Publications by authors named "Huihui Fan"

57 Publications

Epigenomic Reprogramming toward Mesenchymal-Epithelial Transition in Ovarian-Cancer-Associated Mesenchymal Stem Cells Drives Metastasis.

Cell Rep 2020 12;33(10):108473

Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA; Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

A role for cancer cell epithelial-to-mesenchymal transition (EMT) in cancer is well established. Here, we show that, in addition to cancer cell EMT, ovarian cancer cell metastasis relies on an epigenomic mesenchymal-to-epithelial transition (MET) in host mesenchymal stem cells (MSCs). These reprogrammed MSCs, termed carcinoma-associated MSCs (CA-MSCs), acquire pro-tumorigenic functions and directly bind cancer cells to serve as a metastatic driver/chaperone. Cancer cells induce this epigenomic MET characterized by enhancer-enriched DNA hypermethylation, altered chromatin accessibility, and differential histone modifications. This phenomenon appears clinically relevant, as CA-MSC MET is highly correlated with patient survival. Mechanistically, mirroring MET observed in development, MET in CA-MSCs is mediated by WT1 and EZH2. Importantly, EZH2 inhibitors, which are clinically available, significantly inhibited CA-MSC-mediated metastasis in mouse models of ovarian cancer.
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http://dx.doi.org/10.1016/j.celrep.2020.108473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747301PMC
December 2020

Eltrombopag, oral immunosuppressant and androgen combination therapy in twelve patients with refractory severe aplastic anemia.

Hematology 2020 Dec;25(1):341-347

Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, People's Republic of China.

: Eltrombopag monotherapy or eltrombopag combined with immunosuppressant has achieved robust hematologic responses in severe aplastic anemia (SAA). In patients with refractory SAA, for whom hematopoietic stem cell transplantation is unavailable, we attempted to combine eltrombopag with oral immunosuppressant and androgen, to further improve hematologic response. : We collected and analyzed data retrospectively from twelve refractory SAA cases who had received combination therapy of eltrombopag, oral immunosuppressant and androgen. All these patients had received intensive immunosuppressive treatment (IST) for more than 6 months and were evaluated as nonresponders. : A total of 12 SAA patients were treated with a combination of eltrombopag, an oral immunosuppressant (cyclosporine,  = 9; tacrolimus,  = 3) and androgen. The median maximum dose of eltrombopag was 75 mg/day (range, 75-150). After a median follow-up of 8.5 months (7-23), the overall response rate (ORR) was 42% (5/12, including trilineage,  = 4; hemoglobin + platelet,  = 1). Two of 5 responders reached normal blood counts. Optimal hematological response rates were reached at 6 months. The median increase in neutrophil, hemoglobin and platelet count were 1.64 × 10 /L (0.71-2.66), 53 g/L (25-66.5) and 25 × 10 /L (14-230), respectively. In general, the combination therapy was well tolerated; however, two patients suffered from non-lethal upper extremity venous thrombosis when they were platelet transfusion-dependent. : Eltrombopag, oral immunosuppressant and androgen combination therapy in patients with IST-refractory SAA is feasible and could restore multi-lineage hematopoiesis. Thrombosis risk of eltrombopag still needs to be monitored.
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http://dx.doi.org/10.1080/16078454.2020.1815129DOI Listing
December 2020

Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer.

JCI Insight 2020 06 4;5(11). Epub 2020 Jun 4.

Magee-Womens Research Institute, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.

BACKGROUNDEpidemiologic studies suggest that metformin has antitumor effects. Laboratory studies indicate metformin impacts cancer stem-like cells (CSCs). As part of a phase II trial, we evaluated the impact of metformin on CSC number and on carcinoma-associated mesenchymal stem cells (CA-MSCs) and clinical outcomes in nondiabetic patients with advanced-stage epithelial ovarian cancer (EOC).METHODSThirty-eight patients with stage IIC (n = 1)/III (n = 25)/IV (n = 12) EOC were treated with either (a) neoadjuvant metformin, debulking surgery, and adjuvant chemotherapy plus metformin or (b) neoadjuvant chemotherapy and metformin, interval debulking surgery, and adjuvant chemotherapy plus metformin. Metformin-treated tumors, compared with historical controls, were evaluated for CSC number and chemotherapy response. Primary endpoints were (a) a 2-fold or greater reduction in aldehyde dehydrogenase-positive (ALDH+) CD133+ CSCs and (b) a relapse-free survival at 18 months of more than 50%.RESULTSMetformin was well tolerated. Median progression-free survival was 18.0 months (95% CI 14.0-21.6) with relapse-free survival at 18 months of 59.3% (95% CI 38.6-70.5). Median overall survival was 57.9 months (95% CI 28.0-not estimable). Tumors treated with metformin had a 2.4-fold decrease in ALDH+CD133+ CSCs and increased sensitivity to cisplatin ex vivo. Furthermore, metformin altered the methylation signature in CA-MSCs, which prevented CA-MSC-driven chemoresistance in vitro.CONCLUSIONTranslational studies confirm an impact of metformin on EOC CSCs and suggest epigenetic change in the tumor stroma may drive the platinum sensitivity ex vivo. Consistent with this, metformin therapy was associated with better-than-expected overall survival, supporting the use of metformin in phase III studies.TRIAL REGISTRATIONClinicalTrials.gov NCT01579812.
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http://dx.doi.org/10.1172/jci.insight.133247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308054PMC
June 2020

Efficacy and safety of porcine ALG compared to rabbit ATG as first-line treatment for children with acquired aplastic anemia.

