Journal articles on the topic 'Abi'
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Leymarie, Juliette, Gérard Lascève, and Alain Vavasseur. "Interaction of stomatal responses to ABA and CO2 in Arabidopsis thaliana." Functional Plant Biology 25, no. 7 (1998): 785. http://dx.doi.org/10.1071/pp98031.
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Stomatal responses to ABA and CO2 were investigated in Arabidopsis thaliana (L.) Heynh. wild-type and ABA insensitive mutants (abi1-1, abi2-1, abi1-1abi2-1) at the whole plant and at the isolated epidermis levels. In wild-type plants, feeding roots with ABA (1–50 µM) triggered a rapid drop in leaf conductance which levelled off during the following photoperiods, and strongly inhibited the increase in conductance induced by light. The rapid response was strongly inhibited in abi1-1, abi2-1 and abi1-1abi2-1 double mutants, but a residual long-term decrease in leaf conductance was still observed. In wild-type plants, exogenous ABA strongly enhanced the response to CO2 removal. Conversely, in the absence of CO2 the effect of ABA was drastically reduced in epidermal strip experiments. These results reveal a strong interaction between sensing of ABA and CO2 in stomata of A. thaliana. Despite an initially wide stomatal aperture in abi-1, abi-2 and double mutant plants, their stomatal responses to light and CO2 removal were half those of wild-type plants. Moreover these responses were totally independent of the presence of ABA, suggesting that ABI1 and ABI2 are either directly involved in the interaction between the two signalling pathways or, alternatively located upstream of this point of interaction.
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Kaliff, Maria, Jens Staal, Mattias Myrenås, and Christina Dixelius. "ABA Is Required for Leptosphaeria maculans Resistance via ABI1- and ABI4-Dependent Signaling." Molecular Plant-Microbe Interactions® 20, no. 4 (April 2007): 335–45. http://dx.doi.org/10.1094/mpmi-20-4-0335.
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Abscisic acid (ABA) is a defense hormone with influence on callose-dependent and -independent resistance against Leptosphaeria maculans acting in the RLM1Col pathway. ABA-deficient and -insensitive mutants in Ler-0 background (aba1-3 and abi1-1) displayed susceptibility to L. maculans, along with a significantly decreased level of callose depositions, whereas abi2-1 and abi3-1 remained resistant, together with the abi5-1 mutant of Ws-0 background. Suppressor mutants of abi1-1 confirmed that the L. maculans-susceptible response was due to the dominant negative nature of the abi1-1 mutant. Highly induced camalexin levels made ABA mutants in Col-0 background (aba2-1, aba3-1, and abi4-1) appear resistant, but displayed enhanced susceptibility as double mutants with pad3-1, impaired in camalexin biosynthesis. β-Aminobutyric acid (BABA) pretreatment of Ler-0 contributed to an elevated level of endogenous ABA after L. maculans inoculation. Comparisons between (RLM1Col)pad3 and rlm1Lerpad3 showed that ABA and BABA enhancement of callose deposition requires induction from RLM1Col·ABI1, but not ABI2, was found to be involved in a feedback mechanism that modulates RLM1Col expression. Genetic analysis showed further that this feedback occurs upstream of ABI4 and that components downstream of ABI4 modulate ABI1 activity. ABA and BABA treatments of the L. maculans-susceptible callose synthase mutant pmr4 showed that ABA also induces a callose-independent resistance. Similar treatments enhanced callose depositions and induced resistance to L. maculans in oilseed rape, and BABA-induced resistance was found to be independent of salicylic acid.
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York, John W., Brent L. Johnson, Michael Cicchillo, Spence M. Taylor, David L. Cull, and Corey Kalbaugh. "Aortobiiliac Bypass to the Distal External Iliac Artery versus Aortobifemoral Bypass: A Matched Cohort Study." American Surgeon 79, no. 1 (January 2013): 61–66. http://dx.doi.org/10.1177/000313481307900131.
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Vascular bypass has long been the standard surgical treatment for symptomatic aortoiliac occlusive disease (AIOD). Conventional wisdom has been that aortobifemoral bypass (ABF) be performed for AIOD because of the inevitable progression of iliac atherosclerosis leading to bypass thrombosis. However, ABF is prone to significant groin incision complications such as infection and lymphocele. The purpose of this study was to determine if aortobiiliac bypass (ABI) to the distal external iliac artery performs similarly to ABF in cases in which minimal atherosclerosis is present in the distal iliac arteries. Of patients undergoing aortic reconstruction for symptomatic AIOD between July 1998 and December 2008, 37 were found to have minimal atherosclerosis in the distal external iliac arteries and underwent ABI. These were compared with patients undergoing ABF using a retrospective matched cohort design. The indication for ABI was claudication in 86.5 per cent and critical limb ischemia in 13.5 per cent. There was no difference found in overall bypass patency. The 1-, 3-, and, 5-year patencies were 97, 92, and 79 per cent in the ABI group and 93, 85, and 76 per cent in the ABF group, respectively ( P = 0.8). The incidence of groin wound complications in the ABF group was 14.6 per cent. ABI to the distal external iliac artery achieves equivalent graft patencies to ABF without added risk of associated groin wound complications. These data suggest that ABI be preferentially considered to ABF in situations when the very distal external iliac arteries are patent and free of significant atherosclerotic disease.
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Ryu, Jae Ryun, Asier Echarri, Ran Li, and Ann Marie Pendergast. "Regulation of Cell-Cell Adhesion by Abi/Diaphanous Complexes." Molecular and Cellular Biology 29, no. 7 (January 21, 2009): 1735–48. http://dx.doi.org/10.1128/mcb.01483-08.
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ABSTRACT Actin polymerization provides the driving force for the formation of cell-cell junctions and is mediated by two types of actin nucleators, Arp2/3 and formins. Proteins required for coordinately linking cadherin-mediated adhesion to Arp2/3-dependent versus formin-dependent nucleation have yet to be defined. Here we show a role for Abi, the Abi-binding partner Nap1, and the Nap1-binding protein Sra1 in the regulation of cadherin-dependent adhesion. We found that Abi, which is known to interact with Wave, leading to activation of the Arp2/3 complex, is also capable of interacting with the Diaphanous (Dia)-related formins in the absence of Wave. Knockdown of Abi, Nap1, Sra1, or Dia markedly inhibited cell-cell junctions, whereas knockdown of Wave or Arp2/3 produced mild and transient phenotypes. Dia and Abi colocalized with β-catenin at cell-cell junctions. Further, Dia and Wave bound to overlapping sites on Abi1, and Wave competed with Dia for Abi1 binding. Notably, an active Dia1 C-terminal fragment that localizes to cell-cell junctions rescued the abnormal junctions induced by depletion of Abi or Nap1 in epithelial cells. These findings uncover a novel link between cadherin-mediated adhesion and the regulation of actin dynamics through the requirement for an Abi/Dia complex for the formation and stability of cell-cell junctions.
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Kong, Yinfei, Songbin Chen, Yang Yang, and Chengcai An. "ABA-insensitive (ABI) 4 and ABI5 synergistically regulateDGAT1expression inArabidopsisseedlings under stress." FEBS Letters 587, no. 18 (August 10, 2013): 3076–82. http://dx.doi.org/10.1016/j.febslet.2013.07.045.
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Kuhn, D. T., and G. Packert. "Paternal imprinting of inversion Uab1 causes homeotic transformations in Drosophila." Genetics 118, no. 1 (January 1, 1988): 103–7. http://dx.doi.org/10.1093/genetics/118.1.103.
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Abstract Paternal transmission of the bithorax-complex (BX-C) rearrangement, inversion Uab1, causes a specific dominant gain of function phenotype in most abdominal segments. This represents a case of paternal imprinting since the mutant phenotype will occur only if inversion Uab1 is paternally transmitted. The transformations in males are toward genital arch tissue. For females the transformations are to tissue found on abdominal segment 7 (Ab7) and to structures normally restricted to the genital disc. Ninety-six percent of transformed areas appear on Ab5 and Ab6 in both sexes and on Ab7 in females, coinciding with the Abd-B domain. Four percent of the transformations occurred on Ab1 through Ab4, coinciding with the abd-A domain. The mutant phenotype can be dramatically enhanced by modifying genes such as the posterior BX-C mutant tuh-3. Expressivity is modulated by maternal effect alleles interacting with tuh-3. A region of function within inversion Uab1 appears to be programmed during spermatogenesis to function in a legacy dependent manner during embryogenesis.
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Grove, Matthew, Galina Demyanenko, Asier Echarri, Patricia A. Zipfel, Marisol E. Quiroz, Ramona M. Rodriguiz, Martin Playford, et al. "Abi2-Deficient Mice Exhibit Defective Cell Migration, Aberrant Dendritic Spine Morphogenesis, and Deficits in Learning and Memory." Molecular and Cellular Biology 24, no. 24 (December 15, 2004): 10905–22. http://dx.doi.org/10.1128/mcb.24.24.10905-10922.2004.
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ABSTRACT The Abl-interactor (Abi) family of adaptor proteins has been linked to signaling pathways involving the Abl tyrosine kinases and the Rac GTPase. Abi proteins localize to sites of actin polymerization in protrusive membrane structures and regulate actin dynamics in vitro. Here we demonstrate that Abi2 modulates cell morphogenesis and migration in vivo. Homozygous deletion of murine abi2 produced abnormal phenotypes in the eye and brain, the tissues with the highest Abi2 expression. In the absence of Abi2, secondary lens fiber orientation and migration were defective in the eye, without detectable defects in proliferation, differentiation, or apoptosis. These phenotypes were consistent with the localization of Abi2 at adherens junctions in the developing lens and at nascent epithelial cell adherens junctions in vitro. Downregulation of Abi expression by RNA interference impaired adherens junction formation and correlated with downregulation of the Wave actin-nucleation promoting factor. Loss of Abi2 also resulted in cell migration defects in the neocortex and hippocampus, abnormal dendritic spine morphology and density, and severe deficits in short- and long-term memory. These findings support a role for Abi2 in the regulation of cytoskeletal dynamics at adherens junctions and dendritic spines, which is critical for intercellular connectivity, cell morphogenesis, and cognitive functions.
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Chorzalska, Anna Dorota, John Morgan, Max Petersen, Diana O. Treaba, Adam J. Olszewski, John L. Reagan, and Patrycja Dubielecka. "Loss of Abelson Interactor-1 Is Linked to Inflammatory Hematopoiesis and Accelerated Aging of Hematopoietic System." Blood 132, Supplement 1 (November 29, 2018): 1285. http://dx.doi.org/10.1182/blood-2018-99-118393.
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Abstract Background: Hematopoietic stem cells (HSC) ensure homeostasis and lifelong maintenance of hematopoietic system, but with age, they gradually lose quiescence, self-renewal potential, and system restoration capacity. HSC aging results in a differentiation shift towards myeloid lineage, anemia, thrombocytosis, decrease in T and B cells, imbalance in macrophage function, and increased osteoclast activity. Mechanisms involved in HSC aging include increased mTOR activity and ROS production, impaired autophagy, epigenetic reprograming, and cumulative DNA damage. Intriguingly, cellular and molecular similarities between aging and inflammation have led to a novel concept of "inflammation-associated aging of hematopoiesis". Understanding the molecular mechanisms responsible for this process may impact strategies targeting age-related diseases, including neoplasms. However, to date only few primary animal models of inflammation have shown bone marrow failure, so new animal models need to be established to provide mechanistic insight into the long-term implications of chronic inflammation on the hematopoietic system. We have previously shown that bone marrow-specific deletion of an adapter protein Abelson interactor-1 (Abi1) leads to a myeloproliferative neoplasm (MPN)-like disease in 35-56-week-old mice, mechanistically associated with increased activity of Src Family Kinases (SFKs), STAT3 and NF-κB. At both transcript and protein levels, Abi-1 is also significantly reduced in HSCs and granulocytes from patients with primary myelofibrosis (PMF), and Abi-1-deficient HSC in human PMF show increased SFK-STAT3-NF-κB signaling (Chorzalska, ASH 2017). Methods: Myeloid/lymphoid, stem/progenitor populations profiling by FACS, bone marrow transplantation assays, transcriptomics and proteomics analyses as well pro-inflammatory cytokine profiling and histopathology analyses were performed on the transgenic Abi-1KO mice carrying bone marrow-selective knockout at 4 weeks post-recombination, upon confirming both inducible inactivation of the Abi1flox allele and loss of Abi-1 protein in the marrow (Fig.1A, B). Results: To better understand initial systemic events that lead to the development of MPN-like disease in aged Abi-1KO mice we have now characterized early changes within the hematopoietic system associated with loss of Abi-1. Blood count analysis indicated leukocytosis, anemia and thrombocytosis, and an increase in the fraction of myeloid (CD11b+/Gr-1+) as well as macrophage/monocyte (F4/80+) cells at the expense of lymphoid (B220+) cells in Abi-1KO relative to Abi-1WT mice (Fig.1C). Previously reported 2.6-fold increase in Abi-1KO LT-HSCs (Chorzalska, ASH 2017) was now shown to be associated with 30% increase in number of LT-HSCs is in the S/G2/M phases of the cell cycle relative to Abi-1WT LT-HSCs (Fig. 1D). Lethally irradiated recipient C57BL/6 wild-type mice transplanted with bone marrow cells from Abi-1KO relative to Abi-1WT mice (in the absence of competitor cells) showed progressive loss of chimerism in primary and secondary recipients (Fig. E). Genome-wide gene expression analysis of Abi-1WT vs. Abi-1KO LSK cells showed significant overexpression of genes regulated by or involved in regulation of the NF-κB pathway (Fig. 1F). Plasma cytokine levels showed 2-fold increase in IL-1B, IL-12, IL-17, IL-23, IL-27, and MCP-1 and nearly 10-fold increase in INFγ (Fig. 1G). Label-free, intensity-based quantitative proteomic analysis of bone marrow from 20-week-old Abi-1KO and Abi-1WT mice showed abundance of peptides derived from Mac-1, myeloperoxidase, STAT1, STAT3, and SFKs - Hck and Fgr, confirming not only activation of SFKs and STAT3 signaling, but also increase in proteins associated with myeloid lineages (Fig. 1H). Loss of bone density (Fig. 1I) and a significant decrease in thymus size (Fig. 1J) were observed in Abi-1KO mice relative to Abi-1WT mice. Conclusions: In sum, phenotypic analyses performed 4-10-weeks post Abi1 gene inactivation indicate changes consistent with accelerated aging of hematopoietic system that are mechanistically linked to inflammatory SFK-STAT3-NF-κB signaling. To our knowledge this is the first animal model linking accelerated inflammation-driven aging of hematopoietic system to development of an MPN in aged mice. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding. Reagan:Pfizer: Research Funding; Alexion: Honoraria; Takeda Oncology: Research Funding.
