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1.  CD44 targets Na+/H+ exchanger 1 to mediate MDA-MB-231 cells' metastasis via the regulation of ERK1/2 
Chang, G | Wang, J | Zhang, H | Zhang, Y | Wang, C | Xu, H | Zhang, H | Lin, Y | Ma, L | Li, Q | Pang, T
British Journal of Cancer  2014;110(4):916-927.
Background:
CD44, a transmembrane glycoprotein expressed in a variety of cells and tissues, has been implicated in tumour metastasis. But the molecular mechanisms of CD44-mediated tumour cell metastasis remain to be elucidated.
Methods:
The downregulation of CD44 was determined by immunofluorescence. Moreover, the motility of breast cancer cells was detected by wound-healing and transwell experiments. Then the spontaneous metastasis of CD44-silenced MDA-MB-231 cells was tested by histology with BALB/c nude mice.
Results:
A positive correlation between CD44 and Na+/H+ exchanger isoform 1 (NHE1) was found in two breast cancer cells. CD44 downregulation could inhibit the metastasis of MDA-MB-231 cells and the expressions of Na+/H+ exchanger 1. Moreover, CD44 overexpression upregulated the metastasis of MCF-7 cells, but the elevated metastatic ability was then inhibited by Cariporide. Interestingly, during these processes only the p-ERK1/2 was suppressed by CD44 downregulation and the expression of matrix metalloproteinases and metastatic capacity of MDA-MB-231 cells were greatly inhibited by the MEK1 inhibitor PD98059, which even had a synergistic effect with Cariporide. Furthermore, CD44 downregulation inhibits breast tumour outgrowth and spontaneous lung metastasis.
Conclusions:
Taken together, this work indicates that CD44 regulates the metastasis of breast cancer cells through regulating NHE1 expression, which could be used as a novel strategy for breast cancer therapy.
doi:10.1038/bjc.2013.809
PMCID: PMC3929887  PMID: 24434427
CD44; Na+/H+ exchanger 1; matrix metalloproteinase; breast cancer; metastasis
2.  Effect of Different Inclusion Level of Condensed Distillers Solubles Ratios and Oil Content on Amino Acid Digestibility of Corn Distillers Dried Grains with Solubles in Growing Pigs 
The purpose of this experiment was to determine and compare the digestibility of crude protein (CP) and amino acids (AA) in full-oil (no oil extracted) and de-oiled (oil extracted) corn distillers dried grains with solubles (DDGS) with different condensed distillers solubles (CDS) ratios. Six barrows (29.6±2.3 kg) fitted with ileal T-cannula were allotted into a 6×6 Latin square design. Each period was comprised of a 5-d adaption period followed by a 2-d collection of ileal digesta. The five test diets contained 62% DDGS as the sole source of AA. A nitrogen-free diet was used to measure the basal endogenous losses of CP and AA. Chromic oxide (0.3%) was used as an index in each diet. The results showed that CP and AA were very similar in 5 DDGS, but the standardized ileal digestibility (SID) of lysine (from 56.16% to 71.15%) and tryptophan (from 54.90% to 68.38%) had the lowest values and largest variation within the essential AA, which suggests reduced availability of AA and different levels of Maillard reactions in the five DDGS. The apparent ileal digestibility and SID of CP and most of AA in full-oil DDGS (sources 1 and 2) were greater (p<0.05) than de-oiled DDGS (sources 3, 4, and 5). Comparing the AA SID in the 5 DDGS, full-oil with low CDS ratio DDGS (source 1) had non-significantly higher values (p >0.05) than full-oil with high CDS ratio DDGS (source 2); however, the SID of most AA of de-oiled with low CDS ratios DDGS (source 3) were non-significantly lower (p>0.05) than de-oiled with high CDS ratio DDGS (source 4); and the de-oiled DDGS with middle CDS ratio (source 5) but with different drying processing had the lowest SID AA values. In conclusion, de-oiled DDGS had lower SID of CP and AA than full-oil DDGS; a higher CDS ratio tended to decrease the SID of AA in full-oil DDGS but not in de-oiled DDGS; and compared with CDS ratio, processing, especially drying, may have more of an effect on AA digestibility of DDGS.
