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1.  The fate of recent duplicated genes following a fourth-round whole genome duplication in a tetraploid fish, common carp (Cyprinus carpio) 
Scientific Reports  2015;5:8199.
Whole genome duplication (WGD) results in extensive genetic redundancy. In plants and yeast, WGD is followed by rapid gene deletions and intense expression differentiation with slow functional divergence. However, the early evolution of the gene differentiation processes is poorly understood in vertebrates because almost all studied WGDs are extremely ancient, and the genomes have returned to a diploid status. Common carp had a very recent fourth round of WGD dated to 8 million years ago. It therefore constitutes an ideal model to study early-stage functional divergence and expression differentiation in vertebrates. We identified 1,757 pairs of recently duplicated genes (RDGs) originating from this specific WGD and found that most ancestral genes were retained in duplicate. Most RDGs were conserved and under selective pressure. Gene expression analysis across six tissues revealed that 92.5% of RDG pairs were co-expressed in at least one tissue and that the expression of nearly half pairs ceased to be strongly correlated, indicating slow spatial divergence but rapid expression dissociation. Functional comparison revealed that 25% of pairs had functional divergence, of which neo- and sub-functionalization were the main outcomes. Our analysis revealed slow gene loss but rapid and intense expression and function differentiation after WGD.
doi:10.1038/srep08199
PMCID: PMC4314655  PMID: 25645996
2.  Genetic history of an archaic hominin group from Denisova Cave in Siberia 
Nature  2010;468(7327):1053-1060.
Using DNA extracted from a finger bone found in Denisova Cave in southern Siberia, we have sequenced the genome of an archaic hominin to about 1.9-fold coverage. This individual is from a group that shares a common origin with Neanderthals. This population was not involved in the putative gene flow from Neanderthals into Eurasians; however, the data suggest that it contributed 4–6% of its genetic material to the genomes of present-day Melanesians. We designate this hominin population ‘Denisovans’ and suggest that it may have been widespread in Asia during the Late Pleistocene epoch. A tooth found in Denisova Cave carries a mitochondrial genome highly similar to that of the finger bone. This tooth shares no derived morphological features with Neanderthals or modern humans, further indicating that Denisovans have an evolutionary history distinct from Neanderthals and modern humans.
doi:10.1038/nature09710
PMCID: PMC4306417  PMID: 21179161
3.  Dietary Flavonoids Modulate CYP2C to Improve Drug Oral Bioavailability and Their Qualitative/Quantitative Structure–Activity Relationship 
The AAPS Journal  2014;16(2):258-268.
This study aims to improve the drug oral bioavailability by co-administration with flavonoid inhibitors of the CYP2C isozyme and to establish qualitative and quantitative (QSAR) structure–activity relationships (SAR) between flavonoids and CYP2C. A total of 40 naturally occurring flavonoids were screened in vitro for CYP2C inhibition. Enzyme activity was determined by measuring conversion of tolbutamide to 4-hydroxytolbutamide by rat liver microsomes. The percent inhibition and IC50 of each flavonoid were calculated and used to develop SAR and QSAR. The most effective flavonoid was orally co-administered in vivo with a cholesterol-reducing drug, fluvastatin, which is normally metabolized by CYP2C. The most potent CYP2C inhibitor identified in vitro was tamarixetin (IC50 = 1.4 μM). This flavonoid enhanced the oral bioavailability of fluvastatin in vivo, producing a >2-fold increase in the area under the concentration–time curve and in the peak plasma concentration. SAR analysis indicated that the presence of a 2,3-double bond in the C ring, hydroxylation at positions 5, 6, and 7, and glycosylation had important effects on flavonoid–CYP2C interactions. These findings should prove useful for predicting the inhibition of CYP2C activity by other untested flavonoid-like compounds. In the present study, tamarixetin significantly inhibited CYP2C activity in vitro and in vivo. Thus, the use of tamarixetin could improve the therapeutic efficacy of drugs with low bioavailability.
doi:10.1208/s12248-013-9549-4
PMCID: PMC3933575  PMID: 24431079
bioavailability; CYP2C; flavonoid; structure–activity relationship; tamarixetin
4.  Dosimetric benefits of robust treatment planning for intensity modulated proton therapy for base-of-skull cancers 
Practical radiation oncology  2014;4(6):384-391.
Purpose
The clinical advantage of intensity modulated proton therapy (IMPT) may be diminished by range and patient setup uncertainties. We evaluated the effectiveness of robust optimization that incorporates uncertainties into the treatment planning optimization algorithm for treatment of base of skull cancers.
