used to assess statistical significance. Multivariate analysis was applied to identify the prognostic factors.
Results
After a median follow-up of 68 months (range, 5–127 months), the 5-year LFFS, DMFS and OS were 70.0, 78.2 and 71.2 %, respectively. Tumor size, histological subtypes, margin status and postoperative RT were independent predictors for OS. Postoperative RT was associated with a significant reduced local recurrence risk versus surgery alone (hazard ratio [HR] = 0.408, 95 % confidence interval [CI] 0.235–0.707, P = 0.001), with 5-year LFFS of 81.1 and 63.6 %, respectively (log-rank, P = 0.004). The log-rank test showed that postoperative RT had a tendency of improving OS compared with surgery alone, with 5-year OS of 74.8 and 65.0 %, respectively (P = 0.089). Multivariate analysis demonstrated that postoperative RT significantly reduced mortality rate compared with surgery alone (HR = 0.512, 95 % CI 0.296–0.886, p = 0.017), especially in patients with liposarcoma (p = 0.034).
Conclusion
Postoperative radiotherapy reduce both local recurrence and STS mortality in patients with localized primary STS. The efficacy of RT on survival warrants further prospective study.
Electronic supplementary material
The online version of this article (doi:10.1186/s13014-016-0605-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13014-016-0605-y
PMCID: PMC4766748  PMID: 26911328
Soft tissue sarcoma; Surgery; Radiotherapy; Local recurrence; Overall survival
3.  Quantifying the economic impact of government and charity funding of medical research on private research and development funding in the United Kingdom 
BMC Medicine  2016;14:32.
Background
Government- and charity-funded medical research and private sector research and development (R&D) are widely held to be complements. The only attempts to measure this complementarity so far have used data from the United States of America and are inevitably increasingly out of date. This study estimates the magnitude of the effect of government and charity biomedical and health research expenditure in the United Kingdom (UK), separately and in total, on subsequent private pharmaceutical sector R&D expenditure in the UK.
Methods
The results for this study are obtained by fitting an econometric vector error correction model (VECM) to time series for biomedical and health R&D expenditure in the UK for ten disease areas (including ‘other’) for the government, charity and private sectors. The VECM model describes the relationship between public (i.e. government and charities combined) sector expenditure, private sector expenditure and global pharmaceutical sales as a combination of a long-term equilibrium and short-term movements.
Results
There is a statistically significant complementary relationship between public biomedical and health research expenditure and private pharmaceutical R&D expenditure. A 1 % increase in public sector expenditure is associated in the best-fit model with a 0.81 % increase in private sector expenditure. Sensitivity analysis produces a similar and statistically significant result with a slightly smaller positive elasticity of 0.68. Overall, every additional £1 of public research expenditure is associated with an additional £0.83–£1.07 of private sector R&D spend in the UK; 44 % of that additional private sector expenditure occurs within 1 year, with the remainder accumulating over decades. This spillover effect implies a real annual rate of return (in terms of economic impact) to public biomedical and health research in the UK of 15–18 %. When combined with previous estimates of the health gain that results from public medical research in cancer and cardiovascular disease, the total rate of return would be around 24–28 %.
Conclusion
Overall, this suggests that government and charity funded research in the UK crowds in additional private sector R&D in the UK. The implied historical returns from UK government and charity funded investment in medical research in the UK compare favourably with the rates of return achieved on investments in the rest of the UK economy and are greatly in excess of the 3.5 % real annual rate of return required by the UK government to public investments generally.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-016-0564-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-016-0564-z
PMCID: PMC4765095  PMID: 26908129
Biomedical and health research; Elasticities; Medical research charities; Pharmaceuticals; Rate of return; Research investment; Value of health; Vector Error Correction Model
4.  Genetic Variation in Metastasis-Associated in Colon Cancer-1 and the Risk of Breast Cancer Among the Chinese Han Population 
Medicine  2016;95(6):e2801.
Abstract
Metastasis-associated in colon cancer-1 (MACC1), a newly identified oncogene, is involved in angiogenesis, invasiveness, and metastasis in many cancers. Epidemiological studies have indicated the associations between MACC1 polymorphisms and cancer risk. However, the association between genetic polymorphisms in MACC1 and breast cancer (BC) was not clear. This study aimed to evaluate the relationship between MACC1 polymorphisms and BC risk.
We genotyped 4 single-nucleotide polymorphisms (SNPs) in MACC1 (rs975263, rs1990172, rs3735615, rs4721888) to determine the haplotypes in 560 BC patients and 583 age-, sex-, and ethnicity-matched healthy individuals. Genotypes were determined using the Sequenom MassARRAY method. We estimated the odds ratios (ORs) and 95% confidence intervals (95% CIs) using the chi-square test.