doi:10.5713/ajas.14.0161
PMCID: PMC4283178  PMID: 25557681
Amino Acid Digestibility; Condensed Distillers Solubles Ratio; Corn Distillers Dried Grains with Solubles; Full-oil and De-oiled; Growing Pigs; Processing
3.  Determination and Prediction of the Amino Acid Digestibility of Sunflower Seed Meals in Growing Pigs 
This experiment was conducted to evaluate the chemical composition and amino acid (AA) digestibility of sunflower seed meal (SFSM) and to use this data to develop prediction equations for estimating AA digestibility for growing pigs. Ten SFSM were collected from five provinces in China. Twelve barrows (38.8±4.6 kg), fitted with ileal T-cannula were allotted into two 6×6 Latin square designs. Each of six experimental periods comprised a 5-d adaption period followed by a 2-d collection of ileal digesta. The ten test diets contained 50% SFSM as the sole source of AA. Another nitrogen-free diet was used to measure the basal endogenous losses of crude protein (CP) and AA. Chromic oxide (0.3%) was used as an inert marker in each diet. There was considerable variation (CV>10%) among the ten SFSM in chemical composition (dry matter [DM]). The concentration of CP and ether extract (EE) ranged from 29.33% to 39.09% and 0.88% to 11.33%, respectively. Crude fibre (CF), neutral detergent fibre and acid detergent fibre ranged from 21.46% to 36.42%, 38.15% to 55.40%, and 24.59% to 37.34%, respectively. There was variation among the ten SFSM in apparent ileal digestibility (AID) and standardized ileal digestibility (SID) for lysine and threonine, which ranged from 63.16 to 79.21 and 55.19% to 72.04% for AID and 67.03% to 82.07% and 61.97% to 77.01% for SID, respectively. The variation in CP and methionine ranged from 60.13% to 74.72% and 74.79% to 88.60% for AID and 66.70% to 79.31% and 77.16% to 90.27% for SID, respectively. Methionine was a good indicator to predict AA digestibility. These results indicate that conventional chemical composition of SFSM was variable (CV>10%) among the ten SFSM (DM). The results of AID, SID and prediction equations could be used to evaluate the digestibility of SFSM in growing pigs.
doi:10.5713/ajas.14.0109
PMCID: PMC4283192  PMID: 25557679
Sunflower Seed Meal; Chemical Composition; Amino Acid Digestibility; Growing Pigs; Prediction Equations
4.  Electric field manipulation of magnetic and transport properties in SrRuO3/Pb(Mg1/3Nb2/3)O3-PbTiO3 heterostructure 
Scientific Reports  2014;4:6991.
The electric field manipulation of magnetic properties is currently of great interest for the opportunities provided in low-energy-consuming spintronics devices. Here, we report the effect of electric field on magnetic and transport properties of the ferromagnetic SrRuO3 film which is epitaxially grown on Pb(Mg1/3Nb2/3)O3-PbTiO3 ferroelectric substrate. With the application of electric field on the substrate, the magnetization, Curie temperature and resistivity of SrRuO3 are effectively modified. The mechanism of the electric field manipulation of these properties is ascribed to the rotations of RuO6 oxygen octahedra caused by the electric-field-induced strain, which changes the overlap and hybridization between the Ru 4d orbitals and O 2p orbitals, resulting in the modification of the magnetic and electronic properties.
doi:10.1038/srep06991
PMCID: PMC4227015  PMID: 25384967
5.  Identification of Novel Single Nucleotide Polymorphisms Associated with Acute Respiratory Distress Syndrome by Exome-Seq 
PLoS ONE  2014;9(11):e111953.
Acute respiratory distress syndrome (ARDS) is a lung condition characterized by impaired gas exchange with systemic release of inflammatory mediators, causing pulmonary inflammation, vascular leak and hypoxemia. Existing biomarkers have limited effectiveness as diagnostic and therapeutic targets. To identify disease-associating variants in ARDS patients, whole-exome sequencing was performed on 96 ARDS patients, detecting 1,382,399 SNPs. By comparing these exome data to those of the 1000 Genomes Project, we identified a number of single nucleotide polymorphisms (SNP) which are potentially associated with ARDS. 50,190SNPs were found in all case subgroups and controls, of which89 SNPs were associated with susceptibility. We validated three SNPs (rs78142040, rs9605146 and rs3848719) in additional ARDS patients to substantiate their associations with susceptibility, severity and outcome of ARDS. rs78142040 (C>T) occurs within a histone mark (intron 6) of the Arylsulfatase D gene. rs9605146 (G>A) causes a deleterious coding change (proline to leucine) in the XK, Kell blood group complex subunit-related family, member 3 gene. rs3848719 (G>A) is a synonymous SNP in the Zinc-Finger/Leucine-Zipper Co-Transducer NIF1 gene. rs78142040, rs9605146, and rs3848719 are associated significantly with susceptibility to ARDS. rs3848719 is associated with APACHE II score quartile. rs78142040 is associated with 60-day mortality in the overall ARDS patient population. Exome-seq is a powerful tool to identify potential new biomarkers for ARDS. We selectively validated three SNPs which have not been previously associated with ARDS and represent potential new genetic biomarkers for ARDS. Additional validation in larger patient populations and further exploration of underlying molecular mechanisms are warranted.
doi:10.1371/journal.pone.0111953
PMCID: PMC4221189  PMID: 25372662
6.  Pediatric pseudoxanthoma elasticum with cardiovascular involvement 
The British journal of dermatology  2013;169(5):10.1111/bjd.12462.
Summary
Background
Pseudoxanthoma elasticum (PXE) is characterized by aberrant mineralization of connective tissues, causing considerable morbidity and mortality. The disease is typically of late onset, the skin manifestations first being noted in teens or later. Another aberrant mineralization disorder, generalized arterial calcification of infancy (GACI), is present at birth and can demonstrate a phenotypic overlap with PXE.
Objectives
A patient with PXE was noted to have skin findings as early as at 6-years of age, with cardiovascular involvement. The purpose of this study was to examine the genetic basis of this phenotypic presentation in the spectrum of PXE/GACI.
Methods
The patient’s genotype was studied by sequencing ABCC6 and ENPP1, genes known to be associated with PXE and/or GACI.
