Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria11See Editorial by Quigg, p. 2315

Crry, a complement regulatory protein, modulates renal interstitial disease induced by proteinuria.BackgroundRecent studies have suggested a role for urinary complement components in mediating tubulointerstitial damage, which is known to have a good correlation with progression of chronic renal diseases. Although accumulating evidence suggests that complement regulatory proteins play an important protective role in glomeruli, their role in renal tubules remains unclear. In order to establish the role of a complement regulatory protein, Crry, in renal tubular injury, we employed a molecular biological approach to block the expression of Crry in tubules of animals with proteinuria induced with puromycin aminonucleoside nephritis (PAN).Methods and ResultsTwo different antisense oligodeoxynucleotides (ODNs) against Crry were designed and applied to cultured rat mesangial cells in vitro in order to establish their efficacy. Antisense ODN treatment resulted in decreased expression of Crry protein associated with increased sensitivity to complement attack in cell lysis assays compared with control ODN treatment or no treatment (44.7, 1.50, and 1.34%, respectively). Antisense ODNs did not affect the expression of Thy1 as a control, confirming the specificity of our ODNs. In vivo, we performed selective right renal artery perfusion to administer antisense ODNs to the kidney and showed prominent uptake of ODNs by proximal tubular cells. Reduced expression of Crry protein was demonstrated in proximal tubular cells in antisense ODNs-treated kidneys. Normal rats treated with the antisense ODNs did not show any pathological changes. However, in PAN, rats with massive proteinuria showed increased deposition of C3 and C5b-9 in tubules in antisense-treated kidneys, and histological assessment revealed more severe tubulointerstitial injury in antisense-treated animals compared with controls.ConclusionThese results establish a pathogenic role for complement in leading to tubulointerstitial injury during proteinuria and, to our knowledge for the first time, show a protective role of a complement regulatory protein, Crry, in renal interstitial disease

Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation

Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. We describe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib

日本の百寿者及び非百寿者における死亡前1年間に発生する医療費の比較

Importance: Although research has shown that centenarians tend to experience shorter periods of serious illness compared with other age groups, few studies have focused on the medical expenditures of centenarians as a potential indicator of the scale of medical resources used in their last year of life. Objective: To compare Japanese centenarians' and noncentenarians' monthly medical expenditures during the year before death according to age and sex. Design, setting, and participants: This retrospective cohort study used linked national health and long-term care insurance data collected from April 2013 to March 2018 in Nara Prefecture, Japan, for residents aged 75 years or older who were insured under the Medical Care System for older adults and died between April 2014 and March 2018. Data were analyzed from April 2013 to March 2018. Exposures: Age of 100 years or older (centenarians) vs 75 to 99 years (noncentenarians). Main outcomes and measures: The numbers of unique inpatients and outpatients and medical expenditures related to decedents' hospitalization and outpatient care were extracted and analyzed based on sex and age group. The Jonckheere-Terpstra test was used to identify trends in unadjusted medical expenditures by age group, and generalized estimating equations were used to estimate monthly median expenditures by age group with adjustment for comorbidity burden and functional status. Results: Of 34 317 patients aged 75 to 109 years (16 202 men [47.2%] and 18 115 women [52.8%]) who died between April 2014 and March 2018, 872 (2.5%) were aged 100 to 104 years (131 men [15.0%] and 741 women [85.0%]) and 78 (0.2%) were aged 105 to 109 years (fewer than 10 were men). The analysis of unadjusted medical expenditures in the last year of life showed a significant trend of lower expenditures for the older age groups; the median adjusted total expenditures during the 30 days before death by age group were $6784 (IQR,$4884-$9703) for ages 75 to 79 years,$5894 (IQR, $4292-$8536) for 80 to 84 years, $5069 (IQR,$3676-$7150) for 85 to 89 years,$4205 (IQR, $3085-$5914) for 90 to 94 years, $3522 (IQR,$2626-$4861) for 95 to 99 years,$2898 (IQR, $2241-$3835) for 100 to 104 years, and $2626 (IQR,$1938-$3527) for 105 to 109 years. The proportion of inpatients among all patients in the year before death also decreased with increasing age: 4311 of all 4551 patients aged 75 to 79 years (94.7%); 43 of all 78 patients aged 105 to 109 years (55.1%); 2831 of 2956 men aged 75 to 79 years (95.8%); 50.0% of men aged 105 to 109 years (the number is not reported owing to the small sample size); 1480 of 1595 women aged 75 to 79 years (92.8%); and 55.7% of women aged 105 to 109 years (the number of women is not reported to prevent back-calculation of the number of men). Specifically, 274 of 872 patients aged 100 to 104 years (31.4%) and 35 of 78 patients aged 105 to 109 years (44.9%) had not been admitted to a hospital in the year before death. Conclusions and relevance: This cohort study found that medical expenditures in the last year of life tended to be lower for centenarians than for noncentenarians aged 75 years or older in Japan. The proportion of inpatients also decreased with increasing age. These findings may inform future health care services coverage and policies for centenarians.博士（医学）・甲第801号・令和3年12月21日© 2021 Nakanishi Y. et al.JAMA Network Open. Open Access: This is an open access article distributed under the terms of the CC-BY License(https://creativecommons.org/licenses/by/4.0/)

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL

B1 SOX Coordinate Cell Specification with Patterning and Morphogenesis in the Early Zebrafish Embryo

The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through in situ hybridization, RT–PCR, and microarray analyses. Importantly, these phenotypic analyses revealed that the B1 SOX proteins regulate the following distinct processes: (1) early dorsoventral patterning by controlling bmp2b/7; (2) gastrulation movements via the regulation of pcdh18a/18b and wnt11, a non-canonical Wnt ligand gene; (3) neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively) and ascl1a (negatively), and regional transcription factor genes, e.g., hesx1, zic1, and rx3; and (4) neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. Chromatin immunoprecipitation analysis of the her3, hesx1, neurog1, pcdh18a, and cyp26a1 genes further suggests a direct regulation of these genes by B1 SOX. We also found an interesting overlap between the early phenotypes of the B1 sox quadruple knockdown embryos and the maternal-zygotic spg embryos that are devoid of pou5f1 activity. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo through partnering in part with Pou5f1 and possibly with other factors, and suggest that the B1 sox functions are central to coordinating cell fate specification with patterning and morphogenetic processes occurring in the early embryo