There were significant differences between patients and controls in the MACC1 rs975263 allelic (T vs C: OR = 0.76, 95% CI = 0.61–0.95, P = 0.014) and genotypic groups (TC vs TT: OR = 0.70, 95% CI = 0.54–0.92, P = 0.009; TC+CC vs TT: OR = 0.71, 95% CI = 0.55–0.92, P = 0.008). Analysis of clinical features demonstrated significant associations between rs975263 and Scarff–Bloom–Richardson (SBR) grade 3 cancer (P = 0.006) and postmenopausal women (P = 0.018). Compared with the rs4721888 CC genotype, the frequency of rs4721888 GC and GC+CC variants was higher in patients. Further analysis revealed that the variant genotypes were positively associated with lymph node metastasis. However, we failed to find any relationships between rs1990172 or rs3735615 polymorphism and BC risk. In addition, haplotype analysis indicated that the CTGG and CTCG haplotypes (rs975263, rs1990172, rs3735615, rs4721888) were significantly associated with decreased susceptibility to BC (P = 0.029 and 0.019 respectively).
Our results suggest that rs975263 and rs4721888 polymorphisms in MACC1 are associated with the risk of BC susceptibility and may be involved in the progression of BC in Chinese women.
doi:10.1097/MD.0000000000002801
PMCID: PMC4753940  PMID: 26871844
5.  Design and synthesis of novel hydroxyanthraquinone nitrogen mustard derivatives as potential anticancer agents via a bioisostere approach 
A series of hydroxyanthraquinones having an alkylating N-mustard pharmacophore at 1′-position were synthesized via a bioisostere approach to evaluate their cytotoxicity against four tumor cell lines (MDA-MB-231, HeLa, MCF-7 and A549). These compounds displayed significant in vitro cytotoxicity against MDA-MB-231 and MCF-7 cells, reflecting the excellent selectivity for the human breast cancer. Among them, compound 5k was the most cytotoxic with IC50 value of 0.263 nM and is more potent than DXR (IC50 = 0.294 nM) in inhibiting the growth of MCF-7 cells. The excellent cytotoxicity and good selectivity of compound 5k suggest that it could be a promising lead for further design and development of anticancer agents, especially for breast cancer.
doi:10.1016/j.ejmech.2015.08.006
PMCID: PMC4747102  PMID: 26291039
Anthraquinone; Nitrogen mustard; Synthesis; Antitumor activity
6.  Improving sodium laser guide star brightness by polarization switching 
Scientific Reports  2016;6:19859.
Optical pumping with circularly polarized light has been used to enhance the brightness of sodium laser guide star. But the benefit is reduced substantially due to the precession of sodium atoms in geomagnetic field. Switching the laser between left and right circular polarization at the Larmor frequency is proposed to improve the return. With ESO’s laser guide star system at Paranal as example, numerical simulation shows that the return flux is increased when the angle between geomagnetic field and laser beam is larger than 60°, as much as 50% at 90°. The proposal is significant since most astronomical observation is at angle between 60° and 90° and it only requires a minor addition to the delivery optics of present laser system.
doi:10.1038/srep19859
PMCID: PMC4750368  PMID: 26797503
7.  Early Local Recurrence Presents Adverse Effect on Outcomes of Primary Breast Sarcoma 
Medicine  2016;95(1):e2422.
Abstract
Primary breast sarcomas (PBSs) are spectrum heterogeneous sarcomas in breast and the optimal treatment for them is still under discussion. Our study was to investigate clinical characteristics and identify potential prognostic factors for this rare malignancy.
The authors retrospectively reviewed 38 patients with PBSs between October 2000 and February 2014 in FuDan University Shanghai Cancer Center. Local control rate and overall survival (OS) were determined by Kaplan–Meier actuarial method. Univariate analysis and Cox proportional hazards model were applied to identify potential prognostic factors.
With median follow-up of 40.19 months, 14 patients (14/38) were found with local recurrence. Extensive operation like mastectomy was not superior to local resection (P = 0.167). Three-year recurrence-free survival and OS rate were 61.9% and 89%, respectively. Larger tumor size and local recurrence were indicated as unfavorable prognostic factors in univariate analysis. Cox model identified narrow interval of recurrence free survival as an unfavorable factor (P = 0.048).
Surgery remains crucial treatment for PBSs. Mastectomy, however, is not routinely necessary if clear margin could be achieved by local excision. Early recurrence indicates a poor OS.
