Mutational analysis of DNMT3A improves the prognostic stratification of patients with acute myeloid leukemia.

Nucleophosmin1 (NPM1) mutations are the most frequently detected gene mutations in acute myeloid leukemia (AML) and are considered a favorable prognostic factor. We retrospectively analyzed the prognosis of 605 Japanese patients with de novo AML, including 174 patients with NPM1-mutated AML. Although patients with NPM1-mutated AML showed a high remission rate, this was not a favorable prognostic factor for overall survival (OS); this is contrary to generally accepted guidelines. Comprehensive gene mutation analysis showed that mutations in codon R882 of DNA methyltransferase 3A (DNMT3AR882 mutations) were a strong predicative factor indicating poor prognosis in all AML (p < 0.0001) and NPM1-mutated AML cases (p = 0.0020). Furthermore, multivariate analysis of all AML cases showed that DNMT3AR882 mutations and the co-occurrence of internal tandem duplication in FMS-like tyrosine kinase 3 (FLT3-ITD), NPM1 mutations, and DNMT3AR882 mutations (triple mutations) were independent factors predicting a poor prognosis related to OS, with NPM1 mutations being an independent factor for a favorable prognosis (hazard ratios: DNMT3AR882 mutations, 1.946; triple mutations, 1.992, NPM1 mutations, 0.548). Considering the effects of DNMT3AR882 mutations and triple mutations on prognosis and according to the classification of NPM1-mutated AML into three risk groups based on DNMT3AR882 /FLT3-ITD genotypes, we achieved the improved stratification of prognosis (p < 0.0001). We showed that DNMT3AR882 mutations are an independent factor for poor prognosis; moreover, when confounding factors that include DNMT3AR882 mutations were excluded, NPM1 mutations were a favorable prognostic factor. This revealed that ethnological prognostic discrepancies in NPM1 mutations might be corrected through prognostic stratification based on the DNMT3A status.

Quenching effect of cerium oxide nanoparticles on singlet oxygen: validation of the potential for reaction with multiple reactive oxygen species.

Here we studied cerium oxide nanoparticles (nanoceria) as an agent for the future treatment of oxidative damage by validating and evaluating its scavenging activity towards reactive oxygen species (ROS) in vitro. Nanoceria has been shown to mimic the activities of superoxide dismutase and catalase, degrading superoxide (O2•-) and hydrogen peroxide (H2O2). We examined the antioxidative activity of nanoceria, focusing on its ability to quench singlet oxygen (1O2) in an aqueous solution. Electron paramagnetic resonance (EPR) was used to determine the rates of second-order reactions between nanoceria and three ROS (1O2, O2•-, and H2O2) in aqueous solution, and its antioxidative abilities were demonstrated. Nanoceria shows a wide range of ultraviolet-light absorption bands and thus 1O2 was produced directly in a nanoceria suspension using high-frequency ultrasound. The quenching or scavenging abilities of nanoceria for 1O2 and hypoxanthine-xanthine oxidase reaction-derived O2•- were examined by EPR spin-trapping methods, and the consumption of H2O2 was estimated by the EPR oximetry method. Our results indicated that nanoceria interact not only with two previously reported ROS but also with 1O2. Nanoceria were shown to degrade O2•- and H2O2, and their ability to quench 1O2 may be one mechanism by which they protect against oxidative damage such as inflammation.

Evaluation of cerium oxide as a phosphate binder using 5/6 nephrectomy model rat.

BACKGROUND: The number of chronic kidney disease (CKD) patients continues to increase worldwide. CKD patients need to take phosphate binders to manage serum phosphorus concentrations. Currently, several types of phosphate binder, including lanthanum carbonate, are used. However, they each have disadvantages. METHODS: In this study, we evaluated cerium oxide as a new phosphate binder in vitro and in vivo. First, cerium oxide was mixed with phosphoric acid at pH 2.5 or 7.0, and residual phosphoric acid was measured by absorption photometry using colorimetric reagent. Second, cerium oxide was fed to 5/6 nephrectomy model rats (5/6Nx), a well-known renal damage model. All rats were measured food intake, water intake, feces volume, and urine volume, and collected serum and urine were analyzed for biochemical markers. RESULTS: Cerium oxide can adsorb phosphate at acidic and neutral pH, while lanthanum carbonate, which is a one of popular phosphate binder, does not dissolve at neutral pH. Cerium oxide-treatment reduced serum phosphate concentrations of 5/6Nx rats without an increase in serum alanine transaminase levels that would indicate hepatotoxicity, and cerium oxide-treatment maintained serum creatinine and blood urea nitrogen levels, while those of normal 5/6Nx rats increased slightly. CONCLUSIONS: These results suggest that cerium oxide can be a potential phosphate binder. Decreased body weight gain and increased water intake and urine volume in 5/6Nx rats were thought to be an effect of nephrectomy because these changes did not occur in sham operation rats. Additional investigations are needed to evaluate the longer-term safety and possible accumulation of cerium oxide in the body.

