Vehicle Group Research Articles

Striking Long Term Beneficial Effects of Single Dose Psilocybin and Psychedelic Mushroom Extract in the SAPAP3 Rodent Model of OCD-Like Excessive Self-Grooming.

Obsessive compulsive disorder (OCD) is a highly prevalent disorder that causes serious disability. Available treatments leave 40% or more of people with OCD significantly symptomatic. There is an urgent need for novel therapeutic approaches. Mice that carry a homozygous deletion of the SAPAP3 gene (SAPAP3 KO) manifest a phenotype of excessive self-grooming, tic-like head-body twitches and anxiety. These behaviors closely resemble pathological self-grooming behaviors observed in humans in conditions that overlap with OCD. Following a preliminary report that the tryptaminergic psychedelic, psilocybin, may reduce symptoms in patients with OCD, we undertook a randomized controlled trial of psilocybin in 50 SAPAP3 KO mice (28 male, 22 female). Mice that fulfilled inclusion criteria were randomly assigned to a single intraperitoneal injection of psilocybin (4.4 mg/kg), psychedelic mushroom extract (encompassing the same psilocybin dose) or vehicle control and were evaluated after 2, 4 and 21 days by a rater blind to treatment allocation for grooming characteristics, head-body twitches, anxiety and other behavioral features. Mice treated with vehicle (n=18) manifested a 118.71±95.96 % increase in total self-grooming (the primary outcome measure) over the 21-day observation period. In contrast, total self-grooming decreased by 14.60%±17.90% in mice treated with psilocybin (n=16) and by 19.20±20.05% in mice treated with psychedelic mushroom extract (n=16) (p=.001 for effect of time; p=.0001 for time × treatment interaction). 5 mice were dropped from the vehicle group because they developed skin lesions; 4 from the psilocybin group and none from the psychedelic mushroom extract group. Secondary outcome measures such as head-body twitches and anxiety all showed a significant improvement over 21 days. Notably, in mice that responded to psilocybin (n=12) and psychedelic mushroom extract (n=13), the beneficial effect of a single treatment persisted up to 7 weeks. Mice initially treated with vehicle and non-responsive, showed a clear and lasting therapeutic response when treated with a single dose of psilocybin or psychedelic mushroom extract and followed for a further 3 weeks. While equivalent to psilocybin in overall effect on self-grooming, psychedelic mushroom extract showed superior effects in alleviating head-body twitches and anxiety. These findings strongly justify clinical trials of psilocybin in the treatment of OCD and further studies aimed at elucidating mechanisms that underlie the long-term effects to alleviate excessive self-grooming observed in this study.

О поиске источников шума группой взаимодействующих АНПА с применением генетического алгоритма

Marine unmanned systems are increasingly used in tasks related to search and observation missions. Protection of water areas, survey and inspection operations, tracking of marine animals are examples of such missions. Most of these tasks can be solved more efficiently by use a group of interacting marine drones, compared to single vehicle. The article considers the problem of passive detection and localization of noise objects in a given water area by use a group of autonomous underwater vehicles (AUV). It is assumed that antennas of scalar vector receivers are installed on board the AUV to detect and determine the direction to the noise source. Some ways of organizing the group work of such AUV are considered. A centralized version is investigated, when the collected current information from all AUV is transmitted to one AUV leader. On the base of received information processing, AUV leader forms a group work plan, including the motion parameters for all AUV, to detect and determine the location of noise sources. An approach based on the use of a genetic algorithm is considered, and several versions of its implementation are investigated. The results of model experiments are presented, which demonstrate the efficiency of the proposed algorithms.

Emodin attenuates hypoxic-ischemic brain damage by inhibiting neuronal apoptosis in neonatal mice

Neonatal hypoxic-ischemic brain damage (HIBD) can lead to mortality and severe neurological dysfunction. Emodin is a natural anthraquinone derivative that is easy to obtain and has good neuroprotective effects. This study aimed to investigate the neuroprotective effect of emodin on neonatal mouse HIBD. The modified Rice–Vannucci method was used to induce HIBD in mouse pups. Eighty postnatal 7-day (P7) C57BL/6 neonatal mice were randomly divided into the sham group (sham), vehicle group (vehicle), and emodin group (emodin). TTC staining and whole-brain morphology were used to evaluate the infarct volume and morphology of the brain tissue. The condition of the neurons was observed through Nissl staining, HE staining, FJC staining, immunofluorescence and Western blot for NeuN, IBA-1, and GFAP. The physiological status of the mice was evaluated using weight measurements. The neural function of the mice was assessed using the negative geotaxis test, righting reflex test, and grip test. TUNEL staining was used to detect apoptosis in brain cells. Finally, Western blot and immunofluorescence were used to detect the expression levels of apoptosis-related proteins, such as P53, cleaved caspase-3, Bax and Bcl-2, in the brain. Experiments have shown that emodin can reduce the cerebral infarct volume, brain oedema, neuronal apoptosis, and degeneration and improve the reconstruction of brain tissue morphology, neuronal morphology, physiological conditions, and neural function. Additionally, emodin inhibited the expression of proapoptotic proteins such as P53, Bax and cleaved caspase-3 and promoted the expression of the antiapoptotic protein Bcl-2. Emodin attenuates HIBD by inhibiting neuronal apoptosis in neonatal mice.