Results
Screening of the ABCC6 gene revealed two pathogenetic mutations, p.R1141X and g.del23-29. Analysis of the ENPP1 gene failed to demonstrate the presence of mutations.
Conclusions
This study demonstrates the presence of cutaneous findings of PXE in an 8-year old pediatric patient, with cardiovascular involvement, illustrating the phenotypic spectrum of PXE.
doi:10.1111/bjd.12462
PMCID: PMC3809148  PMID: 23746223
7.  A morphometric study of the lumbar spinous process in the Chinese population 
Our goal was to analyze the anatomical parameters of the lumbar spine spinous process for an interspinous stabilization device designed for the Chinese population and to offer an anatomical basis for its clinical application. The posterior lumbar spines (T12-S1) of 52 adult cadavers were used for measuring the following: distance between two adjacent spinous processes (DB), distance across two adjacent spinous processes (DA), thickness of the central spinous processes (TC), thickness of the superior margin of the spinous processes (TS), thickness of the inferior margin of the spinous processes (TI), and height of the spinous processes (H). Variance and correlation analyses were conducted for these data, and the data met the normal distribution and homogeneity of variance. DB decreased gradually from L1-2 to L5-S1. DA increased from T12-L1 to L2-3 and then decreased from L2-3 to L4-5. The largest H in males was noted at L3 (25.45±5.96 mm), whereas for females the largest H was noted at L4 (18.71±4.50 mm). Usually, TS of the adjacent spinous process was lower than TI. Based on the anatomical parameters of the lumbar spinous processes obtained in this study, an “H”-shaped coronal plane (posterior view) was proposed as an interspinous stabilization device for the Chinese population. This study reports morphometric data of the lumbar spinous processes in the Chinese population, which provides an anatomical basis for future clinical applications.
doi:10.1590/1414-431X20144164
PMCID: PMC4288498  PMID: 25493388
Lumbar spine; Morphometry; Spinal stenosis; Spinous process
8.  Risk factors for locoregional recurrence after postmastectomy radiotherapy in breast cancer patients with four or more positive axillary lymph nodes 
Li, Q. | Wu, S. | Zhou, J. | Sun, J. | Li, F. | Lin, Q. | Guan, X. | Lin, H. | He, Z.
Current Oncology  2014;21(5):e685-e690.
Background
We investigated risk factors for locoregional recurrence (lrr) in breast cancer patients with 4 or more positive axillary lymph nodes receiving postmastectomy radiotherapy (pmrt).
Methods
Medical records (1998–2007) were retrospectively reviewed for the population of interest. The Kaplan–Meier method was used to calculate the survival rate; Cox regression models were used for univariate and multivariate analysis of predictors of breast cancer lrr.
Results
The study enrolled 439 patients. Median duration of follow-up was 54 months. The 5-year rates of locoregional recurrence-free survival (lrrfs), distant metastasis–free survival (dmfs), and breast cancer–specific survival (bcss) were 87.8%, 59.5%, and 70.7% respectively. In patients with lrr and no concomitant metastasis, and in those without lrr, the 5-year rates of dmfs were 21.1% and 65.7% respectively (p < 0.001), and the 5-year rates of bcss were 34.5% and 76.4% respectively (p < 0.001).
Univariate analysis showed that menopausal status (p = 0.041), pN stage (p = 0.006), and positivity for her2 [human epidermal growth factor receptor 2 (p = 0.003)] or the triple-negative disease subtype (p < 0.001) were determinants of lrrfs. Multivariate analysis showed that pN3 stage [hazard ratio (hr): 2.241; 95% confidence interval (ci): 1.270 to 3.957; p = 0.005], her2 positivity (hr: 2.705; 95% ci: 1.371 to 5.335; p = 0.004), and triple-negative disease subtype (hr: 4.617; 95% ci: 2.192 to 9.723; p < 0.001) were independent prognostic factors of lrrfs.
Conclusions
In breast cancer patients with 4 or more positive axillary lymph nodes who undergo pmrt for breast cancer, lrr significantly influences survival. Patients who developed lrr carried a high risk for distant metastasis and death. Pathologic stage (pN3), her2 positivity, and the triple-negative disease subtype are risk factors that significantly influence lrrfs.
doi:10.3747/co.21.2000
PMCID: PMC4189573  PMID: 25302039
Breast cancer; mastectomy; radiotherapy; locoregional recurrence; prognostic analysis
9.  RESTING HEART RATE AND THE RISK OF DEATH AND CARDIOVASCULAR COMPLICATIONS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS 
Diabetologia  2012;55(5):1283-1290.
Aim
An association between resting heart rate and mortality has been described in the general population and in patients with cardiovascular disease. There are, however, few data exploring this relationship in patients with type 2 diabetes mellitus. The current study addresses this issue.
Methods
The relationship between baseline resting heart rate and all-cause mortality, cardiovascular death and major cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) was examined in 11,140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study.
Results
A higher resting heart rate was associated with a significantly increased risk of all-cause mortality (fully adjusted hazard ratio [HR] 1.15 per 10 bpm, 95% confidence interval [CI] 1.08,1.21, p<0.001), cardiovascular death, and major cardiovascular outcomes without adjustment and after adjusting for age and sex and multiple co-variates. The increased risk associated with a higher baseline resting heart rate is most obvious in patients with previous macrovascular complications (fully adjusted HR for death 1.79 for upper [mean 91 bpm] v lowest [mean 58 bpm] fifth of resting heart rate in this sub-group, 95% CI 1.28,2.50, p<0.001).