doi:10.1097/MD.0000000000002422
PMCID: PMC4706266  PMID: 26735546
8.  Spatial and temporal colonization dynamics of segmented filamentous bacteria is influenced by gender, age and experimental infection with Helicobacter hepaticus in Swiss Webster mice 
In this study, we examined colonization dynamics of segmented filamentous bacteria (SFB) in intestine of Swiss Webster (SW) mice infected with Helicobacter hepaticus (Hh). At 8 weeks post-inoculation with Hh (WPI), cecal and colonic SFB levels in the control males were significantly lower compared to those at 16 WPI. Hh infection in both genders did not alter SFB levels in the jejunum and ileum, but increased SFB levels in the cecum and colon of males compared to the controls (P<0.05) at 8 WPI. At 16 WPI, the Hh-infected females contained lower levels of SFB in the jejunum, cecum and colon compared to the female controls. Irrespective of gender, aging and Hh infection, the Il-17A mRNA levels decreased from the small intestine to the cecum and then to the colon, whereas the Foxp3 mRNA levels were comparable in these intestinal regions. There were significant differences in Il-17A mRNA levels in the ileum (P<0.05, R2 = 0.31), with females having greater Il-17A mRNA levels than males, and higher SFB colonization levels related to more Il-17A mRNA. These results indicate that aging and gender play an important role in colonization dynamics of intestinal SFB and ileal SFB-associated Th17 response.
doi:10.1016/j.micinf.2014.10.005
PMCID: PMC4302023  PMID: 25448636
Segmented filamentous bacteria; Colonization dynamics; H. hepaticus; Il-17A expression; Swiss Webster mice
9.  Use of CEA and CA15-3 to Predict Axillary Lymph Node Metastasis in Patients with Breast Cancer 
Journal of Cancer  2016;7(1):37-41.
Purpose: The clinical significance of preoperative serum levels of carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) in breast cancer is controversial. The purpose of this study was to assess the clinical value of preoperative serum levels of CEA and CA 15-3 on the risk of axillary lymph node metastasis (ALNM) in patients with breast cancer.
Methods: This retrospective study analyzed 1148 breast cancer patients whose preoperative CEA and CA 15-3 levels were measured. The association of these tumor markers and clinicopathologic parameters with ALNM was determined by univariate and multivariate analysis.
Results: A median of 15 lymph nodes were removed. Seven hundred seventy-eight (67.8%) patients had node-negative disease and 370 (32.2%) had ALNM. Univariate analysis showed that tumor location (P = 0.024), stage (P = 0.001), grade (P < 0.001), lymphovascular invasion (LVI) (P < 0.001), CEA level (P < 0.001), CA15-3 level (P < 0.001), and breast cancer subtype (BCS) (P < 0.001) were significantly associated with ALNM. ALNM was present in 4.5% of patients with normal CEA and 11.6% of patients with elevated CEA. ALNM was present in 8.0% of patients with normal CA15-3 and 17.0% of patients with high CA15-3. Multivariate logistic regression analysis showed that tumor location, stage, grade, LVI, CEA, CA15-3, and BCS were significantly and independently associated with ALNM (P < 0.05 for all).
Conclusion: The probability of ALNM was greater in patients with elevated preoperative serum levels of CEA and CA15-3. CEA and CA15-3 appear to be independent predictors of ALNM in breast cancer.
doi:10.7150/jca.13090
PMCID: PMC4679379  PMID: 26722358
Breast cancer; axillary lymph node metastases; CEA; CA15-3.
10.  Prognostic value of lymph node ratio in patients with small-cell carcinoma of the cervix based on data from a large national registry 
OncoTargets and therapy  2015;9:67-73.
Objective
To investigate the prognostic value of the lymph node ratio (LNR) in patients with small-cell carcinoma of the cervix (SCCC) after cancer-directed surgery using a population-based national registry (Surveillance Epidemiology and End Results [SEER]).
Methods
We retrospectively reviewed the data of SCCC patients in the SEER database from 1980 to 2012. The prognostic impact of LNR with respect to cause-specific survival (CSS) and overall survival (OS) was analyzed.
Results
A total of 118 patients with SCCC were identified. The median follow-up was 30.5 months. All these patients were treated with cancer-directed surgery and lymphadenectomy. Sixty (50.8%) patients had nodal metastases. The median LNR was 0.16 in patients with positive lymph nodes. Univariate analysis showed that prognostic factors such as International Federation of Gynecology and Obstetrics (FIGO) stage, nodal status, LNR, and local treatment modalities affected CSS and OS (P<0.05). Multivariate analysis showed that LNR was an independent prognostic factor for CSS and OS. Patients with a higher LNR had worse CSS (hazard ratio [HR]: 8.832; 95% confidence interval [CI]: 3.762–20.738; P<0.001) and OS (HR: 8.462; 95% CI: 3.613–19.821; P<0.001). LNR was associated with CSS and OS by stage, especially in FIGO stage I–II patients.
Conclusion
LNR is an independent prognostic factor in SCCC patients and it may help to individualize adjuvant therapy.
doi:10.2147/OTT.S96206
PMCID: PMC4694687  PMID: 26730205
small-cell carcinoma of the cervix; SEER; lymph node ratio; lymph node; prognostic factors
11.  Breast Cancer Subtype is Associated With Axillary Lymph Node Metastasis 
Medicine  2015;94(48):e2213.
Abstract
The purpose of this study was to assess whether breast cancer subtype (BCS) as determined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 can predict the axillary lymph node metastasis in breast cancer.
