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1.  Double-bundle anatomical versus single-bundle isometric medial patellofemoral ligament reconstruction for patellar dislocation 
International Orthopaedics  2013;37(4):617-624.
Purpose
The purpose of this study was to evaluate reconstruction of the medial patellofemoral ligament (MPFL) using the double-bundle anatomical or single-bundle isometric procedure with respect to the patients’ clinical outcomes.
Methods
In this retrospective study, we evaluated the clinical outcome of double-bundle anatomical versus single-bundle isometric reconstruction of the MPFL for patellar dislocation patients. Sixty-three patients were included in this study from August 2004 to January 2008. From August 2004 to September 2006, MPFL reconstruction using a single-bundle isometric technique was performed in 21 patients (26 knees). Since October 2006, the double-bundle anatomical reconstruction of the MPFL has been used as the routine surgical procedure. It was performed in 37 patients (44 knees). Fifty-eight patients (70 knees) could be followed up. According to the different techniques, we divided the patients into two groups: group D with double-bundle anatomical reconstruction (37 patients) and group S with single-bundle isometric reconstruction (21 patients). Clinical evaluation consisted of the number with a patellar re-dislocation, patellar apprehension sign, Kujala score, subjective questionnaire score, the patella lateral shift rate and patellar tilt angle measured by cross-sectional CT scan.
Results
According to the Kujala score and the subjective questionnaire score, the outcome of the double-bundle group was better than the outcome of the single-bundle group especially in the long-term. Patellar re-dislocation occurred in three patients in the group S, while no re-dislocation occurred in the group D. In total, 26.9 % of group S was considered to have patellar instability, compared to 4.54 % of the group D. After operation, the patellar tilt angle (PTA) and the patella lateral shift rate (PLSR) were restored to the normal range, with statistical significance (P < 0.05) compared to the preoperative state.
Conclusion
Single- and double-bundle reconstruction of the MPFL can both effectively restore patella stability and improve knee function. However, outcomes in the follow-up period showed that the double-bundle surgery procedure was much better than in single-bundle surgery.
doi:10.1007/s00264-013-1788-6
PMCID: PMC3609965  PMID: 23371425
2.  Premorbid Body Mass Index and Risk of Amyotrophic Lateral Sclerosis 
Objective
To determine if Amyotrophic Lateral Sclerosis (ALS) risk varies according to body mass index (BMI) captured up to three decades earlier.
Methods
At baseline 537,968 women and 562,942 men in five ongoing cohorts reported height, current weight and weight at age 18/21. During 14-28 years of follow-up 1,153 participants developed ALS. Cohort-specific Cox proportional hazards models were used to estimate rates that were then pooled with random effects models.
Results
Lower BMI at baseline was associated with ALS; for each 5-unit increase in BMI, ALS rates were 21% lower (95%CI: 14% to 27%). Compared to individuals with healthy BMI, ALS rates were significantly lower among the overweight (RR=0.76 [95%CI: 0.62-0.93]) and obese (RR=0.73 [95%CI: 0.55-0.96]). Among never-smokers the association persisted: RR=0.75 (95%CI: 0.65-0.85) for each 5-unit increase. Excluding the first seven years of follow-up, the associations were materially unchanged suggesting that weight loss from undiagnosed disease does not fully explain the findings. Overall, 75% of men and women had a healthy BMI at age 18/21, 15% of men and 8% of women were overweight or obese; there was no association with ALS risk although power was limited.
Conclusion
These findings support an association between lower premorbid BMI and ALS.
doi:10.3109/21678421.2012.735240
PMCID: PMC3615420  PMID: 23134505
Amyotrophic Lateral Sclerosis; Body Mass Index; Risk; Epidemiology; Cohort; Nutrition
3.  Chlorotoxin-conjugated graphene oxide for targeted delivery of an anticancer drug 
Current chemotherapy for glioma is rarely satisfactory due to low therapeutic efficiency and systemic side effects. We have developed a glioma-targeted drug delivery system based on graphene oxide. Targeted peptide chlorotoxin-conjugated graphene oxide (CTX-GO) sheets were successfully synthesized and characterized. Doxorubicin was loaded onto CTX-GO (CTX-GO/DOX) with high efficiency (570 mg doxorubicin per gram CTX-GO) via noncovalent interactions. Doxorubicin release was pH-dependent and showed sustained-release properties. Cytotoxicity experiments demonstrated that CTX-GO/DOX mediated the highest rate of death of glioma cells compared with free doxorubicin or graphene oxide loaded with doxorubicin only. Further, conjugation with chlorotoxin enhanced accumulation of doxorubicin within glioma cells. These findings indicate that CTX-GO is a promising platform for drug delivery and provide a rationale for developing a glioma-specific drug delivery system.
doi:10.2147/IJN.S58783
PMCID: PMC3964034  PMID: 24672236
glioma; nanosheet; pH-dependent; cytotoxicity
4.  Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma 
Cancer research  2013;73(6):1733-1741.
