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1.  Prognostic value and predictive threshold of tumor volume for patients with locally advanced nasopharyngeal carcinoma receiving intensity-modulated radiotherapy 
Background
Gross target volume of primary tumor (GTV-P) is very important for the prognosis prediction of patients with nasopharyngeal carcinoma (NPC), but it is unknown whether the same is true for locally advanced NPC patients treated with intensity-modulated radiotherapy (IMRT). This study aimed to clarify the prognostic value of tumor volume for patient with locally advanced NPC receiving IMRT and to find a suitable cut-off value of GTV-P for prognosis prediction.
Methods
Clinical data of 358 patients with locally advanced NPC who received IMRT were reviewed. Receiver operating characteristic (ROC) curves were used to identify the cut-off values of GTV-P for the prediction of different endpoints [overall survival (OS), local relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS)] and to test the prognostic value of GTV-P when compared with that of the American Joint Committee on Cancer T staging system.
Results
The 358 patients with locally advanced NPC were divided into two groups by the cut-off value of GTV-P as determined using ROC curves: 219 (61.2%) patients with GTV-P ≤46.4 mL and 139 (38.8%) with GTV-P >46.4 mL. The 3-year OS, LRFS, DMFS, and DFS rates were all higher in patients with GTV-P ≤46.4 mL than in those with GTV-P > 46.4 mL (all P < 0.05). Multivariate analysis indicated that GTV-P >46.4 mL was an independent unfavorable prognostic factor for patient survival. The ROC curve verified that the predictive ability of GTV-P was superior to that of T category (P < 0.001). The cut-off values of GTV-P for the prediction of OS, LRFS, DMFS, and DFS were 46.4, 57.9, 75.4 and 46.4 mL, respectively.
Conclusion
In patients with locally advanced NPC, GTV-P >46.4 mL is an independent unfavorable prognostic indicator for survival after IMRT, with a prognostic value superior to that of T category.
doi:10.1186/s40880-016-0159-2
PMCID: PMC5112747  PMID: 27852284
Nasopharyngeal carcinoma; Intensity-modulated radiotherapy; Gross target volume of primary tumor; Prognosis
2.  Enhancing stability and efficiency of perovskite solar cells with crosslinkable silane-functionalized and doped fullerene 
Nature Communications  2016;7:12806.
The instability of hybrid perovskite materials due to water and moisture arises as one major challenge to be addressed before any practical application of the demonstrated high efficiency perovskite solar cells. Here we report a facile strategy that can simultaneously enhance the stability and efficiency of p–i–n planar heterojunction-structure perovskite devices. Crosslinkable silane molecules with hydrophobic functional groups are bonded onto fullerene to make the fullerene layer highly water-resistant. Methylammonium iodide is introduced in the fullerene layer for n-doping via anion-induced electron transfer, resulting in dramatically increased conductivity over 100-fold. With crosslinkable silane-functionalized and doped fullerene electron transport layer, the perovskite devices deliver an efficiency of 19.5% with a high fill factor of 80.6%. A crosslinked silane-modified fullerene layer also enhances the water and moisture stability of the non-sealed perovskite devices by retaining nearly 90% of their original efficiencies after 30 days' exposure in an ambient environment.
Perovskite solar cells reach high efficiencies but their stability remains a challenge. Here, Bai et al. functionalize the fullerene-based transport layer with hydrophobic and crosslinkable molecules to prepare devices reaching 19% efficiency and degrading by 10% over a month in ambient conditions.
doi:10.1038/ncomms12806
PMCID: PMC5059465  PMID: 27703136
4.  Accelerated partial breast irradiation in an Asian population: dosimetric findings and preliminary results of a multicatheter interstitial program 
OncoTargets and therapy  2016;9:5561-5566.
Introduction
Accelerated partial breast irradiation (APBI) using the multicatheter method has excellent cosmesis and low rates of long-term toxicity. However, there are few studies looking at the feasibility of this procedure and the outcomes in an Asian population. This study aims to look at outcomes at our hospital.
Methods
We identified 121 patients treated with APBI at our center between 2008 and 2014. The median follow-up for our patient group was 30 months (range 3.7–66.5). The prescribed dose per fraction was 3.4 Gy in 10 fractions. In this study population, 71% of the patients were Chinese while 15% (n=19) were of other Asian ethnicity.
Results
In this study, the median breast volume was 850 cc (range 216–2,108) with 59.5% (n=72) patients with a breast volume of <1,000 cc. The average planning target volume was 134 cc (range 28–324). The number of catheters used ranged from 8 to 25 with an average of 18 catheters used per patient. We achieved an average dose homogeneity index of 0.76 in our patients. The average D90(%) was 105% and the average D90(Gy) was 3.6 Gy per fraction. The median volume receiving 100% of the prescribed dose (V100) was 161.7 cc (range 33.9–330.1), 150% of the prescribed dose (V150) and 200% of the prescribed dose (V200) was 39.4 cc (range 14.6–69.6) and 14.72 cc (range 6.48–22.25), respectively. Our dosimetric outcomes were excellent even in patients with breast volume under 1,000 cc. There were no cases of grade 3 skin toxicity or acute pneumonitis. Two patients had a postoperative infection and two patients had fat necrosis postprocedure.