Patients who received breast conserving surgery or mastectomy and axillary lymph node dissection were identified from 2 cancer centers. The associations between clinicopathological variables and axillary lymph node involvement were evaluated in univariate and multivariate regression analyses.
A total of 3471 patients met the inclusion criteria, and 53.0% had axillary lymph node metastases at diagnosis. Patients with hormone receptor (HR)−/human epidermal growth factor receptor 2 (HER2)− subtype had a higher grade disease and the lowest rate of lymphovascular invasion. Univariate and multivariable logistic regression analyses showed that BCS was significantly associated with lymph node involvement. Patients with the HR−/HER2− subtype had the lowest odds of having nodal positivity than those with other BCSs. HR+/HER2− (odds ratio [OR] 1.651, 95% confidence interval [CI]: 1.349–2.021, P < 0.001), HR+/HER2+ (OR 1.958, 95%CI 1.542–2.486, P < 0.001), and HR−/HER2+ (OR 1.525, 95%CI 1.181–1.970, P < 0.001) tumors had higher risk of nodal positivity than the HR−/HER2− subtype. The other independent predictors of nodal metastases included tumor size, tumor grade, and lymphovascular invasion.
Breast cancer subtype can predict the presence of axillary lymph node metastasis in breast cancer. HR−/HER2− is associated with a reduced risk of axillary lymph node metastasis compared to other BCSs. Our findings may play an important role in guiding axillary treatment considerations if further confirmed in larger sample size studies.
doi:10.1097/MD.0000000000002213
PMCID: PMC4674213  PMID: 26632910
12.  Enhancing the methanol tolerance of platinum nanoparticles for the cathode reaction of direct methanol fuel cells through a geometric design 
Scientific Reports  2015;5:16219.
Mastery over the structure of nanoparticles might be an effective way to enhance their performance for a given application. Herein we demonstrate the design of cage-bell nanostructures to enhance the methanol tolerance of platinum (Pt) nanoparticles while remaining their catalytic activity for oxygen reduction reaction. This strategy starts with the synthesis of core-shell-shell nanoparticles with Pt and silver (Ag) residing respectively in the core and inner shell regions, which are then agitated with saturated sodium chloride (NaCl) solution to eliminate the Ag component from the inner shell region, leading to the formation of bimetallic nanoparticles with a cage-bell structure, defined as a movable Pt core enclosed by a metal shell with nano-channels, which exhibit superior methanol-tolerant property in catalyzing oxygen reduction reaction due to the different diffusion behaviour of methanol and oxygen in the porous metal shell of cage-bell structured nanoparticles. In particular, the use of remarkably inexpensive chemical agent (NaCl) to promote the formation of cage-bell structured particles containing a wide spectrum of metal shells highlights its engineering merit to produce highly selective electrocatalysts on a large scale for the cathode reaction of direct methanol fuel cells.
doi:10.1038/srep16219
PMCID: PMC4649704  PMID: 26578100
13.  Developing a Novel Gene-Delivery Vector System Using the Recombinant Fusion Protein of Pseudomonas Exotoxin A and Hyperthermophilic Archaeal Histone HPhA 
PLoS ONE  2015;10(11):e0142558.
Non-viral gene delivery system with many advantages has a great potential for the future of gene therapy. One inherent obstacle of such approach is the uptake by endocytosis into vesicular compartments. Receptor-mediated gene delivery method holds promise to overcome this obstacle. In this study, we developed a receptor-mediated gene delivery system based on a combination of the Pseudomonas exotoxin A (PE), which has a receptor binding and membrane translocation domain, and the hyperthermophilic archaeal histone (HPhA), which has the DNA binding ability. First, we constructed and expressed the rPE-HPhA fusion protein. We then examined the cytotoxicity and the DNA binding ability of rPE-HPhA. We further assessed the efficiency of transfection of the pEGF-C1 plasmid DNA to CHO cells by the rPE-HPhA system, in comparison to the cationic liposome method. The results showed that the transfection efficiency of rPE-HPhA was higher than that of cationic liposomes. In addition, the rPE-HPhA gene delivery system is non-specific to DNA sequence, topology or targeted cell type. Thus, the rPE-HPhA system can be used for delivering genes of interest into mammalian cells and has great potential to be applied for gene therapy.
doi:10.1371/journal.pone.0142558
PMCID: PMC4640596  PMID: 26556098
14.  Tumor-induced VEGF-C overexpression in retroperitoneal lymph nodes in VX2 carcinoma-bearing rabbits 
Objective
To establish the retroperitoneal lymph node (RLN) metastasis model of cervical carcinoma in rabbits and evaluate the relationship of vascular endothelial growth factor-C (VEGF-C) expression and the lymph node status.
