Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of asymmetrically substituted dodecafluorinated phthalocyanines has been synthesized via the Kobayashi ring expansion reaction of the corresponding dodecafluorinated boron subphthalocyanine with differently substituted 1,3-diiminoisoindolines. The mild reaction conditions employed during this ring expansion reaction gave rise exclusively to 3:1 asymmetrically substituted dodecafluorinated phthalocyanines. Metal insertion into the metal-free phthalocyanines was accomplished by heating at 40 degrees C in N,N-dimethylformamide in the presence of zinc bromide. The resulting zinc dodecafluorophthalocyanines were formulated as Cremophor EL oil-water emulsions and evaluated as photosensitizers in vitro against EMT-6 mouse mammary tumor cells. As compared to the previously studied zinc hexadecafluorophthalocyanine, these new asymmetrical zinc dodecafluorophthalocyanines exhibited improved photodynamic activity.
 ...
PMID:Synthesis and photodynamic activity of novel asymmetrically substituted fluorinated phthalocyanines. 1617 94

Three carboranyltetraphenylporphyrins containing 40 or 80 boron atoms were synthesized and evaluated for their biodistribution and toxicity in EMT-6 tumor-bearing mice. Copper (II) meso-5,10,15,20-tetrakis[3-methoxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 6, and copper (II) meso-5,10,15,20-tetrakis[3-hydroxy-4-(o-carboranylmethoxy)phenyl]porphyrin, 8, are B40 congeners with different lipophilicities, each less than their B80 congener, copper (II) meso-5,10,15,20-tetrakis[m-(3,5-di-o-carboranylmethoxybenzyloxy)phenyl]porphyrin, 18. Two days after the last of a series of i.p. injections in BALB/c mice bearing EMT-6 mammary tumors, a dose of 185 mg/kg 6 (54 mg/kg B) delivered over 3.5 times the concentration of boron to tumor (169 microg/g B) than did 118 mg/kg 8 (36 mg/kg B), which delivered 35 microg/g B, or 87 mg/kg 18 (30 mg/kg B), which delivered 46 microg/g B. The tumor-to-blood and tumor-to-brain boron concentration ratios at that time for all three porphyrins exceeded 80:1. Two days after the last injection, there resulted moderate thrombocytopenia that essentially disappeared two days later from 6 and 18, and mild leukocytosis from 6, 8, and 18, all of which were clinically inconsequential. Thus, 6 may rank among the most clinically promising carboranyl porphyrins ever made to deliver 10B to tumors for boron neutron-capture therapy (BNCT) that has also been tested for its toxicity in vivo.
 ...
PMID:Total syntheses of three copper (II) tetracarboranylphenylporphyrins containing 40 or 80 boron atoms and their biological properties in EMT-6 tumor-bearing mice. 1665 Oct

Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-X(L)-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-X(L) to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.
 ...
PMID:Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies. 1713 79

In this work, the potential of graphite furnace atomic absorption spectrometry for the direct determination of B in plant tissues has been investigated. Three certified reference materials (NIST SRM 1570a spinach leaves, NIST SRM 1573a tomato leaves and BCR CRM 679 white cabbage) were selected for this study, the goal always being to develop a fast procedure that could be robust enough to provide a satisfactory performance for all of them, without any modifications in the conditions applied. The use of a suitable chemical modifier was found to be essential for obtaining a reproducible and sufficiently sensitive signal for boron solutions. In this regard, the performance of the combination of citric acid plus W (added as a permanent modifier) was noteworthy, resulting in well-defined signal profiles, a remarkable analyte stabilization during the pyrolysis step (up to 2100 degrees C) and minimal memory effects. This mixture of modifiers provided a good performance for the direct analysis of solid samples as well, but only if a suitable temperature program, favoring the interaction between the analyte and the modifiers, was used. Thus, such a temperature program, with two pyrolysis steps and the addition of NH(4)NO(3) in order to carry out the in situ sample microdigestion, was optimized. Under these conditions, the peak areas obtained for both solid samples and aqueous standards were comparable. Finally, the analysis of the samples was carried out. In all cases, a good agreement with the certified values was obtained, while R.S.D. values ranged between 6 and 10%. It can be concluded that the method proposed shows significant advantages for the determination of this complicated element in solid samples such as the use of aqueous standards for calibration, a high sample throughput (20 min per sample), a suitable limit of detection (0.3 microg g(-1)) and reduced risk of analyte losses and contamination.
 ...
PMID:Solid sampling-graphite furnace atomic absorption spectrometry for the direct determination of boron in plant tissues. 1738 95

