scholarly journals Deletion of Braun lipoprotein gene (lpp) and curing of plasmid pPCP1 dramatically alter the virulence of Yersinia pestis CO92 in a mouse model of pneumonic plague

Microbiology ◽  
2009 ◽  
Vol 155 (10) ◽  
pp. 3247-3259 ◽  
Author(s):  
Stacy L. Agar ◽  
Jian Sha ◽  
Wallace B. Baze ◽  
Tatiana E. Erova ◽  
Sheri M. Foltz ◽  
...  
Keyword(s):  
Mouse Model ◽  
Yersinia Pestis ◽  
Mutant Strain ◽  
Tissue Injury ◽  
Virulence Plasmid ◽  
Wild Type ◽  
Pneumonic Plague ◽  
Cytokines And Chemokines ◽  
Tissue Homogenates

Deletion of the murein (Braun) lipoprotein gene, lpp, attenuates the Yersinia pestis CO92 strain in mouse models of bubonic and pneumonic plague. In this report, we characterized the virulence of strains from which the plasminogen activating protease (pla)-encoding pPCP1 plasmid was cured from either the wild-type (WT) or the Δlpp mutant strain of Y. pestis CO92 in the mouse model of pneumonic infection. We noted a significantly increased survival rate in mice infected with the Y. pestis pPCP−/Δlpp mutant strain up to a dose of 5000 LD50. Additionally, mice challenged with the pPCP − /Δlpp strain had substantially less tissue injury and a strong decrease in the levels of most cytokines and chemokines in tissue homogenates and sera when compared with the WT-infected group. Importantly, the Y. pestis pPCP − /Δlpp mutant strain was detectable in high numbers in the livers and spleens of some of the infected mice. In the lungs of pPCP − /Δlpp mutant-challenged animals, however, bacterial numbers dropped at 48 h after infection when compared with tissue homogenates from 1 h post-infection. Similarly, we noted that this mutant was unable to survive within murine macrophages in an in vitro assay, whereas survivability of the pPCP− mutant within the macrophage environment was similar to that of the WT. Taken together, our data indicated that a significant and possibly synergistic attenuation in bacterial virulence occurred in a mouse model of pneumonic plague when both the lpp gene and the virulence plasmid pPCP1 encoding the pla gene were deleted from Y. pestis.

scholarly journals Mutation of the Maturase Lipoprotein Attenuates the Virulence of Streptococcus equi to a Greater Extent than Does Loss of General Lipoprotein Lipidation

2006 ◽  
Vol 74 (12) ◽  
pp. 6907-6919 ◽  
Author(s):  
Andrea Hamilton ◽  
Carl Robinson ◽  
Iain C. Sutcliffe ◽  
Josh Slater ◽  
Duncan J. Maskell ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mutant Strain ◽  
Natural Host ◽  
Wild Type ◽  
Animal Suffering ◽  
Organ Cultures ◽  
Mucus Production ◽  
Streptococcus Equi

ABSTRACT Streptococcus equi is the causative agent of strangles, a prevalent and highly contagious disease of horses. Despite the animal suffering and economic burden associated with strangles, little is known about the molecular basis of S. equi virulence. Here we have investigated the contributions of a specific lipoprotein and the general lipoprotein processing pathway to the abilities of S. equi to colonize equine epithelial tissues in vitro and to cause disease in both a mouse model and the natural host in vivo. Colonization of air interface organ cultures after they were inoculated with a mutant strain deficient in the maturase lipoprotein (ΔprtM 138 - 213, with a deletion of nucleotides 138 to 213) was significantly less than that for cultures infected with wild-type S. equi strain 4047 or a mutant strain that was unable to lipidate preprolipoproteins (Δlgt 190 - 685). Moreover, mucus production was significantly greater in both wild-type-infected and Δlgt 190 - 685-infected organ cultures. Both mutants were significantly attenuated compared with the wild-type strain in a mouse model of strangles, although 2 of 30 mice infected with the Δlgt 190 - 685 mutant did still exhibit signs of disease. In contrast, only the ΔprtM 138 - 213 mutant was significantly attenuated in a pony infection study, with 0 of 5 infected ponies exhibiting pathological signs of strangles compared with 4 of 4 infected with the wild-type and 3 of 5 infected with the Δlgt 190 - 685 mutant. We believe that this is the first study to evaluate the contribution of lipoproteins to the virulence of a gram-positive pathogen in its natural host. These data suggest that the PrtM lipoprotein is a potential vaccine candidate, and further investigation of its activity and its substrate(s) are warranted.