Methods
Forty-eight rabbits were injected with VX2 cells or RPMI solution at muscular mucosae of the myometrium 0.5 cm away from the cervix. Animals were treated with or without cis-diamminedichloroplatinum(II) (cisplatin: DDP) and sacrificed on days 15, 21, and 27 post-VX2 or RPMI injections. Tumor mass and RLNs were examined histopathologically. Quantitative real-time PCR was used to examine the changes in VEGF-C mRNA expression. Levels of VEGF-C protein expression in tissues were determined using immunohistochemistry staining.
Results
Development of VX2 cervical carcinoma and the RLNs metastasis was confirmed with pathological examination. Significantly increased tumor volume was observed on days 15, 21, and 27 postinjection (P<0.05). The enlargement of RLNs was found on day 21. Expression of VEGF-C was significantly upregulated in peripheral white blood cells, tumor mass, and RLNs in an association with cancer progression. DDP resulted in a suppression of VEGF-C expression, whereas the influences on tumor mass and lymphatic metastasis were insignificant.
Conclusion
Elevated VEGF-C expressions in peripheral white blood cells and RLNs are associated with tumor progression and lymphatic metastasis. DDP treatment inhibits VEGF-C expression and fails to protect against metastatic cervical cancer.
doi:10.2147/DDDT.S89810
PMCID: PMC4639523  PMID: 26604693
VEGF-C; retroperitoneal lymph nodes; VX2; cisplatin; lymphatic metastasis; peripheral blood
15.  Management experiences of primary angiosarcoma of breast: a retrospective study from single institute in the People’s Republic of China 
OncoTargets and therapy  2015;8:3237-3243.
Background
Primary angiosarcoma of breast (PAOB) is a rare and highly aggressive malignancy. There is no general agreement on optimal treatments or prognostic factors for this orphan disease. The objective of this study was to investigate the clinicopathologic features and management experiences of PAOB.
Methods
We performed a retrospective review of medical and pathologic records of 17 consecutive patients diagnosed with PAOB between January 2000 and February 2014 at FuDan University Shanghai Cancer Center. We evaluated the clinical characteristics, multimodality treatments, and associated clinical outcomes.
Results
A total of 16 patients were included in this retrospective study (median age at PAOB presentation 33.5 years, range: 19–56 years). Palpable tumor with or without breast skin ecchymosis presented as the most common initial symptom. All patients underwent surgery with curative intent. Median disease-free survival and overall survival (OS) were 9 months and 13.6 months, respectively. One-year and 3-year disease-free survival rates were 43.8% and 6.3%, with OS rates of 93.8% and 78.1%, respectively. High histologic grade indicated poorer OS by univariate analysis (P=0.01). However, neither adjuvant chemotherapy nor radiotherapy contributed to clinical outcomes in our series.
Conclusion
PAOB is considered as an infrequent breast neoplasm with aggressive characteristics. Histologic grade and early metastasis (within 12 months after diagnosis) are associated with poor prognosis. Regardless of grade, additional benefit was not observed with adjuvant therapy.
doi:10.2147/OTT.S92769
PMCID: PMC4640151  PMID: 26604790
primary angiosarcoma; breast neoplasm; histologic grade; adjuvant therapy
17.  18F-FDG Kinetics Parameters Depend on the Mechanism of Injury in Early Experimental Acute Respiratory Distress Syndrome 
PET with 18F-FDG allows for noninvasive assessment of regional lung metabolism reflective of neutrophilic inflammation. This study aimed at determining during early acute lung injury whether local 18F-FDG phosphorylation rate and volume of distribution were sensitive to the initial regional inflammatory response and whether they depended on the mechanism of injury: endotoxemia and surfactant depletion.
Methods
Twelve sheep underwent homogeneous unilateral surfactant depletion (alveolar lavage) and were mechanically ventilated for 4 h (positive end-expiratory pressure, 10 cm H2O; plateau pressure, 30 cm H2O) while receiving intravenous endotoxin (lipopolysaccharide-positive [LPS+] group; n = 6) or not (lipopolysaccharide-negative group; n = 6). 18F-FDG PET emission scans were then acquired. 18F-FDG phosphorylation rate and distribution volume were calculated with a 4-compartment model. Lung tissue expression of inflammatory cytokines was measured using real-time quantitative reverse transcription polymerase chain reaction.
Results
18F-FDG uptake increased in LPS+ (P = 0.012) and in surfactant-depleted sheep (P < 0.001). These increases were topographically heterogeneous, predominantly in dependent lung regions, and without interaction between alveolar lavage and LPS. The increase of 18F-FDG uptake in the LPS+ group was related both to increases in the 18F-FDG phosphorylation rate (P < 0.05) and to distribution volume (P < 0.01). 18F-FDG distribution volume increased with infiltrating neutrophils (P <0.001) and phosphorylation rate with the regional expression of IL-1β (P = 0.026), IL-8 (P = 0.011), and IL-10 (P = 0.023).
