Publications by authors named "Xiaohong Jing"

18 Publications

  • Page 1 of 1

Effect of systemic rehabilitation nursing intervention on psychological status and postoperative recovery of laryngeal cancer patients in perioperative period.

Minerva Med 2020 Jul 29. Epub 2020 Jul 29.

Otolaryngology Department, The Second Affiliated Hospital of Xi'an Jiaotong University (Xibei) Hospital, Xi'an, China -

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http://dx.doi.org/10.23736/S0026-4806.20.06847-0DOI Listing
July 2020

Perturbation biology links temporal protein changes to drug responses in a melanoma cell line.

PLoS Comput Biol 2020 07 15;16(7):e1007909. Epub 2020 Jul 15.

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, U.S.A.

Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. Cancer drugs targeting these alterations often work initially, but resistance is common. Combinations of targeted drugs may overcome or prevent resistance, but their selection requires context-specific knowledge of signaling pathways including complex interactions such as feedback loops and crosstalk. To infer quantitative pathway models, we collected a rich dataset on a melanoma cell line: Following perturbation with 54 drug combinations, we measured 124 (phospho-)protein levels and phenotypic response (cell growth, apoptosis) in a time series from 10 minutes to 67 hours. From these data, we trained time-resolved mathematical models that capture molecular interactions and the coupling of molecular levels to cellular phenotype, which in turn reveal the main direct or indirect molecular responses to each drug. Systematic model simulations identified novel combinations of drugs predicted to reduce the survival of melanoma cells, with partial experimental verification. This particular application of perturbation biology demonstrates the potential impact of combining time-resolved data with modeling for the discovery of new combinations of cancer drugs.
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http://dx.doi.org/10.1371/journal.pcbi.1007909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384681PMC
July 2020

Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience.

Cancer Med 2020 09 7;9(17):6093-6101. Epub 2020 Jul 7.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Purpose: The enucleation rate for retinoblastoma has dropped from over 95% to under 10% in the past 10 years as a result of improvements in therapy. This reduces access to tumor tissue for molecular profiling, especially in unilateral retinoblastoma, and hinders the confirmation of somatic RB1 mutations necessary for genetic counseling. Plasma cell-free DNA (cfDNA) has provided a platform for noninvasive molecular profiling in cancer, but its applicability in low tumor burden retinoblastoma has not been shown. We analyzed cfDNA collected from 10 patients with available tumor tissue to determine whether sufficient tumorderived cfDNA is shed in plasma from retinoblastoma tumors to enable noninvasive RB1 mutation detection.

Methods: Tumor tissue was collected from eye enucleations in 10 patients diagnosed with advanced intra-ocular unilateral retinoblastoma, three of which went on to develop metastatic disease. Tumor RB1 mutation status was determined using an FDA-cleared tumor sequencing assay, MSK-IMPACT. Plasma samples were collected before eye enucleation and analyzed with a customized panel targeting all exons of RB1.

Results: Tumor-guided genotyping detected 10 of the 13 expected somatic RB1 mutations in plasma cfDNA in 8 of 10 patients (average variant allele frequency 3.78%). Without referring to RB1 status in the tumor, de novo mutation calling identified 7 of the 13 expected RB1 mutations (in 6 of 10 patients) with high confidence.

Conclusion: Plasma cfDNA can detect somatic RB1 mutations in patients with unilateral retinoblastoma. Since intraocular biopsies are avoided in these patients because of concern about spreading tumor, cfDNA can potentially offer a noninvasive platform to guide clinical decisions about treatment, follow-up schemes, and risk of metastasis.
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http://dx.doi.org/10.1002/cam4.3144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476838PMC
September 2020

Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis.

Aging (Albany NY) 2020 04 8;12(7):6385-6400. Epub 2020 Apr 8.

Department of Pharmacy, Binzhou Medical University, Yantai 264003, China.

