Proper gene regulation is critical for both neuronal development and maintenance as the brain matures. We previously demonstrated that Akirin2, an essential nuclear protein that interacts with ...transcription factors and chromatin remodeling complexes, is required for the embryonic formation of the cerebral cortex. Here we show that Akirin2 plays a mechanistically distinct role in maintaining healthy neurons during cortical maturation. Restricting Akirin2 loss to excitatory cortical neurons resulted in progressive neurodegeneration via necroptosis and severe cortical atrophy with age. Comparing transcriptomes from Akirin2-null postnatal neurons and cortical progenitors revealed that targets of the tumor suppressor p53, a regulator of both proliferation and cell death encoded by Trp53, were consistently upregulated. Reduction of Trp53 rescued neurodegeneration in Akirin2-null neurons. These data: (1) implicate Akirin2 as a critical neuronal maintenance protein, (2) identify p53 pathways as mediators of Akirin2 functions, and (3) suggest Akirin2 dysfunction may be relevant to neurodegenerative diseases.
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•Akirin2 is a nuclear protein involved in proliferation but maintained in postmitotic neurons•Postnatal Akirin2 knockout in cortical neurons leads to slow neurodegeneration•RNASeq identifies the dysregulation of p53-related genes in knockout neurons•Akirin2-null neurons die by necroptosis that depends on p53 upregulation
Biological sciences; Molecular biology; Neuroscience; Cell biology
Myosins are motor proteins in cells. They move along actin by changing
shape after making stereospecific interactions with the actin subunits. As these are arranged helically, a succession of steps ...will follow
a helical path. However, if the myosin heads are long enough to span the actin
helical repeat (∼36 nm), linear motion is possible. Muscle myosin
(myosin II) heads are about 16 nm long, which is insufficient
to span the repeat. Myosin V, however, has heads of about 31 nm
that could span 36 nm (refs 4, 5) and thus allow single two-headed molecules to transport
cargo by walking straight. Here we use electron microscopy
to show that while working, myosin V spans the helical repeat. The
heads are mostly 13 actin subunits apart, with values of 11 or 15 also found.
Typically the structure is polar and one head is curved, the other straighter.
Single particle processing reveals the polarity of the underlying actin filament,
showing that the curved head is the leading one. The shape of the leading
head may correspond to the beginning of the working stroke of the motor. We
also observe molecules attached by one head in this conformation.
Enhanced tumor cell survival through expression of inhibitors of apoptosis (IAP) is a hallmark of cancer. Survivin, an IAP absent from most normal tissues, is overexpressed in many malignancies and ...associated with a poorer prognosis. We report the first-in-human dose study of LY2181308, a second-generation antisense oligonucleotide (ASO) directed against survivin mRNA.
A dose-escalation study evaluating the safety, pharmacokinetics, and pharmacodynamics of LY2181308 administered intravenously for 3 hours as a loading dose on 3 consecutive days and followed by weekly maintenance doses. Patients were eligible after signing informed consent, had exhausted approved anticancer therapies and agreed to undergo pre- and posttreatment tumor biopsies to evaluate reduction of survivin protein and gene expression.
A total of 40 patients were treated with LY2181308 at doses of 100 to 1,000 mg. Twenty-six patients were evaluated at the recommended phase 2 dose of 750 mg, at which level serial tumor sampling and (11)CLY2183108 PET (positron emission tomography) imaging demonstrated that ASO accumulated within tumor tissue, reduced survivin gene and protein expression by 20% and restored apoptotic signaling in tumor cells in vivo. Pharmacokinetics were consistent with preclinical modeling, exhibiting rapid tissue distribution, and terminal half-life of 31 days.
The tumor-specific, molecularly targeted effects demonstrated by this ASO in man underpin confirmatory studies evaluating its therapeutic efficacy in cancer.
The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of ...tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K i* values of 0.38 ± 0.29 and 1.5 ± 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC50 = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.
Purpose: Histone acetyltransferases and histone deacetylases (HDAC) control the acetylation state of histones and other proteins regulating
transcription and protein function. Several structurally ...diverse HDAC inhibitors have been developed as cancer therapeutic
agents and in vitro have been shown to cause differentiation, cell cycle arrest, or apoptosis. Here, we have evaluated depsipeptide, a natural
tetrapeptide HDAC inhibitor, against a panel of pediatric solid tumor models in vivo and evaluated pharmacokinetic and pharmacodynamic variables with tumor sensitivity.