Efficacy and safety of anagrelide as a first-line drug in cytoreductive treatment-naïve essential thrombocythemia patients in a real-world setting.

OBJECTIVE: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting. METHOD: Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. RESULTS: The rate of achieving a platelet count of <600 × 109 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. CONCLUSION: In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.

Left dorsolateral prefrontal cortex atrophy is associated with frontal lobe function in Alzheimer's disease and contributes to caregiver burden.

OBJECTIVE: Caregivers of patients with dementia experience physical and mental deterioration. We have previously reported a correlation between caregiver burden and the Frontal Assessment Battery (FAB) total scores of patients with Alzheimer's disease (AD), especially regarding the dependency factor from the Zarit Burden Interview. The present study aimed to identify an objective biomarker for predicting caregiver burden. METHODS: The participants were 26 pairs of caregivers and patients with AD and mild-to-moderate dementia. Correlations between regional gray matter volumes in the patients with AD and the FAB total scores were explored by using whole-brain voxel-based morphometric analysis. Path analysis was used to estimate the relationships between regional gray matter volumes, FAB total scores, and caregiver burden based on the Zarit Burden Interview. RESULTS: The voxel-based morphometric revealed a significant positive correlation between the FAB total scores and the volume of the left dorsolateral prefrontal cortex. This positive correlation persisted after controlling for the effect of general cognitive dysfunction, which was assessed by using the Mini-Mental State Examination. Path analysis revealed that decreases in FAB scores, caused by reduced frontal lobe volumes, negatively affected caregiver burden. CONCLUSIONS: The present study revealed that frontal lobe function, based on FAB scores, was affected by the volume of the left dorsolateral prefrontal cortex. Decreased scores were associated with greater caregiver burden, especially for the dependency factor. These findings may facilitate the development of an objective biomarker for predicting caregiver burden.

Frontal lobe function in elderly patients with Alzheimer's disease and caregiver burden.

AIM: Understanding of the relationship between caregiver burden and the degree of behavioural deficits in patients with Alzheimer's disease (AD) is relatively limited. Therefore, it is worthwhile to examine the correlations between the various relevant factors to improve the efficacy of care for patients with AD. The aim of this study was to investigate the specific contributions of frontal lobe dysfunction in AD patients to caregiver burden, while controlling for other predictor variables. METHODS: Participants included 30 pairs of caregivers and patients with AD. The Zarit Burden Interview and Frontal Assessment Battery were used to measure the caregiver burden and patients' frontal lobe function, respectively. To investigate the effects of frontal lobe dysfunction on caregiver burden, hierarchical regression equations with steps incorporating additional predictor variables were fitted. We also performed a correlation analysis between the individual subdomains of the Zarit Burden Interview and the predictor variables. RESULTS: Our study suggests that the degree of frontal lobe dysfunction in AD patients predicts their caregiver burden, when other factors of daily functional limitations and neuropsychiatric symptoms are controlled. Daily functional limitations and neuropsychiatric symptoms affected caregivers' psychosocial burden, whereas frontal lobe dysfunction affected caregivers' burden due to the increase in the dependency of the patients. CONCLUSION: Our findings indicate that to ameliorate the disabilities of patients and reduce caregiver burden, there is a need for interventions that focus on psychosocial burdens, as shown in previous studies, as well as on excessive dependency due to frontal lobe dysfunction.

Successful management of recurrent bleeding with tocilizumab in an acquired hemophilia A patient with rheumatoid arthritis.

A 61-year-old woman with rheumatoid arthritis was diagnosed as having acquired hemophilia A with extensive subcutaneous bleeding. The patient was treated with a corticosteroid, and her symptoms improved temporarily. However, these recurred during the tapering of her corticosteroid dose, and neither the re-increase in the dose nor the addition of cyclophosphamide could control her bleeding tendency. After the administration of an anti-IL-6 receptor antibody (tocilizumab), the doses of corticosteroid and cyclophosphamide could be tapered. Tocilizumab combined with another immunosuppression therapy might be effective in the treatment of acquired hemophilia A.

