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BackgroundTall cell variant (TCV) and diffuse sclerosing variant (DSV) of papillary thyroid cancer are aggressive subtypes, for which tumors ≤1 cm have not been exclusively studied.MethodsThe SEER database (1988-2009) was used to compare characteristics of TCV ≤1 cm (mTCV) and DSV ≤1 cm (mDSV) with classic papillary thyroid microcarcinoma (mPTC). Survival was analyzed with the Kaplan-Meier method and log-rank test, and risk factors for nodal metastases with chi-square analysis and binary logistic regression.ResultsThere were 97 mTCV, 90 mDSV, and 18,260 mPTC patients. mTCV incidence increased by 79.9% (p=0.153) over the study period, while mDSV incidence decreased by 10.3% (p=0.315). Compared to classic mPTC, mTCV tended to be larger on average (7.1 mm vs. 5.3 mm, p7 mm (odds ratio (OR) 4.4 [CI 1.5-13.6]) and nodal metastasis with multifocality (OR 5.4 [CI 1.3-23.4]) and extrathyroidal extension (OR 5.8 [CI 1.3-25.4]). No statistically significant predictors of extrathyroidal extension or nodal metastasis in mDSV were observed.ConclusionsAggressive variants of mPTC tend to exhibit more aggressive pathologic characteristics than classic mPTC, but survival appears to be similar. Treatment with total thyroidectomy and central lymphadenectomy may be warranted if the diagnosis can be made pre- or intraoperatively.

The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1--a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing--contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.

The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion seven-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7 that is transferred to frizzled (FZD) to initiate canonical β-catenin signaling. GPR124 remains enigmatic: although its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124 and FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function using the mouse deletion mutant Gpr124ΔC. Despite inefficiently expressed GPR124ΔC protein, Gpr124ΔC/ΔC mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124−/− embryonic lethality, forebrain avascularity and hemorrhage. Gpr124ΔC/ΔC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124ΔC protein expression. Furthermore, Gpr124ΔC and the recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124- regulated CNS forebrain angiogenesis and BBB function are exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion seven-pass transmembrane receptors. [ABSTRACT FROM AUTHOR]

Author(s): Bin Zhang (corresponding author) [1]; Le Xuan Truong Nguyen [1, 2]; Ling Li [1]; Dandan Zhao [1]; Bijender Kumar [1]; Herman Wu [1]; Allen Lin [1]; Francesca Pellicano [3]; [...], Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR-ABL, which led to inhibition of the RAN-exportin-5-RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR-ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.

Introduction African Americans represent 13% of the US population, and yet 35% of patients on chronic dialysis are African American (1, 2). This excess chronic kidney disease (CKD) risk can [...], Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOLI-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.

OBJECTIVES: Reduced bone mineral density (BMD) can negatively affect lifelong skeletal health by increasing the risk for developing osteopenia and osteoporosis. This study evaluated the relationship between BMD and cumulative doses of intravenous (IV) methotrexate (MTX) and glucocorticoids in pediatric acute lymphoblastic leukemia (ALL) survivors. The association between BMD and vitamin D concentrations measured at the time of entry into the long-term follow-up program was also assessed. METHODS: This retrospective study included pediatric ALL survivors who had received a dual-energy X-ray absorptiometry (DXA) scan after the end of therapy (EOT) or within the 6 months prior to the EOT. Low/intermediate and high cumulative IV MTX doses were defined as doses less than 20,000 mg/m2 and greater than or equal to 20,000 mg/m2, respectively. Descriptive statistics, Student t test, and linear regression were used to analyze the data. RESULTS: A total of 62 patients, with 34 patients in the low/intermediate and 28 patients in the high cumulative IV MTX dose groups, were analyzed. The median time from EOT to DXA scan was 2.3 years. The mean DXA lumbar spine z score was significantly lower in the high cumulative IV MTX dose group compared with the low/intermediate dose group (-0.86 vs -0.14; p = 0.008). Cumulative glucocorticoid doses and vitamin D concentrations were not associated with BMD. CONCLUSIONS: Pediatric patients who had received cumulative IV MTX doses of greater than or equal to 20,000 mg/m2 during their ALL treatment had lower BMD than those who had received lower cumulative doses. [ABSTRACT FROM AUTHOR]