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1.  An investigation of drug-resistant Acinetobacter baumannii infections in a comprehensive hospital of East China 
Background
To investigate the drug resistant gene profiles and molecular typing of Acinetobacter baumannii isolates collected from clinical specimens in a comprehensive hospital, Jiangsu province.
Methods
This study included 120 patients in a comprehensive hospital with drug-resistant A. baumannii infections on clinical specimens from October 2011 to December 2013. Antibiotic susceptibility test was determined by Vitek 2 Compact system. OXA-51, OXA-23, OXA-24, OXA-58, VIM, IMP, SHV, GES, TEM, AmpC, qacEΔ1-sul1, intI l, CarO, aac(6′)-Ib, and aac(6′)-II were analyzed by PCR. The analysis of molecular typing for 50 multidrug resistant A. baumannii isolates was performed by PFGE.
Results
A total of 64(53%) isolates were multidrug-resistant A.baumannii. The antibiotic susceptibility tests showed that the resistant rates to common antibiotics of mutidrug-resistant A. baumannii were extremely high, most of which over 60%. One hundred and ten isolates harbored OXA-51 (91.7%), 100 for OXA-23(83.3%), 103 for VIM-1(85.8%), 90 for AmpC(75.00%), 50 for aac(6′)-Ib(41.7%), 77 for the loss of CarO (64.2%), 85 for intl1(70.8%), and 64 for qacEΔ1-sul1(53.33%), while OXA-24 was undetected. Fifty multidrug-resistant A. baumannii isolates belong to 14 clones according to the PFGE DNA patterns. Main clone A includes 24 isolates, while clone B and clone C includes 6 and 9 isolates, respectively and others with no common source identified.
Conclusion
There is high morbidity of A. baumannii infections in the hospital, especially in ICU and sputum is the most common sample type.The mainly drug-resistant genes of A. baumannii are OXA-51, OXA-23, and VIM-1 in the hospital. Clonal dissemination provides evidence for the prevalence of multidrug-resistant A. baumannii among clinical isolates. It is suggested that there is an urgent need for effective control and prevention measures.
doi:10.1186/s12941-015-0066-4
PMCID: PMC4328433  PMID: 25643932
Acinetobacter baumannii; Drug-resistant gene; PCR; PFGE
2.  Structural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity-determining moieties of the molecules 
This article describes the structural and biochemical characterization of a new class of high-affinity and selective human deoxycytidine kinase inhibitors.
Deoxycytidine kinase (dCK) is a key enzyme in the nucleoside salvage pathway that is also required for the activation of several anticancer and antiviral nucleoside analog prodrugs. Additionally, dCK has been implicated in immune disorders and has been found to be overexpressed in several cancers. To allow the probing and modulation of dCK activity, a new class of small-molecule inhibitors of the enzyme were developed. Here, the structural characterization of four of these inhibitors in complex with human dCK is presented. The structures reveal that the compounds occupy the nucleoside-binding site and bind to the open form of dCK. Surprisingly, a slight variation in the nature of the substituent at the 5-position of the thiazole ring governs whether the active site of the enzyme is occupied by one or two inhibitor molecules. Moreover, this substituent plays a critical role in determining the affinity, improving it from >700 to 1.5 nM in the best binder. These structures lay the groundwork for future modifications that would result in even tighter binding and the correct placement of moieties that confer favorable pharmacodynamics and pharmacokinetic properties.
doi:10.1107/S1399004713025030
PMCID: PMC3919262  PMID: 24419380
deoxycytidine kinase; inhibitors; nucleotide salvage pathway
3.  Employee Perception of Breastfeeding-Friendly Support and Benefits of Breastfeeding as a Predictor of Intention to Use Breast-Pumping Breaks After Returning to Work Among Employed Mothers 
Breastfeeding Medicine  2014;9(1):16-23.
Abstract
Background: Although increasing numbers of large companies are complying with demands for a breastfeeding-friendly workplace by providing lactation rooms and breast-pumping breaks, the effectiveness for intention to use breast-pumping breaks to express breast milk among employed mothers is uncertain. To explore the impact of employees' perceived breastfeeding support from the workplace and the benefits of breastfeeding on a woman's intention to use breast-pumping breaks after returning to work, we conducted a survey at a female labor-intensive electronics manufacturer in Taiwan.
Subjects and Methods: A structured questionnaire survey was administered to 715 working mothers employed in an electronics manufacturing plant in Tainan Science Park in Southern Taiwan. Questionnaire content included female employee demographics, employment characteristics, and breastfeeding behavior after returning to work, as well as employees' perception of breastfeeding-friendly support and awareness of the benefits of breastfeeding when raising their most recently born child.
