Increasing evidence suggests that renal inflammation contributes to the pathogenesis and progression of diabetic kidney disease (DKD) and that anti-inflammatory therapies might have renoprotective ...effects in DKD. Immune cells and resident renal cells that activate innate immunity have critical roles in triggering and sustaining inflammation in this setting. Evidence from clinical and experimental studies suggests that several innate immune pathways have potential roles in the pathogenesis and progression of DKD. Toll-like receptors detect endogenous danger-associated molecular patterns generated during diabetes and induce a sterile tubulointerstitial inflammatory response via the NF-κB signalling pathway. The NLRP3 inflammasome links sensing of metabolic stress in the diabetic kidney to activation of pro-inflammatory cascades via the induction of IL-1β and IL-18. The kallikrein-kinin system promotes inflammatory processes via the generation of bradykinins and the activation of bradykinin receptors, and activation of protease-activated receptors on kidney cells by coagulation enzymes contributes to renal inflammation and fibrosis in DKD. In addition, hyperglycaemia leads to protein glycation and activation of the complement cascade via recognition of glycated proteins by mannan-binding lectin and/or dysfunction of glycated complement regulatory proteins. Data from preclinical studies suggest that targeting these innate immune pathways could lead to novel therapies for DKD.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Primordial germ cells (PGCs), the precursors of sperm and eggs, are established in perigastrulation-stage embryos in mammals. Signals from extra-embryonic tissues induce a unique gene regulatory ...network in germline-competent cells for PGC specification. This network also initiates comprehensive epigenome resetting, including global DNA demethylation and chromatin reorganization. Mouse germline development has been studied extensively, but the extent to which such knowledge applies to humans was unclear. Here, we review the latest advances in human PGC specification and epigenetic reprogramming. The overall developmental dynamics of human and mouse germline cells appear to be similar, but there are crucial mechanistic differences in PGC specification, reflecting divergence in the regulation of pluripotency and early development.
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IJS, NUK, SBMB, UL, UM, UPUK
A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its ...stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated +8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2(-)/FLT3-ITD(+) genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Since the efficacy of mycophenolate mofetil (MMF) to treat immunoglobulin A (IgA) nephropathy is controversial, we extended our original study by following 40 Chinese patients with established IgA ...nephropathy for 6 years. All patients were maintained on their angiotensin blockade medication and half were randomized to receive MMF for 6 months. After 6 years, 11 patients required dialysis (2 from the MMF and 9 from the control group). Significantly, only 3 treated (as compared to 10 control) patients reached the composite end point of serum creatinine doubling or end-stage renal disease. Linear regression showed the annualized decline in the estimated glomerular filtration rate was significantly less in the MMF-treated group. Urinary protein excretion and the albumin-to-creatinine ratio were lower with MMF treatment during the first 24 months, beyond which there was no difference between groups. Multivariable Cox regression analysis showed that the baseline estimated glomerular filtration rate and proteinuria, and change in the urine albumin-to-creatinine ratio at 1 year to be important predictors of progression to end-stage renal disease. We found that among Chinese patients with IgA nephropathy who had mild histologic lesions and persistent proteinuria despite maximal angiotensin blockade, MMF treatment may result in transient and partial remission of proteinuria in the short-term and renoprotection in the long-term.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondrial DNA (mtDNA) mutations cause inherited diseases and are implicated in the pathogenesis of common late-onset disorders, but how they arise is not clear
. Here we show that mtDNA mutations ...are present in primordial germ cells (PGCs) within healthy female human embryos. Isolated PGCs have a profound reduction in mtDNA content, with discrete mitochondria containing ~5 mtDNA molecules. Single-cell deep mtDNA sequencing of in vivo human female PGCs showed rare variants reaching higher heteroplasmy levels in late PGCs, consistent with the observed genetic bottleneck. We also saw the signature of selection against non-synonymous protein-coding, tRNA gene and D-loop variants, concomitant with a progressive upregulation of genes involving mtDNA replication and transcription, and linked to a transition from glycolytic to oxidative metabolism. The associated metabolic shift would expose deleterious mutations to selection during early germ cell development, preventing the relentless accumulation of mtDNA mutations in the human population predicted by Muller's ratchet. Mutations escaping this mechanism will show shifts in heteroplasmy levels within one human generation, explaining the extreme phenotypic variation seen in human pedigrees with inherited mtDNA disorders.