Conclusion
Multicatheter high dose rate APBI is a safe and feasible procedure that can be carried out with minimal toxicity in Asian patients with breast volumes under 1,000 cc.
doi:10.2147/OTT.S106758
PMCID: PMC5021060  PMID: 27660474
breast; Asian; multicatheter; brachytherapy
5.  A high-throughput-compatible assay to measure the degradation of endogenous Huntingtin proteins 
Acta Pharmacologica Sinica  2016;37(10):1307-1314.
Aim:
The accumulation of disease-causing proteins is a common hallmark of many neurodegenerative disorders. Measuring the degradation of such proteins using high-throughput-compatible assays is highly desired for the identification of genetic and chemical modulators of degradation. For example, Huntington's disease (HD) is an incurable hereditary neurodegenerative disorder caused by the cytotoxicity of mutant huntingtin protein (mHTT). The high-throughput measurement of mHTT degradation is important in HD drug discovery and research. Existing methods for such purposes have limitations due to their dependence on protein tags or pan protein synthesis inhibitors. Here, we report a high-throughput-compatible pulse-chase method (CH-chase) for the measurement of endogenous tag-free huntingtin protein (HTT) degradation based on Click chemistry and Homogeneous Time Resolved Fluorescence (HTRF) technologies.
Methods:
The pulsed-labeled proteins were conjugated with biotin using the click reaction strain-promoted alkyne-azide cycloaddition (SPAAC), and the chase signals were calculated by measuring the reduction percentage of the HTT HTRF signals after pull-down with streptavidin beads.
Results:
We validated that the signals were within the linear detection range and were HTT-specific. We successfully measured the degradation of endogenous HTT in a high-throughput-compatible format using 96-well plates. The predicted changes of HTT degradation by known modifiers were observed, which confirmed that the assay is suitable for the identification of HTT degradation modifiers.
Conclusion:
We have established the first high-throughput-compatible assay capable of measuring endogenous, tag-free HTT degradation, providing a valuable tool for HD research and drug discovery. The method could be applied to other proteins and can facilitate research on other neurodegenerative disorders and proteinopathies.
doi:10.1038/aps.2016.31
PMCID: PMC5057231  PMID: 27264314
click chemistry; SPAAC; high-throughput; pulse-chase; protein degradation; Huntington's disease; PolyQ
6.  Achieving ultranarrow graphene perfect absorbers by exciting guided-mode resonance of one-dimensional photonic crystals 
Scientific Reports  2016;6:32312.
Graphene perfect absorbers with ultranarrow bandwidth are numerically proposed by employing a subwavelength dielectric grating to excite the guided-mode resonance of one-dimensional photonic crystals (1DPCs). Critical coupling of the guided-mode resonance of 1DPCs to graphene can produce perfect absorption with a ultranarrow bandwidth of 0.03 nm. The quality factor of the absorption peak reaches a ultrahigh value of 20000. It is also found that the resonant absorption peaks can be tuned by controlling the dispersion line of the guided mode and the period of the grating. When the parameters of the grating and the 1DPCs are suitably set, the perfect absorption peaks can be tuned to any randomly chosen wavelength in the visible wavelength range.
doi:10.1038/srep32312
PMCID: PMC5006081  PMID: 27577721
7.  Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway 
Cell Death & Disease  2016;7(8):e2324-.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells.
doi:10.1038/cddis.2016.227
PMCID: PMC5108316  PMID: 27490929
8.  HMGB1-RAGE Axis Makes No Contribution to Cardiac Remodeling Induced by Pressure-Overload 
PLoS ONE  2016;11(6):e0158514.
High-mobility group box1 (HMGB1) exerts effects on inflammation by binding to receptor for advanced glycation end products (RAGE) or Toll-like receptor 4. Considering that inflammation is involved in pressure overload-induced cardiac hypertrophy, we herein attempted to investigate whether HMGB1 plays a role in myocardial hypertrophy in RAGE knockout mice as well as in the growth and apoptosis of cardiomyocytes. The myocardial expression of RAGE was not significantly changed while TLR4 mRNA was upregulated in response to transverse aortic constriction (TAC) for 1 week. The myocardial expression of HMGB1 protein was markedly increased in TAC group when compared to the sham group. Heart weight to body weight ratio (HW/BW) and lung weight to body weight ratio (LW/BW) were evaluated in RAGE knockout (KO) and wild-type (WT) mice 1 week after TAC. Significant larger HW/BW and LW/BW ratios were found in TAC groups than the corresponding sham groups, but no significant difference was found between KO and WT TAC mice. Similar results were also found when TAC duration was extended to 4 weeks. Cultured neonatal rat cardiomyocytes were treated with different concentrations of recombinant HMGB1, then cell viability was determined using MTT and CCK8 assays and cell apoptosis was determined by Hoechst staining and TUNEL assay. The results came out that HMGB1 exerted no influence on viability or apoptosis of cardiomyocytes. Besides, the protein expression levels of Bax and Bcl2 in response to different concentrations of HMGB1 were similar. These findings indicate that HMGB1 neither exerts influence on cardiac remodeling by binding to RAGE nor induces apoptosis of cardiomyocytes under physiological condition.
doi:10.1371/journal.pone.0158514
PMCID: PMC4927190  PMID: 27355349
9.  Differential Expression Patterns of EGF, EGFR, and ERBB4 in Nasal Polyp Epithelium 
PLoS ONE  2016;11(6):e0156949.