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Mat Idris, Mohd Faiz Hakimi bin, Ishak bin Suliaman, Ahmad Zahid bin Salleh, Sofyuddin bin Yusof, Abdillah Hisham bin Abdul Wahab, and Mohd A’Tarahim bin Mohd Razali. "Al-Asha‘irah: Faktor Perkembangan dan Metodologi Argumentasinya [Al-Asha'irah: Developmental Factors and Methodology of Argument]." Jurnal Islam dan Masyarakat Kontemporari 11 (October 1, 2015): 99–109. http://dx.doi.org/10.37231/jimk.2015.11.3.141.
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This paper aims to trace the history of how al-Asha‘irah emerged, factors that contributed to its development, prominent figures in this stream, and the stream’s method of proving with dalil (reasoning based on analogy). This stream was founded by ‘Ali Ibn Isma‘il Ibn Ishaq Ibn Salim Ibn Isma‘il Ibn ‘Abd Allah Ibn Musa Ibn Bilal Ibn Abi Burdah Ibn Abi Musa al-Ash‘ari. The stream employed two methods of proving with dalil. They referred to naqli dalil, which refers to the Quran and hadith, and they employed sensible dalil to strenghten the reasoning obtained from the Quran and hadith.
Keywords: Al- Asha‘irah, methodology, school of thought.
Artikel ini bertujuan melakukan sorotan tentang sejarah kemunculan aliran al-Asha‘irah, faktor-faktor yang menyumbang kepada perkembangannya, tokoh-tokoh aliran ini serta metodologi pendalilannya. Aliran ini diasaskan oleh ‘Ali Ibn Isma‘il Ibn Ishaq Ibn Salim Ibn Isma‘il Ibn ‘Abd Allah Ibn Musa Ibn Bilal Ibn Abi Burdah Ibn Abi Musa al-Ash‘ari. Aliran ini menggunakan dua metodologi pendalilan iaitu dalil naqli dengan merujuk kepada al-Qur’an dan hadith, dan penggunaan dalil akal bagi memperkuatkan pendalilan yang diambil dari al-Qur’an dan hadit.
Kata kunci: Al- Asha‘irah, metodologi, aliran pemikiran, argumentasi
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Xiao, Shimin, Li Jiang, Changhu Wang, and David W. Ow. "Arabidopsis OXS3 family proteins repress ABA signaling through interactions with AFP1 in the regulation of ABI4 expression." Journal of Experimental Botany 72, no. 15 (July 7, 2021): 5721–34. http://dx.doi.org/10.1093/jxb/erab237.
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Abstract Abscisic acid (ABA) and the AP2/ERF (APETALA2/ETHYLENE-RESPONSIVE FACTOR)-type transcription factor called ABA INSENSITIVE 4 (ABI4) play pivotal roles in plant growth responses to environmental stress. An analysis of seedling development in Arabidopsis ABA hypersensitive mutants suggested that OXS3 (OXIDATIVE STRESS 3), OXS3b, O3L3 (OXS3 LIKE 3), O3L4, and O3L6 were negative regulators of ABI4 expression. We therefore characterized the roles of the OXS3 family members in ABA signaling. All the above five OXS3 proteins were found to interact with AFP1 (ABI FIVE BINDING PROTEIN 1) in yeast two hybrid assays. Seven OXS3 family members including two other members O3L1 and O3L5 were found to interact with histone H2A.X, although OXS3b, O3L3, and O3L5 showed weaker interactions. ChIP-qPCR analysis showed that the absence of some of these OXS3 family proteins was associated with increased occupancy of histone γ-H2A.X at the ABI4 promoter, which also corresponded with de-repression of ABI4 expression. Repression of ABI4 expression, however, required both AFP1 and OXS3, OXS3b or O3L6. We conclude that in the absence of stress, OXS3 family proteins regulate γ-H2A.X deposition at the ABI4 promoter and that together with AFP1, OXS3 family proteins function to prevent ABA-induced growth arrest by co-repressing ABI4 through decreased promoter occupancy of histone γ-H2A.X.
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Kröger, Knut, Nils Lehmann, Susanne Moebus, Axel Schmermund, Andreas Stang, Hagen Kälsch, Marcus Bauer, Karl-Heinz Jöckel, Raimund Erbel, and Stephan Möhlenkamp. "Impact of atherosclerotic risk factors on different ankle-brachial-index criteria - results of the Heinz Nixdorf recall study." Vasa 42, no. 2 (March 1, 2013): 120–26. http://dx.doi.org/10.1024/0301-1526/a000255.
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Background: On the basis of the Heinz Nixdorf RECALL Study (HNR) we estimated the impact of classical atherosclerotic risk factors on different ankle-brachial-index (ABI) criteria. Patients and methods: In a subgroup of participants (n = 2586) who had normal ABI at baseline ABI measurement was repeated at a 5 years follow-up and 3 different ABIs were defined: ABI-high calculated from the higher pressure, ABI-low from the lower pressure of both foot arteries of each leg. Pure-ABI-low was defined by exclusion of participants with ABI-high from those with ABI-low. Mönckebergs Mediacalcinosis (MC) was accepted in case of ABI-high > 1.4 in one leg. Results: According to ABI-high 2 %, to ABI-low 7.8 % and pure-ABI-low 5.8 % of the participants developed peripheral arterial disease (PAD) (ABI < 0.9) and 3.6 % developed MC within the 5 years. Age did not play any role whereas female gender, diabetes mellitus and smoking were associated with an increased relative risk of pathologic ABI-high and ABI-low. Looking at the pure-ABI-low group only, female gender and smoking showed significant associations. None of the analysed risk factors except gender had an impact on the development of MC. Conclusions: Classical risk factors have different impact on incidence of PAD as defined by different ABI criteria.
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Chorzalska, Anna Dorota, John Morgan, Diana Olguta Treaba, Adam J. Olszewski, Nathan Kingston, Yan Cheng, Kara Lombardo, et al. "Bone Marrow-Specific Loss of ABI1 Induces Myelofibrosis through a Mechanism Involving Activation of NFκB." Blood 128, no. 22 (December 2, 2016): 1203. http://dx.doi.org/10.1182/blood.v128.22.1203.1203.
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Abstract Primary myelofibrosis (PMF) is an age-related myeloproliferative neoplasm (MPN) characterized by progressive bone marrow fibrosis, increasingly ineffective hematopoiesis, vascular and inflammatory complications, and progression to acute myeloid leukemia (AML) in 20% of cases. PMF is the rarest and the most severe of MPNs, with unfavorable prognosis and challenging treatment. Constitutive activation of the JAK-STAT pathway is an essential contributor to the pathogenesis of PMF. Nonetheless, clinically available JAK inhibitors do not show consistent disease-modifying effects at the molecular and malignant stem cell levels, underscoring the need to identify other targetable pathogenic mechanisms in PMF and related MPNs. We recently described a new signaling cascade involved in the maintenance of the malignant phenotype of stem cells in chronic myeloid leukemia that affects their adhesiveness, interaction with the microenvironment and resistance to imatinib (Chorzalska et al., Leukemia 2014). These phenotypic changes were caused by loss of Abelson interactor-1 (Abi-1) which regulates integrin α4 and the Src family kinases (SFKs) signaling pathways. To further delineate how organ-specific absence of Abi-1 affects hematopoiesis and hematopoietic stem cells, we generated a conditional, inducible bone marrow-specific Abi-1 transgenic mouse knockout model. For this purpose, we crossed conditional Abi-1(fl/fl) knockout mice with transgenic Tg(Mx1-cre+/-) mice (B6.Cg-Tg(Mx1-cre+ 1Cgn/J) that express Cre recombinase under the control of the polyinosinic:polycytidylic acid (poly(I:C)) or interferon-inducible Mx1 promoter. Obtained Abi-1(fl/fl);Tg(Mx1- cre(+)) animals were subjected to bone marrow-specific Abi-1 deletion induced by intraperitoneal administration of poly(I:C), resulting in organ-specific Abi-1 knockout (Abi-1 KO). Abi-1(fl/fl);Tg(Mx1- cre(-)) animals subjected to the same poly(I:C) treatment (Abi-1 WT) were used as controls in all experiments (Figure 1A). We confirmed the absence of Abi-1 protein in the Abi-1 KO bone marrow by immunoblotting (Figure 1B). Abi-1 KO mice developed deranged hematopoiesis with progressive anemia, thrombocythemia, megakaryocytosis, and myeloid hyperplasia (Figure 1C). They also developed progressive splenomegaly with 1.4x, 2.4x, and 4.8x enlargement of the spleen at 4, 28, and 50 weeks after recombination, respectively, and progressive femur pallor (Figure 1D) with bone marrow fibrosis confirmed by trichrome and silver staining (Figure 1D). Using fluorescence-activated cell sorting, we determined that Abi-1 KO resulted in more than two-fold expansion of the most primitive long-term hematopoietic stem cells (Lin-CD34-Sca-1+c-Kit+ CD135-) in the bone marrow and 3.75-fold increase of LSK cells (Lin- Sca-1+c-Kit+) in the peripheral blood compared with controls (Figure 1E). Increased activities of the SFKs and NFκB were observed in Abi-1 KO bone marrow, and confirmed in human CD34+ cells isolated from the marrow of patients with PMF or AML (Figure 1F,G). Furthermore, CD34+ hematopoietic progenitors and granulocytes from PMF patients, as well as CD34+ hematopoietic progenitors from AML patients, showed decreased levels of ABI1 transcript (Figure 1H). Taken together, our results indicate that a targeted deactivation of Abi-1 in the bone marrow causes expansion of hematopoietic stem cells, myeloid hyperplasia with thrombocytosis and overproduction of collagen and reticulin fibers. The Abi-1 KO murine phenotype meets the Mouse Models of Human Cancers Consortium criteria for a myeloproliferative neoplasm with features resembling human PMF (Kogan et al., Blood 2002). These data indicate that loss of Abi-1 is sufficient for initiation of bone marrow fibrosis, and that Abi-1-SFKs-NFκB cross-talk may represent a new molecular target for the treatment of PMF. Bone marrow-specific, conditional Abi-1 KO animals represent a new model of PMF offering a unique opportunity to interrogate the molecular details of the Abi-1-driven mechanism that leads to the development of stem cell-derived MPNs, and to elucidate potential novel therapeutic approaches that directly address their pathogenesis. Disclosures Olszewski: Bristol-Myers Squibb: Consultancy; Genentech: Research Funding; TG Therapeutics: Research Funding. Reagan:Alexion: Honoraria; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.
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&NA;. "ABI 007." Drugs in R & D 4, no. 5 (2003): 303–5. http://dx.doi.org/10.2165/00126839-200304050-00004.
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&NA;. "ABI 007." Drugs in R & D 5, no. 3 (2004): 155–59. http://dx.doi.org/10.2165/00126839-200405030-00003.