A growing body of evidence indicates that the renal proximal tubular epithelial cell (PTEC) plays an important role in the pathogenesis of diabetic nephropathy (DN). Microalbuminuria that intensifies ...over time to overt proteinuria, a hallmark of DN, is already known to activate the PTEC to induce tubulointerstitial inflammation. In addition to proteins, a number of diabetic substrates including high glucose per se, advanced glycation end-products and their carbonyl intermediates, angiotensin II, and ultrafiltered growth factors activate a number of signaling pathways including nuclear factor kappa B, protein kinase C, extracellular signal-regulated kinase 1/2, p38, signal transducer and activator of transcription-1 and the generation of reactive oxygen species, to culminate in tubular cell hypertrophy and the accumulation in the interstitium of a repertoire of chemokines, cytokines, growth factors and adhesion molecules capable of orchestrating further inflammation and fibrosis. More recently, the kallikrein-kinin system (KKS) and toll-like receptors (TLRs) in PTECs have been implicated in this process. While in vitro data suggest that the KKS contributes to the progression of DN, there are conflicting in vivo results on its precise role, which may in part be strain-dependent. On the other hand, there are both in vitro and in vivo data to suggest a role for both TLR2 and TLR4 in DN. In this review, we offer a critical appraisal of the events linking the participation of the PTEC to the pathogenesis of DN, which we believe may be collectively termed diabetic tubulopathy.
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk ...cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The topology of pure Bi is controversial because of its very small (∼10 meV) band gap. Here we perform high-resolution angle-resolved photoelectron spectroscopy measurements systematically on 14-202 ...bilayer Bi films. Using high-quality films, we succeed in observing quantized bulk bands with energy separations down to ∼10 meV. Detailed analyses on the phase shift of the confined wave functions precisely determine the surface and bulk electronic structures, which unambiguously show nontrivial topology. The present results not only prove the fundamental property of Bi but also introduce a capability of the quantum-confinement approach.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end‐stage kidney disease (ESKD). Despite improvements in glycaemic control and blood pressure ...management with renin‐angiotensin‐aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression to ESKD in some patients. DKD is a heterogeneous disease entity in terms of its clinical manifestations, histopathology and the rate of progression, which makes it difficult to develop effective therapeutics. It was formerly considered that albuminuria preceded kidney function decline in DKD, but recent epidemiological studies revealed that a distinct group of patients presented kidney dysfunction without developing albuminuria. Other comorbidities, such as hypertension, obesity and gout, also affect the clinical course of DKD. The pathophysiology of DKD is complex and multifactorial, involving both metabolic and haemodynamic factors. These induce activation of intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy and epigenetic changes, which result in kidney inflammation and fibrosis. Recently, two groups of antidiabetic drugs, sodium‐glucose cotransporter 2 (SGLT2) inhibitors and glucagon‐like peptide‐1 (GLP‐1) receptor agonists, were demonstrated to provide renoprotection on top of their glucose‐lowering effects. Several other therapeutic agents are also being developed and evaluated in clinical trials.
SUMMARY AT A GLANCE
This article reviewed recent advances in the pathogenesis and treatment of diabetic kidney disease (DKD). Special focus is put on the phenotypic heterogeneity of DKD, and the recent studies that showed the therapeutic benefits of SGLT2 inhibitors and GLP‐1 receptor agonists. Potential future therapeutic strategies are also explored.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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