Neural oscillations track recovery of consciousness in acute traumatic brain injury patients.

Electroencephalography (EEG), easily deployed at the bedside, is an attractive modality for deriving quantitative biomarkers of prognosis and differential diagnosis in severe brain injury and disorders of consciousness (DOC). Prior work by Schiff has identified four dynamic regimes of progressive recovery of consciousness defined by the presence or absence of thalamically-driven EEG oscillations. These four predefined categories (ABCD model) relate, on a theoretical level, to thalamocortical integrity and, on an empirical level, to behavioral outcome in patients with cardiac arrest coma etiologies. However, whether this theory-based stratification of patients might be useful as a diagnostic biomarker in DOC and measurably linked to thalamocortical dysfunction remains unknown. In this work, we relate the reemergence of thalamically-driven EEG oscillations to behavioral recovery from traumatic brain injury (TBI) in a cohort of N = 38 acute patients with moderate-to-severe TBI and an average of 1 week of EEG recorded per patient. We analyzed an average of 3.4 hr of EEG per patient, sampled to coincide with 30-min periods of maximal behavioral arousal. Our work tests and supports the ABCD model, showing that it outperforms a data-driven clustering approach and may perform equally well compared to a more parsimonious categorization. Additionally, in a subset of patients (N = 11), we correlated EEG findings with functional magnetic resonance imaging (fMRI) connectivity between nodes in the mesocircuit-which has been theoretically implicated by Schiff in DOC-and report a trend-level relationship that warrants further investigation in larger studies.

Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment.

Angelman Syndrome (AS) is a severe neurodevelopmental disorder due to impaired expression of UBE3A in neurons. There are several genetic mechanisms that impair UBE3A expression, but they differ in how neighboring genes on chromosome 15 at 15q11-q13 are affected. There is evidence that different genetic subtypes present with different clinical severity, but a systematic quantitative investigation is lacking. Here we analyze natural history data on a large sample of individuals with AS (n = 250, 848 assessments), including clinical scales that quantify development of motor, cognitive, and language skills (Bayley Scales of Infant Development, Third Edition; Preschool Language Scale, Fourth Edition), adaptive behavior (Vineland Adaptive Behavioral Scales, Second Edition), and AS-specific symptoms (AS Clinical Severity Scale). We found that clinical severity, as captured by these scales, differs between genetic subtypes: individuals with UBE3A pathogenic variants and imprinting defects (IPD) are less affected than individuals with uniparental paternal disomy (UPD); of those with UBE3A pathogenic variants, individuals with truncating mutations are more impaired than those with missense mutations. Individuals with a deletion that encompasses UBE3A and other genes are most impaired, but in contrast to previous work, we found little evidence for an influence of deletion length (class I vs. II) on severity of manifestations. The results of this systematic analysis highlight the relevance of genomic regions beyond UBE3A as contributing factors in the AS phenotype, and provide important information for the development of new therapies for AS. More generally, this work exemplifies how increasing genetic irregularities are reflected in clinical severity.

Motion Coherence and Luminance Contrast Interact in Driving Visual Gamma-Band Activity.

Synchronized neuronal population activity in the gamma-frequency range (>30 Hz) correlates with the bottom-up drive of various visual features. It has been hypothesized that gamma-band synchronization enhances the gain of neuronal representations, yet evidence remains sparse. We tested a critical prediction of the gain hypothesis, which is that features that drive synchronized gamma-band activity interact super-linearly. To test this prediction, we employed whole-head magnetencephalography in human subjects and investigated if the strength of visual motion (motion coherence) and luminance contrast interact in driving gamma-band activity in visual cortex. We found that gamma-band activity (64-128 Hz) monotonically increased with coherence and contrast, while lower frequency activity (8-32 Hz) decreased with both features. Furthermore, as predicted for a gain mechanism, we found a multiplicative interaction between motion coherence and contrast in their joint drive of gamma-band activity. The lower frequency activity did not show such an interaction. Our findings provide evidence that gamma-band activity acts as a cortical gain mechanism that nonlinearly combines the bottom-up drive of different visual features.

Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes.

BACKGROUND AND AIMS: To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo. APPROACH AND RESULTS: The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune-inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA-positive and protein-rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by toll-like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal-regulated kinase), JNK, and p38 mitogen-activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen. CONCLUSIONS: PHHs are able to sense HBV particles through TLR2, leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV.

