Acute Coronary Syndrome Management in Cancer Patients

Abstract

Purpose of Review

Coronary artery disease and cancer often co-exist. Patients with cancer have been excluded by most major cardiology trials and registries and their management remains largely empiric. Cancer patients experience an approximately 10-times increased mortality compared to the general population. Conservative therapy of ACS in cancer therapy results in 1-year mortality of 74%. This review article aims to describe the mechanisms of acute coronary syndromes in cancer patients, their clinical presentation, and their management.

Recent Findings

Newer studies have shed light on the mechanisms of ACS in cancer patients, which are different and related to the type of malignancy and its associated therapy. Medication-specific coronary effects (vasospasm, endothelial dysfunction, spontaneous thrombosis, accelerated atherosclerosis), radiation vasculitis, cancer cell coronary embolism, and coronary compression from thoracic malignancies are unique ACS mechanisms in cancer patients.

Summary

Close collaboration between oncologists and cardiologists for thoughtful patient selection and decision making strategies is necessary to provide optimal medical care.

Toward a Risk-Tailored Therapeutic Policy in Mantle Cell Lymphoma

Abstract

Purpose of Review

Mantle cell lymphoma (MCL) prognosis is strictly related to the characteristics of the disease, which can range from very indolent cases to highly aggressive and refractory ones. Here we will review the current knowledge on MCL biomarkers.

Recent Findings

Biomarker-informed diagnosis is essential for differentiating MCL from other mature B cell tumors. Diagnosis of MCL relies on the identification of the t(11;14) translocation by FISH or the consequently aberrant expression of cyclin D1 by immunohistochemistry. For the few cases staining negative for cyclin D1, SOX11 may help to define the diagnosis. Prognostic biomarkers have been proposed to stratify MCL patients, including baseline clinical aspects (leukemic non-nodal presentation, in situ presentation, Mantle cell International Prognostic Index—MIPI), pathological aspects (blastoid morphology, Ki-67 proliferation index, SOX11 expression), genetic aspects (immunoglobulin gene mutation status, TP53 deletion or mutation, CDKN2A deletion), and depth of response after treatment (PET imaging, molecular minimal residual disease). Such tools are increasingly used as a guide for therapeutic decisions. Watchful waiting approach is recommended for patients harboring favorable clinico-biological features, such as leukemic non-nodal presentation, low MIPI score, non-blastoid disease, low Ki-67 proliferation rate, mutated immunoglobulin genes, and the lack of SOX11 expression. For patients in need of frontline therapy, the decision of whether to undertake intensive regimens is based upon patient's age and comorbidities. Central nervous system prophylaxis is recommended for cases showing blastoid morphology. The duration of remission is tightly correlated to the depth of response. With the aim of achieving a longer duration of remission and survival, younger patients may pursue more intensive regimens incorporating high-dose cytarabine, followed by myeloablative consolidation chemotherapy, autologous stem cell transplantation, and rituximab maintenance. Older patients could, on the other hand, benefit from lower intensity immunochemotherapy followed or not by a maintenance therapy depending on which frontline regimen is used.

Summary

Despite the identification of several potential useful biomarkers that may inform the treatment decisions and the design of clinical trials, the treatment choice remains nowadays determined by the patient age and fitness rather than by the individual patient characteristics. Tailoring therapy toward a risk-adapted strategy to accommodate the wide spectrum of disease is an urgent challenge, and clinical trials may explore the feasibility of a biomarker-defined therapeutic policy.

Pervious concrete reactive barrier containing nano-silica for nitrate removal from contaminated water

Abstract

In this research, the effectiveness of using pervious concrete as a reactive barrier to decrease the concentration of nitrates in polluted water was investigated. Parameters of concrete mix design including water to cement ratio (W/C), aggregate to cement ratio (A/C), the amount of nano-silica (NS), and fine aggregates (FA) were studied based on Taguchi method. Properties of concrete such as compressive strength, density, permeability, and porosity, as well as pH measurement and the column method were carried out to assess the nitrate removal capacity of pervious concrete. Also, SEM-EDX, XRD, and FTIR were used to analyze the results. It was found that the optimum mix design in terms of nitrate removal corresponded to the mix with W/C = 0.26, A/C = 5, NS = 6%, and FA = 20%. Based on the results, it can be said that adding NS (up to 6%) and FA (up to 20%) to pervious concrete had the best influence on nitrate removal and compressive strength. Addition of NS increased the nitrate removal capacity due to increase in surface positive charges and provision of new surface functional groups.

Contribution of Sociodemographic Factors to Different Engagement of Children in Peer Violence

Violence and Gender, Ahead of Print.

Effects of Freeze-Dried Grape Powder on High-Density Lipoprotein Function in Adults with Metabolic Syndrome: A Randomized Controlled Pilot Study

Metabolic Syndrome and Related Disorders, Ahead of Print.

Relationship Between Handgrip Strength and Nonalcoholic Fatty Liver Disease: Nationwide Surveys

Metabolic Syndrome and Related Disorders, Ahead of Print.

High Body Mass Index Masks Body Composition Differences in Physically Active Versus Sedentary Participants

Metabolic Syndrome and Related Disorders, Ahead of Print.

Deep(er) Learning

Animals successfully thrive in noisy environments with finite resources. The necessity to function with resource constraints has led evolution to design animal brains (and bodies) to be optimal in their use of computational power while being adaptable to their environmental niche. A key process undergirding this ability to adapt is the process of learning. Although a complete characterization of the neural basis of learning remains ongoing, scientists for nearly a century have used the brain as inspiration to design artificial neural networks capable of learning, a case in point being deep learning. In this viewpoint, we advocate that deep learning can be further enhanced by incorporating and tightly integrating five fundamental principles of neural circuit design and function: optimizing the system to environmental need and making it robust to environmental noise, customizing learning to context, modularizing the system, learning without supervision, and learning using reinforcement strategies. We illustrate how animals integrate these learning principles using the fruit fly olfactory learning circuit, one of nature's best-characterized and highly optimized schemes for learning. Incorporating these principles may not just improve deep learning but also expose common computational constraints. With judicious use, deep learning can become yet another effective tool to understand how and why brains are designed the way they are.