scholarly journals Inactivation of Peroxiredoxin 6 by the Pla Protease of Yersinia pestis

2015 ◽  
Vol 84 (1) ◽  
pp. 365-374 ◽  
Author(s):  
Daniel L. Zimbler ◽  
Justin L. Eddy ◽  
Jay A. Schroeder ◽  
Wyndham W. Lathem
Keyword(s):  
Yersinia Pestis ◽  
Lung Damage ◽  
Rapid Progression ◽  
Dependent Manner ◽  
Wild Type ◽  
Peroxiredoxin 6 ◽  
Pneumonic Plague ◽  
Content Type

Pneumonic plague represents the most severe form of disease caused byYersinia pestisdue to its ease of transmission, rapid progression, and high mortality rate. TheY. pestisouter membrane Pla protease is essential for the development of pneumonic plague; however, the complete repertoire of substrates cleaved by Pla in the lungs is not known. In this study, we describe a proteomic screen to identify host proteins contained within the bronchoalveolar lavage fluid of mice that are cleaved and/or processed byY. pestisin a Pla-dependent manner. We identified peroxiredoxin 6 (Prdx6), a host factor that contributes to pulmonary surfactant metabolism and lung defense against oxidative stress, as a previously unknown substrate of Pla. Pla cleaves Prdx6 at three distinct sites, and these cleavages disrupt both the peroxidase and phospholipase A2activities of Prdx6. In addition, we found that infection with wild-typeY. pestisreduces the abundance of extracellular Prdx6 in the lungs compared to that after infection with ΔplaY. pestis, suggesting that Pla cleaves Prdx6 in the pulmonary compartment. However, following infection with either wild-type or Δpla Y. pestis, Prdx6-deficient mice exhibit no differences in bacterial burden, host immune response, or lung damage from wild-type mice. Thus, while Pla is able to disrupt Prdx6 functionin vitroand reduce Prdx6 levelsin vivo, the cleavage of Prdx6 has little detectable impact on the progression or outcome of pneumonic plague.

scholarly journals Tn-Seq Analysis Identifies Genes Important for Yersinia pestis Adherence during Primary Pneumonic Plague

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Kara R. Eichelberger ◽  
Victoria E. Sepúlveda ◽  
John Ford ◽  
Sara R. Selitsky ◽  
Piotr A. Mieczkowski ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Subsequent Development ◽  
Transcriptional Analysis ◽  
Minor Effect ◽  
Wild Type ◽  
Single Strain ◽  
Pneumonic Plague ◽  
Content Type

ABSTRACT Following inhalation, Yersinia pestis rapidly colonizes the lung to establish infection during primary pneumonic plague. Although several adhesins have been identified in Yersinia spp., the factors mediating early Y. pestis adherence in the lung remain unknown. To identify genes important for Y. pestis adherence during primary pneumonic plague, we used transposon insertion sequencing (Tn-seq). Wild-type and capsule mutant (Δcaf1) Y. pestis transposon mutant libraries were serially passaged in vivo to enrich for nonadherent mutants in the lung using a mouse model of primary pneumonic plague. Sequencing of the passaged libraries revealed six mutants that were significantly enriched in both the wild-type and Δcaf1 Y. pestis backgrounds. The enriched mutants had insertions in genes that encode transcriptional regulators, chaperones, an endoribonuclease, and YPO3903, a hypothetical protein. Using single-strain infections and a transcriptional analysis, we identified a significant role for YPO3903 in Y. pestis adherence in the lung and showed that YPO3903 regulated transcript levels of psaA, which encodes a fimbria previously implicated in Y. pestis adherence in vitro. Deletion of psaA had a minor effect on Y. pestis adherence in the lung, suggesting that YPO3903 regulates other adhesins in addition to psaA. By enriching for mutations in genes that regulate the expression or assembly of multiple genes or proteins, we obtained screen results indicating that there may be not just one dominant adhesin but rather several factors that contribute to early Y. pestis adherence during primary pneumonic plague. IMPORTANCE Colonization of the lung by Yersinia pestis is a critical first step in establishing infection during primary pneumonic plague, a disease characterized by high lethality. However, the mechanisms by which Y. pestis adheres in the lung after inhalation remain elusive. Here, we used Tn-seq to identify Y. pestis genes important for adherence early during primary pneumonic plague. Our mutant enrichment strategy resulted in the identification of genes important for regulation and assembly of genes and proteins rather than adhesin genes themselves. These results reveal that there may be multiple Y. pestis adhesins or redundancy among adhesins. Identifying the adhesins regulated by the genes identified in our enrichment screen may reveal novel therapeutic targets for preventing Y. pestis adherence and the subsequent development of pneumonic plague.