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Zhou, Weihua, Angelica Lin, Zitong Zhao, John Yang, Kari Wilder-Romans, Jie Xu, Sumeet Solanki, et al. "Abstract 3498: GTP-dependent signaling links metabolism, non-homologous end joining and treatment responses in cancer and normal tissues." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3498. http://dx.doi.org/10.1158/1538-7445.am2023-3498.
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Abstract Introduction/Objectives: Purines regulate DNA repair in brain tumors through uncertain mechanisms. We sought to define the mechanisms by which purines regulate DNA repair and therapy response. Methods: Crispr/Cas9, siRNA, and CDNA overexpression and immunoblot were used to modulate and confirm protein levels. γ-H2AX and Rad51 foci were enumerated using immunofluorescence. Fluorescent reporter assays were performed to detect DNA repair activity. Phosphoproteomics was used to identify GTP-dependent (de)phosphorylation events after RT and antibodies generated against novel sites. Celltiter-glo or clonogenic assay were performed to evaluate drug/RT responses. IHC was used to detect protein expression. Animal models of glioblastoma and normal tissue (irradiation of GI system) were used to assess DNA repair and treatment responses in vivo. Results: Pharmacogenomic inhibition of GTP (but not ATP) synthesis sensitized GBM cells to RT, slowed the repair of RT-induced DSBs and inhibited the activity of non-homologous end joining (NHEJ), but not homologous recombination (HR). These effects could be rescued by GTP (but not ATP) supplementation. We found a GTP-dependent RT-induced dephosphorylation event on Abl interactor 1 (Abi-1) serine 323 (S323) using phosphoproteomics. We generated a new antibody for p-Abi-1 (S323), validated its specificity, and confirmed that RT causes a GTP-dependent dephosphorylation of Abi-1 (S323). Knockout of Abi-1 slowed RT-induced DSB repair and this was rescued by re-expression of dephosphomimetic Abi-1 (S323A) but not phosphomimetic Abi-1 (S323D). Abi-1 canonically binds to the small GTP-activated protein Rac1. Expression of constitutively active Rac1 promoted the dephosphorylation of Abi-1 (S323) and DSB repair while these effects were blocked by dominant negative Rac1. Pharmacogenomic inhibition of protein phosphatase 5 reversed the GTP- and Rac1-mediated dephosphorylation of Abi-1 and DSB repair. These findings have therapeutic relevance. In GBM PDX samples, levels of p-Abi-1 (S323) negatively correlated with Rac1 activity and predicted favorable efficacy of genotoxic treatments. In orthotopic GBM mouse models, inhibition of Rac1 enhanced RT responses and suppressed Abi-1 S323 dephosphorylation. Abi-1 knockout enhanced efficacy of numerous genotoxic treatments and could be rescued by Abi-1 S323A (but not Abi-1 S323D) re-expression. This regulation is generalizable beyond brain cancer, as GTP supplementation promoted DNA repair and p-Abi1 (S323) dephosphorylation in normal astrocytes and enteroids and protected mice from RT-mediated gastrointestinal injury. Conclusions: GTP promotes DNA repair by activating Rac1 and PP5 to dephosphorylate Abi-1 and stimulate NHEJ. Disrupting this regulation could improve brain tumor treatment responses while augmenting it could help protect normal tissues from genotoxic injury. Citation Format: Weihua Zhou, Angelica Lin, Zitong Zhao, John Yang, Kari Wilder-Romans, Jie Xu, Sumeet Solanki, Jing Li, Annabel Yang, Andrew Scott, Ayesha Kothari, Erik Peterson, Navyateja Korimerla, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra Obrien, Sean Ferris, Shuang Zhao, Jann N. Sarkaria, Meredith Morgan, Theodore S. Lawrence, Costas A. Lyssiotis, Yatrik Shah, Daniel R. Wahl. GTP-dependent signaling links metabolism, non-homologous end joining and treatment responses in cancer and normal tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3498.
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Roblin, Patricia M., Tamara Reznik, Andrei Kutlin, and Margaret R. Hammerschlag. "In Vitro Activities of Rifamycin Derivatives ABI-1648 (Rifalazil, KRM-1648), ABI-1657, and ABI-1131 against Chlamydia trachomatis and Recent Clinical Isolates of Chlamydia pneumoniae." Antimicrobial Agents and Chemotherapy 47, no. 3 (March 2003): 1135–36. http://dx.doi.org/10.1128/aac.47.3.1135-1136.2003.
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ABSTRACT ABI-1648 (rifalazil) is a semisynthetic rifamycin with potent bactericidal activity against intracellular respiratory bacteria, including Mycobacterium tuberculosis, and a long half-life (∼60 h) and thus can be administered once weekly. We therefore tested the in vitro activities of ABI-1648, its derivatives ABI-1657 and ABI-1131, azithromycin, and levofloxacin against 10 strains of Chlamydia trachomatis and 10 recent clinical isolates of Chlamydia pneumoniae. The MICs at which 90% of the isolates were inhibited and the minimal bactericidal concentration at which 90% of the isolates were killed for ABI-1648, ABI-1657, and ABI-1131 were 0.0025 μg/ml for C. trachomatis and 0.00125 to 0.0025 μg/ml for C. pneumoniae. ABI-1648, ABI-1657, and ABI-1131 were 10- to 1,000-fold more active than azithromycin and levofloxacin.
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Wohlfahrt, Peter, Daniel Palouš, Michaela Ingrischová, Alena Krajčoviechová, Jitka Seidlerová, Markéta Galovcová, Jan Bruthans, et al. "A high ankle-brachial index is associated with increased aortic pulse wave velocity: the Czech post-MONICA study." European Journal of Cardiovascular Prevention & Rehabilitation 18, no. 6 (March 1, 2011): 790–96. http://dx.doi.org/10.1177/1741826711398840.
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Background: Ankle brachial index (ABI) has been increasingly used in general practice to identify individuals with low ABI at high cardiovascular risk. However, there has been no consensus on the clinical significance of high ABI. The aim of our study was to compare aortic stiffness as a marker of cardiovascular risk in individuals with low (<1.0), normal (1.0–1.4), and high ABI (>1.4). Methods: A total of 911 individuals from the Czech post-MONICA study (a randomly selected 1% representative population sample, aged 54 ± 13.5 years, 47% of men) were examined. ABI was measured using a handheld Doppler and aortic pulse wave velocity (aPWV) using the Sphygmocor device. Results: Of the 911 individuals, 28 (3.1%) had low ABI and 23 (2.5%) high ABI. There was a U-shaped association between aPWV and ABI. aPWV was significantly higher in individuals with low and high ABI compared with the normal ABI group (11.1 ± 2.8, 8.3 ± 2.3, p < 0.001; 10.8 ± 2.5, 8.3 ± 2.3 m/s, p < 0.001, respectively). In a model adjusted for age, sex, systolic, diastolic, mean blood pressure and examiner, aPWV remained increased in both extreme ABI groups compared with the normal ABI group. In logistic regression analysis, aPWV together with glucose level, male sex, and a history of deep venous thrombosis were independent predictors of high ABI, while cholesterol was not. Conclusion: This is the first study showing increased aortic stiffness in individuals with high ABI, presumably responsible for increased left ventricular mass described previously in this group. These findings suggest increased cardiovascular risk of high ABI individuals.
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Tehan, Peta Ellen, Alex Louise Barwick, Mathew Sebastian, and Vivienne Helaine Chuter. "Diagnostic accuracy of the postexercise ankle–brachial index for detecting peripheral artery disease in suspected claudicants with and without diabetes." Vascular Medicine 23, no. 2 (February 12, 2018): 116–25. http://dx.doi.org/10.1177/1358863x17751259.
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The postexercise ankle–brachial index (ABI) is recommended in patients with normal resting ABI when peripheral artery disease (PAD) is suspected. The aims of this study were to determine the comparative diagnostic accuracy of the resting and postexercise ABI for detecting PAD, and, the effect of the presence of diabetes on these. Three methods of interpretation currently in use were also investigated: a reduction in postexercise ABI by >20% compared to resting ABI, an ABI value of ≤0.90 postexercise, or a reduction in systolic ankle pressure of >30 mmHg postexercise. This retrospective study used colour duplex ultrasound (CDU) as the reference standard. In 278 limbs (whole group), the resting ABI had an overall area under the curve (AUC) of 0.71, with the postexercise ABI yielding a similar diagnostic accuracy of AUC 0.72. In the non-diabetes group ( n=171), the resting ABI had an overall AUC of 0.74 and the postexercise ABI had a similar AUC of 0.76. In the diabetes group ( n=107), overall accuracy was reduced compared to the non-diabetes group, with the resting ABI having an overall AUC of 0.65 and the postexercise ABI yielding a similar accuracy with an AUC of 0.64. The overall diagnostic accuracy of the postexercise ABI for diagnosing PAD was not greatly improved compared to resting ABI. Given the lower overall diagnostic accuracy in the diabetes group, both the resting and the postexercise ABI results in diabetes populations should be interpreted with caution. There is a risk of undiagnosed disease if relying on these results alone to determine lower limb vascular status.
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Echarri, Asier, Margaret J. Lai, Matthew R. Robinson, and Ann Marie Pendergast. "Abl Interactor 1 (Abi-1) Wave-Binding and SNARE Domains Regulate Its Nucleocytoplasmic Shuttling, Lamellipodium Localization, and Wave-1 Levels." Molecular and Cellular Biology 24, no. 11 (June 1, 2004): 4979–93. http://dx.doi.org/10.1128/mcb.24.11.4979-4993.2004.
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ABSTRACT The Abl interactor 1 (Abi-1) protein has been implicated in the regulation of actin dynamics and localizes to the tips of lamellipodia and filopodia. Here, we show that Abi-1 binds the actin nucleator protein Wave-1 through an amino-terminal Wave-binding (WAB) domain and that disruption of the Abi-1-Wave-1 interaction prevents Abi-1 from reaching the tip of the lamellipodium. Abi-1 binds to the Wave homology domain of Wave-1, a region that is required for translocation of Wave-1 to the lamellipodium. Mouse embryo fibroblasts that lack one allele of Abi-1 and are homozygous null for the related Abi-2 protein exhibit decreased Wave-1 protein levels. This phenotype is rescued by Abi-1 proteins that retain Wave-1 binding but not by Abi-1 mutants that cannot bind to Wave-1. Moreover, we uncovered an overlapping SNARE domain in the amino terminus of Abi-1 that interacts with Syntaxin-1, a SNARE family member. Further, we demonstrated that Abi-1 shuttles in and out of the nucleus in a leptomycin B (LMB)-dependent manner and that complete nuclear translocation of Abi-1 in the absence of LMB requires the combined inactivation of the SNARE, WAB, and SH3 domains of Abi-1. Thus, Abi-1 undergoes nucleocytoplasmic shuttling and functions at the leading edge to regulate Wave-1 localization and protein levels.
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Peltonen, Essi, Mirjami Laivuori, Damir Vakhitov, Päivi Korhonen, Maarit Venermo, and Harri Hakovirta. "The Cardiovascular-Mortality-Based Estimate for Normal Range of the Ankle–Brachial Index (ABI)." Journal of Cardiovascular Development and Disease 9, no. 5 (May 5, 2022): 147. http://dx.doi.org/10.3390/jcdd9050147.
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Background: The ankle–brachial index (ABI) is a first-line examination in cardiovascular risk evaluation. Since cut-off values for normal ABI vary, the aim of the present study was to identify the cardiovascular-mortality-based estimate for the normal range of the ABI. After determining the reference range for the ABI, the corresponding toe–brachial index (TBI) and toe pressure for normal ABI were analyzed. Methods: All consecutive non-invasive pressure measurements in the vascular laboratory of a large university hospital 2011–2013 inclusive were collected and combined with patient characteristics and official dates and causes of death. Patients with an ABI range of 0.8–1.4 on both lower limbs were included in this study. Results: From 2751 patients, 868 had bilateral ABI values within the inclusion. Both ABI category ranges 0.80–0.89 and 0.90–0.99 had poorer survival compared to ABI categories 1.00–1.29 (p < 0.05). The 1-, 3-, and 5-year cardiovascular-death-free survival for respective ABI categories 0.80–0.99 vs. 1.00–1.29 were 90% vs. 96%, 84% vs. 92%, and 60% vs. 87%. The 1-, 3-, and 5-year overall survival for ABI categories 0.80–0.99 vs. 1.00–1.29 were 85% vs. 92%, 75% vs. 83%, and 42% vs. 74%. Conclusions: Borderline ABI (0.90–0.99) associates with higher overall and cardiovascular mortality compared to ABI values 1.00–1.29.
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Yerra, Suresh, Shravan Kumar, Indrani Garre, and Achukatla Kumar. "Correlation between Ankle Brachial Index with Coronary Artery Disease and Gender." Indian Journal of Cardiovascular Disease in Women WINCARS 03, no. 04 (December 2018): 231–36. http://dx.doi.org/10.1055/s-0039-1681127.
