Publications by authors named "Xiaoying Jia"

50 Publications

Bergamottin, a bioactive component of bergamot, inhibits SARS-CoV-2 infection in golden Syrian hamsters.

Antiviral Res 2022 08 19;204:105365. Epub 2022 Jun 19.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China; University of the Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused an ongoing pandemic, coronavirus disease-2019 (COVID-19), which has become a major global public health event. Antiviral compounds remain the predominant means of treating COVID-19. Here, we reported that bergamottin, a furanocoumarin originally found in bergamot, exhibited inhibitory activity against SARS-CoV-2 in vitro, ex vivo, and in vivo. Bergamottin interfered with multiple stages of virus life cycles, specifically blocking the SARS-CoV-2 spike-mediated membrane fusion and effectively reducing viral RNA synthesis. Oral delivery of bergamottin to golden Syrian hamsters at dosages of both 50 mg/kg and 75 mg/kg reduced the SARS-CoV-2 load in nasal turbinates and lung tissues. Pathological damage caused by viral infection was also ameliorated after bergamottin treatment. Overall, our study provides evidence of bergamottin as a promising natural compound, with broad-spectrum anti-coronavirus activity, that could be further developed in the fight against COVID-19 infection during the current pandemic.
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http://dx.doi.org/10.1016/j.antiviral.2022.105365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9212731PMC
August 2022

Dithiocarbazate-Fe, -Co, -Ni, and -Zn Complexes: Design, Synthesis, Structure, and Anticancer Evaluation.

J Med Chem 2022 05 21;65(9):6677-6689. Epub 2022 Apr 21.

Laboratory of Respiratory Disease, Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China.

Non-platinum-metal complexes show great potential as anticancer agents. Herein, a series of dithiocarbazate non-Pt-metal complexes, including [Fe(L)]·Cl·2HO , [Co(L)]·NO·2.5HO , [Ni(L)] , and [Zn(L)] , have been designed and evaluated for their efficacy as antineoplastic agents. Among them, complex exhibited higher anticancer efficacy than complexes , , , and platin against several cancer cell lines. Hemolysis assays revealed that complex showed comparable hemolysis with platin. anticancer evaluations showed that complex could retard tumor xenograft growth effectively with low systemic toxicity. Further studies revealed that complex suppressed cancer cells by triggering multiple mechanisms involving the simultaneous inhibition of mitochondria and glycolytic bioenergetics. Overall, our study provides new insights into the anticancer mechanism of Co complexes, which can be used as a good strategy to overcome the flexibility of cancer cells to chemotherapy adaptation.
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http://dx.doi.org/10.1021/acs.jmedchem.1c02186DOI Listing
May 2022

Isolated complete dislocation of hamate bone with an ulnar nerve injury: a case report and literature review.

Ann Transl Med 2022 Mar;10(6):385

Department of Radiology, Hebei Province Hospital of Chinese Medicine, Hebei Technology Innovation Center of TCM Spleen and Kidney Diseases, Shijiazhuang, China.

Background: Isolated complete dislocation of the hamate bone is a rare wrist injury. Only 22 cases have been reported in the literature. Four of them were associated with nerve injury, but it is a pity that the causes of ulnar nerve injury had never been deeply analyzed. In the case report, it was stated that the ulnar nerve injury was caused by both displacement of uncinate bone and change of position of transverse carpal ligament. The complete dislocation of the hamate bone is mostly caused by direct force, often accompanied by tears of the surrounding ligaments.

Case Description: A 30-year-old woman was treated because her left hand was crushed by a machine roller. Plain film X-ray showed isolated dislocation of the volar hamate and rotation of the hamate bone to the volar side. Clinical manifestations and computed tomography (CT) signs suggest ulnar nerve injury. The patient was quickly transported to the operating room for open reduction and internal fixation of the hamate bone and repair of the dorsal carpal ligament. The patient fully recovered after 12 months.

Conclusions: Isolated complete dislocation of the hamate bone is a rare injury. The most common cause is direct compression force to the wrist. Diagnosis can be made through review of the patient's medical history, physical examination and X-ray, however, CT can accurately evaluate the displacement and rotation of the hamate bone, hamate bone fracture and other concomitant wrist fractures, suggesting compression changes of the median nerve and ulnar nerve to provide a reliable basis for the formulation of a clinical care plan. The case report added the evidence-based practice, and discussed the anatomical mechanism and imaging manifestation of ulnar nerve injury associated with complete dislocation of hamate bone.
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http://dx.doi.org/10.21037/atm-22-1031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011248PMC
March 2022

Screening of Botanical Drugs against SARS-CoV-2 Entry Reveals Novel Therapeutic Agents to Treat COVID-19.

Viruses 2022 02 8;14(2). Epub 2022 Feb 8.

State Key Laboratory of Virology, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.

