Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX, defining molecular alterations in IDH-mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX-deficient glioma models in the presence and absence of the IDH1R132H mutation. ATRX-deficient glioma cells are sensitive to dsRNA-based innate immune agonism and exhibit impaired lethality and increased T-cell infiltration in vivo. However, the presence of IDH1R132H dampens baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1R132H inhibition. IDH1R132H co-expression does not interfere with the ATRX deficiency-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytomas.

Interplay between ATRX and IDH1 mutations governs innate immune responses in diffuse gliomas.

Stimulating the innate immune system has been explored as a therapeutic option for the treatment of gliomas. Inactivating mutations in ATRX , defining molecular alterations in IDH -mutant astrocytomas, have been implicated in dysfunctional immune signaling. However, little is known about the interplay between ATRX loss and IDH mutation on innate immunity. To explore this, we generated ATRX knockout glioma models in the presence and absence of the IDH1 R 132 H mutation. ATRX-deficient glioma cells were sensitive to dsRNA-based innate immune agonism and exhibited impaired lethality and increased T-cell infiltration in vivo . However, the presence of IDH1 R 132 H dampened baseline expression of key innate immune genes and cytokines in a manner restored by genetic and pharmacological IDH1 R132H inhibition. IDH1 R132H co-expression did not interfere with the ATRX KO-mediated sensitivity to dsRNA. Thus, ATRX loss primes cells for recognition of dsRNA, while IDH1 R132H reversibly masks this priming. This work reveals innate immunity as a therapeutic vulnerability of astrocytoma.

Multimodal imaging needle combining optical coherence tomography and fluorescence for imaging of live breast cancer cells labeled with a fluorescent analog of tamoxifen.

SIGNIFICANCE: Imaging needles consist of highly miniaturized focusing optics encased within a hypodermic needle. The needles may be inserted tens of millimeters into tissue and have the potential to visualize diseased cells well beyond the penetration depth of optical techniques applied externally. Multimodal imaging needles acquire multiple types of optical signals to differentiate cell types. However, their use has not previously been demonstrated with live cells. AIM: We demonstrate the ability of a multimodal imaging needle to differentiate cell types through simultaneous optical coherence tomography (OCT) and fluorescence imaging. APPROACH: We characterize the performance of a multimodal imaging needle. This is paired with a fluorescent analog of the therapeutic drug, tamoxifen, which enables cell-specific fluorescent labeling of estrogen receptor-positive (ER+) breast cancer cells. We perform simultaneous OCT and fluorescence in situ imaging on MCF-7 ER+ breast cancer cells and MDA-MB-231 ER- cells. Images are compared against unlabeled control samples and correlated with standard confocal microscopy images. RESULTS: We establish the feasibility of imaging live cells with these miniaturized imaging probes by showing clear differentiation between cancerous cells. CONCLUSIONS: Imaging needles have the potential to aid in the detection of specific cancer cells within solid tissue.

Polyphenisms and polymorphisms: Genetic variation in plasticity and color variation within and among bluefin killifish populations.

The presence of stable color polymorphisms within populations begs the question of how genetic variation is maintained. Consistent variation among populations in coloration, especially when correlated with environmental variation, raises questions about whether environmental conditions affect either the fulcrum of those balanced polymorphisms, the plastic expression of coloration, or both. Color patterns in male bluefin killifish provoke both types of questions. Red and yellow morphs are common in all populations. Blue males are more common in tannin-stained swamps relative to clear springs. Here, we combined crosses with a manipulation of light to explore how genetic variation and phenotypic plasticity shape these patterns. We found that the variation in coloration is attributable mainly to two axes of variation: (1) a red-yellow axis with yellow being dominant to red, and (2) a blue axis that can override red-yellow and is controlled by genetics, phenotypic plasticity, and genetic variation for phenotypic plasticity. The variation among populations in plasticity suggests it is adaptive in some populations but not others. The variation among sires in plasticity within the swamp population suggests balancing selection may be acting not only on the red-yellow polymorphism but also on plasticity for blue coloration.