Eur J Haematol 2020 Jun 5;104(6):562-570. Epub 2020 Mar 5.

Department of Therapeutic Center of Anemia, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Tianjin, China.

Objective: To assess the outcomes of children with acquired aplastic anemia (AA) treated in China with first-line porcine anti-lymphocyte immunoglobulin (p-ALG)/rabbit anti-thymocyte immunoglobulin (r-ATG) combined with cyclosporine A (CSA).

Methods: We performed a single-center, non-randomized, retrospective cohort study to assess the outcomes of 189 children with AA treated in China with first-line p-ALG/r-ATG combined with CSA between 2014 and 2018.

Results: No significant differences were observed in the overall response rates at 3, 6, 12, or 24 months (3 months: 61.9% vs 67.4%, P = .5; 6 months: 70.9% vs 73.9%, P = .69; 12 months: 77.3% vs 73.3%, P = .58; 24 months: 81.6% vs 78.6%, P = .59) after either p-ALG- or r-ATG-based immunosuppressive therapy. No significant differences were observed in overall survival or failure-free survival between the p-ALG group and the r-ATG group.

Conclusion: Our results reveal that the therapeutic efficacy and safety of p-ALG combined with CSA did not differ significantly from those of r-ATG combined with CSA as first-line therapy for pediatric patients with AA. Moreover, p-ALG has the advantage of significantly lower cost compared with r-ATG.
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http://dx.doi.org/10.1111/ejh.13398DOI Listing
June 2020

Naringin-loaded polymeric micelles as buccal tablets: formulation, characterization, release, cytotoxicity and histopathology studies.

Pharm Dev Technol 2020 Jun 22;25(5):547-555. Epub 2020 Jan 22.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, P. R. China.

Naringin (NG) has been proved to have numerous notable biological effects, including anti-inflammatory effect, anti-cancer effect, and anti-ulcer effect, yet there are no clinical preparations of naringin due to its poor solubility and low dissolution rate after oral administration. In this study, in order to overcome these problems, NG was encapsulated into MPEG-PCL micelles (NGMs) by using a thin-film hydration method. NMGs were in a typical core-shell structure, with a mall particle size (23.95 ± 0.51 nm), high drug loading, and encapsulation efficiency. release of NGMs indicated that the dissolution of NG was increased after being encapsulated in the micelles. NGMs were nontoxic in the cytotoxicity and histopathology studies. Furthermore, when the freeze-dried NGMs were compressed into buccal tablets (NGBTs) by direct compression, the release speed of NG under simulated oral cavity condition from NGBTs was higher than the control tablets, with the accumulated dissolution at 93.13% in 8 hours. In conclusion, NGMs and NGBTs represent a promising drug delivery system for NG, which has the potential to improve the current treatment of oral diseases.
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http://dx.doi.org/10.1080/10837450.2020.1715427DOI Listing
June 2020

Integrated Epigenome, Exome, and Transcriptome Analyses Reveal Molecular Subtypes and Homeotic Transformation in Uterine Fibroids.

Cell Rep 2019 12;29(12):4069-4085.e6

Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA. Electronic address:

Uterine fibroids are benign myometrial smooth muscle tumors of unknown etiology that, when symptomatic, are the most common indication for hysterectomy in the United States. Unsupervised clustering of results from DNA methylation analyses segregates normal myometrium from fibroids and further segregates the fibroids into subtypes characterized by MED12 mutation or activation of either HMGA2 or HMGA1 expression. Upregulation of HMGA2 expression does not always appear to be dependent on translocation but is associated with hypomethylation in the HMGA2 gene body. HOXA13 expression is upregulated in fibroids and correlates with expression of typical uterine fibroid genes. Significant overlap of differentially expressed genes is observed between cervical stroma and uterine fibroids compared with normal myometrium. These analyses show a possible role of DNA methylation in fibroid biology and suggest that homeotic transformation of myometrial cells to a more cervical stroma phenotype could be an important mechanism for etiology of the disease.
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http://dx.doi.org/10.1016/j.celrep.2019.11.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956710PMC
December 2019

Interplay of PKD3 with SREBP1 Promotes Cell Growth via Upregulating Lipogenesis in Prostate Cancer Cells.

J Cancer 2019 19;10(25):6395-6404. Epub 2019 Oct 19.

