The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.
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2009 Nov 15;69(22):8645-51. doi: 10.72.CAN-09-1576. Epub
2009 Nov 10.The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo.1, , , , , , , , , .1Lung Cancer Biology Group, Cancer Research UK Laboratories, Clinical Sciences Centre, Hammersmith Hospital Campus of Imperial College London, London, United Kingdom.AbstractLung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of &5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting &6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) showed decreased intratumoral proliferation in live animals treated with the compound at 7 to 14 days. Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that [(18)F]FLT-PET imaging could provide early in vivo evidence of response.PMID:
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External link. Please review our .Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Wa...
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2009 Apr 15;69(8):3579-88. doi: 10.72.CAN-08-3701. Epub
2009 Apr 7.Identification of copy number abnormalities and inactivating mutations in two negative regulators of nuclear factor-kappaB signaling pathways in Waldenstrom's macroglobulinemia.1, , , , , , , , , , , , , , , , , , , , , , .1Mayo Clinic, Scottsdale, Arizona , USA.AbstractWaldenstr?m's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor-associated factor 3 and TNFalpha-induced protein 3, two negative regulators of the nuclear factor-kappaB (NF-kappaB) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-kappaB target genes. Mutational activation of the NF-kappaB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-kappaB pathway activation in the treatment of WM.PMID:
[PubMed - indexed for MEDLINE] Overview of the copy number abnormalities identified in WM. Red blocks repres blue blocks represent chromosome losses. A) Penetrance plot summarizing the copy number imbalances per chromosome. The amplitude of each abnormality corresponds to its prevalence. B) Hierarchical unsupervised clustering done from the genomic imbalances detected by aCGH per chromosome.Cancer Res. ;69(8):.Chromosomal imbalances on chromosome 6. In the graphical output, negative values (left) indicate losses and positive values (right) indicate gains of tumor DNA. A) The simultaneous presence of 6p gain/6q loss was commonly identified. These chromosomal imbalances could involve either a region or the whole chromosomal arm. B) FISH validations of the above described cases. At the left, a sample with a whole 6p arm gain incl at the center, a FISH pattern compatible with the presence of an isochromosome 6p; and at the right, a 6p interstitial gain.Cancer Res. ;69(8):.TNFAIP3 abnormalities. A) Delineation of four minimal deleted regions (MDRs) on 6q based on aCGH data (dashed lines). PRDM1 and TNFAIP3 were localized in MDR2 and MDR3, respectively. B) Partial DNA sequences from a normal sample (top) and one with TNFAIP3 frame-shift deletion ( T155fsX215). The absence of the wild type allele indicates the homozygous status of the mutation. The position of TNFAIP3 mutation at protein level is based on NP_, which represent the accepted full length TNFAIP3 polypeptide. C) The TNFAIP3 transcript expression level was significantly lower in patients with one copy of the gene (1N) when compared with the group with two copies of TNFAIP3 (2N).Cancer Res. ;69(8):.TRAF3 abnormalities. A) Chromosome (left panel) and gene view (right panel) showing mono and biallelic deletions on 14q32.32, including TRAF3 (highlight in red, inside the dashed box). B) cIgM-FISH validations. A TRAF3 monoallelic deletion was identified in a third patient (MC1383) with no aCGH data. The NFKBIA probe was used as a surrogate CEP14 probe. C) Partial DNA sequences of both cases with TRAF3 monoallelic deletion (MC1341 and MC1383), confirming the presence of a mutation in the remaining allele (c.1800G&A and c.1209A&T, leading to D483N and K286X substitutions, respectively). The positions of TRAF3 mutations at the cDNA and protein level are based on NM_ and NP_, which represent the accepted full length TRAF3 transcript and polypeptide, respectively.Cancer Res. ;69(8):.TRAF3 inactivation is associated with activation of the non-canonical NF-kB pathway. A) NF-kB index in WM. Our MM cohort is included for comparison. The patients with TRAF3 and cIAP1-cIAP2 inactivation are highlighted in red and blue, respectively. An association between patients with TRAF3 inactivation and high NF-kB index is clearly observed in WM. The case with the second highest index value showed a very low TRAF3 expression ( see ), suggesting its inactivation. However, no DNA or cDNA was available for performing aCGH or DNA sequencing. The bars correspond to the median values. B) Immunofluorescence staining confirmed the association between TRAF3 inactivation and nuclear localization of NFKB2, indicating p100 to p52 processing (patient MC1353). A patient with close-to-median NF-kB index and active TRAF3 was used as a negative control (MC1344).Cancer Res. ;69(8):.Publication TypesMeSH TermsSubstancesGrant SupportFull Text SourcesOther Literature SourcesMiscellaneous
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External link. Please review our .Potential benefits of integrated COPD management in primary care.