Potential-based dynamic parking navigation for autonomous vehicles: Near-priority vs. distant-priority

We aim to enhance the parking efficiency for a group of autonomous vehicles in a large parking lot during peak hours. Two parking principles, i.e. the near-priority (NP) and distant-priority (DP) principles, are proposed and quantitatively examined. The NP principle characterizes individual parking behavior, where autonomous vehicles tend to select available parking spaces that are closer in proximity. Conversely, the DP principle is proposed from the perspective of the entire parking system, prioritizing the allocation of more distant parking spaces within a certain range around each entrance. Two time indicators, including the overall parking time and the average parking time, are adopted to evaluate the performance of the two principles. A potential-based cellular automata (CA) model is proposed to formulate the dynamic parking process of vehicles in a two-dimensional space, where vehicle navigation is driven by a so-called potential field. Then, two dynamic navigation algorithms are developed for parking navigation under the NP and DP principles. Furthermore, by conducting a set of comparative simulation experiments, we have obtained some management insights into peak parking management in the era of autonomous driving.

UAV group control protocol with adaptive consensus

SummaryIn this paper, a modified consensus protocol algorithm is proposed for controlling a group of identical unmanned aerial vehicles (UAVs), which have been subjected to interfering signals during coordinate information exchange, using an unknown parameter in the consensus protocol. The maximum levels of interfering signals in the proposed protocol were adjusted by incorporating a hysteresis function with a dead zone consistent with the initial coordinates and the interfering signal levels. An adaptation algorithm is proposed to address a priori uncertainty regarding the consensus parameters, involving the correction of an unknown parameter by eliminating control signals exhibiting false sign changes. This correction relies on the coordinates in the phase plane, indicating that the delay in maneuver execution occurs at the beginning of the maneuver. Furthermore, by modeling synchronized motion, UAV group consensus is demonstrated for an ideal case devoid of a priori uncertainty regarding control protocol parameters, interfering signals, or consequences. The convergence of the adaptation algorithm was assessed by defining a vector function to track parameter changes during tuning. The monotonically decreasing nature of the resulting curve, along with the finite duration of the tuning process, provides confirmation of the convergence of the adaptation algorithm.

DIPG-38. VAL-083 IN COMBINATION WITH AZD1775 FOR THE TREATMENT OF DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline gliomas (DMGs) are malignant pediatric brain tumors characterized by H3K27M mutation and global genome hypomethylation. This results in enhanced transcription of MGMT, a DNA-repair enzyme, rendering alkylating chemotherapeutics ineffective. Therefore, we investigated the efficacy of a functionally different DNA damaging agent, Val-083, that induces double strand breaks and triggers S/G2 phase cell cycle arrest for homologous DNA repair. We further evaluated its combined efficacy with Wee1 (G2/M checkpoint) inhibitor, AZD1775, to override cell cycle arrest and propel cells with DNA damage into premature mitosis and apoptosis. METHODS DMG cells were treated with increasing concentration of Val-083 and/or AZD1775 and their viability was evaluated using CellTiter-Glo luminescent assay. Next, the drugs’ mechanisms of action were investigated by immunoblotting for biomarkers involved in DNA damage response and cell cycle arrest. Flow cytometry was used to investigate cell cycle profile and apoptosis. Additionally, in vivo tumor growth inhibition and survival benefit were evaluated using zebrafish and mouse xenograft DMG models. RESULTS The IC50 values of Val-083 range between 0.69 and 4.38 µM while the IC50 values of AZD1775 range between 0.22 to 0.98 µM. Combination of both drugs showed high areas of synergy on multiple DMG lines, DNA double strand breaks and significant increase in cell population at the S (p<0.01) and G2/M (p<0.05) phases. Importantly, on zebrafish xenograft tumor model, combination treatment significantly (p<0.001) inhibited tumor growth in comparison to control and single treatment groups. Furthermore, the combined treatment demonstrated significant (p<0.01) survival benefit (median survival (MS) = 62 days) on tumor-bearing nude mice models, in comparison to vehicle (MS= 44 days), Val-083 (MS= 54.5 days) and AZD1775 (MS= 47 days) treatment groups. CONCLUSION Val-083 in combination with AZD1775 demonstrate promising efficacy in DMG preclinical models, providing a strong rationale for positioning these arms for clinical testing.

