Modeling the Drug delivery Lifecycle of PLG Nanoparticles Using Intravital Microscopy.

Polylactide-co-glycolide (PLG) nanoparticles hold immense promise for cancer therapy due to their enhanced efficacy and biodegradable matrix structure. Understanding their interactions with blood cells and subsequent biodistribution kinetics is crucial for optimizing their therapeutic potential. In this study, three doxorubicin-loaded PLG nanoparticle systems are synthesized and characterized, analyzing their size, zeta potential, morphology, and in vitro release behavior. Employing intravital microscopy in 4T1-tumor-bearing mice, real-time blood and tumor distribution kinetics are investigated. A mechanistic pharmacokinetic model is used to analyze biodistribution kinetics. Additionally, flow cytometry is utilized to identify cells involved in nanoparticle hitchhiking. Following intravenous injection, PLG nanoparticles exhibit an initial burst release (<1 min) and rapidly adsorb to blood cells (<5 min), hindering extravasation. Agglomeration leads to the clearance of one carrier species within 3 min. In stable dispersions, drug release rather than extravasation remains the dominant pathway for drug elimination from circulation. This comprehensive investigation provides valuable insights into the interplay between competing kinetics that influence the lifecycle of PLG nanoparticles post-injection. The findings advance the understanding of nanoparticle behavior and lay the foundation for improved cancer therapy strategies using nanoparticle-based drug delivery systems.

Supplementation of a High-Fat Diet with Pentadecylresorcinol Increases the Representation of Akkermansia muciniphila in the Mouse Small and Large Intestines and May Protect against Complications Caused by Imbalanced Nutrition.

Imbalanced nutrition, such as a high-fat/high-carbohydrate diet, is associated with negative effects on human health. The composition and metabolic activity of the human gut microbiota are closely related to the type of diet and have been shown to change significantly in response to changes in food content and food supplement administration. Alkylresorcinols (ARs) are lipophilic molecules that have been found to improve lipid metabolism and glycemic control and decrease systemic inflammation. Furthermore, alkylresorcinol intake is associated with changes in intestinal microbiota metabolic activity. However, the exact mechanism through which alkylresorcinols modulate microbiota activity and host metabolism has not been determined. In this study, alterations in the small intestinal microbiota (SIM) and the large intestinal microbiota (LIM) were investigated in mice fed a high-fat diet with or without pentadecylresorcinol (C15) supplementation. High-throughput sequencing was applied for jejunal and colonic microbiota analysis. The results revealed that C15 supplementation in combination with a high-fat diet could decrease blood glucose levels. High-throughput sequencing analysis indicated that C15 intake significantly increased (p < 0.0001) the abundance of the probiotic bacteria Akkermansia muciniphila and Bifidobacterium pseudolongum in both the small and large intestines and increased the alpha diversity of LIM (p < 0.05), but not SIM. The preliminary results suggested that one of the mechanisms of the protective effects of alkylresorcinol on a high-fat diet is the modulation of the content of SIM and LIM and metabolic activity to increase the probiotic bacteria that alleviate unhealthy metabolic changes in the host.

Ultrasound-Induced Prenatal Stress: New Possibilities for Modeling Mental Disorders.

The development of animal models of mental disorders is an important task, since such models are useful for studying the neurobiological mechanisms of psychopathologies and for trial of new therapeutic drugs. One way to model pathologies of the nervous system is to impair fetal neurodevelopment through stress of the pregnant future mother, or prenatal stress. The use of variable frequency ultrasound in rodents is a promising method of imitating psychological stress, to which women in modern society are most often subjected. The aim of our study was to investigate the effect of prenatal stress induced by exposure to variable frequency ultrasound (US PS) throughout the gestational period on the adult rat offspring, namely to identify features of behavioral alterations and neurochemical brain parameters that can be associated with certain mental disorders in humans, to determine the possibility of creating a new model of psychopathology. Our study included a study of some behavioral characteristics of male and female rats in the elevated plus maze, open field test, object recognition test, social interaction test, sucrose preference test, latent inhibition test, Morris water maze, forced swimming test, acoustic startle reflex and prepulse inhibition tests. We also determined the activity of the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems in the hippocampus and frontal cortex by HPLC-ED. Concentration of norepinephrine, dopamine, DOPAC, serotonin, and HIAA, as well as DOPAC/dopamine and HIAA/serotonin ratios were determined. A correlation analysis of behavioral and neurochemical parameters in male and female rats was performed based on the data obtained. The results of the study showed that US PS altered the behavioral phenotype of the rat offspring. US PS increased the level of anxious behavior, impaired orientation-research behavior, increased grooming activity, decreased the desire for social contacts, shifted behavioral reactions from social interaction to interaction with inanimate objects, impaired latent inhibition, and decreased the startle reflex. US PS activated the serotonergic, dopaminergic, and noradrenergic neurotransmitter systems of the rat frontal cortex and hippocampus. A correlation between neurochemical and behavioral parameters was revealed. Our study showed that US PS leads to a certain dysfunction on behavioral and neurochemical levels in rats that is most closely associated with symptoms of schizophrenia or autism. We hypothesize that this could potentially be an indicator of face validity for a model of psychopathology based on neurodevelopmental impairment.