Human papillomavirus-associated head and neck squamous cell carcinomas (HPV-HNSCC) originate in the tonsils, the major lymphoid organ that orchestrates immunity to oral infections. Despite its location, the virus escapes immune elimination during malignant transformation and progression. Here, we provide evidence for the role of the PD-1:PD-L1 pathway in HPV-HNSCC immune resistance. We demonstrate membranous expression of PD-L1 in the tonsillar crypts, the site of initial HPV infection. In HPV-HNSCCs that are highly infiltrated with lymphocytes, PD-L1 expression on both tumor cells and CD68+ tumor associated macrophages (TAMs) is geographically localized to sites of lymphocyte fronts, while the majority of CD8+ tumor infiltrating lymphocytes (TILs) express high levels of PD-1, the inhibitory PD-L1 receptor. Significant levels of mRNA for interferon-γ (IFN-γ), a major cytokine inducer of PD-L1 expression, were found in HPV+ PD-L1(+) tumors. Our findings support the role of the PD-1:PD-L1 interaction in creating an “immune-privileged” site for initial viral infection and subsequent adaptive immune resistance once tumors are established and suggest a rationale for therapeutic blockade of this pathway in patients with HPV-HNSCC.
doi:10.1158/0008-5472.CAN-12-2384
PMCID: PMC3602406  PMID: 23288508
PD-1; PD-L1; immune checkpoint; adapative resistance; HPV; head and neck cancers; oropharyngeal cancers; squamous cell carcinomas
5.  Optimal Cut-Off Points for Two-Step Strategy in Screening of Undiagnosed Diabetes: A Population-Based Study in China 
PLoS ONE  2014;9(3):e87690.
To identify optimal cut-off points of fasting plasma glucose for two-step strategy in screening of undiagnosed diabetes in Chinese people, data were selected from two cross-sectional studies of Metabolic Syndrome in Zhejiang Province of China, Zhejiang Statistical Yearbook (2010), and published literatures. Two-step strategy was used among 17437 subjects sampled from population to screen undiagnosed diabetes. Effectiveness (proportion of cases identified), costs (including medical and non-medical costs), and efficiency (cost per case identified) of these different two-step screening strategies were evaluated. This study found the sensitivities of all the two-step screening strategies with further Oral Glucose Tolerance Test (OGTT) at different Fasting Plasma Glucose (FPG) cut-off points from 5.0 to 7.0 (mmol/L) ranged from 0.66 to 0.91. For the FPG point of 5.0 mmol/L, 91 percent of undiagnosed cases were identified. The total cost of detecting one undiagnosed diabetes case ranged from 547.1 to 1294.5 CNY/case, and the strategy with FPG at cut-off point of 6.1 (mmol/L) resulted in the least cost. Considering both sensitivity and cost of screening diabetes, FPG cut-off point at 5.4 mmol/L was optimized for the two-step strategy. In conclusion, different optimal cut-off points of FPG for two-step strategy in screening of undiagnosed diabetes should be used for different screening purposes.
doi:10.1371/journal.pone.0087690
PMCID: PMC3946449  PMID: 24609110
6.  Docetaxel-Loaded Chitosan Microspheres as a Lung Targeted Drug Delivery System: In Vitro and in Vivo Evaluation 
The aim of this study was to prepare docetaxel-loaded chitosan microspheres and to evaluate their in vitro and in vivo characteristics. Glutaraldehyde crosslinked microspheres were prepared using a water-in-oil emulsification method, and characterized in terms of the morphological examination, particle size distribution, encapsulation ratio, drug-loading coefficient and in vitro release. Pharmacokinetics and biodistribution studies were used to evaluate that microspheres have more advantage than the conventional formulations. The emulsion crosslinking method was simple to prepare microspheres and easy to scale up. The formed microspheres were spherical in shape, with a smooth surface and the size was uniform (9.6 ± 0.8 μm); the encapsulation efficiency and drug loading of prepared microspheres were 88.1% ± 3.5% and 18.7% ± 1.2%, respectively. In vitro release indicated that the DTX microspheres had a well-sustained release efficacy and in vivo studies showed that the microspheres were found to release the drug to a maximum extent in the target tissue (lung). The prepared microspheres were found to possess suitable physico-chemical properties and the particle size range. The sustained release of DTX from microspheres revealed its applicability as drug delivery system to minimize the exposure of healthy tissues while increasing the accumulation of therapeutic drug in target sites.