Hepatoprotective Effect of Cannabidiol on the Progression of Experimental Hepatic Cirrhosis in Rats.

Introduction: Liver cirrhosis is a condition characterized by the gradual replacement of normal liver tissue with scar tissue, ultimately leading to liver failure. This slow and progressive disease begins with a chronic inflammatory process induced by a noxious agent. In its advanced stages, the disease lacks effective therapies. Research has demonstrated the significant involvement of the endocannabinoid system in the pathogenesis of this disease. This study evaluated the hepatoprotective effect of cannabidiol (CBD) in the progression of experimental hepatic cirrhosis induced by thioacetamide (TAA) in rats. Methods: A randomized experimental design was employed using Holtzman rats. Hepatic cirrhosis was induced by intraperitoneal administration of TAA at a dose of 150 mg/kg for 6 weeks, with treatment initiated additionally. The groups were as follows: Group 1: TAA + vehicle; Group 2: TAA + CBD 2 mg/kg; Group 3: TAA + CBD 9 mg/kg; Group 4: TAA + CBD 18 mg/kg; Group 5: TAA + silymarin 50 mg/kg; and Group 6: Healthy control. Serum biochemical analysis (total bilirubin, direct bilirubin, ALT, AST, alkaline phosphatase, and albumin) and hepatic histopathological study were performed. The Knodell histological activity index (HAI) was determined, considering periportal necrosis, intralobular degeneration, portal inflammation, fibrosis, and focal necrosis. Results: All groups receiving TAA exhibited an elevation in AST levels; however, only those treated with CBD at doses of 2 mg/kg and 18 mg/kg did not experience significant changes compared to their baseline values (152.8 and 135.7 IU/L, respectively). Moreover, ALT levels in animals treated with CBD showed no significant variation compared to baseline. The HAI of hepatic tissue was notably lower in animals treated with CBD at doses of 9 and 18 mg/kg, scoring 3.0 and 3.25, respectively, in contrast to the TAA + vehicle group, which recorded a score of 7.00. Animals treated with CBD at 18 mg/kg showed a reduced degree of fibrosis and necrosis compared to those receiving TAA alone (p ≤ 0.05). Conclusion: Our findings demonstrate that cannabidiol exerts a hepatoprotective effect in the development of experimental hepatic cirrhosis induced in rats.

Coupled Vibration of a Vehicle Group–Bridge System and Its Application in the Optimal Strategy for Bridge Health Monitoring

The accuracy of bridge performance monitoring and evaluation is easily affected by unfavorable factors such as vehicle coupling and test noise. In order to accurately evaluate the dynamic response and health monitoring threshold of the bridge under different operating conditions, a time-varying dynamic vehicle group model including the main uniform mass and the coupling mass was established, and the influence of road roughness was considered in the coupling equation. A bridge monitoring strategy considering signal noise ratio and vehicle–bridge interaction was proposed, and the effectiveness of the monitoring strategy was verified by taking a simple supported beam as an example. The results showed that the proposed time-varying dynamic vehicle group model could accurately consider the influence of road roughness and estimate the threshold of health monitoring, and the proposed bridge monitoring strategy could filter out a large amount of low signal-to-noise ratio or meaningless data, thus saving computing resources and realizing the lightweight safety monitoring of bridges.

Investigating the Potential of Multilineage Differentiating Stress-Enduring Cells for Osteochondral Healing.