Long noncoding RNAs (lncRNAs) play important roles in the development of vascular diseases. However, the effect of lncRNA NORAD on atherosclerosis remains unknown. This study aimed to investigate the effect NORAD on endothelial cell injury and atherosclerosis. Ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and high-fat-diet (HFD)-fed ApoE mice were used as and models. Results showed that NORAD-knockdown induced cell cycle arrest in G0/G1 phase, aggravated ox-LDL-induced cell viability reduction, cell apoptosis, and cell senescence along with the increased expression of Bax, P53, P21 and cleaved caspase-3 and the decreased expression of Bcl-2. The effect of NORAD on cell viability was further verified via NORAD-overexpression. NORAD- knockdown increased ox-LDL-induced reactive oxygen species, malondialdehyde, p-IKBα expression levels and NF-κB nuclear translocation. Proinflammatory molecules ICAM, VCAM, and IL-8 were also increased by NORAD- knockdown. Additionally, we identified the strong interaction of NORAD and IL-8 transcription repressor SFPQ in HUVECs. In ApoE mice, NORAD-knockdown increased the lipid disorder and atherosclerotic lesions. The results have suggested that lncRNA NORAD attenuates endothelial cell senescence, endothelial cell apoptosis, and atherosclerosis via NF-κB and p53-p21 signaling pathways and IL-8, in which NORAD-mediated effect on IL-8 might through the direct interaction with SFPQ.
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http://dx.doi.org/10.18632/aging.103034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185106PMC
April 2020

Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid.

Nature 2019 01 23;565(7741):654-658. Epub 2019 Jan 23.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Diffuse gliomas are the most common malignant brain tumours in adults and include glioblastomas and World Health Organization (WHO) grade II and grade III tumours (sometimes referred to as lower-grade gliomas). Genetic tumour profiling is used to classify disease and guide therapy, but involves brain surgery for tissue collection; repeated tumour biopsies may be necessary for accurate genotyping over the course of the disease. While the detection of circulating tumour DNA (ctDNA) in the blood of patients with primary brain tumours remains challenging, sequencing of ctDNA from the cerebrospinal fluid (CSF) may provide an alternative way to genotype gliomas with lower morbidity and cost. We therefore evaluated the representation of the glioma genome in CSF from 85 patients with gliomas who underwent a lumbar puncture because they showed neurological signs or symptoms. Here we show that tumour-derived DNA was detected in CSF from 42 out of 85 patients (49.4%) and was associated with disease burden and adverse outcome. The genomic landscape of glioma in the CSF included a broad spectrum of genetic alterations and closely resembled the genomes of tumour biopsies. Alterations that occur early during tumorigenesis, such as co-deletion of chromosome arms 1p and 19q (1p/19q codeletion) and mutations in the metabolic genes isocitrate dehydrogenase 1 (IDH1) or IDH2, were shared in all matched ctDNA-positive CSF-tumour pairs, whereas growth factor receptor signalling pathways showed considerable evolution. The ability to monitor the evolution of the glioma genome through a minimally invasive technique could advance the clinical development and use of genotype-directed therapies for glioma, one of the most aggressive human cancers.
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http://dx.doi.org/10.1038/s41586-019-0882-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457907PMC
January 2019

Impact of high-fat diet on the proteome of mouse liver.

J Nutr Biochem 2016 05 26;31:10-9. Epub 2016 Jan 26.

Department of Medicine, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA. Electronic address:

Chronic overnutrition, for instance, high-fat diet (HFD) feeding, is a major cause of rapidly growing incidence of metabolic syndromes. However, the mechanisms underlying HFD-induced adverse effects on human health are not clearly understood. HFD-fed C57BL6/J mouse has been a popular model employed to investigate the mechanisms. Yet, there is no systematic and comprehensive study of the impact of HFD on the protein profiles of the animal. Here, we present a proteome-wide study of the consequences of long-term HFD feeding. Utilizing a powerful technology, stable isotope labeling of mammals, we detected and quantitatively compared 965 proteins extracted from livers of chow-diet-fed and HFD-fed mice. Among which, 122 proteins were significantly modulated by HFD. Fifty-four percent of those 122 proteins are involved in metabolic processes and the majority participate in lipid metabolism. HFD up-regulates proteins that play important roles in fatty acid uptake and subsequent oxidation and are linked to the transcription factors PPARα and PGC-1α. HFD suppresses lipid biosynthesis-related proteins that play major roles in de novo lipogenesis and are linked to SREBP-1 and PPARγ. These data suggest that HFD-fed mice tend to develop enhanced fat utilization and suppressed lipid biosynthesis, understandably a self-protective mechanism to counteract to excessive fat loading, which causes liver steatosis. Enhanced fatty acid oxidation increases reactive oxygen species and inhibits glucose oxidation, which are associated with hyperglycemia and insulin resistance. This proteomics study provides molecular understanding of HFD-induced pathology and identifies potential targets for development of therapeutics for metabolic syndromes.
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http://dx.doi.org/10.1016/j.jnutbio.2015.12.012DOI Listing
May 2016