Results: Higher education (odds ratio [OR] 2.33), non–clean room worksite (OR 1.51), awareness of breast-pumping breaks (OR 4.70), encouragement by colleagues to use breast-pumping breaks (OR 1.76), and greater awareness of the benefits of breastfeeding (OR 1.08) were significant predictors of the use of breast-pumping breaks after returning to work, whereas the perception of inefficiency when using breast-pumping breaks reduced an employed mother's intention to use breast-pumping breaks (OR 0.55).
Conclusions: This study finds an association between an appreciation of the benefits provided by the employer and the likelihood of increased usage of breastfeeding breaks. Workplaces and employers can help employed mothers to understand the benefits of breastfeeding, which may increase the intention of the mother to take breast-pumping breaks after returning to work.
doi:10.1089/bfm.2013.0082
PMCID: PMC3903328  PMID: 24304034
4.  Small-molecule IAP antagonists sensitize cancer cells to TRAIL-induced apoptosis: Roles of XIAP and cIAPs 
Molecular cancer therapeutics  2013;13(1):5-15.
Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) is a promising anti-cancer agent because it shows apoptosis-inducing activity in transformed, but not in normal cells. As with most anti-cancer agents, however, its clinical use is restricted by either inherent or acquired resistance by cancer cells. We demonstrate here that small-molecule SMAC mimetics that antagonize the Inhibitor of Apoptosis Proteins (IAPs) potently sensitize previously resistant human cancer cell lines, but not normal cells, to TRAIL-induced apoptosis, and that they do so in a caspase-8-dependent manner. We further show that the compounds have no cytotoxicity as single agents. Also, we demonstrate that several IAP family members likely participate in the modulation of cellular sensitivity to TRAIL. Finally, we note that the compounds that sensitize cancer cells to TRAIL are the most efficacious in binding to XIAP, and in inducing cIAP-1 and cIAP-2 degradation. Our studies thus describe valuable compounds that allow elucidation of the signaling events occurring in TRAIL resistance, and demonstrate that these agents act as potent TRAIL-sensitizing agents in a variety of cancer cell lines.
doi:10.1158/1535-7163.MCT-13-0153
PMCID: PMC3947130  PMID: 24194568
TRAIL; XIAP; cIAP; caspase-8; apoptosis
5.  Oncogene-like induction of cellular invasion from centrosome amplification 
Nature  2014;510(7503):167-171.
Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear 1. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost 2. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors 3, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 4 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
doi:10.1038/nature13277
PMCID: PMC4061398  PMID: 24739973
6.  Oncogene-like induction of cellular invasion from centrosome amplification 
Nature  2014;510(7503):167-171.
Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear1. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost2. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors3, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB24 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.
doi:10.1038/nature13277
PMCID: PMC4061398  PMID: 24739973
7.  BRCA1 haploinsufficiency for replication stress suppression in primary cells 
Nature Communications  2014;5:5496.
BRCA1—a breast and ovarian cancer suppressor gene—promotes genome integrity. To study the functionality of BRCA1 in the heterozygous state, we established a collection of primary human BRCA1+/+ and BRCA1mut/+ mammary epithelial cells and fibroblasts. Here we report that all BRCA1mut/+ cells exhibited multiple normal BRCA1 functions, including the support of homologous recombination- type double-strand break repair (HR-DSBR), checkpoint functions, centrosome number control, spindle pole formation, Slug expression and satellite RNA suppression. In contrast, the same cells were defective in stalled replication fork repair and/or suppression of fork collapse, that is, replication stress. These defects were rescued by reconstituting BRCA1mut/+ cells with wt BRCA1. In addition, we observed ‘conditional’ haploinsufficiency for HR-DSBR in BRCA1mut/+ cells in the face of replication stress. Given the importance of replication stress in epithelial cancer development and of an HR defect in breast cancer pathogenesis, both defects are candidate contributors to tumorigenesis in BRCA1-deficient mammary tissue.
BRCA1 is a key breast and ovarian cancer suppressor involved in DSB repair. Here, the authors show that cells heterozygous for several BRCA1 mutations are universally defective in the response to replication stress, which could contribute to the BRCA1 breast cancer development pathway.
doi:10.1038/ncomms6496
PMCID: PMC4243249  PMID: 25400221
8.  Development of new deoxycytidine kinase inhibitors and non-invasive in vivo evaluation using Positron Emission Tomography 
Journal of medicinal chemistry  2013;56(17):6696-6708.