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia.

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10-3 ), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.

First Results on the Scalar WIMP-Pion Coupling, Using the XENON1T Experiment.

We present first results on the scalar coupling of weakly interacting massive particles (WIMPs) to pions from 1 t yr of exposure with the XENON1T experiment. This interaction is generated when the WIMP couples to a virtual pion exchanged between the nucleons in a nucleus. In contrast to most nonrelativistic operators, these pion-exchange currents can be coherently enhanced by the total number of nucleons and therefore may dominate in scenarios where spin-independent WIMP-nucleon interactions are suppressed. Moreover, for natural values of the couplings, they dominate over the spin-dependent channel due to their coherence in the nucleus. Using the signal model of this new WIMP-pion channel, no significant excess is found, leading to an upper limit cross section of 6.4×10^{-46} cm^{2} (90% confidence level) at 30 GeV/c^{2} WIMP mass.

Constraining the Spin-Dependent WIMP-Nucleon Cross Sections with XENON1T.

We report the first experimental results on spin-dependent elastic weakly interacting massive particle (WIMP) nucleon scattering from the XENON1T dark matter search experiment. The analysis uses the full ton year exposure of XENON1T to constrain the spin-dependent proton-only and neutron-only cases. No significant signal excess is observed, and a profile likelihood ratio analysis is used to set exclusion limits on the WIMP-nucleon interactions. This includes the most stringent constraint to date on the WIMP-neutron cross section, with a minimum of 6.3×10^{-42} cm^{2} at 30 GeV/c^{2} and 90% confidence level. The results are compared with those from collider searches and used to exclude new parameter space in an isoscalar theory with an axial-vector mediator.

Modulation of neuronal oscillatory activity in the beta- and gamma-band is associated with current individual anxiety levels.

Human faces are among the most salient visual stimuli and act both as socially and emotionally relevant signals. Faces and especially faces with emotional expression receive prioritized processing in the human brain and activate a distributed network of brain areas reflected, e.g., in enhanced oscillatory neuronal activity. However, an inconsistent picture emerged so far regarding neuronal oscillatory activity across different frequency-bands modulated by emotionally and socially relevant stimuli. The individual level of anxiety among healthy populations might be one explanation for these inconsistent findings. Therefore, we tested the hypothesis whether oscillatory neuronal activity is associated with individual anxiety levels during perception of faces with neutral and fearful facial expressions. We recorded neuronal activity using magnetoencephalography (MEG) in 27 healthy participants and determined their individual state anxiety levels. Images of human faces with neutral and fearful expressions, and physically matched visual control stimuli were presented while participants performed a simple color detection task. Spectral analyses revealed that face processing and in particular processing of fearful faces was characterized by enhanced neuronal activity in the theta- and gamma-band and decreased activity in the beta-band in early visual cortex and the fusiform gyrus (FFG). Moreover, the individuals' state anxiety levels correlated positively with the gamma-band response and negatively with the beta response in the FFG and the amygdala. Our results suggest that oscillatory neuronal activity plays an important role in affective face processing and is dependent on the individual level of state anxiety. Our work provides new insights on the role of oscillatory neuronal activity underlying processing of faces.

Dark Matter Search Results from a One Ton-Year Exposure of XENON1T.

We report on a search for weakly interacting massive particles (WIMPs) using 278.8 days of data collected with the XENON1T experiment at LNGS. XENON1T utilizes a liquid xenon time projection chamber with a fiducial mass of (1.30±0.01) ton, resulting in a 1.0 ton yr exposure. The energy region of interest, [1.4,10.6] keV_{ee} ([4.9,40.9] keV_{nr}), exhibits an ultralow electron recoil background rate of [82_{-3}^{+5}(syst)±3(stat)] events/(ton yr keV_{ee}). No significant excess over background is found, and a profile likelihood analysis parametrized in spatial and energy dimensions excludes new parameter space for the WIMP-nucleon spin-independent elastic scatter cross section for WIMP masses above 6 GeV/c^{2}, with a minimum of 4.1×10^{-47} cm^{2} at 30 GeV/c^{2} and a 90% confidence level.

Nuclear receptors control pro-viral and antiviral metabolic responses to hepatitis C virus infection.