Methods and materials
We compared 2 IMPT planning methods for 10 patients with base of skull chordomas and chondrosarcomas: (1) conventional optimization, in which uncertainties are dealt with by creating a planning target volume (PTV); and (2) robust optimization, in which uncertainties are dealt with by optimizing individual spot weights without a PTV. We calculated root-mean-square deviation doses (RMSDs) for every voxel to generate RMSD volume histograms (RVHs). The area under the RVH curve was used for relative comparison of the 2 methods’ plan robustness. Potential benefits of robust planning, in terms of target dose coverage and homogeneity and sparing of organs at risk (OARs) were evaluated using established clinical metrics. Then the plan evaluation metrics were averaged and compared with 2-sided paired t tests. The impact of tumor volume on the effectiveness of robust optimization was also analyzed.
Results
Relative to conventionally optimized plans, robustly optimized plans were less sensitive for both targets and OARs. In the nominal scenario, robust and conventional optimization resulted in similar D95% doses (D95% clinical target volume [CTV]: 63.3 and 64.8 Gy relative biologic effectiveness [RBE]), P <.01]) and D5%-D95% (D5%-D95% CTV: 8.0 and 7.1 Gy[RBE], [P < .01); irradiation of OARs was less with robust optimization (brainstem V60: 0.076 vs 0.26 cm3 [P <.01], left temporal lobe V70: 0.22 vs 0.41 cm3, [P = .068], right temporal lobe V70: 0.016 vs 0.11 cm3, [P = .096], left cochlea Dmean: 28.1 vs 30.1 Gy[RBE], [P = .023], right cochlea Dmean: 23.7 vs 25.2 Gy [RBE], [P = .059]). Results in the worst-case scenario were analogous.
Conclusions
Robust optimization is effective for creating clinically feasible IMPT plans for tumors of the base of skull.
doi:10.1016/j.prro.2013.12.001
PMCID: PMC4238033  PMID: 25407859
5.  Draft Genome Sequence of the Cellulolytic Bacterium Clavibacter sp. CF11, a Strain Producing Cold-Active Cellulase 
Genome Announcements  2015;3(1):e01304-14.
Clavibacter sp. strain CF11, which was isolated from soil at a tomato-planting greenhouse in Inner Mongolia, North China, has a high capability for producing cold-active cellulase at low temperatures. Here, we report the draft genome sequence of strain CF11, which comprises 2,437 protein-coding sequences and 49 RNA-coding sequences.
doi:10.1128/genomeA.01304-14
PMCID: PMC4293624  PMID: 25555737
6.  Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice*  
Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson’s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and α-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and α-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and α-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.
doi:10.1631/jzus.B1400229
PMCID: PMC4288945  PMID: 25559956
Paraquat; Pulmonary fibrosis; Rapamycin; Transforming growth factor-β1; α-Smooth muscle actin; Methylprednisolone
7.  MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44 
Background
Metastasis have considered as an important clinical obstacle in the treatment of human cancer including bladder cancer. Post-transcriptional regulation has emerged as robust effectors of metastasis. MiRNAs are involved in cancer development and progression, acting as tumor suppressors or oncogenes. In this study, we focus on it that microRNA-34a functions as an anti-metastatic microRNA and suppress angiogenesis in bladder cancer by directly targeting CD44.
Methods
The expression of mir-34a was detected by quantitative real-time PCR. Oligonucleotide and lentivirus were used to overexpress miR-34a. Tube formation assay and transwell assay were used to examine the effect on bladder cancer tube formation, migration and invasion in vitro. Animal models were used to examine the effect on metastasis and angiogenesis in vivo. Luciferase assay was carried out to verify the precise target of miR-34a.
Results
We not only proved that mir-34a was significantly downregulated in bladder cancer tissues and cell lines but also that circulating miR-34a levels are reduced in bladder cancer, and their levels were positively relevance. Gain-of-function experiments investigated that increased mir-34a expression suppressed tube formation and reduced cell migration and invasion. In vivo metastasis, assays also demonstrated that overexpression of mir34a markedly inhibited bladder cancer metastasis. CD31, an endothelial cell–specific marker which stained in T24 tumors to evaluate for blood vessel density, the immunohistochemistry results showed that blood vessel quantification reduced dramatically in the T24 tumors over-expressing mir-34a. Combining with our previous studies and bioinformatics analysis, we expected that CD44 gene was a direct target of mir-34a, siRNA-mediated knockdown of CD44 partially phenocopied mir-34a overexpression suggesting that the pro-apoptotic role of mir-34a may be mediated primarily through CD44 regulation, whereas restoring the expression of CD44 attenuated the function of mir-34a in bladder cancer cells. Additionally, we identified that EMT (epithelial-mesenchymal transition) related proteins could be regulated by mir-34a which indicated that mir-34a could partially reserve EMT.