Department of Clinical Laboratory, The Fifth Affiliated Hospital, Southern Medical University, Guangzhou, China.

Protein kinase D (PKD) has been implicated in cancer cell survival, proliferation, migration and angiogenesis. However, it is still unknown whether PKD regulates cell proliferation through lipid metabolism in cancer cells. Here we report a novel function of PKD3, a member of PKD family, in regulating of prostate cancer cell proliferation by modulation of SREBP1-mediated lipogenesis. We show that silencing of PKD3 significantly reduces lipid content and expression of the lipogenic genes encoding FASN and ATP-citrate lyase (ACLY). Moreover, endogenous PKD3 interacts with sterol regulatory element binding protein 1(SREBP1) in DU145 cells. Interestingly, PKD3 silencing decreases not only the level of matured-SREBP1 (68KD) but also the binding of SREBP1 to the promoter of gene. In addition, overexpression of SREBP1 reverses the suppression of cell growth caused by PKD3 depletion. Finally, immune-histochemical staining indicate that PKD3 expression is positively correlated with expression of FASN and SREBP1 in prostate cancers. Taken together, these data suggest that targeting PKD3-mediated lipogenesis may be a potential therapeutic approach to block prostate cancer progression.
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http://dx.doi.org/10.7150/jca.31254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856730PMC
October 2019

Direct Access to Allenylphosphine Oxides via a Metal Free Coupling of Propargylic Substrates with P(O)H Compounds.

Org Lett 2019 Dec 11;21(23):9438-9441. Epub 2019 Nov 11.

School of Pharmaceutical Sciences , Zhengzhou University , Zhengzhou , Henan 450001 , P. R. China.

A direct and convenient approach for the coupling of propargylic substrates with diphenylphosphine oxide in the presence of TfO and 2,6-lutidine has been developed. The method provides a general approach for the construction of attractive allenylphosphoryl skeletons with high atom and step economy under metal free conditions.
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http://dx.doi.org/10.1021/acs.orglett.9b03645DOI Listing
December 2019

Performance Evaluation of Mindray SAL 8000: a New Integrated Clinical Chemistry and Immunoassay Analyzer System.

Clin Lab 2019 Jul;65(7)

Background: The Mindray SAL 8000 is an integrated serum analyzer for photometric, electrochemical, and im-munological assays. The technical, analytical, and workflow performance of the system were evaluated in this study.

Methods: The technical evaluation was performed using protocols adopted from the guidelines of the China Food and Drug Administration (CFDA). The precision, linearity, interference, and method comparison were carried out according to the Clinical and Laboratory Standards Institute (CLSI) protocols. The verification of carryover and turnaround time were conducted using specimens containing different analytes.

Results: The technical performance was acceptable for all evaluated aspects. The repeatability and within-labora-tory coefficients of variation (CVs) ranged between 0.22% and 4.23% for routine chemistry and between 1.05% and 6.89% for immunochemistry, respectively. All evaluated analytes exhibited linearity over the ranges claimed by the manufacturer. Significant interferences were observed during low concentration TBIL and P measure-ments due to the presence of lipemia. Method comparisons showed good agreement with the comparison systems and with the correlation coefficients ≥ 0.988 except for anti-HBs (r = 0.812). No significant intra-module and inter-module carryovers were detected. For all the 1,220 samples, 25%, 54%, 63%, 79%, 91%, and 100% samples com-pleted analysis in 16.3 minutes, 30 minutes, 60 minutes, 120 minutes, 180 minutes, and 320 minutes, respectively.

Conclusions: The Mindray SAL 8000 integrated system achieved optimal technical performance and met most of the criteria regarding analytical performance. The workflow study of the system met the turnaround time (TAT) requirements of laboratories. Therefore, it is a good candidate to be used in medium and large-sized laboratories.
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http://dx.doi.org/10.7754/Clin.Lab.2019.181228DOI Listing
July 2019

Iron Deficiency in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Cross-Sectional Survey from a Single Institution in China.

Med Sci Monit 2018 Oct 11;24:7256-7263. Epub 2018 Oct 11.

Anemia Therapy Center, Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences (PUMC and CAMS), Tianjin, China (mainland).

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that often manifests with chronic intravascular hemolysis. Iron deficiency in patients with PNH is most often due to urinary losses of iron secondary to chronic intravascular hemolysis. MATERIAL AND METHODS This cross-sectional survey assessed the prevalence of iron deficiency in a Chinese population of PNH patients who were enrolled between May 2012 and October 2014. RESULTS A total of 742 PNH cases were selected by FLARE and classified as classical PNH (15.36%), PNH in the setting of another specified bone marrow disorder (12.26%), and subclinical PNH (72.38%). The median age of all the patients was 32 years (range 5-77 years). The overall prevalence of iron deficiency was 17.9% among all the PNH patients enrolled in the survey, 76.3% (87/144) among those with classical PNH, 33.0% (30/91) among those with PNH in the setting of another specified bone marrow disorder, and 3.0% (16/537) among the subclinical PNH patients. The incidence of iron deficiency among classical PNH patients was higher than that in the other 2 subcategories (P-value=0.000). Multivariate analyses showed that age and disease duration were independent risk factors for iron deficiency in classical patients. CONCLUSIONS This survey shows that PNH patients were prone to iron deficiency, especially patients with classical PNH.
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http://dx.doi.org/10.12659/MSM.910614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194753PMC
October 2018

A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers.

