Nitric oxide (NO) has been suggested to play a key role in the pathogenesis of pulmonary hypertension (PH). To determine which mechanism exists to affect NO production, we examined the concentration ...of endogenous nitric oxide synthase (NOS) inhibitors and their catabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) activity and protein expression (DDAH1 and DDAH2) in pulmonary artery endothelial cells (PAECs) of rats given monocrotaline (MCT). We also measured NOS and arginase activities and NOS protein expression. Twenty-four days after MCT administration, PH and right ventricle (RV) hypertrophy were established. Endothelium-dependent, but not endothelium-independent, relaxation and cGMP production were significantly impaired in pulmonary artery specimens of MCT group. The constitutive NOS activity and protein expression in PAECs were significantly reduced in MCT group, whereas the arginase, which shares l-arginine as a common substrate with NOS, activity was significantly enhanced in PAECs of MCT group. The contents of monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA), were increased in PAECs of MCT group. The DDAH activity and DDAH1, but not DDAH2, protein expression were significantly reduced in PAECs of MCT group. These results suggest that the impairment of cGMP production as a marker of NO production is possibly due to the blunted endothelial NOS activity resulting from the downregulation of endothelial NOS protein, accumulation of endogenous NOS inhibitors, and accelerated arginase activity in PAECs of PH rats. The decreased overall DDAH activity accompanied by the downregulation of DDAH1 would bring about the accumulation of endogenous NOS inhibitors.
Background
The details of the sequential use of imatinib for first‐line treatment followed by second‐generation tyrosine kinase inhibitors (2G‐TKIs) for pediatric chronic myeloid leukemia (CML) are ...still unknown. This study analyzed clinical responses and adverse effects of the use of 2G‐TKIs following imatinib in pediatric chronic phase (CP)‐CML.
Procedures
The Japanese Pediatric Leukemia/Lymphoma Study Group conducted a retrospective study of patients with newly diagnosed CML from 1996 to 2011. A total of 152 cases that received imatinib as first‐line therapy were analyzed.
Results
Excluding 46 cases treated with hematopoietic stem cell transplantation before nilotinib and dasatinib became available, 31 of 106 patients changed to 2G‐TKIs. The primary reason for changing from imatinib was poor response, followed by intolerance, with the main reason for the latter being musculoskeletal events. Switches from imatinib to 2G‐TKIs with intolerance occurred significantly earlier than switches with poor response. Sixteen and 15 patients were treated with nilotinib and dasatinib, respectively, following imatinib therapy. After switching to 2G‐TKIs, the response status improved in 63% of evaluable patients. The adverse effect profiles of nilotinib and dasatinib tended to be different, with hyperbilirubinemia observed in 33% of nilotinib‐treated patients, but in none of the cases with dasatinib.
Conclusion
This retrospective study represents the first series of children and adolescents in whom sequential use of imatinib followed by 2G‐TKIs was reported. These data provide useful insights into the selection of 2G‐TKIs as first‐line treatment for children and adolescents with CP‐CML.
This article discusses current obstacles to the rapid development of safe and effective treatments for rare cancers, and considers measures required to overcome these challenges. In order to develop ...novel clinical options for rare cancers, which tend to remain left out of novel therapeutic development because of their paucity, efficient recruitment of eligible patients, who tend to be widely dispersed across the country and treated at different centers, is necessary. For this purpose, it is important to establish rare cancer registries that are linked with clinical studies, to organize a central pathological diagnosis system and biobanks for rare cancers, and to consolidate patients with rare cancers to facilities that can conduct clinical studies meeting international standards. Establishing an all‐Japan cooperative network is essential. Clinical studies of rare cancers have considerable limitations in study design and sample size as a result of paucity of eligible patients and, as a result, the level of confirmation of the efficacy and safety shown by the studies is relatively low. Therefore, measures to alleviate these weaknesses inherent to external conditions need to be explored. It is also important to reform the current research environment in order to develop world‐leading treatment for rare cancers, including promotion of basic research, collaboration between industry and academia, and improvement of the infrastructure for clinical studies. Collaboration among a wide range of stakeholders is required to promote the clinical development of treatment for rare cancers under a nationwide consensus.
This article discusses current obstacles to the rapid development of safe and effective treatments for rare cancers, and considers measures required to overcome these challenges.
The Y chromosome plays a critical role in spermatogenesis. Formerly, it had been difficult to generate knockout mice with specific Y chromosome mutations using conventional gene-targeting strategies. ...Recently, a transcription activator-like effector nuclease (TALEN) was successfully used for editing a mouse Y chromosome-linked gene. Here, we report the generation of a mouse model with a mutation in EIF2S3Y, a Y chromosome-linked gene, and analysis of its phenotype. The mouse carrying a targeted mutation of EIF2S3Y was infertile and had hypoplastic testes. Histological and electron microscopic analyses showed that differentiation of spermatogonia was arrested at the stage of spermatogonial stem cells (undifferentiated spermatogonia) and that the progression of spermatogenesis was interrupted, resulting in azoospermia. Using TALEN, we verified that EIF2S3Y performs a key function in differentiation of spermatogonial stem cells.