Viruses lack the basic machinery needed to replicate and therefore must hijack the host's metabolism to propagate. Virus-induced metabolic changes have yet to be systematically studied in the context of host transcriptional regulation, and such studies shoul offer insight into host-pathogen metabolic interplay. In this work we identified hepatitis C virus (HCV)-responsive regulators by coupling system-wide metabolic-flux analysis with targeted perturbation of nuclear receptors in primary human hepatocytes. We found HCV-induced upregulation of glycolysis, ketogenesis and drug metabolism, with glycolysis controlled by activation of HNF4α, ketogenesis by PPARα and FXR, and drug metabolism by PXR. Pharmaceutical inhibition of HNF4α reversed HCV-induced glycolysis, blocking viral replication while increasing apoptosis in infected cells showing virus-induced dependence on glycolysis. In contrast, pharmaceutical inhibition of PPARα or FXR reversed HCV-induced ketogenesis but increased viral replication, demonstrating a novel host antiviral response. Our results show that virus-induced changes to a host's metabolism can be detrimental to its life cycle, thus revealing a biologically complex relationship between virus and host.

Physiological processes non-linearly affect electrophysiological recordings during transcranial electric stimulation.

Transcranial electric stimulation (tES) is a promising tool to non-invasively manipulate neuronal activity in the human brain. Several studies have shown behavioral effects of tES, but stimulation artifacts complicate the simultaneous investigation of neural activity with EEG or MEG. Here, we first show for EEG and MEG, that contrary to previous assumptions, artifacts do not simply reflect stimulation currents, but that heartbeat and respiration non-linearly modulate stimulation artifacts. These modulations occur irrespective of the stimulation frequency, i.e. during both transcranial alternating and direct current stimulations (tACS and tDCS). Second, we show that, although at first sight previously employed artifact rejection methods may seem to remove artifacts, data are still contaminated by non-linear stimulation artifacts. Because of their complex nature and dependence on the subjects' physiological state, these artifacts are prone to be mistaken as neural entrainment. In sum, our results uncover non-linear tES artifacts, show that current techniques fail to fully remove them, and pave the way for new artifact rejection methods.

Measuring the cortical correlation structure of spontaneous oscillatory activity with EEG and MEG.

Power correlations of orthogonalized signals have recently been introduced for MEG as a powerful tool to non-invasively investigate functional connectivity in the human brain. Little is known about the applicability of this approach to EEG, and how compatible the results are between EEG and MEG. To address this, we systematically compared power correlations of simultaneously recorded and source co-registered 64-channel EEG and 275-channel MEG in resting human subjects. For both modalities, connectivity peaked at around 16 Hz. For this frequency range, seed-based correlation maps showed comparable patterns across modalities, with generally more distinct patterns for MEG. A brain-wide pattern correlation analysis also revealed maximum similarity around 16 Hz. Correcting for different signal-to-noise ratio (SNR) across frequencies and modalities revealed pattern correlation between modalities close to one across a broad frequency range from 1 to 32 Hz and only slightly smaller for higher frequencies. The decrease above 32 Hz likely reflected higher susceptibility to muscle artifacts for EEG than for MEG. Our results show that power correlation of orthogonalized signals is feasible for studying functional connectivity with 64-channel EEG. Furthermore, besides differences in SNR, for frequencies from about 8 to 32 Hz, EEG and MEG measure the same correlation patterns across the entire brain.

Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients.