Inositol Hexakisphosphate Kinase-2 in Cerebellar Granule Cells Regulates Purkinje Cells and Motor Coordination via Protein 4.1N

Inositol hexakisphosphate kinases (IP6Ks) regulate various biological processes. Among pyrophosphates generated by IP6Ks, diphosphoinositol pentakisphosphate (IP7), and bis-diphosphoinositol tetrakisphosphate have been extensively characterized. IP7 is produced in mammals by a family of inositol hexakisphosphate kinases, IP6K1, IP6K2, and IP6K3, which have distinct biological functions. We report that IP6K2 binds protein 4.1.N with high affinity and specificity. Nuclear translocation of 4.1N, which is required for its principal functions, is dependent on IP6K2. Both of these proteins are highly expressed in granule cells of the cerebellum where their interaction regulates Purkinje cell morphology and cerebellar synapses. The deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. Moreover, the disruption of IP6K2–4.1N interactions impairs cell viability. Thus, IP6K2 and its interaction with 4.1N appear to be major determinants of cerebellar disposition and psychomotor behavior.

SIGNIFICANCE STATEMENT Inositol phosphates are produced by a family of inositol hexakisphosphate kinases (IP6Ks)—IP6K1, IP6K2, and IP6K3. Of these, the physiological roles of IP6K2 in the brain have been least characterized. In the present study, we report that IP6K2 binds selectively to the neuronal protein 4.1N. Both of these proteins are highly expressed in granule cells of the cerebellum. Using IP6K2 knock-out (KO) mice, we establish that IP6K2–4.1N interactions in granule cells regulate Purkinje cell morphology, the viability of cerebellar neurons, and psychomotor behavior.

Dnmt3a2 in the Nucleus Accumbens Shell Is Required for Reinstatement of Cocaine Seeking

Epigenetic mechanisms have gained increasing attention as regulators of synaptic plasticity and responsiveness to drugs of abuse. In particular, it has been shown that the activity of the DNA methyltransferase 3a (Dnmt3a) mediates certain long-lasting effects of cocaine. Here we examined the role of the Dnmt isoforms, Dnmt3a1 and Dnmt3a2, within the nucleus accumbens (NAc) on transcriptional activity of immediate early genes (IEGs) and acute and long-lasting responsiveness to cocaine and cocaine conditioned cues. Using primary striatal cultures, we show that transcription of Dnmt3a2, but not that of Dnmt3a1, is activated by dopamine D1 receptor signaling and that knockdown of Dnmt3a2 using viral vector-mediated expression of Dnmt3a2-specific shRNAs impairs induction of the IEGs, Arc, FosB, and Egr2. Acute cocaine administration increases expression of Dnmt3a2 but not that of Dnmt3a1 in the NAc shell. In contrast, in the NAc core, expression of Dnmt3a1 and Dnmt3a2 was unaffected by cocaine administration. shRNA-mediated knockdown of Dnmt3a2 in vivo impairs the induction of IEGs, including Egr2 and FosB indicating that Dnmt3a2 regulates cocaine-dependent expression of plasticity genes in the rat NAc shell. Cocaine self-administration experiments in rats revealed that Dnmt3a2 regulates drug cue memories that drive reinstatement of cocaine seeking as well as incubation of this phenomenon within the NAc shell. Dnmt3a2 does not influence the primary reinforcing effects of cocaine. Thus, Dnmt3a2 mediates long-lasting cocaine cue memories within the NAc shell. Targeting Dnmt3a2 expression or function may interfere with cocaine craving and relapse.

SIGNIFICANCE STATEMENT In humans, drug craving can occur in response to conditioned cues, even after extended periods of abstinence. In rats, cue-induced cocaine seeking has been shown to increase progressively during the first 2 months of abstinence from drug self-administration. This phenomenon, referred to as incubation of cocaine seeking, is consistent with the hypothesis that in humans craving increases over time and remains high following prolonged abstinence. Those long-lasting behavioral changes are likely to be mediated by epigenetic effects and neuroplastic changes within the mesolimbic brain reward system. Here we show that a specific isoform of DNA-methyltransferases in the NAc shell regulates drug cue memories that drive reinstatement of cocaine seeking after both early abstinence and incubation of cocaine craving.

Peripheral Gene Therapeutic Rescue of an Olfactory Ciliopathy Restores Sensory Input, Axonal Pathfinding, and Odor-Guided Behavior

Cilia of olfactory sensory neurons (OSNs) are the primary site of odor binding; hence, their loss results in anosmia, a clinical manifestation of pleiotropic ciliopathies for which there are no curative therapies. We used OSN-specific Ift88 knock-out mice (Ift88^osnKO) of both sexes to examine the mechanisms of ciliopathy-induced olfactory dysfunction and the potential for gene replacement to rescue odorant detection, restore olfactory circuitry, and restore odor-guided behaviors. Loss of OSN cilia in Ift88^osnKO mice resulted in substantially reduced odor detection and odor-driven synaptic activity in the olfactory bulb (OB). Defects in OSN axon targeting to the OB were also observed in parallel with aberrant odor-guided behavior. Intranasal gene delivery of wild-type IFT88 to Ift88^osnKO mice rescued OSN ciliation and peripheral olfactory function. Importantly, this recovery of sensory input in a limited number of mature OSNs was sufficient to restore axonal targeting in the OB of juvenile mice, and with delayed onset in adult mice. In addition, restoration of sensory input re-established course odor-guided behaviors. These findings highlight the spare capacity of the olfactory epithelium and the plasticity of primary synaptic input into the central olfactory system. The restoration of peripheral and central neuronal function supports the potential for treatment of ciliopathy-related anosmia using gene therapy.

SIGNIFICANCE STATEMENT Ciliopathies, for which there are no curative therapies, are genetic disorders that alter cilia morphology and/or function in numerous tissue types, including the olfactory system, leading to sensory dysfunction. We show that in vivo intranasal gene delivery restores peripheral olfactory function in a ciliopathy mouse model, including axonal targeting in the juvenile and adult olfactory bulb. Gene therapy also demonstrated restoration of olfactory perception by rescuing odor-guided behaviors. Understanding the therapeutic window and viability for gene therapy to restore odor detection and perception may facilitate translation of therapies to ciliopathy patients with olfactory dysfunctions.