Myeloid cell differentiation is the process by which stem cells develop into mature monocytes or granulocytes. This process is achieved by the sequential activation of variety of genes. Disruption of ...this process can result in immunodeficiency, bone marrow failure syndrome, or leukemia. Acute promyelocytic leukemia (APL) is characterized by the t(15;17) translocation and can be treated by a combination of all-trans retinoic acid (ATRA) and anthracycline. This treatment can induce leukemic cell differentiation, leading to extremely high remission rates. XAB2, a molecule involved in nucleotide excision repair (NER), is downregulated during granulocyte differentiation and shows reduced expression in NB4 APL-derived cells in vitro. Differentiation of APL by ATRA treatment reduced XAB2 expression levels in vivo. These observations suggest that cellular differentiation is associated with reduced NER activity and provides new insights into combined differentiation induction. NB4 cells were more susceptible than the immature myeloid leukemic cell lines, Kasumi-3 and Kasumi-1, to the DNA interstrand crosslinking agent cisplatin.
Ataxia-telangiectasia (A-T) patients occasionally develop diabetes mellitus. However, only limited attempts have been made to gain insight into the molecular mechanism of diabetes mellitus ...development in A-T patients. We found that Atm−/− mice were insulin resistant and possessed less subcutaneous adipose tissue as well as a lower level of serum adiponectin than Atm+/+ mice. Furthermore, in vitro studies revealed impaired adipocyte differentiation in Atm−/− cells caused by the lack of induction of C/EBPα and PPARγ, crucial transcription factors involved in adipocyte differentiation. Interestingly, ATM was activated by stimuli that induced differentiation, and the binding of ATM to C/EBPβ and p300 was involved in the transcriptional regulation of C/EBPα and adipocyte differentiation. Thus, our study sheds light on the poorly understood role of ATM in the pathogenesis of glucose intolerance in A-T patients and provides insight into the role of ATM in glucose metabolism.
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•ATM, linked to ataxia telangiectasia, regulates adipocyte differentiation•The adipocyte differentiation defect in A-T contributes to type 2 diabetes•Transcriptional activation of C/EBPα and PPARγ depends on ATM•Binding of ATM to C/EBPβ and p300 induces transcriptional regulation of C/EBPα
Ataxia telangiectasia (A-T) patients develop diabetes mellitus. ATM, linked to A-T, is known to be involved in the DNA damage checkpoint. Takagi et al. reveal that ATM regulates adipocyte differentiation and attenuates differentiation of adipocytes in A-T patients, contributing to glucose metabolism in vivo.
During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the ...process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress.
Ataxia telangiectasia is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Quality of life is severely impaired ...by neurological symptoms. However, curative options for the neurological symptoms are limited. Recent studies have demonstrated short-term improvement in neurological symptoms with betamethasone therapy. However, the long-term and adverse effects of betamethasone are unclear. The aim of this study was to evaluate the long-term effects, benefits, and adverse effects of low-dose betamethasone in ataxia telangiectasia.
Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years. After cessation of betamethasone, the patients were observed for two additional years. Neurological assessments were performed, and adverse effects were monitored every three months throughout the four-year study period.
Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated. After the cessation of betamethasone treatment, neurological symptoms worsened in all patients. As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases.
Although these findings are in agreement with previous studies suggesting that short-term betamethasone treatment transiently benefits patients with ataxia telangiectasia, the long-term benefits and risks should be carefully considered.
Topoisomerase II alpha (TOP2A) has a crucial role in proper chromosome condensation and segregation. Here we report the interaction of TOP2A with ataxia telangiectasia mutated (ATM) and its ...phosphorylation in an ATM‐dependent manner after DNA damage. In vitro kinase assay and site‐directed mutagenesis studies revealed that serine 1512 is the target of phosphorylation through ATM. Serine 1512 to Alanine mutation of TOP2A showed increased stability of the protein, retaining TOP2A activity at least with regard to cell survival activity. Ataxia telangiectasia‐derived cell lines showed high levels of TOP2A that were associated with hypersensitivity to the TOP2 inhibitor etoposide. These findings suggest that ATM‐dependent TOP2A modification is required for proper regulation of TOP2 stability and subsequently of the sensitivity to TOP2 inhibitor. In a lymphoblastoid cell line derived from a patient who developed MLL rearrangement, positive infant leukemia, defective ATM expression, and increased TOP2A expression were shown. It was intriguing that hypersensitivity to TOP2 inhibitor and susceptibility to MLL gene rearrangement were shown by low‐dose etoposide exposure in this cell line. Thus, our findings have clinically important implications for the pathogenesis of infantile acute leukemia as well as treatment‐associated secondary leukemia following exposure to TOP2 inhibitors.
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