Search

Purpose: Cancer-related fatigue (CRF) biology remains poorly understood. Responsible mechanisms may be central or peripheral and originate anywhere from the brain to muscle fiber. Objective measurement is complex and previously limited to specialized laboratories. Portable electroencephalography (EEG) and electromyography (EMG) may enhance objective measurement. This study evaluated the feasibility and acceptability of portable EMG-EEG in CRF assessment.Methods: A prospective observational feasibility study compared ten outpatients with inoperable, treatment-naïve non-small cell lung cancer and CRF to ten healthy volunteers. All completed a sustained isometric hand-grip contraction at 30% maximal level until self-perceived exhaustion. 128-channel EEG and 2-channel EMG signals of forearm muscles were recorded. Device acceptability was evaluated by questionnaire.Results: The task was evaluated in two stages; first and last 20 s. CRF cohort perceived exhaustion earlier than volunteers (mean 137 ± 76 s vs 208 ± 51 s). As fatigue progressed, EMG amplitude increased significantly (CRF p = 0.02; volunteers: p = 0.04) in both groups as did EMG beta band power (CRF p = 0.008; volunteers: p = 0.006). The increase was significantly less in CRF (amplitude p = 0.032; beta power: p = 0.014). EEG beta band power in the contralateral motor cortex increased significantly (CRF p = 0.03; volunteers: p = 0.019) in both cohorts but to greater extent (p = 0.024) in CRF. One hundred percent device acceptability was reported.Conclusions: A laboratory-based evaluation was successfully adapted to the outpatient setting during routine visits. High acceptability supports clinical utility. In CRF, a higher degree of cortical activation was required to drive a much lower level of muscle performance. This suggests impairment of both central and peripheral mechanisms in CRF. [ABSTRACT FROM AUTHOR]

In the contemporary world, environmental protection and improvement priority a global society, together with efforts to achieve lasting world peace, economic growth, social justice and democracy. Economic development based on the irresponsible use of natural resources has been caused by a number of consequences. No dilemma that a strong economy and healthy environment and correspond to each condition.

Angiogenesis, or neovascularization, is a complex process leading to formation of new blood vessels from the pre-existing vascular network of the tissue. Angiogenesis plays a central role in various physiological and pathological conditions, including embryonic development, reproduction, inflammation and wound healing, infertility, heart diseases, ulcers, rheumatoid arthritis, diabetic blindness and cancer. It is a multistep process involving EC activation, basement membrane and extracellular matrix (ECM) degradation, EC proliferation, migration and differentiation, synthesis of new basement membrane and maturation of new blood vessels. Tumor vasculature is considered to be of an "immature" nature with series of structural abnormalities. There are reciprocal paracrine interactions between ECs, tumor cells, stroma and ECM. Angiogenesis plays a key role in transformation of normal to malignant cell, tumor progression and metastasis. It is similar to the metastatic process in that it requires EC attachment, proteolysis, and locomotion to proceed. A close relationship exists between the tumor and ECs invasiveness of the tissue. The switch to the angiogenic phenotype involves a change in the local equilibrium between positive and negative regulators of the growth of microvessels. Basic fibroblast growth factor (bFGF) and vas­cular endothelial growth factor (VEGF) are positive regulators of angiogenesis. Intimate cross-talk exists among bFGF and the different members of the VEGF family during angiogenesis, lymphangiogenesis, and vasculogenesis. A substantial body of experimental evidence supports the hypothesis that angiogenesis and angiogenic factors may be strong prognostic and predictive factors in breast carcinoma. This article reviews the current knowledge on angiogenesis and its positive regulators: bFGF and VEGF. .

In addition to classical prognostic/predictive factors, significant biological markers have been identified to provide potentially relevant information regarding natural or clinical course of breast cancer. Steroid receptor status of the primary breast cancer have been proven to be a predictor of response to endocrine therapy since up to 80 % of patients with steroid receptor-positive tumors respond to endocrine treatment. In order to improve the predictive value of steroid receptor status, attention has been paid to estrogen-regulated proteins, including pS2 and cathepsin D among others that may be indicators of a functional signal transduction pathway through which tumor cells respond to estrogen stimulation. It has been shown that pS2 protein may be constitutive product as well as estrogen-regulated product in breast carcinoma. pS2 appears to be positively correlated with ER, associated with a good prognosis and a predictor of response to endocrine treatment of primary and metastatic breast cancer. The expression cathepsin D may be both constitutive and overexpressed as a result of estrogen-induced transcription. It was believed that the main role of cathepsin D was to degrade protein, but many other biological functions of cathepsin D were recognized. Cathepsin D level in primary breast cancer has been demonstrated as an independent marker of poor prognosis associated with increased risk for metastasis and shorter survival times. Our recent results show direct correlation of cathepsin D positivity with pS2 expression. Additionally, we found that cathepsin D is statistically significantly associated with pS2 both in node-negative and node-positive patients bearing tumors smaller than 2 cm. .