scholarly journals Murine monoclonal antibodies against RBD of SARS-CoV-2 neutralize authentic wild type SARS-CoV-2 as well as B.1.1.7 and B.1.351 viruses and protect in vivo in a mouse model in a neutralization dependent manner

2021 ◽  
Author(s):  
Fatima Amanat ◽  
Shirin Strohmeier ◽  
Wen-Hsin Lee ◽  
Sandhya Bangaru ◽  
Andrew B Ward ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Dependent Manner ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Murine Monoclonal Antibodies

After first emerging in December 2019 in China, severe acute respiratory syndrome 2 (SARS-CoV-2) has since caused a pandemic leading to millions of infections and deaths worldwide. Vaccines have been developed and authorized but supply of these vaccines is currently limited. With new variants of the virus now emerging and spreading globally, it is essential to develop therapeutics that are broadly protective and bind conserved epitopes in the receptor binding domain (RBD) or the whole spike of SARS-CoV-2. In this study, we have generated mouse monoclonal antibodies (mAbs) against different epitopes on the RBD and assessed binding and neutralization against authentic SARS-CoV-2. We have demonstrated that antibodies with neutralizing activity, but not non-neutralizing antibodies, lower viral titers in the lungs when administered in a prophylactic setting in vivo in a mouse challenge model. In addition, most of the mAbs cross-neutralize the B.1.351 as well as the B.1.1.7 variants in vitro.

Abstract T P237: Effect of Danger Associated Molecular Pattern Receptor Complex Proteins CD24 and Siglec-G on Stroke Outcome and Microglial Responses

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Jonathan R Weinstein ◽  
Josiah Hanson ◽  
Lauren Hood ◽  
Diana Chao ◽  
Sean P Murphy ◽  
...  
Keyword(s):  
Infarct Volume ◽  
High Mobility ◽  
Artery Occlusion ◽  
Receptor Complex ◽  
Wild Type ◽  
Vessel Occlusion ◽  
Doppler Flowmetry ◽  
Cytokines And Chemokines ◽  
Molecular Pattern

Background: Both microglia and Toll-like receptors (TLRs) are critical in stroke pathophysiology. In ischemic brain, microglia sense endogenous TLR agonists (danger associated molecular patterns or DAMPs) and respond with varied immune reactions. CD24 and Siglec-G form a receptor complex that modulates TLR4 function and controls responses to DAMPs. The role of CD24 and Siglec-G in stroke is unknown. Methods: We performed 45 min middle cerebral artery occlusion (MCAO) on 12 - 14 week old wild-type, TLR4-/-, CD24-/- and Siglec-G-/- male mice and assessed total and regional adjusted infarct volumes at 48 hours with 2,3,5-triphenyltetrazolium staining. Number of mice per group was determined by power analysis. Cerebral blood flow was assessed with laser doppler flowmetry. In vitro, we examined the effects of endogenous TLR4 agonists heat shock protein-70 and high mobility group box 1 on cytokine (TNFα, IL-6) and chemokine (CXCL10, CCL5) release from microglia derived from wild-type, TLR4-/-, CD24-/- and Siglec-G-/- mice. Results: Following exclusions for weight, temperature and sub-optimal vessel occlusion/reperfusion, total infarct volumes (mean±SEM) were 51±8 mm3 (n = 21), 51±10 mm3 (n = 8), 28±8 mm3 (n = 13) and 54±8 mm3 (n = 19) in wild-type, TLR4-/-, CD24-/- and Siglec-G-/- mice, respectively (p>0.05, one-way ANOVA). Release of cytokines and chemokines was absent (as expected) in microglia from TLR4-/- mice and differentially regulated in microglia from CD24-/- and Siglec-G-/- mice. Conclusions: Genetic deficiency in TLR4, CD24 or Siglec-G modulated microglial response to endogenous TLR4 agonists but did not significantly alter post-stroke infarct volume.