Effects of cerium oxide nanoparticles on adenine-induced chronic kidney disease model rats.

AIM: Cerium oxide, particularly in nanoparticle form (nanoceria), has been investigated for biomedical applications as a promising new agent for treating several pathologies. The aim of the present study was to characterize the pharmacologic effects of nanoceria in an animal model of chronic kidney disease. METHODS: We created the chronic kidney disease animal model by feeding rats a 0.25% adenine diet. Male Wistar rats were divided into five groups: normal diet, 0.25% adenine diet, or adenine diet containing three different doses or durations of nanoceria treatment. Blood was collected weekly from the tail veins of each rat and analyzed for renal function markers. After 5 weeks, various biochemical markers in serum, plasma, and urine were also analyzed. RESULTS: In the adenine-treated group, body weight was significantly decreased, and the kidneys lost much of their healthy reddish color and became lumpy and white in appearance. In addition, levels of serum creatinine, blood urea nitrogen, and plasma uremic toxins were significantly increased in adenine-treated rats compared with controls. Renal functional and structural damage in adenine diet model rats tended to be ameliorated by nanoceria ingestion. The high-dose cerium-treated group maintained reddish areas in the kidneys, and the increases in biomarker levels of creatinine, blood urea nitrogen, and inorganic phosphorus were markedly reduced, regardless of treatment duration. CONCLUSIONS: Ingestion of nanoceria may be effective for improving or preventing renal damage caused by adenine. Geriatr Gerontol Int 2024; 24: 88-95.

Structural and non-coding variants increase the diagnostic yield of clinical whole genome sequencing for rare diseases.

BACKGROUND: Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, the diagnostic yields of many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25-30%. This is in part because although entire genomes are sequenced, analysis is often confined to in silico gene panels or coding regions of the genome. METHODS: We undertook WGS on a cohort of 122 unrelated rare disease patients and their relatives (300 genomes) who had been pre-screened by gene panels or arrays. Patients were recruited from a broad spectrum of clinical specialties. We applied a bioinformatics pipeline that would allow comprehensive analysis of all variant types. We combined established bioinformatics tools for phenotypic and genomic analysis with our novel algorithms (SVRare, ALTSPLICE and GREEN-DB) to detect and annotate structural, splice site and non-coding variants. RESULTS: Our diagnostic yield was 43/122 cases (35%), although 47/122 cases (39%) were considered solved when considering novel candidate genes with supporting functional data into account. Structural, splice site and deep intronic variants contributed to 20/47 (43%) of our solved cases. Five genes that are novel, or were novel at the time of discovery, were identified, whilst a further three genes are putative novel disease genes with evidence of causality. We identified variants of uncertain significance in a further fourteen candidate genes. The phenotypic spectrum associated with RMND1 was expanded to include polymicrogyria. Two patients with secondary findings in FBN1 and KCNQ1 were confirmed to have previously unidentified Marfan and long QT syndromes, respectively, and were referred for further clinical interventions. Clinical diagnoses were changed in six patients and treatment adjustments made for eight individuals, which for five patients was considered life-saving. CONCLUSIONS: Genome sequencing is increasingly being considered as a first-line genetic test in routine clinical settings and can make a substantial contribution to rapidly identifying a causal aetiology for many patients, shortening their diagnostic odyssey. We have demonstrated that structural, splice site and intronic variants make a significant contribution to diagnostic yield and that comprehensive analysis of the entire genome is essential to maximise the value of clinical genome sequencing.

NPM1-mutation-based measurable residual disease assessment after completion of two courses of post-remission therapy is a valuable clinical predictor of the prognosis of acute myeloid leukemia.

Recent studies have reported that measurable residual disease (MRD) analysis using NPM1 mutations helps determine whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in acute myeloid leukemia (AML) patients. However, the optimal timing and cutoff value for measuring MRD using genomic DNA remain undetermined. This study aimed to investigate the optimal timing and cutoff value to ascertain the value of NPM1 mutation in MRD assessment. NPM1-mutated MRD was quantified by real-time polymerase chain reaction of bone marrow samples from 56 patients with NPM1-positive AML who achieved hematological remission. The area under the receiver-operating characteristic curve was greatest when MRD was assessed after two courses of post-remission therapy with a cutoff value of 0.010% (specificity, 68.4%; sensitivity, 87.0%). Patients whose MRD was below the cutoff value throughout the course of treatment had significantly better overall survival and relapse-free survival rates. Of the 33 patients who did not undergo transplantation during the first remission, all of the 11 who were never MRD-negative at any point experienced a relapse. Evaluating MRD with a cutoff value of 0.010% after two courses of post-remission therapy helps predict prognosis and determine the indication for allo-HSCT.