FLT3 defines a promising target for the treatment of acute myeloid leukemia (AML). In contrast to their efficacy in cell lines, FLT3-specific inhibitors as single agents have only modest clinical activity in patients with AML. As demonstrated here, overexpression of anti-apoptotic proteins of the BCL2 family leads to resistance against FLT3 inhibitors in a hematopoietic cell line model with activating FLT3 mutations. The susceptibility to FLT3 inhibition could be restored by treatment with the novel BH3 mimetic ABT-737. Primary AML samples tested in our study showed a high expression of BCL2 protein, but not of BCL-xL or MCL1. BCL2 protein levels were not reduced after dephosphorylation of FLT3 and its downstream target STAT5 in patient samples with FLT3 internal tandem duplications. Interestingly, treatment with ABT-737 caused apoptotic cell death in all primary AML samples at submicromolar level and synergized efficiently with FLT3 inhibition in AML samples with activating FLT3 mutations. In contrast to AML cell lines, BCR-ABL transformed human cells showed resistance to ABT-737, which might be due to the induction of MCL1 by BCR-ABL. Inhibition of BCL2 family members might define a novel highly efficient and specific strategy in the combined or monotreatment of AML.
 ...
PMID:BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. 1755 84

A new test method for boric acid in agar was developed. After digestion with nitric acid, the concentration of boron was measured by ICP-AES or ICP-MS with internal standards. Collaborative studies involving 5 laboratories were conducted to evaluate the new method by using a finely powdered agar sample and a standard sample (NIST SRM SRM1570a). The repeatability and reproducibility were very good. Moreover, HORRAT(R) values were less than 2. Therefore, it was considered that the new method is acceptable for the determination of boric acid in agar.
 ...
PMID:[Development and evaluation of determination methods for boric acid in agar using ICP-AES and ICP-MS]. 1902 84

On their entry into the thymus, developing lymphocyte progenitors depend on signaling from the pre-T cell receptor (pre-TCR), which orchestrates differentiation, cell proliferation, and survival. The exact mechanism of pre-TCR-mediated suppression of T cell death remains unclear and controversial. Here, we identify Bim and Bid, 2 members of the BH3-only group of the BCL2 family, as important regulators of pre-T cell death. Both factors are highly expressed in proapoptotic thymocytes and their expression is suppressed on signaling through the pre-TCR. Their expression is directly regulated by the transcription factors FoxO3a and p53. Bid expression and p53 activity are related to the ongoing rearrangement of the TCR loci and induced DNA damage responses. Bim expression and FoxO3a nuclear translocation are directly controlled by the pre-TCR by means of its downstream kinase Akt/PKB. Interestingly, deletion of either gene on a pre-TCR(-/-) background rescues survival, but fails to induce further progenitor differentiation uncoupling the 2 processes.
 ...
PMID:Regulation of lymphocyte progenitor survival by the proapoptotic activities of Bim and Bid. 1908 89

Human leukemias are considered clonal hematological malignancies initiated by chromosomal aberrations or epigenetic alterations occurring at the level of either pluripotent hematopoietic stem cells (HSCs) or early multipotent progenitors (MPPs). Leukemic cells are transformed, immortalized, actively proliferating cells that are still able to differentiate into cells resembling mature blood cells. Future therapies of leukemias require identification of molecular targets involved in hematopoiesis under normal and leukemic conditions and detailed understanding of the interactions between normal hematopoietic and leukemic cells within the bone marrow micro-environment. This review presents the basic aspects of hematopoiesis and highlights multilevel exploitable targets for leukemia therapy. These include HSC niche components, signaling pathways (SCF/c-kit-R, EPO-R-JAK2/STAT, Wnt, Notch, HOX), inducer-receptor interactions, superfine chromatin structure modifications, fused transcription factors, microRNAs and signaling of cell death through the Bcl-2 apoptotic switch (BH3-only proteins). The classes of therapeutics developed or being under development to eradicate human leukemias include novel antimetabolites, DNA hypomethylating agents, histone deacetylation inhibitors (HDACIs), retinoids and other inducers of differentiation, targeted monoclonal antibodies raised against cell surface proteins, pro-apoptotic receptor agonists (PARAs), BH3 peptidomimetics, cell cycle inhibitors, siRNAs and perhaps microRNAs. Some of these agents induce terminal differentiation while others promote cell cycle arrest and apoptosis in leukemia cells. At last but not least, this article describes the mechanisms of removal of damaged/harmful cells from organs since impairment in clearance of such cells can lead to autoimmune disorders by self-antigens.
 ...
PMID:Multilevel targeting of hematopoietic stem cell self-renewal, differentiation and apoptosis for leukemia therapy. 1930 96