Conclusion
Non-invasive 18F-FDG PET-derived parameters represent histologic and gene expression markers of early lung injury. Pulmonary metabolism assessed with 18F-FDG PET depends on the mechanism of injury and appears to be additive for endotoxemia and surfactant depletion. 18F-FDG PET may be a valuable imaging biomarker of early lung injury.
doi:10.2967/jnumed.114.140962
PMCID: PMC4258066  PMID: 25286924
respiratory distress syndrome; adult; endotoxemia; pulmonary edema; positron emission tomography; fluorodeoxyglucose F18
18.  Assessing the health of the general population in England: how do the three- and five-level versions of EQ-5D compare? 
Background
The EQ-5D is a brief, generic measure of health status that can be easily incorporated into population health surveys. There are two versions of the EQ-5D for use in adult populations, one with 3 response levels in each of the instrument’s 5 dimensions (EQ-5D-3L) and one with 5 levels in each dimension (EQ-5D-5L). We compared the two versions as measures of self-reported health status in representative samples of the English general population.
Methods
EQ-5D-5L data were available from 996 respondents selected at random from residential postcodes who took part in the EQ-5D-5L value set for England study. EQ-5D-3L data were available from 7294 participants included in the 2012 Health Survey for England. Responses on the 3L and 5L versions of EQ-5D were compared by examining score distributions on the two versions, both in terms of the profile (dimensions) and the EQ-VAS. To determine the extent of variations in score according to respondent characteristics, we analysed health status reporting on the descriptive profile, EQ-5D Index, and EQ-VAS of both versions of EQ-5D by age, sex, and educational background. We used X2 to test for differences between respondent categories when analyzing EQ-5D profile data and the t test when analyzing EQ-5D Index and VAS scores.
Results
The 5L version of EQ-5D led to a considerably reduced ceiling effect and a larger proportion of respondents reporting severe health problems compared to the 3L. The 5L version also led to the use of a wider spread of health states; just 3 health states on the 3L covered 75 % of the sample, compared to 12 states on the 5L. Both versions showed poorer health status in older respondents, females, and those in a lower educational category and the EQ-5D-5L descriptive system, though not the Index or VAS, discriminated better between age groups than the 3L. There were no appreciable differences between the two versions in their ability to discriminate between groups defined by gender or educational level.
Conclusions
The new, expanded 5L version of EQ-5D may be a more useful instrument for the measurement of health status in population health surveys than the original 3L version.
doi:10.1186/s12955-015-0356-8
PMCID: PMC4618130  PMID: 26489956
EQ-5D-5L; EQ-5D-3L; Population Survey; England
19.  Clinical Application of the Heart Rate Deceleration Capacity Test to Predict Epirubicin-induced Cardiotoxicity 
Objective:
To investigate the clinical value of heart rate deceleration capacity (DC) in predicting the risk of epirubicin-induced cardiotoxicity.
Methods:
The CK-MB and cTnI levels and DC values of 86 patients were examined before chemotherapy and again after 2 and 4 cycles of chemotherapy. Patients were divided into low-risk group (LRG) (40 cases), medium-risk group (26 cases), and high-risk group (HRG) (20 cases) based on the calculated DC values.
Results:
After 4 cycles of chemotherapy, HRG showed a significantly greater increase in serum CK-MB (17.1 ± 4.9 vs. 14.6 ± 3.7) and cTnI (1.28 ± 0.38 vs. 1.0 ± 0.29) concentrations over the prechemotherapy levels when compared with LRG. After 2 and 4 cycles of chemotherapy, HRG exhibited a significantly greater increase in mean heart rate (2 cycles: 79.6 ± 6.0 vs. 77.6 ± 6.7; 4 cycles: 88.2 ± 10.2 vs. 82.4 ± 6.2) and the supraventricular (2 cycles: 68.9 ± 19.3 vs. 57.2 ± 17.6; 4 cycles: 131.1 ± 29.5 vs. 91.7 ± 16.5) and ventricular arrhythmia counts (2 cycles: 179.0 ± 20.5 vs. 162.3 ± 16.3; 4 cycles: 228.6 ± 44.8 vs. 187.4 ± 22.6) over the prechemotherapy values compared with LRG. When the supraventricular and ventricular arrhythmia counts measured after 4 cycles of chemotherapy were compared with those obtained before chemotherapy, HRG (131.1 ± 29.5 and 228.6 ± 44.8, respectively) showed the largest differences, followed by medium-risk group (107.4 ± 31.9 and 202.0 ± 29.8, respectively) and then LRG (91.7 ± 16.5 and 187.4 ± 22.6, respectively) (P < 0.01). After 4 cycles of chemotherapy, the incidence rates of ventricular arrhythmia greater than Lown's grade 3 (30% vs. 2.5%), QTc (20% vs. 0) elongation, and ST-T (40% vs. 5%) changes in HRG were significantly higher than those observed in LRG (P < 0.05).
