Combined CRAFITY score and α-fetoprotein response predicts treatment outcomes in patients with unresectable hepatocellular carcinoma receiving anti-programmed death-1 blockade-based immunotherapy.

Biomarkers for predicting the treatment efficacy of immune checkpoint inhibitor (ICI)-based therapy in patients with unresectable hepatocellular carcinoma (uHCC) are crucial. Previous studies demonstrated that C-reactive protein and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) score at baseline predicted treatment outcomes and that patients with uHCC with AFP response, defined as > 15% decline in AFP level within the initial 3 months of ICI-based therapy, had favorable outcomes when receiving ICI-based therapy. However, whether the combination of CRAFITY score and AFP response could be used to predict treatment efficacy of programmed death-1 (PD-1) blockade-based therapy in uHCC patients remains unclear. We retrospectively enrolled 110 consecutive uHCC patients from May 2017 to March 2022. The median ICI treatment duration was 2.85 (1.67-6.63) months, and 87 patients received combination therapies. The objective response and disease control rates were 21.8% and 46.4%, respectively. The duration of progression-free survival (PFS) and overall survival (OS) was 2.87 (2.16-3.58) months and 8.20 (4.23-12.17) months, respectively. We categorized patients into three groups based on CRAFITY score (2 vs 0/1) and AFP response: patients with a CRAFITY score of 0/1 and AFP response (Group 1), those with a CRAFITY score of 2 and no AFP response (group 3), and those who did not belong to Group 1 and 3 (i.e., Group 2). The combination of CRAFITY score and AFP response could predict disease control and could predict PFS compared with CRAFITY score or AFP response alone. The combination of CRAFITY score and AFP response was an independent predictor of OS (Group 2 vs Group 1, HR: 4.513, 95% CI 1.990-10.234; Group 3 vs Group 1, HR: 3.551, 95% CI 1.544-8.168). Our findings indicated that the combination of CRAFITY score and AFP response could predict disease control, PFS, and OS in uHCC patients receiving PD-1 blockade-based immunotherapy.

BC RNA Mislocalization in the Fragile X Premutation.

Fragile X premutation disorder is caused by CGG triplet repeat expansions in the 5' untranslated region of FMR1 mRNA. The question of how expanded CGG repeats cause disease is a subject of continuing debate. Our work indicates that CGG-repeat structures compete with regulatory BC1 RNA for access to RNA transport factor hnRNP A2. As a result, BC1 RNA is mislocalized in vivo, as its synapto-dendritic presence is severely diminished in brains of CGG-repeat knock-in animals (a premutation mouse model). Lack of BC1 RNA is known to cause seizure activity and cognitive dysfunction. Our working hypothesis thus predicted that absence, or significantly reduced presence, of BC1 RNA in synapto-dendritic domains of premutation animal neurons would engender cognate phenotypic alterations. Testing this prediction, we established epileptogenic susceptibility and cognitive impairments as major phenotypic abnormalities of CGG premutation mice. In CA3 hippocampal neurons of such animals, synaptic release of glutamate elicits neuronal hyperexcitability in the form of group I metabotropic glutamate receptor-dependent prolonged epileptiform discharges. CGG-repeat knock-in animals are susceptible to sound-induced seizures and are cognitively impaired as revealed in the Attentional Set Shift Task. These phenotypic disturbances occur in young-adult premutation animals, indicating that a neurodevelopmental deficit is an early-initial manifestation of the disorder. The data are consistent with the notion that RNA mislocalization can contribute to pathogenesis.

Early-Onset Network Hyperexcitability in Presymptomatic Alzheimer's Disease Transgenic Mice Is Suppressed by Passive Immunization with Anti-Human APP/Aß Antibody and by mGluR5 Blockade.