Combined inhibition of ribonucleotide reductase and deoxycytidine kinase (dCK) in multiple cancer cell lines depletes deoxycytidine triphosphate pools leading to DNA replication stress, cell cycle arrest and apoptosis. Evidence implicating dCK in cancer cell proliferation and survival stimulated our interest in developing small molecule dCK inhibitors. Following a high throughput screen of a diverse chemical library, a structure-activity relationship study was carried out. Positron Emission Tomography (PET) using 18F-L-1-(2′-deoxy-2′-FluoroArabinofuranosyl) Cytosine (18F-L-FAC), a dCK-specific substrate, was used to rapidly rank lead compounds based on their ability to inhibit dCK activity in vivo. Evaluation of a subset of the most potent compounds in cell culture (IC50 = ∼1 – 12 nM) using the 18F-L-FAC PET pharmacodynamic assay identified compounds demonstrating superior in vivo efficacy.
doi:10.1021/jm400457y
PMCID: PMC3789385  PMID: 23947754
9.  An research on the isolation methods of frozen-thawed human ovarian preantral follicles 
Abstract: Objective: To explore the effective isolation method for preantral follicles from human frozen-thawed ovarian tissue. Methods: The ovarian cortical tissue was frozen by direct cover vitrification (DCV). The frozen-thawed ovarian tissue was used for isolation of preantral follicles with collagenase combined with mechanical method and mechanical method alone, respectively. Results: 1. There was no statistical difference in the survival rates of follicles in various stages between before and after freezing (P > 0.05). 2. The survival rate of secondary follicles was higher, but the survival rate of primordial follicles was lower in mechanical method alone than in collagenase combined with mechanical method (all P < 0.05). 3. The diameters of follicles were larger and E2 levels were higher in mecha-nical method alone than that in collagenase combined with mechanical method (all P < 0.05). Conclusion: After the frozen-thawed ovarian tissue was cultured for 6 days, compared with collagenase combined with mechanical method, mechanical method alone can obtain higher survival rate of secondary follicles, greater follicular diameter and higher E2 level, which are conducive to follicular subsequent development.
PMCID: PMC4161584  PMID: 25232424
Ovarian tissue; follicle isolation; preantral follicles; calcium alginate three-dimensional culture
10.  A putative novel protein, DEPDC1B, is overexpressed in oral cancer patients, and enhanced anchorage-independent growth in oral cancer cells that is mediated by Rac1 and ERK 
Background
The DEP domain is a globular domain containing approximately 90 amino acids, which was first discovered in 3 proteins: Drosophila disheveled, Caenorhabditis elegans EGL-10, and mammalian Pleckstrin; hence the term, DEP. DEPDC1B is categorized as a potential Rho GTPase-activating protein. The function of the DEP domain in signal transduction pathways is not fully understood. The DEPDC1B protein exhibits the characteristic features of a signaling protein, and contains 2 conserved domains (DEP and RhoGAP) that are involved in Rho GTPase signaling. Small GTPases, such as Rac, CDC42, and Rho, regulate a multitude of cell events, including cell motility, growth, differentiation, cytoskeletal reorganization and cell cycle progression.
Results
In this study, we found that it was a guanine nucleotide exchange factor and induced both cell migration in a cultured embryonic fibroblast cell line and cell invasion in cancer cell lines; moreover, it was observed to promote anchorage-independent growth in oral cancer cells. We also demonstrated that DEPDC1B plays a role in regulating Rac1 translocated onto cell membranes, suggesting that DEPDC1B exerts a biological function by regulating Rac1. We examined oral cancer tissue; 6 out of 7 oral cancer tissue test samples overexpressed DEPDC1B proteins, compared with normal adjacent tissue.
Conclusions
DEPDC1B was a guanine nucleotide exchange factor and induced both cell migration in a cultured embryonic fibroblast cell line and cell invasion in cancer cell lines; moreover, it was observed to promote anchorage-independent growth in oral cancer cells. We also demonstrated that DEPDC1B exerts a biological function by regulating Rac1. We found that oral cancer samples overexpressed DEPDC1B proteins, compared with normal adjacent tissue. Suggest that DEPDC1B plays a role in the development of oral cancer. We revealed that proliferation was linked to a novel DEPDC1B-Rac1-ERK1/2 signaling axis in oral cancer cell lines.
doi:10.1186/s12929-014-0067-1
PMCID: PMC4237807  PMID: 25091805
Anchorage-independent growth; Oral cancer; Extracellular-signal-regulated kinases; Rac1; DEPDC1B
11.  The clinical characteristics and treatment outcome of 57 children and adolescents with primary central nervous system germ cell tumors 
Chinese Journal of Cancer  2014;33(8):395-401.