Conclusions
Among patients with type 2 diabetes, a higher resting heart rate is associated with increased risk of death and cardiovascular complications. It remains unclear whether a higher heart rate directly mediates the increased risk or is a marker for other factors that determine a poor outcome.
doi:10.1007/s00125-012-2471-y
PMCID: PMC4170780  PMID: 22286552
Type 2 diabetes mellitus; heart rate; outcome
11.  Prenatal maternal immune activation causes epigenetic differences in adolescent mouse brain 
Translational Psychiatry  2014;4(9):e434-.
Epigenetic processes such as DNA methylation have been implicated in the pathophysiology of neurodevelopmental disorders including schizophrenia and autism. Epigenetic changes can be induced by environmental exposures such as inflammation. Here we tested the hypothesis that prenatal inflammation, a recognized risk factor for schizophrenia and related neurodevelopmental conditions, alters DNA methylation in key brain regions linked to schizophrenia, namely the dopamine rich striatum and endocrine regulatory centre, the hypothalamus. DNA methylation across highly repetitive elements (long interspersed element 1 (LINE1) and intracisternal A-particles (IAPs)) were used to proxy global DNA methylation. We also investigated the Mecp2 gene because it regulates transcription of LINE1 and has a known association with neurodevelopmental disorders. Brain tissue was harvested from 6 week old offspring of mice exposed to the viral analog PolyI:C or saline on gestation day 9. We used Sequenom EpiTYPER assay to quantitatively analyze differences in DNA methylation at IAPs, LINE1 elements and the promoter region of Mecp2. In the hypothalamus, prenatal exposure to PolyI:C caused significant global DNA hypomethylation (t=2.44, P=0.019, PolyI:C mean 69.67%, saline mean 70.19%), especially in females, and significant hypomethylation of the promoter region of Mecp2, (t=3.32, P=0.002; PolyI:C mean 26.57%, saline mean 34.63%). IAP methylation was unaltered. DNA methylation in the striatum was not significantly altered. This study provides the first experimental evidence that exposure to inflammation during prenatal life is associated with epigenetic changes, including Mecp2 promoter hypomethylation. This suggests that environmental and genetic risk factors associated with neurodevelopmental disorders may act upon similar pathways. This is important because epigenetic changes are potentially modifiable and their investigation may open new avenues for treatment.
doi:10.1038/tp.2014.80
PMCID: PMC4203009  PMID: 25180573
12.  Addressing the unmet need for visualizing conditional random fields in biological data 
BMC Bioinformatics  2014;15:202.
Background
The biological world is replete with phenomena that appear to be ideally modeled and analyzed by one archetypal statistical framework - the Graphical Probabilistic Model (GPM). The structure of GPMs is a uniquely good match for biological problems that range from aligning sequences to modeling the genome-to-phenome relationship. The fundamental questions that GPMs address involve making decisions based on a complex web of interacting factors. Unfortunately, while GPMs ideally fit many questions in biology, they are not an easy solution to apply. Building a GPM is not a simple task for an end user. Moreover, applying GPMs is also impeded by the insidious fact that the “complex web of interacting factors” inherent to a problem might be easy to define and also intractable to compute upon.
Discussion
We propose that the visualization sciences can contribute to many domains of the bio-sciences, by developing tools to address archetypal representation and user interaction issues in GPMs, and in particular a variety of GPM called a Conditional Random Field(CRF). CRFs bring additional power, and additional complexity, because the CRF dependency network can be conditioned on the query data.
Conclusions
In this manuscript we examine the shared features of several biological problems that are amenable to modeling with CRFs, highlight the challenges that existing visualization and visual analytics paradigms induce for these data, and document an experimental solution called StickWRLD which, while leaving room for improvement, has been successfully applied in several biological research projects.
Software and tutorials are available at http://www.stickwrld.org/
doi:10.1186/1471-2105-15-202
PMCID: PMC4227292  PMID: 25000815
Parallel coordinates; Graphical probabilistic models; Bioinformatics; Conditional random fields
13.  Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis 
Cell Death & Disease  2014;5(7):e1330-.
Intestinal ischemia has a high mortality and often causes acute lung injury (ALI), which is a serious complication, and is accompanied by high mortality up to 40%. An intense local and systemic inflammation occurs during intestinal ischemia/reperfusion (IR)-induced lung injury resulting from activation of immune responses. It has been reported that one component of complement, C5a, is indispensable for the full development of IR-induced lung injury, whereas the detailed molecular mechanism remains to be elucidated. In this study, we found that intestinal IR induced ALI-like symptoms, and C5a receptor (C5aR) expression was upregulated in alveolar macrophages, which are resident macrophages in lung tissue and are important in pulmonary homeostasis. C5a produced during lung injury binds to C5aR in alveolar macrophages, initiates downstream signaling that promotes autophagy, leading to apoptosis of alveolar macrophages. Using Mφ-ATG5−/− mice, in which the atg5 is deficient specifically in macrophages and autophagy is inhibited, we confirmed that in vivo C5a interacting with C5aR induced autophagy in alveolar macrophages, which promoted alveolar macrophage apoptosis. Further study indicated that autophagy was induced through C5aR-mediated degradation of bcl-2. Taken together, our results demonstrated that C5aR-mediated autophagy induced apoptosis in alveolar macrophages, disrupting pulmonary homeostasis and contributing to the development of ALI. This novel mechanism suggests new therapeutic potential of autophagy regulation in ALI.
doi:10.1038/cddis.2014.274
PMCID: PMC4123068  PMID: 25032853
14.  Coffee consumption and the risk of prostate cancer: the Ohsaki Cohort Study 
British Journal of Cancer  2013;108(11):2381-2389.
