Combined inhibition of HER2 and VEGFR synergistically improves therapeutic efficacy via PI3K-AKT pathway in advanced ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a prevalent malignancy in the female reproductive system, and developing effective targeted therapies for this disease remains challenging. The aim of this study was to use clinically-relevant OC models to evaluate the therapeutic effectiveness of RC48, an antibody-drug conjugate (ADC) targeting HER2, either alone or in combination with the VEGFR inhibitor Cediranib Maleate (CM), for the treatment of advanced OC. METHODS: OC tumor specimens and cell lines were analyzed to determine HER2 and VEGFR expression by Western blot, immunocytochemistry and immunofluorescence. Moreover, the OC cell lines, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models were treated with RC48 and/or CM and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for OC both in vitro and in vivo. Additionally, RNA-Seq was performed to investigate the critical mechanism underlying the combination therapy of RC48 and CM. RESULTS: Our results demonstrated that RC48 alone effectively targeted and inhibited the growth of HER2-positive OC tumors in both cell lines and PDX models. Furthermore, the combination of RC48 and CM synergistically induced tumor regression in human OC cell lines, as well as CDX and PDX models. Mechanistically, we observed that the combination treatment inhibited the growth of OC cells involved inducing apoptosis and suppressing cell motility. RNA-seq analysis provided further mechanistic insights and revealed that co-administration of RC48 and CM downregulated multiple cancer-related pathways, including the AKT/mTOR pathway, cell cycle, and cell proliferation. Notably, our data further confirmed that the PI3K-AKT pathway played a key role in the inhibition of proliferation triggered by combinational treatment of RC48 and CM in OC cells. CONCLUSIONS: These findings provide a preclinical framework supporting the potential of dual targeting HER2 and VEGFR as a promising therapeutic strategy to improve outcomes in patients with OC.

Factors influencing passage of time judgment in individuals' daily lives: evidence from the experience sampling and diary methods.

People often express feeling that time passes quickly or slowly in their daily lives, which is termed passage of time judgment (PoTJ). Past studies have shown that PoTJ is affected by emotional valence and arousal; however, few studies have verified the effects of alertness, attention to time, and time expectation on PoTJ and whether the effects are stable over different time periods. Using the experience sampling method (ESM) and diary method, the present study collected data from 105 participants and examined for the first time whether alertness, attention to time, and time expectation affect PoTJ based on daily life data, as well as whether above factors, emotional valence, and arousal are stable over different time periods. All participants answered a questionnaire five times a day on their in-the-day PoTJ and related factors regarding the last 30 min, and answered the same questionnaire once a day at 23:00 regarding the of-the-day PoTJ. The results showed that alertness and time expectation, as well as emotional valence and arousal, predicted an individual's in-the-day PoTJ over a shorter period (i.e., the last 30 min); in contrast, only time expectation and emotional arousal predicted of-the-day PoTJ over a longer period (i.e., the past day). These results suggest that, alertness and time expectation are important factors influencing PoTJ, in addition to emotional state. Of-the-day PoTJ correlates most strongly with the mean and latest in-the-day PoTJ, implying that overall perception of time passage is influenced by both cumulative temporal experience and recent temporal experience.

Impaired proactive control in individuals with methamphetamine use disorder: Evidence from ERPs.

BACKGROUND: Research suggests that methamphetamine use is associated with impaired cognitive control, which may contribute to impulsive drug use. Cognitive control is dynamically mediated by proactive and reactive control (reflecting various processing stages of cognitive control with different properties), and it is crucial to determine whether methamphetamine use impairs proactive and/or reactive control. To address this issue, we conducted an event-related potential (ERP) study to examine proactive and reactive control in individuals with methamphetamine use disorder (MUD). METHODS: Abstinent individuals with MUD (n = 25) and healthy controls (HC, n = 27) completed a cued task-switching task while brain electrical activity was recorded. Cue- and target-locked ERP components modulated by task switching were linked to proactive and reactive control, respectively. RESULTS: No behavioral differences between the groups were found. However, the HC group showed cue-locked switch-positivity (i.e., more positive amplitudes for switch than repeat trials) in both the early and late time windows, although the MUD group only showed late switch-positivity, which was smaller than the HC group. Independent of switch or congruent condition, the MUD group had smaller target-locked positivity than the HC group. CONCLUSIONS: These findings suggest that individuals with MUD exhibit reduced proactive control and mobilize extra reactive control efforts to compensate. Our study contributes to a better understanding of cognitive control impairment in individuals with MUD and has implications for potential interventions.