Conclusion
Our study defines a major metastasis and angiogenesis suppressive role for mir-34a, a microRNA functions as a tumor suppressor in bladder cancer by directly targeting CD44, which would be helpful as a therapeutic approach to block bladder cancer metastasis.
doi:10.1186/s13046-014-0115-4
PMCID: PMC4311467  PMID: 25551284
Bladder cancer cell; miR-34a; CD44; Metastatic; Angiogenesis
8.  One-stage partial vertebrectomy, titanium mesh implantation and pedicle screw fixation in the treatment of thoracolumbar burst fractures through a posterior approach 
Clinics  2014;69(12):804-808.
OBJECTIVE:
To analyze the clinical results of a partial vertebrectomy with titanium mesh implantation and pedicle screw fixation using a posterior approach to reconstruct the spine in the treatment of thoracolumbar burst fractures.
METHOD:
From January 2006 to August 2008, 20 patients with severe thoracolumbar fractures were treated.For vertebral bodies associated with one injured intervertebral disk, subtotal vertebrectomy surgery and single-segment fusion were performed. For vertebral bodies with two injured adjacent intervertebral disks, partial vertebrectomy surgery and two-segment fusion were performed.
RESULTS:
All 20 patients were followed up for 12 to 24 months (average of 18 months). There were no complications such as wound infections, hemopneumothorax or abdominal infections in any of the patients. The neurological status of all of the patients was improved by at least one American Spinal Injury Association grade by the last follow-up. The anterior vertebral body height was an average of 50.77% before surgery, 88.51% after surgery and 87.86% at the last follow up; the sagittal Cobb angle was improved, on average, from 26.15° to 5.39° and was 5.90° at the last follow up. The percentage of spinal stenosis was improved, on average, from 26.07% to 4.93%° and was 6.15% at the last follow up. There were significant differences in the anterior vertebral body height pre- and post-surgery and in the sagittal Cobb angle and the percentage of spinal stenosis (p<0) in all patients.
CONCLUSIONS:
This surgical procedure is simple and can accomplish decompression, reduction, fixation and fusion of the spine in one stage. This approach could be widely used in orthopedics.
doi:10.6061/clinics/2014(12)03
PMCID: PMC4286664  PMID: 25627991
Thoracolumbar Burst Fracture; Partial Vertebrectomy; Posterior Approach
9.  Relationships between actual and desired workplace characteristics and job satisfaction for community health workers in China: a cross-sectional study 
BMC Family Practice  2014;15(1):180.
Background
Community health workers are the main providers of community health services in China and have been important in the process of health system reform that has been in place since 2009. Therefore, it is critical that healthcare managers and policy decision makers motivate current staff and improve their job satisfaction. This study examined workplace characteristics and their contribution to job satisfaction in community health workers in Heilongjiang Province, China.
Methods
A cross-sectional survey of 448 community health workers, from three cities in Heilongjiang province, was conducted between October 1, 2012 and December 31, 2012. Multistage sampling procedures were used to measure socioeconomic and demographic status, job satisfaction, and both actual and desired workplace characteristics. Factor analysis was conducted to determine the main factors contributing to workplace characteristics, and multiple linear regression analysis was performed to assess the key determinants of job satisfaction.
Results
Eight groups of factors were identified as the most important workplace characteristics. These comprised system and policy; fringe benefits; work itself; work relationships; professional development; recognition; work environment; and remuneration. In all cases, all desired workplace characteristics were higher than the associated actual workplace characteristics. The main determinants of job satisfaction were occupation, years worked in health service institution, and five subscales representing the gap between desired and actual workplace characteristics, which were system and policy; fringe benefits; working relationship; professional development; and remuneration.
Conclusions
These findings suggested that managers wishing to enhance job satisfaction should assess workplace characteristics comprehensively and design mechanisms that reduce the gap between actual and desired workplace characteristics.
doi:10.1186/s12875-014-0180-y
PMCID: PMC4240823  PMID: 25403924
Actual workplace characteristics; Desired workplace characteristics; Job satisfaction; China
10.  The Effects of Respiratory Motion on Passively Scattered Proton Therapy vs. IMRT for Stage III Lung Cancer - Are Proton Plans More Sensitive to Breathing Motion? 
International journal of radiation oncology, biology, physics  2013;87(3):10.1016/j.ijrobp.2013.07.007.
Purpose
(1) To quantify and compare the effects of respiratory motion on paired passively scattered proton therapy (PSPT) and intensity modulated photon therapy (IMRT) plans. (2) To establish the relationship between the magnitude of tumor motion and the respiratory induced dose difference for both modalities.