scholarly journals The Role of a P1-Type ATPase from Pseudomonas fluorescens SBW25 in Copper Homeostasis and Plant Colonization

2007 ◽  
Vol 20 (5) ◽  
pp. 581-588 ◽  
Author(s):  
Xue-Xian Zhang ◽  
Paul B. Rainey
Keyword(s):  
Pseudomonas Fluorescens ◽  
Mutant Strain ◽  
Copper Ions ◽  
Biological Significance ◽  
Copper Homeostasis ◽  
Plant Colonization ◽  
Wild Type ◽  
Pseudomonas Fluorescens Sbw25 ◽  
Plant Surfaces

The genome of the plant-colonizing bacterium Pseudomonas fluorescens SBW25 possesses a putative copper-transporting P1-type ATPase (CueA) that is induced on the plant surfaces. Using a chromosomally-integrated cueA-'lacZ fusion, we show that transcription of cueA can be induced (in vitro) by ions of copper, silver, gold, and mercury. To investigate the biological significance of cueA, a nonpolar cueA deletion mutant (SBW25ΔcueA) was constructed. This mutant strain displayed a twofold reduction in its tolerance to copper compared with the wild-type strain; however, no change was observed in the sensitivity of the mutant strain to silver, gold, or mercury ions. To obtain insight into the ecological significance of cueA, the competitive ability of SBW25ΔcueA was determined relative to wild-type SBW25 in three environments (none contained added copper): minimal M9 medium, the root of sugar beet (Beta vulgaris), and the root of pea (Pisum sativum). Results showed that the fitness of SBW25ΔcueA was not different from the wild type in laboratory medium but was compromised in the two plant environments. Taken together, these data demonstrate a functional role for CueA in copper homeostasis and reveal an ecologically significant contribution to bacterial fitness in the plant rhizosphere. They also suggest that copper ions accumulate on plant surfaces.

scholarly journals Effect of MarA-Like Proteins on Antibiotic Resistance and Virulence in Yersinia pestis

2009 ◽  
Vol 78 (1) ◽  
pp. 364-371 ◽  
Author(s):  
Ida M. Lister ◽  
Joan Mecsas ◽  
Stuart B. Levy
Keyword(s):  
Escherichia Coli ◽  
Antibiotic Resistance ◽  
Mouse Model ◽  
Yersinia Pestis ◽  
Antibiotic Susceptibility ◽  
Deletion Mutant ◽  
Transcriptional Regulator ◽  
Drug Susceptibility ◽  
Wild Type ◽  
Lung Colonization

ABSTRACT MarA, an AraC/XylS transcriptional regulator in Escherichia coli, affects drug susceptibility and virulence. Two MarA-like proteins have been found in Yersinia pestis: MarA47 and MarA48. Deletion or overexpression of these proteins in the attenuated KIM 1001 Δpgm strain led to a change in multidrug susceptibility (including susceptibility to clinically relevant drugs). Additionally, lung colonization by the marA47 or marA48 deletion mutant was decreased about 10-fold in a pneumonic plague mouse model. Complementation of the deletions by replacing the deleted genes on the chromosome restored wild-type characteristics. These findings show that two MarA homologs in Y. pestis affect antibiotic susceptibility and virulence.

scholarly journals Mutation in the relA Gene of Vibrio cholerae Affects In Vitro and In Vivo Expression of Virulence Factors

