Associations of Cerebral Small Vessel Disease on the Features of Hematoma and Hematoma Expansion in Intracerebral Hemorrhage.

INTRODUCTION: Several early noncontrast CT (NCCT) signs of spontaneous intracerebral hemorrhage (ICH) can predict hematoma expansion (HE). However, the associations of underlying cerebral small vessel disease (SVD) on early NCCT signs and HE have been less explored. METHODS: We conducted an analysis of all patients with spontaneous supratentorial ICH and received follow-up imaging between 2016 and 2020 at a stroke center. The early NCCT signs were categorized as shape or density signs. HE was defined as an increase in hematoma volume ≥6 mL or 33% from baseline. The severity of SVD was assessed by both a 3-point CT-based and a 4-point magnetic resonance imaging (MRI)-based SVD score. Regression models were used to examine the associations between SVD score and hematoma volume, NCCT signs, and HE. RESULTS: A total of 328 patients (median age: 64 years; 38% female) were included. The median baseline ICH volume was 8.6 mL, with 38% of the patients had shape signs and 52% had density signs on the initial NCCT. Higher MRI-SVD scores were associated with smaller ICH volumes (p = 0.0006), fewer shape (p = 0.001), or density signs (p = 0.0003). Overall, 16% of patients experienced HE. A higher MRI-SVD score was inversely associated with HE (adjusted odds ratio 0.71, 95% CI: 0.53-0.96). Subgroup analysis revealed that this association was primarily observed in patients who were younger (<65 years), male, had deep hemorrhage, or did not meet the criteria for cerebral amyloid angiopathy diagnosis. CONCLUSIONS: In patients with spontaneous ICH, a more severe SVD was associated with smaller hematoma volume, fewer NCCT signs, and a lower risk of HE. Further research is required to investigate why a higher burden of severely diseased cerebral small blood vessels is associated with less bleeding.

Synergistically Enhancing Immunotherapy Efficacy in Glioblastoma with Gold-Core Silica-Shell Nanoparticles and Radiation.

Purpose: Glioblastoma is a highly aggressive brain tumor with universally poor outcomes. Recent progress in immune checkpoint inhibitors has led to increased interest in their application in glioblastoma. Nonetheless, the unique immune milieu in the brain has posed remarkable challenges to the efficacy of immunotherapy. We aimed to leverage the radiation-induced immunogenic cell death to overcome the immunosuppressive network in glioblastoma. Methods: We developed a novel approach using the gold-core silica-shell nanoparticles (Au@SiO2 NPs) in combination with low-dose radiation to enhance the therapeutic efficacy of the immune checkpoint inhibitor (atezolizumab) in brain tumors. The biocompatibility, immune cell recruitment, and antitumor ability of the combinatorial strategy were determined using in vitro assays and in vivo models. Results: Our approach successfully induced the migration of macrophages towards brain tumors and promoted cancer cell apoptosis. Subcutaneous tumor models demonstrated favorable safety profiles and significantly enhanced anticancer effects. In orthotopic brain tumor models, the multimodal therapy yielded substantial prognostic benefits over any individual modalities, achieving an impressive 40% survival rate. Conclusion: In summary, the combination of Au@SiO2 NPs and low-dose radiation holds the potential to improve the clinical efficacy of immune checkpoint inhibitors. The synergetic strategy modulates tumor microenvironments and enhances systemic antitumor immunity, paving a novel way for glioblastoma treatment.

Tailored therapeutic decision of rheumatoid arthritis using proteomic strategies: how to start and when to stop?

Unpredictable treatment responses have been an obstacle for the successful management of rheumatoid arthritis. Although numerous serum proteins have been proposed, there is a lack of integrative survey to compare their relevance in predicting treatment outcomes in rheumatoid arthritis. Also, little is known about their applications in various treatment stages, such as dose modification, drug switching or withdrawal. Here we present an in-depth exploration of the potential usefulness of serum proteins in clinical decision-making and unveil the spectrum of immunopathology underlying responders to different drugs. Patients with robust autoimmunity and inflammation are more responsive to biological treatments and prone to relapse during treatment de-escalation. Moreover, the concentration changes of serum proteins at the beginning of the treatments possibly assist early recognition of treatment responders. With a better understanding of the relationship between the serum proteome and treatment responses, personalized medicine in rheumatoid arthritis will be more achievable in the near future.