An escalating pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has severely impacted global health. There is a severe lack of specific treatment options for diseases caused by SARS-CoV-2. In this study, we used a pseudotype virus (pv) containing the SARS-CoV-2 S glycoprotein to screen a botanical drug library containing 1037 botanical drugs to identify agents that prevent SARS-CoV-2 entry into the cell. Our study identified four hits, including angeloylgomisin O, schisandrin B, procyanidin, and oleanonic acid, as effective SARS-CoV-2 S pv entry inhibitors in the micromolar range. A mechanistic study revealed that these four agents inhibited SARS-CoV-2 S pv entry by blocking spike (S) protein-mediated membrane fusion. Furthermore, angeloylgomisin O and schisandrin B inhibited authentic SARS-CoV-2 with a high selective index (SI; 50% cytotoxic concentration/50% inhibition concentration). Our drug combination studies performed in cellular antiviral assays revealed that angeloylgomisin O has synergistic effects in combination with remdesivir, a drug widely used to treat SARS-CoV-2-mediated infections. We also showed that two hits could inhibit the newly emerged alpha (B.1.1.7) and beta (B.1.351) variants. Our findings collectively indicate that angeloylgomisin O and schisandrin B could inhibit SARS-CoV-2 efficiently, thereby making them potential therapeutic agents to treat the coronavirus disease of 2019.
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http://dx.doi.org/10.3390/v14020353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877376PMC
February 2022

Screening and identification of Lassa virus endonuclease-targeting inhibitors from a fragment-based drug discovery library.

Antiviral Res 2022 01 26;197:105230. Epub 2021 Dec 26.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China; University of the Chinese Academy of Sciences, Beijing, 100049, China. Electronic address:

Lassa virus (LASV) belongs to the Old World genus Mammarenavirus, family Arenaviridae, and order Bunyavirales. Arenavirus contains a segmented negative-sense RNA genome, which is in line with the bunyavirus and orthomyxoviruses. The segmented negative-sense RNA viruses utilize a cap-snatching strategy to provide primers cleavaged from the host capped mRNA for viral mRNA transcription. As a similar strategy and the conformational conservation shared with these viruses, the endonuclease (EN) would serve as an attractive target for developing broad-spectrum inhibitors. Using the LASV minigenome (MG) system, we screened a fragment-based drug discovery library and found that two hits, F1204 and F1781, inhibited LASV MG activity. Both hits also inhibited the prototype arenavirus Lymphocytic choriomeningitis virus (LCMV) MG activity. Furthermore, both hits effectively inhibited authentic LCMV and severe fever with thrombocytopenia syndrome virus (SFTSV) infections. Similarly, both hits could inhibit the activity of LASV, LCMV, and SFTSV EN. The combination of either compound with an arenavirus entry inhibitor had significant synergistic antiviral effects. Moreover, both hits were found to be capable of binding to LASV EN with a binding affinity at the micromolar level. These findings provide a basis for developing the hits as potential candidates for the treatment of segmented negative-sense RNA virus infections.
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http://dx.doi.org/10.1016/j.antiviral.2021.105230DOI Listing
January 2022

Screening and Identification of Lujo Virus Entry Inhibitors From an Food and Drug Administration-Approved Drugs Library.

Front Microbiol 2021 2;12:793519. Epub 2021 Dec 2.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.

Lujo virus (LUJV) belongs to the Old World (OW) genus (family Arenaviridae). It is categorized as a biosafety level (BSL) 4 agent. Currently, there are no U.S. Food and Drug Administration (FDA)-approved drugs or vaccines specifically for LUJV or other pathogenic OW mammarenaviruses. Here, a high-throughput screening of an FDA-approved drug library was conducted using pseudotype viruses bearing LUJV envelope glycoprotein (GPC) to identify inhibitors of LUJV entry. Three hit compounds, trametinib, manidipine, and lercanidipine, were identified as LUJV entry inhibitors in the micromolar range. Mechanistic studies revealed that trametinib inhibited LUJV GPC-mediated membrane fusion by targeting C410 [located in the transmembrane (TM) domain], while manidipine and lercanidipine inhibited LUJV entry by acting as calcium channel blockers. Meanwhile, all three hits extended their antiviral spectra to the entry of other pathogenic mammarenaviruses. Furthermore, all three could inhibit the authentic prototype mammarenavirus, lymphocytic choriomeningitis virus (LCMV), and could prevent infection at the micromolar level. This study shows that trametinib, manidipine, and lercanidipine are candidates for LUJV therapy and highlights the critical role of calcium in LUJV infection. The presented findings reinforce the notion that the key residue(s) located in the TM domain of GPC provide an entry-targeted platform for designing mammarenavirus inhibitors.
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http://dx.doi.org/10.3389/fmicb.2021.793519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8675865PMC
December 2021

Mechanism through Which Retrocyclin Targets Flavivirus Multiplication.

J Virol 2021 07 12;95(15):e0056021. Epub 2021 Jul 12.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.

Currently, there are no approved drugs for the treatment of flavivirus infection. Accordingly, we tested the inhibitory effects of the novel θ-defensin retrocyclin-101 (RC-101) against flavivirus infection and investigated the mechanism underlying the potential inhibitory effects. First, RC-101 robustly inhibited both Japanese encephalitis virus (JEV) and Zika virus (ZIKV) infections. RC-101 exerted inhibitory effects on the entry and replication stages. Results also indicated that the nonstructural protein NS2B-NS3 serine protease might serve as a potential viral target. Furthermore, RC-101 inhibited protease activity at the micromolar level. We also demonstrated that with respect to the glycoprotein E protein of flavivirus, the DE loop of domain III (DIII), which is the receptor-binding domain of the E protein, might serve as another viral target of RC-101. Moreover, a JEV DE mutant exhibited resistance to RC-101, which was associated with deceased binding affinity of RC-101 to DIII. These findings provide a basis for the development of RC-101 as a potential candidate for the treatment of flavivirus infection. Retrocyclin is an artificially humanized circular θ-defensin peptide, containing 18 residues, previously reported to possess broad antimicrobial activity. In this study, we found that retrocyclin-101 inhibited flavivirus (ZIKV and JEV) infections. Retrocyclin-101 inhibited NS2B-NS3 serine protease activity, suggesting that the catalytic triad of the protease is the target. Moreover, retrocyclin-101 bound to the DE loop of the E protein of flavivirus, which prevented its entry.
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http://dx.doi.org/10.1128/JVI.00560-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274595PMC
July 2021

RNA Interference Screening Reveals Requirement for Platelet-Derived Growth Factor Receptor Beta in Japanese Encephalitis Virus Infection.