Epidermal growth factor receptors play an important role in airway epithelial cell growth and differentiation. The current study investigates the expression profiles of EGF, EGFR and ERBB4 in patients with nasal polyps (NP), and their response to glucocorticosteroid (GC) treatment. Fifty patients with NP (40 without GC treatment and 10 with oral GC) and 20 control subjects with septal deviation were recruited into the study. Protein levels of EGF, EGFR, and ERBB4 were evaluated by immune-staining. In healthy nasal epithelium, EGF and EGFR localized within p63+ basal cells, while ERBB4 localized within ciliated cells. GC-naïve NP epithelium showed weak expression of EGF in 90% of samples versus 5% of controls. EGFR was significantly increased in the epithelium with basal cell hyperplasia from GC-naïve NPs (78%, 31/40) compared to controls (23%, 4/17). EGFR was also found in some degranulating goblet cells. ERBB4 expression was significantly higher in hyperplastic epithelium from GC-naïve NPs (65%, 26/40) than in controls (6%, 1/17). GC treatment restored the EGF expression and normalized the EGFR and ERBB4 expression in NPs. Differential expression patterns of EGF, EGFR, and ERBB4 are essential in epithelial restitution and remodeling in nasal epithelium.
doi:10.1371/journal.pone.0156949
PMCID: PMC4902223  PMID: 27285994
10.  Pharmacological modulation of autophagy to protect cardiomyocytes according to the time windows of ischaemia/reperfusion  
British Journal of Pharmacology  2015;172(12):3072-3085.
Background and Purpose
Targeted modulation of autophagy induced by myocardial ischaemia/reperfusion has been the subject of intensive investigation, but it is debatable whether autophagy is beneficial or harmful. Hence, we evaluated the effects of pharmacological manipulation of autophagy on the survival of cardiomyocytes in different time windows of ischaemia/reperfusion.
Experimental Approach
We examined the autophagy and apoptosis in cardiomyocytes subjected to different durations of anoxia/re-oxygenation or ischaemia/reperfusion, and evaluated the effects of the autophagic enhancer rapamycin and inhibitor wortmannin on cell survival.
Key Results
In neonatal rat cardiomyocytes (NRCs) or murine hearts, autophagy was increased in response to anoxia/reoxygenation or ischaemia/reperfusion in a time-dependent manner. Rapamycin-enhanced autophagy in NRCs led to higher cell viability and less apoptosis when anoxia was sustained for ≦6 h. When anoxia was prolonged to 12 h, rapamycin did not increase cell viability, induced less apoptosis and more autophagic cell death. When anoxia was prolonged to 24 h, rapamycin increased autophagic cell death, while wortmannin reduced autophagic cell death and apoptosis. Similar results were obtained in mice subjected to ischaemia/reperfusion. Rapamycin inhibited the opening of mitochondrial transition pore in NRCs exposed to 6 h anoxia/4 h re-oxygenation but did not exert any effect when anoxia was extended to 24 h. Similarly, rapamycin reduced the myocardial expression of Bax in mice subjected to short-time ischaemia, but this effect disappeared when ischaemia was extended to 24 h.
Conclusions and Implications
The cardioprotection of autophagy is context-dependent and therapies involving the modification of autophagy should be determined according to the duration of ischaemia/reperfusion.
doi:10.1111/bph.13111
PMCID: PMC4459024  PMID: 25660104
11.  Genetic overlap between type 2 diabetes and major depressive disorder identified by bioinformatics analysis 
Oncotarget  2016;7(14):17410-17414.
Our study investigated the shared genetic etiology underlying type 2 diabetes (T2D) and major depressive disorder (MDD) by analyzing large-scale genome wide association studies statistics. A total of 496 shared SNPs associated with both T2D and MDD were identified at p-value ≤ 1.0E-07. Functional enrichment analysis showed that the enriched pathways pertained to immune responses (Fc gamma R-mediated phagocytosis, T cell and B cell receptors signaling), cell signaling (MAPK, Wnt signaling), lipid metabolism, and cancer associated pathways. The findings will have potential implications for future interventional studies of the two diseases.
doi:10.18632/oncotarget.8202
PMCID: PMC4951221  PMID: 27007159
type 2 diabetes; major depressive disorder; single nucleotide polymorphisms; bioinformatics; Gerotarget
12.  How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies 
Scientific Reports  2016;6:20872.