Cancer Cell 2018 04 2;33(4):690-705.e9. Epub 2018 Apr 2.

Department of Epidemiology and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.
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http://dx.doi.org/10.1016/j.ccell.2018.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959730PMC
April 2018

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma.

Cell Rep 2018 04;23(1):313-326.e5

Leukemia Therapeutics LLC., Hull, MA 02045, USA.

Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival.
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http://dx.doi.org/10.1016/j.celrep.2018.03.075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075733PMC
April 2018

Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas.

Cell Rep 2018 04;23(1):239-254.e6

Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer, Houston, TX 77030, USA.

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.
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http://dx.doi.org/10.1016/j.celrep.2018.03.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961503PMC
April 2018

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas.

Cell Rep 2018 04;23(1):194-212.e6

Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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http://dx.doi.org/10.1016/j.celrep.2018.03.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002769PMC
April 2018

Preparation, characterization, and evaluation of amphotericin B-loaded MPEG-PCL-g-PEI micelles for local treatment of oral .

Int J Nanomedicine 2017 6;12:4269-4283. Epub 2017 Jun 6.

Department of Pharmacology.

Fatal infections in the mucosal system can occur in association with immune-compromised diseases and dysbacteriosis. Currently, amphotericin B (AmB) is considered to be the most effective antibiotic in the treatment of infections, but its clinical application is limited by side effects and poor bioavailability. In order to use AmB in the local treatment of oral infections, AmB/MPEG-PCL-g-PEI (monomethoxy poly(ethylene glycol)-poly(epsilon-caprolactone)-graft-polyethylenimine, MPP) micelles were prepared. A series of characterizations were performed. The micelles allowed a sustained in vitro release in both normal oral conditions (pH 6.8) and infection conditions (pH 5.8). Then, buccal tablets containing freeze-dried powder of AmB/MPP micelles were produced by direct compression process and evaluated as regards to weight variation, hardness, and friability. In vitro drug release of the buccal tablets was measured in both the United States Pharmacopeia dissolution apparatus and the dissolution rate test apparatus, which was previously designed for simulating in vivo conditions of the oral cavity. The buccal tablets could sustainably release within 8 h and meet the antifungal requirements. Regarding safety assessment of AmB/MPP micelles, in vivo histopathological data showed no irritation toward buccal mucosa of the rats in both optical microscopy and ultrastructure observation of the tissues. MTT experiment proved that AmB/MPP micelles reduced the cytotoxicity of AmB. The micelles delivered through the gastrointestinal route were also found to be non-systemic toxicity by liquid chromatography-mass spectrometry analysis. Furthermore, the antifungal action of AmB/MPP micelles was evaluated. Although AmB/MPP had no obvious improvement as compared to AmB alone in the antifungal effect on planktonic , the micelles significantly enhanced the antifungal activity against the biofilm state of . Thus, it was concluded that AmB/MPP micelles represent a promising novel drug delivery system for the local treatment of oral infections.
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http://dx.doi.org/10.2147/IJN.S124264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473597PMC
October 2017

[Outcomes of very severe aplastic anemia patients with different absolute neutrophil counts after frontline immnunosuppressive therapy].

Zhonghua Xue Ye Xue Za Zhi 2016 Apr;37(4):329-33

Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China.

Objective: To analyze early hematopoietic response and long-term survival of very severe aplastic anemia (VSAA) patients with different absolute neutrophil counts (ANC) after frontline immnunosuppressive therapy (IST).

Methods: Clinical data and outcome of 145 VSAA patients treated with rabbit antithymocyte globulin combined with cyclosporine were retrospectively analyzed. Hematopoietic responses to IST and long-term survival were statistically analyzed for VSAA patients in different ANC subgroups.

Results: Pre-IST ANC=0.05×10(9)/L acted as the best cutoff level to predict IST response at 3, 6 months. For 145 VSAA patients, early death rate was 13.4% (11/82) vs 1.6% (1/63), respectively, in the ANC≤0.05×10(9)/L group and ANC>0.05×10(9)/L group (P<0.05). Hematopoietic response rates to IST was 22.0% vs 54.0% (P=0.000) at 3 months, 34.1% vs 63.5% (P=0.000) at 6 months; the overall five-year survival rate was only (62.5±5.4) % vs (91.4±3.7) % (P=0.000) and five-year event-free survival rate was (42.3±5.5) % vs (63.1±6.5) % (P=0.003), respectively, in the ANC≤0.05×10(9)/L group and ANC>0.05×10(9)/L group.