Background:
Epidemiological evidence regarding the effect of coffee on the incidence of prostate cancer is inconsistent. We aimed to investigate coffee consumption and the risk of prostate cancer risk in a general Japanese population.
Methods:
We conducted a prospective cohort study in Ohsaki city, Japan, where 18 853 men aged 40–79 years participated in a baseline survey. Coffee consumption was assessed via a validated self-administered questionnaire. During 11 years of follow-up (from January 1 1995 to December 31, 2005), 318 incident cases of prostate cancer were detected. The Cox proportional hazards regression model was used to calculate the hazard ratios (HRs) and 95% confidence interval (CIs).
Results:
There was a significant inverse association between coffee consumption and the incidence risk of prostate cancer. Compared with those who did not drink coffee, the multivariate adjusted HRs were 0.81 (95% CI: 0.61–1.07), 0.73 (95% CI: 0.53–1.00), and 0.63 (095% CI: 0.39–1.00) for those who drank coffee occasionally, 1–2 cups per day, and ⩾3 cups per day, respectively, with a P for trend of 0.02.
Conclusion:
This prospective finding from a Japanese population adds evidence that coffee intake is inversely associated with the incidence of prostate cancer.
doi:10.1038/bjc.2013.238
PMCID: PMC3681030  PMID: 23674088
coffee; incidence; neoplasm; prospective study; prostate
15.  The E3 ligase PIRH2 polyubiquitylates CHK2 and regulates its turnover 
Cell Death and Differentiation  2013;20(6):812-822.
The serine threonine kinase checkpoint kinase 2 (CHK2) is a DNA damage checkpoint protein important for the ATM-p53 signaling pathway. In addition to its phosphorylation, CHK2 is also ubiquitylated, and both post-translational modifications are important for its function. However, although the mechanisms that regulate CHK2 phosphorylation are well established, those that control its ubiquitylation are not fully understood. In this study, we demonstrate that the ubiquitin E3 ligase PIRH2 (p53-induced protein with a RING (Really Interesting New Gene)-H2 domain) interacts with CHK2 and mediates its polyubiquitylation and proteasomal degradation. We show that the deubiquitylating enzyme USP28 forms a complex with PIRH2 and CHK2 and antagonizes PIRH2-mediated polyubiquitylation and proteasomal degradation of CHK2. We also provide evidence that CHK2 ubiquitylation by PIRH2 is dependent on its phosphorylation status. Cells deficient in Pirh2 displayed accumulation of Chk2 and enhanced hyperactivation of G1/S and G2/M cell-cycle checkpoints. This hyperactivation was, however, no longer observed in Pirh2−/−Chk2−/− cells, providing evidence for the importance of Chk2 regulation by Pirh2. These findings indicate that PIRH2 has central roles in the ubiquitylation of Chk2 and its turnover and in the regulation of its function.
doi:10.1038/cdd.2013.7
PMCID: PMC3647240  PMID: 23449389
CHK2; PIRH2; ubiquitin; USP28
16.  Downregulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer 
Li, Q | Yao, Y | Eades, G | Liu, Z | Zhang, Y | Zhou, Q
Oncogene  2013;33(20):2589-2600.
The major goal of breast cancer prevention is to reduce the incidence of ductal carcinoma in situ (DCIS), an early stage of breast cancer. However, the biology behind DCIS formation is not well understood. It is suspected that cancer stem cells (CSCs) are already programmed in pre-malignant DCIS lesions and that these tumor-initiating cells may determine the phenotype of DCIS. MicroRNA (miRNA) profiling of paired DCIS tumors revealed that loss of miR-140 is a hallmark of DCIS lesions. Previously, we have found that miR-140 regulates CSCs in luminal subtype invasive ductal carcinoma. Here, we find that miR-140 has a critical role in regulating stem cell signaling in normal breast epithelium and in DCIS. miRNA profiling of normal mammary stem cells and cancer stem-like cells from DCIS tumors revealed that miR-140 is significantly downregulated in cancer stem-like cells compared with normal stem cells, linking miR-140 and dysregulated stem cell circuitry. Furthermore, we found that SOX9 and ALDH1, the most significantly activated stem-cell factors in DCIS stem-like cells, are direct targets of miR-140. Currently, targeted therapies (tamoxifen) are only able to reduce DCIS risk in patients with estrogen receptor α (ERα)-positive disease. We examined a model of ERα-negative/basal-like DCIS and found that restoration of miR-140 via a genetic approach or with the dietary compound sulforaphane decreased SOX9 and ALDH1, and reduced tumor growth in vivo. These results support that a miR-140/ALDH1/SOX9 axis is critical to basal CSC self-renewal and tumor formation in vivo, suggesting that the miR-140 pathway may be a promising target for preventative strategies in patients with basal-like DCIS.