Curcumin is a natural product with multiple biological activities and numerous potential therapeutic applications. However, its poor systemic bioavailability fails to explain the potent pharmacological effects and hinders its clinical application. Using experimental and theoretical approaches, we compared curcumin and its degradation products for its biological activities against Alzheimer’s disease (AD), including the superoxide anion radical (O2.–)-scavenging activity, Aβ fibrils (fAβ) formation-inhibiting activity, and enzymatic inhibition activity. We showed that compared to the parent compound curcumin, the degradation products mixture possessed higher O2.–-scavenging activity and stronger inhibition against fAβ formation. The docking simulations revealed that the bioactive degradation products should make important contribution to the experimentally observed enzymatic inhibition activities of curcumin. Given that curcumin is readily degraded under physiological condition, our findings strongly suggested that the degradation products should make important contribution to the diverse biological activities of curcumin. Our novel findings not only provide novel insights into the complex pharmacology of curcumin due to its poor bioavailability, but also open new avenues for developing therapeutic applications of this natural product.
doi:10.1038/srep20872
PMCID: PMC4757858  PMID: 26887346
13.  Nuclear Multidrug Resistance-Related Protein 1 Is Highly Associated with Better Prognosis of Human Mucoepidermoid Carcinoma through the Suppression of Cell Proliferation, Migration and Invasion 
PLoS ONE  2016;11(2):e0148223.
Objectives
Multidrug resistance-related protein 1 (MRP1) overexpression is a well acknowledged predictor of poor response to chemotherapy, but MRP1 also correlated to better prognosis in some reports, especially for patients not pretreated with chemotherapy. In our previous study, we found nuclear translocation of MRP1 in mucoepidermoid carcinoma (MEC) for the first time. The purpose of this study was to further investigate the function of nuclear MRP1 in MEC.
Materials and Methods
Human MEC tissue samples of 125 patients were selected and stained using immunohistochemistry. The expression level of total MRP1/nuclear MRP1 of each sample was evaluated by expression index (EI) which was scored using both qualitative and quantitative analysis. The correlations between the clinicopathologic parameters and the EI of nuclear MRP1 were analyzed using Spearman’s rank correlation analysis, respectively. The effects of RNAi-mediated downregulation of nuclear MRP1 on MEC cells were assessed using flow cytometric analysis, MTT assay, plate colony formation assay, transwell invasion assay and monolayer wound healing assay.
Results
In this study, we found the EI of nuclear MRP1 was negatively correlated to the pathologic grading (r = -0.498, P<0.01) / clinical staging (r = -0.41, P<0.01) / tumor stage (r = -0.28, P = 0.02) / nodal stage (r = -0.29, P<0.01) of MEC patients. The RNAi-mediated downregulation of nuclear MRP1 further proved that the downregulation of nuclear MRP1 could increase the cell replication, growth speed, colony formation efficiency, migration and invasion ability of MEC cells.
Conclusion
Our results suggested that nuclear MRP1 is highly associated with better prognosis of human mucoepidermoid carcinoma and further study of its function mechanism would provide clues in developing new treatment modalities of MEC.
doi:10.1371/journal.pone.0148223
PMCID: PMC4734599  PMID: 26829120
14.  Transduction of Recombinant M3-p53-R12 Protein Enhances Human Leukemia Cell Apoptosis 
Journal of Cancer  2016;7(10):1360-1373.
Tumor suppressor protein p53 plays important roles in initiating cell cycle arrest and promoting tumor cell apoptosis. Previous studies have shown that p53 is either mutated or defective in approximately 50% of human cancers; therefore restoring normal p53 activity in cancer cells might be an effective anticancer therapeutic approach. Herein, we designed a chimeric p53 protein flanked with the MyoD N-terminal transcriptional activation domain (amino acids 1-62, called M3) and a poly-arginine (R12) cell penetrating signal in its N-and C-termini respectively. This chimeric protein, M3-p53-R12, can be expressed in E. coli and purified using immobilized metal ion chromatography followed by serial refolding dialysis. The purified M3-p53-R12 protein retains DNA-binding activity and gains of cell penetrating ability. Using MTT assay, we demonstrated that M3-p53-R12 inhibited the growth of K562, Jurkat as well as HL-60 leukemia cells carrying mutant p53 genes. Results from FACS analysis also demonstrated that transduction of M3-p53-R12 protein induced cell cycle arrest of these leukemia cells. Of special note, M3-p53-R12 has no apoptotic effect on normal mesenchymal stem cells (MSC) and leukocytes, highlighting its differential effects on normal and tumor cells. To sum up, our results reveal that purified recombinant M3-p53-R12 protein has functions of suppressing the leukemia cell lines' proliferation and launching cell apoptosis, suggesting the feasibility of using M3-p53-R12 protein as an anticancer drug. In the future we will test whether this chimeric protein can preferentially trigger the death of malignant cancer cells without affecting normal cells in animals carrying endogenous or xenographic tumors.
doi:10.7150/jca.15155
PMCID: PMC4934045  PMID: 27390612
apoptosis; cancer; leukemia; MyoD; p53; and protein drug.