Conclusion: VSAA patients with extremely low ANC (≤0.05×10(9)/L) had high early death rate and with very low response rate to frontline IST and poor survival, so it is urgent to seek for the alternative frontline therapy that will bring faster and better outcome for these patients.
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http://dx.doi.org/10.3760/cma.j.issn.0253-2727.2016.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343096PMC
April 2016

[Effects of pre-immunosupressive therapy iron overload on hematologic response of severe aplastic anemia].

Zhonghua Xue Ye Xue Za Zhi 2016 Apr;37(4):324-8

Anemia Therapeutic Centre, Institute of Hematology and Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China.

Objective: To explore the effects of serum ferritin (SF) and iron overload (IO) pre-immunosupressive treatment (IST) on hematologic response of severe aplastic anemia (SAA/VSAA) patients treated with IST.

Methods: 257 SAA/VSAA patients who underwent first-line IST from Feb, 2003 to Dec, 2011 in Anemia Therapeutic Centre, Institute of Hematology and Blood Diseases Hospital were retrospectively analyzed, the status of SF before IST and the IO-affected factors were studied. The effects of IO on hematologic response of SAA/VSAA patients were evaluated as well.

Results: The median level of SF of 257 patients was 387 (6-2 004) μg/L. 36 patients (14%) had IO, including 20 SAA and 16 VSAA patients. According to univariate logistical regression analyses, IO was influenced by age>14 years (P=0.010) and blood transfusion (P<0.001). The multivariate logistic regression analysis showed that blood transfusion [P=0.001, OR=0.218 (95% CI 0.092-0.520)] was the only independent prognostic factor. SAA (but not for VSAA) patients with IO had much lower hematologic response rate in 6 month after IST (P=0.037). Absolute reticulocyte count and IO correlated with response at 6 month by univariate logistical regression analysis (P=0.014, 0.037). The multivariate logistic regression analysis showed that IO [P=0.021, OR=4.092 (95% CI 1.235-13.563)], ARC ≥20×10(9)/L [P=0.040, OR=2.743 (95% CI 1.049-7.175)] were independent prognostic factors.

Conclusion: 84.8% patients had high serum ferritin before IST, and 14.0% reached IO. Adult and more blood transfusion caused IO more likely. IO correlated with response at 6 month, and was independent prognostic factor.
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http://dx.doi.org/10.3760/cma.j.issn.0253-2727.2016.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343093PMC
April 2016

Moderate-dose cyclophosphamide in the treatment of relapsed/refractory T-cell large granular lymphocytic leukemia-associated pure red cell aplasia.

Hematology 2016 Apr 16;21(3):138-43. Epub 2016 Mar 16.

a Department of Anemia Therapeutic Centre , Institute of Hematology and Blood Diseases Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences (CAMS & PUMC) , Tianjin , China.

Background: T-cell large granular lymphocyte leukemia (T-LGLL) is a rare disorder characterized by clonal proliferation of large granular lymphocytes (commonly CD3+/CD8+/CD57+). However, the available data regarding the optimal treatment for relapsed/refractory T-LGLL patients are limited.

Methods: We retrospectively reviewed 10 patients treated with immunosuppressive therapy consisting of intravenous moderate-dose cyclophosphamide (MD-CTX) together with oral cyclosporine A for relapsed/refractory T-LGLL in our hospital between July 2006 and March 2013.

Results: The overall response rate to MD-CTX was 60% (6/10; hematologic complete remission rate, 50%; hematologic partial remission rate, 10%). The median time to response was 28.5 days (range, 20-118 days). The relapse rate of MD-CTX was 50% (3/6); two of these three patients achieved hematologic complete remission after receiving a second course of MD-CTX. Neutropenia was the major adverse event of the MD-CTX regimen. The median time to neutropenia was 5.5 days (range, 1-10 days) and the median neutropenia duration was 5 days (range, 3-15 days). None of the patients developed severe infection.

Conclusions: The MD-CTX regimen appears efficacious and safe in the treatment of relapsed/refractory T-LGLL patients.
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http://dx.doi.org/10.1080/10245332.2015.1101977DOI Listing
April 2016

A review of neurotoxicity of microcystins.

Environ Sci Pollut Res Int 2016 Apr 9;23(8):7211-9. Epub 2016 Feb 9.

Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, No.7 Donghu South Road, Wuhan, 430072, China.

Cyanobacterial blooms-produced microcystins are secondary metabolites which can accumulate in the food chain and contaminate water, thus posing a potential threat to the health of aquatic animals and even humans. Microcystin toxicity affects not only the liver but also the other organs, i.e., the brain. The serious neurotoxicity effects caused by microcystins then lead to various symptoms. This review focuses on the neurotoxicity of microcystins. Microcystins can cross blood-brain barrier with the transport of Oatps/OATPs, causing neurostructural, functional, and behavioral changes. In this review, potential uptake mechanisms and neurotoxicity mechanisms are summarized, including neurotransmissions, neurochannels, signal transduction, oxidative stress, and cytoskeleton disruption. However, further researches are needed for detailed studies on signaling pathways and the downstream pathways of neurotoxicity of microcystins.
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http://dx.doi.org/10.1007/s11356-016-6073-yDOI Listing
April 2016

A proteomic study on liver impairment in rat pups induced by maternal microcystin-LR exposure.