Experimental Design: Depsipeptide was administered at the maximum tolerated dose (4.4 mg/kg administered every 7 days × 3 i.v. repeated q21d for
a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors, 11 kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas,
and 7 osteosarcomas). Pharmacokinetic variables were determined, as were changes in histone and p53 acetylation, induction
of p53 and p53 genotype, and alterations in Akt phosphorylation.
Results: Of 39 tumors evaluated, three showed objective tumor regressions two brain tumors (primitive neuroectodermal tumor and atypical
teratoid malignant rhabdoid tumor) and one Wilms' tumor. Depsipeptide inhibited growth of many tumor lines but achieved stable
disease (<25% increase in volume during treatment cycle 1) in only two tumor models (anaplastic astrocytoma, two rhabdomyosarcomas,
and a Wilms' tumor). Pharmacokinetic analysis showed that the population estimated AUC 0-24 was 1,123 ng h/mL, similar to the exposure following 13 mg/m 2 in ongoing phase I trials. Pharmacodynamic changes in histone acetylation (H2A, H2B, H3, and H4) in three depsipeptide-sensitive
and three intrinsically resistant tumors followed a similar pattern; maximal increases in histone acetylation occurred at
8 hours and were elevated for up to 96 hours. In two sensitive tumor lines, IRS56 and BT27 (both wild-type p53) p53 increased
in treated tumors being maximal at 8 hours and associated with induction of p21 cip1 , whereas p53 was stable in tumors with mutant p53. Sensitivity to depsipeptide did not correlate with p53 genotype, p53 acetylation,
cleaved poly(ADP-ribose) polymerase, or phosphorylation of Akt (Ser 473 ).
Conclusions: Our results show that depsipeptide inhibits its target in vivo causing increased histone acetylation; however, this does not correlate with drug sensitivity. The relatively low objective
response rate 3 of 39 (8%) tumor lines showing greater than or equal to partial response and 4 (10%) stable disease administered
at dose levels that give clinically relevant drug exposures suggests that as a single agent depsipeptide may have limited
clinical utility against pediatric solid tumors in a first-line setting.
Introduction: Median urinary iodine concentration (UIC) is the most commonly used indicator of population iodine nutrition. However, its validity as an indicator of dietary intake relies on a stable ...relationship between dietary iodine intake and urinary excretion. Physiological alterations in normal pregnancy, such as increased glomerular filtration rate, potentially invalidate UIC as an assessment tool in pregnancy.
Objective: The objective of the study was to document the impact of advancing gestation on UIC in normal pregnancy and determine whether the current reference intervals for general population iodine monitoring are appropriate for use in the context of pregnancy.
Design: Tasmania has a well-described history of mild iodine deficiency (school-age median UIC of 84 μg/liter). We assessed UIC in 759 urine samples from 431 women attending the Antenatal Clinic at the Royal Hobart Hospital, Tasmania’s primary teaching hospital.
Main Outcome: The overall median UIC during pregnancy was 75 μg/liter (95% confidence interval 70.03–79.97 μg/liter) at a median gestation of 19.4 wk. Stratification by gestation, however, revealed a dynamic relationship between ioduria and gestation. Median UIC was elevated in early pregnancy and subsequently declined with advancing gestation.
Conclusion: In this mildly iodine-deficient population, current reference intervals for UIC overestimated the adequacy of iodine nutrition during the first and early second trimester of pregnancy. Gestation-specific UIC reference intervals are required to classify iodine nutrition during pregnancy. This is particularly important in populations with borderline iodine deficiency.
We show that a surface-grafted polymer brush, 1-n-butyl-3-vinyl imidazolium bromide-based poly(ionic liquids), is able to reduce the interfacial friction by up to 66% and 42% in dodecane and water, ...respectively. AFM-based force spectroscopy reveals that the polymer brush adopts distinctively different interfacial conformations: swollen in water but collapsed in dodecane. Minimal surface adhesion was observed with both polymer conformations, which can be attributed to steric repulsion as the result of a swollen conformation in water or surface solvation when the hydrophobic fraction of the polymer was exposed to the dodecane. The work brings additional insight on the polymer lubrication mechanism, which expands the possible design of the polymer architecture for interfacial lubrication and modification.