doi:10.1038/onc.2013.226
PMCID: PMC3883868  PMID: 23752191
microRNAs; ductal carcinoma in situ; cancer stem cells; basal-like breast cancer
17.  Immunolocalization of NGF and its Receptors in Ovarian Surface Epithelium of the Wild Ground Squirrel during the Breeding and Nonbreeding Seasons 
The ovarian surface epithelium (OSE) plays an important role in normal ovarian physiology. During each reproductive cycle, the OSE takes part in the cyclical ovulatory ruptures and repair. The aim of this study was to investigate the immunolocalization of nerve growth factor (NGF) and its receptors, tyrosine kinase A (TrkA) and p75, in the OSE cells of the wild ground squirrels during the breeding and nonbreeding seasons. There were marked variations in ovarian weight and size between the breeding and the nonbreeding seasons. Histologically, cuboidal cells and squamous cells were identified in the OSE of both seasons. Yet, stronger immunostaining of NGF, TrkA and p75 were observed in cuboidal cells and squamous cells in the breeding season as compared to the nonbreeding season. In addition, plasma gonadotropin concentrations were higher in the breeding season than in the nonbreeding season, suggesting that the expression patterns of NGF, TrkA and p75 in the OSE were correlated with changes in plasma gonadotropins. These findings suggested that NGF and its receptor TrkA and p75 may be involved in the regulation of seasonal changes in the OSE of wild ground squirrel.
doi:10.4081/ejh.2014.2363
PMCID: PMC4083325  PMID: 24998925
ground squirrel; NGF; OSE; p75; TrkA
18.  Cardiac motion compensation and resolution modeling in simultaneous PET-MR: a cardiac lesion detection study 
Physics in medicine and biology  2013;58(7):10.1088/0031-9155/58/7/2085.
Cardiac motion and Partial Volume Effects (PVE) are two of the main causes of image degradation in cardiac PET. Motion generates artifacts and blurring while PVE lead to erroneous myocardial activity measurements. Newly available simultaneous PET-MR scanners offer new possibilities in cardiac imaging as MRI can assess wall contractility while collecting PET perfusion data. In this perspective, we develop a list-mode iterative reconstruction framework incorporating both tagged-MR derived non-rigid myocardial wall motion and position dependent detector Point Spread Function (PSF) directly into the PET system matrix. In this manner, our algorithm performs both motion “deblurring” and PSF deconvolution while reconstructing images with all available PET counts. The proposed methods are evaluated in a beating non-rigid cardiac phantom whose hot myocardial compartment contains small transmural and non-transmural cold defects. In order to accelerate imaging time, we investigate collecting full and half k-space tagged MR data to obtain tagged volumes that are registered using non-rigid B-spline registration to yield wall motion information. Our experimental results show that tagged-MR based motion correction yielded an improvement in defect/myocardium contrast recovery of 34-206% as compared to motion uncorrected studies. Likewise, lesion detectability improved by respectively 115-136% and 62-235% with MR-based motion compensation as compared to gating and no motion correction and made it possible to distinguish non-transmural from transmural defects, which has clinical significance given inherent limitations of current single modality imaging in identifying the amount of residual ischemia. The incorporation of PSF modeling within the framework of MR-based motion compensation significantly improved defect/myocardium contrast recovery (5.1-8.5%, p<0.01) and defect detectability (39-56%, p<0.01). No statistical difference was found in PET contrast and lesion detectability based on motion fields obtained with half and full k-space tagged data.
doi:10.1088/0031-9155/58/7/2085
PMCID: PMC3657754  PMID: 23470288
19.  Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation 
Cell Death & Disease  2014;5(4):e1187-.
In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated, which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK) cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both BMP-2 and TNF-α/IL-1β. However, previous studies suggested that the effects of BMP-2 and TNF-α/IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of MAPKs in a BMP-2 and TNF-α/IL-1β co-existed condition. Treatment with TNF-α/IL-1β inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1 cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent osteoblastic differentiation. We then confirmed that BMP-2, TNF-α, and IL-1β alone can activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2 signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined that TNF-α/IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38 and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude that TNF-α/IL-1β- and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2 in the clinic to enhance osteoblastic differentiation and bone formation.
doi:10.1038/cddis.2014.101
PMCID: PMC4001295  PMID: 24743742
BMP-2; TNF-α; IL-1β; Runx2; MAPK; osteoblastic differentiation
20.  MicroRNA-185 regulates chemotherapeutic sensitivity in gastric cancer by targeting apoptosis repressor with caspase recruitment domain 
Cell Death & Disease  2014;5(4):e1197-.