Cortical and hippocampal network hyperexcitability appears to be an early event in Alzheimer's disease (AD) pathogenesis, and may contribute to memory impairment. It remains unclear if network hyperexcitability precedes memory impairment in mouse models of AD and what are the underlying cellular mechanisms. We thus evaluated seizure susceptibility and hippocampal network hyperexcitability at ~3 weeks of age [prior to amyloid beta (Aß) plaque deposition, neurofibrillary pathology, and cognitive impairment] in a triple transgenic mouse model of familial AD (3xTg-AD mouse) that harbors mutated human Aß precursor protein (APP), tau and presenilin 1 (PS1) genes. Audiogenic seizures were elicited in a higher proportion of 3xTg-AD mice compared with wild type (WT) controls. Seizure susceptibility in 3xTg-AD mice was attenuated either by passive immunization with anti-human APP/Aß antibody (6E10) or by blockade of metabotropic glutamate receptor 5 (mGluR5) with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). In in vitro hippocampal slices, suppression of synaptic inhibition with the GABAA receptor antagonist, bicuculline, induced prolonged epileptiform (>1.5 s in duration) ictal-like discharges in the CA3 neuronal network in the majority of the slices from 3xTg-AD mice. In contrast, only short epileptiform (<1.5 s in duration) interictal-like discharges were observed following bicuculline application in the CA3 region of WT slices. The ictal-like activity in CA3 region of the hippocampus was significantly reduced in the 6E10-immunized compared to the saline-treated 3xTg-AD mice. MPEP acutely suppressed the ictal-like discharges in 3xTg-AD slices. Remarkably, epileptiform discharge duration positively correlated with intraneuronal human (transgenic) APP/Aß expression in the CA3 region of the hippocampus. Our data suggest that in a mouse model of familial AD, hypersynchronous network activity underlying seizure susceptibility precedes Aß plaque pathology and memory impairment. This early-onset network hyperexcitability can be suppressed by passive immunization with an anti-human APP/Aß antibody and by mGluR5 blockade in 3xTg-AD mice.

APP Causes Hyperexcitability in Fragile X Mice.

Amyloid-beta protein precursor (APP) and metabolite levels are altered in fragile X syndrome (FXS) patients and in the mouse model of the disorder, Fmr1KO mice. Normalization of APP levels in Fmr1KO mice (Fmr1KO /APPHET mice) rescues many disease phenotypes. Thus, APP is a potential biomarker as well as therapeutic target for FXS. Hyperexcitability is a key phenotype of FXS. Herein, we determine the effects of APP levels on hyperexcitability in Fmr1KO brain slices. Fmr1KO /APPHET slices exhibit complete rescue of UP states in a neocortical hyperexcitability model and reduced duration of ictal discharges in a CA3 hippocampal model. These data demonstrate that APP plays a pivotal role in maintaining an appropriate balance of excitation and inhibition (E/I) in neural circuits. A model is proposed whereby APP acts as a rheostat in a molecular circuit that modulates hyperexcitability through mGluR5 and FMRP. Both over- and under-expression of APP in the context of the Fmr1KO increases seizure propensity suggesting that an APP rheostat maintains appropriate E/I levels but is overloaded by mGluR5-mediated excitation in the absence of FMRP. These findings are discussed in relation to novel treatment approaches to restore APP homeostasis in FXS.

Extracellular glutamate exposure facilitates group I mGluR-mediated epileptogenesis in the hippocampus.

Stimulation of group I mGluRs elicits several forms of translation-dependent neuronal plasticity including epileptogenesis. The translation process underlying plasticity induction is controlled by repressors including the fragile X mental retardation protein (FMRP). In the absence of FMRP-mediated repression, a condition that occurs in a mouse model (Fmr1(-/-)) of fragile X syndrome, group I mGluR-activated translation is exaggerated causing enhanced seizure propensity. We now show that glutamate exposure (10 µm for 30 min) reduced FMRP levels in wild-type mouse hippocampal slices. Downregulation of FMRP was dependent on group I mGluR activation and was blocked by a proteasome inhibitor (MG-132). Following glutamate exposure, synaptic stimulation induced prolonged epileptiform discharges with properties similar to those observed in Fmr1(-/-) preparations. In both cases, prolonged epileptiform discharges were blocked by group I mGluR antagonists (LY367385 + MPEP) and their induction was prevented by protein synthesis inhibitor (anisomycin). The results suggest that stimulation of group I mGluRs during glutamate exposure caused proteolysis of FMRP. Reduction of FMRP led to enhanced synaptic group I mGluR-mediated translation. Elevated translation facilitated the recruitment of group I mGluR-mediated prolonged epileptiform discharges.

Burger or yogurt? Indulgent consumption in impression management contexts.

We conducted three studies to investigate indulgent choice in settings with and without impression management by public-private manipulation with evaluation. Study 1 showed that the participants were less indulgent under public scrutiny due to the employment of impression management. Study 2 focused on the impression management context to test the moderate effect of self-consciousness in two impression managed contexts. Study 3 focused on context without impression management to test the moderate effects of self-awareness on choices. We found that depending on differences in primed personality, individuals tended to make choices other than those they favoured privately when anticipating that others might form impressions of them based on the decisions made. The findings of all three studies support our basic prediction that people are less indulgent under impression management and suggest that people tend to manage their impression by eating healthier (less indulgently) in public.

Message framing in social networking sites.