doi:10.3390/ijms15033519
PMCID: PMC3975351  PMID: 24577314
docetaxel; microspheres; release; pharmacokinetics; biodistribution
7.  Synthesis, Antifungal Activities and Qualitative Structure Activity Relationship of Carabrone Hydrazone Derivatives as Potential Antifungal Agents 
Aimed at developing novel fungicides for relieving the ever-increasing pressure of agricultural production caused by phytopathogenic fungi, 28 new hydrazone derivatives of carabrone, a natural bioactive sesquisterpene, in three types were designed, synthesized and their antifungal activities against Botrytis cinerea and Colletotrichum lagenarium were evaluated. The result revealed that all the derivatives synthesized exhibited considerable antifungal activities in vitro and in vivo, which led to the improved activities for carabrone and its analogues and further confirmed their potential as antifungal agents.
doi:10.3390/ijms15034257
PMCID: PMC3975396  PMID: 24619221
carabrone; hydrazone derivatives; chemical modification; antifungal activity; structure-activity relationship
8.  Discovery of Novel Wall Teichoic Acid Inhibitors as Effective anti-MRSA β-lactam Combination Agents 
Chemistry & biology  2013;20(2):272-284.
Summary
Innovative strategies are needed to combat drug resistance associated with methicillin-resistant Staphylococcus aureus (MRSA). Here, we investigate the potential of wall teichoic acid (WTA) biosynthesis inhibitors as combination agents to restore β-lactam efficacy against MRSA. Performing a whole cell pathway-based screen we identified a series of WTA inhibitors (WTAIs) targeting the WTA transporter protein, TarG. Whole genome sequencing of WTAI resistant isolates across two methicillin-resistant Staphylococci spp. revealed TarG as their common target, as well as a broad assortment of drug resistant bypass mutants mapping to earlier steps of WTA biosynthesis. Extensive in vitro microbiological analysis and animal infection studies provide strong genetic and pharmacological evidence of the potential effectiveness of WTAIs as anti-MRSA β-lactam combination agents. This work also highlights the emerging role of whole genome sequencing in antibiotic mode-of-action and resistance studies.
doi:10.1016/j.chembiol.2012.11.013
PMCID: PMC3762323  PMID: 23438756
Staphylococcus aureus; MRSA; MRSE; imipenem; wall teichoic acid; antibiotic resistance; β-lactam potentiation; combination agent; chemical biology; Next Generation Sequencing
9.  Emodin As an Effective Agent in Targeting Cancer Stem-Like Side Population Cells of Gallbladder Carcinoma 
Stem Cells and Development  2012;22(4):554-566.
Side population (SP) cells are previously identified from bone marrow based on their capacity to efflux of the fluorescent dye Hoechst 33342. Recent studies demonstrate that SP cells isolated from various cancer cell lines and primary tumors possess stem-cell-like properties. Thus, targeting tumor SP cells may provide new strategies for treatment in clinic. We previously showed that 1,3,8-trihydroxy-6-methylanthraquinone (emodin), a reactive oxygen species (ROS) generator, enhanced sensitivity of gallbladder cancer SGC-996 cells to cisplatin (CDDP) via generation of ROS and downregulation of multidrug-resistance-associated protein 1 (MRP1). To determine whether emodin also acts effectively on cancer stem cells of gallbladder carcinoma, we use SP cells as a model of cancer stem-cell-like cells. Here, we found that emodin, via ROS-related mechanism and suppressing the function of ATP-binding cassette super-family G member (ABCG2), which is known to be associated with Hoechst dye efflux activity of SP cells, not only reduced the ratio, inhibited clone formation, and eliminated sphere formation of SP cells effectively, but also promoted obviously the intracellular accumulation of doxorubicin, the main substrate of the efflux pump ABCG2. In addition, emodin could sensitize CDDP, via inhibition of expression of ABCG2, to overcome chemoresistance of SP cells. Importantly, similar to the experiment in vitro, emodin/CDDP co-treatment in vivo suppressed the tumor growth derived from SP cells through downregulating ABCG2 expression. Our results suggest that emodin is an effective agent targeting cancer stem-like SP cells of gallbladder carcinoma, either alone or acts as a chemotherapy enhancer.