Effect of cortical extracellular GABA on motor response.

To elucidate how the flattening of sensory tuning due to a deficit in tonic inhibition slows motor responses, we simulated a neural network model in which a sensory cortical network ([Formula: see text]) and a motor cortical network ([Formula: see text]) are reciprocally connected, and the [Formula: see text] projects to spinal motoneurons (Mns). The [Formula: see text] was presented with a feature stimulus and the reaction time of Mns was measured. The flattening of sensory tuning in [Formula: see text] caused by decreasing the concentration of gamma-aminobutyric acid (GABA) in extracellular space resulted in a decrease in the stimulus-sensitive [Formula: see text] pyramidal cell activity while increasing the stimulus-insensitive [Formula: see text] pyramidal cell activity, thereby prolonging the reaction time of Mns to the applied feature stimulus. We suggest that a reduction in extracellular GABA concentration in sensory cortex may interfere with selective activation in motor cortex, leading to slowing the activation of spinal motoneurons and therefore to slowing motor responses.

Plasma Metabolites Forecast Occurrence and Prognosis for Patients With Diffuse Large B-Cell Lymphoma.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma with considerable heterogeneity and different clinical prognosis. However, plasma metabomics used to forecast occurrence and prognosis of DLBCL are rarely addressed. Method: A total of 65 volunteers including 22 healthy controls (Ctrl), 25 DLBCL patients newly diagnosed (ND), and 18 DLBCL patients achieving complete remission (CR) were enrolled. A gas chromatography mass spectrometry-based untargeted plasma metabolomics analysis was performed. Results: Multivariate statistical analysis displayed distinct metabolic features among Crtl, ND, and CR groups. Surprisingly, metabolic profiles of newly diagnosed DLBCL patients undergoing different prognosis showed clear and distinctive clustering. Based on the candidate metabolic biomarkers (glucose and aspartate) and clinical indicators (lymphocyte, red blood count, and hemoglobin), a distinct diagnostic equation was established showing improved diagnostic performance with an area under curve of 0.936. The enrichment of citric acid cycle, deficiency of branched chain amino acid, methionine, and cysteine in newly diagnosed DLBCL patients was closely associated with poor prognosis. In addition, we found that malate and 2-hydroxy-2-methylbutyric acid were positively correlated with the baseline tumor metabolic parameters (metabolically active tumor volume and total lesion glycolysis), and the higher abundance of plasma malate, the poorer survival. Conclusion: Our preliminary data suggested plasma metabolomics study was informative to characterize the metabolic phenotypes and forecast occurrence and prognosis of DLBCL. Malate was identified as an unfavorable metabolic biomarker for prognosis-prediction of DLBCL, which provided a new insight on risk-stratification and therapeutic targets of DLBCL. More studies to confirm these associations and investigate potential mechanisms are in the process.

Water-soluble chlorin e6-hydroxypropyl chitosan as a high-efficiency photoantimicrobial agent against Staphylococcus aureus.

The development of new antimicrobial agents is important to combat infections caused by pathogenic bacteria. Herein, Hydroxypropyl chitosan (HPCS), a hydrophilic modified product of chitosan (CS), was employed as a carrier of the photosensitizer chlorin e6 (Ce6) through an amide bond to obtain the products (HPCS-Ce6 conjugates) with a degree of substitution (DS) ranging from 2.95% to 5.25%. The UV-vis absorption spectra and 1H NMR spectra confirmed the successful synthesis of the products. The products have a better and more stable reactive oxygen species (ROS) generation capacity and higher bacterial affinity than Ce6. At a very low dose (1.8 µg/mL), the highest DS product (HPCS-Ce6-3) can effectively kill Staphylococcus aureus (S. aureus) under 660 nm irradiation. In addition, the HPCS-Ce6 conjugates showed high biocompatibility in the CCK-8 test. The HPCS-Ce6 conjugates could be a photodynamic antibacterial agent with good water solubility, high biocompatibility, and antibacterial activity.