Online social networking sites represent significant new opportunities for Internet advertisers. However, results based on the real world cannot be generalized to all virtual worlds. In this research, the moderating effects of need for cognition (NFC) and knowledge were applied to examine the impact of message framing on attitudes toward social networking sites. A total of 216 undergraduates participated in the study. Results reveal that for social networking sites, while high-NFC individuals form more favorable attitudes toward negatively framed messages than positively framed messages, low-NFC individuals form more favorable attitudes toward positively framed messages than negatively framed messages. In addition, low-knowledge individuals demonstrate more favorable attitudes toward negatively framed messages than positively framed messages; however, the framing effect does not differentially affect the attitudes of high-knowledge individuals. Furthermore, the framing effect does not differentially affect the attitudes of high-NFC individuals with high knowledge. In contrast, low-NFC individuals with low knowledge hold more favorable attitudes toward positively framed messages than negatively framed messages.

Persistent receptor activity underlies group I mGluR-mediated cellular plasticity in CA3 neuron.

Plastic changes in cortical activities induced by group I metabotropic glutamate receptor (mGluR) stimulation include epileptogenesis, expressed in vitro as the conversion of normal neuronal activity to persistent, prolonged synchronized (ictal) discharges. At present, the mechanism that maintains group I mGluR-induced plasticity is not known. We examined this issue using hippocampal slices from guinea pigs and mice. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG), 30-50 µm)] stimulation of group I mGluRs induces persistent prolonged synchronized (ictal-like) discharges in CA3 that are associated with three identified excitatory cellular responses-suppression of spike afterhyperpolarizations, activation of a voltage-dependent cationic current, and increase in neuronal input resistance. Persistent prolonged synchronized discharges and the underlying excitatory cellular responses maintained following induction were reversibly blocked by mGluR1 antagonists [(S)-+-α-amino-4-carboxy-2-methylbenzeneacetic acid (LY 367385), 50, 100 µm; CPCCOEt (hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, 100 µm], and to a lesser extent by the mGluR5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine hydrochloride, 50 µm]. Activation of persistent cellular responses to DHPG were unaffected by tetrodotoxin (0.5-1 µm) or perfusion with low Ca(2+)(0.2 mm)-Mn(2+)(0.5 mm) media-conditions that suppress endogenous glutamate release. The pharmacological profile of the blocking action of the group I mGluR antagonist MCPG [(RS)-α-methyl-4-carboxyphenylglycine, 50-500 µm] on persistent cellular responses was different from that on cellular responses directly activated by DHPG. These data indicate that transient stimulation of group I mGluRs alters receptor properties, rendering them persistently active in the absence of applied agonist or endogenous glutamate activation. Persistent receptor activities, primarily involving mGluR1, maintain excitatory cellular responses and emergent prolonged synchronized discharges.

Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome.

Many neuropsychiatric symptoms of fragile X syndrome (FXS) are believed to be a consequence of altered regulation of protein synthesis at synapses. We discovered that lovastatin, a drug that is widely prescribed for the treatment of high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent one of the robust functional consequences of increased protein synthesis in FXS, epileptogenesis. These data suggest that lovastatin is potentially disease modifying and could be a viable prophylactic treatment for epileptogenesis in FXS.

The impact of self-confidence on the compromise effect.

This research reports an investigation into whether the personality aspect of self-confidence affects the compromise effect. We hypothesize that highly self-confident people have greater certainty in making decisions and are more attracted to risk-taking, which makes them less likely to choose the safe or middle option in a large choice set. The three studies involved are conducted using between- and within-subjects experimental designs. Various product categories are used to generalize the findings. Study 1 looks at purchasing decisions and utilizes three scales of self-confidence, risk preference, and uncertainty; it demonstrates that consumers with high self-confidence are less likely to choose a compromise option due to high certainty in their decision-making. Study 2 discovers that people with low self-confidence are more likely to choose the middle option in a risky condition than in a nonrisky condition. Study 3 decomposes self-confidence into general and specific self-confidence, and reveals that people with low general self-confidence and low specific self-confidence are more likely to choose the middle option.

Dual regulation of fragile X mental retardation protein by group I metabotropic glutamate receptors controls translation-dependent epileptogenesis in the hippocampus.