15.  Bhlhe40 Represses PGC-1α Activity on Metabolic Gene Promoters in Myogenic Cells 
Molecular and Cellular Biology  2015;35(14):2518-2529.
PGC-1α is a transcriptional coactivator promoting oxidative metabolism in many tissues. Its expression in skeletal muscle (SKM) is induced by hypoxia and reactive oxidative species (ROS) generated during exercise, suggesting that PGC-1α might mediate the cross talk between oxidative metabolism and cellular responses to hypoxia and ROS. Here we found that PGC-1α directly interacted with Bhlhe40, a basic helix-loop-helix (bHLH) transcriptional repressor induced by hypoxia, and protects SKM from ROS damage, and they cooccupied PGC-1α-targeted gene promoters/enhancers, which in turn repressed PGC-1α transactivational activity. Bhlhe40 repressed PGC-1α activity through recruiting histone deacetylases (HDACs) and preventing the relief of PGC-1α intramolecular repression caused by its own intrinsic suppressor domain. Knockdown of Bhlhe40 mRNA increased levels of ROS, fatty acid oxidation, mitochondrial DNA, and expression of PGC-1α target genes. Similar effects were also observed when the Bhlhe40-mediated repression was rescued by a dominantly active form of the PGC-1α-interacting domain (PID) from Bhlhe40. We further found that Bhlhe40-mediated repression can be largely relieved by exercise, in which its recruitment to PGC-1α-targeted cis elements was significantly reduced. These observations suggest that Bhlhe40 is a novel regulator of PGC-1α activity repressing oxidative metabolism gene expression and mitochondrion biogenesis in sedentary SKM.
doi:10.1128/MCB.00387-15
PMCID: PMC4475930  PMID: 25963661
16.  Formononetin, a novel FGFR2 inhibitor, potently inhibits angiogenesis and tumor growth in preclinical models 
Oncotarget  2015;6(42):44563-44578.
Most anti-angiogenic therapies currently being evaluated in clinical trials target vascular endothelial growth factor (VEGF) pathway, however, the tumor vasculature can acquire resistance to VEGF-targeted therapy by shifting to other angiogenesis mechanisms. Therefore, other potential therapeutic agents that block non-VEGF angiogenic pathways need to be evaluated. Here we identified formononetin as a novel agent with potential anti-angiogenic and anti-cancer activities. Formononetin demonstrated inhibition of endothelial cell proliferation, migration, and tube formation in response to basic fibroblast growth factor 2 (FGF2). In ex vivo and in vivo angiogenesis assays, formononetin suppressed FGF2-induced microvessel sprouting of rat aortic rings and angiogenesis. To understand the underlying molecular basis, we examined the effects of formononetin on different molecular components in treated endothelial cell, and found that formononetin suppressed FGF2-triggered activation of FGFR2 and protein kinase B (Akt) signaling. Moreover, formononetin directly inhibited proliferation and blocked the oncogenic signaling pathways in breast cancer cell. In vivo, using xenograft models of breast cancer, formononetin showed growth-inhibitory activity associated with inhibition of tumor angiogenesis. Moreover, formononetin enhanced the effect of VEGFR2 inhibitor sunitinib on tumor growth inhibition. Taken together, our results indicate that formononetin targets the FGFR2-mediated Akt signaling pathway, leading to the suppression of tumor growth and angiogenesis.
PMCID: PMC4792576  PMID: 26575424
formononetin; angiogenesis; breast cancer; FGFR2; Akt
17.  Increased Compliance With Supervised Rehabilitation Improves Functional Outcome and Return to Sport After Anterior Cruciate Ligament Reconstruction in Recreational Athletes 
Orthopaedic Journal of Sports Medicine  2015;3(12):2325967115620770.
Background:
Successful return to sport is an important outcome measure after anterior cruciate ligament (ACL) reconstruction and a reason for patients’ decisions to elect surgery. Rehabilitation programs supervised by physical therapists are routinely prescribed after ACL reconstruction surgery. However, the added advantage of supervised physical therapy after ACL reconstruction is still debatable.
Hypothesis:
Attending more supervised physical therapy sessions after arthroscopic ACL reconstruction in recreational athletes increases their chance of successful return to sport.
Study Design:
Cohort study; Level of evidence, 3.
Methods:
The authors analyzed 93 recreational athletes who underwent arthroscopic ACL reconstruction. After arthroscopic single-bundle ACL reconstruction, patients were advised to attend 20 supervised physical therapy sessions. Patients’ demographics, surgical details, and outcome measures (Knee injury and Osteoarthritis Outcome Score [KOOS], Lysholm scale, and Short Form–36 Health Survey [SF-36]) were recorded presurgery and at 1-year follow-up. Ability to return to sports was documented through patients’ self-report. The attendance at physical therapy by each patient was obtained by examining database records and assessed as fully compliant (>15 sessions), moderately compliant (6-15 sessions), or noncompliant (<6 sessions).
