Background Chronic myeloid leukemia is a hematologic malignancy associated with the fusion of two genes: BCR and ABL1. This fusion results from a translocation between chromosomes 9 and 22, which is ...called the Philadelphia chromosome. Although the Philadelphia chromosome is present in more than 90% of patients with chronic myeloid leukemia, 5-8% of patients with chronic myeloid leukemia show complex variant translocations. Herein, we report a unique case of a three-way translocation variant in chronic phase chronic myeloid leukemia. Case presentation A 40-year-old Asian male who presented with leukocytosis was diagnosed with chronic phase chronic myeloid leukemia. Cytogenetic karyotyping analysis showed 46,XY,t(4;9;22)(q21;q34;q11.2). He was treated with bosutinib and then changed to dasatinib because of intolerance, and MR4.5 (BCR-ABL/ABL ⦠0.0032%, international scale) was achieved after 17 months of continuous treatment. Conclusion This was the 14th case of t(4;9;22), in particular, a new variant Ph translocation involved in chromosome 4q21 and the first successful case treated with tyrosine kinase inhibitors in the world. We summarize previous case reports regarding three-way variant chromosome translocation, t(4;9;22) and discuss how this rare translocation is linked to prognosis. Keywords: t(4;9;22)(q21;Q34; Q11.2), CML, Philadelphia chromosome, Three-way variant
Clinically, it has been reported that chronic pain induces depression, anxiety, and reduced quality of life. The endogenous opioid system has been implicated in nociception, anxiety, and stress. The ...present study was undertaken to investigate whether chronic pain could induce anxiogenic effects and changes in the opioidergic function in the amygdala in mice. We found that either injection of complete Freund's adjuvant (CFA) or neuropathic pain induced by sciatic nerve ligation produced a significant anxiogenic effect at 4 weeks after the injection or surgery. Under these conditions, the selective mu-opioid receptor agonist D-Ala2,N-MePhe4,Gly5-ol-enkephalin (DAMGO)- and the selective delta-opioid receptor agonist (+)-4-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl-N,N-diethylbenzamide (SNC80)-stimulated 35SGTPgammaS binding in membranes of the amygdala was significantly suppressed by CFA injection or nerve ligation. CFA injection was associated with a significant increase in the kappa-opioid receptor agonist 2-(3,4-dichlorophenyl)-N-methyl-N-(1S)-1-phenyl-2-(1-pyrrolidinyl)ethylacetamide hydrochloride (ICI199,441)-stimulated 35SGTPgammaS binding in membranes of the amygdala. The intracerebroventricular administration and microinjection of a selective mu-opioid receptor antagonist, a selective delta-opioid receptor antagonist, and the endogenous kappa-opioid receptor ligand dynorphin A caused a significant anxiogenic effect in mice. We also found that thermal hyperalgesia induced by sciatic nerve ligation was reversed at 8 weeks after surgery. In the light-dark test, the time spent in the lit compartment was not changed at 8 weeks after surgery. Collectively, the present data constitute the first evidence that chronic pain has an anxiogenic effect in mice. This phenomenon may be associated with changes in opioidergic function in the amygdala.
It has often been proposed that opioid addiction does not arise as a consequence of opioid treatment for pain. Recently, we demonstrated that activated protein kinase C (PKC) in the spinal cord ...associated with chronic pain-like hyperalgesia suppressed the morphine-induced rewarding effect in mice. In the present study, we investigated whether a gene deletion for an endogenous μ-opioid peptide β-endorphin could affect pain-like behavior and the suppression of the morphine-induced rewarding effect by the direct activation of PKC in the spinal cord. We found that activation of spinal PKC by intrathecal (i.t.) treatment with phorbol 12,13-dibutyrate (PDBu), a specific PKC activator, caused thermal hyperalgesia, pain-like behaviors and suppression of the morphine-induced rewarding effect. This suppression of morphine reward was eliminated in mice that lacked β-endorphin. In contrast, thermal hyperalgesia and pain-like behaviors were not affected in β-endorphin knockout mice. These results suggest that the activation of PKC in the spinal cord may play an essential role in the suppression of the morphine-induced rewarding effect in mice with neuropathic pain through the constant release of β-endorphin.