Methods and Materials
In a randomized clinical trial comparing PSPT and IMRT, radiotherapy plans have been designed following common planning protocols. Four-dimensional (4D) dose was computed for PSPT and IMRT plans for a patient cohort with respiratory motion ranging 3-17 mm. Image registration and dose accumulation were performed using grayscale-based deformable image registration algorithms. The dose-volume histogram (DVH) differences (4D-3D) were compared for PSPT and IMRT. Changes in 4D-3D dose were correlated to the magnitude of tumor respiratory motion.
Results
The average 4D-3D dose to 95% of the internal target volume was close to zero, with 19/20 patients within 1% of prescribed dose for both modalities. The mean 4D-3D between the two modalities were not statistically significant (p <0.05) for all DVH indices (mean ± SD) except the lung V5 (PSPT: +1.1±0.9%, IMRT: +0.4±1.2%) and maximum cord dose (PSPT: +1.5±2.9 Gy, IMRT: 0.0±0.2 Gy). Changes in 4D-3D dose were correlated to tumor motion for only two indices: Dose to 95% PTV, and heterogeneity index.
Conclusions
With our current margin formalisms, target coverage was maintained in the presence of respiratory motion up to 17 mm for both PSPT and IMRT. Only 2/11 of 4D-3D indices (Lung V5 and spinal cord max) were statistically distinguishable between PSPT and IMRT, contrary to the notion that proton therapy will be more susceptible to respiratory motion. Due to the lack of strong correlations with 4D-3D dose differences in PSPT and IMRT, the extent of tumor motion was not an adequate predictor of potential dosimetric error caused by breathing motion.
doi:10.1016/j.ijrobp.2013.07.007
PMCID: PMC3825187  PMID: 24074932
IMRT; Proton Therapy; Lung Radiation Therapy; 4D Dose Calculation; Respiratory Motion
11.  Identifying radiation exposure biomarkers from mouse blood transcriptome 
Ionising radiation is a pleiotropic stress agent that may induce a variety of adverse effects. Molecular biomarker approaches possess promise to assess radiation exposure, however, the pleiotropic nature of ionising radiation induced transcriptional responses and the historically poor inter-laboratory performance of omics-derived biomarkers serve as barriers to identification of unequivocal biomarker sets. Here, we present a whole-genome survey of the murine transcriptomic response to physiologically relevant radiation doses, 2 Gy and 8 Gy. We used this dataset with the Random Forest algorithm to correctly classify independently generated data and to identify putative metabolite biomarkers for radiation exposure.
doi:10.1504/IJBRA.2013.054701
PMCID: PMC4180524  PMID: 23797995
ionising radiation exposure; radiation response biomarkers; murine blood transcriptome; reporter metabolites; inter-laboratory omics variation; random forests
12.  Self-Healing of Unentangled Polymer Networks with Reversible Bonds 
Macromolecules  2013;46(18):10.1021/ma401111n.
Self-healing polymeric materials are systems that after damage can revert to their original state with full or partial recovery of mechanical strength. Using scaling theory we study a simple model of autonomic self-healing of unentangled polymer networks. In this model one of the two end monomers of each polymer chain is fixed in space mimicking dangling chains attachment to a polymer network, while the sticky monomer at the other end of each chain can form pairwise reversible bond with the sticky end of another chain. We study the reaction kinetics of reversible bonds in this simple model and analyze the different stages in the self-repair process. The formation of bridges and the recovery of the material strength across the fractured interface during the healing period occur appreciably faster after shorter waiting time, during which the fractured surfaces are kept apart. We observe the slowest formation of bridges for self-adhesion after bringing into contact two bare surfaces with equilibrium (very low) density of open stickers in comparison with self-healing. The primary role of anomalous diffusion in material self-repair for short waiting times is established, while at long waiting times the recovery of bonds across fractured interface is due to hopping diffusion of stickers between different bonded partners. Acceleration in bridge formation for self-healing compared to self-adhesion is due to excess non-equilibrium concentration of open stickers. Full recovery of reversible bonds across fractured interface (formation of bridges) occurs after appreciably longer time than the equilibration time of the concentration of reversible bonds in the bulk.
doi:10.1021/ma401111n
PMCID: PMC3857756  PMID: 24347684
Self-healing; polymer networks; reversible; scaling theory
13.  Fibulin-1 is epigenetically down-regulated and related with bladder cancer recurrence 
BMC Cancer  2014;14(1):677.
Background
Bladder cancer is one of the most common cancers worldwide. Fibulin-1, a multi-functional extracellular matrix protein, has been demonstrated to be involved in many kinds of cancers, while its function in bladder cancer remains unclear. So here we investigated the expression and function of fibulin-1 in Bladder cancer.