Geomorphologic forms and processes have primary and eliminatory significance in the process of determining the proper locations for trash disposal. Those forms are results of long-term morphogenetic processes and they implicate the dependence between the landfill and a landscape where it is situated. Determining proper location for landfill is crucial because it becomes a factor of permanent alternation of the landscape. The basic task that a possible location should satisfy is as least as possible impact zone. Concerning this request, the best locations are those on fossil geomorphologic forms that are out of active geomorphologic processes (erosive fluvial terraces and blind karst valleys). The selection of location for landfills has its economic consequences that are determined in the light of theory of development thresholds and cost-benefit analysis. The work contains comparative threshold graph with short- and long-term economic effects (costs) of locating a landfill on flood plain and an erosive terrace. There’s also given a matrix of suitability that explains economical, social, ecological, technical and esthetical factors relevant for selecting the adequate location for landfills.

The composition of the Ar/O2/C gas system in the presence of traces of either B, Si or Ca was calculated under the assumption of thermal equilibrium in the temperature range 500.5500 K. The mole concentration of oxygen was taken to be 1.4 %. Two sets of calculations were carried out. In the first one the presence of solid phase (graphite) was ignored and the calculations were performed for a single-phase (gas) system, at variable ratios C/O (0.5, 0.96, 1 and 2). In the second set of calculations the presence of solid carbon (graphite) was taken into account and the composition of the gas system in equilibrium with solid carbon, at p = 1 atm, was determined. The results presented show that the equilibrium composition, particularly the concentration of different compounds involving the trace elements , is very sensitive to the amounts, and the ratio of the amounts of oxygen and carbon. Increasing the O/C ratio results in increasing partial pressures of molecular and atomic oxygen, which favours the formation of oxides of the trace elements and moves their atomization temperatures to higher values. On the other hand, increasing the C/O ratio (C/O >1) favours atomization, but also carbide formation in the lower-temperature region. It was found that, over a relatively wide temperature interval (1000 < T < 3500 K), the composition of theAr/O2/C/X (X = B, Si, Ca) system, with comparable amounts of oxygen and carbon (C/O = 1), does not significantly depend on the presence of the solid phase. The results of calculations enable a reasonable interpretation of numerous experiments carried out on similar systems.

It is shown that steroid hormone receptors by themselves are not sufficiently strong prognostic factors in management of breast cancer. For that reason, simultaneous consideration of different biomarkers seems to be more appropriate for clinical use, i.e. selections of patients with high/inter-mediate/low risk of disease outcome. However, the amount of tumor material available from breast carcinoma can preclude determination of estrogen- regulated biomarkers together with estrogen receptor and progesterone receptor. The aim of this study was to assess the possibility of estrogen receptor and progesterone receptor determination by a single-point instead of five-point biochemical method. Our results demonstrated that the correlation between measurements of estrogen and progesterone receptor contents obtained by the five-point and single-point assay in the total population was very high. Consequently, we could use the single-point assay instead of five-point assay for estrogen receptor and progesterone receptor determination, thus making possible determination of other molecular biomarkers from the same breast carcinoma.

Background: Cellular biomarkers may predict tumor cell behavior in breast cancer. One of the most paradoxical biomarker in breast cancer is cathepsin D. Patients and methods: The study includes 152 patients with histologically verified breast carcinoma. Clinicopathological findings were classified according to classical breast carcinoma-host features (age and menopausal status) and carcinoma features (lymph node status, tumor size type and grade). Estrogen and progesterone receptors were assayed in accordance with the recommendation of the EORTC. Cathepsin D concentrations were determined using immunoradiometric assay. The results were analyzed using non-parametric statistical methods. Results: All differences in the proportion of breast carcinoma classified as cathepsin D-positive and disagreements on the association of cathepsin D status with clinicopathological features of breast cancer are the result of varying cut-off values used by different authors. Using the cut-off value, which defines estrogen-regulated vs. nonestrogen-regulated cathepsin D expres sion, this study points to the cathepsin D status as a complementary biolog ical information to ER and PR status, and a dependent biomarker in relation to age of patients and lymph node status. Conclusion: The classification of tumors according to the cathepsin D status within ER and PR status could provide more information on the association between cathepsin D status and clinical-pathological features of breast cancer.