doi:10.1089/scd.2011.0709
PMCID: PMC3564469  PMID: 22974371
10.  Quantitative Proteomics Study of Larval Settlement in the Barnacle Balanus amphitrite 
PLoS ONE  2014;9(2):e88744.
Barnacles are major sessile components of the intertidal areas worldwide, and also one of the most dominant fouling organisms in fouling communities. Larval settlement has a crucial ecological effect not only on the distribution of the barnacle population but also intertidal community structures. However, the molecular mechanisms involved in the transition process from the larval to the juvenile stage remain largely unclear. In this study, we carried out comparative proteomic profiles of stage II nauplii, stage VI nauplii, cyprids, and juveniles of the barnacle Balanus amphitrite using label-free quantitative proteomics, followed by the measurement of the gene expression levels of candidate proteins. More than 700 proteins were identified at each stage; 80 were significantly up-regulated in cyprids and 95 in juveniles vs other stages. Specifically, proteins involved in energy and metabolism, the nervous system and signal transduction were significantly up-regulated in cyprids, whereas proteins involved in cytoskeletal remodeling, transcription and translation, cell proliferation and differentiation, and biomineralization were up-regulated in juveniles, consistent with changes associated with larval metamorphosis and tissue remodeling in juveniles. These findings provided molecular evidence for the morphological, physiological and biological changes that occur during the transition process from the larval to the juvenile stages in B. amphitrite.
doi:10.1371/journal.pone.0088744
PMCID: PMC3923807  PMID: 24551147
11.  Preparation and the Biopharmaceutical Evaluation for the Metered Dose Transdermal Spray of Dexketoprofen 
Journal of Drug Delivery  2014;2014:697434.
The objective of the present work was to develop a metered dose transdermal spray (MDTS) formulation for transdermal delivery of dexketoprofen (DE). DE release from a series of formulations was assessed in vitro. Various qualitative and quantitative parameters like spray pattern, pump seal efficiency test, average weight per metered dose, and dose uniformity were evaluated. The optimized formulation with good skin permeation and an appropriate drug concentration and permeation enhancer (PE) content was developed incorporating 7% (w/w, %) DE, 7% (v/v, %) isopropyl myristate (IPM), and 93% (v/v, %) ethanol. In vivo pharmacokinetic study indicated that the optimized formulation showed a more sustainable plasma-concentration profile compared with the Fenli group. The antiinflammatory effect of DE MDTS was evaluated by experiments involving egg-albumin-induced paw edema in rats and xylene-induced ear swelling in mice. Acetic acid-induced abdominal constriction was used to evaluate the anti-nociceptive actions of DE MDTS. Pharmacodynamic studies indicated that the DE MDTS has good anti-inflammatory and anti-nociceptive activities. Besides, skin irritation studies were performed using rat as an animal model. The results obtained show that the MDTS can be a promising and innovative therapeutic system used in transdermal drug delivery for DE.
doi:10.1155/2014/697434
PMCID: PMC3934676  PMID: 24660066
12.  Increased difference between slow and forced vital capacity is associated with reduced exercise tolerance in COPD patients 
Background
A higher slow vital capacity (VC) compared with forced vital capacity (FVC) indicates small airway collapse and air trapping. We hypothesized that a larger difference between VC and FVC (VC-FVC) would predict impaired exercise capacity in patients with chronic obstructive pulmonary disease (COPD).
Methods
Pulmonary function and incremental cardiopulmonary exercise responses were assessed in 97 COPD patients. Patients were then divided into two groups: one in which VC > FVC (n = 77) and the other in which VC ≤ FVC (n = 20).