Methods
We used real-time PCR, Western blot analysis and immunohistochemistry to determine the expression of fibulin-1 in Bladder cancer cells and patient tissues respectively. Methylation-specific PCR and quantitative sequencing were used to examine the methylation status of FBLN1 gene promoter. Eukaryotic expression plasmid and lentiviral vector were used to overexpress fibulin-1 in Bladder cancer cells 5637, HT-1376 to investigate its function in vitro and in vivo.
Results
We identified that fibulin-1 was significantly down-regulated in bladder cancer, and its dysregulation was associated with non-muscle-invasive bladder cancer (NMIBC) grade and recurrence. The promoter region of FBLN1 was generally methylated in bladder cancer cell lines and tissues, further investigation in patient tissues showed that the methylation status was associated with the fibulin-1 expression. Overexpression of fibulin-1 significantly suppressed tumor growth, induced tumor cell apoptosis, decreased cell motility, and inhibited angiogenesis in cultured bladder cancer cells and xenograft tumor in nude mice.
Conclusions
Altogether, our results indicated that fibulin-1 expression is associated with NMIBC grade and recurrence, it is epigenetically down-regulated and functions as a tumor suppressor gene and angiogenesis inhibitor in bladder cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-677) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-677
PMCID: PMC4180143  PMID: 25234557
Fibulin-1; Bladder cancer; Promoter hypermethylation; Tumor suppressor gene; Cancer recurrence
15.  Claims, liabilities, injures and compensation payments of medical malpractice litigation cases in China from 1998 to 2011 
Background
Although China experienced great improvement in their health system, disputes between patients and doctors have increasingly intensified, reaching an unprecedented level. Retrospective analysis of medical malpractice litigation can discover the characteristics and fundamental cause of these disagreements.
Methods
We analyzed medical malpractice litigation data from 1998 to 2011 for characteristics of claims via a litigation database within a nationwide database of cases (1086 cases) in China, including claims, liabilities, injures, and compensation payments.
Results
Among the cases analyzed, 76 percent of claims received compensation in civil judgment (640 out of 841), while 93 percent were fault liability in paid judgment (597 out of 640). The average time span between the occurrence of the injury dispute and closure of claims was 3 years. Twenty-two percent of claims (183 of 841) were caused by injury, poisoning, and other external causes. Seventy-nine percent of claims (472 of 597) were contributed to by errors in medical technology. The median damage compensation payment for death was significantly lower than for serious injuries (P < 0.001; death, $13270 [IQR, $7617–$23181]; serious injury, $23721 [IQR, $10367–$57058]). Finally, there was no statistically significant difference in the median mental compensation between minor injury, serious injury, and death (P = 0.836).
Conclusion
The social reasons for the conflict and high payment were catastrophic out-of-pocket health-care expense in addition to the high expectations for treatment in China. There were no distinguishing features between China and other countries with respect to time of suits, facilities, and specialties in these claims. The compensation for damages in different medical injuries was unfair in China.
doi:10.1186/1472-6963-14-390
PMCID: PMC4261607  PMID: 25218509
Claims; Compensation; Medical malpractice; Medical litigation
16.  Evaluation of the systematic error in using 3D dose calculation in scanning beam proton therapy for lung cancer 
The objective of this study was to evaluate and understand the systematic error between the planned three-dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single-field and multi-field optimized scanning beam proton therapy plans were generated for 10 patients with stage II–III lung cancer with a mix of tumor motion and size. 3D doses in CT data sets for different respiratory phases and the time weighted average CT, as well as the four-dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose volume histogram (DVH) and voxel-based techniques and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses using the internal GTV override technique. The DVH and voxel-based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single-field or multi-field optimized) did not affect the observed systematic error.
In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient-specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.
PMCID: PMC4161985  PMID: 25207565
4DCT; motion management; dose calculation; proton therapy; pencil beam scanning
17.  A single-field integrated boost treatment planning technique for spot scanning proton therapy 
Purpose
Intensity modulated proton therapy (IMPT) plans are normally generated utilizing multiple field optimization (MFO) techniques. Similar to photon based IMRT, MFO allows for the utilization of a simultaneous integrated boost in which multiple target volumes are treated to discrete doses simultaneously, potentially improving plan quality and streamlining quality assurance and treatment delivery. However, MFO may render plans more sensitive to the physical uncertainties inherent to particle therapy. Here we present clinical examples of a single-field integrated boost (SFIB) technique for spot scanning proton therapy based on single field optimization (SFO) treatment-planning techniques.
Methods and materials
We designed plans of each type for illustrative patients with central nervous system (brain and spine), prostate and head and neck malignancies. SFIB and IMPT plans were constructed to deliver multiple prescription dose levels to multiple targets using SFO or MFO, respectively. Dose and fractionation schemes were based on the current clinical practice using X-ray IMRT in our clinic. For inverse planning, dose constraints were employed to achieve the desired target coverage and normal tissue sparing. Conformality and inhomogeneity indices were calculated to quantify plan quality. We also compared the worst-case robustness of the SFIB, sequential boost SFUD, and IMPT plans.