Primary central nervous system germ cell tumors (CNS-GCTs) in children and adolescents have unique clinical features and methods of treatment compared with those in adults. There is little information about Chinese children and adolescents with CNS-GCTs. Therefore, in this study we retrospectively analyzed the clinical features and treatment outcome of Chinese children and adolescents with primary CNS-GCTs. Between January 2002 and December 2012, 57 untreated patients from a single institution were enrolled. They were diagnosed with CNS-GCTs after pathologic or clinical assessment. Of the 57 patients, 41 were males and 16 were females, with a median age of 12.8 years (range, 2.7 to 18.0 years) at diagnosis; 43 (75.4%) had non-germinomatous germ cell tumors (NGGCTs) and 14 (24.6%) had germinomas; 44 (77.2%) had localized disease and 13 (22.8%) had extensive lesions. Fifty-three patients completed the prescribed treatment, of which 18 underwent monotherapy of surgery, radiotherapy, or chemotherapy, and 35 underwent multimodality therapies that included radiotherapy combined with chemotherapy or surgery combined with chemotherapy and/or radiotherapy. PEB (cisplatin, etoposide, and bleomycin) protocol was the major chemotherapy regimen. The median follow-up time was 32.3 months (range, 1.2 to 139 months). Fourteen patients died of relapse or disease progression. The 3-year event-free survival (EFS) and overall survival rates for all patients were 72.2% and 73.8%, respectively. The 3-year EFS was 92.9% for germinomas and 64.8% for NGGCTs (P = 0.064). The 3-year EFS rates for patients with NGGCTs who underwent monotherapy and multimodality therapies were 50.6% and 73.5%, respectively (P = 0.042). Our results indicate that multimodality therapies including chemotherapy plus radiotherapy were better treatment option for children and adolescents with CNS-GCTs.
doi:10.5732/cjc.013.10112
PMCID: PMC4135369  PMID: 25011460
Primary central nervous system germ cell tumors; chemotherapy; radiotherapy; survival rate; children
12.  Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor 
ACS medicinal chemistry letters  2013;4(9):846-851.
The neurotensin 1 receptor (NTR1) is an important therapeutic target for a range of disease states including addiction. A high throughput screening campaign, followed by medicinal chemistry optimization, led to the discovery of a non-peptidic β-arrestin biased agonist for NTR1. The lead compound, 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)- piperazin-1-yl)quinazoline, 32 (ML314), exhibits full agonist behavior against NTR1 (EC50 = 2.0 μM) in the primary assay and selectivity against NTR2. The effect of 32 is blocked by the NTR1 antagonist SR142948A in a dose dependent manner. Unlike peptide based NTR1 agonists, compound 32 has no significant response in a Ca2+ mobilization assay and is thus a biased agonist that activates the β-arrestin pathway rather than the traditional Gq coupled pathway. This bias has distinct biochemical and functional consequences that may lead to physiological advantages. Compound 32 displays good brain penetration in rodents, and studies examining its in vivo properties are underway.
doi:10.1021/ml400176n
PMCID: PMC3940307  PMID: 24611085
NTR1; neurotensin; GPCR; SR142948A; quinazoline; agonist; β-arrestin bias
13.  Adamantyl-Substituted Retinoid-Derived Molecules That Interact with the Orphan Nuclear Receptor Small Heterodimer Partner: Effects of Replacing the 1-Adamantyl or Hydroxyl Group on Inhibition of Cancer Cell Growth, Induction of Cancer Cell Apoptosis, and Inhibition of Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase-2 Activity 
Journal of medicinal chemistry  2008;51(18):5650-5662.