2003 ◽  
Vol 185 (16) ◽  
pp. 4672-4682 ◽  
Author(s):  
Shruti Haralalka ◽  
Suvobroto Nandi ◽  
Rupak K. Bhadra
Keyword(s):  
Amino Acid ◽  
Vibrio Cholerae ◽  
Mutant Strain ◽  
Virulence Factors ◽  
Antibiotic Production ◽  
Wild Type ◽  
Altered Expression ◽  
Transcript Levels

ABSTRACT The relA gene product determines the level of (p)ppGpp, the effector nucleotides of the bacterial stringent response that are also involved in the regulation of other functions, like antibiotic production and quorum sensing. In order to explore the possible involvement of relA in the regulation of virulence of Vibrio cholerae, a relA homolog from the organism (relA VCH) was cloned and sequenced. The relA VCH gene encodes a 738-amino-acid protein having functions similar to those of other gram-negative bacteria, including Escherichia coli. A ΔrelA::kan allele was generated by replacing ∼31% of the open reading frame of wild-type relA of V. cholerae El Tor strain C6709 with a kanamycin resistance gene. The V. cholerae relA mutant strain thus generated, SHK17, failed to accumulate (p)ppGpp upon amino acid deprivation. Interestingly, compared to the wild type, C6709, the mutant strain SHK17 exhibited significantly reduced in vitro production of two principal virulence factors, cholera toxin (CT) and toxin-coregulated pilus (TCP), under virulence gene-inducing conditions. In vivo experiments carried out in rabbit ileal loop and suckling mouse models also confirmed our in vitro results. The data suggest that (p)ppGpp is essential for maximal expression of CT and TCP during in vitro growth, as well as during intestinal infection by virulent V. cholerae. Northern blot and reverse transcriptase PCR analyses indicated significant reduction in the transcript levels of both virulence factors in the relA mutant strain SHK17. Such marked alteration of virulence phenotypes in SHK17 appears most likely to be due to down regulation of transcript levels of toxR and toxT, the two most important virulence regulatory genes of V. cholerae. In SHK17, the altered expression of the two outer membrane porin proteins, OmpU and OmpT, indicated that the relA mutation most likely affects the ToxR-dependent virulence regulatory pathway, because it had been shown earlier that ToxR directly regulates their expression independently of ToxT.

scholarly journals Efficacy of BB-83698, a Novel Peptide Deformylase Inhibitor, in a Mouse Model of Pneumococcal Pneumonia

2004 ◽  
Vol 48 (1) ◽  
pp. 80-85 ◽  
Author(s):  
E. Azoulay-Dupuis ◽  
J. Mohler ◽  
J. P. Bédos
Keyword(s):  
Mouse Model ◽  
Lung Tissue ◽  
Resistant Strain ◽  
Peptide Deformylase ◽  
In Vitro Activity ◽  
Wild Type ◽  
Virulent Strains ◽  
Resistant Strains

ABSTRACT The efficacy of BB-83698, a novel potent peptide deformylase inhibitor, was evaluated in a mouse model of acute pneumonia. The Streptococcus pneumoniae isolates tested included four virulent strains (one penicillin-susceptible wild-type strain, one macrolide-resistant strain, and two quinolone-resistant mutants [a mutant carrying mutations in ParC and GyrA and an efflux mutant] isogenic to the wild type) and two poorly virulent penicillin-resistant strains. Pneumonia was induced by intratracheal inoculation of 105 CFU (virulent strains) into immunocompetent mice or 107 CFU (less virulent strains) into leukopenic mice. Animals received three or six subcutaneous injections of antibiotics at 12- or 24-h intervals, with antibiotic treatment initiated at 3, 6, 12, or 18 h postinfection (p.i.). BB-83698 showed potent in vitro activity against all strains (MICs, 0.06 to 0.25 μg/ml). In the in vivo model, all control animals died within 2 to 5 days of infection. BB-83698 (80 mg/kg of body weight twice daily or 160 mg/kg once daily) protected 70 to 100% of the animals, as measured 10 days p.i., regardless of the preexisting resistance mechanisms. In contrast, the survival rates for animals treated with the comparator antibiotics were 30% for animals treated with erythromycin (100 mg/kg) and infected with the macrolide-resistant strain, 34% for animals treated with amoxicillin (200 mg/kg every 8 h) and infected with the penicillin-resistant strain, and 0 and 78% for animals treated with ciprofloxacin (250 mg/kg) and infected with the ParC and GyrA mutant and the efflux mutant, respectively. At 80 mg/kg, BB-83698 generated a peak concentration in lung tissue of 61.9 μg/ml within 1 h and areas under the concentration-times curves of 57.4 and 229.4 μg · h/ml for plasma and lung tissue, respectively. The emergence of S. pneumoniae isolates with reduced susceptibilities to BB-83698 was not observed following treatment with a suboptimal dosing regimen. In conclusion, the potent in vitro activity of BB-83698 against S. pneumoniae, including resistant strains, translates into good in vivo efficacy in a mouse pneumonia model.