Excess copper is toxic to life. Copper has been shown to induce apoptosis in various cell lines and tissues. However, due to the lack of appropriate gene knockout animal models, data concerning the underlying pathways of copper-induced apoptosis are insufficient, especially with regards to in vivo systems. The nematode Caenorhabditis elegans is a good model to study basic biological processes, including stress responses and apoptosis. In the present study, we investigated copper-induced germline apoptosis in the C. elegans strains carrying mutated alleles of homologs to known mammalian genes that are involved in apoptosis regulation. We show here that exposing C. elegans to copper causes dose- and time-dependent germline apoptosis. The knockout of checkpoint genes hus-1, clk-2, the Bcl-2 homolog ced-9, and the BH3-only domain egl-1 did not prevent cells of the germline from copper-induced apoptosis. The loss-of-function of the tumor suppressor gene, p53/cep-1, caused a significant increase in germline apoptosis with exposure to copper, and the depletion of p53 antagonist ABL1 significantly enhanced apoptosis. The knockout of the caspase gene ced-3 and the Apaf-1 homolog ced-4 abrogated both copper-induced and physiological germline apoptosis. Germline apoptosis stopped increase in the strains lin-45(ku51), mek-2(n1989), mpk-1(ku1) under copper stresses, respectively. Copper-induced apoptosis was blocked in the loss-of-function alleles of both JNK and p38 MAPK cascades excepting pmk-3, one of the three p38 MAPK components. Together, the results of this study suggest that caspase and Apaf-1 are required for copper-induced germline apoptosis while DNA damage response genes are not essential, and that the Raf-MEK-ERK, ASK1/2-MKK7-JNK, ASK1/2-MKK3/6-p38 signaling pathways are indispensable in mediating this apoptotic response.
 ...
PMID:Copper-induced germline apoptosis in Caenorhabditis elegans: the independent roles of DNA damage response signaling and the dependent roles of MAPK cascades. 1949 12

A novel approach to obtain a fractionation free (11)B/(10)B isotope ratio based on oxygen isotopes determined in situ from the same filament loading by N-TIMS is described. The method uses only a few nanograms of B to produce BO(2)(-) ions. First, the oxygen isotopes are determined at a lower filament temperature using ReO(4)(-) ions and employing (187)Re/(185)Re for internal normalization. Subsequently, the filament temperature is increased to get sufficient BO(2)(-) ions and predetermined (18)O/(16)O isotopes from the same filament loading is used to correct for boron mass fractionation. The validity of the method has been demonstrated by analyzing a NIST-SRM-951 boron isotopic certified standard, two synthetic B mixtures, and two coral reference materials. An average analytical precision of 0.6 per thousand (n = 6) has been demonstrated. This is an important and crucial step forward in making the application of BO(2)(-) ions by N-TIMS routine in coral, foraminifera, and other samples where only limited amounts of boron are available. This new method does not require any additional effort in loading or in carrying out the mass spectrometric analysis but eliminates the need of assuming a fixed (18)O/(16)O ratio and thus provides higher accuracy for applications in paleo-oceanography, geochemistry, and cosmo-chemistry.
 ...
PMID:Fractionation correction methodology for precise and accurate isotopic analysis of boron by negative thermal ionization mass spectrometry based on BO2(-) ions and using the 18O/16O ratio from ReO4(-) for internal normalization. 1965 Jun 34


<< Previous 1 2 3 4 5 6 7 Next >>