Group I metabotropic glutamate receptors (mGluRs) stimulation activates translation-dependent epileptogenesis in the hippocampus. This translation is regulated by repressors, including BC1 RNA and fragile X mental retardation protein (FMRP). Recent data indicate that group I mGluR stimulation exerts bidirectional control over FMRP level by activating translation and ubiquitin-proteasome system (UPS)-dependent proteolysis for the up- and downregulation of the protein, respectively. At present, the temporal relationship of translation and proteolysis on FMRP and their interplay for group I mGluR-mediated translation and epileptogenesis are unknown. We addressed these issues by using mouse hippocampal slices. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG)] stimulation of group I mGluRs caused a biphasic change in FMRP level. An initial decrease (within 10 min) was followed by an increase at 30 min. When slices were pretreated with translation inhibitor (anisomycin or cycloheximide), group I mGluRs elicited a sustained decrease in FMRP. This decrease was prevented by a proteasome inhibitor [Z-Leu-Leu-Leu-CHO (MG-132)]. When slices were pretreated with MG-132 alone, DHPG no longer elicited any change in FMRP. MG-132 also suppressed increase in other proteins, including postsynaptic density-95 and α-calcium/calmodulin-dependent protein kinase II, normally elicited by group I mGluR stimulation. Physiological experiments showed that proteasome inhibitor suppressed group I mGluR-induced prolonged synchronized discharges. However, proteasome inhibitor did not affect group I mGluR-induced prolonged synchronized discharges in Fmr1(-/-) preparations, where functional FMRP is absent. The results suggest that constitutive FMRP in hippocampal cells acts as a brake on group I mGluR-mediated translation and epileptogenesis. FMRP downregulation via UPS removes this brake enabling group I mGluR-mediated translation and epileptogenesis.

Regulatory BC1 RNA and the fragile X mental retardation protein: convergent functionality in brain.

BACKGROUND: BC RNAs and the fragile X mental retardation protein (FMRP) are translational repressors that have been implicated in the control of local protein synthesis at the synapse. Work with BC1 and Fmr1 animal models has revealed that phenotypical consequences resulting from the absence of either BC1 RNA or FMRP are remarkably similar. To establish functional interactions between BC1 RNA and FMRP is important for our understanding of how local protein synthesis regulates neuronal excitability. METHODOLOGY/PRINCIPAL FINDINGS: We generated BC1-/- Fmr1-/- double knockout (dKO) mice. We examined such animals, lacking both BC1 RNA and FMRP, in comparison with single knockout (sKO) animals lacking either one repressor. Analysis of neural phenotypical output revealed that at least three attributes of brain functionality are subject to control by both BC1 RNA and FMRP: neuronal network excitability, epileptogenesis, and place learning. The severity of CA3 pyramidal cell hyperexcitability was significantly higher in BC1-/- Fmr1-/- dKO preparations than in the respective sKO preparations, as was seizure susceptibility of BC1-/- Fmr1-/- dKO animals in response to auditory stimulation. In place learning, BC1-/- Fmr1-/- dKO animals were severely impaired, in contrast to BC1-/- or Fmr1-/- sKO animals which exhibited only mild deficits. CONCLUSIONS/SIGNIFICANCE: Our data indicate that BC1 RNA and FMRP operate in sequential-independent fashion. They suggest that the molecular interplay between two translational repressors directly impacts brain functionality.

BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability.

Regulatory RNAs have been suggested to contribute to the control of gene expression in eukaryotes. Brain cytoplasmic (BC) RNAs are regulatory RNAs that control translation initiation. We now report that neuronal BC1 RNA plays an instrumental role in the protein-synthesis-dependent implementation of neuronal excitation-repression equilibria. BC1 repression counter-regulates translational stimulation resulting from synaptic activation of group I metabotropic glutamate receptors (mGluRs). Absence of BC1 RNA precipitates plasticity dysregulation in the form of neuronal hyperexcitability, elicited by group I mGluR-stimulated translation and signaled through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway. Dysregulation of group I mGluR function in the absence of BC1 RNA gives rise to abnormal brain function. Cortical EEG recordings from freely moving BC1(-/-) animals show that group I mGluR-mediated oscillations in the gamma frequency range are significantly elevated. When subjected to sensory stimulation, these animals display an acute group I mGluR-dependent propensity for convulsive seizures. Inadequate RNA control in neurons is thus causally linked to heightened group I mGluR-stimulated translation, neuronal hyperexcitability, heightened gamma band oscillations, and epileptogenesis. These data highlight the significance of small RNA control in neuronal plasticity.

Cellular plasticity for group I mGluR-mediated epileptogenesis.