Antimicrob Agents Chemother 2021 05 18;65(6). Epub 2021 May 18.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China

Mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide and is associated with high morbidity and mortality. To identify potential host therapeutic targets, a high-throughput receptor tyrosine kinase small interfering RNA library screening was performed with recombinant JEV particles. Platelet-derived growth factor receptor beta (PDGFRβ) was identified as a hit after two rounds of screening. Knockdown of blocked JEV infection and transcomplementation of PDGFRβ could partly restore its infectivity. The PDGFRβ inhibitor imatinib, which has been approved for the treatment of malignant metastatic cancer, protected mice against JEV-induced lethality by decreasing the viral load in the brain while abrogating the histopathological changes associated with JEV infection. These findings demonstrated that PDGFRβ is important in viral infection and provided evidence for the potential to develop imatinib as a therapeutic intervention against JEV infection.
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http://dx.doi.org/10.1128/AAC.00113-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316074PMC
May 2021

Screening of Botanical Drugs against Lassa Virus Entry.

J Virol 2021 Feb 3. Epub 2021 Feb 3.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China

Lassa virus (LASV) belongs to the Old World genus (family ). At present, there are no approved drugs or vaccines specific for LASV. In this study, high-throughput screening of a botanical drug library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two hit compounds, bergamottin and casticin, were identified as micromolar range inhibitors of LASV entry. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Analysis of adaptive mutants demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin antiviral activity extends to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 also conferred resistance to casticin in these viruses. Unlike casticin, bergamottin showed little effect on LASV GPC-mediated membrane fusion, instead inhibiting LASV entry by blocking endocytic trafficking. Notably, both compounds showed inhibitory effects on authentic lymphocytic choriomeningitis virus. Our study shows that both casticin and bergamottin are candidates for LASV therapy and that the conserved F446 in LASV GPC is important in drug resistance in mammarenaviruses. Currently, there is no approved therapy to treat Lassa fever (LASF). Our goal was to identify potential candidate molecules for LASF therapy. Herein, we screened a botanical drug library and identified two compounds, casticin and bergamottin, that inhibited LASV entry via different mechanisms.
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http://dx.doi.org/10.1128/JVI.02429-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103687PMC
February 2021

Inhibition of Na/K ATPase blocks Zika virus infection in mice.

Commun Biol 2020 07 15;3(1):380. Epub 2020 Jul 15.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, 430071, Wuhan, China.

Zika virus (ZIKV) is an infectious disease that has become an important concern worldwide, it associates with neurological disorders and congenital malformations in adults, also leading to fetal intrauterine growth restriction and microcephaly during pregnancy. However, there are currently no approved vaccines or specific antiviral drugs for preventing or treating ZIKV infection. Here, we show that two FDA-approved Na/K-ATPase inhibitors, ouabain and digoxin, can block ZIKV infection at the replication stage by targeting Na/K-ATPase. Furthermore, ouabain reduced the viral burden of ZIKV in adult mice, penetrated the placental barrier to enter fetal tissues, and protected fetal mice from ZIKV infection-induced microcephaly in a pregnant mouse model. Thus, ouabain has therapeutic potential for ZIKV.
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http://dx.doi.org/10.1038/s42003-020-1109-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363852PMC
July 2020

Cost-effectiveness of tildrakizumab for the treatment of moderate-to-severe psoriasis in the United States.

J Dermatolog Treat 2022 Mar 30;33(2):740-748. Epub 2020 Jun 30.

Southern California Clinical and Translational Science Institute, Los Angeles, CA, USA.

Objective: To evaluate the relative cost-effectiveness of tildrakizumab and other biologic and targeted systemic treatments compared with a mix of topical therapies, phototherapies, and other conventional systemic therapies as first-line treatment for moderate-to-severe plaque psoriasis from a United States payer's perspective.

Methods: A Markov model consisting of health states based on Psoriasis Area Severity Index (PASI) response rate categories and death was developed. The probabilities of achieving PASI responses were derived from a network meta-analysis based on published efficacy data. Health care costs and effectiveness measured in quality-adjusted life-years (QALYs) were estimated. Incremental costs per QALY gained of each biologic/targeted first-line treatment versus a mix of conventional treatments were compared to provide relative cost-effectiveness among biologic and targeted first-line treatments.

Results: Over 10 years, the incremental cost per QALY gained compared with a mix of topical therapies, phototherapies, and other oral systemic therapies was lowest for brodalumab, infliximab, apremilast, and tildrakizumab, followed by secukinumab, ixekizumab, guselkumab, adalimumab, ustekinumab, and etanercept. The position of tildrakizumab relative to the other treatments remained the same across multiple scenarios.

Conclusions: Tildrakizumab is among the most cost-effective first-line therapies for moderate-to-severe plaque psoriasis and is more cost-effective than secukinumab, ixekizumab, guselkumab, adalimumab, ustekinumab, and etanercept.
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http://dx.doi.org/10.1080/09546634.2020.1773382DOI Listing
March 2022

mTOR and S6K1 drive polycystic kidney by the control of Afadin-dependent oriented cell division.