[Cervical vestibular evoked myogenic potential elicited by different types air conducted sounds among normal young Chinese people].

Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2015 Jul;29(13):1175-8

Objective: To observe waveform difference among cervical vestibular evoked myogenic potentials (cVEMP) elicited with different types of air conducted sound in normal young Chinese subjects.

Method: Twenty adult volunteers (40 ears) were recruited as research subjects including 10 males and 10 females aged between 19 and 30.500 Hz Tone Burst, 1000 Hz Tone Burst and Click were employed as stimulus for conventional air conducted sound-cVEMP (ACS-cVEMP) examinations in bilateral ears of each subject. The response rate, threshold, P1 latency, N1 latency, P1-N1 latency interval, amplitude and inter-aural asymmetry were recorded and compared among groups.

Result: The response rate was 97.5% in 500Hz Tone Burst (39/40), 87.5% in 1 000Hz Tone Burst (35/40)and 67.5% in Click (27/40), There were no statistically significant difference between 500Hz Tone Burst and 1000Hz Tone Burst (P > 0.05) but there were statistically significant difference between click and the other groups (P < 0.05). We collected the waveform parameters (the threshold, P1 latency, N1 latency, P1-N1 latency interval, amplitude) which had statistically significant difference between 500 Hz Tone Burst and the other groups (P < 0.05). The inter-aural asymmetrys had no statistically significant differents among groups.

Conclusion: The response rate and parameter could be affected by different types of air conducted sound in normal young Chinese subjects. 500 Hz Tone Burst was the best stimulus of type what we have known.
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July 2015

Perturbation biology nominates upstream-downstream drug combinations in RAF inhibitor resistant melanoma cells.

Elife 2015 Aug 18;4. Epub 2015 Aug 18.

Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, United States.

Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.
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http://dx.doi.org/10.7554/eLife.04640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539601PMC
August 2015

[Bio-modification of polyhydroxyalkanoates and its biocompatibility with chondrocytes].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2014 Aug;28(8):1023-9

Objective: To study the hydrophilicity and the cell biocompatibility of the poly(3-hydroxybutyrate-co- 3-hydroxyvalerate) (PHBV) and poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) coated with a fusion protein polyhydroxyalkanoates granule binding protein (PhaP) fused with Arg-Gly-Asp (RGD) peptide (PhaP-RGD).

Methods: PHBV and PHBHHx films were fabricated by solvent evaporation. Scanning electronic microscope (SEM) was used to study the morphology of the films. PhaP-RGD fusion proteins were expressed and purified by the technology of protein engineering; PHBV and PHBHHx films were immersed in the PhaP-RGD with an amount of 3.5 mg/mL protein/per sample respectively. The hydrophilicity of the surface were detected by the contact angle measurements. Septal cartilage cells obtained from human septal cartilage were cultured in vitro. The 2nd passage chondrocytes were incubated on PHBV unmodified with PhaP-RGD in group A1, PHBV modified with PhaP-RGD in group A2, PHBHHx unmodified with PhaP-RGD in group Bl, PHBHHx modified with PhaP-RGD in group B2, and on the cell culture plates in group C. After cultured for 3 days, the proliferation of cells was detected by the DAPI staining; the proliferation viability of cells was detected by the MTT assay after cultured for 3 and 7 days; after cultured for 7 days, the adhesion and morphology of the cells on the surface of the biomaterial films were observed by SEM and the matrix of the cells was detected through the toluidine blue staining.

