Season Greetings

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Correction to: Anatomical locations in the oral cavity where surgical resections of oral squamous cell carcinomas are associated with a close or positive margin—a retrospective study

The following note was inadvertently omitted from the published paper: This work was performed in (partial) fulfillment of the requirements for the first author's obtaining the degree Dr. med. dent.

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Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib

Abstract

Background

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.

Objective

To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.

Patients and Methods

In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib.

Results

Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.

Conclusion

EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

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Management of abnormal deep inferior epigastric vessels in microsurgical breast reconstruction: a report of 3 complex cases

Abstract

The deep inferior epigastric artery perforator flap is the gold standard in microsurgical breast reconstruction. It is now increasingly offered in patients with previous abdominal scars and in such cases, computed tomography angiography (CTA) is routinely implemented. However, previous injury of the deep inferior epigastric vessels may be difficult to detect with CTA. We report three cases of successful bilateral breast reconstruction, in which a unilateral DIEA was found to be abnormal. In the first two cases, the unilateral DIE vessels were found to be damaged and the flaps salvaged based on the deep superior epigastric artery. In the third patient, previous DIEA injury resulted in vessel recanalization, which was only evident following initial anastomotic failure. In this case, the damaged DIEA segment was subsequently removed and the flap successfully revascularized. All three patients had an uneventful post-operative recovery and all flaps survived with no complications. Based on our experience, we believe that awareness of the potential pitfalls and careful planning for lifeboats are essential to avoid flap loss in such circumstances.

Level of Evidence: Level V, therapeutic study.

https://ift.tt/2UAyGtH

Developmental toxicity and apoptosis in zebrafish embryos induced by low-dose γ-ray irradiation

Abstract

In this paper, the developmental toxicity and apoptosis in zebrafish (Danio rerio) embryos induced by 0.01, 0.05, and 0.10-Gy γ-ray irradiation were investigated and verified by single cell gel electrophoresis, acridine orange staining, flow cytometry, transmission electron microscopy, digital gene expression sequencing, and Western blot analysis. DNA damage, deformity rates, and apoptosis of zebrafish embryos were found to increase significantly with the increase of irradiation dose, and survival and hatching rates significantly decreased when the irradiation dose exceeds 0.10 and 0.05 Gy, respectively. Exposure to 0.10-Gy γ-ray irradiation resulted in the swelling of cell mitochondria of zebrafish embryos and changes in their intracellular vacuoles. mRNA and protein expression levels of Shh (sonic hedgehog 19 KDa) and Smo (smoothened 86 KDa) of Hh signaling pathway associated with the development of early embryos significantly increased with the increase of irradiation dose. Expression of the AKT (56 KDa) and PiK3r3 (55 KDa) genes, which are anti-apoptotic and involved with the PI3K/Akt signaling pathway, significantly decreased, while expression of the bada gene, which is pro-apoptotic, significantly increased. The results show that γ-ray irradiations of 0.01 and 0.05 Gy can induce developmental toxicity and apoptosis in zebrafish embryos via Hh and PI3K/Akt signaling pathways, respectively.

https://ift.tt/2UC36Mc

Lesions to the Fronto-Parietal Network Impact Alpha-Band Phase Synchrony and Cognitive Control

Abstract

Long-range phase synchrony in the α-oscillation band (near 10 Hz) has been proposed to facilitate information integration across anatomically segregated regions. Which areas may top-down regulate such cross-regional integration is largely unknown. We previously found that the moment-to-moment strength of high-α band (10–12 Hz) phase synchrony co-varies with activity in a fronto-parietal (FP) network. This network is critical for adaptive cognitive control functions such as cognitive flexibility required during set-shifting. Using electroencephalography (EEG) in 23 patients with focal frontal lobe lesions (resected tumors), we tested the hypothesis that the FP network is necessary for modulation of high-α band phase synchrony. Global phase-synchrony was measured using an adaptation of the phase-locking value (PLV) in a sliding window procedure, which allowed for measurement of changes in EEG-based resting-state functional connectivity across time. As hypothesized, the temporal modulation (range and standard deviation) of high-α phase synchrony was reduced as a function of FP network lesion extent, mostly due to dorsolateral prefrontal cortex (dlPFC) lesions. Furthermore, patients with dlPFC lesions exhibited reduced cognitive flexibility as measured by the Trail-Making Test (set-shifting). Our findings provide evidence that the FP network is necessary for modulatory control of high-α band long-range phase synchrony, and linked to cognitive flexibility.