Comparative effects of cannabinoid CB1 receptor agonist and antagonist on timing impulsivity induced by d-amphetamine in a differential reinforcement of low-rate response task in male rats.

RATIONALE: In human beings and experimental animals, maladaptive impulsivity is manifested by the acute injection of psychostimulants, such as amphetamine. Cannabinoid CB1 receptors have been implicated in the regulation of stimulant-induced impulsive action, but the role of CB1 receptors in timing-related impulsive action by amphetamine remains unknown. METHODS: Male rats were used in evaluating the effects of CB1 receptor antagonist and agonist (SR141716A and WIN55,212-2, respectively) systemically administered individually and combined with d-amphetamine on a differential reinforcement of low-rate response (DRL) task, an operant behavioral test of timing and behavioral inhibition characterized as a type of timing impulsive action. RESULTS: A distinct pattern of DRL behavioral changes was produced by acute d-amphetamine (0, 0.5, 1.0, and 1.5 mg/kg) treatment in a dose-dependent fashion, whereas no significant dose effect was detected for acute SR141716A (0, 0.3, 1, and 3 mg/kg) or WIN55,212-2 (0, 0.5, 1, and 2 mg/kg) treatment. Furthermore, DRL behavior altered by 1.5 mg/kg d-amphetamine was reversed by a noneffective dose of SR141716A (3 mg/kg) pretreatment. The minimally influenced DRL behavior by 0.5 mg/kg d-amphetamine was affected by pretreatment with a noneffective dose of WIN55,212-2 (1 mg/kg). CONCLUSION: These findings reveal that the activation and blockade of CB1 receptors can differentially modulate the timing impulsive action of DRL behavior induced by acute amphetamine treatment. Characterizing how CB1 receptors modulate impulsive behavior will deepen our understanding of the cannabinoid psychopharmacology of impulsivity and may be helpful in developing an optimal pharmacotherapy for reducing maladaptive impulsivity in patients with some psychiatric disorders.

Tumor cell-targeting radiotherapy in the treatment of glioblastoma multiforme using linear accelerators.

Although boron neuron capture therapy (BNCT) has enabled the delivery of stronger radiation dose to glioblastoma multiforme (GBM) cells for precision radiotherapy (RT), patients in need are almost unable to access the treatment due to insufficient operating devices. Therefore, we developed targeted sensitization-enhanced radiotherapy (TSER), a strategy that could achieve precision cell-targeted RT using common linear accelerators. TSER, which involves the combination of GoldenDisk (GD; a spherical radioenhancer), 5-aminolevulinic acid (5-ALA), low-intensity ultrasound (US), and low-dose RT, exhibited synergized radiosensitization effects. Both 5-ALA and hyaluronic-acid-immobilized GD can selectively accumulate in GBM to induce chemical and biological enhancement of radiosensitization, resulting in DNA damage, escalation of reactive oxygen species levels, and cell cycle redistribution, in turn sensitizing GBM cells to radiation under US. TSER showed an enhanced therapeutic effect and survival in the treatment of an orthotropic GBM model with only 20% of the radiation dose compared to that of a 10-Gy RT. The strategy with the potential to inhibit GBM progress and rescue the organ at risk using low-dose RT, thereby improving the quality of life of GBM patients, shedding light on achieving cell-targeted RT using universally available linear accelerators. STATEMENT OF SIGNIFICANCE: We invented GoldenDisk (GD), a radioenhancer with hyaluronic-acid (HAc)-coated gold nanoparticle (AuNP)-core/silica shell nanoparticle, to make radiotherapy (RT) safer and smarter. The surface modification of HAc and silica allows GD to target CD44-overexpressed glioblastoma multiforme (GBM) cells and stay structurally stable in cytoplasm throughout the course of RT. By combining GD with low-energy ultrasound and an FDA-approved imaging agent, 5-aminolevulinic acid (5-ALA), GBM cells were sensitized to RT leaving healthy tissues in the vicinity unaffected. The ionized radiation can further be transferred to photoelectronic products with higher cytotoxicity by GD upon collision, achieving higher therapeutic efficacy. With the newly-developed strategy, we are able to achieve low-dose precision RT with the use of only 20% radiation dose.