ALKBH5-mediated N6-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation.

Long noncoding RNAs (lncRNAs) have crucial functions in the tumorigenesis and metastasis of cancers. N6-methyladenosine (m6A) modification of RNA is an important epigenetic regulatory mechanism in various malignancies. Nevertheless, the mechanism of m6A-modified lncRNA in diffuse large B cell lymphoma (DLBCL) has remained poorly defined. In the present study, we showed that lncRNA TRERNA1 was associated with the poor prognosis of DLBCL patients. TRERNA1 with internal m6A modification was highly correlated with the demethylase ALKBH5 expression. We further demonstrated that TRERNA1 was a potential downstream target of ALKBH5-mediated m6A modification by m6A-RNA sequencing and m6A-RIP assays. Decreased m6A methylation of TRERNA1 regulated by ALKBH5 was shown to regulate cell proliferation in vitro and in vivo. The results of mechanism analyses revealed that TRERNA1 recruited EZH2 to epigenetically silence the expression of the cyclin-dependent kinases inhibitor p21 by H3K27me3 modification of its promoter region. In addition, ALKBH5 further inhibited p21 expression. Taken together, our results elucidate the functional roles and epigenetic alterations of TRERNA1 through m6A modification in DLBCL. TRERNA1, the expression of which is upregulated by ALKBH5, acts as a scaffold that decreases p21 expression. The results of the present study provide novel targets for the diagnosis and treatment of DLBCL.

Chlorin e6 conjugated chitosan as an efficient photoantimicrobial agent.

The development of antibacterial agents with high bacteria-binding capability and antibacterial efficiency is highly desirable. Herein, cationic polysaccharide chitosan (CS) was combined with photosensitizer Chlorin e6 (Ce6) to construct a novel photodynamic antibacterial agent (CS-Ce6 conjugates) for combating gram-positive bacteria Staphylococcus aureus (S. aureus) and gram-negative bacteria Escherichia coli (E. coli). CS-Ce6 conjugates with different degrees of substitution (DS) were synthesized and characterized by a spectroscopic method and organic elemental analysis to understand the relationship between structure and antibacterial effect. CS-Ce6 conjugates revealed good reactive oxygen species (ROS) generation ability and photodynamic antibacterial effect. Meanwhile, they both were positively correlated with DS in the range of 4.81% ~ 11.56% resulting in stronger photodynamic antibacterial ability. These findings highlight that CS-Ce6 conjugates have the potential as an effective photodynamic bactericidal agent in the antibacterial field.

A general strategy to synthesis chitosan oligosaccharide-O-Terpenol derivatives with antibacterial properties.

The objectives of the present study are to synthesize a series of chitosan oligosaccharide-O-Terpenol (COS-O-Ter) derivatives and their implication to evaluate in vitro antibacterial activity. Herein, a general strategy is described for preparing COS-O-Ter derivatives, including substitution and deprotection reactions. The structures of COS-O-Ter derivatives were characterized by FT-IR, 1H NMR, XRD, TGA, and elemental analysis. COS-O-Ter derivatives revealed the excellent solubility and in vitro antibacterial activity. Moreover, their antibacterial activities were more sensitive to Staphylococcus aureus (S. aureus) than Escherichia coli (E. coli) indicating the effective potential application of COS-O-Ter derivatives as natural antibacterial agents. The aforementioned study opens a pave to expand the application scope of COS and its derivatives in the food and pharmaceutical industries.

Metabolomic approach to characterize the metabolic phenotypes and varied response to ouabain of diffuse large B-cell lymphoma cells.

Germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtype diffuse large B-cell lymphoma (DLBCL) showed differential prognosis. Our results suggested that ouabain induced stronger inhibition of growth in Su-DHL4 (GCB), and it triggered obvious apoptosis in Su-DHL4 rather than in OCI-Ly3 (ABC). Two subtype cell lines also showed distinct metabolic phenotypes involving remarkable enrichment of Ribulose-5-Phosphate, hypoxanthine, and guanine in Su-DHL4 cells. Ouabain disturbed metabolic patterns of both cell lines dose-dependently manifested inhibition of free fatty acids and amino acids metabolism, among which ornithine was further identified as potential quantitative marker. Up-regulated Ribulose-5-Phosphate and NADPH/NADP+ level, SOD1, and CAT expression by ouabain enabled OCI-Ly3 cells to resist ROS, while enhanced hypoxanthine and guanine oxidation promoting ROS generation by ouabain, and lowered capacity of scavenging ROS indicated by lowered SOD1 and CAT expression and NADPH/NADP+ levels in Su-DHL4 cells made it more vulnerable to apoptosis through caspase 7 pathway.