This Week in The Journal

Modeling Schizophrenia's Abnormal Cortical Neural Synchrony in Monkeys

Face Repetition Probability Does Not Affect Repetition Suppression in Macaque Inferotemporal Cortex

Repetition suppression, which refers to reduced neural activity for repeated stimuli, is typically explained by bottom-up or local adaptation mechanisms. However, recent theories have emphasized the role of top-down processes, suggesting that this response reduction reflects the fulfillment of perceptual expectations. To support this, an influential human fMRI study showed that the magnitude of suppression is modulated by the probability of a repetition. No such repetition probability effect was found in macaque inferior temporal (IT) cortex for spiking activity despite the presence of repetition suppression. Contrary to the human fMRI studies that showed an effect of repetition probability, the macaque single-unit study used a large variety of unfamiliar stimuli and the monkeys were not required to attend the stimuli. Here, as in the human fMRI studies, we used faces as stimuli and made the monkeys attend to the stimulus content. We simultaneously recorded spiking activity and local field potentials (LFPs) in the middle lateral face patch (ML) of one monkey (male) and a face-responsive region of another (female). Although we observed significant repetition suppression of spiking activity and high gamma-band LFPs in both animals, there were no effects of repetition probability even when repetitions were task relevant and repetition probability affected behavioral decisions. In conclusion, despite the use of face stimuli and a stimulus-related task, no neural signature of repetition probability was present for faces in a face responsive patch of macaque IT. This further challenges a general perceptual expectation account of repetition suppression.

SIGNIFICANCE STATEMENT Repetition suppression is a reduced brain activity for repeated stimuli commonly observed across species. In the predictive coding framework, such suppression is thought to reflect fulfilled perceptual expectations. Although this hypothesis is supported by several human fMRI studies reporting an effect of repetition probability on repetition suppression, this could not be replicated in single-cell recordings in monkey inferior temporal (IT) cortex. Subsequent studies narrowed down the conditions for the effect to requiring attention and being limited to particular stimulus categories such as faces. Here, we show that, even under these conditions, repetition suppression in monkey IT neurons is still unaffected by repetition probability, even in a task with a behavioral effect, challenging the perceptual expectation account of repetition suppression.

Estrogen Treatment Reverses Prematurity-Induced Disruption in Cortical Interneuron Population

Development of cortical interneurons continues until the end of human pregnancy. Premature birth deprives the newborns from the supply of maternal estrogen and a secure intrauterine environment. Indeed, preterm infants suffer from neurobehavioral disorders. This can result from both preterm birth and associated postnatal complications, which might disrupt recruitment and maturation of cortical interneurons. We hypothesized that interneuron subtypes, including parvalbumin-positive (PV⁺), somatostatin-positive (SST⁺), calretinin-positive (CalR⁺), and neuropeptide Y-positive (NPY⁺) interneurons, were recruited in the upper and lower cortical layers in a distinct manner with advancing gestational age. In addition, preterm birth would disrupt the heterogeneity of cortical interneurons, which might be reversed by estrogen treatment. These hypotheses were tested by analyzing autopsy samples from premature infants and evaluating the effect of estrogen supplementation in prematurely delivered rabbits. The PV⁺ and CalR⁺ neurons were abundant, whereas SST⁺ and NPY⁺ neurons were few in cortical layers of preterm human infants. Premature birth of infants reduced the density of PV⁺ or GAD67⁺ neurons and increased SST⁺ interneurons in the upper cortical layers. Importantly, 17 β-estradiol treatment in preterm rabbits increased the number of PV⁺ neurons in the upper cortical layers relative to controls at postnatal day 14 (P14) and P21 and transiently reduced SST population at P14. Moreover, protein and mRNA levels of Arx, a key regulator of cortical interneuron maturation and migration, were higher in estrogen-treated rabbits relative to controls. Therefore, deficits in PV⁺ and excess of SST⁺ neurons in premature newborns are ameliorated by estrogen replacement, which can be attributed to elevated Arx levels. Estrogen replacement might enhance neurodevelopmental outcomes in extremely preterm infants.

SIGNIFICANCE STATEMENT Premature birth often leads to neurodevelopmental delays and behavioral disorders, which may be ascribed to disturbances in the development and maturation of cortical interneurons. Here, we show that preterm birth in humans is associated with reduced population of parvalbumin-positive (PV⁺) neurons and an excess of somatostatin-expressing interneurons in the cerebral cortex. More importantly, 17 β-estradiol treatment increased the number of PV⁺ neurons in preterm-born rabbits, which appears to be mediated by an elevation in the expression of Arx transcription factor. Hence the present study highlights prematurity-induced reduction in PV⁺ neurons in human infants and reversal in their population by estrogen replacement in preterm rabbits. Because preterm birth drops plasma estrogen level 100-fold, estrogen replacement in extremely preterm infants might improve their developmental outcome and minimize neurobehavioral disorders.

Correction: Perez and Merchant, "The Synaptic Properties of Cells Define the Hallmarks of Interval Timing in a Recurrent Neural Network"

Neural Firing Patterns Are More Schematic and Less Sensitive to Changes in Background Visual Scenes in the Subiculum than in the Hippocampus

Literature suggests that the hippocampus is central to processing visual scenes to remember contextual information, but the roles of its downstream structure, subiculum, remain unknown. Here, single units were recorded simultaneously in the dorsal CA1 and subiculum while male rats made spatial choices using visual scenes as cues in a T-maze. The firing fields of subicular neurons were schematically organized following the task structure, largely divided into pre-choice and post-choice epochs, whereas those of CA1 cells were more punctate and bound to specific locations. When the rats were tested with highly familiar scenes, neurons in the CA1 and subiculum were indistinguishable in coding the task-related information (e.g., scene, choice) through rate remapping. However, when the familiar scenes were blurred parametrically, the neurons in the CA1 responded sensitively to the novelty in task demand and changed its representations parametrically following the physical changes of the stimuli, whereas these functional characteristics were absent in the subiculum. These results suggest that the unique function of the hippocampus is to acquire contextual representations in association with discrete positions in space, especially when facing new and ambiguous scenes, whereas the subiculum may translate the position-bound visual contextual information of the hippocampus into schematic codes once learning is established.