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the histone deacetylase inhibitor, depsipeptide, in children with ...refractory or recurrent solid tumors.
Depsipeptide was administered as a 4-hour infusion weekly for 3 consecutive weeks every 28 days at dose levels of 10 mg/m2, 13 mg/m2, 17 mg/m2, and 22 mg/m2. Pharmacokinetics and histone acetylation studies were performed in the first course. The levels of H3 histone and acetyl-H3 histone were evaluated in peripheral blood mononuclear cells (PBMC) using immunofluorescence techniques.
There were 24 patients, and 18 who were assessable were enrolled. DLTs included reversible, asymptomatic T-wave inversions, without any associated changes in troponin levels or evidence of ventricular dysfunction, in the inferior leads in two patients at 22 mg/m2 and in the lateral leads in one patient at 13 mg/m2 (n = 1), and transient asymptomatic sick sinus syndrome and hypocalcemia in one patient at 17 mg/m2. At the MTD (17 mg/m2), the median depsipeptide clearance was 6.8 L/h/m(2) with an area under the plasma depsipeptide concentration-time curve from 0 to infinity of 2,414 ng/mL/h, similar to adults. Accumulation of acetylated H3 histones was seen in all patients in a dose independent manner, with maximal accumulation at a median of 4 hours, (range, 0 hours to 20 hours) after the end of the infusion. No objective tumor responses were observed.
Depsipeptide is well tolerated in children with recurrent or refractory solid tumors when administered weekly for 3 consecutive weeks every 28 days and inhibits histone deacetylase activity in PBMC in a dose-independent manner. The recommended phase II dose in children with solid tumors is 17 mg/m2.
BACKGROUND: Despite evidence in support of the health benefits associated with fruit and vegetable (FV) intake, national data indicate that FV consumption among school‐aged children is below ...recommended levels, particularly among low‐income children. School meals offered through the School Breakfast Program and National School Lunch Program can provide an important contribution to child FV intake. This study examines the proportion of fruits and vegetables consumed from school meals programs among ethnically diverse, low socioeconomic status children.
METHODS: Participants (n = 103) included fourth to sixth grade boys and girls from 4 urban elementary schools in St. Paul, Minnesota serving primarily low‐income populations. Research staff interviewed children during school hours and recorded dietary intake via 24‐hour recall. Analysis included descriptive statistics using cross tabulations and means.
RESULTS: Average reported mean (SD) daily FV intake was 3.6 (2.5) servings, with 80% of children consuming fewer than 5 daily servings of FV. On average, children consumed over half of their daily FV intake within school. Children with low FV intake (<5 FV servings daily) consumed a higher proportion of their daily intake at school than children with higher FV intake (≥5 FV servings daily) (39% vs 59%; p = .002).
CONCLUSIONS: Child FV intake is below recommended levels. School meals provide an important contribution to the daily FV intake among ethnically diverse, low socioeconomic status children, particularly among those with the lowest FV intake. School meals programs promoting FV intake within the school environment may provide an opportunity to encourage increased FV consumption.
Most tuberculosis (TB) cases in low-incidence settings are thought to be due to reactivation of latent TB infection (LTBI) in high-risk populations 1–3. Assessment of patients at emergency ...departments (EDs) is a potential opportunity to achieve early TB diagnosis, and interrupt transmission. An earlier study in London found that 39% of patients diagnosed with TB had attended an ED in the preceding 6 months 4. Of these, 76% had a chest radiograph performed, of which 86% and 40% were abnormal in cases of pulmonary and extrapulmonary TB, respectively. Attendance at EDs provides an opportunity to identify individuals with LTBI, who may be at risk for progression to active disease and unlikely to engage with healthcare services
via
other routes.
LTBI screening among high-risk groups at EDs could be implemented to identify those at risk of progression to TB disease. Large-scale studies are required to investigate effective TB disease screening strategies in EDs.
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