Nat Commun 2020 06 24;11(1):3200. Epub 2020 Jun 24.

Institut Necker-Enfants Malades, 14 rue Maria Helena Vieira Da Silva, CS, 61431, Paris, France.

mTOR activation is essential and sufficient to cause polycystic kidneys in Tuberous Sclerosis Complex (TSC) and other genetic disorders. In disease models, a sharp increase of proliferation and cyst formation correlates with a dramatic loss of oriented cell division (OCD). We find that OCD distortion is intrinsically due to S6 kinase 1 (S6K1) activation. The concomitant loss of S6K1 in Tsc1-mutant mice restores OCD but does not decrease hyperproliferation, leading to non-cystic harmonious hyper growth of kidneys. Mass spectrometry-based phosphoproteomics for S6K1 substrates revealed Afadin, a known component of cell-cell junctions required to couple intercellular adhesions and cortical cues to spindle orientation. Afadin is directly phosphorylated by S6K1 and abnormally decorates the apical surface of Tsc1-mutant cells with E-cadherin and α-catenin. Our data reveal that S6K1 hyperactivity alters centrosome positioning in mitotic cells, affecting oriented cell division and promoting kidney cysts in conditions of mTOR hyperactivity.
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http://dx.doi.org/10.1038/s41467-020-16978-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314806PMC
June 2020

Health utility estimation in children and adolescents: a review of health technology assessments.

Curr Med Res Opin 2020 07 22;36(7):1209-1224. Epub 2020 May 22.

Health Outcomes, Sanofi, Reading, UK.

Health utility estimates for children and adolescents are critical for cost-utility analyses informing health technology assessment (HTA) authorities' decisions governing access to pediatric treatments. However, in a recent review, only 29% of published pediatric cost-utility models used a utility measure validated for children. We examined utility estimates used in pediatric HTAs. A targeted review of pediatric HTAs was performed, focusing on agencies reporting utility estimate sources and methods. Searches identified 11 HTAs in pediatric indications and five in mixed populations with separate analyses for adults and children. Among 13 appraisals reporting methodological detail, five used pediatric utility estimates (based on the Health Utilities Index [HUI],  = 3; Atopic Dermatitis Quality of Life [ADQoL],  = 1; or mapping,  = 1). Issues were identified with mapping, use of adult data for some health states, and assumptions about ADQoL responses. In the remaining eight appraisals, adult utility estimates were applied. Caregiver utility was included in two of 16 appraisals. Only 38% of pediatric HTAs reviewed used pediatric utility estimates, and HTA authorities raised concerns about these data in many cases; only 12% of HTAs included caregiver utility. Although several preference-based utility measures are available for pediatric populations, limited data and guidance on selection of measures are available. When estimating pediatric utility weights, alternative measures should be reviewed for suitability given the model population and health condition. Pediatric and adult utility estimates should be applied appropriately as patients age over time, and caregiver and/or family member utility should be included, where relevant. Gaps exist in utility measures for children aged <4 years and caregivers.
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http://dx.doi.org/10.1080/03007995.2020.1762553DOI Listing
July 2020

Comparative cost-effectiveness of tildrakizumab and other commonly used treatments for moderate-to-severe psoriasis.

J Dermatolog Treat 2021 Nov 1;32(7):693-700. Epub 2020 Apr 1.

Southern California Clinical and Translational Science Institute, Los Angeles, CA, USA.

Objectives: To compare the cost-effectiveness of tildrakizumab with other commonly used biologics and apremilast as the first-line treatment for moderate-to-severe plaque psoriasis from a US health plan's perspective.

Methods: A 10-year cost-effectiveness model was developed to compare the incremental cost per extra month with a Psoriasis Area and Severity Index (PASI) 75 response. Patients were assumed to receive one of the treatments evaluated as their first-line treatment at the outset of the analysis. Nonresponders (PASI <75) discontinued their current treatment; 25% went on to receive a mix of topical therapies, phototherapies, and other systemic therapies, while 75% received a second-line therapy before receiving a mix of topical therapies, phototherapies, and other systemic therapies. Direct medical costs were calculated based on drug acquisition, administration, and monitoring costs.

Results: The incremental cost per extra month a patient had a PASI 75 response was lowest for brodalumab ($3,685), infliximab ($4,102), apremilast ($4,770), and tildrakizumab ($5,150), followed by risankizumab ($5,319), secukinumab ($5,675), guselkumab ($5,784), ixekizumab ($5,900), adalimumab ($5,943), ustekinumab ($6,131), etanercept ($6,618), and certolizumab pegol ($13,476).

Conclusion: Tildrakizumab was among the most cost-effective first-line treatments for moderate-to-severe psoriasis and was more cost-effective than risankizumab, secukinumab, guselkumab, ixekizumab, adalimumab, ustekinumab, etanercept, and certolizumab pegol.
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http://dx.doi.org/10.1080/09546634.2019.1698700DOI Listing
November 2021

The Budget Impact of Introducing Tildrakizumab to a United States Health Plan for Managing Moderate-to-Severe Plaque Psoriasis.

Pharmacoecon Open 2020 Dec;4(4):669-677

Roivant Sciences Ltd, New York, NY, USA.

Objective: The aim of this study was to evaluate the budget impact of introducing tildrakizumab for moderate-to-severe plaque psoriasis from a US health plan perspective.