BACKGROUND & AIMS: GALAD and BALAD-2 are statistical models for estimating the likelihood of the presence of hepatocellular carcinoma (HCC) in individual patients with chronic liver disease and the survival of patients with HCC, respectively. Both models use objective measures, particularly the serum markers α-fetoprotein (AFP), AFP-L3, and des-γ-carboxyprothrombin. We aimed to validate these models in an international cohort of patients with HCC and assess their clinical performance. METHODS: We collected data on cancer diagnosis and outcomes of 6834 patients (2430 with HCC and 4404 with chronic liver disease) recruited from Germany, Japan, and Hong Kong. We also collected data from 229 patients with other hepatobiliary tract cancers (cholangiocarcinoma or pancreatic adenocarcinoma) and 92 healthy individuals (controls). For reference, the original UK cohort (on which the GALAD model initially was built and BALAD-2 was validated) was included in the analysis. We assessed the effects of tumor size and etiology on GALAD model performance, and its ability to correctly discriminate HCC from other hepatobiliary cancers. We assessed the performance of BALAD-2 in patients with different stages of HCC. RESULTS: In all cohorts, the area under the receiver operating characteristic curve (AUROC), quantifying the ability of GALAD to discriminate patients with HCC from patients with chronic liver disease, was greater than 0.90-similar to the series on which the model originally was built (AUROC, 0.97). GALAD discriminated patients with HCC from those with other hepatobiliary cancers with an AUROC value of 0.95; values were slightly lower for patients with small unifocal HCCs, ranging from 0.85 to 0.95. Etiology and treatment of chronic viral hepatitis had no effect on the performance of this model. BALAD-2 analysis assigned patients with HCC to 4 distinct prognostic groups-overall and when patients were stratified according to disease stage. CONCLUSIONS: We validated the performance of the GALAD and BALAD-2 models for the diagnosis of HCC and predicting patient survival, respectively (based on levels of the serum markers AFP, AFP-L3, and des-γ-carboxyprothrombin), in an international cohort of almost 7000 patients. These systems might be used in HCC surveillance and determination of patient prognosis.

Spectral Signatures of Saccade Target Selection.

Action generation relies on a widely distributed network of brain areas. However, little is known about the spatiotemporal dynamics of neuronal activity in the network that gives rise to voluntary action in humans. Here, we used magnetoencephalography (MEG) and source analysis (n = 15, 7 female subjects) to investigate the spectral signatures of human cortical networks engaged in active and intrinsically motivated viewing behavior. We compared neuronal activity of externally cued saccades with saccades to freely chosen targets. For planning and execution of both saccade types, we found an increase in gamma band (~64-128 Hz) activity and a concurrent decrease in beta band (~12-32 Hz) activity in saccadic control areas, including the intraparietal sulcus and the frontal eye fields. Guided compared to voluntary actions were accompanied by stronger transient increases in the gamma and low frequency (<16 Hz) range immediately following the instructional cue. In contrast, action selection between competing alternatives was reflected by stronger sustained fronto-parietal gamma increases that occurred later in time and persisted until movement execution. This sustained enhancement for free target selection was accompanied by a spatially widespread reduction of lower frequency power (~8-45 Hz) in parietal and extrastriate areas. Our results suggest that neuronal population activity in the gamma frequency band in a distributed network of fronto-parietal areas reflects the intrinsically driven process of selection among competing behavioral alternatives.

Intrahepatic B-cell follicles of chronically hepatitis C virus-infected individuals lack signs of an ectopic germinal center reaction.

Chronic infection with hepatitis C virus (HCV) often affects the B-cell compartment, leading to the occurrence of autoimmunity and B-cell lymphoproliferation, in particular mixed cryoglobulinemia and B-cell lymphomas. HCV presumably causes these lymphoproliferations by chronic antigenic stimulation and/or direct mutagenic effects on B cells. It has been speculated that the interaction of HCV with B cells and the expansion of antigen-triggered B cells happens in germinal center-like structures in the livers of HCV carriers. We studied rearranged immunoglobulin V(H) genes from seven B-cell follicles microdissected from the livers of three unselected chronic HCV patients. The follicles consisted of polyclonal naive and memory B-cell populations with only rare indication of minor clonal expansions and no evidence for active somatic hypermutation. Frequent detection of V(H) rearrangements using the VH1-69 gene segment nevertheless indicated that at least a fraction of the B cells is HCV-specific and/or autoreactive. Thus, the typical intrahepatic B-cell follicles in chronic HCV carriers do not function as ectopic germinal centers for clonal expansion and affinity maturation of B cells. Hence, autoreactive and HCV-specific B-cell clones might either develop in secondary lymphoid organs or in intrahepatic follicles only under particular, yet undefined, circumstances.

Poly(I:C) treatment leads to interferon-dependent clearance of hepatitis B virus in a hydrodynamic injection mouse model.