(E)-4-[3-(1-Adamantyl)-4′-hydroxyphenyl]-3-chlorocinnamic acid (3-Cl-AHPC) induces the cell-cycle arrest and apoptosis of leukemia and cancer cells. Studies demonstrated that 3-Cl-AHPC bound to the atypical orphan nuclear receptor small heterodimer partner (SHP). Although missing a DNA-binding domain, SHP heterodimerizes with the ligand-binding domains of other nuclear receptors to repress their abilities to induce or inhibit gene expression. 3-Cl-AHPC analogues having the 1-adamantyl and phenolic hydroxyl pharmacophoric elements replaced with isosteric groups were designed, synthesized, and evaluated for their inhibition of proliferation and induction of human cancer cell apoptosis. Structure–anticancer activity relationship studies indicated the importance of both groups to apoptotic activity. Docking of 3-Cl-AHPC and its analogues to an SHP computational model that was based on the crystal structure of ultraspiracle complexed with 1-stearoyl-2-palmitoylglycero-3-phosphoethanolamine suggested why these 3-Cl-AHPC groups could influence SHP activity. Inhibitory activity against Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp-2) was also assessed. The most active Shp-2 inhibitor was found to be the 3′-(3,3-dimethylbutynyl) analogue of 3-Cl-AHPC.
doi:10.1021/jm800456k
PMCID: PMC4097887  PMID: 18759424
14.  Identification of a New RXRα Antagonist Targeting the Coregulator-Binding Site 
ACS Medicinal Chemistry Letters  2014;5(7):736-741.
Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding pocket (LBP). Here, we report the identification and characterization of a new RXRα transcriptional antagonist by using structure-based virtual screening. The new antagonist binds with submicromolar affinity to RXRα (Kd = 4.88 × 10–7 M) and selectively inhibits RXRα transactivation. The compound does not bind to the LBP but to a hydrophobic groove on the surface of RXRα. The new compound also effectively suppresses AKT activation and promotes apoptosis of cancer cells in a RXRα-dependent manner by inhibiting tRXRα interaction with the p85α subunit of PI3K. Thus, the compound represents a new RXRα modulator that regulates the nongenomic actions of RXRα by surface binding.
doi:10.1021/ml5000405
PMCID: PMC4094270  PMID: 25057340
RXRα; coregulator-binding site; RXRα antagonist; nongenomic actions; virtual screening
15.  Molecular profiling of human mammary gland links breast cancer risk to a p27+ cell population with progenitor characteristics 
Cell stem cell  2013;13(1):117-130.
SUMMARY
Early full-term pregnancy is one of the most effective natural protections against breast cancer. To investigate this effect, we have characterized the global gene expression and epigenetic profiles of multiple cell types from normal breast tissue of nulliparous and parous women, and carriers of BRCA1 or BRCA2 mutations. We found significant differences in CD44+ progenitor cells, where the levels of many stem cell-related genes and pathways, including the cell cycle regulator p27, are lower in parous women without BRCA1/BRCA2 mutations. We also noted a significant reduction in the frequency of CD44+p27+ cells in parous women, and showed using explant cultures that parity-related signaling pathways play a role in regulating the number of p27+ cells and their proliferation. Our results suggest that pathways controlling p27+ mammary epithelial cells and the numbers of these cells relate to breast cancer risk, and can be explored for cancer risk assessment and prevention.
doi:10.1016/j.stem.2013.05.004
PMCID: PMC3703476  PMID: 23770079
16.  Correlations between depression behaviors and sleep parameters after repeated corticosterone injections in rats 
Acta Pharmacologica Sinica  2014;35(7):879-888.
Aim:
Disrupted sleep may be a prodromal symptom or a predictor of depressive disorders. In this study we investigated the relationship between depression symptoms and disrupted sleep using a novel model of stress-mimicked sleep disorders in rats.
Methods:
SD rats were injected with corticosterone (10, 20 or 40 mg/kg, sc) or vehicle for 7 d. Their sleep-wake behavior was monitored through implanted EEG and EMG electrodes. Their depressive behaviors were assessed using forced swim test, open field test and sucrose preference test.
Results:
The corticosterone-treated rats showed significantly reduced sleep time, disinhibition of rapid-eye-movement (REM) sleep and altered power spectra during non-REM sleep. All depressive behavioral tests did not show significant difference across the groups. However, individual correlation analysis revealed statistically significance: the immobility time (despair) was negatively correlated with REM sleep latency, slow wave sleep (SWS) time ratio, SWS bouts and delta power density, and it was positively correlated with REM sleep bouts and beta power density. Meanwhile, sucrose preference (anhedonia) was positively correlated with total sleep time and light sleep bouts, and it was negatively correlated with the REM sleep time ratio.
Conclusion:
In stress-mimicked rats, sleep disturbances are a predictor of depressive disorders, and certain symptoms of depression may be related to the disruption of several specific sleep parameters.
doi:10.1038/aps.2014.44
PMCID: PMC4088289  PMID: 24989251
depression; sleep; corticosterone; stress; EEG; open field test; forced swim test; sucrose preference test
17.  Pulmonary alveolar proteinosis 
Journal of Thoracic Disease  2014;6(6):E77-E80.