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Characterization of the Inner and Outer Fiber Layers in the Developing Cerebral Cortex of Gyrencephalic Ferrets

Abstract

Changes in the cerebral cortex of mammals during evolution have been of great interest. Ferrets, monkeys, and humans have more developed cerebral cortices compared with mice. Although the features of progenitors in the developing cortices of these animals have been intensively investigated, those of the fiber layers are still largely elusive. By taking the advantage of our in utero electroporation technique for ferrets, here we systematically investigated the cellular origins and projection patterns of axonal fibers in the developing ferret cortex. We found that ferrets have 2 fiber layers in the developing cerebral cortex, as is the case in monkeys and humans. Axonal fibers in the inner fiber layer projected contralaterally and subcortically, whereas those in the outer fiber layer sent axons to neighboring cortical areas. Furthermore, we performed similar experiments using mice and found unexpected similarities between ferrets and mice. Our results shed light on the cellular origins, the projection patterns, the developmental processes, and the evolution of fiber layers in mammalian brains.

https://ift.tt/2EcRbyu

Development and Emergence of Individual Variability in the Functional Connectivity Architecture of the Preterm Human Brain

Abstract

Individual variability in human brain networks underlies individual differences in cognition and behaviors. However, researchers have not conclusively determined when individual variability patterns of the brain networks emerge and how they develop in the early phase. Here, we employed resting-state functional MRI data and whole-brain functional connectivity analyses in 40 neonates aged around 31–42 postmenstrual weeks to characterize the spatial distribution and development modes of individual variability in the functional network architecture. We observed lower individual variability in primary sensorimotor and visual areas and higher variability in association regions at the third trimester, and these patterns are generally similar to those of adult brains. Different functional systems showed dramatic differences in the development of individual variability, with significant decreases in the sensorimotor network; decreasing trends in the visual, subcortical, and dorsal and ventral attention networks, and limited change in the default mode, frontoparietal and limbic networks. The patterns of individual variability were negatively correlated with the short- to middle-range connection strength/number and this distance constraint was significantly strengthened throughout development. Our findings highlight the development and emergence of individual variability in the functional architecture of the prenatal brain, which may lay network foundations for individual behavioral differences later in life.

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The Role of the Human Auditory Corticostriatal Network in Speech Learning

Abstract

We establish a mechanistic account of how the mature human brain functionally reorganizes to acquire and represent new speech sounds. Native speakers of English learned to categorize Mandarin lexical tone categories produced by multiple talkers using trial-by-trial feedback. We hypothesized that the corticostriatal system is a key intermediary in mediating temporal lobe plasticity and the acquisition of new speech categories in adulthood. We conducted a functional magnetic resonance imaging experiment in which participants underwent a sound-to-category mapping task. Diffusion tensor imaging data were collected, and probabilistic fiber tracking analysis was employed to assay the auditory corticostriatal pathways. Multivariate pattern analysis showed that talker-invariant novel tone category representations emerged in the left superior temporal gyrus (LSTG) within a few hundred training trials. Univariate analysis showed that the putamen, a subregion of the striatum, was sensitive to positive feedback in correctly categorized trials. With learning, functional coupling between the putamen and LSTG increased during error processing. Furthermore, fiber tractography demonstrated robust structural connectivity between the feedback-sensitive striatal regions and the LSTG regions that represent the newly learned tone categories. Our convergent findings highlight a critical role for the auditory corticostriatal circuitry in mediating the acquisition of new speech categories.

https://ift.tt/2EeVKZh

Temporally Unconstrained Decoding Reveals Consistent but Time-Varying Stages of Stimulus Processing

Abstract

In this article, we propose a method to track trial-specific neural dynamics of stimulus processing and decision making with high temporal precision. By applying this novel method to a perceptual template-matching task, we tracked representational brain states associated with the cascade of neural processing, from early sensory areas to higher order areas that are involved in integration and decision making. We address a major limitation of the traditional decoding approach: that it relies on consistent timing of these processes over trials. Using a TUDA approach, we found that the timing of the cognitive processes involved in perceptual judgments can vary considerably over trials. This revealed that the sequence of processing states was consistent for all subjects and trials, even when the timing of these states varied. Furthermore, we found that the specific timing of states on each trial was related to the quality of performance over trials. Altogether, this work not only highlights the serious pitfalls and misleading interpretations that result from assuming stimulus processing to be synchronous across trials but can also open important avenues to investigate learning and quantify plasticity.