Environ Pollut 2016 May 2;212:197-207. Epub 2016 Feb 2.

Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology of China, Institute of Hydrobiology, Chinese Academy of Sciences, Donghu South Road 7, Wuhan 430072, PR China.

There is mounting evidence indicating that microcystins (MCs) are heptapeptide toxins. Recent studies have also shown that MCLR can transfer from mother to offspring, but it is unclear whether maternal MCLR can influence the liver of offspring or not. In this study, pregnant SD rats were injected intraperitoneally with a saline solution (control) or 10 μg/kg MCLR per day from gestational day 8 (GD8) to postnatal day 15 (PD15) for a total of 4 weeks. 2-DE and MALDI-TOF-TOF mass spectrometry were used to screen for MCLR target proteins in the livers of rat pups. Our results demonstrated that MCLR could accumulate in the livers of neonatal rats. Proteomics studies also showed that MCLR significantly influenced many proteins, including those involved in the cytoskeleton, metabolism and particularly oxidative stress. In addition, MCLR induced cellular structural damage and resulted in the production of intracellular reactive oxygen species (ROS) and lipid peroxidation. Moreover, protein phosphatase (PP) activity was inhibited and some serum biochemistry parameters were altered. These results suggest an early molecular mechanism behind the hepatotoxicity induced by maternal MC exposure and highlight the importance of monitoring MC concentrations in new-born mammals.
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http://dx.doi.org/10.1016/j.envpol.2015.12.055DOI Listing
May 2016

Erratum to: Quantitatively evaluating detoxification of the hepatotoxic microcystin-LR through the glutathione (GSH) pathway in SD rats.

Environ Sci Pollut Res Int 2016 Mar;23(6):5995

Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.

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http://dx.doi.org/10.1007/s11356-016-6081-yDOI Listing
March 2016

Quantitatively evaluating detoxification of the hepatotoxic microcystin-LR through the glutathione (GSH) pathway in SD rats.

Environ Sci Pollut Res Int 2015 Dec 21;22(23):19273-84. Epub 2015 Oct 21.

College of Fisheries, Huazhong Agricultural University, Wuhan, 430070, Hubei, China.

Glutathione (GSH) plays crucial roles in antioxidant defense and detoxification metabolism of microcystin-LR (MC-LR). However, the detoxification process of MC-LR in mammals remains largely unknown. This paper, for the first time, quantitatively analyzes MC-LR and its GSH pathway metabolites (MC-LR-GSH and MC-LR-Cys) in the liver of Sprague-Dawley (SD) rat after MC-LR exposure. Rats received intraperitoneal (i.p.) injection of 0.25 and 0.5 lethal dose 50 (LD50) of MC-LR with or without pretreatment of buthionine-(S,R)-sulfoximine (BSO), an inhibitor of GSH synthesis. The contents of MC-LR-GSH were relatively low during the experiment; however, the ratio of MC-LR-Cys to MC-LR reached as high as 6.65 in 0.5 LD50 group. These results demonstrated that MC-LR-GSH could be converted to MC-LR-Cys efficiently, and this metabolic rule was in agreement with the data of aquatic animals previously reported. MC-LR contents were much higher in BSO + MC-LR-treated groups than in the single MC-LR-treated groups. Moreover, the ratio of MC-LR-Cys to MC-LR decreased significantly after BSO pretreatment, suggesting that the depletion of GSH induced by BSO reduced the detoxification of MCs. Moreover, MC-LR remarkably induced liver damage, and the effects were more pronounced in BSO pretreatment groups. In conclusion, this study verifies the role of GSH in the detoxification of MC-LR and furthers our understanding of the biochemical mechanism for SD rats to counteract toxic cyanobacteria.
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http://dx.doi.org/10.1007/s11356-015-5531-2DOI Listing
December 2015

A functional module-based exploration between inflammation and cancer in esophagus.

Sci Rep 2015 Oct 22;5:15340. Epub 2015 Oct 22.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, China.