Results
Patients with VC > FVC had lower FEV1 and peak oxygen uptake (VO2/kg) compared with patients with VC ≤ FVC. There was a significant inverse correlation for the entire group between VC-FVC and peak VO2/kg (r = -0.404; p < 0.001). There was also a direct correlation between FEV1% pred and peak VO2/kg (r = 0.418; p < 0.001). The results of the multivariate regression analysis with peak VO2/kg as the dependent variable showed that VC-FVC, FEV1(% pred) and age were all significant independent predictors of peak VO2/kg. The model explained 35.9% of the peak VO2/kg variance.
Conclusions
The difference between VC and FVC, easily measured by spirometry, can be used not only as an index of severity of airflow limitation, but also to predict exercise performance in COPD patients.
doi:10.1186/1471-2466-14-16
PMCID: PMC3938036  PMID: 24507622
Chronic obstructive pulmonary disease; Spirometry; Exercise
13.  Transforming Growth Factor-β1 Downregulates Vascular Endothelial Growth Factor-D Expression in Human Lung Fibroblasts via the Jun NH2-Terminal Kinase Signaling Pathway 
Molecular Medicine  2014;20(1):120-134.
Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells. Transforming growth factor (TGF)-β1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGF-C in human proximal tubular epithelial cells. However, the effects of TGF-β1 on VEGF-D regulation are unknown. To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue. We demonstrate that TGF-β1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts. This TGF-β1 effect can be abolished by inhibitors of TGF-β type I receptor kinase and Jun NH2-terminal kinase (JNK), but not by Smad3 knockdown. In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared with control lung. In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by TGF-β1 in lung fibroblasts, through which they may mediate tissue remodeling in IPF.
doi:10.2119/molmed.2013.00123
PMCID: PMC3960396  PMID: 24515257
14.  Human Papillomavirus-Related Carcinomas of the Sinonasal Tract 
High risk human papillomavirus (HPV) is an established cause of head and neck carcinomas arising in the oropharynx. The presence of HPV has also been reported in some carcinomas arising in sinonasal tract, but little is known about their overall incidence or their clinicopathologic profile. The surgical pathology archives of The Johns Hopkins Hospital were searched for all carcinomas arising in the sinonasal tract from 1995 to 2011, and tissue microarrays were constructed. P16 immunohistochemistry and DNA in situ hybridization for high-risk types of HPV were performed. Demographic and clinical outcomes data were extracted from patient medical records. Of 161 sinonasal carcinomas, 34 (21%) were positive for high risk HPV DNA, including type 16 (82%), type 31/33 (12%), and type 18 (6%). HPV-positive carcinomas consisted of 28 squamous cell carcinomas and variants (15 non- or partially-keratinizing, 4 papillary, 5 adenosquamous, 4 basaloid), 1 small cell carcinoma, 1 sinonasal undifferentiated carcinoma, and 4 carcinomas that were difficult to classify but exhibited adenoid cystic carcinoma-like features. Immunohistochemistry for p16 was positive in 59/161 (37%) cases, and p16 expression strongly correlated with the presence of HPV DNA: 33 of 34 (97%) HPV positive tumors exhibited high p16 expression, whereas only 26 of 127 (20%) HPV negative tumors were p16 positive (p < .0001). The HPV-related carcinomas occurred in 19 men and 15 women ranging in age from 33 to 87 years (mean 54). A trend toward improved survival was observed in the HPV-positive group (hazard ratio=0.58, 95% confidence interval [0.26, 1.28]). The presence of high risk HPV in 21% of sinonasal carcinomas confirms HPV as an important oncologic agent of carcinomas arising in the sinonasal tract. While non-keratinizing squamous cell carcinoma is the most common histologic type, there is a wide morphologic spectrum of HPV-related disease that includes a variant that resembles adenoid cystic carcinoma. The distinctiveness of these HPV-related carcinomas of the sinonasal tract with respect to risk factors, clinical behavior, and response to therapy remains to be clarified.
doi:10.1097/PAS.0b013e3182698673
PMCID: PMC3545097  PMID: 23095507
Human papillomavirus; sinonasal carcinoma; squamous cell carcinoma; adenoid cystic carcinoma; sinonasal undifferentiated carcinoma
15.  Tongue muscle plasticity following hypoglossal nerve stimulation in aged rats 
Muscle & nerve  2012;47(2):230-240.
Introduction
Age-related decreases in tongue muscle mass and strength have been reported. It may be possible to prevent age-related tongue muscle changes using neuromuscular electrical stimulation (NMES). Our hypothesis was that alterations in muscle contractile properties and myosin heavy chain composition would be found following NMES.