SIGNIFICANCE STATEMENT Although the potential functional significance has been recognized for decades for the subiculum, its exact roles in a goal-directed memory task still remain elusive. In the current study, we present experimental evidence that may indicate that the neural population in the subiculum could translate the location-bound spatial representations of the hippocampus into more schematic representations of task demands. Our findings also imply that the visual scene-based codes conveyed by the hippocampus and subiculum may be identical in a well learned task, whereas the hippocampus may be more specialized in representing altered visual scenes than the subiculum.

Suppressed Sensory Response to Predictable Object Stimuli throughout the Ventral Visual Stream

Prediction plays a crucial role in perception, as prominently suggested by predictive coding theories. However, the exact form and mechanism of predictive modulations of sensory processing remain unclear, with some studies reporting a downregulation of the sensory response for predictable input whereas others observed an enhanced response. In a similar vein, downregulation of the sensory response for predictable input has been linked to either sharpening or dampening of the sensory representation, which are opposite in nature. In the present study, we set out to investigate the neural consequences of perceptual expectation of object stimuli throughout the visual hierarchy, using fMRI in human volunteers. Participants of both sexes were exposed to pairs of sequentially presented object images in a statistical learning paradigm, in which the first object predicted the identity of the second object. Image transitions were not task relevant; thus, all learning of statistical regularities was incidental. We found strong suppression of neural responses to expected compared with unexpected stimuli throughout the ventral visual stream, including primary visual cortex, lateral occipital complex, and anterior ventral visual areas. Expectation suppression in lateral occipital complex scaled positively with image preference and voxel selectivity, lending support to the dampening account of expectation suppression in object perception.

SIGNIFICANCE STATEMENT It has been suggested that the brain fundamentally relies on predictions and constructs models of the world to make sense of sensory information. Previous research on the neural basis of prediction has documented suppressed neural responses to expected compared with unexpected stimuli. In the present study, we demonstrate robust expectation suppression throughout the entire ventral visual stream, and underlying this suppression a dampening of the sensory representation in object-selective visual cortex, but not in primary visual cortex. Together, our results provide novel evidence in support of theories conceptualizing perception as an active inference process, which selectively dampens cortical representations of predictable objects. This dampening may support our ability to automatically filter out irrelevant, predictable objects.

Amplification and Suppression of Distinct Brainwide Activity Patterns by Catecholamines

The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects of catecholaminergic modulation on network dynamics are homogeneous across the brain. However, the brain is equipped with a variety of catecholamine receptors with distinct functional effects and heterogeneous density across brain regions. Consequently, catecholaminergic effects on brainwide network dynamics might be more spatially specific than assumed. We tested this idea through the analysis of fMRI measurements performed in humans (19 females, 5 males) at "rest" under pharmacological (atomoxetine-induced) elevation of catecholamine levels. We used a linear decomposition technique to identify spatial patterns of correlated fMRI signal fluctuations that were either increased or decreased by atomoxetine. This yielded two distinct spatial patterns, each expressing reliable and specific drug effects. The spatial structure of both fluctuation patterns resembled the spatial distribution of the expression of catecholamine receptor genes: α₁ norepinephrine receptors (for the fluctuation pattern: placebo > atomoxetine), D₂-like dopamine receptors (pattern: atomoxetine > placebo), and β norepinephrine receptors (for both patterns, with correlations of opposite sign). We conclude that catecholaminergic effects on the forebrain are spatially more structured than traditionally assumed and at least in part explained by the heterogeneous distribution of various catecholamine receptors. Our findings link catecholaminergic effects on large-scale brain networks to low-level characteristics of the underlying neurotransmitter systems. They also provide key constraints for the development of realistic models of neuromodulatory effects on large-scale brain network dynamics.

SIGNIFICANCE STATEMENT The catecholamines norepinephrine and dopamine are an important class of modulatory neurotransmitters. Because of the widespread and diffuse release of these neuromodulators, it has commonly been assumed that their effects on neural interactions are homogeneous across the brain. Here, we present results from the human brain that challenge this view. We pharmacologically increased catecholamine levels and imaged the effects on the spontaneous covariations between brainwide fMRI signals at "rest." We identified two distinct spatial patterns of covariations: one that was amplified and another that was suppressed by catecholamines. Each pattern was associated with the heterogeneous spatial distribution of the expression of distinct catecholamine receptor genes. Our results provide novel insights into the catecholaminergic modulation of large-scale human brain dynamics.

Age-Related Trajectories of Functional Coupling between the VTA and Nucleus Accumbens Depend on Motivational State

Over-engagement of the mesolimbic dopamine system is thought to enhance motivation in adolescents. Whereas human neuroimaging has characterized event-evoked responses of the mesolimbic system in adolescents, research has yet to characterize state-dependent engagement (i.e., seconds to minutes) of this system in goal-relevant contexts. In the current longitudinal study, we characterized age-related changes in state-dependent coupling in male and female human participants ranging in age from adolescence to adulthood. Analyses focused on two key regions of the mesolimbic dopamine system, the ventral tegmental area (VTA) and nucleus accumbens (NAcc). Although there were no differences in VTA–NAcc functional coupling in a resting-state context, VTA–NAcc functional coupling was enhanced in preadolescence/early adolescence and decreased into adulthood in a motivational context, in which individuals had to translate goal-relevant cues into instrumental actions. Furthermore, we found that task-related activation in orbitofrontal cortex, middle temporal gyrus, and visual association cortex partially mediated age-related changes in state-dependent VTA–NAcc functional coupling. These results extend prior models of neurodevelopment by showing a relationship between cortical event-evoked activation and state-dependent increases in subcortical engagement of mesolimbic systems.