Prognostic impact of CEBPA bZIP domain mutation in acute myeloid leukemia.

Mutations of CCAAT/enhancer-binding protein alpha (CEBPAmu) are found in 10% to 15% of de novo acute myeloid leukemia (AML) cases. Double-mutated CEBPA (CEBPAdm) is associated with a favorable prognosis; however, single-mutated CEBPA (CEBPAsm) does not seem to improve prognosis. We investigated CEBPAmu for prognosis in 1028 patients with AML, registered in the Multi-center Collaborative Program for Gene Sequencing of Japanese AML. It was found that CEBPAmu in the basic leucine zipper domain (bZIP) was strongly associated with a favorable prognosis, but CEBPAmu out of the bZIP domain was not. The presence of CEBPAmu in bZIP was a strong indicator of a higher chance of achieving complete remission (P < .001), better overall survival (OS; P < .001) and a lower risk of relapse (P < .001). The prognostic significance of CEBPAmu in bZIP was also observed in the subgroup with CEBPAsm (all patients: OS, P = .008; the cumulative incidence of relapse, P = .063; patients aged ≤70 years and with intermediate-risk karyotype: OS, P = .008; cumulative incidence of relapse, P = .026). Multivariate analysis of 744 patients aged ≤70 years showed that CEBPAmu in bZIP was the most potent predictor of OS (hazard ratio, 0.3287; P < .001). CEBPAdm was validated as a cofounding factor, which was overlapping with CEBPAmu in bZIP. In summary, these findings indicate that CEBPAmu in bZIP is a potent marker for AML prognosis. It holds potential in the refinement of treatment stratification and the development of targeted therapeutic approaches in CEBPA-mutated AML.

[Difficult hemodialysis induction due to subclavian steal syndrome in a patient with Takayasu's arteritis].

The patient was a 53-year-old woman who had bilateral renal arterial constriction due to Takayasu's arteritis, and developed end-stage renal failure. When transient loss of consciousness occurred in 2002, she was diagnosed with subclavian steal syndrome (SSS). The renal failure worsened in June 2004, and there was concern that the left SSS could become aggravated as a consequence of creating an arterio-venous (AV) shunt. Although peritoneal dialysis was strongly recommended, she elected to undergo hemodialysis. We confirmed that there was no reduction of cerebral blood flow using brain single photon emission computed tomography (SPECT). Right and left examinations indicated the site at which an AV shunt should be created and subsequently, the AV shunt was created on the left fore-arm. Brain SPECT findings were again confirmed after dialysis, at the time of hemodialysis induction, and again 2 years after hemodialysis induction, showing no reduction in cerebral blood flow. She has no apparent symptoms or signs of left SSS, to date. Although it is known that an SSS could arise after AV shunt creation, there has been no report of the creation of an AV shunt in a case of SSS. The present case suggests that cerebral blood flow measurement using brain SPECT is useful for evaluating cerebral hemodynamics before AV fistula creation among patients with Takayasu's arteritis.

Successful treatment of acute promyelocytic leukemia in a patient undergoing hemodialysis with arsenic trioxide.

A man undergoing hemodialysis was diagnosed with acute promyelocytic leukemia (APL). He received arsenic trioxide as a single agent and achieved complete molecular remission without severe adverse events. Arsenic trioxide can be used safely and effectively for patients with APL under hemodialysis.

Successful treatment of acute promyelocytic leukemia in a patient under hemodialysis with arsenic trioxide.

A man with chronic kidney disease (CKD) under hemodialysis was diagnosed with acute promyelocytic leukemia (APL). He received arsenic trioxide as a single agent and achieved complete molecular remission without severe adverse events. Arsenic trioxide (ATO) can be used safely and effectively for APL with CKD.

