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Gene mutations were found in acute myeloid leukemia (AML) and their importance has been noted. To clarify the importance and stability of mutations, we examined gene mutations in paired samples at diagnosis and relapse of 34 adult AML patients. Five acquired gene mutations were detected at relapse. Of the 45 gene mutations at diagnosis, 11 of them were lost at relapse. The acquired mutations at relapse were all class I mutations as Fms-like tyrosine kinase 3 ( FLT3 ) and rat sarcoma viral oncogene homolog ( RAS) mutations. The disappeared mutations at relapse were 3 of 11 internal tandem duplications of FLT3 (FLT3- ITD) (27.3%), 3 of 3 FLT3 tyrosine kinase domain ( FLT3 -TKD) (100%), 3 of 13 Nucleophosmin 1 (23.1%) and 2 of 5 CCAAT/enhancer-binding protein-α (40%) mutations. However, epigenetics-modifying gene ( DNMT3a , TET2 and IDH1/2 ) mutations had no change between diagnosis and relapse samples, and may become minimal residual disease marker. The frequency of FLT3 -ITD at relapse in patients with DNMT3a mutation at diagnosis is significantly higher than those in patients without them ( P =0.001). Moreover, the high frequency of FLT3 -ITD at relapse is also seen in AML cases that initially present with any epigenetics-modifying gene mutations ( P <0.001). Our results indicate that epigenetics-modifying gene mutations may cause genetic instability and induce FLT3 -ITD, leading to resistance to therapy and relapse.

We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter ( P =0.0006) and cumulative incidence of relapse (CIR) significantly higher ( P =0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3 -ITD ( FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P =0.0010; CIR: P =0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS ( P =0.0007). In stratification based on FLT3 -ITD and CEBPA status and ‘simplified analysis of co-mutations’ using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P =0.0002. CIR: P <0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.

Concentrations of persistent organochlorine pesticides such as DDTs, hexachlorocyclohexanes (HCHs), chlordane compounds (CHLs), hexachlorobenzene (HCB), and polychlorinated biphenyls (PCBs), were determined in a wide variety of foodstuffs and human tissues collected from Shanghai and its vicinity in China in 2000-2001. Among the organochlorines analyzed, DDT and its metabolites were prominent compounds in most of the foodstuffs. In particular, mussels contained noticeable residues of DDTs (34,000 ng/g lipid weight), which are one to three orders greater than those reported levels in bivalves from other Asian countries. Concentrations of HCHs, CHLs, HCB, and PCBs in foodstuffs were generally low, suggesting small amounts of inputs into the environment. Temporal trends examined by comparing the results of previous studies of organochlorine levels in Chinese foodstuffs in 1970s and 1992 revealed a greater amounts of declines of DDTs and HCHs residues and the average daily intakes during the past 30 years. In contrast, very high concentrations of DDTs and HCHs were detected in human tissues from Shanghai, with the maximum values as high as 19,000 ng/g lipid weight (mean: 7,600 ng/g) and 17,000 ng/g (mean: 7,400 ng/g), respectively. Considering that foodstuffs are a main source of human exposure to contaminants, the greater concentrations of DDTs and HCHs in Chinese people might be due to past extensive usage of these compounds as agricultural pesticides. Continuous monitoring and epidemiological studies of organochlorine pesticides in humans are warranted in China. To our knowledge, this is the first report to present the residue levels of persistent organochlorine pesticides and PCBs in human tissues of China.

Background: A blood pressure drop after bevacizumab administration and its clinical significance have not been previously reported. Methods: Blood pressure data at 0, 90, and 180 min after a total of 162 bevacizumab administrations in 81 advanced colorectal cancer patients were retrospectively investigated. Results: Twenty-five patients (30%) demonstrated an average temporary drop of 20 mm Hg or more in systolic blood pressure. We classified these 25 patients as group A and the others as group B. Median time-to-treatment failure (TTF) was significantly longer in group A than in group B (291 vs 162 days; P =0.02). Furthermore, the proportion of patients who required intervention with antihypertensive drugs during bevacizumab treatment was significantly higher in group A than in group B (36% vs 4%; P <0.01). Conclusion: This study suggests that a temporary blood pressure drop after bevacizumab administration could be a predictive marker for bevacizumab treatment.

Objective: We investigated the efficacy and safety of dotinurad, a selective urate reabsorption inhibitor, in hyperuricemic patients with advanced chronic kidney disease (CKD) (stage G3-5). Patients and Methods: We retrospectively analyzed the cases of 34 patients (mean age, 68.6 [+ or -] 13.3 years; 17 men and 17 women) after 12 months of dotinurad treatment based on the changes in uric acid (UA) and the urine protein-to-creatinine ratio (UPCR) plus the annual change in estimated glomerular filtration rate (eGFR). Hyperuricemia (UA [greater than or equal to]6.0 mg/dL) and advanced CKD (mean eGFR: 32.0 [+ or -] 13.3 mL/min/1.73[m.sup.2]; stage G3, n=17; G4, n=13; G5, n=4) were present in all of the patients. The cases of 34 matched individuals with similar propensity scores (who were not taking dotinurad) were analyzed as a control group. Results: UA values decreased significantly in the dotinurad group (7.1 [+ or -]0.8 mg/dL to 5.9 [+ or -] 1.0 mg/dL, p<0.05) but those did not change in the control group. UPCR did not change in either group. Low-density lipoprotein cholesterol also decreased significantly in the dotinurad group (98.8 [+ or -]43.4 mg/dL to 82.9 [+ or -]33.1 mg/dL, p<0.05). With the 12-month dotinurad treatment, the annual change in the patients' eGFR was significantly improved from -6.0 [+ or -] 12.9 mL/min/1.73 [m.sup.2]/year to -0.9 [+ or -]4.6 mL/min/1.73 [m.sup.2]/year (p<0.05), but there was no change in the control group. Conclusion: Dotinurad can decrease UA levels and might attenuate renal function decline in individuals with hyperuricemia and advanced CKD. Keywords: chronic kidney disease, dotinurad, hyperuricemia, uric acid, renal function

In vitro reporter gene assays using vertebrate cell lines or yeast have been used for assessment of the estrogenic chemicals. However, estrogen receptor alpha (ER alpha )- and ER beta -mediated reporter gene system in fish has yet to be developed. In the present study, we developed an ER alpha - and ER beta -mediated reporter gene assay in fish and estimated estrogenic activities of 17 beta -estradiol (E2), p-nonylphenol (NP), bisphenol A (BPA), p,p'-DDE, and genistein (Gen) using the in vitro reporter assay. The activity was intensely induced by transfection with either ER alpha or ER beta expression plasmid under E2 or Gen administration, whereas it was significantly induced by transfection with ER alpha expression plasmid, but not with ER beta expression plasmid under NP administration. On the other hand, the activity was induced more intensely by transfection with ER alpha expression plasmid than ER beta expression plasmid under BPA or p,p'-DDE administration. These results indicate that there are obvious differences in the activity through ER alpha and ER beta among the estrogenic chemicals examined in vitro. Thus, the in vitro reporter assay provides an excellent system for elucidating the action mechanism of estrogenic chemicals in fishes.