TGF-beta1 is a pluripotent cytokine with diverse effects in the normal development of mammary glands, and in the development of malignant tumors of the breast. The aim of the study was to determine the levels of TGF-beta1 in the group of advanced breast cancer, in which increased TGF-beta1 levels were most likely to be expected. TGF-beta1 levels were also compared with estradiol levels. Our results suggested that TGF-beta1 synthesis may be regulated by estrogen or anti-estrogen through ER. Finding of increased TGF-beta1 levels, due to its possible role in predicting invasive phenotype in later phases of tumor progression, may indicate the tendency of tumor tissue towards autonomy.

Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild traumatic brain injury (rmTBI) and chronic variable stress mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [ 18 F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an i ncrease in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.

Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome- based identification to be successful and explored various features of these data.

Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD., (© 2023. The Author(s).)

Large-scale functional networks have been characterized in both rodent and human brains, typically by analyzing fMRI-BOLD signals. However, the relationship between fMRI-BOLD and underlying neural activity is complex and incompletely understood, which poses challenges to interpreting network organization obtained using this technique. Additionally, most work has assumed a disjoint functional network organization (i.e., brain regions belong to one and only one network). Here, we employ wide-field Ca 2+ imaging simultaneously with fMRI-BOLD in mice expressing GCaMP6f in excitatory neurons. We determine cortical networks discovered by each modality using a mixed-membership algorithm to test the hypothesis that functional networks exhibit overlapping organization. We find that there is considerable network overlap (both modalities) in addition to disjoint organization. Our results show that multiple BOLD networks are detected via Ca 2+ signals, and networks determined by low-frequency Ca 2+ signals are only modestly more similar to BOLD networks. In addition, the principal gradient of functional connectivity is nearly identical for BOLD and Ca 2+ signals. Despite similarities, important differences are also detected across modalities, such as in measures of functional connectivity strength and diversity. In conclusion, Ca 2+ imaging uncovers overlapping functional cortical organization in the mouse that reflects several, but not all, properties observed with fMRI-BOLD signals., (© 2024. The Author(s).)

Understanding how the brain's macroscale dynamics are shaped by underlying microscale mechanisms is a key problem in neuroscience. In animal models, we can now investigate this relationship in unprecedented detail by directly manipulating cellular-level properties while measuring the whole-brain response using resting-state fMRI. Here, we focused on understanding how blood-oxygen-level-dependent (BOLD) dynamics, measured within a structurally well-defined striato-thalamo-cortical circuit in mice, are shaped by chemogenetically exciting or inhibiting D1 medium spiny neurons (MSNs) of the right dorsomedial caudate putamen (CPdm). We characterize changes in both the BOLD dynamics of individual cortical and subcortical brain areas, and patterns of inter-regional coupling (functional connectivity) between pairs of areas. Using a classification approach based on a large and diverse set of time-series properties, we found that CPdm neuromodulation alters BOLD dynamics within thalamic subregions that project back to dorsomedial striatum. In the cortex, changes in local dynamics were strongest in unimodal regions (which process information from a single sensory modality) and weakened along a hierarchical gradient towards transmodal regions. In contrast, a decrease in functional connectivity was observed only for cortico-striatal connections after D1 excitation. Our results show that targeted cellular-level manipulations affect local BOLD dynamics at the macroscale, such as by making BOLD dynamics more predictable over time by increasing its self-correlation structure. This contributes to ongoing attempts to understand the influence of structure-function relationships in shaping inter-regional communication at subcortical and cortical levels., Competing Interests: MM, OS, JB, MR, VZ, BF, NW No competing interests declared, (© 2023, Markicevic et al.)

Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

In the past decade, the idea that single populations of neurons support cognition and behavior has gradually given way to the realization that connectivity matters and that complex behavior results from interactions between remote yet anatomically connected areas that form specialized networks. In parallel, innovation in brain imaging techniques has led to the availability of a broad set of imaging tools to characterize the functional organization of complex networks. However, each of these tools poses significant technical challenges and faces limitations, which require careful consideration of their underlying anatomical, physiological, and physical specificity. In this review, we focus on emerging methods for measuring spontaneous or evoked activity in the brain. We discuss methods that can measure large-scale brain activity (directly or indirectly) with a relatively high temporal resolution, from milliseconds to seconds. We further focus on methods designed for studying the mammalian brain in preclinical models, specifically in mice and rats. This field has seen a great deal of innovation in recent years, facilitated by concomitant innovation in gene-editing techniques and the possibility of more invasive recordings. This review aims to give an overview of currently available preclinical imaging methods and an outlook on future developments. This information is suitable for educational purposes and for assisting scientists in choosing the appropriate method for their own research question., (© 2021. The Author(s).)