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Abstract Background Ankle brachial index (ABI) has been shown to be a specific and sensitive for the diagnosis of peripheral artery disease (PAD). Both PAD and coronary artery disease (CAD) are caused by atherosclerosis, which is a narrowing of the arteries due to the build-up of plaque and fatty material inside the lumen. The aim of our study is to find out the relation between ABI and coronary angiographic findings with cardiovascular risk factors and gender in patients admitted in a tertiary care center with a provisional diagnosis of CAD. Methods It is a cross-sectional observational study, in which patients admitted with suspected CAD are included. In this study, patient characteristics such as demographics, family history, past history of CAD, and other comorbidities were included, and also the risk factors for atherosclerosis such as hypertension, diabetes, dyslipidemia, and smoking history were enquired by using a predetermined proforma. In all study patients, ABI was measured prior to coronary artery angiogram (CAG). ABI ≤ 0.9 was considered as PAD, and ABI between 0.9 and 1.4 was considered as normal. Then, all patients included in the study underwent CAG. The results of the ABI reports were compared with the angiographic findings and atherosclerotic risk factors. Results In this study, 90 patients were included who were admitted for CAG. Twenty-two patients have ABI ≤ 1.09 among them, 9 patients have no CAD, and 13 patients have CAD on CAG. Sixty-eight patients have ABI ≥ 1.10, with 28 patients having no CAD and 40 patients having CAD. There is difference in the right and left mean ABI with right ABI less than left ABI, and it is statistically significant (p = 0.014). By binary logistic regression, the determinants of CAD are left ventricle ejection fraction (EF) and age, and ABI was not a predictor. In our study, out of 90 patients, only 1 had ABI < 0.9 (1.1%). Therefore, it is not worth doing ABI in all patients undergoing CAG to rule out peripheral vascular disease (PVD). This is true in male and female patients and even in the diabetics. In comparing male and female ABI, there is no significance between ABI in both the sexes. Conclusion This study findings concluded that ABI is not a useful method in assessing the risk factors and the severity of CAD in suspected patients. Only left ventricle EF and age were the predictors of the presence of CAD, and ABI was not a predictor. This study have shown the difference in the right and left mean ABI with right ABI less than left ABI, which is an important finding. This study has also shown the similar prevalence of ABI in both sexes. However, to make more accurate results on ABI (right vs. left), we should plan studies with larger sample size in future.
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Dorff, Tanya B., David I. Quinn, Jacek K. Pinski, Amir Goldkorn, Sarmad Sadeghi, Denice Tsao-Wei, Susan G. Groshen, Peter Kuhn, and Mitchell E. Gross. "Randomized phase II trial of abiraterone +/- dasatinib for patients with metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 167. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.167.
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167 Background: Signaling via Src pathway is thought to be a mediator of resistance to androgen targeted therapy in mCRPC. We sought to determine whether adding the Src inhibitor dasatinib (Das) to abiraterone (Abi) would prolong progression free survival (PFS). Methods: Eligible patients had mCRPC which had progressed on androgen targeted therapies but no prior chemotherapy. Abi was prescribed at 1000 mg daily with prednisone 5 mg BID (both arms) and Das 100 mg daily added for Arm B. Primary endpoint was PFS at 24 weeks. Interim analysis planned after 48 subjects randomized but study terminated early due to lack of funding. PFS was evaluated using logrank testing and responses were compared using Fisher’s exact test. Circulating tumor cells (CTC) were evaluated with EPIC platform. Results: 26 men were randomized, 14 to Abi+Das and 12 to Abi. Median age was 67 (56-85), baseline PSA 19.8 (0.84-1387). Only 1 patient had received ketoconazole, none had received enzalutamide. With 30 months median follow-up, median PFS was 15.7 (95% CI:8.2, 31.1+) months for Abi+Das and 9 (95% CI: 4.4, 45.6+) months for Abi (p = 0.30). 86% were progression free at 24 weeks with Abi+Das compared to 75% on Abi. RECIST responses were seen in 5/14 (35%, 95% CI: 17%, 66%) with 2 CR on Abi+Das and 1/12 (8%, 95% CI (0%, 37%) on Abi (p = 0.16). With a specificity of 83%, the probability that the true rate of CR in intervention arm is higher or doubled (ex: 35% vs 17%) is 71%. Grade > 3 toxicities more common on Das arm included hypertension (43% vs 8% Abi), pleural effusion/dyspnea (14% vs 0 Abi), and gastrointestinal (25% vs 8%). CTC were detected at baseline in 8/17 evaluable patients (3/8 Abi, 5/9 Abi+Das), median 2.7 CTC/mL blood (range 0.5-59.7) At week 4, CTC increased in 1/8 (12.5%) on Abi vs 4/9 (44.4%) on Abi+Das but by week 12 CTC increases persisted in 2/8 (25%) on Abi and 1/9 (11%) on Abi+Das. Conclusions: Das did not significantly prolong PFS in combination with Abi although power was limited due to incomplete study cohort. Abi+Das was associated with robust objective responses including RECIST CR. Clinical trial information: NCT01685125.
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Sekulic, Dragan, Aleksandar Tomic, Andreja Dimic, Aleksandar Mitrovic, Lazar Davidovic, Dragana Paunovic, Dalibor Nikolic, et al. "Virtual ankle-brachial index - Can we predict the immediate outcome of femorodistal bypass surgery?" Vojnosanitetski pregled, no. 00 (2023): 33. http://dx.doi.org/10.2298/vsp230516033s.
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Background/Aim. The best treatment for the occlusion of the largest artery in the thigh is a femorodistal (FD) bypass. Ankle-brachial index (ABI) and multi-detector computed tomographic (MDCT) angiography are the gold standards for diagnosing peripheral arterial occlusive disease. The finite element method can help measure the quantity of blood flow and arterial pressure in the arteries in the leg. The aim of this study was to examine the possibility of using finite element analysis (FEA) method in predicting the outcome of FD bypass surgery. Methods. The research involved 45 patients who were indicated for FD arterial reconstruction from December 1, 2021, to March 31, 2023. MDCT angiography of the arteries of the lower extremities was done pre-operatively and post-operatively in all patients, based on which models were made using the finite element method, for measurement ABI. All patients had their ABI measured pre-operatively and post-operatively using the Doppler ultrasound and sphygmomanometer. Based on the findings of the pre-operative MDCT angiography, a post-operative virtual surgical model was made using the finite element method, for measurement of ABI too. The values of ABI were divided into 5 groups: ABI measured preoperatively (ABI pre-op), ABI measured postperatively (ABI post-op), ABI measured on FEA models based on the MDCT findings [ABI (sim) pre-op], ABI sim post-op, ABI measured on virtual surgery model [ABI sim post-op (virtual)]. The ABI of the models were statistically compared with pre-operative and post-operative measurements done on patients. Results. The values based on the virtual ABI model did not show significant differences compared to the values obtained using Doppler sonography /sphygmomanometer and MDCT angiography (p< 0.001). A strong statistically significant correlation was shown between the virtual ABI and the values obtained by the other two methods (p< 0.001). Conclusion. Virtual simulation based on the MDCT angiography parameters of peripheral blood vessels can be successfully used to predict the immediate outcome of the FD bypass surgery.
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Jahn, Jürgen, Werner Zimmermann, Theodoros Moysidis, and Knut Kröger. "Ankle brachial index and pneumoplethysmographic pulse-volume recordings for detection of peripheral arterial disease." Vasa 43, no. 3 (May 1, 2014): 202–8. http://dx.doi.org/10.1024/0301-1526/a000350.
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Background: The measurement of the ankle-brachial index (ABI) is a straightforward method for the detection of atherosclerosis in the lower limbs. Pneumoplethysmographic pulse-volume recordings (PVR) investigations are supposed to be less valid. Thus we compared the sensitivity of ABI and PVR in detection of PAD and its improvement by combining both methods. Patients and methods: 122 consecutive patients admitted for PAD treatment were included. All patients (81 females; mean age 70 ± 15 years) had angiographic imaging of their peripheral arteries, a standardized personal interview and a determination of the ABI based on the highest (ABI high) and lowest (ABI low) ankle pressure. PVR parameters were oscillometric index (OI) and time to normalisation (TN) after exercise. Results: There was a small variation of ABI with different segmental manifestations of PAD. The OI did not vary with different segmental manifestations. TN was longest in iliac artery manifestation and got shorter with more distal manifestation. Correlation of TN and ABI high and ABI low was low. Sensitivity of ABI high in all legs was 78 %, but only 40 % in isolated crural manifestation. ABI low has higher sensitivities with 87 % in all legs, but a much lower specificity. Combining ABI and TN increases both sensitivity and specificity. The best sensitivity and specificity was seen using ABI low + TN in combination in all kinds of manifestations with 94 % and 96 %, respectively. Conclusions: Combined assessment of ABI low and TN in post-exercise PVR seems to be a highly sensitive but also specific method to look for PAD compared to ABI high alone.
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Chaudru, Ségolène, Pierre-Yves de Müllenheim, Alexis Le Faucheur, Vincent Jaquinandi, Adrien Kaladji, and Guillaume Mahe. "Knowledge about ankle-brachial index procedure among residents: being experienced is beneficial but is not enough." Vasa 45, no. 1 (February 2016): 37–41. http://dx.doi.org/10.1024/0301-1526/a000493.
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Abstract. Background: Ankle-brachial index (ABI) at rest is the main clinical tool to diagnose the presence of lower extremity peripheral artery disease (PAD). The method for ABI procedure (i.e., measurement, calculation and interpretation) is standardised and guidelines were published in 2012. This study sought to: i) assess knowledge about the three major steps of the ABI procedure (i.e., measurement, calculation and interpretation) among residents from different medical schools, ii) compare the ABI knowledge of experienced residents (i.e., who have already performed ABI procedure more than 20 times) with the knowledge of inexperienced residents, and iii) describe the most common errors by residents. Methods: Residents from six medical schools were invited to complete a questionnaire about the ABI procedure. Results: Sixty-eight residents completed the questionnaire. None of them knew how to perform the entire ABI procedure. Overall, 22 %, 13 % and 41 % of residents correctly answered questions about ABI measurement, ABI calculation and ABI interpretation, respectively. Score comparisons underlined the fact that experienced residents (n = 26) answered ABI measurement questions to a significantly better level and had a significantly higher total score than inexperienced residents (n = 42) (P = 0.0485 and P = 0.0332, respectively). Errors were similar for most of the residents. Conclusions: Our study confirms that experienced residents have significantly better ABI procedure knowledge than inexperienced residents. However, none of them are able to perform the entire ABI procedure without any mistake with regard to current guidelines. It is important that training be given to residents in medical schools in order to improve their ABI procedure knowledge.
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Emamekhoo, Hamid, Mohammad Alyamani, Zhenfei Li, Paul Elson, Petros Grivas, Brian I. Rini, Marianne Petro, et al. "The association of D4, 3-keto-abi (D4A) and response to abiraterone in castration-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 34, no. 2_suppl (January 10, 2016): 245. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.245.
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245 Background: Abiraterone (Abi), a potent inhibitor of 17α-hydroxylase/17,20-lyase (CYP17A1), is a standard treatment for men with metastatic CRPC. Abi is converted to D4A by 3β-hydroxysteroid dehydrogenase (3βHSD). D4A inhibits CYP17A1, 3βHSD, and steroid-5α-reductase (SRD5A) and has direct androgen receptor antagonist activity, which together make it a more potent agent than Abi in xenograft models. It is not known if conversion to D4A in patients (pts) correlates with response or resistance to Abi. Methods: Blood was collected (single time point on Abi) from CRPC pts who started Abi during 2011-2015. Abi and D4A were extracted from serum and analyzed by mass spectrometry. The purpose of this ongoing study is to assess the potential correlation between D4A and response to treatment. Results: 32 patients with CRPC had blood collected. 4 pts (12.5%) received ketoconazole and 6 (18.8%) chemotherapy prior to Abi. Median pre-Abi prostate-specific antigen (PSA) was 14.3 ng/ml (0.6-646.1). Median time from initiation of androgen deprivation therapy (ADT) to CRPC was 34.3 months (m) (6-129.6) and median time from CRPC to Abi initiation was 4.8 m (0-14.9). PSA decline > 50% (PSA50) on Abi was seen in 68% (12/31) and 73% (19/26) of pts at 3 and 6 m, respectively. Treatment with Abi was ongoing in 23/32 pts (74%), and discontinued in 8 pts (26%) due to disease progression (no follow up data on 1 pt) with median duration of Abi treatment 14.6 m (2.9-44.4 m) at last follow up. As the absolute concentration of detected levels of Abi and D4A varied significantly among pts, the percentage of the total extracted metabolites was used to assess correlation with response. Abi and D4A comprised 94.3% (73.8-97.4%) and 5.7% (2.6-26.2%), respectively, of total levels. Conclusions: Abi absorption and metabolism significantly vary among pts. Most of these pts had prolonged duration of response to Abi (74% ongoing treatment and median treatment duration 13.3 m in 8 pts that came off treatment). Longer follow up, accrual of pts with shorter duration of response, and sampling at multiple time points on Abi and at progression is ongoing to further evaluate the impact of D4A on treatment response.