CHIR258, a Novel Multi-Targeted Tyrosine Kinase Inhibitor, for the Treatment of t(4;14) Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 641-641 ◽  
Author(s):  
Suzanne Trudel ◽  
Zhi Hua Li ◽  
Ellen Wei ◽  
Marion Wiesmann ◽  
Katherine Rendahl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Mouse Model ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
Wild Type ◽  
Myeloma Cells

Abstract The t(4;14) translocation that occurs uniquely in a subset (15%) of multiple myeloma (MM) patients results in the ectopic expression of the receptor tyrosine kinase, Fibroblast Growth Factor Receptor3 (FGFR3). Wild-type FGFR3 induces proliferative signals in myeloma cells and appears to be weakly transforming in a hematopoeitic mouse model. The subsequent acquisition of FGFR3 activating mutations in some MM is associated with disease progression and is strongly transforming in several experimental models. The clinical impact of t(4;14) translocations has been demonstrated in several retrospective studies each reporting a marked reduction in overall survival. We have previously shown that inhibition of activated FGFR3 causes morphologic differentiation followed by apoptosis of FGFR3 expressing MM cell lines, validating activated FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these poor-prognosis patients. CHIR258 is a small molecule kinase inhibitor that targets Class III–V RTKs and inhibits FGFR3 with an IC50 of 5 nM in an in vitro kinase assay. Potent anti-tumor and anti-angiogenic activity has been demonstrated in vitro and in vivo. We employed the IL-6 dependent cell line, B9 that has been engineered to express wild-type FGFR3 or active mutants of FGFR3 (Y373C, K650E, G384D and 807C), to screen CHIR258 for activity against FGFR3. CHIR258 differentially inhibited FGF-mediated growth of B9 expressing wild-type and mutant receptors found in MM, with an IC50 of 25 nM and 80 nM respectively as determined by MTT proliferation assay. Growth of these cells could be rescued by IL-6 demonstrating selectivity of CHIR258 for FGFR3. We then confirmed the activity of CHIR258 against FGFR3 expressing myeloma cells. CHIR258 inhibited the viability of FGFR3 expressing KMS11 (Y373C), KMS18 (G384D) and OPM-2 (K650E) cell lines with an IC50 of 100 nM, 250 nM and 80 nM, respectively. Importantly, inhibition with CHIR258 was still observed in the presence of IL-6, a potent growth factors for MM cells. U266 cells, which lack FGFR3 expression, displayed minimal growth inhibition demonstrating that at effective concentrations, CHIR258 exhibits minimal nonspecific cytotoxicity on MM cells. Further characterization of this finding demonstrated that inhibition of cell growth corresponded to G0/G1 cell cycle arrest and dose-dependent inhibition of downstream ERK phosphorylation. In responsive cell lines, CHIR258 induced apoptosis via caspase 3. In vitro combination analysis of CHIR258 and dexamethasone applied simultaneously to KMS11 cells indicated a synergistic interaction. In vivo studies demonstrated that CHIR258 induced tumor regression and inhibited growth of FGFR3 tumors in a plasmacytoma xenograft mouse model. Finally, CHIR258 produced cytotoxic responses in 4/5 primary myeloma samples derived from patients harboring a t(4;14) translocation. These data indicate that the small molecule inhibitor, CHIR258 potently inhibits FGFR3 and has activity against human MM cells setting the stage for a Phase I clinical trial of this compound in t(4;14) myeloma.

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