Methods: A budget impact model estimated costs before and after the adoption of tildrakizumab to a hypothetical US health plan with 1 million covered lives over 5 years. Additionally, the model included adalimumab, brodalumab, etanercept, guselkumab, ixekizumab, secukinumab, ustekinumab, and apremilast; biosimilars were not included. Model input data were obtained from the published literature, clinical trials, and prescription data. Market uptake for tildrakizumab was assumed as 1% annually over 5 years. Patients initiating or switching treatments required induction dosing; all others treated required maintenance dosing. The model compared the total annual costs for tildrakizumab versus treatment without tildrakizumab to calculate budget impact in 2018 US dollars. Scenarios exploring alternative assumptions for adverse events and market uptake rates were assessed, and a one-way sensitivity analysis was conducted.

Results: Within a health plan of 1 million members with an estimated 1048 patients receiving biologics or apremilast for psoriasis, the total annual health plan cost after introducing tildrakizumab decreased by $5585, $137,025, $205,538, $274,051, and $342,563 in years 1-5, respectively, resulting in a cumulative reduction of $964,763 over 5 years. The impact on total cost was largely due to drug acquisition costs. The incremental per member per month (PMPM) cost reductions were negligible in year 1, $0.01 in year 2, $0.02 in years 3-4, and $0.03 in year 5. Scenario and sensitivity analyses confirmed the model robustness.

Conclusions: The introduction of tildrakizumab with a 1% annual uptake over 5 years has the potential to reduce the cost of treating patients with moderate-to-severe plaque psoriasis for a US health plan.
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http://dx.doi.org/10.1007/s41669-020-00208-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688845PMC
December 2020

Screening of Natural Extracts for Inhibitors against Japanese Encephalitis Virus Infection.

Antimicrob Agents Chemother 2020 02 21;64(3). Epub 2020 Feb 21.

State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China

The mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwide that is associated with high morbidity and mortality. Currently, there are no effective drugs approved for the treatment of JEV infection. Drug-repurposing screening is an alternative approach to discover potential antiviral agents. In this study, high-content screening (HCS) of a natural extracts library was performed, and two hit FDA-approved Na/K-ATPase inhibitors, ouabain and digoxin, were identified as having robust efficiency against JEV infection with the selectivity indexes over 1,000. The results indicated that ouabain and digoxin blocked the JEV infection at the replication stage by targeting the Na/K-ATPase. Furthermore, it was proven that ouabain significantly reduced the morbidity and mortality caused by JEV in a BALB/c mouse model. This work demonstrated that Na/K-ATPase could serve as the target of treatment of JEV infection, and ouabain has the potential to be developed as an effective anti-JEV drug.
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http://dx.doi.org/10.1128/AAC.02373-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038234PMC
February 2020

Screening and Identification of Lassa Virus Entry Inhibitors from an FDA-Approved Drug Library.

J Virol 2018 08 31;92(16). Epub 2018 Jul 31.

University of the Chinese Academy of Sciences, Beijing, China

(LASV) belongs to the genus (family ) and causes severe hemorrhagic fever in humans. At present, there are no Food and Drug Administration (FDA)-approved drugs or vaccines specific for LASV. Here, high-throughput screening of an FDA-approved drug library was performed against LASV entry by using pseudotype virus bearing LASV envelope glycoprotein (GPC). Two hit compounds, lacidipine and phenothrin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that both compounds inhibited LASV entry by blocking low-pH-induced membrane fusion. Accordingly, lacidipine showed virucidal effects on the pseudotype virus of LASV. Adaptive mutant analyses demonstrated that replacement of T40, located in the ectodomain of the stable-signal peptide (SSP), with lysine (K) conferred LASV resistance to lacidipine. Furthermore, lacidipine showed antiviral activity against LASV, the closely related Mopeia virus (MOPV), and the New World arenavirus Guanarito virus (GTOV). Drug-resistant variants indicated that V36M in the ectodomain of the SSP mutant and V436A in the transmembrane domain of the GP2 mutant conferred GTOV resistance to lacidipine, suggesting the interface between SSP and GP2 is the target of lacidipine. This study shows that lacidipine is a candidate for LASV therapy, reinforcing the notion that the SSP-GP2 interface provides an entry-targeted platform for arenavirus inhibitor design. Currently, there is no approved therapy to treat Lassa fever; therefore, repurposing of approved drugs will accelerate the development of a therapeutic stratagem. In this study, we screened an FDA-approved library of drugs and identified two compounds, lacidipine and phenothrin, which inhibited Lassa virus entry by blocking low-pH-induced membrane fusion. Additionally, both compounds extended their inhibition against the entry of Guanarito virus, and the viral targets were identified as the SSP-GP2 interface.
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http://dx.doi.org/10.1128/JVI.00954-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069169PMC
August 2018

Heat stress induced, ligand-independent MET and EGFR signalling in hepatocellular carcinoma.

Int J Hyperthermia 2018 09 6;34(6):812-823. Epub 2017 Nov 6.

a Department of Radiology , Mayo Clinic School of Medicine , Rochester , MN , USA.

Purpose: The aims of the present study were 2-fold: first, to test the hypothesis that heat stress induces MET and EGFR signalling in hepatocellular carcinoma (HCC) cells and inhibition of this signalling decreases HCC clonogenic survival; and second, to identify signalling pathways associated with heat stress induced MET signalling.