Multilineage differentiating stress-enduring (Muse) cells, a pluripotent stem cell subset of mesenchymal stem cells (MSCs), have shown promise for various tissue repairs due to their stress tolerance and multipotent capabilities. We aimed to investigate the differentiation potential in vitro, the dynamics in vivo, and the reparative contribution of Muse cells to osteochondral lesions. Labeled MSCs were cultured and sorted into Muse and non-Muse (MSCs without Muse cells) groups. These cells were then formed into spheroids, and chondrogenic differentiation was assessed in vitro. Twenty-one immunocompromised mice were used as the in vivo models of osteochondral lesions. Live imaging, macroscopic evaluation, and histological and immunohistochemical analyses were conducted at the 4- and 8-week time points. Muse cell spheroids were formed, which were larger and stained more intensely with toluidine blue than non-Muse spheroids, indicating better chondrogenic differentiation. Live imaging confirmed luminescence in all 4-week model knees, but only in a few knees at 8 weeks, suggesting cell persistence. Macroscopically and histologically, no significant differences were observed between the Muse and non-Muse groups at 4 and 8 weeks; however, both groups showed better cartilage repair than that of the vehicle group at 8 weeks. No collagen type II generation was observed in the repaired tissues. The implantation of the spheroids of Muse and non-Muse cells resulted in better healing of osteochondral lesions than that of the controls, and Muse cells had a higher chondrogenic differentiation potential in vitro than non-Muse cells.

Investigating the Possible Ameliorating Impact of Black Seed (Nigella sativa) Hydroethanolic Extract on Liver and Brain Tissue in a Rat Model of Polycystic Ovary

Background: Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder in women of reproductive age, which may affect various organs, including the brain and liver. Objectives: This study aimed to investigate the potential ameliorating effects of black seed (Nigella sativa) hydroethanolic extract on the liver and brain tissues in a rat model of polycystic ovary. Methods: In this experimental study, eighteen female rats were divided into three groups: control (PCO rats on day 0 after induction of PCO), vehicle (PCO rats receiving saline via gavage for 28 days), and black seed extract (BSE) (PCO rats receiving BSE via gavage for 28 days). Polycystic ovary was induced by a single intraperitoneal injection of 2 mg/kg estradiol valerate. Liver tissue was evaluated for the average number of damaged hepatocytes (segmented nucleus and cytoplasm shrinkage), number of Kupffer cells, and number of lipid droplets, while brain tissue was assessed for vacuolization, apoptosis, and cell shrinkage. Results: In the BSE group, liver weight significantly decreased, while brain weight increased compared to the vehicle and control groups. Moreover, there was a significant decrease in the number of damaged hepatocytes and Kupffer cells in the BSE group compared to the vehicle group in the liver tissue. In the brain tissue, there was a significant reduction in the number of vacuolations in the BSE group compared to the vehicle group. Conclusions: Black seed extract demonstrated potential ameliorating effects on the adverse impacts of PCO in the liver (reducing damaged hepatocytes and Kupffer cells) and brain (reducing vacuolations). Further histologic and molecular analyses are needed to investigate the protective effects of BSE thoroughly.

Shi-pi-xiao-ji formula suppresses hepatocellular carcinoma by reducing cellular stiffness through upregulation of acetyl-coA acetyltransferase 1.

Previous studies have shown that the Shi-pi-xiao-ji (SPXJ) herbal decoction formula is effective in suppressing hepatocellular carcinoma (HCC), but the underlying mechanisms are not known. Therefore, this study investigated whether the antitumor effects of the SPXJ formula in treating HCC were mediated by acetyl-coA acetyltransferase 1 (ACAT1)-regulated cellular stiffness. Through a series of experiments, we concluded that SPXJ inhibits the progression of HCC by upregulating the expression level of ACAT1, lowering the level of cholesterol in the cell membrane, and altering the cellular stiffness, which provides a new idea for the research of traditional Chinese medicine against HCC. To investigate the anti-tumor effects of the SPXJ formula on the malignant progression of HCC. HCC cells were cultured in vitro with SPXJ-containing serum prepared by injecting SPXJ formula into wild-type mice. The apoptotic rate and proliferative, invasive, and migratory abilities of control and SPXJ-treated HCC cells were compared. Atomic force microscopy was used to determine the cell surface morphology and the Young's modulus values of the control and SPXJ-treated HCC cells. Plasma membrane cholesterol levels in HCC cells were detected using the Amplex Red cholesterol detection kit. ACAT1 protein levels were estimated using western blotting. Compared with the vehicle group, SPXJ serum considerably reduced proliferation of HCC cells, increased stiffness and apoptosis of HCC cells, inhibited migration and invasion of HCC cells, decreased plasma membrane cholesterol levels, and upregulated ACAT1 protein levels. However, treatment of HCC cells with the water-soluble cholesterol promoted proliferation, migration, and invasion of HCC cells as well as decreased cell stiffness and plasma membrane cholesterol levels, but did not alter the apoptotic rate and ACAT1 protein expression levels compared with the vehicle control. SPXJ formula inhibited proliferation, invasion, and migration of HCC cells by decreasing plasma membrane cholesterol levels and altering cellular stiffness through upregulation of ACAT1 protein expression.