Results:
Patients in the fully compliant group had significantly greater odds (odds ratio [OR], 18.5; 95% CI, 1.9-184.5; P = .013) of a successful return to sport as compared with the noncompliant group. Patients in the moderately compliant group also had greater odds of returning to sport as compared with the noncompliant group (OR, 4.2; 95% CI, 1.0-16.6; P = .043). Patients in the fully compliant group had significantly greater scores on the Lysholm (P < .001), KOOS Sports and Recreation subscale (P = .021), KOOS Symptoms subscale (P = .040), and SF-36 physical component summary (PCS) (P = .012) as compared with the noncompliant group. Moderately compliant patients had significantly greater scores on the Lysholm (P = .004), KOOS Sports and Recreation (P = .026), KOOS Symptoms (P = .041), KOOS Quality of Life (P = .022), and SF-36 PCS (P = .004) as compared with noncompliant patients.
Conclusion:
In recreational athletes, moderate to full compliance with a supervised physical therapy program predicts improved knee function and a greater chance of returning to sport 1 year after ACL reconstruction.
doi:10.1177/2325967115620770
PMCID: PMC4687837  PMID: 26740958
compliance with physical therapy; physical therapy; return to sports; anterior cruciate ligament reconstruction
18.  Comparison of thoracolaparoscopic esophagectomy with cervical anastomosis with McKeown esophagectomy for middle esophageal cancer 
Background
In China, the middle esophageal squamous cell cancer is the most common tumor type, and Mckeown esophagectomy (ME) is preferably adopted by thoracic surgeon. But, the surgical trauma of ME is great. Thoracolaparoscopic esophagectomy (TE) was developed to decrease the operative stress; however, the safety and efficacy were not defined. In this study, clinical outcomes were compared between patients who received ME and TE.
Methods
The data of 113 patients who suffered from middle-thoracic esophageal cancer during the same period were collected. Sixty-two patients received ME (ME group), and 51 patients received TE (TE group). Patients’ demographics and short-term clinicopathologic outcomes were comparable between the two groups. Survival rate was estimated using the Kaplan–Meier method, and comparisons between groups were performed with log–rank test.
Results
Patients in TE group had lower body mass index (BMI). Preoperative tumor stage in TE group was much earlier. Both overall and thoracic operation time were longer in TE group. The blood loss during operation and postoperative day (POD) 1 was less in TE group, which contributed to the less blood transfusion. In TE group, postoperative incidence of pulmonary complications and atrial fibrillation (p = 0.035 and p = 0.033) was lower; the inflammatory response and incision pain were significantly alleviated; the ICU and in-hospital stay was shorter as well because of less surgical trauma. No statistically significant difference was found between two groups in terms of overall survival or disease-free survival.
Conclusions
The efficacy and safety of TE were supported by the selected patients in this cohort study. Although it is lack of randomness in this research, some advantages of TE were gratifying such as lower postoperative complications and similar survival with ME. A multicenter prospective randomized study is now required.
doi:10.1186/s12957-015-0727-y
PMCID: PMC4635614  PMID: 26542373
Esophageal cancer; Mckeown esophagectomy; Thoracolaparoscopic esophagectomy; Cervical anastomosis
19.  The Laminin Receptor Is a Cellular Attachment Receptor for Classical Swine Fever Virus 
Journal of Virology  2015;89(9):4894-4906.
ABSTRACT
Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), a highly contagious, economically important viral disease in many countries. The Erns and E2 envelope glycoproteins are responsible for the binding to and entry into the host cell by CSFV. To date, only one cellular receptor, heparan sulfate (HS), has been identified as being involved in CSFV attachment. HS is also present on the surface of various cells that are nonpermissive to CSFV. Hence, there must be another receptor(s) that has been unidentified to date. In this study, we used a set of small interfering RNAs (siRNAs) against a number of porcine cell membrane protein genes to screen cellular proteins involved in CSFV infection. This approach resulted in the identification of several proteins, and of these, the laminin receptor (LamR) has been demonstrated to be a cellular receptor for several viruses. Confocal analysis showed that LamR is colocalized with CSFV virions on the membrane, and a coimmunoprecipitation assay indicated that LamR interacts with the CSFV Erns protein. In inhibition assays, anti-LamR antibodies, soluble laminin, or LamR protein significantly inhibited CSFV infection in a dose-dependent manner. Transduction of PK-15 cells with a recombinant lentivirus expressing LamR yielded higher viral titers. Moreover, an attachment assay demonstrated that LamR functions during virus attachment. We also demonstrate that LamR acts as an alternative attachment receptor, especially in SK6 cells. These results indicate that LamR is a cellular attachment receptor for CSFV.