Inflammation contributing to the underlying progression of diverse human cancers has been generally appreciated, however, explorations into the molecular links between inflammation and cancer in esophagus are still at its early stage. In our study, we presented a functional module-based approach, in combination with multiple data resource (gene expression, protein-protein interactions (PPI), transcriptional and post-transcriptional regulations) to decipher the underlying links. Via mapping differentially expressed disease genes, functional disease modules were identified. As indicated, those common genes and interactions tended to play important roles in linking inflammation and cancer. Based on crosstalk analysis, we demonstrated that, although most disease genes were not shared by both kinds of modules, they might act through participating in the same or similar functions to complete the molecular links. Additionally, we applied pivot analysis to extract significant regulators for per significant crosstalk module pair. As shown, pivot regulators might manipulate vital parts of the module subnetworks, and then work together to bridge inflammation and cancer in esophagus. Collectively, based on our functional module analysis, we demonstrated that shared genes or interactions, significant crosstalk modules, and those significant pivot regulators were served as different functional parts underlying the molecular links between inflammation and cancer in esophagus.
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http://dx.doi.org/10.1038/srep15340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4614801PMC
October 2015

[The study of genetic instability in patients with Dyskeratosis congenital].

Zhonghua Xue Ye Xue Za Zhi 2015 Sep;36(9):770-4

Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300020, China.

Objective: To investigate the genetic instability in patients with Dyskeration congenita.

Methods: The spontaneous chromosome instability of lymphocytes from 4 DC patients, 29 FA patients and 24 healthy volunteers was assessed with comet assay. The percent of DNA in comet head (HeadDNA%), the percent of DNA in comet tail (TailDNA%), tail moment (TM), olive tail moment (OTM), the comet cell percentage (CCP) were compared between groups. And the results of MMC test, PNH clones and karotype were analysed additionally. The correlation between TM, OTM, CCP and the severity degree of bone marrow failure in DC group were evaluated.

Results: ①PNH clones and karotype abnormalities were not found in 4 DC patients. ②TM (6.77 ± 0.90), OTM(6.19 ± 0.80) and CCP [(46.00 ± 5.03) %] in DC were significantly higher than those in normal control group [0.61 ± 0.49, 0.66 ± 0.42, (5.91 ± 3.19)%, P<0.05], however, not distinguished from FA patients [7.81 ± 3.58, 6.65 ± 2.21, (56.03 ± 13.47) %, P ≥ 0.05]. The aberrant cell percent at the MMC concentration of 80 μg/L in DC group was significantly lower than that in FA group [(21.00 ± 3.16) % vs (31.97 ± 6.33)%, P=0.003]. ③The correlation between TM, OTM, CCP and the severity of bone marrow failure in DC group were not found (P>0.05).

Conclusion: DC patients were of significantly increased genetic instability and normal DNA repair, which was different from that in FA patients. And there was no correlation between the degree of genetic instability and the severity of bone marrow failure in DC patients presenting as aplastic anemia.
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http://dx.doi.org/10.3760/cma.j.issn.0253-2727.2015.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342708PMC
September 2015

Genome-wide DNA methylome reveals the dysfunction of intronic microRNAs in major psychosis.

BMC Med Genomics 2015 Oct 14;8:62. Epub 2015 Oct 14.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang, China.

Background: DNA methylation is thought to be extensively involved in the pathogenesis of many diseases, including major psychosis. However, most studies focus on DNA methylation alteration at promoters of protein-coding genes, despite the poor correlation between DNA methylation and gene expression.

Methods: We analyzed differentially methylated regions and differentially expressed genes in patients with schizophrenia and bipolar disorder and normal subjects. Gene expression and DNA methylation were analyzed with RNA-seq and MeDIP-seq of post-mortem brain tissue (brain region BA9) cohort in five schizophrenia, seven bipolar disorder cases and six controls, respectively.

Results: Here, we performed a large-scale integrative analysis using MeDIP-seq, coupled with RNA-seq, on brain samples from major psychotic and normal subjects and observed obvious discrepancy between DNA methylation and gene expression. We found that differentially methylated regions (DMRs) were distributed across different types of genomic elements, especially introns. These intronic DMRs were significantly enriched for diverse regulatory elements, such as enhancers and binding sites of certain transcriptional factors (e.g., Pol3). Notably, we found that parts of intronic DMRs overlapped with some intragenic miRNAs, such as hsa-mir-7-3. These intronic DMR-related miRNAs were found to target many differentially expressed genes. Moreover, functional analysis demonstrated that differential target genes of intronic DMR-related miRNAs were sufficient to capture many important biological processes in major psychosis, such as neurogenesis, suggesting that miRNAs may function as important linkers mediating the relationships between DNA methylation alteration and gene expression changes.

Conclusions: Collectively, our study indicated that DNA methylation alteration could induce expression changes indirectly by affecting miRNAs and the exploration of DMR-related miRNAs and their targets enhanced understanding of the molecular mechanisms underlying major psychosis.
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http://dx.doi.org/10.1186/s12920-015-0139-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604612PMC
October 2015

Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy.

Oncotarget 2015 Nov;6(35):37600-12

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.