Laboratory Tests on the Possibility of Using Flax Fibers as a Plant-Origin Reinforcement Component in Composite Friction Materials for Vehicle Braking Systems.

Braking systems are extremely important in any vehicle. They convert the kinetic energy of motion into thermal energy that is dissipated into the atmosphere. Different vehicle groups have different nominal and maximum speeds and masses, so the amount of thermal energy that needs to be absorbed by the friction pads and then dissipated can vary significantly. Conventional friction materials are composite materials capable of withstanding high temperatures (in the order of 500-600 °C) and high mechanical loads resulting from braking intensity and vehicle weight. In small vehicles traveling at low speeds, where both the amount of thermal energy and its density are limited, the use of slightly weaker friction materials with better ecological properties can be considered. This work proposes a prototype composite friction material using flax fibers as reinforcement instead of the commonly used aramid. A number of samples were prepared and subjected to laboratory tests. The samples were prepared using components of plant origin, specifically flax fibers. This component acted as reinforcement in the composite friction material, replacing aramid commonly used for this purpose. The main tribological characteristics were determined, such as the values of the coefficients of friction and the coefficients of abrasive wear rate. For this purpose, an authorial method using ball-cratering contact was used. The results were analyzed using statistical methods. It was found that the composite material using flax fibers does not differ significantly in its tribological properties from conventional solutions; so, it can be assumed that it can be used in the vehicle's braking system.

Effects of radiation mitigating amino acid mixture on mice of different sexes.

To date, few FDA-approved medical countermeasures are available for addressing hematopoietic acute radiation syndrome (H-ARS). In this study, we present our latest research findings focusing on the evaluation of a novel radiation mitigator known as the mitigating amino acid mixture (MAAM). MAAM is composed of five amino acids as the recently reported amino acid-based oral rehydration solution for mitigating gastrointestinal (GI)-ARS. CD2F1 male and female mice were exposed to 60Co-γ total body irradiation (TBI) at 9.0 or 9.5 Gy. Following irradiation, mice were orally administered with MAAM or a saline vehicle control once daily for a duration of 14 days, commencing 24 h after TBI. Mouse survival and body weight change were monitored for 30 days after irradiation. Complete blood counts (CBCs), bone marrow (BM) stem and progenitor cell survival (clonogenicity), and a serum cytokine antibody array were analyzed using samples from day 30 surviving mice. Our data revealed that MAAM treatment significantly enhanced survival rates in irradiated male CD2F1 mice, and the survival rate increased from 25% in the vehicle control group to 60% in the MAAM-treated group (p < 0.05) after 9.0 Gy TBI. The number of BM colonies significantly increased from 41.8 ± 6.4 /104 cells (in the vehicle group) to 78.5 ± 17.0 /104 cells (in the MAAM group) following 9.0 Gy TBI. Furthermore, MAAM treatment led to a decrease in the levels of six cytokines/proteins [cluster of differentiation 40 (CD40), interleukin (IL)-17A, C-X-C motif chemokine 10 (CXCL10/CRG-2), cutaneous T cell-attracting chemokine (CTACK), macrophage inflammatory protein (MIP)-3β, and IL-1β] and an increase in the levels of five other cytokines/proteins [IL-3Rβ, IL-5, leptin, IL-6, and stem cell factor (SCF)] in mouse serum compared to the vehicle group after 9.0 Gy TBI. However, similar alleviating effects of MAAM were not observed in the irradiated CD2F1 female mice. The serum cytokine profile in the irradiated female mice was different compared to the irradiated male mice. In summary, our data suggest that the beneficial effects of the mitigative amino acid combination treatment after radiation exposure may depend on sex.

Therapeutic Effects of Intranasal Administration of Resveratrol on the Rat Model of Brain Ischemia

