A gain-of-function mutation in microRNA 142 is sufficient to cause the development of T-cell leukemia in mice

MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR-142) is frequently mutated in patients with follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR-142 mutation in blood cancers, the CRISPR-Cas9 system was utilized to successfully generate miR-142-55A>G mutant knock-in (Ki) mice, simulating the most frequent mutation in patients with miR-142 mutated AML/MDS. Bone marrow cells from miR-142 mutant heterozygous Ki mice were transplanted, and we found that the miR-142 mutant/wild-type cells were sufficient for the development of CD8⁺ T-cell leukemia in mice post-transplantation. RNA-sequencing analysis in hematopoietic stem/progenitor cells and CD8⁺ T-cells revealed that miR-142-Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild-type miR-142-3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt–mTOR pathway was suppressed in miR-142-55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR-142-3p. Thus, in addition to the loss of function due to the halving of wild-type miR-142-3p alleles, mutated miR-142-3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.     

Effectiveness and current status of multidisciplinary care for patients with chronic kidney disease in Japan: a nationwide multicenter cohort study

Background

Multidisciplinary care is well established in clinical practice, but its effectiveness in patients with chronic kidney disease (CKD) remains unclear. The aim of this study was to determine whether multidisciplinary care could help to avoid worsening kidney function in patients with CKD.

Methods

This nationwide study had a multicenter retrospective observational design and included 3015 Japanese patients with CKD stage 3–5 who received multidisciplinary care. We assessed the annual decrease in estimated glomerular filtration rate (ΔeGFR) and urinary protein in the 12 months before and 24 months after the start of multidisciplinary care. All-cause mortality and initiation of renal replacement therapy were investigated according to baseline characteristics.

Results

Most of the patients had CKD stage 3b or higher and a median eGFR of 23.5 mL/min/1.73 m². The multidisciplinary care teams consisted of health care professionals from an average of four disciplines. ΔeGFR was significantly smaller at 6, 12, and 24 months after initiation of multidisciplinary care (all P < 0.0001), regardless of the primary cause of CKD and its stage when multidisciplinary intervention was started. Urinary protein level also decreased after initiation of multidisciplinary care. After a median follow-up of 2.9 years, 149 patients had died and 727 had started renal replacement therapy.

Conclusion

Multidisciplinary care may significantly slow the decline in eGFR in patients with CKD and might be effective regardless of the primary disease, including in its earlier stages. Multidisciplinary care is recommended for patients with CKD stage 3–5.

Trial registration

UMIN00004999.

     

Prognostic impact and gene expression analysis of peri-tumoral alveolar macrophage in resected lung adenocarcinoma

The prognostic significance and role of extratumoral alveolar macrophages (exAMs) in lung adenocarcinoma (LUAD) patients remain unknown. In this study, we investigated the prognostic impact and gene expression of exAMs in LUAD patients. The density of alveolar macrophages (AMs) in the peri-tumoral lung field (p-exAMs) and distant lung field (d-exAMs) was evaluated in 217 LUAD patients with lymph node metastasis. Patients with high p-exAMs showed significantly shorter recurrence-free (RFS) and shorter overall survival (OS) than those with low p-exAMs (p = 0.02 and p = 0.03, respectively), whereas there was no survival difference between patients with high d-exAMs and those with low d-exAMs. Multivariate analysis revealed that high p-exAMs was an independent predictive factor for RFS (HR: 1.54; 95% confidence interval [CI]:1.10–2.16; p = 0.01). Later, we collected AMs from the tumor periphery and distant segments in 13 resected lungs by bronchoalveolar lavage (BAL) procedure and compared mRNA expression. AMs in the tumor periphery expressed significantly higher levels of IL-10 and CCL2 than those in the distant segment (p < 0.01 and p = 0.03, respectively). Additionally, IL-10 and CCL2 significantly induced the growth and migration of the PC9 cells in vitro. This study suggests that p-exAMs should be considered as a tumor-promoting component in the tumor microenvironment.     

GFAP variant p. Tyr366Cys demonstrated widespread brain cavitation in neonatal Alexander disease.

Alexander disease is a rare form of leukodystrophy caused by heterozygous mutations in the gene encoding glial fibrillary acidic protein (GFAP). Brain cavitation in the white matter, predominantly distributed in the frontal periventricular area, has been described in some cases. Here, we present a case of a 1-year-old boy with neonatal Alexander disease caused by the p. Tyr366Cys GFAP variant, with rapid and widespread white matter cavitation. This case broadens the radiological spectrum of Alexander disease and suggests a possible genotype-phenotype correlation between the p. Tyr366Cys variant and cavitation.