SIGNIFICANCE STATEMENT Adolescence is characterized by increased motivated behavior, which is thought to result from an over-engagement of mesolimbic dopamine systems. Rodent models show increases in state-dependent engagement of mesolimbic systems in adolescence. However, human neuroimaging research has mainly focused on event-evoked responses (i.e., reward cues). We show that in motivational contexts, there is increased state-dependent coupling across mesolimbic systems in preadolescence/early adolescence that decreases into adulthood and is further predicted by event-evoked cortical responses. Critically, these developmental trajectories were specific to motivationally relevant contexts and were not apparent during resting state. These findings extend emerging models of human development and suggest that state-dependent increases in dopamine signaling may underlie heightened motivation.

Evidence for Compartmentalized Axonal Mitochondrial Biogenesis: Mitochondrial DNA Replication Increases in Distal Axons As an Early Response to Parkinson's Disease-Relevant Stress

Dysregulation of mitochondrial biogenesis is implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). However, it is not clear how mitochondrial biogenesis is regulated in neurons, with their unique compartmentalized anatomy and energetic demands. This is particularly relevant in PD because selectively vulnerable neurons feature long, highly arborized axons where degeneration initiates. We previously found that exposure of neurons to chronic, sublethal doses of rotenone, a complex I inhibitor linked to PD, causes early increases in mitochondrial density specifically in distal axons, suggesting possible upregulation of mitochondrial biogenesis within axons. Here, we directly evaluated for evidence of mitochondrial biogenesis in distal axons and examined whether PD-relevant stress causes compartmentalized alterations. Using BrdU labeling and imaging to quantify replicating mitochondrial DNA (mtDNA) in primary rat neurons (pooled from both sexes), we provide evidence of mtDNA replication in axons along with cell bodies and proximal dendrites. We found that exposure to chronic, sublethal rotenone increases mtDNA replication first in neurites and later extending to cell bodies, complementing our mitochondrial density data. Further, isolating axons from cell bodies and dendrites, we discovered that rotenone exposure upregulates mtDNA replication in distal axons. Utilizing superresolution stimulated emission depletion (STED) imaging, we identified mtDNA replication at sites of mitochondrial–endoplasmic reticulum contacts in axons. Our evidence suggests that mitochondrial biogenesis occurs not only in cell bodies, but also in distal axons, and is altered under PD-relevant stress conditions in an anatomically compartmentalized manner. We hypothesize that this contributes to vulnerability in neurodegenerative diseases.

SIGNIFICANCE STATEMENT Mitochondrial biogenesis is crucial for maintaining mitochondrial and cellular health and has been linked to neurodegenerative disease pathogenesis. However, regulation of this process is poorly understood in CNS neurons, which rely on mitochondrial function for survival. Our findings offer fundamental insight into these regulatory mechanisms by demonstrating that replication of mitochondrial DNA, an essential precursor for biogenesis, can occur in distal regions of CNS neuron axons independent of the soma. Further, this process is upregulated specifically in axons as an early response to neurodegeneration-relevant stress. This is the first demonstration of the compartmentalized regulation of CNS neuronal mitochondrial biogenesis in response to stress and may prove a useful target in development of therapeutic strategies for neurodegenerative disease.

Temporal Expectation Modulates the Cortical Dynamics of Short-Term Memory

Increased memory load is often signified by enhanced neural oscillatory power in the alpha range (8–13 Hz), which is taken to reflect inhibition of task-irrelevant brain regions. The corresponding neural correlates of memory decay, however, are not yet well understood. In the current study, we investigated auditory short-term memory decay in humans using a delayed matching-to-sample task with pure-tone sequences. First, in a behavioral experiment, we modeled memory performance over six different delay-phase durations. Second, in a MEG experiment, we assessed alpha-power modulations over three different delay-phase durations. In both experiments, the temporal expectation for the to-be-remembered sound was manipulated so that it was either temporally expected or not. In both studies, memory performance declined over time, but this decline was weaker when the onset time of the to-be-remembered sound was expected. Similarly, patterns of alpha power in and alpha-tuned connectivity between sensory cortices changed parametrically with delay duration (i.e., decrease in occipitoparietal regions, increase in temporal regions). Temporal expectation not only counteracted alpha-power decline in heteromodal brain areas (i.e., supramarginal gyrus), but also had a beneficial effect on memory decay, counteracting memory performance decline. Correspondingly, temporal expectation also boosted alpha connectivity within attention networks known to play an active role during memory maintenance. The present data show how patterns of alpha power orchestrate short-term memory decay and encourage a more nuanced perspective on alpha power across brain space and time beyond its inhibitory role.

SIGNIFICANCE STATEMENT Our sensory memories of the physical world fade quickly. We show here that this decay of short-term memory can be counteracted by so-called temporal expectation; that is, knowledge of when to expect a sensory event that an individual must remember. We also show that neural oscillations in the "alpha" (8–13 Hz) range index both the degree of memory decay (for brief sound patterns) and the respective memory benefit from temporal expectation. Spatially distributed cortical patterns of alpha power show opposing effects in auditory versus visual sensory cortices. Moreover, alpha-tuned connectivity changes within supramodal attention networks reflect the allocation of neural resources as short-term memory representations fade.

Long-Term Depression Induced by Optogenetically Driven Nociceptive Inputs to Trigeminal Nucleus Caudalis or Headache Triggers

The peripheral trigeminovascular pathway mediates orofacial and craniofacial pain and projects centrally to the brainstem trigeminal nucleus caudalis (TNc). Sensitization of this pathway is involved in many pain conditions, but little is known about synaptic plasticity at its first central synapse. We have taken advantage of optogenetics to investigate plasticity selectively evoked at synapses of nociceptive primary afferents onto TNc neurons. Based on immunolabeling in the trigeminal ganglia, TRPV1-lineage neurons comprise primarily peptidergic and nonpeptidergic nociceptors. Optical stimulation of channelrhodopsin-expressing axons in the TRPV1/ChR2 mouse in TNc slices thus allowed us to activate a nociceptor-enriched subset of primary afferents. We recorded from lamina I/II neurons in acutely prepared transverse TNc slices, and alternately stimulated two independent afferent pathways, one with light-activated nociceptive afferents and the other with electrically-activated inputs. Low-frequency optical stimulation induced robust long-term depression (LTD) of optically-evoked EPSCs, but not of electrically-evoked EPSCs in the same neurons. Blocking NMDA receptors or nitric oxide synthase strongly attenuated LTD, whereas a cannabinoid receptor 1 antagonist had no effect. The neuropeptide PACAP-38 or the nitric oxide donors nitroglycerin or sodium nitroprusside are pharmacologic triggers of human headache. Bath application of any of these three compounds also persistently depressed optically-evoked EPSCs. Together, our data show that LTD of nociceptive afferent synapses on trigeminal nucleus neurons is elicited when the afferents are activated at frequencies consistent with the development of central sensitization of the trigeminovascular pathway.