Metabolic markers for diagnosis and risk-prediction of multiple myeloma.

AIMS: To discriminate metabolic biomarkers for diagnosis and risk prediction of multiple myeloma (MM) on a basis of metabolic characteristics in systemic circulation and local pathogenic niche. MAIN METHODS: A gas chromatography mass spectrometry-based untargeted metabolomics analysis was performed within the bone marrow (BM) supernatants and peripheral plasma from healthy donors and patients with MM. KEY FINDINGS: Distinct metabolic features between MM patients and healthy volunteers were profiled in both BM and plasma. Metabolic profiles of subgroups in which MM patients undergo high/medium/low risk displayed risk-dependent metabolic shift especially in BM. In MM patients, up-regulated glutamate level and down-regulated glutamine level in BM indicated enhanced glutamate metabolism which provided NH4+ for ammonia utilization. This resulted in increased level of urea and creatinine produced from urea cycle, arginine and proline metabolism in both BM and plasma collected from MM patients. The disorders of tricarboxylic acid cycle and carnitine synthesis were unique in BM of MM patients. Receiver operating characteristic curve analysis indicated that aspartate was a candidate plasma biomarker for diagnosis with the highest sensitivity and specificity in both BM and plasma. Threonine was identified as a preferential plasma biomarker for risk prediction due to significant relation with various risk indexes of MM in both BM and plasma. SIGNIFICANCE: The perturbed glutamate metabolism and carnitine synthesis in BM of MM patients provided a new sight on pathogenesis of MM. The plasma level of aspartate and threonine may become a preferential metabolic marker for diagnosis and risk prediction of MM, respectively.

Ouabain regulates kidney metabolic profiling in rat offspring of intrauterine growth restriction induced by low-protein diet.

AIMS: Intrauterine growth restriction (IUGR) can increase the risk of hypertension and kidney disease at adulthood due to fetal programming. In our previous study, we found that supplementation with low concentration of ouabain during pregnancy could restore glomerulus numbers at birth, rescuing kidney development. However, the metabolic pattern of kidney in IUGR offspring and the effect of ouabain have not been evaluated. MAIN METHODS: In this study, based on GC-MS and LC-MS platforms, we used the protein restriction rat model to explore the molecular mechanisms of kidney damage induced by IUGR and the protective effect of ouabain. KEY FINDINGS: The results showed that malnutrition could induce IUGR in rat offspring at the 20th gestational day but ouabain treatment could partially reverse the body and kidney weight loss. Ouabain treatment could upregulate arginine, N-acetylornithine and carbamoyl phosphate as well as adenine nucleotide and guanine nucleotide downregulated by low-protein diet. Moreover, six metabolites were identified to be significantly correlated with fetal kidney weight, with 3 metabolites involved in arginine metabolism (arginine, N-acetylornithine, urea) and UDP-glucuronate correlated positively, while lysine and anthranilate correlated negatively. SIGNIFICANCE: The results suggested that the underlying mechanism of ouabain against renal maldevelopment involved the metabolic regulation, particularly the arginine metabolism, which played an important role in the development of fetal kidney.

Metabolomics analysis identifies lysine and taurine as candidate prognostic biomarkers for AML-M2 patients.

There is an ongoing search for potential biomarkers for acute myeloid leukemia (AML) patients using metabolic analysis. However, only few studies to date have focused on bone marrow samples or a specific subtype of AML. In the present study, we used gas chromatography time-of-flight mass spectrometry of plasma and bone marrow supernatants to compare the metabolic characteristics of patients with AML with maturation (AML-M2). This approach identified significantly altered metabolites. We next performed pathway analysis and determined relative mRNA expression by qRT-PCR. Our results show that lysine, methionine and serine were significantly decreased in AML-M2 patients compared with healthy control. Moreover, plasma abundance of lysine was negatively associated with patients' risk stratification. Taurine had higher plasma abundance in AML-M2 patients and plasma level of taurine was positively related with AML-M2 risk status, while the expression level of taurine transporter showed a negative correlation. Receiver operating characteristic curve analysis showed these four metabolites had high diagnostic value with lysine showing the highest sensitivity and specificity. These results suggest that plasma abundances of lysine and taurine may serve as potential metabolic biomarkers for the prognosis of patients with AML-M2.