Gastric cancer remains the second leading cause of cancer deaths worldwide. Resistance to chemotherapy is a significant barrier for effective cancer treatment. Here, we identified miR-185 to be a contributor to chemosensitivity in gastric cancer. We observed low levels of miR-185 in gastric cancer cell lines and clinical tissues, compared with gastric epithelium cell line and noncancerous tissues. Furthermore, enforced expression of miR-185 increased the sensitivity of gastric cancer cells to low-dose chemotherapeutic agents, which alone cannot trigger significant apoptosis. Conversely, knockdown of endogenous miR-185 prevented high-dose chemotherapy-induced apoptosis. In elucidating the molecular mechanism by which miR-185 participated in the regulation of chemosensitivity in gastric cancer, we discovered that apoptosis repressor with caspase recruitment domain (ARC) is a direct target of miR-185. The role of miR-185 was confirmed in gastric tumor xenograft model. The growth of established tumors was suppressed by a combination therapy using enforced miR-185 expression and a low dose of anticancer drugs. Finally, we found that RUNX3 (Runt-related transcription factor) was involved in the activation of miR-185 at the transcriptional level. Taken together, our results reveal that RUNX3, miR-185 and ARC regulate the sensitivity of gastric cancer cells to chemotherapy.
doi:10.1038/cddis.2014.148
PMCID: PMC4001303  PMID: 24763054
miR-185; chemosensitivity; gastric cancer; ARC; RUNX3
21.  Selective 14-3-3γ induction quenches p-β-catenin Ser37/Bax-enhanced cell death in cerebral cortical neurons during ischemia 
Cell Death & Disease  2014;5(4):e1184-.
Ischemia-induced cell death is a major cause of disability or death after stroke. Identifying the key intrinsic protective mechanisms induced by ischemia is critical for the development of effective stroke treatment. Here, we reported that 14-3-3γ was a selective ischemia-inducible survival factor in cerebral cortical neurons reducing cell death by downregulating Bax depend direct 14-3-3γ/p-β-catenin Ser37 interactions in the nucleus. 14-3-3γ, but not other 14-3-3 isoforms, was upregulated in primary cerebral cortical neurons upon oxygen–glucose deprivation (OGD) as measured by quantitative PCR, western blot and fluorescent immunostaining. The selective induction of 14-3-3γ in cortical neurons by OGD was verified by the in vivo ischemic stroke model. Knocking down 14-3-3γ alone or inhibiting 14-3-3/client interactions was sufficient to induce cell death in normal cultured neurons and exacerbate OGD-induced neuronal death. Ectopic overexpression of 14-3-3γ significantly reduced OGD-induced cell death in cultured neurons. Co-immunoprecipitation and fluorescence resonance energy transfer demonstrated that endogenous 14-3-3γ bound directly to more p-β-catenin Ser37 but not p-Bad, p-Ask-1, p-p53 and Bax. During OGD, p-β-catenin Ser37 but not p-β-catenin Ser45 was increased prominently, which correlated with Bax elevation in cortical neurons. OGD promoted the entry of 14-3-3γ into the nuclei, in correlation with the increase of nuclear p-β-catenin Ser37 in neurons. Overexpression of 14-3-3γ significantly reduced Bax expression, whereas knockdown of 14-3-3γ increased Bax in cortical neurons. Abolishing β-catenin phosphorylation at Ser37 (S37A) significantly reduced Bax and cell death in neurons upon OGD. Finally, 14-3-3γ overexpression completely suppressed β-catenin-enhanced Bax and cell death in neurons upon OGD. Based on these data, we propose that the 14-3-3γ/p-β-catenin Ser37/Bax axis determines cell survival or death of neurons during ischemia, providing novel therapeutic targets for ischemic stroke as well as other related neurological diseases.
doi:10.1038/cddis.2014.152
PMCID: PMC4001306  PMID: 24743739
14-3-3; β-catenin; Bax; neuron; astrocyte; stroke
22.  The origin and functional transition of P34 
Heredity  2012;110(3):259-266.
P34, a storage protein and major soybean allergen, has undergone a functional transition from a cysteine peptidase to a syringolide receptor. An exploration of the evolutionary mechanism of this functional transition is made. To identify homologous genes of P34, syntenic network was constructed using syntenic relationships from the Plant Genome Duplication Database. The collected homologous genes, along with SPE31, a highly homologous protein to P34 from the seeds of Pachyrhizus erosus, were used to construct a phylogenetic tree. The results show that multiple gene duplications, exon shuffling and following granulin domain loss and some critical point mutations are associated with the functional transition. Although some tests suggested the existence of positive selection, the possibility that random fixation under relaxation of purifying selection results in the functional transition is also supported. In addition, the genes Glyma08g12340 and Medtr8g086470 may belong to a new group within the papain family.
doi:10.1038/hdy.2012.81
PMCID: PMC3668652  PMID: 23211789
functional transition; molecular evolution; P34; SPE31; syntenic network
23.  Cav-1 deletion impaired hematopoietic stem cell function 
Bai, L | Shi, G | Zhang, L | Guan, F | Ma, Y | Li, Q | Cong, Y-S | Zhang, L
Cell Death & Disease  2014;5(3):e1140-.