Insomnia is a common problem for people with chronic pain. Cortical GABAergic neurons are part of the neurobiological substrate that underlies homeostatic sleep regulation. In the present study, we ...confirmed that sciatic nerve ligation caused thermal hyperalgesia and tactile allodynia in mice. In this experimental model for neuropathic pain, we found an increase in wakefulness and a decrease in non-rapid eye movement sleep under a neuropathic pain-like state. Under these conditions, membrane-bound GABA (γ-aminobutyric acid) transporters (GATs) on activated glial fibrillary acidic protein-positive astrocytes were significantly increased in the cingulate cortex, and extracellular GABA levels in this area after depolarization were rapidly decreased by nerve injury. Furthermore, sleep disturbance induced by sciatic nerve ligation was improved by the intracingulate cortex injection of a GAT-3 inhibitor. These findings provide novel evidence that sciatic nerve ligation decreases extracellular-released GABA in the cingulate cortex of mice. These phenomena may, at least in part, explain the insomnia in patients with neuropathic pain.
Neuropathic pain-like stimuli suppress the GABAergic transmission with increased GABA (γ-aminobutyric acid) transporters located on activated astrocytes in the cingulate cortex related to sleep disturbance.
Hintergrund: Die chronische myeloische Leukämie ist eine hämatologische Malignität, die mit der Fusion von zwei Genen einhergeht: BCR und ABL1. Diese Fusion resultiert aus einer Translokation ...zwischen den Chromosomen 9 und 22, auch als Philadelphia Chromosom bekannt. Obwohl das Philadelphia-Chromosom bei mehr als 90% der Patienten mit chronischer myeloischer Leukämie vorhanden ist, weisen 5-8% der Patienten mit chronischer myeloischer Leukämie komplexe Translokationsvarianten auf. Wir berichten hier über einen Fall einer dreifachen Translokationsvariante bei chronischer myeloischer Leukämie in der chronischen Phase. Vorstellung des Falles: Bei einem 40-jährigen asiatischen Mann, der sich mit Leukozytose vorstellte, wurde eine chronische myeloischen Leukämie in chronischer Phase diagnostiziert. Die zytogenetische Karyotypisierungsanalyse ergab 46,XY,t(4;9;22)(q21;q34;q11.2). Er wurde behandelt mit Bosutinib und dann wegen Unverträglichkeit auf Dasatinib umgestellt, und nach 17 Monaten kontinuierlicher Behandlung wurde MR4,5 (BCR-ABL/ABL ≤ 0,0032%, internationale Skala) erreicht. Schlussfolgerung: Dies war der 14. Fall von t(4;9;22), im Speziellen einer neue Variante der Ph-Translokation, bei der das Chromosom 4q21 beteiligt ist, und der erste weltweit erfolgreiche Fall, der mit Tyrosinkinase-Inhibitoren behandelt wurde. Wir fassen frühere Fallberichte über die dreifache Chromosomenverschiebung t(4;9;22) zusammen und erörtern, wie diese seltene Verschiebung mit der Prognose zusammenhängt.
Recent studies have indicated the interaction between GABAergic and opioidergic neurons. Therefore, the present study was designed to investigate whether chronic treatment of etizolam could affect ...the opioidergic system. A significant enhancement of the morphine-induced antinociception after chronic treatment of etizolam was observed using warm-plate test. Like the antinociceptive effect, etizolam produced a significant increase in G-protein activity by morphine in the mouse pons/medulla. Under these conditions, the level of phosphorylated-PKC in the pons/medulla was significantly decreased after etizolam treatment. However, the protein levels of GABAA receptor α1 and γ2 subunits were not changed by etizolam. These findings suggest that an enhancement of the μ-opioidergic function by chronic etizolam treatment may be associated with the decrease in PKC activity and no change in GABAA receptor subunits in the mouse brain.
Plants subjected to abiotic stress can regulate gene expression post-transcriptionally by means of small RNAs such as microRNAs. Cool-temperature stress causes abnormal tapetum hypertrophy in rice ...anthers, leading to pollen sterility. As a first step toward understanding the molecular mechanisms of cool tolerance in developing anthers of rice, we report here a comprehensive comparative analysis of microRNAs between cool-sensitive Sasanishiki and cool-tolerant Hitomebore cultivars. High-throughput Illumina sequencing revealed 241 known and 46 novel microRNAs. Interestingly, 15 of these microRNAs accumulated differentially in the two cultivars at the uninucleate microspore stage under cool conditions. Inverse correlations between expression patterns of microRNAs and their target genes were confirmed by quantitative RT-PCR analysis, and cleavage sites of some of the target genes were determined by 5’ RNA ligase-mediated RACE experiments. Thus, our data are useful resources to elucidate microRNA-mediated mechanism(s) of cool tolerance in rice anthers at the booting stage.
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