Epstein-Barr Virus-Positive Adrenal Diffuse Large B-Cell Lymphoma after Treatment for Angioimmunoblastic T-Cell Lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) can be complicated by Epstein-Barr virus (EBV)-positive B-cell lymphoma. B-cell lymphoma may develop simultaneously at the time of AITL diagnosis or after treatment for AITL. EBV-associated B-cell lymphoma can occur in nodal and extranodal sites. We report a case of EBV-positive diffuse large B-cell lymphoma (DLBCL) of the left adrenal gland that developed after treatment for AITL. The patient presented with systemic lymphadenopathy and biopsy of one lymph node showed AITL. A complete response (CR) was achieved after initial chemotherapy for AITL, but 9 months later the left adrenal gland was enlarged. The diagnosis of EBV-positive DLBCL was made based on the histopathological findings of the left adrenal gland biopsy. Thus, EBV-positive DLBCL developed after AITL CR was achieved. Multi-drug chemotherapy combined with rituximab was administered for adrenal DLBCL, but only a partial response was achieved. We confirmed that EBV-positive B-cell lymphoma developed after treatment for AITL. An adrenal primary is rare, and this is only the second case of EBV-positive B-cell lymphoma to be reported after treatment for AITL. Clinicians should keep in mind that when nodal and extranodal lesions are seen after AITL treatment, another biopsy should be performed for the accurate determination of whether these lesions indicate AITL relapse or new-onset EBV-positive B-cell lymphoma. LEARNING POINTS: We report a case of EBV-positive B-cell lymphoma of the adrenal gland after treatment for angioimmunoblastic T-cell lymphoma (AITL)When patients present with signs and symptoms suggestive of relapse after AITL treatment, another biopsy should be performed for the accurate determination of whether these lesions indicate AITL relapse or new-onset of EBV-positive B-cell lymphoma.The involvement of extranodal sites may indicate a poor prognosis of EBV-positive B-cell lymphoma after AITL treatment.

Hepatic Hodgkin Lymphoma Presenting as Solitary Hepatic Mass Following Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorder in a Patient With Rheumatoid Arthritis.

Lymphoproliferative disorders (LPDs) occur frequently in patients with rheumatoid arthritis (RA) under methotrexate treatment. Some LPDs spontaneously regressed after methotrexate discontinuation, but classic Hodgkin lymphoma (CHL)-type LPDs frequently relapse, and chemotherapy is usually required for the treatment. CHL usually spreads in contiguous lymph nodes and then infiltrates in organs at an advanced stage. Thus, hepatic Hodgkin lymphoma (HHL) without lymphadenopathy is extremely rare at diagnosis. We present a case of methotrexate-associated LPDs associated with systemic lymphadenopathy and hepatosplenic mass in a 71-year-old woman with RA under methotrexate treatment over 10 years. Although spontaneous remission occurred after methotrexate discontinuation, she developed HHL presenting as a solitary hepatic mass without lymphadenopathy 3 years after spontaneous regression. She received brentuximab vedotin (BV) combination chemotherapy without bleomycin to avoid pulmonary toxicity. Complete metabolic response was achieved after four courses of BV combination chemotherapy, and the activity of RA was kept to be in remission. Our case suggested that the recurrence lesions of LPDs may present at unexpected site, which is not coincide with the primary site, and BV combination chemotherapy is a promising regimen for limited-stage CHL-type LPDs in patients with RA owing to its anti-lymphoma effect on CHL-type LPDs and a possible targeted therapy for RA.

[Epidemiological study of influenza-like illness under enhanced surveillance in Saku, Nagano Prefecture, outpatients during the 2008-09 influenza season].

Many influenza-like illness (ILI) outpatients visit healthcare facilities such as internal medicine and pediatric clinics every year. In Japan, however, ILI is reported only by sentinel healthcare facilities. We studied the number of ILI subjects visiting sentinel and non-sentinel healthcare facilities during the 2008-09 season in Saku, Nagano prefecture, obtaining the numbers of cases from sentinel and non-sentinel facilities. Most ILI subjects visited internal and pediatric facilities, and some visited otorhinolaryngological clinics not included as sentinel sites. We also estimated the total number of influenza cases based on data from sentinel facilities and total surveyed facilities, including non-sentinel. We divided facilities into hospitals with pediatrics, pediatric clinics, internal medicine and pediatric clinics, hospitals and clinics with internal medicine but no pediatrics, and otorhinolaryngological clinics. Estimated sentinel-site ILI cases was 2862, including 1020 for hospitals with pediatrics and 1,674 for clinics with internal medicine and pediatrics. The estimated number of ILI cases from total facilities surveyed was significantly lower, at 503 for hospitals with pediatrics, and 741 for clinics with internal medicine and pediatrics. Estimated ILI cases from categories not including sentinel sites were 967 for hospitals and clinics with internal medicine but no pediatrics, and 71 for otorhinolaryngological clinics. The estimated number of total ILI cases differed by 18.5%, depending on facility categories. This indicates that more detailed analysis is needed to accurately estimate ILI cases.