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Lowentritt, Benjamin H., Carmine Rossi, Shawn Du, Erik Muser, Frederic Kinkead, Dexter Waters, Patrick Lefebvre, Dominic Pilon, and Neeraj Agarwal. "Real-world time-to-castration resistance (CR) among patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) initiating apalutamide (APA), enzalutamide (ENZ), or abiraterone acetate (ABI) from an oncology database." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 65. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.65.
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65 Background: CR is an important clinical indicator of disease progression and worsening overall survival among pts with mCSPC. This study describes real-world time-to-CR progression in an oncology setting among pts with mCSPC who initiated APA, ENZ, or ABI in the United States. Methods: Clinical data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry Electronic DataMart (1/1/2013 – 07/31/2022) were evaluated. Metastatic pts without evidence of CR before initiating a next-generation androgen inhibitor (AAI) were classified into exclusive treatment cohorts based on the start date (index date) for APA, ENZ, or ABI. CR was identified by a Flatiron algorithm searching for: 1) mention of CR in patient charts, 2) rising prostate-specific antigen (PSA) levels documented from laboratory testing, or 3) mention of rising PSA while on hormonal therapy from unstructured data sources. Pts had ≥12 months (mo) of clinical data pre-index date and were followed from the index date until the end of clinical activity (including death) or data availability. The proportion of pts developing CR was described separately for each cohort using Kaplan-Meier analysis up to 24 mo post-index, with no adjustment for baseline confounders. CR progression rates in the current analysis were descriptively compared to those observed in Phase 3 trials where available. Results: A total of 155 APA, 385 ENZ and 711 ABI pts were evaluated. Mean age at index was ~73 years in each group. Mean follow-up was 12.8 mo (APA), 13.4 mo (ENZ) and 20.6 mo (ABI). Use of androgen deprivation therapy prior to initiation of AAI was observed in ~85% of pts. The median time between documented metastasis and the index date was 2.3 mo (APA), 2.8 mo (ENZ), and 2.3 mo (ABI). Progression rates to CR are shown. By 24 mo, the median time-to-CR was not reached with any treatment studied. By 24 mo, progression to CR was observed in 26% of APA pts in this analysis (32% in TITAN); 36% of ENZ pts in this analysis (25% in ARCHES); and 33% of ABI pts in this analysis (progression to CR not reported in LATITUDE). Conclusions: In this real-world database, the observed proportions of pts progressing to CRPC for the APA and ENZ cohorts were generally consistent with results of Phase 3 trials and include a small proportion of pts with early progression to CRPC. Increased physician awareness of the benefits of early initiation of an AAI along with identification of baseline biomarkers associated with early progression to CRPC may improve clinical outcomes. [Table: see text]
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Taki, Tomohiko, Noriko Shibuya, Masafumi Taniwaki, Ryoji Hanada, Kazuhiro Morishita, Fumio Bessho, Masayoshi Yanagisawa, and Yasuhide Hayashi. "ABI-1, a Human Homolog to Mouse Abl-Interactor 1, Fuses theMLL Gene in Acute Myeloid Leukemia With t(10;11)(p11.2;q23)." Blood 92, no. 4 (August 15, 1998): 1125–30. http://dx.doi.org/10.1182/blood.v92.4.1125.
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Abstract Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) andCALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes asrc homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL. © 1998 by The American Society of Hematology.
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Taki, Tomohiko, Noriko Shibuya, Masafumi Taniwaki, Ryoji Hanada, Kazuhiro Morishita, Fumio Bessho, Masayoshi Yanagisawa, and Yasuhide Hayashi. "ABI-1, a Human Homolog to Mouse Abl-Interactor 1, Fuses theMLL Gene in Acute Myeloid Leukemia With t(10;11)(p11.2;q23)." Blood 92, no. 4 (August 15, 1998): 1125–30. http://dx.doi.org/10.1182/blood.v92.4.1125.416k40_1125_1130.
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Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) andCALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes asrc homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL. © 1998 by The American Society of Hematology.
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Schweizer, Michael Thomas, Xian Chong Zhou, Hao Wang, Sunakshi Bassi, Michael Anthony Carducci, Mario A. Eisenberger, and Emmanuel S. Antonarakis. "The effect of prior abiraterone (Abi) treatment on subsequent response to docetaxel in men with castrate resistant prostate cancer (CRPC)." Journal of Clinical Oncology 32, no. 4_suppl (February 1, 2014): 136. http://dx.doi.org/10.1200/jco.2014.32.4_suppl.136.
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136 Background: Taxanes are hypothesized to mediate their effect in CRPC, at least in part, by disrupting androgen receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen-directed agents (e.g., Abi) and Tax. Methods: We retrospectively evaluated Tax efficacy in CRPC patients (N=119) who did (Abi+Tax; n=24) or did not (Tax; n=95) receive prior Abi. To ensure a contemporaneous control group, this analysis only included men who started Tax between 12/2007 (the date we began using Abi at our center) and 5/2013. Univariate and propensity score-weighted multivariable analyses for PSA progression-free survival (PSA-PFS) and all-cause progression-free survival (PFS) were conducted to evaluate the effect of prior Abi on responses to Tax. Results: Men in the Abi+Tax group had a significantly higher risk of progression than those in the Tax group. In univariate analysis, PSA-PFS was shorter in the Abi+Tax group (HR 2.00; 95%CI 1.13–3.52; P=0.016), as was PFS (HR 1.97; 95%CI 1.13–3.41; P=0.016). Median PSA-PFS was 4.1 mo in the Abi+Tax group and 6.3 mo in the Tax group (P=0.014). Median PFS was also shorter in the Abi+Tax group (4.1 vs 6.8 mo; P=0.014). In multivariable analysis, prior Abi treatment remained a predictor of shorter PSA-PFS and PFS (Table). PSA declines ≥50% were also less frequent in the Abi+Tax group (37% vs 63%, P=0.04). Conclusions: Men receiving Abi prior to Tax were more likely to develop progression on Tax (and less likely to have a PSA response) than Abi-naive patients. Cross-resistance between Abi and Tax may limit taxane efficacy in Abi-pretreated patients. [Table: see text]
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Singh, Siddharth, Kent R. Bailey, Amit Noheria, and Iftikhar J. Kullo. "Frailty Across the Spectrum of Ankle-Brachial Index." Angiology 63, no. 3 (July 6, 2011): 229–36. http://dx.doi.org/10.1177/0003319711413457.
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We investigated the burden of frailty across the spectrum of ankle-brachial index (ABI < 0.9, 0.9 ≤ ABI < 1.1, 1.1 ≤ ABI < 1.4 and ≥1.4) using data from the National Health and Nutritional Examination Survey (NHANES) in respondents aged >50 years. Criteria used to identify frailty status included weight loss, slow walking speed, weakness, exhaustion, and low physical activity. Participants meeting 1 to 2 criteria were classified as prefrail, and those meeting ≥3 criteria were classified as frail. Prevalence of frailty in respondents with ABI < 0.9 (17.5%) and 0.9 ≤ ABI < 1.1 (6.7%) was higher than in participants with normal ABI-1.1 ≤ ABI < 1.4 (4.7%). In multivariable multinomial logistic regression models, ABI < 0.9 predicted frailty (odds ratio [OR] = 2.31, 95% confidence interval [CI] = 1.08-4.94) and prefrailty (OR = 1.36, 95% CI = 0.90-2.07). Higher prevalence of frailty was seen in participants with ABI ≥ 1.4 (7.3%), P = .39. Frailty predicted general and cardiovascular mortality in participants with ABI < 0.9. Frailty mediates increased morbidity and mortality seen in peripheral arterial disease (PAD).
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Attard, Gerhardt, Michael Borre, Howard Gurney, Yohann Loriot, Corina Andresen, Ranjith Kalleda, Trinh Pham, and Mary-Ellen Taplin. "A phase IV, randomized, double-blind, placebo (PBO)-controlled study of continued enzalutamide (ENZA) post prostate-specific antigen (PSA) progression in men with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 5004. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.5004.
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5004 Background: We hypothesized resistance to the androgen receptor inhibitor ENZA is due to increases in androgens and can be overcome by combination with the androgen synthesis inhibitor abiraterone (abi). The phase 4 PLATO trial (NCT01995513) is evaluating the safety and efficacy of continued ENZA + abi/prednisone (abi/P) vs PBO + abi/P after PSA progression on ENZA. Methods: In Period (P) 1, men with chemotherapy-naïve mCRPC received ENZA (160 mg); men with no PSA increase from baseline at wk 13 and 21 continued treatment until PSA progression (≥ 25% increase and ≥ 2 ng/mL above nadir). Eligible men were then randomized 1:1 in P2 to ENZA + abi/P (1000 mg/10 mg) or PBO + abi/P. The primary endpoint (EP) was progression-free survival (PFS; radiographic or unequivocal clinical progression, or death on study) in P2, with a prespecified sensitivity analysis of radiographic PFS (rPFS); protected secondary EPs were time to PSA progression (TTPP) and PSA response ≥ 50% in P2. Results: 509 men enrolled in P1. At data cutoff (Oct 7, 2016), 84 were active, 174 discontinued, and 251 were randomized in P2 (ENZA + abi/P, n = 126; PBO + abi/P, n = 125). Median treatment duration in P2 was 5.6 mo for both arms. PFS event by radiographic/clinical/death was 38%/25%/2% for ENZA + abi/P and 55%/18%/1% for PBO + abi/P. Median PFS was 5.7 mo for ENZA + abi/P and 5.6 mo for PBO + abi/P (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.61, 1.12; P = 0.22). Median TTPP was 2.8 mo for both arms (HR, 0.87; 95% CI, 0.62, 1.24; P = 0.45). PSA response rate was 0.8% for ENZA + abi/P and 2.5% for PBO + abi/P ( P = 0.31). Median rPFS was 10.0 mo for ENZA + abi/P and 7.0 mo for PBO + abi/P (HR, 0.67; 95% CI, 0.47, 0.94; P = 0.02). The most common (≥ 15%) adverse events for ENZA + abi/P vs PBO + abi/P were back pain (21% vs 23%), hypertension (20% vs 7%), nausea (17% vs 9%), and fatigue (14% vs 15%). Conclusions: ENZA + abi/P post PSA progression on ENZA was associated with increased hypertension and nausea and did not result in a statistically significant improvement in composite PFS. The signal seen in rPFS needs further evaluation. Clinical trial information: NCT01995513.
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Terada, Naoki, Benjamin Louis Maughan, Shusuke Akamatsu, Takashi Kobayashi, Toshinari Yamasaki, Takahiro Inoue, Tomomi Kamba, Osamu Ogawa, and Emmanuel S. Antonarakis. "Exploring optimal sequence of abiraterone and enzalutamide in patients with castration-resistant prostate cancer: The Kyoto-Baltimore collaboration." Journal of Clinical Oncology 35, no. 6_suppl (February 20, 2017): 219. http://dx.doi.org/10.1200/jco.2017.35.6_suppl.219.
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219 Background: Abiraterone (ABI) and enzalutamide (ENZA) are novel hormonal treatments for castration-resistant prostate cancer (CRPC) used before and after docetaxel (DTX) chemotherapy. We aimed to evaluate and compare the efficacy of sequential treatment with ABI followed by ENZA or vice versa in patients with CRPC, using combined data from two institutions. Methods: We retrospectively evaluated data on 352 consecutive patients who had received both ABI and ENZA for CRPC at Kyoto University Hospital and at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. Using Kaplan-Meier analysis and log-rank tests, we compared PSA progression-free survival (PSA-PFS) and overall survival (OS) in patients treated with sequential ABI-to-ENZA versus ENZA-to-ABI without intervening therapies. Results: The number of patients receiving ABI-to-ENZA and ENZA-to-ABI were 163 (pre-DTX: 116, post-DTX: 47) and 189 (pre-DTX: 85, post-DTX: 104), respectively. The > 50% PSA response rates to ABI and ENZA were 47% and 52% in the first-line CRPC setting, and were 9% and 29% in the second-line setting. In the pre-DTX population, median PSA-PFS was not significantly different between ABI (median: 194 days) and ENZA (median: 126 days) in the first-line setting (p = 0.411), but there was an advantage favoring ENZA (median: 91 days) compared to ABI (median: 55 days) in the second-line setting (p = 0.008). Furthermore, the combined PSA-PFS was significantly longer in the ABI-to-ENZA sequence (median: 455 days) than in the ENZA-to-ABI sequence (median: 296 days) (p < 0.001). There was no statistical difference in OS between the two sequences (p = 0.598). Conclusions: The ABI-to-ENZA sequence may have more favorable efficacy in terms of combined PSA-PFS than the ENZA-to-ABI sequence, although no differences in OS were observed. This may possibly be attributable to higher PSA response rates and longer PSA-PFS to second-line ENZA compared to ABI (i.e., ENZA retains activity after ABI but not vice versa).