Solution-phase decomposition of ferrocene into wüstite-iron oxide core-shell nanoparticles.

We report an improved method for the controlled solvent-phase decomposition of ferrocene into highly crystalline monodisperse iron oxide nanoparticles at relatively low temperatures. Solution-phase decomposition of ferrocene into nanoparticles has received little attention in the literature, due to the percieved stability of ferrocene. However, we synthesised wüstite FeO-iron oxide core-shell nanoparticles by thermally decomposing ferrocene in 1-octadecene solvent and in the presence of oleic acid and oleylamine, as surfactants. We report procedures that provide cubic and spherical core-shell iron oxide nanoparticles whose size (29.3 ± 2.3 nm for spheres, 38.6 ± 6.9 nm for distorted cubes and 23.5 ± 2.4 nm for distorted cubes with concave faces) and shape can be controlled through simple adjustments to reaction parameters. Transmission electron microscopy, scanning transmission electron microscopy, energy dispersive X-ray spectroscopy, electron energy-loss spectroscopy and powder X-ray diffraction analysis methods were used to characterise the nanoparticles.

Oncolytic vesicular stomatitis viruses selectively target M2 macrophages.

Macrophages have been identified as key players within the tumor microenvironment, with classically (M1) and alternatively (M2) activated macrophages exhibiting anti-tumoral and pro-tumoral functions, respectively. The goal of this study was to determine the response of macrophage populations to infection with oncolytic vesicular stomatitis virus (VSV). THP-1 monocytes were differentiated into various macrophage subsets and infected with wild-type (rwt virus) or matrix (M) protein mutant (rM51R-M virus) strains of VSV. Monocytes and M2 macrophages were susceptible to infection and killing by both rwt and rM51R-M viruses. rM51R-M virus also increased expression of the M1 markers p-STAT1, CD80, and TNF-α in pro-tumoral M2 macrophages, suggesting reprogramming towards an M1-like pro-inflammatory state. Meanwhile, rwt virus was more effective than rM51R-M virus at replicating in M2 macrophages and at inhibiting the development of invasive podosome structures. This was all in contrast to anti-tumoral M1 macrophages, which remained resistant to VSV-induced cytopathic effects. These results indicate that macrophage populations are differentially susceptible to VSV and that rwt and rM51R-M viruses may modulate the tumor-promoting phenotype of M2 macrophages by distinct mechanisms.

A new selective fluorescent probe based on tamoxifen.

Developing targeted validation probes that can interrogate biology is of interest for both chemists and biologists. The synthesis of suitable compounds provides a means for avoiding the costly labeling of cells with specific antibodies and the bias associated with the interpretation of biological validation experiments. The chemotherapeutic agent, tamoxifen has been routinely used in the treatment of breast cancer for decades. Once metabolized, the active form of tamoxifen (4-hydroxytamoxifen) competes with the binding of estrogens to the estrogen receptors (ER). Its selectivity in ER modulation makes it an ideal candidate for the development of materials to be used as chemical probes. Here we report the synthesis of a fluorescent BODIPY®FL conjugate of tamoxifen linked through an ethylene glycol moiety, and present proof-of-principle results in ER positive and ER negative cell lines. Optical microscopy indicates that the fluorescent probe binds selectively to tamoxifen sensitive breast cancer cell lines. The compound showed no affinity for the tamoxifen resistant breast cancer lines. The specificity of the new compound make it a valuable addition to the chemical probe tool kit for estrogen receptors.

Functional and population genomic divergence within and between two species of killifish adapted to different osmotic niches.