[Epidemiological study of health impact on influenza outpatients during 2008-2009 influenza season, Shonai, Yamagata].

To make up for the lack of data on influenza-like illness (ILI), we studied patterns among 6,828 ILI patients seen at 34 healthcare facilities during the 2008-2009 influenza season in Shonai, Yamagata, Japan. Healthcare facilities were classified into 1) hospitals, 2) pediatric clinics, 3) internal medicine and pediatric clinics, 4) internal medicine clinics, and 5) others. The majority went to hospitals, but the highest percentage in all outpatient visits was 13.7% seen at pediatric clinics during the peak epidemiological week. Based on estimated incidence and hospitalization data for pandemic (H1N1) 2009 from Ministry of Health, Labour and Welfare, Japan, we estimated the number of ILI patients at 59,600-89,400 and the number hospitalized for pandemic (H1N1) 2009 at 895-2,240 in Shonai. If those with ILI follow the same consultation patterns as outpatients in the 2008/09 influenza season, this indicates an estimated 23,800-35,700 with ILI will go to hospitals and 20,040-30,060 to pediatric clinics during the H1N1 pandemic. This in turns means that an urgent need will arise for appropriate measures reducing this potentially huge burden during pandemic (H1N1) 2009 outbreak in Japan.

Comparison of starting doses of anagrelide as a first-line therapy in patients with cytoreductive therapy-naïve essential thrombocythemia: difference between starting at 0.5 and 1.0 mg/day.

Anagrelide is widely used for cytoreductive therapy in patients with essential thrombocythemia who are at high risk for thrombosis. The recommended starting dose in the package insert of anagrelide varies by country. A high starting dose leads to an early onset of action, but causes a higher incidence of adverse events. This relationship indicates that both the onset of action and side effects of anagrelide are dose dependent. We retrospectively compared the efficacy and safety of anagrelide as a first-line drug between patients with essential thrombocythemia who started at 0.5 or 1.0 mg/day. Incidence of total adverse events and anagrelide-related palpitation, discontinuation rates, and the median daily dose of anagrelide were lower in the 0.5 mg/day group than in the 1.0 mg/day group; however, comparable platelet-lowering effects were achieved in both groups. These data suggest that a low starting dose of anagrelide followed by dose escalation may result in fewer adverse events and lower discontinuation rates, while providing desirable platelet-lowering effects. Initiating anagrelide at a lower dose may be a useful approach in actual clinical practice.

Enhanced spontaneous and benzo(a)pyrene-induced mutations in the lung of Nrf2-deficient gpt delta mice.

The lung is an organ that is sensitive to mutations induced by chemicals in ambient air, and transgenic mice harboring guanine phosphoribosyltransferase (gpt) gene as a target gene are a well-established model system for assessing genotoxicity in vivo. Transcription factor Nrf2 mediates inducible and constitutive expression of cytoprotective enzymes against xenobiotics and mutagens. To address whether Nrf2 is also involved in DNA protection, we generated nrf2+/-::gpt and nrf2-/-::gpt mice. The spontaneous mutation frequency of the gpt gene in the lung was approximately three times higher in nrf2-null (nrf2-/-) mice than nrf2 heterozygous (nrf2+/-) and wild-type (nrf2+/+) mice, whereas in the liver, the mutation frequency was higher in nrf2-/- and nrf2+/- mice than in nrf2+/+ wild-type mice. By contrast, no difference in mutation frequency was observed in testis among the three genotypes. A single intratracheal instillation of benzo(a)pyrene (BaP) increased the lung mutation frequency 3.1- and 6.1-fold in nrf2+/- and nrf2-/- mice, respectively, compared with BaP-untreated nrf2+/- mice, showing that nrf2-/- mice are more susceptible to genotoxic carcinogens. Surprisingly, mutation profiles of the gpt gene in BaP-treated nrf2+/- mice was substantially different from that in BaP-untreated nrf2-/- mice. In nrf2-/- mice, spontaneous and BaP-induced mutation hotspots were observed at nucleotides 64 and 140 of gpt, respectively. These results thus show that Nrf2 aids in the prevention of mutations in vivo and suggest that Nrf2 protects genomic DNA against certain types of mutations.