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):130-4.Potential benefits of integrated COPD management in primary care.1, .1Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.AbstractChronic obstructive pulmonary disease (COPD) represents a major and progressive cause of morbidity and mortality worldwide, resulting in an important financial and health burden in coming decades. Pulmonary rehabilitation (PR) has been proven to be the most effective treatment in all patients in whom respiratory symptoms are associated with diminished functional capacity or reduced quality of life. Nevertheless, despite wide recommendation and proven efficacy, the use of PR is limited in daily practice. Reasons for these include low accessibility and availability, high costs, and lack of motivation to continue a healthy life style after treatment. By contrast, it has been demonstrated that primary care patients can be reactivated by formulating personal targets and designing individualized treatment plans in collaboration with their general practitioner or practice nurse. Based on these personal plans and targets, specific education must be provided and development of self management skills should be actively encouraged. Ideally, elements of pulmonary rehabilitation are tailored into a comprehensive primary care integrated disease management program. In that way, the benefits of PR can be extended to a substantially larger part of the COPD population, to reach even those with milder stages of disease. Favorable long-term effects on exercise tolerance and quality of life in a number of studies have been demonstrated in recent years, but broad introduction in the primary care setting still needs further justification in the form of a proper cost effectiveness analysis.PMID:
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, 25 December 2015, Pages 72–85
Biochar and biochar-compost as soil amendments: Effects on peanut yield, soil properties and greenhouse gas emissions in tropical North Queensland, Australia, , , , , , , a College of Science, Technology and Engineering and Centre for Tropical Environmental and Sustainability Science, James Cook University, PO Box 6811, Cairns, Queensland 4870, Australiab Hawkesbury Institute for the Environment, University of Western Sydney, Science Road, Richmond, New South Wales 2753, Australiac Northern Gulf Resource Management Group, 317 Byrnes Street, Mareeba, Queensland 4880, Australiad Peanut Company of Australia, 133 Haly Street, Kingaroy, PO Box 26, Kingaroy, Queensland 4610, Australia&Soil was amended with biochar, compost and their co-composted mixture at field scale.&Leaf chlorophyll, N, P and K were increased by organic amendments.&Peanut yield was increased by 18&24% and nodulation by 9&25% by organic amendments.&Soil OC, N, P, NO3&, NH4+, CEC and soil water content were significantly improved by organic amendments.&Greenhouse gas emissions were reduced by organic amendments.This study investigated the effects of biochar and compost, applied individually or together, on soil fertility, peanut yield and greenhouse gas (GHG) emissions on a Ferralsol in north Queensland, Australia. The treatments were (1) inorganic fertilizer only (F) (2) 10 t ha&1 biochar + F (B + F); (3) 25 t compost + F (Com + F) ha&1; (4) 2.5 t B ha&1 + 25 t Com ha&1 mixed on site + F; and (5) 25 t ha&1 co-composted biochar-compost + F (COMBI + F). Application of B and COMBI increased seed yield by 23% and 24%, respectively. Biochar, compost and their mixtures significantly improved plant nutrient availability and use, which appeared critical in improving peanut performance. Soil organic carbon (SOC) increased from 0.93% (F only) to 1.25% (B amended), soil water content (SWC) from 18% (F only) to over 23% (B amended) and CEC from 8.9 cmol(+)/kg (F only) to over 10.3 cmol(+)/kg (organic amended). Peanut yield was significantly positively correlated with leaf chlorophyll content, nodulation number (NN), leaf nutrient concentration, SOC and SWC for the organic amendments. Fluxes of CO2 were highest for the F treatment and lowest for the COMBI treatment, whereas N2O flux was highest for the F treatment and all organic amended plots reduced N2O flux relative to the control. Principal component analysis indicates that 24 out of 30 characters in the first principal component (PRIN1) individually contributed substantial effects to the total variation between the treatments. Our study concludes that applications of B, Com, B + Com or COMBI have strong potential to, over time, improve SOC, SWC, soil nutrient status, peanut yield and abate GHG fluxes on tropical Ferralsols.KeywordsBiochar; Carbon sequestration; Co-composted biochar-compost; CO2 and N2O fluxes; Ferralsol; Soil fertility
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