We report a 68-year-old female who presented with chronic cough and progressive dyspnoea. Computed tomography of the thorax and subsequent bronchoscopy confirmed the diagnosis of pulmonary alveolar proteinosis (PAP), which was treated with whole lung lavage. This case is reported in view of the low incidence of PAP.
doi:10.3978/j.issn.2072-1439.2014.03.33
PMCID: PMC4073400  PMID: 24977032
Pulmonary alveolar proteinosis (PAP); rare lung diseases; surfactant
18.  CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways 
Molecular Biology of the Cell  2014;25(5):566-582.
Continuous signaling of CXCR4 in MCF-7 cells results in epithelial-to-mesenchymal transition (EMT), up-regulation of metastasis-associated cytokines, cell migration, and metastasis. The EMT phenotype was reversed in 3D rBM with combined inhibition of CXCR4 and CXCR2 together or in combination with MEK or PI3K, supporting development for combinational therapy treatment in breast cancer.
Aberrant expression of CXCR4 in human breast cancer correlates with metastasis to tissues secreting CXCL12. To understand the mechanism by which CXCR4 mediates breast cancer metastasis, MCF-7 breast carcinoma cells were transduced to express wild-type CXCR4 (CXCR4WT) or constitutively active CXCR4 (CXCR4ΔCTD) and analyzed in two-dimensional (2D) cultures, three-dimensional reconstituted basement membrane (3D rBM) cultures, and mice using intravital imaging. Two-dimensional cultures of MCF-7 CXCR4ΔCTD cells, but not CXCR4WT, exhibited an epithelial-to-mesenchymal transition (EMT) characterized by up-regulation of zinc finger E box–binding homeobox 1, loss of E-cadherin, up-regulation of cadherin 11, p120 isoform switching, activation of extracellular signal-regulated kinase 1/2, and matrix metalloproteinase-2. In contrast to the 2D environment, MCF-7 CXCR4WT cells cultured in 3D rBM exhibited an EMT phenotype, accompanied by expression of CXCR2, CXCR7, CXCL1, CXCL8, CCL2, interleukin-6, and granulocyte–macrophage colony stimulating factor. Dual inhibition of CXCR2 with CXCR4, or inhibition of either receptor with inhibitors of mitogen-activated protein kinase 1 or phosphatidylinositol 3-kinase, reversed the aggressive phenotype of MCF-7 CXCR4-expressing or MDA-MB-231 cells in 3D rBM. Intravital imaging of CXCR4-expressing MCF-7 cells revealed that tumor cells migrate toward blood vessels and metastasize to lymph nodes. Thus CXCR4 can drive EMT along with an up-regulation of chemokine receptors and cytokines important in cell migration, lymphatic invasion, and tumor metastasis.
doi:10.1091/mbc.E13-07-0360
PMCID: PMC3937084  PMID: 24403602
19.  Genetic Interaction Screens Identify a Role for Hedgehog Signaling in Drosophila Border Cell Migration 
Background
Cell motility is essential for embryonic development and physiological processes such as the immune response, but also contributes to pathological conditions such as tumor progression and inflammation. However, our understanding of the mechanisms underlying migratory processes is incomplete. Drosophila border cells provide a powerful genetic model to identify the roles of genes that contribute to cell migration.
Results
Members of the Hedgehog signaling pathway were uncovered in two independent screens for interactions with the small GTPase Rac and the polarity protein Par-1 in border cell migration. Consistent with a role in migration, multiple Hh signaling components were enriched in the migratory border cells. Interference with Hh signaling by several different methods resulted in incomplete cell migration. Moreover, the polarized distribution of E-Cadherin and a marker of tyrosine kinase activity were altered when Hh signaling was disrupted. Conservation of Hh-Rac and Hh-Par-1 signaling was illustrated in the wing, in which Hh-dependent phenotypes were enhanced by loss of Rac or par-1.
Conclusions
We identified a pathway by which Hh signaling connects to Rac and Par-1 in cell migration. These results further highlight the importance of modifier screens in the identification of new genes that function in developmental pathways.
doi:10.1002/dvdy.23926
PMCID: PMC3721345  PMID: 23335293
cell migration; border cells; Drosophila; Hedgehog; Par-1; Rac
20.  Association between Phosphorylated AMP-Activated Protein Kinase and Acetyl-CoA Carboxylase Expression and Outcome in Patients with Squamous Cell Carcinoma of the Head and Neck 
PLoS ONE  2014;9(4):e96183.