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Age-Related Differences in Brain Morphology and the Modifiers in Middle-Aged and Older Adults

Abstract

Brain structural morphology differs with age. This study examined age-differences in surface-based morphometric measures of cortical thickness, volume, and surface area in a well-defined sample of 8137 generally healthy UK Biobank participants aged 45–79 years. We illustrate that the complexity of age-related brain morphological differences may be related to the laminar organization and regional evolutionary history of the cortex, and age of about 60 is a break point for increasing negative associations between age and brain morphology in Alzheimer's disease (AD)-prone areas. We also report novel relationships of age-related cortical differences with individual factors of sex, cognitive functions of fluid intelligence, reaction time and prospective memory, cigarette smoking, alcohol consumption, sleep disruption, genetic markers of apolipoprotein E, brain-derived neurotrophic factor, catechol-O-methyltransferase, and several genome-wide association study loci for AD and further reveal joint effects of cognitive functions, lifestyle behaviors, and education on age-related cortical differences. These findings provide one of the most extensive characterizations of age associations with major brain morphological measures and improve our understanding of normal structural brain aging and its potential modifiers.

https://ift.tt/2Epv5Kc

Transcriptomic Landscape of von Economo Neurons in Human Anterior Cingulate Cortex Revealed by Microdissected-Cell RNA Sequencing

Abstract

The von Economo neurons (VENs) are specialized large bipolar projection neurons with restricted distribution in the human brain, and they are far more abundant in humans than in non-human primates. However, VEN functions remain elusive due to the difficulty of isolating VENs and dissecting their connections in the brain. Here, we combined laser-capture-microdissection with RNA sequencing to describe the transcriptomic profile of VENs from human anterior cingulate cortex (ACC). Using pyramidal neurons as reference cells, we identified 344 genes with VEN-associated expression differences, including 215 higher and 129 lower expression genes. Functional enrichment and protein–protein interaction network analyses showed that these genes with VEN-associated expression differences are involved in VEN morphogenesis and functions, such as dendrite branching and axon myelination, and many of them are associated with human social-emotional disorders. With the use of in situ hybridization and immunohistochemistry assays, we validated four novel VEN markers (VAT1L, CHST8, LYPD1, and SULF2). Collectively, we generated a full-spectrum expression profile of VENs from human ACC, greatly enlarging the pool of genes with VEN-associated expression differences that can help researchers to understand the role of VENs in normal and disordered human brains.

https://ift.tt/2Eg5nqH

Early Loss of Vision Results in Extensive Reorganization of Plasticity-Related Receptors and Alterations in Hippocampal Function That Extend Through Adulthood

Abstract

Although by adulthood cortical structures and their capacity for processing sensory information have become established and stabilized, under conditions of cortical injury, or sensory deprivation, rapid reorganization occurs. Little is known as to the impact of this kind of adaptation on cellular processes related to memory encoding. However, imaging studies in humans suggest that following loss or impairment of a sensory modality, not only cortical but also subcortical structures begin to reorganize. It is likely that these processes are supported by neurotransmitter receptors that enable synaptic and cortical plasticity. Here, we explored to what extent the expression of plasticity-related proteins (GABA-A, GABA-B, GluN1, GluN2A, GluN2B) is altered following early vision loss, and whether this impacts on hippocampal function. We observed that in the period of 2–4 months postnatally in CBA/J-mice that experience hereditary postnatal retinal degeneration, systematic changes of GABA-receptor and NMDA-receptor subunit expression occurred that emerged first in the hippocampus and developed later in the cortex, compared to control mice that had normal vision. Changes were accompanied by significant impairments in hippocampal long-term potentiation and hippocampus-dependent learning. These data indicate that during cortical adaptation to early loss of vision, hippocampal information processing is compromised, and this status impacts on the acquisition of spatial representations.

https://ift.tt/2EqGjho

Different Decision-Making Responses Occupy Different Brain Networks for Information Processing: A Study Based on EEG and TMS