Neurobiological changes in striatal glutamate are associated with trait impulsivity of differential reinforcement of low-rate-response behavior in male rats.

Impulsive action can be measured using rat's responses on a differential reinforcement of low-rate-response (DRL) task in which performance may be varied between rats. Nevertheless, neurobiological profiles underlying the trait impulsivity of DRL behavior remain largely unknown. Here, in vivo non-invasive proton magnetic resonance spectroscopy (1H-MRS) and Western blot assay were performed to assess neurobiological changes in the dorsal striatum (DS) and nucleus accumbens (NAc) in relation to individual differences in DRL behavior. A cohort of rats was subjected to acquire a DRL task over 14 daily sessions. High impulsive (HI) and low impulsive (LI) rats were screened by behavioral measures displaying a lower response efficiency and performing more nonreinforced responses in HI rats and vice versa. MRS measurements indicated that the HI group had a lower NAc glutamate (Glu) level than did the LI group, whereas no such difference was found in the other five metabolites in this area. Moreover, no intergroup difference was observed in any metabolite in the DS. The results of Western blot assay revealed that protein expressions of GluN1 (but not GluN2B) subunit of N-methyl-D-aspartate receptors in the DS and NAc were higher in the HI group than in the LI group. This inherent timing impulsivity was not attributed to risky behavioral propensity because both Hl and LI rats could acquire a risk-dependent choice. The findings of this study, supported by certain correlations among behavioral, brain imaging, and neuroreceptor indices, provide evidence of the neurobiological changes of striatal Glu underlying trait impulsive action of DRL behavior.

Task-Dependent Differences in Operant Behaviors of Rats With Acute Exposure to High Ambient Temperature: A Potential Role of Hippocampal Dopamine Reuptake Transporters.

Behavioral or cognitive functions are known to be influenced by thermal stress from the change in ambient temperature (Ta). However, little is known about how increased Ta (i.e., when the weather becomes warm or hot) may affect operant conditioned behavior and the neural substrates involved. The present study thus investigated the effects of high Ta on operant behaviors maintained on a fixed-ratio 1 (FR1) and a differential reinforcement for low-rate responding 10 s (DRL 10-s) schedule of reinforcement. The rats were randomly assigned to three groups receiving acute exposure to Ta of 23°C, 28°C, and 35°C, respectively, for evaluating the effects of high Ta exposure on four behavioral tests. Behavioral responses in an elevated T-maze and locomotor activity were not affected by Ta treatment. Regarding operant tests, while the total responses of FR1 behavior were decreased only under 35°C when compared with the control group of 23°C, those of DRL 10-s behavior were significantly reduced in both groups of 28°C and 35°C. Distinct patterns of inter-response time (IRT) distribution of DRL behavior appeared among the three groups; between-group differences of behavioral changes produced by high Ta exposure were confirmed by quantitative analyses of IRT data. Western blot assays of dopamine (DA) D1 and D2 receptor, DA transporter (DAT) and brain-derived neurotrophic factor (BDNF) were conducted for the sample tissues collected in six brain areas from all the subjects after acute high Ta exposure. Significant Ta-related effects were only revealed in the dorsal hippocampus (dHIP). In which, the DAT levels were increased in a Ta-dependent fashion that was associated with operant behavior changes under high Ta exposure. And, there as an increased level of D1 receptors in the 28°C group. In summary, these data indicate that the performance of operant behavior affected by the present high Ta exposure is task-dependent, and these changes of operant behaviors cannot be attributed to gross motor function or anxiety being affected. The regulation of dHIP DAT may be involved in this operant behavioral change under high Ta exposure.