Adaptation to salinity affects species distributions, promotes speciation, and guides many evolutionary patterns in fishes. To uncover the basis of a complex trait like osmoregulation, genome-level analyses are sensible. We combine population genomic scans with genome expression profiling to discover candidate genes and pathways associated with divergence between osmotic environments. We compared transcriptome sequence divergence between multiple freshwater and saltwater populations of the rainwater killifish, Lucania parva. We also compared sequence divergence between L. parva and its sister species, Lucania goodei, a freshwater specialist. We found highly differentiated single nucleotide polymorphisms (SNPs) between freshwater and saltwater L. parva populations in cell junction and ion transport genes, including V-type H(+) ATPase. Between species, we found divergence in reproduction and osmotic stress genes. Genes that were differentially expressed between species during osmotic acclimation included genes involved in ion transport and cell volume regulation. Gene sets that were divergent in coding sequence and divergent in expression did not overlap, although they did converge in function. Like many studies using genomic scans, our approach may miss some loci that contribute to adaptation but have complicated patterns of allelic variation. Our study suggests that gene expression and coding sequence may evolve independently as populations adapt to a complex physiological challenge.

Comparison of the effectiveness of Conners' CPT and the CPT-identical pairs at distinguishing between smokers and nonsmokers with schizophrenia.

Sustained attention deficits and high rates of smoking are often observed in patients with schizophrenia. This has led to the hypothesis that patients may smoke as an attempt to ameliorate cognitive deficits related to abnormal nicotinic structure and function. Continuous performance tasks (CPT) are often used to index sustained attention deficits in patients with schizophrenia, however, there are important differences between tasks that may impact performance in smokers and nonsmokers with schizophrenia differently. The Conners' CPT (C-CPT) has a high signal-to-noise ratio and is commonly used to assess impulsivity. The CPT-Identical Pairs (CPT-IP) has a low signal-to-noise ratio and is commonly used to assess negative symptoms in patients with schizophrenia. We sought to determine whether there were differences of sustained attention between patient smokers vs. nonsmokers, and if one CPT would provide a better separation of sustained attention between groups. Results revealed that both instruments detect more impaired sustained attention deficits in patient smokers compared to nonsmokers. Patient smokers performed significantly worse on the majority of the CPT-IP composite scores compared to the C-CPT composite scores. These results do not support the self-medication theory, as patient smokers performed worse than patient nonsmokers. Researchers studying sustained attention in schizophrenia may wish to consider the CPT-IP over the C-CPT, as well as control for smoking status.

Effects of moderate-dose treatment with varenicline on neurobiological and cognitive biomarkers in smokers and nonsmokers with schizophrenia or schizoaffective disorder.

CONTEXT: The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder. It is not yet clear which nicotinic acetylcholine receptor (nAChR) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder. OBJECTIVE: Because α4ß2 is a key nAChR subtype for nicotinic actions, we investigated the effect of varenicline tartrate, a relatively specific α4ß2 partial agonist and antagonist, on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans. DESIGN: A double-blind, parallel, randomized, placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks (short-term treatment) and 8 weeks (long-term treatment), using a slow titration and moderate dosing strategy for retaining α4ß2-specific effects while minimizing adverse effects. SETTING: Outpatient clinics. PARTICIPANTS: A total of 69 smoking and nonsmoking patients; 64 patients completed week 2, and 59 patients completed week 8. Intervention Varenicline. MAIN OUTCOME MEASURES: Prepulse inhibition, sensory gating, antisaccade, spatial working memory, eye tracking, processing speed, and sustained attention. RESULTS: A moderate dose of varenicline (1) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment (P = .006), (2) reduced startle reactivity (P = .02) regardless of baseline smoking status, and (3) improved executive function by reducing the antisaccadic error rate (P = .03) regardless of smoking status. A moderate dose of varenicline had no significant effect on spatial working memory, predictive and maintenance pursuit measures, processing speed, or sustained attention by Conners' Continuous Performance Test. Clinically, there was no evidence of exacerbation of psychiatric symptoms, psychosis, depression, or suicidality using a gradual titration (1-mg daily dose). CONCLUSIONS: Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers. Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits.

Temperature-dependent crystal structure of the isopropanol clathrate of Dianin's compound.

The title compound undergoes two order-disorder transitions between 15 and 299 K, dictated by ordering of the guest molecules in the host cages, and resulting in three related crystal structures. We anticipate behaviour of this kind to be widespread, and speculate that the concept of "the crystal structure" for individual Dianin's clathrates may be elusive.