BackgroundResveratrol is a natural phenolic compound widely found in plants. Previous studies have suggested its neuroprotective role in cerebral ischemia due to its anti-oxidative, anti-inflammatory, and anti-apoptotic effects. Intranasal administration of resveratrol enhances its capacity to penetrate the blood-brain barrier, increasing therapeutic efficacy and safety. ObjectiveWe aimed to examine the therapeutic potential of intranasal administration of resveratrol treatment in rats exposed to cerebral ischemia. MethodsSixty-four male rats were divided into three groups: the sham group, which was exposed to only surgical stress; the vehicle and resveratrol groups, which received intranasal vehicle or 50 mg/kg resveratrol for 7 days following middle cerebral artery occlusion, respectively. We assessed the modified neurologic severity scores, wire hanging tests, blood-brain barrier disruption, brain water content, and infarct volume. Levels of matrix metalloproteinase-9, nuclear factor-kappa B, B-cell lymphoma protein 2, and B-cell lymphoma protein 2-associated X messenger RNA expression were examined. ResultsAt 3- and 7-days post-ischemia, rats receiving intranasal resveratrol had lower modified neurological severity scores and a smaller brain infarct volume than the rats receiving vehicle. Additionally, the intranasal resveratrol-treated rats showed significantly prolonged wire-hanging performance at the 7-day mark post-ischemia compared to the vehicle group. The blood-brain barrier disruption and brain water content were significantly lower in the resveratrol group than in the vehicle group. Furthermore, the resveratrol-treated group displayed lower expression of Matrix Metalloproteinase-9 and Nuclear Factor-Kappa B in contrast to the vehicle group, while the difference in expression levels of B-cell lymphoma protein 2-associated X and B-cell lymphoma protein 2 were not significant. ConclusionIntranasal administration of resveratrol showed neuroprotective effects on ischemic stroke by improving neurobehavioral function, reducing blood-brain barrier disruption, cerebral edema, and infarct volume. This treatment also downregulated Matrix Metalloproteinase-9 and Nuclear Factor-Kappa B expression, indicating its potential as a therapeutic option for ischemic stroke.

Allogeneic Disc Progenitor Cells Safely Increase Disc Volume and Improve Pain, Disability, and Quality of Life in Patients With Lumbar Disc Degeneration-Results of an FDA-Approved Biologic Therapy Randomized Clinical Trial.

Progenitor cells derived from intervertebral disc tissue demonstrated immunomodulatory and regenerative properties in preclinical studies. We report the safety and efficacy results of a US Food and Drug Administration-approved clinical trial of these cells for the treatment of symptomatic degenerative disc disease. Sixty patients with symptomatic single-level lumbar degenerative disc disease (mean age 37.9 years, 60% men) were enrolled in a randomized, double-blinded, placebo-controlled Phase I/Phase II study at 13 clinical sites. They were randomized to receive single intradiscal injections of either low-dose cells (N = 20), high-dose cells (N = 20), vehicle alone (N = 10), or placebo (N = 10). The primary endpoint was mean visual analog scale (VAS) pain improvement >30% at 52 weeks. Disc volume was radiologically assessed. Adverse events (AEs), regardless of whether they were related to treatment, were reported. Patients were assessed at baseline and at 4, 12, 26, 52, 78, and 104 weeks posttreatment. At week 52, the high-dose group had a mean VAS percentage decrease from baseline (-62.8%, P = 0.0005), achieving the endpoint of back pain improvement >30%; the mean change was also significantly greater than the minimal clinically important difference of a 20-point decrease (-42.8, P = 0.001). This clinical improvement was maintained at week 104. The vehicle group had a smaller significant decrease in VAS (-52.8%, P = 0.044), while the low-dose and placebo groups showed nonsignificant improvements. Only the high-dose group had a significant change in disc volume, with mean increases of 249.0 mm3 (P = 0.028) at 52 weeks and 402.1 mm3 (P = 0.028) at 104 weeks. A minority of patients (18.3%) reported AEs that were severe. Overall, 6.7% of patients experienced serious AEs, all in the vehicle (n = 1) or placebo (n = 3) groups, none treatment related. High-dose allogeneic disc progenitor cells produced statistically significant, clinically meaningful improvements in back pain and disc volume at 1 year following a single intradiscal injection and were safe and well tolerated. These improvements were maintained at 2 years post-injection. NCT03347708-Study to Evaluate the Safety and Preliminary Efficacy of Injectable Disc Cell Therapy, a Treatment for Symptomatic Lumbar Intervertebral Disc Degeneration.

Intravesical local administration of pembrolizumab for treatment of bladder cancer: A novel strategy to minimize toxicity.