Results
The SFIB technique produced more conformal dose distributions than plans generated by sequential boost using a SFUD technique (conformality index for prescription isodose levels; 0.585 ± 0.30 vs. 0.435 ± 0.24, SFIB vs. SFUD respectively, Wilcoxon matched-pair signed rank test, p < 0.01). There was no difference in the conformality index between SFIB and IMPT plans (0.638 ± 0.27 vs. 0.633 ± 0.26, SFIB vs. IMPT, respectively). Heterogeneity between techniques was not significantly different. With respect to clinical metrics, SFIB plans proved more robust than the corresponding IMPT plans.
Conclusions
SFIB technique for scanning beam proton therapy (SSPT) is now routinely employed in our clinic. The SFIB technique is a natural application of SFO and offers several advantages over SFUD, including more conformal plans, seamless treatment delivery and more efficient planning and QA. SFIB may be more robust than IMPT and has been the treatment planning technique of choice for some patients.
doi:10.1186/1748-717X-9-202
PMCID: PMC4262206  PMID: 25212571
Proton therapy; Spot scanning; Single-field optimization; Single field integrated boost; SFIB
18.  Evaluation of characteristics and surgical outcomes in cervical spondylotic amyotrophy 
Indian Journal of Orthopaedics  2014;48(5):511-517.
Background:
Cervical spondylotic amyotrophy (CSA) is a rare clinical syndrome resulting from cervical spondylosis. Surgical treatment includes anterior cervical decompression and fusion (ACDF), and laminoplasty with or without foraminotomy. Some studies indicate that ACDF is an effective method for treating CSA because anterior decompression with or without medial foraminotomy can completely eliminate anterior and/or anterolateral lesions. We retrospectively evaluated outcome of surgical outcome by anterior cervical decompression and fusion (ACDF).
Materials and Methods:
28 CSA patients, among whom 12 had proximal type CSA and 16 had distal type CSA, treated by ACDF, were evaluated clinicoradiologically. The improvement in atrophic muscle power was assessed by manual muscle testing (MMT) and the recovery rate of the patients was determined on the basis of the Japanese Orthopedic Association (JOA) scores. Patient satisfaction was also examined.
Results:
The percentage of patients, who gained 1 or more grades of muscle power improvement, as determined by MMT, was 91.7% for those with proximal type CSA and 37.5% for those with distal type CSA (P < 0.01). The JOA score-based recovery rates of patients with proximal type and distal type CSA were 60.8% and 41.8%, respectively (P < 0.05). Patient satisfaction was 8.2 for those with proximal type CSA and 6.9 for those with distal type CSA (P < 0.01). A correlation was observed among the levels of improvement in muscle power, JOA score based recovery rate, patient satisfaction and course of disease (P < 0.05).
Conclusion:
ACDF can effectively improve the clinical function of patients with CSA and result in good patient satisfaction despite the surgical outcomes for distal type CSA being inferior to those for proximal type CSA. Course of disease is the fundamental factor that affects the surgical outcomes for CSA. We recommend that patients with CSA undergo surgical intervention as early as possible.
doi:10.4103/0019-5413.139875
PMCID: PMC4175868  PMID: 25298561
Amyotrophy; anterior cervical decompression and fusion; cervical spondylosis; Spine; cervical vertebrae; spondylitis; decompression; amyotrophy
19.  Role of microRNA-mediated MMP regulation in the treatment and diagnosis of malignant tumors 
Cancer Biology & Therapy  2013;14(9):796-805.
Matrix metalloproteinases (MMPs) play important roles in tumor cell proliferation and apoptosis and contribute to tumor growth, angiogenesis, migration, and invasion primarily via extracellular matrix (ECM) degradation and/or the activation of pre-pro-growth factors. Recently, there has been considerable interest in the posttranscriptional regulation of MMPs via microRNAs (miRs). In this review, we highlight the complicated interactive network comprised of different MMPs and their regulating microRNAs, as well as the ways in which these interactions influence cancer development, including tumor angiogenesis, growth, invasion, and metastasis. Based on the conclusive roles that microRNAs play in the regulation of MMPs during cancer progression, we discuss the potential use of microRNA-mediated MMP regulation in the diagnosis and treatment of tumors from the clinical perspective. In particular, microRNA-mediated MMP regulation may lead to the development of promising new MMP inhibitors that target MMPs more selectively, and this approach may also target multiple molecules in a network, leading to the efficient regulation of distinct biological processes relevant to malignant tumors. A thorough understanding of the mechanisms underlying microRNA-mediated MMP regulation during tumor progression will help to provide new insights into the diagnosis and treatment of malignant tumors.
doi:10.4161/cbt.25936
PMCID: PMC3909548  PMID: 23917402
matrix metalloproteinase; microRNAs; angiogenesis; tumor growth; migration; invasion; extracellular matrix
20.  Statistical Assessment of Proton Treatment Plans Under Setup and Range Uncertainties 
Purpose
To evaluate a method for quantifying the effect of setup errors and range uncertainties on dose distribution and dose–volume histogram using statistical parameters; and to assess existing planning practice in selected treatment sites under setup and range uncertainties.