A tightly controlled balance between hematopoietic stem and progenitor cell compartments is required to maintain normal blood cell homeostasis throughout life, and this balance is regulated by intrinsic and extrinsic cellular factors. Cav-1 is a 22-kDa protein that is located in plasma membrane invaginations and is implicated in regulating neural stem cell and embryonic stem cell proliferation. However, the role of Cav-1 in hematopoietic stem cell (HSC) function is largely unknown. In this study, we used Cav-1−/− mice to investigate the role of Cav-1 in HSCs function during aging. The results showed that Cav-1−/− mice displayed a decreased percentage of B cells and an increased percentage of M cells in the bone marrow and peripheral blood, and these changes were due to an increased number of HSCs. FACS analysis showed that the numbers of Lin−Sca1+c-kit+ cells (LSKs), long-term HSCs (LT-HSCs), short-term HSCs and multipotent progenitors were increased in Cav-1−/− mice compared with Cav-1+/+ mice, and this increase became more pronounced with aging. An in vitro clonogenic assay showed that LT-HSCs from Cav-1−/− mice had reduced ability to self-renew. Consistently, an in vivo competitive transplantation assay showed that Cav-1−/− mice failed to reconstitute hematopoiesis. Moreover, a Cav-1 deletion disrupted the quiescence of LSKs and promoted cell cycle progression through G2/M phase. In addition, we found that Cav-1 deletion impaired the ability of HSCs to differentiate into mature blood cells. Taken together, these data suggest that Cav-1-deficient cells impaired HSCs quiescence and induced environmental alterations, which limited HSCs self-renewal and function.
doi:10.1038/cddis.2014.105
PMCID: PMC3973224  PMID: 24675458
Cav-1; HSC; quiescence
24.  Clinical efficacy of a medically supervised outpatient high-protein, low-calorie diet program is equivalent in prediabetic, diabetic and normoglycemic obese patients 
Nutrition & Diabetes  2014;4(2):e105-.
Objective:
Type 2 diabetes mellitus (T2DM) affects approximately 10% of Americans, while 79 million Americans are estimated to have glucose intolerance or prediabetes (pre-DM). The present study was designed to determine whether obese patients with pre-DM or T2DM would lose weight as effectively as obese normoglycemic patients, in a medically supervised high-protein, low-calorie-weight management program.
Method:
Patients enrolled in a self-paid, university-based, outpatient weight loss program using prescribed very-low-calorie diet (VLCD) (500–800 cal per day) or LCD diet (800–1200 cal per day), recommended exercise and group behavioral counseling were studied retrospectively. Patients entering the program for the first time and attending weekly clinic visits for more than 4 weeks were included in the analysis.
Results:
A total of 2093 obese patients, of whom 583 patients with pre-DM (fasting glucose ⩾100 and <126 mg dl−1), 367 patients with T2DM and 1143 normoglycemic patients entered the program from 1991 to 2010, who met all the inclusion criteria were included in the analysis. The body weight at baseline was 104.0±20.0 kg for DM, 101.4±18.4 for pre-DM and 99.0±18.8 kg for non-DM. Weight loss and percent of weight loss within 12 months were analyzed using a linear mixed-effects model. There was no significant difference in weight loss between DM vs non-DM (P=0.4597) and pre-DM vs non-DM (P=0.6006) in 12 months. The length of enrollment in the program was positively correlated to weight loss rates in all patients (P<0.001).
Conclusion:
This study demonstrates that obese, pre-DM and DM patients all lost weight as effectively with VLCD or LCD over 12 months. Given the impact of weight loss on the progression of comorbid conditions, these data support the hypothesis that medically supervised diets, including VLCD and LCD, should be more widely used in the prevention and treatment of obese patients with pre-DM or T2DM.
doi:10.1038/nutd.2014.1
PMCID: PMC3940825  PMID: 24513578
VLCD; diabetes mellitus; weight loss; obesity; prediabetes
25.  Triptolide induces apoptosis in human leukemia cells through caspase-3-mediated ROCK1 activation and MLC phosphorylation 
Liu, L | Li, G | Li, Q | Jin, Z | Zhang, L | Zhou, J | Hu, X | Zhou, T | Chen, J | Gao, N
Cell Death & Disease  2013;4(12):e941-.
The diterpene triepoxide triptolide is a major active component of Tripterygium wilfordii Hook F, a popular Chinese herbal medicine with the potential to treat hematologic malignancies. In this study, we investigated the roles of triptolide in apoptosis and cell signaling events in human leukemia cell lines and primary human leukemia blasts. Triptolide selectively induced caspase-dependent cell death that was accompanied by the loss of mitochondrial membrane potential, cytochrome c release, and Bax translocation from the cytosol to the mitochondria. Furthermore, we found that triptolide dramatically induced ROCK1 cleavage/activation and MLC and MYPT phosphorylation. ROCK1 was cleaved and activated by caspase-3, rather than RhoA. Inhibiting MLC phosphorylation by ML-7 significantly attenuated triptolide-mediated apoptosis, caspase activation, and cytochrome c release. In addition, ROCK1 inhibition also abrogated MLC and MYPT phosphorylation. Our in vivo study showed that both ROCK1 activation and MLC phosphorylation were associated with the tumor growth inhibition caused by triptolide in mouse leukemia xenograft models. Collectively, these findings suggest that triptolide-mediated ROCK1 activation and MLC phosphorylation may be a novel therapeutic strategy for treating hematological malignancies.
doi:10.1038/cddis.2013.469
PMCID: PMC3877542  PMID: 24309928
triptolide; leukemia; apoptosis; ROCK1; MLC; MYPT

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