Conclusions:
DC test was shown to be an effective predictor of the risk of epirubicin-induced cardiotoxicity.
doi:10.1097/FJC.0000000000000289
PMCID: PMC4598070  PMID: 26080056
heart rate deceleration capacity; epirubicin; cardiotoxicity; predictive value
20.  Using the Lymph Node Ratio to Evaluate the Prognosis of Stage II/III Breast Cancer Patients Who Received Neoadjuvant Chemotherapy and Mastectomy 
Purpose
This study was conducted to investigate the prognostic value of lymph node ratio (LNR) in stage II/III breast cancer patients who undergo mastectomy after neoadjuvant chemotherapy.
Materials and Methods
Clinical and pathological data describing stage II/III breast cancer patients were included in this retrospective study. The primary outcomes were locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS).
Results
Among 277 patients, there were 43 ypN0, 64 ypN1, 89 ypN2, and 81 ypN3 cases. Additionally, there were 43, 57, 92 and 85 cases in the LNR 0, 0.01-0.20, 0.21-0.65, and > 0.65 groups, respectively. The median follow-up was 49.5 months. Univariate analysis showed that both ypN stage and LNR were prognostic factors of LRFS, DMFS, DFS, and OS (p < 0.05). Multivariate analysis showed that LNR was an independent prognostic factor of LRFS, DMFS, DFS, and OS (p < 0.05), while ypN stage had no effect on prognosis (p > 0.05).
Conclusion
The integrated use of LNR and ypN may be suitable for evaluation the prognosis of stage II/III breast cancer patients who undergo mastectomy after neoadjuvant chemotherapy.
doi:10.4143/crt.2014.039
PMCID: PMC4614219  PMID: 25672578
Breast neoplasms; Mastectomy; Neoadjuvant therapy; Lymph nodes; Prognosis
21.  Cloning, Expression, and Characterization of a Thermophilic Endoglucanase, AcCel12B from Acidothermus cellulolyticus 11B 
The gene ABK52392 from the thermophilic bacterium Acidothermus cellulolyticus 11B was predicted to be endoglucanase and classified into glycoside hydrolase family 12. ABK52392 encodes a protein containing a catalytic domain and a carbohydrate binding module. ABK52392 was cloned and functionally expressed in Escherichia coli. After purification by Ni-NTA agarose affinity chromatography and Q-Sepharose® Fast Flow chromatography, the properties of the recombinant protein (AcCel12B) were characterized. AcCel12B exhibited optimal activity at pH 4.5 and 75 °C. The half-lives of AcCel12B at 60 and 70 °C were about 90 and 2 h, respectively, under acidic conditions. The specific hydrolytic activities of AcCel12B at 70 °C and pH 4.5 for sodium carboxymethylcellulose (CMC) and regenerated amorphous cellulose (RAC) were 118.3 and 104.0 U·mg−1, respectively. The Km and Vmax of AcCel12B for CMC were 25.47 mg·mL−1 and 131.75 U·mg−1, respectively. The time course of hydrolysis for RAC was investigated by measuring reducing ends in the soluble and insoluble phases. The total hydrolysis rate rapidly decreased after the early stage of incubation and the generation of insoluble reducing ends decreased earlier than that of soluble reducing ends. High thermostability of the cellulase indicates its potential commercial significance and it could be exploited for industrial application in the future.
doi:10.3390/ijms161025080
PMCID: PMC4632791  PMID: 26506341
Acidothermus cellulolyticus 11B; endoglucanase; AcCel12B; thermostability; reaction slowdown
22.  Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A 
Nature Communications  2015;6:8048.
Autophagy is a cellular catabolic process critical for cell viability and homoeostasis. Inhibition of mammalian target of rapamycin (mTOR) complex-1 (mTORC1) activates autophagy. A puzzling observation is that amino acid starvation triggers more rapid autophagy than pharmacological inhibition of mTORC1, although they both block mTORC1 activity with similar kinetics. Here we find that in addition to mTORC1 inactivation, starvation also causes an increase in phosphatase activity towards ULK1, an mTORC1 substrate whose dephosphorylation is required for autophagy induction. We identify the starvation-stimulated phosphatase for ULK1 as the PP2A–B55α complex. Treatment of cells with starvation but not mTORC1 inhibitors triggers dissociation of PP2A from its inhibitor Alpha4. Furthermore, pancreatic ductal adenocarcinoma cells, whose growth depends on high basal autophagy, possess stronger basal phosphatase activity towards ULK1 and require ULK1 for sustained anchorage-independent growth. Taken together, concurrent mTORC1 inactivation and PP2A–B55α stimulation fuel ULK1-dependent autophagy.