Methods and Materials
Twenty passively scattered proton lung cancer plans, 10 prostate, and 1 brain cancer scanning-beam proton plan(s) were analyzed. To account for the dose under uncertainties, we performed a comprehensive simulation in which the dose was recalculated 600 times per given plan under the influence of random and systematic setup errors and proton range errors. On the basis of simulation results, we determined the probability of dose variations and calculated the expected values and standard deviations of dose–volume histograms. The uncertainties in dose were spatially visualized on the planning CT as a probability map of failure to target coverage or overdose of critical structures.
Results
The expected value of target coverage under the uncertainties was consistently lower than that of the nominal value determined from the clinical target volume coverage without setup error or range uncertainty, with a mean difference of −1.1% (−0.9% for breath-hold), −0.3%, and −2.2% for lung, prostate, and a brain cases, respectively. The organs with most sensitive dose under uncertainties were esophagus and spinal cord for lung, rectum for prostate, and brain stem for brain cancer.
Conclusions
A clinically feasible robustness plan analysis tool based on direct dose calculation and statistical simulation has been developed. Both the expectation value and standard deviation are useful to evaluate the impact of uncertainties. The existing proton beam planning method used in this institution seems to be adequate in terms of target coverage. However, structures that are small in volume or located near the target area showed greater sensitivity to uncertainties.
doi:10.1016/j.ijrobp.2013.04.009
PMCID: PMC3755369  PMID: 23688812
21.  The complete genome sequence of a Neandertal from the Altai Mountains 
Nature  2013;505(7481):43-49.
We present a high-quality genome sequence of a Neandertal woman from Siberia. We show that her parents were related at the level of half siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neandertal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neandertals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high quality Neandertal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neandertals and Denisovans.
doi:10.1038/nature12886
PMCID: PMC4031459  PMID: 24352235
22.  Rapid Detection of Mycobacterium tuberculosis and Pyrazinamide Susceptibility Related to pncA Mutations in Sputum Specimens through an Integrated Gene-to-Protein Function Approach 
Journal of Clinical Microbiology  2014;52(1):260-267.
Testing the pyrazinamide (PZA) susceptibility of Mycobacterium tuberculosis isolates is challenging. In a previous paper, we described the development of a rapid colorimetric test for the PZA susceptibility of M. tuberculosis by a PCR-based in vitro-synthesized-pyrazinamidase (PZase) assay. Here, we present an integrated approach to detect M. tuberculosis and PZA susceptibility directly from sputum specimens. M. tuberculosis was detected first, using a novel long-fragment quantitative real-time PCR (LF-qPCR), which amplified a fragment containing the whole pncA gene. Then, the positive amplicons were sequenced to find mutations in the pncA gene. For new mutations not found in the Tuberculosis Drug Resistance Mutation Database (www.tbdreamdb.com), the in vitro PZase assay was used to test the PZA resistance. This approach could detect M. tuberculosis within 3 h with a detection limit of 7.8 copies/reaction and report the PZA susceptibility within 2 days. In an initial testing of 213 sputum specimens, the LF-qPCR found 53 positive samples with 92% sensitivity and 97% specificity compared to the culture test for M. tuberculosis detection. DNA sequencing of the LF-qPCR amplicons revealed that 49 samples were PZA susceptible and 1 was PZA resistant. In the remaining 3 samples, with new pncA mutations, the in vitro PZase assay found that 1 was PZA susceptible and 2 were PZA resistant. This integrated approach provides a rapid, efficient, and relatively low-cost solution for detecting M. tuberculosis and PZA susceptibility without culture.
doi:10.1128/JCM.02285-13
PMCID: PMC3911477  PMID: 24226918
23.  Gallic Acid Ameliorated Impaired Glucose and Lipid Homeostasis in High Fat Diet-Induced NAFLD Mice 
PLoS ONE  2014;9(6):e96969.