Materials And Methods: MET and EGFR HCC cells were pre-treated with inhibitors to MET, EGFR, PI3K/mTOR or vehicle and subjected to heat stress or control ± HGF or EGF growth factors and assessed by colony formation assay, Western blotting and/or quantitative mass spectrometry. IACUC approved partial laser thermal or sham ablation was performed on orthotopic N1S1 and AS30D HCC tumours and liver/tumour assessed for phospho-MET and phospho-EGFR immunostaining.

Results: Heat-stress induced rapid MET and EGFR phosphorylation that is distinct from HGF or EGF in HCC cells and thermal ablation induced MET but not EGFR phosphorylation at the HCC tumour ablation margin. Inhibition of the MET and EGFR blocked both heat stress and growth factor induced MET and EGFR phosphorylation and inhibition of MET decreased HCC clonogenic survival following heat stress. Pathway analysis of quantitative phosphoproteomic data identified downstream pathways associated with heat stress induced MET signalling including AKT, ERK, Stat3 and JNK. However, inhibition of heat stress induced MET signalling did not block AKT signalling.

Conclusions: Heat-stress induced MET and EGFR signalling is distinct from growth factor mediated signalling in HCC cells and MET inhibition enhances heat stress induced HCC cell killing via a PI3K/AKT/mTOR-independent mechanism.
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http://dx.doi.org/10.1080/02656736.2017.1385859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175538PMC
September 2018

Identification of Post-Translational Modifications from Serum/Plasma by Immunoaffinity Enrichment and LC-MS/MS Analysis Without Depletion of Abundant Proteins.

Methods Mol Biol 2017 ;1619:119-125

Proteomic Service Group, Cell Signaling Technology, 3 Trask Lane, Danvers, MA, 01923, USA.

Immunoaffinity enrichment combined with LC-MS/MS enables identification of Post-translational modifications (PTMs) from serum/plasma samples without abundant protein depletion. Here we described the workflow in details in identifying various types of PTMs such as lysine acetylation and arginine methylation from cancer serum. The method described is compatible with all common proteomic analysis platforms and quantitative methods.
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http://dx.doi.org/10.1007/978-1-4939-7057-5_9DOI Listing
March 2018

Danshen (Salvia miltiorrhiza) Compounds Improve the Biochemical Indices of the Patients with Coronary Heart Disease.

Evid Based Complement Alternat Med 2016 5;2016:9781715. Epub 2016 Jun 5.

Department of Geriatrics, Affiliated Hospital, Changchun University of Traditional Chinese Medicine, Changchun 130000, China.

Danshen was able to reduce the risk of the patients with coronary heart disease (CHD), but the mechanism is still widely unknown. Biochemical indices (lipid profile, markers of renal and liver function, and homocysteine (Hcy)) are closely associated with CHD risk. We aimed to investigate whether the medicine reduces CHD risk by improving these biochemical indices. The patients received 10 Danshen pills (27 mg/pill) in Dashen group, while the control patients received placebo pills, three times daily. The duration of follow-up was three months. The serum biochemical indices were measured, including lipid profiles (LDL cholesterol (LDL-C), HDL-C, total cholesterol (TC), triglycerides (TG), apolipoprotein (Apo) A, ApoB, ApoE, and lipoprotein (a) (Lp(a))); markers of liver function (gamma-glutamyl transpeptidase (GGT), total bilirubin (TBil), indirect bilirubin (IBil), and direct bilirubin (DBil)); marker of renal function (uric acid (UA)) and Hcy. After three-month follow-up, Danshen treatment reduced the levels of TG, TC, LDL-C, Lp(a), GGT, DBil, UA, and Hcy (P < 0.05). In contrast, the treatment increased the levels of HDL-C, ApoA, ApoB, ApoE, TBil, and IBil (P < 0.05). Conclusion. Danshen can reduce the CHD risk by improving the biochemical indices of CHD patients.
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http://dx.doi.org/10.1155/2016/9781715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913020PMC
July 2016

Quantitative Profiling of Post-translational Modifications by Immunoaffinity Enrichment and LC-MS/MS in Cancer Serum without Immunodepletion.

Mol Cell Proteomics 2016 Feb 3;15(2):692-702. Epub 2015 Dec 3.

From the § Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923.

A robust method was developed and optimized for enrichment and quantitative analysis of posttranslational modifications (PTMs) in serum/plasma samples by combining immunoaffinity purification and LC-MS/MS without depletion of abundant proteins. The method was used to survey serum samples of patients with acute myeloid leukemia (AML), breast cancer (BC), and nonsmall cell lung cancer (NSCLC). Peptides were identified from serum samples containing phosphorylation, acetylation, lysine methylation, and arginine methylation. Of the PTMs identified, lysine acetylation (AcK) and arginine mono-methylation (Rme) were more prevalent than other PTMs. Label-free quantitative analysis of AcK and Rme peptides was performed for sera from AML, BC, and NSCLC patients. Several AcK and Rme sites showed distinct abundance distribution patterns across the three cancer types. The identification and quantification of posttranslationally modified peptides in serum samples reported here can be used for patient profiling and biomarker discovery research.
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http://dx.doi.org/10.1074/mcp.O115.052266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739682PMC
February 2016

Complementary PTM Profiling of Drug Response in Human Gastric Carcinoma by Immunoaffinity and IMAC Methods with Total Proteome Analysis.

Proteomes 2015 Aug 7;3(3):160-183. Epub 2015 Aug 7.

Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.