Reduced response inhibition after exposure to drug-related cues in male heroin abstainers.

RATIONALE: Deficits in response inhibition associated with heroin use could last several months after abstinence in heroin users, and their response inhibition can also be interfered with task-irrelevant drug-related cues. However, it is unclear whether exposure to drug-related cues affects subsequent response inhibition in heroin users following abstinence. OBJECTIVES: The present study aimed to investigate how drug-related cues with different durations between stimulus presentations, referred to as stimulus onset asynchronies (SOAs), affect subsequent response inhibition in heroin abstainers (HAs) with different length of abstinence. METHODS: Sixty-seven male HAs performed a modified Go/NoGo task in which a motor response to frequent Go targets and no response to rare NoGo targets were required and a Go or NoGo target was displayed after either a heroin-related or a neutral picture presented for the 200 ms and 600 ms SOAs. RESULTS: The HAs responded significantly faster to Go targets following the neutral pictures for the 600 ms SOA compared to other conditions. They also made more commission errors following heroin-related pictures compared to neutral pictures regardless of the SOAs. The shorter-term HAs made more commission errors compared to the longer-term HAs following the 200 ms SOA, and it was only a trend when the SOA was 600 ms. Additionally, negative correlations between the duration of current abstinence and commission errors were observed following cues with the 200 ms SOA. CONCLUSIONS: Impaired response inhibition in HAs can be improved through protracted drug abstinence. However, that effect can be reduced by exposure to drug-related cues, which may increase the risk of relapse.

Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma.

BACKGROUND: Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME. METHODS: Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor). RESULTS: We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC. CONCLUSIONS: Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.

Graphene oxide arms oncolytic measles virus for improved effectiveness of cancer therapy.

BACKGROUND: Replication-competent oncolytic viruses (OVs) have been proven to be a potent anticancer weapon for clinical therapy. The preexisting neutralizing antibody in patients is a big challenge for oncolytic efficacy of OVs. Graphene oxide sheets (GOS) possess excellent biological compatibility and are easy to decorate for targeted delivery. METHODS: We generated PEI-GOS-PEG-FA (Polyethyleneimine-Graphene oxide sheets-Polyethylene glycol-Folic acid). After intravenous injection, the distribution of PEI-GOS-PEG-FA in tumor-bearing mice was visualized by the IVIS Lumina XR system. Then, the oncolytic measles virus (MV-Edm) was coated with PEI-GOS-PEG-FA to form a viral-GOS complex (GOS/MV-Edm). The oncolytic effects of GOS/MV-Edm were investigated both in vitro and in vivo. RESULTS: GOS/MV-Edm exhibited higher infectivity and enhanced oncolysis. In tumor-bearing mice, GOS/MV-Edm had significantly elevated viral replication within the tumor mass, and achieved an improved antitumor effect. Then, we confirmed that GOS/MV-Edm entered cancer cells via the folate receptor instead of CD46, a natural cognate receptor of MV-Edm. GOS/MV-Edm remained the infectivity in murine cells that lack CD46. Finally, we found that GOS/MV-Edm was effectively protected from neutralization in the presence of antiserum both in vitro and in vivo. In passively antiserum immunized tumor-bearing mice, the survival was remarkably improved with intravenous injection of GOS/MV-Edm. CONCLUSION: Our findings demonstrate that GOS/MV-Edm displays significantly elevated viral replication within the tumor mass, leading to an improved antitumor effect in solid tumor mouse model. Our study provided a novel strategy to arm OVs for more efficient cancer therapy. That may become a promising therapeutic strategy for cancer patients.

Perceptual judgments via sensory-motor interaction assisted by cortical GABA.