Starvation rapidly triggers autophagy by inactivating mTORC1 signalling, however mTORC1 inhibition does not fully recapitulate this rapid induction. Wong et al. identify a parallel starvation-senstive pathway regulating autophagy, mediated by protein phosphatase 2A-dependent dephosphorylation of ULK1.
doi:10.1038/ncomms9048
PMCID: PMC4552084  PMID: 26310906
23.  Environmental Pollution Liability Insurance in China: In Need of Strong Government Backing 
Ambio  2013;43(5):687-702.
Environmental pollution liability insurance was officially introduced in China only in 2006, as part of new market-based approaches for managing environmental risks. By 2012, trial applications of pollution insurance had been launched in 14 provinces and cities. More than ten insurance companies have entered the pollution insurance market with their own products and contracts. Companies in environmentally sensitive sectors and high-risk industries bought pollution insurance, and a few successful compensation cases have been reported. Still, pollution insurance faces a number of challenges in China. The absence of a national law weakens the legal basis of pollution insurance, and poor technical support stagnates further implementation. Moreover, current pollution insurance products have limited risk coverage, high premium rates, and low loss ratios, which make them fairly unattractive to polluters. Meanwhile, low awareness of environmental and social liabilities leads to limited demand for pollution insurance products by industrial companies. Hence, the pollution insurance market is not yet flourishing in China. To improve this situation, this economic instrument needs stronger backing by the Chinese state.
Electronic supplementary material
The online version of this article (doi:10.1007/s13280-013-0436-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s13280-013-0436-0
PMCID: PMC4132471  PMID: 23999850
Pollution insurance; China; Environmental risk management; Compensation; Pollution; Insurance companies
24.  Effects of bone marrow-derived mesenchymal stem cells transfected with survivin on pulmonary fibrosis in mice 
The aim of the present study was to investigate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) transfected with survivin on lung fibrosis in mice. Mice with bleomycin-induced pulmonary fibrosis were allocated at random to group A, B or C, and injected with 1×106 survivin gene-expressing BMSCs, 1×106 BMSCs or normal saline, respectively. A total of 6 mice were sacrificed from each group on days 7, 14 and 28 after treatment. The extent of alveolitis and pulmonary fibrosis was assessed and the apoptotic rates of the BMSCs and survivin-expressing BMSCs were detected. The content of surfactant protein A (SP-A) in the lung and hydroxyproline (Hyp) in the serum was measured. The mRNA expression levels of transforming growth factor (TGF)-β1 and matrix metalloproteinase (MMP)-9 in the lung tissue of the mice was detected. Furthermore, the protein expression levels of caspase-3 and −9 were detected. The apoptotic rates of the BMSCs (group B) and survivin-expressing BMSCs (group A) were 14.466±1.953 and 7.718±0.493%, respectively. The degree of lung fibrosis in groups A and B was reduced compared with that in group C. The hydroxyproline content in groups A and B was reduced compared with that in group C, and the SP-A content in groups A and B was increased compared with that in group C. The mRNA expression levels of TGF-β1 in group A were reduced compared with those in group B, and the levels in group B were reduced compared with those in group C. By contrast, the mRNA expression levels of MMP-9 in group A were increased compared with those in groups B and C, and the levels in group B were increased compared with those in group A. The expression levels of caspase-3 and −9 in group A were elevated compared with those in groups B and C. In conclusion, BMSCs are effective in preventing bleomycin-induced lung fibrosis, and survivin may enhance the protective effects of BMSCs.
doi:10.3892/etm.2015.2715
PMCID: PMC4665949  PMID: 26640562
mesenchymal stem cells; survivin; pulmonary fibrosis; mice
25.  Upregulation of miR-181s reverses mesenchymal transition by targeting KPNA4 in glioblastoma 
Scientific Reports  2015;5:13072.
The goal of this work was to explore the most effective miRNAs affecting glioblastoma multiforme (GBM) phenotype transition and malignant progression. We annotated 491 TCGA samples’ miRNA expression profiles according to their mRNA-based subtypes and found that the mesenchymal tumors had significantly decreased miR-181 family expression compared with the other three subtypes while the proneural subtype harbored extremely high miR-181 family expression. Patients with high miR-181 family expression had longer overall survival (p = 0.0031). We also confirmed that NF-κB-targeting genes and the EMT (epithelial-mesenchymal transition) pathway were inversely correlated with miR-181 family expression and that the entire miR-181 family inhibited glioma cell invasion and proliferation; of these, miR-181b was the most effective suppressor. Furthermore, miR-181b was validated to suppress EMT by targeting KPNA4 and was associated with survival outcome in the TCGA and CGGA datasets and in another independent cohort. The EMT-inhibitory effect of miR-181b was lost after KPNA4 expression was restored. We also identified the antitumorigenic activity of miR-181b in vitro and in vivo. Our results showed that miR-181 family expression was closely correlated with TCGA subtypes and patients’ overall survival, indicating that miR-181b, a tumor-suppressive miRNA, could be a novel therapeutic candidate for treating gliomas.
doi:10.1038/srep13072
PMCID: PMC4539550  PMID: 26283154

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