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently., Competing Interests: ST, PM, FR, CC, WY, BC, AR, JS, MM, VZ, SB, AG, ML, SP, ML No competing interests declared, EB is employed half-time by the University of Cambridge and half-time at GlaxoSmithKline plc (GSK); he holds stock in GSK. All other authors have no conflict of interests to declare., (© 2020, Trakoshis et al.)

Abnormal brain development manifests itself at different spatial scales. However, whether abnormalities at the cellular level can be diagnosed from network activity measured with functional magnetic resonance imaging (fMRI) is largely unknown, yet of high clinical relevance. Here a putative mechanism reported in neurodevelopmental disorders, that is, excitation-to-inhibition ratio (E:I), was chemogenetically increased within cortical microcircuits of the mouse brain and measured via fMRI. Increased E:I caused a significant "reduction" of long-range connectivity, irrespective of whether excitatory neurons were facilitated or inhibitory Parvalbumin (PV) interneurons were suppressed. Training a classifier on fMRI signals, we were able to accurately classify cortical areas exhibiting increased E:I. This classifier was validated in an independent cohort of Fmr1y/- knockout mice, a model for autism with well-documented loss of parvalbumin neurons and chronic alterations of E:I. Our findings demonstrate a promising novel approach towards inferring microcircuit abnormalities from macroscopic fMRI measurements., (© The Author(s) 2020. Published by Oxford University Press.)

The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics." We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Previous work has demonstrated that neuroimaging biomarkers which capture functional connectivity of the brain can be used to define a specific and robust endophenotype in Fmr1 -/y mice, a well-established animal model of human Fragile-X Syndrome (FXS). However, it is currently unknown whether this macroscopic measure of brain connectivity is sufficiently sensitive to reliably detect changes caused by pharmacological interventions. Here we inhibited the activity of the metabotropic glutamate receptor-5 (mGluR5) using AFQ056/Mavoglurant, a drug that is assumed to normalize excitatory/inhibitory neural signaling imbalances in FXS. We employed resting-state-fMRI (rs-fMRI) and diffusion-weighted imaging (DWI) to test whether Mavoglurant re-established brain connectivity - at least partly - within some of the affected circuits in Fmr1 -/y mice that are related to social behavior deficits. In line with previous findings, we observed that Fmr1 -/y mice exhibited impaired social interaction, reduced connectivity in three main functional networks and altered network topology. At the group level, Mavoglurant did neither rescue abnormal social behavioral nor white matter abnormalities; however, for some, but not all of these circuits Mavoglurant had a genotype-specific effect of restoring functional connectivity. These results show that rs-fMRI connectivity is sufficiently sensitive to pick up system-level changes after the pharmacological inhibition of mGluR5 activity. However, our results also show that the effects of Mavoglurant are confined to specific networks suggesting that behavioral benefits might be restricted to narrow functional domains., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out ( En2 -/- ) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knock-outs. MRI-based resting-state functional connectivity in adult En2 -/- mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2 -/- but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2 -/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2 -/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Therefore, fearful responses to somatosensory stimuli in En2 -/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes. SIGNIFICANCE STATEMENT Overreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene Engrailed-2 ( En2 -/- mice). Compared with WT controls, En2 -/- mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations., (Copyright © 2019 the authors 0270-6474/19/391526-14$15.00/0.)

Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.

The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer's disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2 -/- mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor's involvement in neurodevelopmental diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the influence of molecular biomarkers (estrogen receptor - ER, progesterone receptor - PR, and human epidermal growth factor receptor2 - HER2) and pathological parameters on metastasis free interval (MFI) in adjuvantly tamoxifen-treated breast cancer patients, during different follow up periods (0-2.5 years, 2.5-5 years and 5-12 years)., Methods: The study included 113 postmenopausal breast cancer patients with known pathological parameters. Steroid receptors were determined by ligand-binding assay and HER2 amplification status by chromogenic in situ hybridization (CISH)., Results: During the first 2.5 years of therapy patients with ER <5 fmol/mg, PR <5 fmol/mg or pT2 (≥2cm) tumors had higher probability of distant metastasis. For the period between 2.5-5 years, analysis of MFI according to pathological parameters and molecular biomarkers, separately, did not show any statistically significant difference. Patients with pT≥2 cm and HER2 amplification had much greater chance of developing distant metastasis when compared to other phenotypes (HER2-negative/pT1, HER2-negative/pT2 and HER2-positive/pT1). Patiens with ER ≥160 fmol/mg and PR ≥45 fmol/mg had good prognosis after 5 years of tamoxifen therapy., Conclusion: Our study indicates that there is a change of influence of the analyzed pathological parameters on MFI, depending on different follow up periods. Steroid receptor status, tumor size and HER2 status (alone or in combination) are significant parameters for the course of disease of postmenopausal ER-positive breast cancer patients, but during different periods of follow up.