Gaining insight into normal cellular signaling and disease biology is a critical goal of proteomic analyses. The ability to perform these studies successfully to extract the maximum value and discovery of biologically relevant candidate biomarkers is therefore of primary importance. Many successful studies in the past have focused on total proteome analysis (changes at the protein level) combined with phosphorylation analysis by metal affinity enrichment (changes at the PTM level). Here, we use the gastric carcinoma cell line MKN-45 treated with the c-Met inhibitor SU11274 and PKC inhibitor staurosporine to investigate the most efficient and most comprehensive strategies for both total protein and PTM analysis. Under the conditions used, total protein analysis yielded few changes in response to either compound, while analysis of phosphorylation identified thousands of sites that changed differentially between the two treatments. Both metal affinity and antibody-based enrichments were used to assess phosphopeptide changes, and the data generated by the two methods was largely complementary (non-overlapping). Label-free quantitation of peptide peak abundances was used to accurately determine fold-changes between control and treated samples. Protein interaction network analysis allowed the data to be placed in a biologically relevant context, and follow-up validation of selected findings confirmed the accuracy of the proteomic data. Together, this study provides a framework for start-to-finish proteomic analysis of any experimental system under investigation to maximize the value of the proteomic study and yield the best chance for uncovering actionable target candidates.
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http://dx.doi.org/10.3390/proteomes3030160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217380PMC
August 2015

Immunoaffinity enrichment and mass spectrometry analysis of protein methylation.

Mol Cell Proteomics 2014 Jan 15;13(1):372-87. Epub 2013 Oct 15.

Cell Signaling Technology Inc., 3 Trask Lane, Danvers, Massachusetts 01923;

Protein methylation is a common posttranslational modification that mostly occurs on arginine and lysine residues. Arginine methylation has been reported to regulate RNA processing, gene transcription, DNA damage repair, protein translocation, and signal transduction. Lysine methylation is best known to regulate histone function and is involved in epigenetic regulation of gene transcription. To better study protein methylation, we have developed highly specific antibodies against monomethyl arginine; asymmetric dimethyl arginine; and monomethyl, dimethyl, and trimethyl lysine motifs. These antibodies were used to perform immunoaffinity purification of methyl peptides followed by LC-MS/MS analysis to identify and quantify arginine and lysine methylation sites in several model studies. Overall, we identified over 1000 arginine methylation sites in human cell line and mouse tissues, and ∼160 lysine methylation sites in human cell line HCT116. The number of methylation sites identified in this study exceeds those found in the literature to date. Detailed analysis of arginine-methylated proteins observed in mouse brain compared with those found in mouse embryo shows a tissue-specific distribution of arginine methylation, and extends the types of proteins that are known to be arginine methylated to include many new protein types. Many arginine-methylated proteins that we identified from the brain, including receptors, ion channels, transporters, and vesicle proteins, are involved in synaptic transmission, whereas the most abundant methylated proteins identified from mouse embryo are transcriptional regulators and RNA processing proteins.
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http://dx.doi.org/10.1074/mcp.O113.027870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879628PMC
January 2014

Quantitative profiling of DNA damage and apoptotic pathways in UV damaged cells using PTMScan Direct.

Int J Mol Sci 2012 Dec 21;14(1):286-307. Epub 2012 Dec 21.

Cell Signaling Technology, 3 Trask Lane, Danvers, MA 01923, USA.

Traditional methods for analysis of peptides using liquid chromatography and tandem mass spectrometry (LC-MS/MS) lack the specificity to comprehensively monitor specific biological processes due to the inherent duty cycle limitations of the MS instrument and the stochastic nature of the analytical platform. PTMScan Direct is a novel, antibody-based method that allows quantitative LC-MS/MS profiling of specific peptides from proteins that reside in the same signaling pathway. New PTMScan Direct reagents have been produced that target peptides from proteins involved in DNA Damage/Cell Cycle and Apoptosis/Autophagy pathways. Together, the reagents provide access to 438 sites on 237 proteins in these signaling cascades. These reagents have been used to profile the response to UV damage of DNA in human cell lines. UV damage was shown to activate canonical DNA damage response pathways through ATM/ATR-dependent signaling, stress response pathways and induce the initiation of apoptosis, as assessed by an increase in the abundance of peptides corresponding to cleaved, activated caspases. These data demonstrate the utility of PTMScan Direct as a multiplexed assay for profiling specific cellular responses to various stimuli, such as UV damage of DNA.
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http://dx.doi.org/10.3390/ijms14010286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565264PMC
December 2012

Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: a controlled clinical study.

Epilepsia 2012 Oct 5;53(10):1782-9. Epub 2012 Sep 5.

Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China.

Purpose: This study was designed to evaluate the therapeutic effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with refractory partial epilepsy.

Methods: Sixty-four patients with refractory focal epilepsy were screened and 60 patients were randomly divided into two groups by stimulation intensity: 90% (group 1) or 20% (group 2) of resting motor threshold (rMT). Seizure frequency and interictal EEG epileptic discharges were compared between the baseline and follow-up periods.

Key Findings: Seizures significantly decreased following 2-weeks high intensity (90% rMT) rTMS treatment compared with baseline level (p < 0.05). rTMS also decreased interictal epilepsy discharges and improved the scales of Symptom Checklist-90 significantly (p < 0.05). Seizures and spikes in the follow-up period in the patients who received low intensity (20% rMT) rTMS did not show any difference compared with baseline data (p > 0.05, respectively).