UNLABELLED: We have previously shown that poly(I:C) activates murine hepatic cells to produce interferon (IFN) and suppresses hepatitis B virus (HBV) replication in vitro. Therefore, we addressed whether poly(I:C) is able to induce the clearance of HBV in vivo. The chronic HBV replication mouse model was established by the hydrodynamic injection (HI) of pAAV-HBV1.2 into the tail veins of wild-type and IFN-α/ßR-, IFN-γ-, and CXCR3-deficient C57BL/6 mice. Fourteen days post-HI of pAAV-HBV1.2, mice were administered poly(I:C) by intraperitoneal injection, intramuscular injection, or HI. Only treatment of poly(I:C) by HI led to HBV clearance in wild-type C57BL/6 mice. Serum HBsAg disappeared within 40 days postinfection (dpi) in mice that received poly(I:C) by HI, and this was accompanied by the appearance of anti-HBs antibodies. HBV-specific T-cell and antibody responses were significantly enhanced by HI of poly(I:C). HBV replication intermediates and HBcAg-positive hepatocytes were eliminated in the liver. HI of poly(I:C) induced the production of IFNs in mice and enhanced the levels of cytokines, IFN-stimulated genes, and T-cell markers in the liver. Importantly, poly(I:C)-induced HBV clearance was impaired in IFN-α/ßR-, IFN-γ-, and CXCR3-deficient mice, indicating that the induction of type I IFN and the stimulation and recruitment of T cells into the liver are essential for HBV clearance in this model. Taken together, the application of poly(I:C) by HI into the liver enhances innate and adaptive immune responses and leads to HBV clearance in an HBV mouse model, implicating the potential of intrahepatic Toll-like receptor 3 (TLR3) activation for the treatment of chronic hepatitis B patients. IMPORTANCE: It has become well accepted that immunomodulation is a potentially useful approach to treat chronic viral infection. Recently, combinations of antiviral treatment and therapeutic vaccinations were evaluated for therapies of chronic hepatitis B virus (HBV) infection. Activation of the innate immune branch may also be important for viral control and contributes to HBV clearance. Our present study demonstrated that hepatic TLR3 activation led to clearance of hepatitis B virus in an HBV mouse model. For the first time, we showed that HBV clearance in this model is dependent not only on type I interferon (IFN) but also on type II IFN, indicating a coordinated action of innate and adaptive immune responses. T-cell recruitment appeared to be critical for the success of TLR3-mediated antiviral action. These findings implicate the potential of intrahepatic TLR3 activation for the treatment of chronic HBV infection.

Chemical modifications on siRNAs avoid Toll-like-receptor-mediated activation of the hepatic immune system in vivo and in vitro.

OBJECTIVES: The therapeutic application of small interfering RNAs (siRNAs) is limited by the induction of severe off-target effects, especially in the liver. Therefore, we assessed the potential of differently modified siRNAs to induce the hepatic innate immune system in vitro and in vivo. METHODS: Primary isolated liver cells were transfected with siRNAs against apolipoprotein B1 (APOB1), luciferase (LUC) or galactosidase (GAL). For in vivo use, siRNAs were formulated in lipid nanoparticles (LNPs) and administered intravenously to C57BL/6 mice. Liver tissue was collected 6-48 h after injection and knock-down efficiency or immune responses were determined by quantitative reverse-transcription-linked PCR. RESULTS: Unmodified GAL siRNA transiently induced the expression of TNF-α, IL-6, IL-10, IFN-ß and IFN-sensitive gene 15 in vivo, whereas a formulation of 2'-O-methylated-LUC siRNA had no such effects. Formulation of unmodified APOB1-specific siRNA suppressed APOB1 mRNA levels by ~80% in the liver 48h after application. The results were paralleled in vitro, where transfection of liver cells with unmodified siRNAs, but not with chemically modified siRNAs, led to cell-type-specific induction of immune genes. These immune responses were not observed in MYD88-deficient mice or in chloroquine-treated cells in vitro. CONCLUSIONS: Our data indicate that siRNAs activate endosomal Toll-like receptors in different liver-derived cell types to various degrees, in vitro. LNP-formulated siRNA selectively leads to hepatic knock-down of target genes in vivo. Here, off-target immune responses are restricted to non-parenchymal liver cells. However, 2'-O-methyl modifications of siRNA largely avoid immune-stimulatory effects, which is a crucial prerequisite for the development of safe and efficient RNA-interference-based therapeutics.

In intermediate stage hepatocellular carcinoma: radioembolization with yttrium 90 or chemoembolization?