Gallic acid (GA), a naturally abundant plant phenolic compound in vegetables and fruits, has been shown to have potent anti-oxidative and anti-obesity activity. However, the effects of GA on nonalcoholic fatty liver disease (NAFLD) are poorly understood. In this study, we investigated the beneficial effects of GA administration on nutritional hepatosteatosis model by a more “holistic view” approach, namely 1H NMR-based metabolomics, in order to prove efficacy and to obtain information that might lead to a better understanding of the mode of action of GA. Male C57BL/6 mice were placed for 16 weeks on either a normal chow diet, a high fat diet (HFD, 60%), or a high fat diet supplemented with GA (50 and 100 mg/kg/day, orally). Liver histopathology and serum biochemical examinations indicated that the daily administration of GA protects against hepatic steatosis, obesity, hypercholesterolemia, and insulin resistance among the HFD-induced NAFLD mice. In addition, partial least squares discriminant analysis scores plots demonstrated that the cluster of HFD fed mice is clearly separated from the normal group mice plots, indicating that the metabolic characteristics of these two groups are distinctively different. Specifically, the GA-treated mice are located closer to the normal group of mice, indicating that the HFD-induced disturbances to the metabolic profile were partially reversed by GA treatment. Our results show that the hepatoprotective effect of GA occurs in part through a reversing of the HFD caused disturbances to a range of metabolic pathways, including lipid metabolism, glucose metabolism (glycolysis and gluconeogenesis), amino acids metabolism, choline metabolism and gut-microbiota-associated metabolism. Taken together, this study suggested that a 1H NMR-based metabolomics approach is a useful platform for natural product functional evaluation. The selected metabolites are potentially useful as preventive action biomarkers and could also be used to help our further understanding of the effect of GA in hepatosteatosis mice.
doi:10.1371/journal.pone.0096969
PMCID: PMC4053315  PMID: 24918580
24.  Work stress, work motivation and their effects on job satisfaction in community health workers: a cross-sectional survey in China 
BMJ Open  2014;4(6):e004897.
Objective
It is well documented that both work stress and work motivation are key determinants of job satisfaction. The aim of this study was to examine levels of work stress and motivation and their contribution to job satisfaction among community health workers in Heilongjiang Province, China.
Design
Cross-sectional survey.
Setting
Heilongjiang Province, China.
Participants
The participants were 930 community health workers from six cities in Heilongjiang Province.
Primary and secondary outcome measures
Multistage sampling procedures were used to measure socioeconomic and demographic status, work stress, work motivation and job satisfaction. Logistic regression analysis was performed to assess key determinants of job satisfaction.
Results
There were significant differences in some subscales of work stress and work motivation by some of the socioeconomic characteristics. Levels of overall stress perception and scores on all five work stress subscales were higher in dissatisfied workers relative to satisfied workers. However, levels of overall motivation perception and scores on the career development, responsibility and recognition motivation subscales were higher in satisfied respondents relative to dissatisfied respondents. The main determinants of job satisfaction were occupation; age; title; income; the career development, and wages and benefits subscales of work stress; and the recognition, responsibility and financial subscales of work motivation.
Conclusions
The findings indicated considerable room for improvement in job satisfaction among community health workers in Heilongjiang Province in China. Healthcare managers and policymakers should take both work stress and motivation into consideration, as two subscales of work stress and one subscale of work motivation negatively influenced job satisfaction and two subscales of work motivation positively influenced job satisfaction.
doi:10.1136/bmjopen-2014-004897
PMCID: PMC4054641  PMID: 24902730
Public Health
25.  Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure 
The Journal of Clinical Investigation  2014;124(7):3047-3060.
The pathogenesis of mucoinfective lung disease in cystic fibrosis (CF) patients likely involves poor mucus clearance. A recent model of mucus clearance predicts that mucus flow depends on the relative mucin concentration of the mucus layer compared with that of the periciliary layer; however, mucin concentrations have been difficult to measure in CF secretions. Here, we have shown that the concentration of mucin in CF sputum is low when measured by immunologically based techniques, and mass spectrometric analyses of CF mucins revealed mucin cleavage at antibody recognition sites. Using physical size exclusion chromatography/differential refractometry (SEC/dRI) techniques, we determined that mucin concentrations in CF secretions were higher than those in normal secretions. Measurements of partial osmotic pressures revealed that the partial osmotic pressure of CF sputum and the retained mucus in excised CF lungs were substantially greater than the partial osmotic pressure of normal secretions. Our data reveal that mucin concentration cannot be accurately measured immunologically in proteolytically active CF secretions; mucins are hyperconcentrated in CF secretions; and CF secretion osmotic pressures predict mucus layer–dependent osmotic compression of the periciliary liquid layer in CF lungs. Consequently, mucin hypersecretion likely produces mucus stasis, which contributes to key infectious and inflammatory components of CF lung disease.
doi:10.1172/JCI73469
PMCID: PMC4072023  PMID: 24892808

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