IMPORTANCE Classical swine fever virus (CSFV) is the causative agent of classical swine fever (CSF), an economically important viral disease affecting the pig industry in many countries. To date, only heparan sulfate (HS) has been identified to be an attachment receptor for CSFV. Here, using RNA interference screening with small interfering RNAs (siRNAs) against a number of porcine membrane protein genes, we identified the laminin receptor (LamR) to be another attachment receptor. We demonstrate the involvement of LamR together with HS in virus attachment, and we elucidate the relationship between LamR and HS. LamR also serves as an attachment receptor for many viral pathogens, including dengue virus, a fatal human flavivirus. The study will help to enhance our understanding of the life cycle of flaviviruses and the development of antiviral strategies for flaviviruses.
doi:10.1128/JVI.00019-15
PMCID: PMC4403484  PMID: 25694590
20.  Mutational Spectrum Analysis of Neurodegenerative Diseases and Its Pathogenic Implication 
One of the most conspicuous features of neurodegenerative diseases (NDs) is the occurrence of dramatic conformation change of individual proteins. We performed a mutational spectrum analysis of disease-causing missense mutations in seven types of NDs at nucleotide and amino acid levels, and compared the results with those of non-NDs. The main findings included: (i) The higher mutation ratio of G:C→T:A transversion to G:C→A:T transition was observed in NDs than in non-NDs, interpreting the excessive guanine-specific oxidative DNA damage in NDs; (ii) glycine and proline had highest mutability in NDs than in non-NDs, which favor the protein conformation change in NDs; (iii) surprisingly low mutation frequency of arginine was observed in NDs. These findings help to understand how mutations may cause NDs.
doi:10.3390/ijms161024295
PMCID: PMC4632750  PMID: 26473852
neurodegenerative diseases; conformation change; mutation; distribution pattern; pathogenesis
21.  Risk of pneumonia in central nervous system injury with alcohol intake: a meta-analysis 
Objective: Central nervous system (CNS) injury can increased the risk of secondary mortality because of its late inflammatory complications. Alcohol intake increases the risk of damage and complications subsequent to a (CNS) injury. How about the risk of pneumonia after CNS injury under the effect of alcoholic drink? Though animal trails of material prosperity and studies for human have been investigated in recent decades, the outcome maintains poor understanding. Pneumonia is one of the serious complication at the time of hospitalization and it should be known as more as possible for steadying patient conditions in intensive care unit and shortening length of stay. Thus, we conducted a meta-analysis of published materials to assess the association between alcohol intake and pneumonia in CNS injury. Methods: Two authors searched the PUBMED, EMBASE, Cochrane Library, and web of science up to September, 2014 for published literatures without any limitations. Reference lists from identified studies were also screened carefully by us for additional data. The summary relative risks (RRs) and 95% confidence intervals (CI) were calculated by statistical analysis software (Stata 12.0) with fixed-effects models to estimate the risk. Result: The results indicated that a higher incidence of pneumonia was found in CNS injury under the influence of alcohol (RR = 1.32, 95% CI = 1.21-1.43), and the risk has no relation to blood alcohol concentration (BAC) (BAC ≥ 80 mg/dl vs < 80 mg/dl, BAC ≥ 100 mg/dl vs < 100 mg/dl). Conclusion: Traumatic brain injury (TBI) and spinal cord injury patients who are under the influence of alcoholic drink have a higher risk of pneumonia.
PMCID: PMC4658959  PMID: 26629070
Central nervous system; pneumonia; alcohol; meta-analysis
22.  Associations between B Vitamins and Parkinson’s Disease 
Nutrients  2015;7(9):7197-7208.
B vitamins may correlate with Parkinson’s disease (PD) through regulating homocysteine level. However, there is no comprehensive assessment on the associations between PD and B vitamins. The present study was designed to perform a meta-analytic assessment of the associations between folate, vitamin B6, and vitamin B12 and PD, including the status of B vitamins in PD patients compared with controls, and associations of dietary intakes of B vitamins and risk of PD. A literature search using Medline database obtained 10 eligible studies included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analysis. Pooled data revealed that there was no obvious difference in folate level between PD patients and healthy controls, and PD patients had lower level of vitamin B12 than controls. Available data suggested that higher dietary intake of vitamin B6 was associated with a decreased risk of PD (odds ratio (OR) = 0.65, 95% confidence intervals (CI) = (0.30, 1.01)), while no significant association was observed for dietary intake of folate and vitamin B12 and risk of PD. PD patients had lower level of vitamin B12 and similar level of folate compared with controls. Dietary intake of vitamin B6 exhibited preventive effect of developing PD based on the available data. As the number of included studies is limited, more studies are needed to confirm the findings and elucidate the underpinning underlying these associations.
doi:10.3390/nu7095333
PMCID: PMC4586528  PMID: 26343714
Parkinson’s disease; B vitamins; dietary intake; meta-analysis
23.  Vitamin D deficiency is associated with increased risk of Alzheimer’s disease and dementia: evidence from meta-analysis 
Nutrition Journal  2015;14:76.
Background
In recent years, the associations between vitamin D status and Alzheimer’s disease (AD) and dementia have gained increasing interests. The present meta-analysis was designed to estimate the association between vitamin D deficiency and risk of developing AD and dementia.