Stimulation of group I metabotropic glutamate receptors (mGluRs) by the agonist (S)-dihydroxyphenylglycine in the hippocampus transforms normal neuronal activity into prolonged epileptiform discharges. The conversion is long lasting in that epileptiform discharges persist after washout of the inducing agonist and serves as a model of epileptogenesis. The group I mGluR model of epileptogenesis took on special significance because epilepsy associated with fragile X syndrome (FXS) may be caused by excessive group I mGluR signaling. At present, the plasticity mechanism underlying the group I mGluR-mediated epileptogenesis is unknown. I(mGluR(V)), a voltage-gated cationic current activated by group I mGluR agonists in CA3 pyramidal cells in the hippocampus, is a possible candidate. I(mGluR(V)) activation is associated with group I mGluR agonist-elicited epileptiform discharges. For I(mGluR(V)) to play a role in epileptogenesis, long-term activation of the current must occur after group I mGluR agonist exposure or synaptic stimulation. We observed that I(mGluR(V)), once induced by group I mGluR agonist stimulation in CA3 pyramidal cells, remained undiminished for hours after agonist washout. In slices prepared from FXS model mice, repeated stimulation of recurrent CA3 pyramidal cell synapses, effective in eliciting mGluR-mediated epileptiform discharges, also induced long-lasting I(mGluR(V)) in CA3 pyramidal cells. Similar to group I mGluR-mediated prolonged epileptiform discharges, persistent I(mGluR(V)) was no longer observed in preparations pretreated with inhibitors of tyrosine kinase, of extracellular signal-regulated kinase 1/2, or of mRNA protein synthesis. The results indicate that I(mGluR(V)) is an intrinsic plasticity mechanism associated with group I mGluR-mediated epileptogenesis.

Effect of perceived benefits on reluctance to trade.

People often tend to be reluctant to trade an owned object for an alternative object. This concept of reluctance to trade is generally called "endowment effect". Loss aversion, which denotes that losses are weighted more heavily than gains, has been applied to interpret the endowment effect. Specifically, no "reluctance to trade" will occur when no loss is involved. In this research, 172 (90 women, 82 men; M age=21 yr., SD= 1.2) and 152 (82 women, 70 men; M age=21 yr., SD= 1.8) undergraduates voluntarily participated in two experiments, respectively. Results of both experiments indicated that participants were willing to trade an owned object for an alternative object when both objects were of the same benefit type and were reluctant to trade when objects were different. Clearly, an exchange was perceived as lower loss when the owned object and the alternative object were of the same benefit type, leading to no reluctance to trade.

Group I metabotropic glutamate receptor-dependent TRPC channel trafficking in hippocampal neurons.

The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) elicited two phases of synchronized neuronal (epileptiform) discharges in hippocampal slices: an initial phase of short duration discharges followed by a phase of prolonged discharges. We assessed the involvement of transient receptor potential canonical (TRPC) channels in these responses. Pre-treatment of hippocampal slices with TRPC channel blockers, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole hydrochloride (SKF96365) or 2-aminoethoxydiphenyl borate, did not affect the short epileptiform discharges but blocked the prolonged epileptiform discharges. SKF96365 suppressed ongoing DHPG-induced prolonged epileptiform discharges. Western blot analysis showed that the total TRPC4 or TRPC5 proteins in hippocampal slices were unchanged following DHPG. DHPG increased TRPC4 and TRPC5 in the cytoplasmic compartment and decreased these proteins in the plasma membrane. Translocation of TRPC4 and TRPC5 was suppressed when the epileptiform discharges were blocked by ionotropic glutamate receptor blockers. Translocation of TRPC4 and TRPC5 was also prevented in slices from phospholipase C (PLC) beta1 knockout mice, even when synchronized discharges were elicited by the convulsant 4-aminopyridine. The results suggest that TRPC channels are involved in generating DHPG-induced prolonged epileptiform discharges. This function of TRPC channels is associated with a neuronal activity- and PLCbeta1-dependent translocation of TRPC4 and TRPC5 proteins from the plasmalemma to the cytoplasmic compartment.

Sadder but wiser or happier and smarter? A demonstration of judgment and decision making.

Researchers have debated whether positive or negative emotions will positively improve decision performance (B. Kuvaas & G. Kaufmann, 2004). The author explored (a) which coping strategies decision makers use when they experience positive or negative emotions and (b) how cognitive processes are influenced by negative and positive emotions. In Experiment 1, participants (N = 120) in positive emotional states (i.e., happier and smarter) were better at problem-focused coping than were participants with negative emotions (i.e., sadder but wiser). In Experiment 2, participants (N = 124) displayed greater accuracy of choice, took longer to research information, and processed a larger amount of information when they were in positive emotional states. The two experiments showed similar results between judgment and decision-making contexts in which positive emotion enhances problem solving.