Results: SEM observation showed that PHBV and PHBHHx films had porous structures. The contact angle of the surface of the PHBV and PHBHHx films modified with PhaP-RGD fusion proteins were significantly reduced when compared with the films unmodified with PhaP-RGD fusion proteins (P < 0.05). Chondrocytes of human nasal septal cartilage incubated on the films could grow in all groups. After 3 days of cultivation in vitro, the cell proliferation and viability of group B2 were the strongest among all groups (P < 0.05); the cell proliferation after cultured for 7 days was significantly stronger than that after cultured for 3 days in groups A1, A2, B1, and B2 (P < 0.05); and the cell proliferation was significantly stronger in groups B1 and B2 than groups A1, A2 and C, in group B2 than group B1, and in group A1 than group A2 (P < 0.05). The results of toluidine blue staining showed that blue metachromasia matrixes were observed in groups A1, A2, B1, and B2; group A1 and group A2 had similar staining degree, and the staining of group B2 was deeper than that of group B1. The adhesion of cells in all groups was good through SEM observation; and the connection of cells formed and stretched into the pores of the materials.

Conclusion: The biomaterial films of PHBHHx modified with PhaP-RGD fusion protein can promote its biocompatibility with chondrocytes.
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August 2014

MicroRNA-21 in glomerular injury.

J Am Soc Nephrol 2015 Apr 21;26(4):805-16. Epub 2014 Aug 21.

Internal Medicine, University of Michigan, Ann Arbor, Michigan; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York;

TGF-β(1) is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-β(1), and miR-21 inhibits apoptosis in cancer cells. TGF-β(1)-transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-β(1) and is higher in kidneys of TGF-β(1)-transgenic mice than wild-type mice. miR-21-deficient TGF-β(1)-transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-β(1)-transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-β/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P<0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-β(1) and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21-deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF-β signaling and functions.
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http://dx.doi.org/10.1681/ASN.2013121274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378097PMC
April 2015

Prediction of individualized therapeutic vulnerabilities in cancer from genomic profiles.

Bioinformatics 2014 Jul 24;30(14):2051-9. Epub 2014 Mar 24.

Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 and Tri-Institutional Training Program in Computational Biology & Medicine, New York, NY 10065, USA.

Motivation: Somatic homozygous deletions of chromosomal regions in cancer, while not necessarily oncogenic, may lead to therapeutic vulnerabilities specific to cancer cells compared with normal cells. A recently reported example is the loss of one of the two isoenzymes in glioblastoma cancer cells such that the use of a specific inhibitor selectively inhibited growth of the cancer cells, which had become fully dependent on the second isoenzyme. We have now made use of the unprecedented conjunction of large-scale cancer genomics profiling of tumor samples in The Cancer Genome Atlas (TCGA) and of tumor-derived cell lines in the Cancer Cell Line Encyclopedia, as well as the availability of integrated pathway information systems, such as Pathway Commons, to systematically search for a comprehensive set of such epistatic vulnerabilities.

Results: Based on homozygous deletions affecting metabolic enzymes in 16 TCGA cancer studies and 972 cancer cell lines, we identified 4104 candidate metabolic vulnerabilities present in 1019 tumor samples and 482 cell lines. Up to 44% of these vulnerabilities can be targeted with at least one Food and Drug Administration-approved drug. We suggest focused experiments to test these vulnerabilities and clinical trials based on personalized genomic profiles of those that pass preclinical filters. We conclude that genomic profiling will in the future provide a promising basis for network pharmacology of epistatic vulnerabilities as a promising therapeutic strategy.

Availability And Implementation: A web-based tool for exploring all vulnerabilities and their details is available at http://cbio.mskcc.org/cancergenomics/statius/ along with supplemental data files.
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http://dx.doi.org/10.1093/bioinformatics/btu164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080742PMC
July 2014

Perturbation biology: inferring signaling networks in cellular systems.

PLoS Comput Biol 2013 19;9(12):e1003290. Epub 2013 Dec 19.

Computational Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.