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is one of the standard treatments recommended for intermediate stage hepatocellular carcinoma (HCC). At the same time, only little is known about the use of radioembolization with Yttrium-90 microspheres (TARE Y-90) for this subset of patients. To perform comparative analysis between both locoregional therapies in intermediate HCCs. Primary endpoint was overall survival (OS), while safety, response rate and time-to-progression (TTP) were considered as secondary endpoints. METHODS: We collected data of 86 HCC patients in two university hospitals at which conventional TACE with doxorubicin or TARE Y-90 using glass microspheres were performed. The median observation period was 10 months. Patients were followed up for signs of toxicity and response. They underwent imaging analysis at baseline and follow-up at regular time intervals. RESULTS: Eighty-six HCC patients with intermediate stage B (BCLC) were treated with either TACE (n = 42) or TARE Y-90 (n = 44). Despite a higher tumour burden in the TARE Y-90 group, the median OS (TACE: 18 months vs. TARE Y-90: 16.4 months) and the median TTP (TACE: 6.8 months vs. TARE Y-90: 13.3 months) were not statistically different. The number of treatment sessions, the average rate of treatment sessions per patient, total hospitalization time and rate of adverse events were significantly higher in the TACE cohort. CONCLUSION: In intermediate HCC stage patients, both treatments resulted in similar survival probabilities despite more advanced disease in the TARE Y-90 group. Still, TARE Y-90 was better tolerated and associated with less hospitalization and treatment sessions.

TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+ T cell immunity in vitro.

Liver sinusoidal endothelial cells (LSECs) are unique organ-resident APCs capable of Ag cross-presentation and subsequent tolerization of naive CD8(+) T cells. Under certain conditions, LSECs can switch from a tolerogenic to an immunogenic state and promote the development of T cell immunity. However, little is known about the mechanisms of LSECs to induce T cell immunity. In this study, we investigated whether functional maturation of LSECs can be achieved by TLR ligand stimulation and elucidated the mechanisms involved in LSEC-induced T cell immunity. We demonstrate that pretreatment of LSECs with palmitoyl-3-cysteine-serine-lysine-4 (P3C; TLR1/2 ligand) but not poly(I:C) (TLR3 ligand) or LPS (TLR4 ligand) reverted their suppressive properties to induce T cell immunity. Importantly, P3C stimulation caused functional maturation of Ag-presenting LSECs and enabled them to activate virus-specific CD8(+) T cells. The LSEC-mediated CD8(+) T cell immunity was initiated by soluble mediators, one of which was IL-12 secreted at a low but sustained level after P3C stimulation. P3C stimulation did not induce programmed death ligand 1 expression on LSECs, thereby favoring T cell proliferation and activation instead of suppression. Our data suggest that LSECs undergo maturation exclusively in response to TLR1/2 ligand stimulation and that the immunological status of LSECs was dependent upon the balance between programmed death ligand 1 and IL-12 expression. These results have implications for our understanding of liver-specific tolerance and autoimmunity and for the development of strategies to overcome T cell tolerance in situations such as chronic viral liver infections or liver cancer.

Altered intrinsic neuronal interactions in the visual cortex of the blind.

In congenital blindness, the brain develops under severe sensory deprivation and undergoes remarkable plastic changes in both structure and function. Visually deprived occipital cortical regions are histologically and morphologically altered and exhibit a strikingly remodeled functional state: absolute levels of neural activity are heightened and are modulated by nonvisual sensory stimulation as well as higher cognitive processes. However, the neuronal mechanisms that underlie this altered functional state remain largely unknown. Here, we show that the visual cortex of the congenitally blind exhibits a characteristic gain in frequency-specific intrinsic neuronal interactions. We studied oscillatory activity in 11 congenitally blind humans and matched sighted control subjects with magnetoencephalography at rest. We found increased spontaneous correlations of delta band (1-3 Hz) and gamma band (76-128 Hz) oscillations across the visual cortex of the blind that were functionally coupled. Local delta phase modulated gamma amplitude. Furthermore, classical resting rhythms (8-20 Hz) were reduced in amplitude but showed no altered correlation pattern. Our results suggest that both decreased inhibition and circuit mechanisms that support active processing are intrinsic features underlying the altered functional state of the visual cortex in congenitally blind individuals.