Methods
Fifty-four young, middle-aged and old Fischer 344/Brown Norway rats were included. Twenty-four rats underwent bilateral electrical stimulation of the hypoglossal nerves for 8 weeks and were compared with control or sham rats. Muscle contractile properties and myosin heavy chain (MHC) in the genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscles were examined.
Results
In comparison with unstimulated control rats, we found reduced muscle fatigue, increased contraction and half decay times and increased twitch and tetanic tension. Increased Type I MHC was found, except for GG in old and middle-aged rats.
Discussion
Transitions in tongue muscle contractile properties and phenotype were found following NMES.
doi:10.1002/mus.23499
PMCID: PMC3556192  PMID: 23169566
muscle contraction; tongue; electrical stimulation; aging; swallowing
16.  Origins of Stereoselectivities in Chiral Phosphoric Acid-Catalyzed Allylborations and Propargylations of Aldehydes 
The Journal of organic chemistry  2013;78(3):1208-1215.
The chiral BINOL-phosphoric acid catalyzed allylboration and propargylation reactions are studied with density functional theory (B3LYP and B3LYP-D3). Two different models were recently proposed for these reactions by Goodman and our group, respectively. In Goodman's model for allylborations, the catalyst interacts with the boronate pseudo-axial oxygen. By contrast, our model for propargylations predicts that the catalyst interacts with the boronate pseudo-equatorial oxygen. In both models, the phosphoric acid stabilizes the transition state by forming a strong hydrogen bond with the oxygen of the boronate, and is oriented by a formyl hydrogen bond (Goodman model), and by other electrostatic attractions in our model. Both of these models have now been reinvestigated for both allylborations and propargylations. For the most effective catalyst for these reactions, the lowest energy transition state corresponds to Goodman's axial model, while the best transition state leading to minor enantiomer involves the equatorial model. The high enantioselectivity observed with only the bulkiest catalyst arises from the steric interactions between the substrates and the bulky groups on the catalyst, and the resulting necessity for distortion of the catalyst in the disfavored transition state.
doi:10.1021/jo302787m
PMCID: PMC3568159  PMID: 23298338
17.  Hemodynamic and Hormonal Changes to Dual Renin Angiotensin System Inhibition in Experimental Hypertension 
Hypertension  2012;61(2):417-424.
We examined the antihypertensive effects of valsartan, aliskiren or both drugs combined on circulating, cardiac and renal components of the renin-angiotensin system (RAS) in congenic mRen2.Lewis hypertensive rats assigned to: vehicle (n=9), valsartan (via drinking water, 30 mg/kg/day; n=10), aliskiren (s.c. by osmotic mini-pumps, 50 mg/kg/day; n=10), or valsartan (30 mg/kg/day) combined with aliskiren (50 mg/kg/day; n=10). Arterial pressure and heart rate were measured by telemetry before and during two weeks of treatment; trunk blood, heart, urine and kidneys were collected for measures of RAS components. Arterial pressure and left ventricular weight/tibia length ratio were reduced by monotherapy of valsartan, aliskiren and further reduced by the combination therapy. Urinary protein excretion was reduced by valsartan and further reduced by the combination. The increases in plasma Ang II induced by valsartan were reversed by the treatment of aliskiren and partially suppressed by the combination. The decreases in plasma Ang-(1–7) induced by aliskiren recovered in the combination group. Kidney Ang-(1–12) was increased by the combination therapy while the increases in urinary creatinine mediated by valsartan were reversed by addition of aliskiren. The antihypertensive and antiproteinuric actions of the combined therapy were associated with marked worsening of renal parenchymal disease and increased peritubular fibrosis. The data show that despite improvements in the surrogate endpoints of blood pressure, ventricular mass and proteinuria, dual blockade of Ang II receptors and renin activity is accompanied by worsening of renal parenchymal disease reflecting a renal homeostatic stress response due to loss of tubuloglomerular feedback by Ang II.
doi:10.1161/HYPERTENSIONAHA.112.201889
PMCID: PMC3576205  PMID: 23232645
angiotensin-(1–12); aliskiren; arterial remodeling; direct renin inhibitors; urinary protein; valsartan
18.  BMVC test, an improved fluorescence assay for detection of malignant pleural effusions 
Cancer Medicine  2014;3(1):162-173.