Abstract

This study used large-scale time-varying network analysis to reveal the diverse network patterns during the different decision stages and found that the responses of rejection and acceptance involved different network structures. When participants accept unfair offers, the brain recruits a more bottom-up mechanism with a much stronger information flow from the visual cortex (O2) to the frontal area, but when they reject unfair offers, it displayed a more top-down flow derived from the frontal cortex (Fz) to the parietal and occipital cortices. Furthermore, we performed 2 additional studies to validate the above network models: one was to identify the 2 responses based on the out-degree information of network hub nodes, which results in 70% accuracy, and the other utilized theta burst stimulation (TBS) of transcranial magnetic stimulation (TMS) to modulate the frontal area before the decision-making tasks. We found that the intermittent TBS group demonstrated lower acceptance rates and that the continuous TBS group showed higher acceptance rates compared with the sham group. Similar effects were not observed after TBS of a control site. These results suggest that the revealed decision-making network model can serve as a potential intervention model to alter decision responses.

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Dorsolateral Prefrontal Cortex Enables Updating of Established Memories

Abstract

Updating established memories in light of new information is fundamental for memory to guide future behavior. However, little is known about the brain mechanisms by which existing memories can be updated. Here, we combined functional magnetic resonance imaging and multivariate representational similarity analysis to elucidate the neural mechanisms underlying the updating of consolidated memories. To this end, participants first learned face–city name pairs. Twenty-four hours later, while lying in the MRI scanner, participants were required to update some of these associations, but not others, and to encode entirely new pairs. Updating success was tested again 24 h later. Our results showed increased activity of the dorsolateral prefrontal cortex (dlPFC) specifically during the updating of existing associations that was significantly stronger than when simple retrieval or new encoding was required. The updating-related activity of the dlPFC and its functional connectivity with the hippocampus were directly linked to updating success. Furthermore, neural similarity for updated items was markedly higher in the dlPFC and this increase in dlPFC neural similarity distinguished individuals with high updating performance from those with low updating performance. Together, these findings suggest a key role of the dlPFC, presumably in interaction with the hippocampus, in the updating of established memories.

https://ift.tt/2EtRvKi

Early Excitatory Activity-Dependent Maturation of Somatostatin Interneurons in Cortical Layer 2/3 of Mice

Abstract

GABAergic interneurons perform distinct functions during cortical development in the mouse brain. Among the diverse GABAergic neurons present in the brain, early-born somatostatin (SST)-expressing inhibitory interneurons, which are innervated by other interneurons and local pyramidal cells (PCs), act in a neural computational role in circuitry regulation. The synapses between the SST⁺ interneurons and other cells form gradually during development. Here, we traced the developmental course of the electrophysiological properties of SST⁺ interneurons at layer 2/3 of the neocortical secondary motor area (M2) in mouse, and the synaptic connectivity between SST⁺ interneurons and PCs. Also, we used toxin-mediated and genetic method to suppress the activities of PCs, and demonstrate that decreasing excitatory input at early stage (before P1) rather than late stage (after P8) would delay the functional maturation of SST⁺ interneurons. In conclusion, our results indicate that early functional activity of PCs is crucial for the intrinsic maturation of SST⁺ interneurons, following which these interneurons participate in local circuitry.

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Neurons in the Macaque Dorsal Premotor Cortex Respond to Execution and Observation of Actions

Abstract

We identified neurons in dorsal premotor cortex (PMd) of the macaque brain that respond during execution and observation of reaching-to-grasp actions, thus fulfilling the mirror neuron (MirN) criterion. During observation, the percentage of grip-selective MirNs in PMd and area F5 were comparable, and the selectivity indices in the two areas were similar. During execution, F5-MirNs were more selective than PMd–MirNs for grip, which was reflected in the higher selectivity indices in F5 than in PMd. PMd displayed grip-related information earlier than F5 during both conditions. In both areas, the number of neurons exhibiting congruent visual and motor selectivity did not differ from that expected by chance. However, both the PMd and F5 neuronal ensembles provided observation–execution matching, suggesting that the congruency may be achieved in a distributed fashion across the selective elements of the population. Furthermore, representational similarity analysis revealed that grip encoding in PMd and F5 is alike during both observation and execution. Our study provides direct evidence of mirror activity in PMd during observation of forelimb movements, and suggests that PMd is a node of the MirN circuit.