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Finkelstein, Ruth R., and Tim J. Lynch. "Overexpression of ABI5 Binding Proteins Suppresses Inhibition of Germination due to Overaccumulation of DELLA Proteins." International Journal of Molecular Sciences 23, no. 10 (May 16, 2022): 5537. http://dx.doi.org/10.3390/ijms23105537.
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Abscisic acid (ABA) and gibberellic acid (GA) antagonistically regulate many aspects of plant growth, including seed dormancy and germination. The effects of these hormones are mediated by a complex network of positive and negative regulators of transcription. The DELLA family of proteins repress GA response, and can promote an ABA response via interactions with numerous regulators, including the ABA-insensitive (ABI) transcription factors. The AFP family of ABI5 binding proteins are repressors of the ABA response. This study tested the hypothesis that the AFPs also interact antagonistically with DELLA proteins. Members of these protein families interacted weakly in yeast two-hybrid and bimolecular fluorescence complementation studies. Overexpression of AFPs in sleepy1, a mutant that over-accumulates DELLA proteins, suppressed DELLA-induced overaccumulation of storage proteins, hyperdormancy and hypersensitivity to ABA, but did not alter the dwarf phenotype of the mutant. The interaction appeared to reflect additive effects of the AFPs and DELLAs, consistent with action in convergent pathways.
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Liu, Longguang, Hongxiao Sun, Fengze Nie, and Xinhua Hu. "Prognostic Value of Abnormal Ankle–Brachial Index in Patients With Coronary Artery Disease: A Meta-Analysis." Angiology 71, no. 6 (March 13, 2020): 491–97. http://dx.doi.org/10.1177/0003319720911582.
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The prognostic value of the ankle–brachial index (ABI) in patients with coronary artery disease (CAD) remains undefined. This meta-analysis sought to investigate the association of abnormal ABI and adverse outcomes in patients with CAD. PubMed, Embase, China National Knowledge Infrastructure, VIP, and Wanfang databases were comprehensively searched for studies published from inception to September 10, 2019. All observational studies investigating the association of abnormal baseline ABI and risk of major adverse cardiovascular events (MACE) or all-cause mortality were selected. Normal ABI is usually defined as between 0.9 and 1.4. The prognostic values were summarized by pooling risk ratio (RR) with 95% confidence intervals (CIs) for abnormal versus normal ABI category. Nine (9384 patients with CAD) studies were included. Abnormal ABI was independently associated with MACE (RR: 2.46; 95% CI: 2.02-2.99) and all-cause mortality (RR: 1.74; 95% CI: 1.32-2.30). Subgroup analysis showed that the pooled RR for MACE was 2.34 (95% CI: 1.73-3.16) for an abnormal low ABI. Abnormal ABI predicts MACE and all-cause mortality in patients with CAD, even after adjusting conventional confounding factors. However, the prognostic value of abnormal ABI is mainly dominated by a low ABI rather than a high ABI.
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Agarwal, Vivek, Tejas Patel, and Sanjay Shah. "To Determine the Relation Between Ankle-Brachial Index with Angiographic Stenosis and Major Cardiovascular Risk Factors In Patients With Suspected Coronary Artery Disease." Journal of Medical Research and Innovation 2, S1 (June 4, 2018): e000138. http://dx.doi.org/10.15419/jmri.138.
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Aims and Objectives: Prevalence of low Ankle-Brachial Index (ABI) in patients with Ischaemic Heart Disease. To compare the relationship between various physiological parameters like age, sex, and BMI with ABI. To compare the relationship between low ABI and number of coronaries involved.
Methodology: Inclusion Criteria: All the 1423 patients aged 23-90 years including 1047 male and 376 female undergoing coronary angiography in VS hospital. Exclusion Criteria: Critically ill or who had severe limb ischemia or patients with amputation were excluded. Statistical analysis was done by using SPSS 20.0 version. Univariate analysis was performed by applying the Pearson chi-squared test.
Results: In this study, 1423 patients were evaluated out of which 66 (4.6%) patients had ABI<0.9. Out of 66 patients with low ABI 60 (91%) were male and 6 (9%) were female, showing high prevalence in the male. In patients having low ABI shows 12 (18.2%) have SVD, 11(16.7%) have DVD, 26(39.4%) have TVD, comparing this with patients having normal ABI, shows P value of 0.035 which is significant. 411 patients were diabetic including 40 (60.6%) patients having low ABI and 371 (27.3%) patients having normal ABI, shows P value of 0.000 which is highly significant.
Conclusion: ABI is helpful in identifying individuals at high risk of coronary involvement. Although the prevalence of low ABI in patients with IHD is 4.6% that is very low but is highly specific (91%). In patients with ischemic heart disease low ABI suggests the involvement of multivessel disease. Direct association between ABI and significant Coronary Artery Disease noted.
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Abboud, Halim, Linsay Monteiro Tavares, Julien Labreuche, Antonio Arauz, Alan Bryer, Pablo M. Lavados, Ayrton Massaro, et al. "Impact of Low Ankle-Brachial Index on the Risk of Recurrent Vascular Events." Stroke 50, no. 4 (April 2019): 853–58. http://dx.doi.org/10.1161/strokeaha.118.022180.
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Background and Purpose— Low ankle-brachial index (ABI) identifies a stroke subgroup with high risk of recurrent stroke, cardiovascular events, and death. However, limited data exist on the relationship between low ABI and stroke in low and middle-income countries. Therefore, we evaluated the prevalence of ABI ≤0.90 (which is diagnostic of peripheral artery disease) in nonembolic stroke patients or transient ischemic attack and assessed the correlation of low ABI with stroke risk, factors, and recurrent vascular events and death. Methods— Patients ≥45 years with acute transient ischemic attack or minor ischemic strokes were recruited consecutively from over 17 low-income and middle-income countries (Latin America [1543 patients], Middle East [1041 patients], North Africa [834 patients], and South Africa [217 patients]). The ABI measurement was performed at a single visit. Stroke recurrence and risk of new vascular events were assessed after 24 months of follow-up. Results— Among 3487 enrolled patients, abnormal ABI (<0.9) was present in 22.3 %. Patients with an ABI of ≤0.9 were more likely ( P <0.05) to be male, older, and have a history of peripheral artery disease, hypertension, and diabetes mellitus. During 2-year follow-up, the rate of major cardiovascular event was higher in patients with ABI <0.9 than those with ABI ≥0.9 (Kaplan-Meier estimates, 22.5%; 95% CI, 19.6–25.8 versus 13.7%; 21.4–15.1; P <0.001), and when ABI was categorized into 4 groups (≤0.6; 95% CI, 0.6–0.9; 0.9–1; 1–1.4), the rate of major cardiovascular event was higher in those with ABI ≤0.6 than the other groups (Kaplan-Meier estimates, 32.6%; 95% CI, 21.0–48.3 for ABI≤0.6 versus 21.7%; 95% CI, 18.8–25.0 for ABI 0.6–0.9 versus 14.3%; 95% CI, 12.4–16.6 for ABI 0.9–1 versus 13.3%; 95% CI, 11.6–15.2 for ABI 1–1.4; P <0.001). Conclusions— Among patients with nonembolic ischemic stroke or transient ischemic attack, those with low ABI had a higher rate of vascular events and death in this population. Screening for ABI in stroke patients may help identify patients at high risk of future events.
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Arenas-Huertero, Francisco, Analilia Arroyo, Li Zhou, Jen Sheen, and Patricia León. "Analysis of Arabidopsis glucose insensitive mutants, gin5 and gin6, reveals a central role of the plant hormone ABA in the regulation of plant vegetative development by sugar." Genes & Development 14, no. 16 (August 15, 2000): 2085–96. http://dx.doi.org/10.1101/gad.14.16.2085.
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Sugars have signaling roles in a wide variety of developmental processes in plants. To elucidate the regulatory components that constitute the glucose signaling network governing plant growth and development, we have isolated and characterized two Arabidopsisglucose insensitive mutants, gin5 and gin6, based on a glucose-induced developmental arrest during early seedling morphogenesis. The T-DNA-tagged gin6 mutant abrogates the glucose-induced expression of a putative transcription factor, ABI4, previously shown to be involved in seed-specific abscisic acid (ABA) responses. Thus, ABI4 might be a regulator involved in both glucose- and seed-specific ABA signaling. The characterization of thegin5 mutant, on the other hand, reveals that glucose-specific accumulation of ABA is essential for hexokinase-mediated glucose responses. Consistent with this result, we show that three ABA-deficient mutants (aba1-1, aba2-1, andaba3-2) are also glucose insensitive. Exogenous ABA can restore normal glucose responses in gin5 and aba mutants but not in gin6 plants. Surprisingly, only abi4 andabi5-1 but not other ABA-insensitive signaling mutants (abi1-1, abi2-1, and abi3-1) exhibit glucose insensitivity, indicating the involvement of a distinct ABA signaling pathway in glucose responses. These results provide the first direct evidence to support a novel and central role of ABA in plant glucose responses mediated through glucose regulation of both ABA levels by GIN5 and ABA signaling by GIN6/ABI4.
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Mostaghel, Elahe A., Rana R. McKay, Eunpi Cho, Zhenwei Zhang, Brett Marck, Alvin M. Matsumoto, Nima Sharifi, Mary-Ellen Taplin, Peter Nelson, and Robert B. Montgomery. "Association of serum androgen and drug levels with response to abiraterone." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 208. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.208.
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208 Background: The association of serum ABI and androgen levels with clinical efficacy in men with CRPC is not well understood. Methods: We measured androgens, ABI and its key metabolites (D4A and 5α) in serum at 4, 8, and 12 weeks (wks) in 29 men with CRPC treated with ABI (for associations with PSA response and time to radiographic progression (TTP)); in 58 men from a study of ABI without prednisone; and in 22 men with localized PCa treated with neoadjuvant ABI for 3 months prior to definitive therapy (including prostate levels). Results: Median (Med) TTP was 36 mo (4-104). 52% had a PSA response (decline >30% at wk12), and 34% early progression (TTP < 6 mo). There was no difference in ABI (at wk4 or average of wks 4/8/12) in men with v without PSA response, or in men with early v late TTP. D4A and 5α at wk4 were higher in early v late progressors (2.9 v 1.5 ng/ml, p=0.05; 10.35 v 6.7 ng/ml, p=0.08). TTP was longer in the lowest v highest quartile of drug levels (ABI: 4wk 48 v 30 wks; 8wk 60 v 16 wks; D4A: 4wk 40 v 16 wks; 8wk 60 v 28 wks; 5a: 8wk 41 v 16 wks, p<0.05 all). The lowest quartile of pre-ABI androgens had shorter TTP (DHEAS 24 v 52 wks; T 30 v 52 wks, p<0.05 both). In both CRPC studies, men with pre-ABI DHEAS > Med had 2-5x higher levels of all steroids (DHEAS 110 v 22 ug/dl, DHEA 184 v 49 ng/dl, AED 46 v 26 ng/dl, and T 9 v 4.9 ng/dl, p<0.05 all). While markedly suppressed by ABI in both groups, levels remained detectable and higher in the ‘high’ group (DHEAS 5.4 v 1.6 ug/dl; DHEA 1.3 v 0.6 ng/dl; p<0.05 both) regardless of ABI levels (37.4 ng/ml, 2.75-89; 36.8 ng/ml, 8.7-121, p=ns). Androgens in serum and prostate after neoadjuvant ABI were higher in men with pre-ABI eugonadal serum DHEAS levels > v < Med, regardless of serum or tissue ABI levels on treatment. Conclusions: In men with pre-ABI serum DHEAS < Med, androgens were suppressed even at low serum ABI levels, whereas in men with pre-ABI DHEAS > Med, levels were not completely suppressed even at high ABI levels, explaining the minimal impact of dose escalated ABI and observed noninferiority of low dose ABI previously reported in men with CRPC. The shorter TTP in the highest quartiles of ABI, D4A and 5α may reflect increased conversion to the AR agonist metabolite 5α. Men with pre-ABI DHEAS > Med may warrant stratification to more potent/combination therapy. Clinical trial information: NCT01503229.