The diagnosis of malignant pleural effusions is an important issue in the management of malignancy patients. Generally, cytologic examination is a routine diagnostic technique. However, morphological interpretation of cytology is sometimes inconclusive. Here an ancillary method named BMVC test is developed for rapid detection of malignant pleural effusion to improve the diagnostic accuracy at low cost. A simple assay kit is designed to collect living cells from clinical pleural effusion and a fluorescence probe, 3,6-Bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC), is used to illuminate malignant cells. The fluorescence intensity is quantitatively analyzed by ImageJ program. This method yields digital numbers for the test results without any grey zone or ambiguities in the current cytology tests due to intra-observer and inter-observer variability. Comparing with results from double-blind cytologic examination, this simple test gives a good discrimination between malignant and benign specimens with sensitivity of 89.4% (42/47) and specificity of 93.3% (56/60) for diagnosis of malignant pleural effusion. BMVC test provides accurate results in a short time period, and the digital output could assist cytologic examination to become more objective and clear-cut. This is a convenient ancillary tool for detection of malignant pleural effusions.
doi:10.1002/cam4.179
PMCID: PMC3930401  PMID: 24408009
Cell-collecting; fluorescence probe; malignant pleural effusions
19.  Structure basis for the unique specificity of medaka enteropeptidase light chain 
Protein & Cell  2014;5(3):178-181.
doi:10.1007/s13238-013-0008-x
PMCID: PMC3967055  PMID: 24481630
20.  Structure basis for the unique specificity of medaka enteropeptidase light chain 
Protein & Cell  2014;5(3):178-181.
doi:10.1007/s13238-013-0008-x
PMCID: PMC3967055  PMID: 24481630
21.  Network Understanding of Herb Medicine via Rapid Identification of Ingredient-Target Interactions 
Scientific Reports  2014;4:3719.
Today, herb medicines have become the major source for discovery of novel agents in countermining diseases. However, many of them are largely under-explored in pharmacology due to the limitation of current experimental approaches. Therefore, we proposed a computational framework in this study for network understanding of herb pharmacology via rapid identification of putative ingredient-target interactions in human structural proteome level. A marketing anti-cancer herb medicine in China, Yadanzi (Brucea javanica), was chosen for mechanistic study. Total 7,119 ingredient-target interactions were identified for thirteen Yadanzi active ingredients. Among them, about 29.5% were estimated to have better binding affinity than their corresponding marketing drug-target interactions. Further Bioinformatics analyses suggest that simultaneous manipulation of multiple proteins in the MAPK signaling pathway and the phosphorylation process of anti-apoptosis may largely answer for Yadanzi against non-small cell lung cancers. In summary, our strategy provides an efficient however economic solution for systematic understanding of herbs' power.
doi:10.1038/srep03719
PMCID: PMC3893644  PMID: 24429698
22.  Truth and Memory: Linking Instantaneous and Retrospective Self-Reported Cigarette Consumption 
The annals of applied statistics  2012;6(4):1689-1706.
Studies of smoking behavior commonly use the time-line follow-back (TLFB) method, or periodic retrospective recall, to gather data on daily cigarette consumption. TLFB is considered adequate for identifying periods of abstinence and lapse but not for measurement of daily cigarette consumption, thanks to substantial recall and digit preference biases. With the development of the hand-held electronic diary (ED), it has become possible to collect cigarette consumption data using ecological momentary assessment (EMA), or the instantaneous recording of each cigarette as it is smoked. EMA data, because they do not rely on retrospective recall, are thought to more accurately measure cigarette consumption. In this article we present an analysis of consumption data collected simultaneously by both methods from 236 active smokers in the pre-quit phase of a smoking cessation study. We define a statistical model that describes the genesis of the TLFB records as a two-stage process of mis-remembering and rounding, including fixed and random effects at each stage. We use Bayesian methods to estimate the model, and we evaluate its adequacy by studying histograms of imputed values of the latent remembered cigarette count. Our analysis suggests that both mis-remembering and heaping contribute substantially to the distortion of self-reported cigarette counts. Higher nicotine dependence, white ethnicity and male sex are associated with greater remembered smoking given the EMA count. The model is potentially useful in other applications where it is desirable to understand the process by which subjects remember and report true observations.
doi:10.1214/12-AOAS557
PMCID: PMC3889075  PMID: 24432181
Bayesian analysis; heaping; latent variables; longitudinal data; smoking cessation
23.  Bmp6 Expression Can Be Regulated Independently of Liver Iron in Mice 
PLoS ONE  2014;9(1):e84906.