SIGNIFICANCE STATEMENT Animal models suggest that sensitization of trigeminovascular afferents plays a major role in craniofacial pain syndromes including primary headaches and trigeminal neuralgia, yet little is known about synaptic transmission and plasticity in the brainstem trigeminal nucleus caudalis (TNc). Here we used optogenetics to selectively drive a nociceptor-enriched population of trigeminal afferents while recording from superficial laminae neurons in the TNc. Low-frequency optical stimulation evoked robust long-term depression at TRPV1/ChR2 synapses. Moreover, application of three different headache trigger drugs also depressed TRPV1/ChR2 synapses. Synaptic depression at these primary afferent synapses may represent a newly identified mechanism contributing to central sensitization during headache.

Enhancement of the Medial Olivocochlear System Prevents Hidden Hearing Loss

Cochlear synaptopathy produced by exposure to noise levels that cause only transient auditory threshold elevations is a condition that affects many people and is believed to contribute to poor speech discrimination in noisy environments. These functional deficits in hearing, without changes in sensitivity, have been called hidden hearing loss (HHL). It has been proposed that activity of the medial olivocochlear (MOC) system can ameliorate acoustic trauma effects. Here we explore the role of the MOC system in HHL by comparing the performance of two different mouse models: an α9 nicotinic receptor subunit knock-out (KO; Chrna9 KO), which lacks cholinergic transmission between efferent neurons and hair cells; and a gain-of-function knock-in (KI; Chrna9L9'T KI) carrying an α9 point mutation that leads to enhanced cholinergic activity. Animals of either sex were exposed to sound pressure levels that in wild-type produced transient cochlear threshold shifts and a decrease in neural response amplitudes, together with the loss of ribbon synapses, which is indicative of cochlear synaptopathy. Moreover, a reduction in the number of efferent contacts to outer hair cells was observed. In Chrna9 KO ears, noise exposure produced permanent auditory threshold elevations together with cochlear synaptopathy. In contrast, the Chrna9L9'T KI was completely resistant to the same acoustic exposure protocol. These results show a positive correlation between the degree of HHL prevention and the level of cholinergic activity. Notably, enhancement of the MOC feedback promoted new afferent synapse formation, suggesting that it can trigger cellular and molecular mechanisms to protect and/or repair the inner ear sensory epithelium.

SIGNIFICANCE STATEMENT Noise overexposure is a major cause of a variety of perceptual disabilities, including speech-in-noise difficulties, tinnitus, and hyperacusis. Here we show that exposure to noise levels that do not cause permanent threshold elevations or hair cell death can produce a loss of cochlear nerve synapses to inner hair cells as well as degeneration of medial olivocochlear (MOC) terminals contacting the outer hair cells. Enhancement of the MOC reflex can prevent both types of neuropathy, highlighting the potential use of drugs that increase α9α10 nicotinic cholinergic receptor activity as a pharmacotherapeutic strategy to avoid hidden hearing loss.

Correction: Stalnaker et al., "Cholinergic Interneurons Use Orbitofrontal Input to Track Beliefs about Current State"

First results on DCVax phase III trial: raising more questions than providing answers

Recently, the long-awaited report on efficacy data of the DCVax trial has appeared in the Journal of Translational Medicine.¹ Patients and physicians alike are eager to critically evaluate the first results of this important trial, which is one of the earliest major attempts to improve outcome in patients with glioblastoma using immunotherapy based on an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax). It is not only one of the first randomized phase III trials of its kind, but in light of recent successes with cancer immunotherapies outside neuro-oncology, there is a huge interest in any form of immune treatment for glioma patients. Any report is highly relevant, not in the least as the treatment is offered commercially to patients, at high cost, and without the effectiveness of the treatment being known to date. In the interplay between concept-based hopes and urgent need for effective treatments, it is of the utmost importance that outcome data are shared with the community.

Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer

Abstract

Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily. Notwithstanding its characterization as an endothelial cell marker, the full spectrum of biological processes associated with ALK1 is essentially unexplored. Here, we present data revealing the genetic network associated with ACVRL1 (the gene encoding for ALK1) expression in human cancer tissues. Computational analysis unveiled a hitherto unknown role for ACVRL1 in relation to genes modulating the functionality of the immune cell compartment. Moreover, we generated a signature of 8 genes co-expressed with ACVRL1 across different tumor types and characterized the c-type lectin domain containing protein (CLEC)14A as a potential downstream target of ACVRL1. Considering the lack of reagents for ALK1 detection that has hampered the field to date, our work provides the opportunity to validate the 8-gene signature and CLEC14A as biomarkers for ALK1 activity. Ultimately, this may help revisit the clinical development of already existing ALK1-blocking compounds as precision medicines for cancer.