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Saly, Lauren, Christine Provvidenza, Hiba Al-Hakeem, Andrea Hickling, Sara Stevens, Lisa Kakonge, Anne W. Hunt, Sheila Bennett, Rhonda Martinussen, and Shannon E. Scratch. "The Teach-ABI Professional Development Module for Educators About Pediatric Acquired Brain Injury: Mixed Method Usability Study." JMIR Human Factors 10 (May 15, 2023): e43129. http://dx.doi.org/10.2196/43129.
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Background Acquired brain injury (ABI) is a leading cause of death and disability in children and can lead to lasting cognitive, physical, and psychosocial outcomes that affect school performance. Students with an ABI experience challenges returning to school due in part to lack of educator support and ABI awareness. A lack of knowledge and training contribute to educators feeling unprepared to support students with ABI. Teach-ABI, an online professional development module, was created to enhance educators’ ABI knowledge and awareness to best support students. Using a case-based approach, Teach-ABI explains what an ABI is, identifies challenges for students with ABI in the classroom, discusses the importance of an individualized approach to supporting students with ABI, and describes how to support a student with an ABI in the classroom. Objective This study aims to assess the usability of and satisfaction with Teach-ABI by elementary school educators. The following questions were explored: (1) Can elementary school teachers use and navigate Teach-ABI?, (2) Are the content and features of Teach-ABI satisfactory?, and (3) What modifications are needed to improve Teach-ABI? Methods Elementary school educators currently employed or in training to be employed in Ontario elementary schools were recruited. Using Zoom, individual online meetings with a research team member were held, where educators actively reviewed Teach-ABI. Module usability was evaluated through qualitative analysis of think-aloud data and semistructured interviews, direct observation, user success rate during task completion, and the System Usability Scale (SUS) scores. The usability benchmark selected was 70% of participants performing more than half of module tasks independently. Results A total of 8 female educators participated in the study. Educators were classroom (n=7) and preservice (n=1) teachers from public (n=7) and private (n=1) school boards. In terms of task performance, more than 85% of participants (ie, 7/8) independently completed 10 out of 11 tasks and 100% of participants independently completed 7 out of 11 tasks, demonstrating achievement of the module usability goal. The average overall SUS score was 86.25, suggesting a high satisfaction level with the perceived usability of Teach-ABI. Overall, participants found Teach-ABI content valuable, useful, and aligned with the realities of their profession. Participants appreciated the visual design, organization, and varying use of education strategies within Teach-ABI. Opportunities for enhancement included broadening content case examples of students with ABI and enhancing the accessibility of the content. Conclusions Validated usability measures combined with qualitative methodology revealed educators’ high level of satisfaction with the design, content, and navigation of Teach-ABI. Educators engaged with the module as active participants in knowledge construction, as they reflected, questioned, and connected content to their experiences and knowledge. This study established strong usability and satisfaction with Teach-ABI and demonstrated the importance of usability testing in building online professional development modules.
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Reeves, Wendy M., Tim J. Lynch, Raisa Mobin, and Ruth R. Finkelstein. "Direct targets of the transcription factors ABA-Insensitive(ABI)4 and ABI5 reveal synergistic action by ABI4 and several bZIP ABA response factors." Plant Molecular Biology 75, no. 4-5 (January 19, 2011): 347–63. http://dx.doi.org/10.1007/s11103-011-9733-9.
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Marar, Mallika, Qi Long, Ronac Mamtani, Vivek Narayan, Neha Vapiwala, and Ravi Bharat Parikh. "Racial disparities in efficacy of first-line abiraterone in metastatic castrate-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology 39, no. 6_suppl (February 20, 2021): 20. http://dx.doi.org/10.1200/jco.2021.39.6_suppl.20.
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20 Background: Prospective studies suggest that abiraterone (Abi) use in mCRPC is associated with improved progression-free survival in African-American (AA) patients (pts) compared to non-Hispanic White (NHW) pts. It is unclear whether racial disparities in Abi effectiveness exist for pts with mCRPC treated in real-world practice. Methods: In this retrospective cohort study, we used the nationwide Flatiron Health electronic health record-derived de-identified database to select pts who received first-line (1L) systemic therapy for mCRPC between January 1, 2012 and December 31, 2018. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression models of comparative effectiveness, using age, race, comorbidity index, prostate-specific antigen (PSA), baseline steroid or opioid use, insurance status, practice type, practice Abi prescribing rate, and practice region as covariates. The primary exposure was treatment with 1L Abi. Overall survival (OS) was the primary outcome, and time-to-next-treatment (TTNT), using Fine-Gray models with death as a competing risk, was the secondary outcome. Racial disparities between Abi vs. no Abi groups were explored with stratified analyses by race and race-treatment interaction terms. Results: Of 3808 pts, 1729 (45.4%) received 1L Abi, 1255 (33.0%) received 1L enzalutamide, and 549 (14.4%) received 1L docetaxel. The cohort included 2165 (68.7%) NHW and 404 (10.6%) AA pts. Pts receiving Abi were older (mean age 74 vs. 72) and more likely to be treated at academic centers (8% vs. 6%) than pts not receiving Abi. Among pts receiving Abi, AAs had improved OS compared to NHWs (Table). Compared to receipt of a non-Abi regimen, receipt of Abi was not associated with OS among AA pts but was associated with decreased OS among NHW pts. A significant race-by-treatment interaction for OS existed among patients receiving 1L Abi (interaction coeff = 0.27 95% CI = 0.02-0.53). There were no race-based disparities found in TTNT. Conclusions: In a large real-world analysis of pts who received 1L systemic therapy for mCRPC, AAs who received Abi had improved OS compared to NHWs – a finding consistent with ABI-RACE (NCT01940276). Among NHW pts, 1L Abi was associated with decreased OS. These real-world data suggest race-based differences in therapeutic response to Abi and future prospective evidence is needed to assess drivers of differential Abi efficacy in mCRPC. [Table: see text]
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Thiery-Vuillemin, Antoine, Fred Saad, Andrew J. Armstrong, Mototsugu Oya, Karina Costa Maia Vianna, Mustafa Özgüroğlu, Craig Gedye, et al. "Tolerability of abiraterone (abi) combined with olaparib (ola) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Further results from the phase III PROpel trial." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): 5019. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.5019.
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5019 Background: The Phase III PROpel (NCT03732820) trial demonstrated at interim analysis a statistically significant clinical benefit from combining ola + abi in the first-line (1L) mCRPC setting vs placebo (pbo) + abi. Benefit was seen irrespective of a pt’s homologous recombination repair mutation (HRRm) status; median radiographic progression-free survival (rPFS) 24.8 for ola + abi vs 16.6 months for pbo + abi (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81; P<0.0001). The safety profile of ola + abi was shown to be consistent with that for the individual drugs. We report additional interim safety analysis from PROpel. Methods: Eligible pts were ≥18 years with mCRPC, had received no prior chemotherapy or next-generation hormonal agent treatment at mCRPC stage, and were unselected by HRRm status. Pts were randomized 1:1 to abi (1000 mg qd) plus prednisone/prednisolone with either ola (300 mg bid) or pbo. Primary endpoint was investigator-assessed rPFS. Safety was assessed in all pts receiving ≥1 dose of study treatment by adverse event (AE) reporting (CTCAE v4.03). Results: 398 pts received ola + abi and 396 pbo + abi (safety analysis set). At data cut-off (July 30, 2021), median total duration of exposure for ola was 17.5 vs 15.7 months for pbo, and for abi 18.2 months in the ola + abi arm and 15.7 in the pbo + abi arm. Anemia (n=183) was the most common AE in the ola + abi arm, and 34% of these 183 events were managed by dose interruption, 23% by dose reduction, and 8% resulted in treatment discontinuation. Anemia and pulmonary embolism (PE) were the only Grade ≥3 AEs in ≥5% of pts (anemia: ola + abi, 15.1% vs pbo + abi, 3.3%; PE: 6.5% vs 1.8%, respectively). Most PEs were detected incidentally on radiographic imaging (69.2% and 71.4% in the ola + abi and pbo + abi arms, respectively) and no pts discontinued. More pts in the ola + abi arm experienced venous thromboembolism (Table). Arterial thromboembolism and cardiac failure AEs were balanced between the treatment arms. No AE of myelodysplastic syndrome/acute myeloid leukemia was reported in either treatment arm. COVID-19 was reported more frequently with ola + abi (8.3% vs 4.5%). Conclusions: PROpel demonstrated a predictable safety profile for ola + abi given in combination to pts with 1L mCRPC unselected by HRRm status. AEs of cardiac failure and arterial thromboembolism were reported at similar frequency in both treatment arms. The majority of PEs were asymptomatic. The safety profile of abiraterone was not adversely impacted by its combination with olaparib. Clinical trial information: NCT03732820. [Table: see text]
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Ledet, Elisa M., Arockia Jayaraj, Ellen B. Jaeger, Melissa Conrad Stoppler, Minqi Huang, Calvin Y. Chao, and A. Oliver Sartor. "Associations between androgen-directed treatments and AR mutational landscapes in the circulating tumor DNA of a real-world metastatic prostate cancer cohort." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 5061. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.5061.
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5061 Background: AR alterations evolve under the selective pressure of testosterone suppression and AR targeted agents. In metastatic, castration-resistant prostate cancer (mCRPC) AR’s mutational landscape and therapeutics targeting is still an unexplored area. Here we evaluate AR mutations in the circulating tumor DNA (ctDNA) of patients treated with AR targeted agents such as abiraterone (abi), enzalutamide (enza) and in combination (abi + enza) setting in a large Tempus real-world mCRPC cohort. Methods: De-identified records of patients with mPC who underwent Tempus xF next-generation sequencing (NGS) ≥ 6 months after treatment initiation of abi, enza, or abi + enza were selected for analysis. If patients had multiple NGS samples, the most recent sample was used. The assay is a targeted liquid biopsy panel that detects single-nucleotide variants and insertions and/or deletions in 105 genes, copy number variants in six genes, and chromosomal rearrangements in seven genes. Results: The cohort included 1,122 patients treated with abi only (n=483), enza only (n=374), or prior exposure to abi + enza (n=265). Pathogenic/likely pathogenic mutations were detected in 15% (n=71) of patients treated with abi,15% (n=56) treated with enza, and 27% (n=71; P<0.001) treated with both.The most frequent AR alterations were L702H (18%, 32%, and 25%) and T878A (34%, 3.6%, and 21%) and H875Y (7%, 12%, and 8.5%) in abi, enza, and abi + enza, respectively (Table). L702H and T878A alterations were found in an additional 8.5%, 3.6% and 9.9% of patients treated with abi, enza, or abi + enza, respectively. Alterations in L702A and H875T were found in 2.8%, 8.9% and 9.9% of patients treated with abi, enza, and abi + enza respectively. Approximately 4.2%, 1.8% and 1.4% (abi, enza, abi +enza) of treated patients had alterations in T878A and H875Y. Other single-hit alterations included 6 patients with W742C and 4 patients with F877L. Conclusions: AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide. [Table: see text]
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Chorzalska, Anna, Javier F. Kim, Karim Roder, Adam J. Olszewski, Dmitry Terentyev, and Patrycja M. Dubielecka. "Downregulation of Mir-181a Restores Chemosensitivity to Imatinib Mesylate in Chronic Myeloid Leukemia Cells Resistant to Tyrosine Kinase Inhibitors." Blood 126, no. 23 (December 3, 2015): 4016. http://dx.doi.org/10.1182/blood.v126.23.4016.4016.