The liver is the primary organ for storing iron and plays a central role in the regulation of body iron levels by secretion of the hormone Hamp1. Although many factors modulate Hamp1 expression, their regulatory mechanisms are poorly understood. Here, we used conditional knockout mice for the iron exporter ferroportin1 (Fpn1) to modulate tissue iron in specific tissues in combination with iron-deficient or iron-rich diets and transferrin (Tf) supplementation to investigate the mechanisms underlying Hamp1 expression. Despite liver iron overload, expression of bone morphogenetic protein 6 (Bmp6), a potent-stimulator of Hamp1 expression that is expressed under iron-loaded conditions, was decreased. We hypothesized that factors other than liver iron must play a role in controlling Bmp6 expression. Our results show that erythropoietin and Tf-bound iron do not underlie the down-regulation of Bmp6 in our mice models. Moreover, Bmp6 was down-regulated under conditions of high iron demand, irrespective of the presence of anemia. We therefore inferred that the signals were driven by high iron demand. Furthermore, we also confirmed previous suggestions that Tf-bound iron regulates Hamp1 expression via Smad1/5/8 phosphorylation without affecting Bmp6 expression, and the effect of Tf-bound iron on Hamp1 regulation appeared before a significant change in Bmp6 expression. Together, these results are consistent with novel mechanisms for regulating Bmp6 and Hamp1 expression.
doi:10.1371/journal.pone.0084906
PMCID: PMC3890292  PMID: 24454764
24.  Enantioselective Homocrotylboration of Aliphatic Aldehydes 
A practical route to optically pure syn-homocrotylation reagents is described, including highly diastereo-and enantioselective preparation of numerous syn-homocrotyl products, as well as several matched mismatched pairs. NMR experiments suggest that the active homocrotylating species is a cyclopropylcarbinyldichloroborane generated by chloride exchange from the PhBCl2 activator. Computational studies support the intermediacy of chloroboranes, and suggest that homoal-lyl/homocrotyl transfers occur through Zimmerman-Traxler transition states.
doi:10.1021/ja311061n
PMCID: PMC3560844  PMID: 23256566
25.  The investigation of 125I seed implantation as a salvage modality for unresectable pancreatic carcinoma 
Background
To assess the efficacy of intraoperative ultrasound-guided implantation of 125I seeds for the treatment of unresectable pancreatic carcinoma, and analyze the associated prognostic factors.
Methods
Twenty-eight patients with pancreatic carcinoma who underwent laparotomy and were considered to have unresectable tumors were included in this study. Nine patients were pathologically diagnosed with Stage II disease, and nineteen patients with Stage III disease. Twenty-eight patients received intraoperative ultrasound-guided 125I seed implantation and received a D90 (at least 90% of the tumor volume received the reference dose) ranging from 60 to 163 Gy, with a median of 120 Gy. Seven patients received an additional 35–50 Gy external beam radiotherapy after seed implantation, and ten patients received two to ten cycles of chemotherapy. Overall survival of the patients was calculated and prognostic factors were evaluated.
Results
Of the patients, 94.1% (16/17) achieved good to medium pain relief. The tumor response rate was 78.6% (22/28), and local control was achieved in 85.7% (24/28) of patients. The 1-, 2- and 3-year survival rates were 30%, 11% and 4%, and the median survival was 10.1 months (95% CI: 9.0-10.9). Analysis using the Cox proportional hazards model suggested that patients younger than 60 years and patients who received a D90 higher than 110 Gy may survive for a longer period.
Conclusions
I seed implantation provides a safe and effective method to relieve pain, control local tumor growth and, to some extent, prolong the survival of patients with stage II and III pancreatic disease, without additional complications. Age and accumulated dose may be factors predictive of a favorable outcome for patients with unresectable pancreatic carcinoma treated with 125I seeds. These findings need to be validated by conducting further studies with larger cohorts.
doi:10.1186/1756-9966-32-106
PMCID: PMC3892087  PMID: 24370348
125I seed; Intraoperative implantation; Ultrasound-guided; Unresectable; Pancreatic carcinoma

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