Recurrent input to sensory cortex, via long-range reciprocal projections between motor and sensory cortices, is essential for accurate perceptual judgments. GABA levels in sensory cortices correlate with perceptual performance. We simulated a neuron-astrocyte network model to investigate how top-down, feedback signaling from a motor network (Nmot) to a sensory network (Nsen) affects perceptual judgments in association with ambient (extracellular) GABA levels. In the Nsen, astrocytic transporters modulated ambient GABA levels around pyramidal cells. A simple perceptual task was implemented: detection of a feature stimulus presented to the Nsen. The Nmot showed distinct perceptual behaviors: hit, fault, and miss. A hit is a correct response to the stimulus, a fault is a wrong response to the stimulus, and a miss is no response to the stimulus. In hits, the feedback signaling increased the gain of Nsen pyramidal cells and accelerated the reaction speed of Nmot pyramidal cells to the stimulus. Without feedback signaling, the Nsen but not Nmot responded to the stimulus, resulting in a miss. With too strong feedback signaling, the Nmot resulted in a fault, namely, stimulus-insensitive but not stimulus-sensitive pyramidal cells wrongly responded. Balancing the feedforward and feedback signaling formed a coherent, ongoing-spontaneous neuronal state, by which the highest hit rate was achieved. A transient reduction in local ambient GABA levels, triggered by the stimulus, contributed to accelerating the reaction speed under noisy environmental conditions. Adjusting the basal ambient GABA level ensured high hit rates. We suggest that motor cortex feedback may accelerate reaction speed to sensory stimulation by promoting coherency in ongoing-spontaneous neuronal activity between sensory and motor cortices, thereby achieving prompt perceptual judgments. Spatiotemporal modulation of ambient GABA levels, possibly by astrocytic transporters, assists in making reliable perceptual judgments.

Improved Perceptual Learning by Control of Extracellular GABA Concentration by Astrocytic Gap Junctions.

Learning of sensory cues is believed to rely on synchronous pre- and postsynaptic neuronal firing. Evidence is mounting that such synchronicity is not merely caused by properties of the underlying neuronal network but could also depend on the integrity of gap junctions that connect neurons and astrocytes in networks too. In this perspective, we set out to investigate the effect of astrocytic gap junctions on perceptual learning, introducing a model for coupled neuron-astrocyte networks. In particular, we focus on the fact that astrocytes are rich of GABA transporters (GATs) which can either uptake or release GABA depending on the astrocyte membrane potential, which is a function of local neural activity. We show that GABAergic signaling is a crucial component of intracolumnar neuronal synchronization, thereby promoting learning by neurons in the same cell assembly that are activated by a shared sensory cue. At the same time, we show that this effect can critically depend on astrocytic gap junctions insofar as these latter could synchronize extracellular GABA levels around many neurons and throughout entire cell assemblies. These results are supported by extensive computational arguments and predict that astrocytic gap junctions could improve perceptual learning by controlling extracellular GABA.

Oncolytic measles virus enhances antitumour responses of adoptive CD8+NKG2D+ cells in hepatocellular carcinoma treatment.

There is an urgent need for novel effective treatment for hepatocellular carcinoma (HCC). Oncolytic viruses (OVs) not only directly lyse malignant cells, but also induce potent antitumour immune responses. The potency and precise mechanisms of antitumour immune activation by attenuated measles virus remain unclear. In this study, we investigated the potency of the measles virus vaccine strain Edmonston (MV-Edm) in improving adoptive CD8+NKG2D+ cells for HCC treatment. We show that MV-Edm-infected HCC enhanced the antitumour activity of CD8+NKG2D+ cells, mediated by at least three distinct mechanisms. First, MV-Edm infection compelled HCC cells to express the specific NKG2D ligands MICA/B, which may contribute to the activation of CD8+NKG2D+ cells. Second, MV-Edm-infected HCC cells stimulated CD8+NKG2D+ cells to express high level of FasL resulting in enhanced induction of apoptosis. Third, intratumoural administration of MV-Edm enhanced infiltration of intravenously injected CD8+NKG2D+ cells. Moreover, we found that MV-Edm and adoptive CD8+NKG2D+ cells, either administered alone or combined, upregulated the immune suppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in HCC. Elimination of IDO1 by fludarabine enhanced antitumour responses. Taken together, our data provide a novel and clinically relevant strategy for treatment of HCC.