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Oxytocin Modulates the Intrinsic Dynamics Between Attention-Related Large-Scale Networks

Abstract

Attention and salience processing have been linked to the intrinsic between- and within-network dynamics of large-scale networks engaged in internal (default network [DN]) and external attention allocation (dorsal attention network [DAN] and salience network [SN]). The central oxytocin (OXT) system appears ideally organized to modulate widely distributed neural systems and to regulate the switch between internal attention and salient stimuli in the environment. The current randomized placebo (PLC)-controlled between-subject pharmacological resting-state fMRI study in N = 187 (OXT, n = 94; PLC, n = 93; single-dose intranasal administration) healthy male and female participants employed an independent component analysis approach to determine the modulatory effects of OXT on the within- and between-network dynamics of the DAN–SN–DN triple network system. OXT increased the functional integration between subsystems within SN and DN and increased functional segregation of the DN with both attentional control networks (SN and DAN). Whereas no sex differences were observed, OXT effects on the DN–SN interaction were modulated by autistic traits. Together, the findings suggest that OXT may facilitate efficient attention allocation by modulating the intrinsic functional dynamics between DN components and large-scale networks involved in external attentional demands (SN and DAN).

https://ift.tt/2Eg5fY4

Emergence of Coordinated Activity in the Developing Entorhinal–Hippocampal Network

Abstract

Correlated activity in the entorhinal–hippocampal neuronal networks, supported by oscillatory and intermittent population activity patterns is critical for learning and memory. However, when and how correlated activity emerges in these networks during development remains largely unknown. Here, we found that during the first postnatal week in non-anaesthetized head-restrained rats, activity in the superficial layers of the medial entorhinal cortex (MEC) and hippocampus was highly correlated, with intermittent population bursts in the MEC followed by early sharp waves (eSPWs) in the hippocampus. Neurons in the superficial MEC layers fired before neurons in the dentate gyrus, CA3 and CA1. eSPW current-source density profiles indicated that perforant/temporoammonic entorhinal inputs and intrinsic hippocampal connections are co-activated during entorhinal–hippocampal activity bursts. Finally, a majority of the entorhinal–hippocampal bursts were triggered by spontaneous myoclonic body movements, characteristic of the neonatal period. Thus, during the neonatal period, activity in the entorhinal cortex (EC) and hippocampus is highly synchronous, with the EC leading hippocampal activation. We propose that such correlated activity is embedded into a large-scale bottom-up circuit that processes somatosensory feedback resulting from neonatal movements, and that it is likely to instruct the development of connections between neocortex and hippocampus.

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Aerosol and pollutant characteristics in Delhi during a winter research campaign

Abstract

Urban areas in developing countries are major sources of carbonaceous aerosols and air pollutants, pointing out the need for a detailed assessment of their levels and origin close to the source. A multi-instrument research campaign was performed in Delhi during December 2015–February 2016 aimed at exploring the pollution levels and the contribution of various sources to particulate matter (PM) concentrations, black carbon (BC) aerosols, and trace gases. The weak winds (< 5–6 m s⁻¹) along with the shallow boundary layer favoured the formation of thick and persistent fog conditions, which along with the high BC (24.4 ± 12.2 μg m⁻³) concentrations lead to the formation of smog. Very high pollution levels were recorded during the campaign, with mean PM₁₀, PM_2.5, CO, NO, and O₃ concentrations of 245.5 ± 109.8 μg m⁻³, 145.5 ± 69.5 μg m⁻³, 1.7 ± 0.5 ppm, 7.9 ± 2.3 ppb, and 31.3 ± 18.4 ppb, respectively. This study focuses on examining the daily/diurnal cycles of the aerosol optical properties (extinction, scattering, absorption coefficients, single scattering albedo), as well as of PM and other pollutant concentrations, along with changes in meteorology (mixing-layer height and wind speed). In addition, the hot-spot pollution sources in the greater Delhi area were determined via bivariate plots and conditional bivariate probability function (CBPF), while the distant sources were examined via the concentration weighted trajectory (CWT) analysis. The results show that the highest aerosol absorption and scattering coefficients, PM, and trace gas concentrations are detected for weak winds (< 2 m s⁻¹) with a preference for eastern directions, revealing high contribution from local sources and accumulation of pollutants within urban Delhi.

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