e14687 Background: A major hallmark of bladder cancer (BCa) is a higher treatment success rate than prostate cancer following stimulation of innate anti-tumor immune response either by intravesical BCG or to FDA approved intravenous anti-PD1 checkpoint antibody (pembrolizumab) approved for BCG resistant BCa since 2021. However, injected pembrolizumab is characterized by a markedly higher incidence (66%) of serious adverse events than the median duration of complete response of ~40% for non-muscle invasive BCa (NMIBC) and 15-20% for invasive BCa. Since the toxicity (fatigue, Pneumonitis and diarrhea) of injected pembrolizumab is linked to systemic breakdown of T-cell mediated immune surveillance we enquired whether analogous to BCG, pembrolizumab can be administered intravesically to safely induce a localized anti-tumor response in mouse model of BCa. Methods: Six weeks old female mice of B6D2F1 strain (n=10) were ad libitum fed carcinogen, N-butyl-N-4-hydroxybutyl nitrosamine (BBN) in drinking water (0.05% w/v) for 12 weeks. The presence of BBN evoked tumor was ascertained by unenhanced T2 weighted MRI at week 11 prior to single intravesical dosing by 24G transurethral catheter under isoflurane anesthesia of 0.1mL vehicle (sterile water) with or without 0.3mg of Pembrolizumab (Lipella Pharmaceuticals). 6 weeks later, T2 weighted MRI was repeated together with T1 mapping by ICE-MRI prior to organ harvest. Results: BBN feeding evoked multiclonal tumors (red*) of comparable size on T2 weighted MRI at week 11 but repeat MRI 7 weeks after treatment revealed that tumor progression and perivesical invasion noted in vehicle group was arrested in pembrolizumab group. Longest dimension of BBN tumor in vehicle treated mice was ≥ 1mm longer (p&lt;0.05) than in pembrolizumab treated mice. T1 mapping revealed thickened bladder wall missed by T2 MRI. Conclusions: These findings on single intravesical dose of pembrolizumab (10mg/kg) in mice are consistent with human study on multiple intravesical dosing of BCG plus pembrolizumab (1-2mg/kg) in BCG resistant NMIBC patients. Intravesical pembrolizumab mirrors the limited systemic uptake of radiolabelled antibodies together with substantially higher ingress into tumor foci. The tumor selective ingress for BCa immunotherapy without any toxicity will be enhanced with Lipella Pharmaceutical’s liposomal delivery of Pembrolizumab.

Artesunate improves learning and memory impairment in rats with vascular cognitive impairment by down-regulating the level of autophagy in cerebral cortex neurons

BackgroundVascular cognitive impairment (VCI) is the second leading cause of dementia. Cognitive impairment is a common consequence of VCI. However, there is no effective treatment for VCI and the underlying mechanism of its pathogenesis remains unclear. This study to investigate whether artesunate (ART) can improve the learning and memory function in rats with VCI by down-regulating he level of autophagy in cerebral cortex neurons. MethodsThe models for VCI were the rat bilateral common carotid artery occlusion (BACCO), which were randomized into three groups including the sham operation group (Sham), model + vehicle group (Model) and model + ART group (ART). Then the animal behaviors were recorded, as well as staining the results of cortical neurons. Western blot was performed to determine the protein expressions of LC3BⅡ/Ⅰ, p-AMPK, p-mTOR, and Beclin-1. ResultsBehavioral outcomes and the protein expressions in Model group were supposedly affected by the induction of autophagy in cerebral cortex neurons. Compared to the Model group, ART improved memory impairment in VCI rats. And the expression of LC3BⅡ/Ⅰ, p-AMPK/AMPK, Beclin-1 is significant decreased in the ART group, while significant increases of p-mTOR/mTOR were showed. These results suggest that ART improved learning and memory impairment in VCI rats by down-regulating the level of autophagy in cerebral cortex neurons. ConclusionThe results suggest that autophagy occurs in cerebral cortex neurons in rats with VCI. It is speculated that ART can improve learning and memory impairment in VCI rats by down-regulating the level of autophagy in cerebral cortex neurons.

Scopolamine infusion in the basolateral amygdala after saccharin intake induces conditioned taste avoidance in rats

RationaleMuscarinic receptor activity in the basolateral amygdala (BLA) is known to be involved in plasticity mechanisms that underlie emotional learning. The BLA is involved in the Attenuation of Neophobia, an incidental taste learning task in which a novel taste becomes familiar and recognized as safe.ObjectiveHere we assessed the role of muscarinic receptor activity in the BLA in incidental taste learning.MethodsYoung adult male Wistar rats were bilaterally implanted with cannulas aimed at BLA. After recovery, rats were randomly assigned to either vehicle or muscarinic antagonist group, for each experiment. We tested the effect of specific and non-specific muscarinic antagonists administered either 1) 20 min before novel taste presentation; 2) immediately after novel taste presentation; 3) immediately after retrieval (the second taste presentation on Day 5 -S2-) or immediately after the fifth taste presentation on Day 8 (S5).ResultsNon-specific muscarinic receptor antagonist scopolamine infused prior to novel taste, while not affecting novel taste preference, abolished AN, i.e., the increased preference observed in control animals on the second presentation. When administered after taste consumption, intra-BLA scopolamine not only prevented AN but caused a steep decrease in the taste preference on the second presentation. This scopolamine-induced taste avoidance was not dependent on taste novelty, nor did it generalize to another novel taste. Targeting putative postsynaptic muscarinic receptors with specific M1 or M3 antagonists appeared to produce a partial taste avoidance, while M2 antagonism had no effect.ConclusionThese data suggest that if a salient gustatory experience is followed by muscarinic receptors antagonism in the BLA, it will be strongly and persistently avoided in the future. The study also shows that scopolamine is not just an amnesic drug, and its cognitive effects may be highly dependent on the task and the structure involved.