Background
Epidemiological studies have indicated that impaired glucose metabolism may increase the risk of squamous cell carcinoma of the head and neck (SCCHN). AMP-activated protein kinase (AMPK) regulates glucose and lipid metabolism via the phosphorylation and subsequent inactivation of its downstream target acetyl-CoA carboxylase (ACC).Thus, we analyzed the expression of pAMPK and its downstream target phosphorylated acetyl-CoA carboxylase (pACC), as well as their impact on the survival of patients with resected SCCHN.
Methods
One hundred eighteen patients with surgically resected SCCHN were enrolled. Immunohistochemical (IHC) staining for pAMPK and pACC was performed using tissue microarrays of operative specimens of SCCHN. The expression was divided into two or three groups according to the IHC score [pAMPK: negative (0), positive (1–3); pACC: negative (0), low expression (1, 2), and high expression (3)]. Statistical analysis was performed to determine the association of pAMPK expression with clinicopathological features and pACC and pErk expression.
Results
The positive rates of pAMPK and pACC expression were 64.4% (76/118) and 68.6% (81/118), respectively. pAMPK was significantly higher in patients aged younger than 60 years (P = 0.024; χ2test) and those with early-stage (T1/T2; P = 0.02; χ2 test) and oral cavity (P = 0.026; Fisher’s exact test) tumors. In multivariate analysis, pAMPK expression was not significantly correlated with overall survival (OS) (adjusted hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.35–1.23), whereas high pACC expression was independently associated with worse OS in node-positive patients (adjusted HR: 17.58; 95% CI: 3.50–88.18).
Conclusions
Strong expression of pACC was found to be an independent prognostic marker for patients with node-positive SCCHN. Our results suggest that pACC may play a role in tumor progression of SCCHN and may help to identify patient subgroups at high risk for poor disease outcome.
doi:10.1371/journal.pone.0096183
PMCID: PMC4000216  PMID: 24769813
21.  Free Glycine Accelerates the Autoproteolytic Activation of Human Asparaginase 
Chemistry & biology  2013;20(4):533-540.
Human asparaginase 3 (hASNase3), which belongs to the N-terminal nucleophile (Ntn) hydrolase superfamily, is synthesized as a single polypeptide that is devoid of asparaginase activity. Intramolecular autoproteolytic processing releases the amino group of Thr168, a moiety required for catalyzing asparagine hydrolysis. Recombinant hASNase3 purifies as the uncleaved, asparaginase-inactive form, and undergoes self-cleavage to the active form at a very slow rate. Here we show that the free amino acid glycine selectively acts to accelerate hASNase3 cleavage both in vitro and in human cells. Other small amino acids such as alanine, serine, or the substrate asparagine are not capable of promoting autoproteolysis. Crystal structures of hASNase3 in complex with glycine in the uncleaved and cleaved enzyme states reveal the mechanism of glycine-accelerated post-translational processing, and explain why no other amino acid can substitute for glycine.
doi:10.1016/j.chembiol.2013.03.006
PMCID: PMC3633088  PMID: 23601642
22.  Impact of a Breastfeeding-Friendly Workplace on an Employed Mother's Intention to Continue Breastfeeding After Returning to Work 
Breastfeeding Medicine  2013;8(2):210-216.
Abstract
Background
Ever-increasing populations of women in their childbearing years are choosing to become employed. Breastfeeding provides unique health advantages to both the infant and mother. A breastfeeding-friendly workplace might be an important factor for predicting breastfeeding rates among working women. To explore the impact of breastfeeding-friendly support on the intention of working mothers to continue breastfeeding, we conducted a survey at a female labor-intensive electronics manufacturer in Taiwan.
Subjects and Methods
A structured questionnaire survey was administered to 715 working mothers employed in an electronics manufacturing plant in Tainan Science Park in Southern Taiwan. Questionnaire content included female employee demographics, employment characteristics, continued breastfeeding behavior after returning to work, access to lactation rooms, and employee perception of the breastfeeding policy and support when raising their most recently born child.
Results
A higher education level (odds ratio [OR]=2.66), lower work load (8 work hours/day) (OR=2.66), lactation room with dedicated space (OR=2.38), use of breast pumping breaks (OR=61.6), and encouragement from colleagues (OR=2.78) and supervisors (OR=2.44) to use breast pumping breaks were significant predictors of continued breastfeeding for more than 6 months after returning to work.