Antidermatophytic Activity and Skin Retention of Clotrimazole Microemulsion and Microemulsion-Based Gel in Comparison to Conventional Cream

Aim: Antifungal activity, skin permeation and skin retention of water-in-oil microemulsion (ME) and microemulsion-based gel (MBG) containing clotrimazole (CTZ) were evaluated in comparison to a conventional CTZ cream. Methods: CTZ-ME and CTZ-MBG containing 1% w/w of CTZ were produced. Antifungal activity against Trichophyton mentagrophytes was assessed by the agar diffusion method. Pig skin was used in the in vitro penetration study using modified Franz diffusion cells. Drug amounts which permeated into the receptor fluid, retained in the skin membrane and remained in the donor compartment were analyzed by a validated HPLC technique. Results: CTZ-ME and CTZ-MBG exhibited inhibition zones against T. mentagrophytes whereas the conventional cream did not reveal any inhibition zone in the assay. While no CTZ was detected in the receptor fluid up to 24 h following the in vitro penetration study from all tested formulations, the amount of CTZ retained in the skin membrane when applying CTZ-ME and CTZ-MBG was remarkably higher than that when applying the cream. Conclusion: Results revealed the capacity of ME and MBG in improving skin bioavailability of CTZ while reducing the risk of systemic side effects. Thereby, ME and MBG could increase the efficacy of CTZ for dermatophytosis treatment in comparison to conventional cream.
Skin Pharmacol Physiol 2018;31:292–297

Age- and Diabetes-Related Changes in the Free Fatty Acid Composition of the Human Stratum Corneum

Of particular importance for Stratum corneum (SC) lipids are the free fatty acids (FFAs). Age-related changes of the SC structure lead to diminished capacity for barrier compensation. The aims of this cross-sectional study were to identify even-numbered especially odd-numbered FFAs within the intercorneocytic lamellar lipid structures of the SC and to explore age- and diabetes-related changes in FFAs. Gas chromatography – flame ionisation detection was used to qualitatively and quantitatively assess FFAs extracted from the SC. 110 subjects aged over 60 years (elderly/healthy), 110 subjects aged 18–40 (young/healthy) and 38 subjects with diabetes mellitus aged 18–40 (young/diabetic) were investigated. Overall, odd-numbered FFAs comprised about 21, 23 and 24% of total FFAs in subgroups elderly/healthy, young/healthy and young/diabetic. The most abundant short-chain FFAs were C16: 0 and C18: 0 and long-chain FFAs were C24: 0 and C26: 0. Only levels of C15: 0 and C17: 0 decreased with age. In contrast, levels of C18: 2 and C19 were significantly decreased and levels of C15, C17, C18: 1 and C23 were significantly increased in young diabetic subjects. In general, compared with younger healthy subjects, FFA composition was only partly significantly altered in older healthy subjects but was significantly altered in younger diabetic subjects.
Skin Pharmacol Physiol 2018;31:283–291

Statistical evaluation of the geochemical variability in overbank sediments in Spain

Abstract

The overall objective of this study is to estimate, detect and specify the main sources of variance which affect the contents of the different elements in overbank sediments across Spain. These sources of variance were assessed and compared by means of a series of analyses of variance (ANOVAs), by regarding two parameters: their significance and their contribution to the total variance. Overbank sediments, sampled in erosion banks, were studied in several locations, in basins which drain different types of geological backgrounds and land uses (urban, mining, agricultural or pristine) across the Iberian Peninsula. Forty-eight elements (mostly in the < 63 μm fraction) were analysed by ICP-OES, ICP-MS and INAA. After an isometric log ratio (ilr) transformation of the data, three ANOVA analyses were performed considering three perspectives: (1) local scale, (2) regional scale: within-profile perspective and (3) regional scale: inter-profile perspective. On a local scale, it was observed that the variability of rare earth elements (REE) depends mostly on the grain size and that heavy metals are also influenced by depth. In the analysis carried out on a regional scale, from a within-profile perspective, depth and duplicates do not influence significantly the variability of the element contents. Finally, from an inter-profile perspective, the selected sources of variance were land use and provenance, whose significance is the highest. While grain size and the selection of depth are of crucial importance in the final results, on local studies, land use and provenance are the ones that influence the most the composition of sediments in regional studies.

Silvery hair with dyschromatosis: Griscelli syndrome Type 3 or Familial gigantic melanocytosis

Journal of Cutaneous Pathology, Volume 0, Issue ja, -Not available-.

Elevated total serum IgE in vitiligo might be protective for other autoimmune diseases

British Journal of Dermatology, EarlyView.

MiR‐146a‐5p correlates with clinical efficacy in patients with psoriasis treated with the tumour necrosis factor‐alpha inhibitor adalimumab

British Journal of Dermatology, EarlyView.

Nanolipid Formulations of Benzoporphyrin Derivative: Exploring the Dependence of Nanoconstruct Photophysics and Photochemistry on Their Therapeutic Index in Ovarian Cancer Cells

Photochemistry and Photobiology, Volume 0, Issue ja, -Not available-.

Better Hearing is Better Seeing: Molecular Photoacoustic Contrast Agents

Photochemistry and Photobiology, Volume 0, Issue ja, -Not available-.

Case of amyloidosis cutis dyschromica with dermoscopy

The Journal of Dermatology, EarlyView.

Acquired digital arteriovenous malformation presenting as erythronychia

The Journal of Dermatology, EarlyView.

Ten‐year follow up of longitudinal melanonychia in childhood: A case report

The Journal of Dermatology, EarlyView.

Aesthetic reconstruction of extensive pubic keloids using bilateral modified keystone flaps

The Journal of Dermatology, EarlyView.

Two Japanese families with hypohidrotic ectodermal dysplasia: Phenotypic differences between affected individuals

The Journal of Dermatology, EarlyView.

Are dermatologists who treat patients with delusional infestation at risk of major complaints and being stalked?

Journal of the European Academy of Dermatology and Venereology, EarlyView.

Completion lymphadenectomy should not necessarily be recommended after a positive sentinel lymph node biopsy

Clinical and Experimental Dermatology, EarlyView.

Secukinumab‐induced paradoxical pustular psoriasis

Clinical and Experimental Dermatology, EarlyView.