Chronic inflammation may play a vital role in the pathogenesis of inflammation-associated tumors. However, the underlying mechanisms bridging ulcerative colitis (UC) and colorectal cancer (CRC) remain unclear. Here, we integrated multidimensional interaction resources, including gene expression profiling, protein-protein interactions (PPIs), transcriptional and post-transcriptional regulation data, and virus-host interactions, to tentatively explore potential molecular targets that functionally link UC and CRC at a systematic level. In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC. Interestingly, further analyses of the virus-host interaction network demonstrated that several virus proteins (including EBNA-LP of EBV and protein E7 of HPV) frequently inter-connected to UC- and CRC-associated module pairs with their validated targets significantly enriched in both modules of the host. Together, our results suggested that multidimensional integration strategy provides a novel approach to discover potential molecular targets that bridge the connections between UC and CRC, which could also be extensively applied to studies on other inflammation-related cancers.
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http://dx.doi.org/10.18632/oncotarget.6067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741951PMC
November 2015

MeSiC: A Model-Based Method for Estimating 5 mC Levels at Single-CpG Resolution from MeDIP-seq.

Sci Rep 2015 Oct 1;5:14699. Epub 2015 Oct 1.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150081, China.

As the fifth base in mammalian genome, 5-methylcytosine (5 mC) is essential for many biological processes including normal development and disease. Methylated DNA immunoprecipitation sequencing (MeDIP-seq), which uses anti-5 mC antibodies to enrich for methylated fraction of the genome, is widely used to investigate methylome at a resolution of 100-500 bp. Considering the CpG density-dependent bias and limited resolution of MeDIP-seq, we developed a Random Forest Regression (RFR) model method, MeSiC, to estimate DNA methylation levels at single-base resolution. MeSiC integrated MeDIP-seq signals of CpG sites and their surrounding neighbors as well as genomic features to construct genomic element-dependent RFR models. In the H1 cell line, a high correlation was observed between MeSiC predictions and actual 5 mC levels. Meanwhile, MeSiC enabled to calibrate CpG density-dependent bias of MeDIP-seq signals. Importantly, we found that MeSiC models constructed in the H1 cell line could be used to accurately predict DNA methylation levels for other cell types. Comparisons with methylCRF and MEDIPS showed that MeSiC achieved comparable and even better performance. These demonstrate that MeSiC can provide accurate estimations of 5 mC levels at single-CpG resolution using MeDIP-seq data alone.
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http://dx.doi.org/10.1038/srep14699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589794PMC
October 2015

Systematically Prioritizing Functional Differentially Methylated Regions (fDMRs) by Integrating Multi-omics Data in Colorectal Cancer.

Sci Rep 2015 Aug 4;5:12789. Epub 2015 Aug 4.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, Heilongjiang 150086, China.

While genome-wide differential DNA methylation regions (DMRs) have been extensively identified, the comprehensive prioritization of their functional importance is still poorly explored. Here, we aggregated multiple data resources rooted in the genome, epigenome and transcriptome to systematically prioritize functional DMRs (fDMRs) in colorectal cancer (CRC). As demonstrated, the top-ranked fDMRs from all of the data resources showed a strong enrichment for known methylated genes. Additionally, we analyzed those top 5% DMR-coupled coding genes using functional enrichment, which resulted in significant disease-related biological functions in contrast to the tail 5% genes. To further confirm the functional importance of the top-ranked fDMRs, we applied chromatin modification alterations of CRC cell lines to characterize their functional regulation. Specifically, we extended the utility of the top-ranked DMR-coupled genes to serve as classification and survival biomarkers, which showed a robust performance across diverse independent data sets. Collectively, our results established an integrative framework to prioritize fDMRs, which could help characterize aberrant DNA methylation-induced potential mechanisms underlying tumorigenesis and uncover epigenome-based biomarkers for clinical diagnosis and prognosis.
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http://dx.doi.org/10.1038/srep12789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523937PMC
August 2015

Chromatin states modify network motifs contributing to cell-specific functions.

Sci Rep 2015 Jul 14;5:11938. Epub 2015 Jul 14.

College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.

Epigenetic modification can affect many important biological processes, such as cell proliferation and apoptosis. It can alter chromatin conformation and contribute to gene regulation. To investigate how chromatin states associated with network motifs, we assembled chromatin state-modified regulatory networks by combining 269 ChIP-seq data and chromatin states in four cell types. We found that many chromatin states were significantly associated with network motifs, especially for feedforward loops (FFLs). These distinct chromatin state compositions contribute to different expression levels and translational control of targets in FFLs. Strikingly, the chromatin state-modified FFLs were highly cell-specific and, to a large extent, determined cell-selective functions, such as the embryonic stem cell-specific bivalent modification-related FFL with an important role in poising developmentally important genes for expression. Besides, comparisons of chromatin state-modified FFLs between cancerous/stem and primary cell lines revealed specific type of chromatin state alterations that may act together with motif structural changes cooperatively contribute to cell-to-cell functional differences. Combination of these alterations could be helpful in prioritizing candidate genes. Together, this work highlights that a dynamic epigenetic dimension can help network motifs to control cell-specific functions.
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http://dx.doi.org/10.1038/srep11938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500950PMC
July 2015