Significance: Low-frequency high intensity rTMS (90% rMT) delivered into the epileptogenic zone had a significant antiepileptic effect on patients with refractory partial seizures. rTMS treatment can also reduce the interictal epileptic discharge frequency and improve the psychological condition of these patients.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03626.xDOI Listing
October 2012

PTMScan direct: identification and quantification of peptides from critical signaling proteins by immunoaffinity enrichment coupled with LC-MS/MS.

Mol Cell Proteomics 2012 May 9;11(5):187-201. Epub 2012 Feb 9.

Cell Signaling Technology, Danvers, Massachusetts 01923, USA.

Proteomic studies of post-translational modifications by metal affinity or antibody-based methods often employ data-dependent analysis, providing rich data sets that consist of randomly sampled identified peptides because of the dynamic response of the mass spectrometer. This can complicate the primary goal of programs for drug development, mutational analysis, and kinase profiling studies, which is to monitor how multiple nodes of known, critical signaling pathways are affected by a variety of treatment conditions. Cell Signaling Technology has developed an immunoaffinity-based LC-MS/MS method called PTMScan Direct for multiplexed analysis of these important signaling proteins. PTMScan Direct enables the identification and quantification of hundreds of peptides derived from specific proteins in signaling pathways or specific protein types. Cell lines, tissues, or xenografts can be used as starting material. PTMScan Direct is compatible with both SILAC and label-free quantification. Current PTMScan Direct reagents target key nodes of many signaling pathways (PTMScan Direct: Multipathway), serine/threonine kinases, tyrosine kinases, and the Akt/PI3K pathway. Validation of each reagent includes score filtering of MS/MS assignments, filtering by identification of peptides derived from expected targets, identification of peptides homologous to expected targets, minimum signal intensity of peptide ions, and dependence upon the presence of the reagent itself compared with a negative control. The Multipathway reagent was used to study sensitivity of human cancer cell lines to receptor tyrosine kinase inhibitors and showed consistent results with previously published studies. The Ser/Thr kinase reagent was used to compare relative levels of kinase-derived phosphopeptides in mouse liver, brain, and embryo, showing tissue-specific activity of many kinases including Akt and PKC family members. PTMScan Direct will be a powerful quantitative method for elucidation of changes in signaling in a wide array of experimental systems, combining the specificity of traditional biochemical methods with the high number of data points and dynamic range of proteomic methods.
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http://dx.doi.org/10.1074/mcp.M111.015883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418847PMC
May 2012

microRNA-dependent modulation of histone acetylation in Waldenstrom macroglobulinemia.

Blood 2010 Sep 2;116(9):1506-14. Epub 2010 Jun 2.

Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.

Waldenström macroglobulinemia (WM) cells present with increased expression of microRNA-206 (miRNA-206) and reduced expression of miRNA-9*. Predicted miRNA-206- and -9*-targeted genes include histone deacetylases (HDACs) and histone acetyl transferases (HATs), indicating that these miRNAs may play a role in regulating histone acetylation. We were able to demonstrate that primary WM cells are characterized by unbalanced expression of HDACs and HATs, responsible for decreased acetylated histone-H3 and -H4, and increased HDAC activity. We next examined whether miRNA-206 and -9* modulate the aberrant expression of HDAC and HATs in WM cells leading to increased transcriptional activity. We found that restoring miRNA-9* levels induced toxicity in WM cells, supported by down-modulation of HDAC4 and HDAC5 and up-regulation of acetyl-histone-H3 and -H4. These, together with inhibited HDAC activity, led to induction of apoptosis and autophagy in WM cells. To further confirm that miRNA-9*-dependent modulation of histone acetylation is responsible for induction of WM cytotoxicity, a novel class of HDAC inhibitor (LBH589) was used; we confirmed that inhibition of HDAC activity leads to toxicity in this disease. These findings confirm that histone-modifying genes and HDAC activity are deregulated in WM cells, partially driven by the aberrant expression of miRNA-206 and -9* in the tumor clone.
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http://dx.doi.org/10.1182/blood-2010-01-265686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938840PMC
September 2010

Clinical and translational studies of a phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenstrom's macroglobulinemia.

Clin Cancer Res 2010 Feb 26;16(3):1033-41. Epub 2010 Jan 26.

Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Waldenström's macroglobulinemia (WM) is a rare, low-grade lymphoproliferative disorder. Based on preclinical studies, we conducted a phase II clinical trial testing the efficacy and safety of the Akt inhibitor perifosine in patients with relapsed/refractory WM.

Patients And Methods: Thirty-seven patients were treated with oral perifosine (150 mg daily) for six cycles. Stable or responding patients were allowed to continue therapy until progression.

Results: The median age was 65 years (range, 44-82). The median number of prior therapy lines was two (range, one to five). Of the 37 patients, 4 achieved partial response (11%), 9 minimal response (24%), and 20 showed stable disease (54%). The median progression-free survival was 12.6 months. Additionally, beta2 microglobulin of >3.5 mg/dL was associated with poor event-free survival (P = 0.002). Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3-4, 13%), gastrointestinal symptoms (grade 1-2, 81%), and arthritis flare (all grades, 11%). Translational studies using gene expression profiling and immunohistochemistry showed that perifosine inhibited pGSK activity downstream of Akt, and inhibited nuclear factor kappaB activity.

Conclusion: Perifosine resulted in at least a minimal response in 35% of patients and a median progression-free survival of 12.6 months in patients with relapsed or relapsed/refractory WM, as well as in vivo inhibition of pGSK activity. The results of this study warrant further evaluation of perifosine in combination with rituximab or other active agents in patients with WM.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-1837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885252PMC
February 2010
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