Effect of placental circulating T cells expressing CD16 on multiple hematological and solid tumor cancers through combination with various monoclonal antibodies.

2554 Background: PT-CD16VS is an allogeneic cell therapy derived from human postpartum placental circulating T (PT) cells that are genetically modified to express CD16 and endogenous T cell receptor (TCR) knockout. PT-CD16VS cells can be combined with various monoclonal antibodies to engage in anti-tumor antibody-dependent cellular cytotoxicity (ADCC) against diverse cancers with a “universal receptor” approach. Here we report the characterization and preclinical evaluation of PT-CD16VS in combination with monoclonal antibodies against both hematological and solid tumor cancers. Methods: PT cells were activated, transduced with a lentiviral vector containing a construct expressing a high affinity CD16 variant, CD16VS, and transfected to knock out the TCR. In vitro,functional activity of PT-CD16VS cells in combination with monoclonal antibodies was assessed in cytotoxicity, cytokine release, and proliferation assays. Invivo, PT-CD16VS was combined with Rituximab in a Raji xenograft model in NSG mice, and with Trastuzumab in a subcutaneous NCI-N87 xenograft model in NSG mice in which tumor volume was measured and tumor samples were evaluated for PT-CD16VS infiltration. Results: In vitro, PT-CD16VS exhibited potent ADCC and cytokine release when combined with Rituximab against CD20+ Burkitt's lymphoma (Daudi and Raji), with Trastuzumab against HER2+ gastric carcinoma (NCI-N87), with Trastuzumab or Avelumab against HER2+/PDL-1+ non-small cell lung carcinoma (NCI-H1975) and Trastuzumab-resistant metastatic mammary adenocarcinoma (JIMT-1), and with Cetuximab against EGFR+ triple negative metastatic mammary adenocarcinoma (MDA-MB-231). Moreover, examples of PT-CD16VS antigen-specific proliferation were demonstrated against Raji and NCI-N87 when cells were combined with Rituximab and Trastuzumab, respectively. In vivo, in combination with Rituximab in the Raji mouse model, PT-CD16VS exhibited significant survival benefit compared to vehicle and Rituximab alone treated groups. In the subcutaneous NCI-N87 solid tumor model, PT-CD16VS with Trastuzumab demonstrated significant reduction in tumor volume compared to vehicle, Trastuzumab, and Enhertu groups. In addition, PT-CD16VS infiltration into the tumor was shown to be Trastuzumab dependent, with infiltrating cells expressing high levels of CD16 and Ki67. Conclusions: Our results show that PT-CD16VS have potent in vitro and in vivo ADCC activity, and a single drug product has the potential to be combined with various monoclonal antibodies to target multiple cancers across hematological and solid tumor indications. This “universal receptor” with antibody-dependent targeting approach, together with the benefits of an allogeneic cell platform, may democratize accessibility of such therapies for patients.

Safe platooning and merging control using constructive barrier feedback

This paper proposes a novel formation control design for safe platooning and merging of a group of vehicles in multi-lane road scenarios. Provided a leader vehicle is independently controlled, the objective is controlling the follower vehicles to drive in the desired lane with a constant desired distance behind the neighboring (preceding) vehicle while preventing collisions with both the neighboring vehicle and the road’s edges. Inspired by the recent concept of constructive barrier feedback, the proposed controller for each follower vehicle is composed of two parts: one is the nominal controller that ensures its tracking of the neighboring vehicle; another is for collision avoidance by using divergent flow as a dissipative term, which slows down the relative velocity in the direction of the neighboring vehicle and road edges without compromising the nominal controller’s performance. The key contribution of this work is that the proposed control method ensures collision-free platooning and merging control in multi-lane road scenarios with computational efficiency and systematic stability analysis. Simulation results are provided to demonstrate the effectiveness of the proposed algorithms.