Cranio-orbital Resection Does Not Appear to Improve Survival of Patients With Lacrimal Gland Carcinoma

Purpose: To ascertain long-term outcome of treatment for primary epithelial malignancies of the lacrimal gland and compare outcomes after cranio-orbital resection or after macroscopic tumor resection with radiotherapy. Methods: Comparative case series of 79 patients (49 male; 62%) treated for primary epithelial malignancies of the lacrimal gland at Moorfields Eye Hospital between 1972 and 2014. Patients were identified from clinical and pathological databases and, where available, the clinical, pathological, and imaging records reviewed. The primary outcome measures were overall survival after diagnosis, disease-free survival, and final visual acuity for patients having cranio-orbital resection (exenteration plus local bone removal), compared with macroscopic tumor resection plus radiotherapy. Results: The mean age at presentation was 48 years (median: 50 years; range: 13–84 years), with 53 (67%) having adenoid cystic carcinoma, 15 (19%), primary adenocarcinoma, and 11 (14%) carcinoma ex-pleomorphic adenoma (malignant mixed tumor). The overall survival probability of the cohort (79 patients) was 0.59 at 5 years and 0.52 at 10 years, with 36/79 (46%) patients suffering tumor-related deaths; 14 patients died from other causes, and 4 patients were lost to follow up after the minimum follow-up period. The probability of disease-free survival at 5 years for patients with adenoid cystic carcinoma, adenocarcinoma, and malignant mixed tumor was 0.52, 0.4, and 0.64, respectively, with the comparable figures at 10 years being 0.44, 0.40, and 0.64. Most importantly, the 9 patients undergoing cranio-orbital resection and the 44 having solely macroscopic tumor resection plus radiotherapy had similar overall survival (p = 0.59) and disease-free survival (p = 0.89). Subgroup analysis of the 2 treatment modalities for patients with adenoid cystic carcinoma (8 cranio-orbital resection and 32 debulking and radiotherapy) demonstrated similar results for disease-free survival (p = 0.87). Likewise, there were no significant differences between rates of recurrences between the 2 different treatments. For the 50 patients who had eye-preserving surgery and long-term visual acuity data, the final acuity was better or equal to 0.6 logMAR (6/24 Snellen) in 25 (50%). Discussion: There is no difference in either survival or tumor recurrence for lacrimal gland carcinoma treated with cranio-orbital resection, or eye-preserving tumor excision and radiotherapy. The authors, therefore, continue to advocate local resection and radiotherapy for almost all patients with primary epithelial malignancies of the lacrimal gland—this treatment having lower morbidity, causing less disfigurement, and, importantly, preserving useful vision in most patients. Accepted for publication June 5, 2018. The authors have no financial or conflicts of interest to disclose. Presented at American Society of Ophthalmic and Reconstructive Surgery 2017 Fall Meeting, New Orleans, LA and British Oculoplastic Surgical Society 2017 Meeting, London, England. Address correspondence and reprint requests to Geoffrey E. Rose, D.Sc., F.R.C.Ophth., Orbital Service, Moorfields Eye Hospital NHS Foundation Trust, City Road, London EC1V 2PD, United Kingdom. E-mail: geoff.rose@moorfields.nhs.uk © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Orbital Emphysema: A Case Report and Comprehensive Review of the Literature

Purpose: The objective of this study was to report a case of persistent and likely self-induced orbital emphysema (OE) following functional endoscopic sinus surgery with dislodgement of a previously placed orbital floor implant and to review the literature surrounding etiologies, pathophysiology, and management of OE. Methods: Case report and review of the literature. Results and Discussion: While blunt trauma resulting in disruption of the medial orbital wall is the most common cause of OE, there are an additional 25 underlying etiologies reported in the current literature. Pathophysiology of OE is somewhat dependent on underlying etiology but often involves a 1-way ball valve mechanism such that air may enter the orbit but not exit. When sufficient air enters the orbit, complications secondary to increased intraorbital pressure, including central retinal artery occlusion and compressive optic neuropathy, can occur. Mild cases of OE are typically observed, with most resolving within 7 to 10 days. Moderate cases are often managed by lateral canthotomy and cantholysis with possible needle decompression. Severe cases may require urgent surgical decompression. While the majority of cases of OE are benign and self-limited, there have been 4 reports in the literature documenting significant vision loss. Conclusions: Although there is often a history of trauma in patients presenting with OE, many other underlying etiologies have been reported with several cases occurring spontaneously. As such, OE should be included on the differential for a patient presenting with a sudden onset of orbital signs. Accepted for publication July 10, 2018. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Michael K. Yoon, M.D., Department of Ophthalmology, Ophthalmic Plastic Surgery, Massachusetts Eye & Ear Infirmary, 243 Charles Street, Boston, MA 02114. E-mail: Michael_Yoon@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Corneal Topographical Changes After Müller’s Muscle-Conjunctival Resection Surgery

Purpose: To evaluate corneal refractive and topographical changes after Müller's muscle conjunctival resection surgery on patients with mild ptosis. Methods: A total of 28 eyes of 28 patients with mild ptosis underwent Müller's muscle conjunctival resection. Visual acuity, margin reflex distance, and cycloplegic refraction were analyzed preoperatively and at first, third, and sixth months postoperatively. Change in corneal topography was analyzed with Sirius System using parameters including corneal astigmatism (CYL), average simulated keratometry value (simK), apical keratometry front (AKf), symmetry index front (SIf), and central corneal thickness (CCT) at the same intervals. Results: Best-corrected visual acuity and cycloplegic refraction did not change significantly at all controls postoperatively. The mean change in corneal astigmatism, simK, SIf, and CCT did not show significant differences. Apical keratometry front showed a significant decrease at 3 and 6 months. Conclusion: The pressure of upper eyelid in patients with ptosis appeared to have resulted in steepening of the superior cornea along this axis. The surgical correction of ptosis induces flattening of superior cornea as shown by significant decrease in apical keratometry front value postoperatively and restores corneal topography to a more regular state. Accepted for publication June 28, 2018. The authors have no financial or conflicts of interest to disclose. The authors alone are responsible for the content and writing of the paper. Address correspondence and reprint requests to Gamze Ozturk Karabulut, M.D., Seyitnizam Mah, Balıklı Çırpıcı Yolu Sok, No: 2/F, Topkapı Merkez Evleri, B-2 Blok, Daire: 8, Zeytinburnu, Istanbul. E-mail: gokarabulut@gmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.