We present a powerful experimental-computational technology for inferring network models that predict the response of cells to perturbations, and that may be useful in the design of combinatorial therapy against cancer. The experiments are systematic series of perturbations of cancer cell lines by targeted drugs, singly or in combination. The response to perturbation is quantified in terms of relative changes in the measured levels of proteins, phospho-proteins and cellular phenotypes such as viability. Computational network models are derived de novo, i.e., without prior knowledge of signaling pathways, and are based on simple non-linear differential equations. The prohibitively large solution space of all possible network models is explored efficiently using a probabilistic algorithm, Belief Propagation (BP), which is three orders of magnitude faster than standard Monte Carlo methods. Explicit executable models are derived for a set of perturbation experiments in SKMEL-133 melanoma cell lines, which are resistant to the therapeutically important inhibitor of RAF kinase. The resulting network models reproduce and extend known pathway biology. They empower potential discoveries of new molecular interactions and predict efficacious novel drug perturbations, such as the inhibition of PLK1, which is verified experimentally. This technology is suitable for application to larger systems in diverse areas of molecular biology.
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http://dx.doi.org/10.1371/journal.pcbi.1003290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868523PMC
August 2014

Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.

Sci Signal 2013 Sep 24;6(294):ra85. Epub 2013 Sep 24.

1Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.
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http://dx.doi.org/10.1126/scisignal.2004014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000046PMC
September 2013

PiHelper: an open source framework for drug-target and antibody-target data.

Bioinformatics 2013 Aug 12;29(16):2071-2. Epub 2013 Jun 12.

Computational Biology Center, Memorial Sloan-Kettering Cancer Center, NY 10065, USA.

Motivation: The interaction between drugs and their targets, often proteins, and between antibodies and their targets, is important for planning and analyzing investigational and therapeutic interventions in many biological systems. Although drug-target and antibody-target datasets are available in separate databases, they are not publicly available in an integrated bioinformatics resource. As medical therapeutics, especially in cancer, increasingly uses targeted drugs and measures their effects on biomolecular profiles, there is an unmet need for a user-friendly toolset that allows researchers to comprehensively and conveniently access and query information about drugs, antibodies and their targets.

Summary: The PiHelper framework integrates human drug-target and antibody-target associations from publicly available resources to help meet the needs of researchers in systems pharmacology, perturbation biology and proteomics. PiHelper has utilities to (i) import drug- and antibody-target information; (ii) search the associations either programmatically or through a web user interface (UI); (iii) visualize the data interactively in a network; and (iv) export relationships for use in publications or other analysis tools.

Availability: PiHelper is a free software under the GNU Lesser General Public License (LGPL) v3.0. Source code and documentation are at http://bit.ly/pihelper. We plan to coordinate contributions from the community by managing future releases.
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http://dx.doi.org/10.1093/bioinformatics/btt345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722529PMC
August 2013

miR-21 mediates hematopoietic suppression in MDS by activating TGF-β signaling.

Blood 2013 Apr 6;121(15):2875-81. Epub 2013 Feb 6.

Albert Einstein College of Medicine, Bronx, NY;

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. We observed that SMAD7, a negative regulator of transforming growth factor-beta (TGF-β) receptor-I kinase, is markedly reduced in MDS and leads to ineffective hematopoiesis by overactivation of TGF-β signaling. To determine the cause of SMAD7 reduction in MDS, we analyzed the 3'UTR of the gene and determined that it contains a highly conserved putative binding site for microRNA-21. We observed significantly elevated levels of miR-21 in MDS marrow samples when compared with age-matched controls. miR-21 was shown to directly bind to the 3'UTR of SMAD7 and reduce its expression in hematopoietic cells. Next, we tested the role of miR-21 in regulating TGF-β signaling in a TGF-β-overexpressing transgenic mouse model that develops progressive anemia and dysplasia and thus serves as a model of human bone marrow failure. Treatment with a chemically modified miR-21 inhibitor led to significant increases in hematocrit and led to an increase in SMAD7 expression in vivo. Inhibition of miR-21 also led to an increase in erythroid colony formation from primary MDS bone marrow progenitors, demonstrating its ability in stimulating hematopoiesis in vitro. Taken together, these studies demonstrate the role of miR-21 in regulating overactivated TGF-β signaling in MDS.
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http://dx.doi.org/10.1182/blood-2011-12-397067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3624935PMC
April 2013

Prostaglandin transporter modulates wound healing in diabetes by regulating prostaglandin-induced angiogenesis.