Methods
A literature search conducted until February 2015 identified 10 study populations, which were included in the meta-analysis. Pooled risk ratios (RRs) and 95 % confidence interval (CI) were calculated with a random-effect model using Stata software package.
Results
Results of our meta-analysis showed that subjects with deficient vitamin D status (25(OH)D level < 50 nmol/L) were at increased risk of developing AD by 21 % compared with those possessing 25(OH)D level > 50 nmol/L. Similar analysis also found a significantly increased dementia risk in vitamin D deficient subjects. There is no evidence for significant heterogeneity among the included studies.
Conclusion
Available data indicates that lower vitamin D status may be associated with increased risk of developing AD and dementia. More studies are needed to further confirm the associations and to evaluate the beneficial effects of vitamin D supplementation in preventing AD and dementia.
doi:10.1186/s12937-015-0063-7
PMCID: PMC4522102  PMID: 26231781
24.  Regional pressure and temperature variations across the injured human brain: comparisons between paired intraparenchymal and ventricular measurements 
Critical Care  2015;19(1):267.
Introduction
Intraparenchymal, multimodality sensors are commonly used in the management of patients with severe traumatic brain injury (TBI). The ‘gold standard’, based on accuracy, reliability and cost for intracranial pressure (ICP) monitoring is within the cerebral ventricle (external strain gauge). There are no standards yet for intracerebral temperature monitoring and little is known of temperature differences between brain tissue and ventricle. The aim of the study therefore was to determine pressure and temperature differences at intraparenchymal and ventricular sites during five days of continuous neuromonitoring.
Methods
Patients with severe TBI requiring emergency surgery. Inclusion criteria: patients who required ICP monitoring were eligible for recruitment. Two intracerebral probe types were used: a) intraventricular, dual parameter sensor (measuring pressure, temperature) with inbuilt catheter for CSF drainage: b) multiparameter intraparenchymal sensor measuring pressure, temperature and oxygen partial pressure. All sensors were inserted during surgery and under aseptic conditions.
Results
Seventeen patients, 12 undergoing neurosurgery (decompressive craniectomy n = 8, craniotomy n = 4) aged 21–78 years were studied. Agreement of measures for 9540 brain tissue-ventricular temperature ‘pairs’ and 10,291 brain tissue-ventricular pressure ‘pairs’ were determined using mixed model to compare mean temperature and pressure for longitudinal data.
There was no significant overall difference for mean temperature (p = 0.92) or mean pressure readings (p = 0.379) between tissue and ventricular sites. With 95.8 % of paired temperature readings within 2SD (−0.4 to 0.4 °C) differences in temperature between brain tissue and ventricle were clinically insignificant. For pressure, 93.5 % of readings pairs fell within the 2SD range (−9.4756 to 7.8112 mmHg). However, for individual patients, agreement for mean tissue-ventricular pressure differences was poor on occasions.
Conclusions
There is good overall agreement between paired temperature measurements obtained from deep white matter and brain ventricle in patients with and without early neurosurgery. For paired ICP measurements, 93.5 % of readings were within 2SD of mean difference. Whilst the majority of paired readings were comparable (within 10 mmHg) clinically relevant tissue-ventricular dissociations were noted. Further work is required to unravel the events responsible for short intervals of pressure dissociation before tissue pressure readings can be definitively accepted as a reliable surrogate for ventricular pressure.
doi:10.1186/s13054-015-0982-x
PMCID: PMC4501211  PMID: 26100266
25.  Associations between Vitamin D Status, Supplementation, Outdoor Work and Risk of Parkinson’s Disease: A Meta-Analysis Assessment 
Nutrients  2015;7(6):4817-4827.
The present study aimed to quantitatively assess the associations between vitamin D and Parkinson’s Disease (PD) risks, which include: (i) risk of PD in subjects with deficient and insufficient vitamin D levels; (ii) association between vitamin D supplementation and risk of PD; and (iii) association between outdoor work and PD risk, through meta-analyzing available data. An electronic literature search supplemented by hand searching up to March 2015 identified seven eligible studies comprising 5690 PD patients and 21251 matched controls. Odds ratio (OR) and 95% confidence interval (CI) of PD risk were assessed through pooling the collected data from eligible studies using Stata software. Pooled data showed that subjects with deficient and insufficient vitamin D levels had increased PD risks compared with matched-controls according to the corresponding OR: 2.08, 95% CI: 1.63 to 2.65, and 1.29, 95% CI: 1.10 to 1.51. Vitamin D supplementation was associated with significantly reduced risk of PD (OR: 0.62, 95% CI: 0.35 to 0.90). Outdoor work was also related to reduced risk of PD (OR: 0.72, 95% CI: 0.63 to 0.81). The findings may stimulate larger, well-designed studies to further verify the associations between vitamin D and PD risk.
doi:10.3390/nu7064817
PMCID: PMC4488816  PMID: 26083115
Parkinson’s disease; vitamin D; outdoor work; meta-analysis

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