Conclusions
The findings of the present study suggest that to encourage and increase the rate of continued breastfeeding, workplaces should establish dedicated breastfeeding rooms and maintain a comfortable and clean environment. Furthermore, employers should provide encouragement and support for working mothers to continue breastfeeding after returning to work.
doi:10.1089/bfm.2012.0119
PMCID: PMC3616406  PMID: 23390987
23.  Synthesis and SAR study of modulators inhibiting tRXRα-dependent AKT activation 
RXRα represents an intriguing and unique target for pharmacologic interventions. We recently showed that Sulindac and a designed analog could bind to RXRα and modulate its biological activity, including inhibition of the interaction of an N-terminally truncated RXRα (tRXRα) with the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI3K). Here we report the synthesis, testing and SAR of a series of novel analogs of Sulindac as potential modulators for inhibiting tRXRα-dependent AKT activation. A new compound 30 was identified to have improved biological activity.
doi:10.1016/j.ejmech.2013.01.012
PMCID: PMC3738195  PMID: 23434637
RXRα; αtRXR modulator; AKT activation; Sulindac analogs
24.  Using Surgical Microscope for Sclera Buckling and Transscleral Cryopexy: An Alternative Procedure of Treatment for Rhegmatogenous Retinal Detachment 
BioMed Research International  2014;2014:364961.
Purpose. To observe the long-term effectiveness of scleral buckling and transscleral cryopexy conducted under a surgical microscope in the treatment of uncomplicated rhegmatogenous retinal detachment. Methods. This was a retrospective analysis in a total of 227 consecutive patients (244 eyes) with uncomplicated rhegmatogenous retinal detachment (proliferative vitreoretinopathy ≤ C2). All patients underwent scleral buckling and transscleral cryopexy under a surgical microscope without using a binocular indirect ophthalmoscope or a contact lens. Results. After initial surgery, complete retinal reattachment was achieved in 226 eyes (92.6%), and retinal redetachment developed in 18 eyes (7.4%). The causes of retinal redetachment included presence of new breaks in eight eyes (44%), failure to completely seal the breaks in five eyes (28%), missed retinal breaks in four eyes (22%), and iatrogenic retinal breaks in one eye (6%). Scleral buckling surgery was performed again in 12 eyes (66%). Four eyes (22%) developed proliferative vitreoretinopathy and then were treated by vitrectomy. The sealing of retinal breaks and complete retinal reattachment were achieved in 241 eyes (98.8%). Conclusion. Probably because of clear visualization of retinal breaks and being controllable under a surgical microscope, the microsurgery of scleral buckling and transscleral cryopexy for uncomplicated retinal detachment exhibits advisable effectiveness.
doi:10.1155/2014/364961
PMCID: PMC3984779  PMID: 24790997
25.  The Expression of Ribonucleotide Reductase M2 in the Carcinogenesis of Uterine Cervix and Its Relationship with Clinicopathological Characteristics and Prognosis of Cancer Patients 
PLoS ONE  2014;9(3):e91644.
Background
To investigate the implication of ribonucleotide reductase M2 (RRM2) in the carcinogenesis of uterine cervix and its relationship with clinicopathological characteristics and prognosis of cancer patients.
Methodology and Principal Findings
The impact of RRM2 on cell viability was investigated in SiHa cervical cancer cells after RRM2 knockdown and the addition of cisplatin, which induces inter- and intra-strand DNA crosslinks. RRM2 immunoreactivity was evaluated by semi-quantitative H score among 29 normal, 30 low-grade dysplasia, 30 high-grade dysplasia and 103 invasive cancer tissue specimens of the uterine cervix, using tissue microarrays. RRM2 was then correlated with the clinicopathological variables of cervical cancer and patient survival. A greater toxic effect on cell viability using cisplatin was reflected by the greater reduction in RRM2 protein expression in SiHa cells. The RRM2 expression in cancer tissues was higher than that in high-grade dysplasia, low-grade dysplasia or normal cervical tissues. RRM2 upregulation was correlated with deep stromal invasion, large tumors and parametrial invasion and predicted poor survival.
Conclusions
RRM2 is a new molecular marker for the diagnosis and clinical outcomes of cervical cancer. It is involved in cervical carcinogenesis and predicts poor survival, and may be a potential therapeutic target including in cisplatin treatment.
doi:10.1371/journal.pone.0091644
PMCID: PMC3956764  PMID: 24637958

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