Am J Pathol 2012 Jul 15;181(1):334-46. Epub 2012 May 15.

Department of Medicine, Albert Einstein College of Medicine, New York City, NY 10461, USA.

Prostaglandin transporter (PGT) mediates prostaglandin (PG) catabolism and PG signal termination. The prostanoid PGE(2), which induces angiogenesis and vasodilation, is diminished in diabetic skin, suggesting that PGT up-regulation could be important in wound healing deficiency, typified by diabetic foot ulcer. We hypothesized that up-regulation of PGT in hyperglycemia could contribute to weakened PGE(2) signaling, leading to impaired angiogenesis and wound healing. In human dermal microvascular endothelial cells (HDMECs), exposure to hyperglycemia increased PGT expression and activity up to threefold, accompanied by reduced levels of PGE(2). Hyperglycemia reduced HDMEC migration by 50% and abolished tube formation. Deficits in PGE(2) expression, HDMEC migration, and tube formation could be corrected by treatment with the PGT inhibitor T26A, consistent with the idea that PGT hyperactivity is responsible for impairments in angiogenesis mediated by PG signaling. In vivo, PGT expression was profoundly induced in diabetes and by wounding, correlating with diminished levels of proangiogenic factors PGE(2) and VEGF in cutaneous wounds of diabetic mice. Pharmacological inhibition of PGT corrected these deficits. PGT inhibition shortened cutaneous wound closure time in diabetic mice from 22 to 16 days. This effect was associated with increased proliferation, re-epithelialization, neovascularization, and blood flow. These data provide evidence that hyperglycemia enhances PGT expression and activity, leading to diminished angiogenic signaling, a possible key mechanism underlying defective wound healing in diabetes.
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http://dx.doi.org/10.1016/j.ajpath.2012.03.012DOI Listing
July 2012

Quantitative analysis of miRNA expression in epithelial cells and tissues.

Methods Mol Biol 2012 ;820:55-70

Internal Medicine, Nephrology, Michigan Diabetes Research and Training Center, University of Michigan, Ann Arbor, MI 48109, USA.

Reliable detection of the microRNA (miRNA) precursor and mature form expression levels is a fundamental starting block for more focused studies of the biogenesis and functional roles of these important post-transcriptional modulators of gene expression. Building on our expertise with miRNA expression programs downstream of TGF-β/Smad signaling in homeostasis as well as in pathological conditions associated with epithelial tissues, we present a series of detailed and broadly applicable protocols for expression profiling of the mature miRNA forms using quantitative real-time PCR TaqMan, both single assays or low-density arrays. We next highlight key steps necessary for the detection of primary precursors of miRNAs (-pri-miRNAs) to address the initial steps of miRNA biogenesis, and we finally review some most widely used computational algorithms for miRNA target prediction used to complement experimental identification of the target mRNAs and proteins.
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http://dx.doi.org/10.1007/978-1-61779-439-1_4DOI Listing
March 2012

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147.

Cancer Sci 2011 Jul 3;102(7):1287-92. Epub 2011 May 3.

Department of Traditional Chinese Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.

The isoquinoline plant alkaloid berberine has anti-tumor effects on a variety of carcinoma cells, mainly through inhibition of cell proliferation, apoptosis induction and cell cycle arrest. However, the mechanisms underlying its role in tumor progression are unknown. In the present study, we investigated the molecular mechanisms involved in berberine-induced cell death in human hepatoma carcinoma cell (HCC) lines HepG2 and SMMC7721. Our results showed that berberine inhibited tumor cell viability in a dose- and time-dependent manner, and induced cell death via apoptosis and autophagy. Moreover, berberine treatment significantly inhibited CD147 expression by HCC cells in a dose-dependent manner. Overexpression of CD147 protein markedly reduced berberine-induced cell death. Our data provide the first experimental evidence that berberine induces cell death in HCC cells via downregulation of CD147 and suggest a new mechanism to explain its anti-tumor effects.
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http://dx.doi.org/10.1111/j.1349-7006.2011.01933.xDOI Listing
July 2011