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Abstract Abelson Interactor protein 1 (Abi-1) is a negative regulator of Abelson kinase and interacts with its oncogenic form Bcr-Abl1 (Brehme et al., PNAS 2009:106;7414). We have recently shown that Abi-1 also modulates interactions between chronic myeloid leukemia (CML) stem/progenitor cells and their microenvironment, and has a role in acquired drug resistance. Our data indicated that abnormally low levels of Abi-1 in CML cells correlate with increased expression of integrin α4, deregulation of Fak/Akt/Erk signaling, enhanced adhesive properties, quiescence, and resistance to imatinib mesylate (IM, Chorzalska et al., Leukemia 2014:28;2165). We have found miR-181a to be significantly upregulated in IM-resistant CML cells, and miRNA expression profiling identified miR-181a as a potential regulator of Abi-1 expression. Furthermore, a bioinformatics analysis matching the miR-181a seed region to conserved ABI1 sequences using TargetScan 6.2 (Lewis, Burge, & Bartel, Cell 2005;120.15) determined that a 3'-untranslated region of ABI1 (position 131-137) is a target for miR-181a. This suggested that miR-181a may regulate Abi-1 levels in IM-resistant CML cells. We hypothesized that decreasing the levels of miR-181a in those cells would restore the intracellular levels of Abi-1, and consequently reduce the expression of integrin α4, decrease the adhesion and quiescence, and restore their sensitivity to IM. To test this hypothesis, we designed and constructed a miRNA sponge (Figure 1) using the methodology established by Kluvier et al. (Methods, 2012:58;113). The sponge can endogenously sequester and functionally reduce levels of miR-181a in CML IM-resistant cells (K562-STI-R cell line), thus allowing to measure the effect of miR-181a loss on Abi-1, integrin α4 levels and chemoresistance. K562-STI-R CML cell line was electroporated with pcDNA3-SanDI vector encoding the miR-181a sponge or a control mismatched miRNA sponge. Using qPCR, we confirmed a 35% percent decrease in miR-181a transcript levels in IM-resistant K562-STI-R CML cell line expressing the design miR-181a sponge, compared with controls (p=0.0015). This was paralleled by a 38% increase in ABI1 mRNA levels (p=0.046) and about 40% increase in Abi-1 protein levels (p=0.03) as evaluated by immunoblotting followed by densitometry, indicating that functionally decreased intracellular levels of miR-181a resulted in increased expression of ABI1. Because we previously demonstrated that down-regulation of ABI1 increases expression of integrin α4 and adhesion of IM-resistant CML cells while decreasing their proliferative potential, we then evaluated ITGA4 transcript levels and expression of integrin α4 in CML cells transfected with the miR-181a sponge. We observed a 20% decrease in ITGA4 transcript and integrin α4 protein levels compared with controls (p=0.051). Phenotypic evaluation of the chemoresistant K562-STI-R cells expressing the miR-181a sponge showed a 36% (p=0.04) increase in the cell number. Decreased number of Annexin V-positive cells suggested that miR-181a sequestration had a modest inhibitory effect on apoptosis. We then evaluated chemosensitivity of the miR-181a sponge-expressing K562-STI-R cells by culturing them in increased concentrations of IM (10, 100 and 200 µM), and measuring apoptosis by Annexin V staining using flow cytometry. We observed 30% (p=0.01), 46% (p=0.023) and 68% (p=0.018) increase in the number of apoptotic cells in miR-181a sponge-expressing cells compared with control cultured at 10, 100 and 200 µM of IM, respectively. In summary, this study provides the first piece of evidence that miR-181a is an epigenetic regulator of ABI1, and that downregulation of miR-181a by a miRNA sponge can effectively increase the intracellular levels of Abi-1 in IM-resistant CML cells, consequently increasing their sensitivity to Bcr-Abl inhibition. Utilization of targeted miRNA inhibitors may represent a new approach to restore chemosensitivity of IM-resistant CML cells. Figure 1. Schematic representation of the design miR-181a sponge and the control sponge. miRNA antisense binding sites (MBS) contain central mismatch at position 9-12 of the miRNA sequence (bulge). For the control sponge, a scrambled sequence at positions 2-8 was generated. The two MBS are separated by a short 4-6 nt sequence spacer. Bold flanking letters indicate overhangs compatible with the restriction endonuclease SanDI. Figure 1. Schematic representation of the design miR-181a sponge and the control sponge. miRNA antisense binding sites (MBS) contain central mismatch at position 9-12 of the miRNA sequence (bulge). For the control sponge, a scrambled sequence at positions 2-8 was generated. The two MBS are separated by a short 4-6 nt sequence spacer. Bold flanking letters indicate overhangs compatible with the restriction endonuclease SanDI. Disclosures Olszewski: Bristol-Myers Squibb, Inc.: Consultancy; Genentech, Inc.: Research Funding.
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Fan, Pang-Dian, and Stephen P. Goff. "Abl Interactor 1 Binds to Sos and Inhibits Epidermal Growth Factor- and v-Abl-Induced Activation of Extracellular Signal-Regulated Kinases." Molecular and Cellular Biology 20, no. 20 (October 15, 2000): 7591–601. http://dx.doi.org/10.1128/mcb.20.20.7591-7601.2000.
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ABSTRACT Recent studies have suggested that members of the Abl interactor (Abi) protein family negatively regulate cell growth and transformation. To date, however, no specific role in these cellular processes has been identified for the Abi family. Here we describe the inhibition by overexpressed Abi-1 of a mitogenic pathway activated by both growth factors and v-Abl. We have identified the guanine nucleotide exchange factors Sos1 and Sos2 as novel binding partners of Abi-1. A domain that is required for interaction with Sos in vivo has been mapped to the amino terminus of Abi-1. Overexpression of Abi-1 inhibits epidermal growth factor (EGF)-induced activation of extracellular signal-regulated kinases (Erks) but does not affect EGF-induced activation of c-Jun N-terminal kinase or Akt. In addition, overexpression of Abi-1 blocks Erk activation induced by v-Abl. In both cases, the maximal inhibitory effect requires an intact amino-terminal Sos-binding domain in Abi-1. Finally, we demonstrate that tyrosine phosphorylation of endogenous Abi-1 in fibroblasts is induced by both v-Abl and serum stimulation, further suggesting a role for Abi-1 in signal transduction initiated by v-Abl and growth factors. Taken together, these findings suggest that overexpressed Abi proteins negatively regulate cell growth and transformation by specifically targeting the Erk pathway.
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Alexandre, Jerome, Stephane Oudard, Luca Campedel, Lisa Golmard, Sylvain Ladoire, Ahmed Khalil, Denis Maillet, et al. "Intra-individual dose escalation of abiraterone (ABI) according to its plasma exposure in patients (pts) with progressive metastatic castration-resistant prostate cancer (mRCPC): Results of the OPTIMABI trial." Journal of Clinical Oncology 41, no. 6_suppl (February 20, 2023): 159. http://dx.doi.org/10.1200/jco.2023.41.6_suppl.159.
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159 Background: Abiraterone acetate (ABI) improves survival in mCRPC. In a previous observational study, worse PSA response and shorter progression-free survival (PFS) were associated with mean ABI plasma through concentration (ABI Cmin) < 8.5 ng/mL within the first three months (ms) of treatment (Carton E et al. Eur J Cancer 2017). The OPTIMABI study, a multicenter non-randomized study (NCT 03458247), aimed to investigate whether a dose escalation of ABI improve PFS in underexposed progressive mCRPC pts. Methods: In step 1, pts with docetaxel-naive progressive mCRPC received ABI at the standard dose of 1000 mg/d + Prednisone 10 mg/d. Mean ABI Cmin was calculated from three monthly dosages. Pts experiencing progression within the first 6 ms and for whom mean ABI Cmin was < 8.5 ng/mL were included in step 2 and received 1000 mg twice daily (2000 mg/d) of ABI. ABI Cmin was assessed every month. The primary endpoint was the non-progression rate at 12 weeks in step 2. Identification of risk factors of 6 ms-PFS was done using Cox regression analysis. Results: From 06/2018 to 09/2021, 81 of 93 pts (median age: 72 yrs) included in step 1 were evaluable for statistical analysis. The median ABI Cmin was 10.0 (IQR: 4.5-15. 0) ng/mL over the first three ms. Inter-individual variability was 59%. The 6 ms-PFS was 68% (IC 95%: 56% - 80%) with no statistical difference between pts with mean ABI Cmin ≥ or < 8.5 ng/mL (log-rank test, p= 0.24). In multivariate analysis, liver metastasis (Hazard ratio, HR = 5.95, CI95% = 1.22–28.92; p=0.027) and creatinine clearance < 60 mL/min (HR = 3.51, CI95% = 1.12–10.99; p=0.031) were independently associated with 6 ms-PFS. Among 21 pts (25.9%), with mean ABI Cmin < 8.5 ng/mL, 8 pts (38.1%) experienced tumor progression within the first 6 ms; four of them could be included in step 2. None of them fulfilled the primary endpoint despite a significant increase in plasma ABI Cmin (p <0.036 by paired t-test). Conclusions: Despite high inter-individual variability of mean ABI Cmin, the OPTIMABI study does not support the strategy of intra-individual dose escalation according to plasma concentration of ABI in mCRPC. Underexposure to ABI (ABI Cmin < 8.5 ng/mL) was not statistically associated with shorter PFS. Clinical trial information: NCT03458247 .
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Hamasaki, Hidetaka, and Yasuteru Hamasaki. "Risk factors for patients with diabetes who have abnormal toe-brachial index and normal ankle-brachial index." Experimental and Clinical Endocrinology & Diabetes 127, no. 05 (February 2, 2018): 326–30. http://dx.doi.org/10.1055/s-0043-122491.
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Abstract Aim To investigate the association of ankle-brachial index (ABI) and toe-brachial index (TBI) with metabolic parameters and the risk factors causing a divergence between ABI and TBI in patients with diabetes. Methods Outpatients who were simultaneously examined for both ABI and TBI were included. Multiple regression analysis was performed to assess the association of ABI and TBI with metabolic parameters. Furthermore, logistic regression analysis was performed to detect the risk factors causing a divergence between ABI and TBI. Results Of the 307 patients that were enrolled, 77 had normal ABI but decreased TBI. ABI was inversely associated with plasma glucose and triglycerides and positively associated with high-density lipoprotein cholesterol. In contrast, TBI was inversely associated with the duration of diabetes, plasma glucose and haemoglobin A1c. Logistic regression analysis showed that smoking history and a history of cardiovascular disease were associated with an increased risk of the divergence between ABI and TBI. Conclusion Our findings suggest that smoking history and a history of cardiovascular disease are important risk factors in patients with diabetes who had normal ABI but decreased TBI. Patients with multiple vascular complications are at a high risk of coexisting peripheral artery disease, even if their ABI is normal.
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Choi, Seong-Woo, Hye-Yeon Kim, Hye-Ran Ahn, Young-Hoon Lee, Sun-Seog Kweon, Jin-Su Choi, Jung-Ae Rhee, et al. "The association of ankle brachial index with left ventricular hypertrophy and left ventricular mass index: the Dong-gu study." Vasa 42, no. 4 (July 1, 2013): 284–91. http://dx.doi.org/10.1024/0301-1526/a000289.
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Background: To investigate the association between ankle-brachial index (ABI), left ventricular hypertrophy (LVH) and left ventricular mass index (LVMI) in a general population. Patients and methods: The study population consisted of 8,246 people aged 50 years and older who participated in the baseline survey of the Dong-gu Study conducted in Korea between 2007 and 2010. Trained research technicians measured LV mass using mode M ultrasound echocardiography and ABI using an oscillometric method. Results: After adjustment for risk factors and common carotid artery intima-media thickness (CCA-IMT) and the number of plaques, higher ABIs (1.10 1.19, 1.20 - 1.29, and ≥ 1.30) were significantly and linearly associated with high LVMI (1.10 - 1.19 ABI: β, 3.33; 95 % CI, 1.72 - 4.93; 1.20 - 1.29 ABI: β, 6.51; 95 % CI, 4.02 - 9.00; ≥ 1.30 ABI: β, 14.83; 95 % CI, 6.18 - 23.48). An ABI of 1.10 - 1.19 and 1.20 - 1.29 ABI was significantly associated with LVH (1.10 - 1.19 ABI: OR, 1.35; 95 % CI, 1.19 - 1.53; 1.20 - 1.29 ABI: OR, 1.59; 95 % CI, 1.31 - 1.92) and ABI ≥ 1.30 was marginally associated with LVH (OR, 1.73; 95 % CI, 0.93 - 3.22, p = 0.078). Conclusions: After adjustment for other cardiovascular variables and CCA-IMT and the number of plaques, higher ABIs are associated with LVH and LVMI in Koreans aged 50 years and older.
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Liu, Yang, Manasi Bapat, Haroon Kamran, Louis Salciccioli, Anna Rozenboym, Jeremy Coplan, and Jason M. Lazar. "The Ankle-Brachial Index Is Related to Left Ventricular Ejection Fraction in Bonnet Macaques." Cardiology 130, no. 2 (2015): 91–95. http://dx.doi.org/10.1159/000368392.
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Low ankle-brachial index (ABI) is a marker of peripheral arterial disease associated with higher cardiovascular risk. ABI has been found to be influenced by left ventricular ejection fraction (LVEF), but this relation is confounded by atherosclerosis. Objectives: Since nonhuman primates have a low incidence of atherosclerosis, we sought to evaluate the effect of LVEF on ABI in 24 healthy female bonnet macaques (age 83 ± 21 months). Methods: LVEF was determined by echocardiography during anesthesia with ketamine. ABI was determined using automatic blood pressure cuff. Results: Mean LVEF was 73 ± 6%. Mean ABI was 1.03 (range 0.78-1.17) with similar right and left lower limb values (p = 0.78). On univariate analysis, mean ABI was significantly correlated with LVEF (r = 0.58, p = 0.003) but not with age, crown-rump length or weight. Mean LVEF increased in a stepwise manner from lowest to highest ABI tertile (68 ± 6 vs. 73 ± 4 vs. 77 ± 5%, p = 0.008). On ordinal regression and forced multivariate linear analyses, ABI status was independently related to LVEF. Conclusions: ABI is influenced by left ventricular systolic function but not age, height, weight or mass index in bonnet macaques. Left ventricular systolic function should be accounted for when considering ABI measurements.