Ten-year retrospect of the investigation of proximal limbs metastasis in cancer: a multi-center study on survival outcome, limb function status and surgical procedures analysis.

BACKGROUND: The aim of study was to evaluate survival outcome and limb function in cancer patients with proximal limbs metastasis. Associated factors on survival outcome and limb function were identified. The comparative analysis between intramedullary nailing and prosthesis surgery in cancer patients with proximal limb metastasis was performed. METHODS: In this five-center retrospective study, patients diagnosed with limbs metastasis were collected. Descriptive statistics was used and log-rank test was performed to analyze the survival in subgroups. The Cox proportional hazards regression analysis was performed to identify the independent prognostic factors. The Musculoskeletal Tumor Society (MSTS) scoring system was used to evaluate limb function after surgery, and t test or analysis of variance (ANOVA) was utilized in subgroup analysis. RESULTS: A total of 316 patients with limb metastasis were included with mean age at 61.0 years. The most common primary tumor was breast, followed by renal cancer and lung cancer. The median overall survival was 24.0 months and the 1-, 3- and 5-year survival rates were 86.9%, 34.7% and 6.8%, respectively. Primary tumor type, visceral metastasis and chemotherapy were proved to be the independent prognostic factors. The mean Musculoskeletal Tumor Society (MSTS) score was 20.5, significant difference was observed in subgroup of solitary/multiple bone metastasis, with/without pathological fracture, and type of surgery. CONCLUSION: The present study concluded that primary tumor type, visceral metastasis and chemotherapy were three factors affecting the survival of patients. Compared with intramedullary nailing, the patients underwent prosthesis surgery showed better limb function, this procedure should be encouraged in patients with indication.

Clinicomics-guided distant metastasis prediction in breast cancer via artificial intelligence.

BACKGROUND: Breast cancer has become the most common malignant tumour worldwide. Distant metastasis is one of the leading causes of breast cancer-related death. To verify the performance of clinicomics-guided distant metastasis risk prediction for breast cancer via artificial intelligence and to investigate the accuracy of the created prediction models for metachronous distant metastasis, bone metastasis and visceral metastasis. METHODS: We retrospectively enrolled 6703 breast cancer patients from 2011 to 2016 in our hospital. The figures of magnetic resonance imaging scanning and ultrasound were collected, and the figures features of distant metastasis in breast cancer were detected. Clinicomics-guided nomogram was proven to be with significant better ability on distant metastasis prediction than the nomogram constructed by only clinical or radiographic data. RESULTS: Three clinicomics-guided prediction nomograms on distant metastasis, bone metastasis and visceral metastasis were created and validated. These models can potentially guide metachronous distant metastasis screening and lead to the implementation of individualized prophylactic therapy for breast cancer patients. CONCLUSION: Our study is the first study to make cliniomics a reality. Such cliniomics strategy possesses the development potential in artificial intelligence medicine.

Localized Increased Permeability of Blood-Brain Barrier for Antibody Conjugates in the Cuprizone Model of Demyelination.

The development of new neurotherapeutics depends on appropriate animal models being chosen in preclinical studies. The cuprizone model is an effective tool for studying demyelination and remyelination processes in the brain, but blood-brain barrier (BBB) integrity in the cuprizone model is still a topic for debate. Several publications claim that the BBB remains intact during cuprizone-induced demyelination; others demonstrate results that could explain the increased BBB permeability. In this study, we aim to analyze the permeability of the BBB for different macromolecules, particularly antibody conjugates, in a cuprizone-induced model of demyelination. We compared the traditional approach using Evans blue injection with subsequent dye extraction and detection of antibody conjugates using magnetic resonance imaging (MRI) and confocal microscopy to analyze BBB permeability in the cuprizone model. First, we validated our model of demyelination by performing T2-weighted MRI, diffusion tensor imaging, quantitative rt-PCR to detect changes in mRNA expression of myelin basic protein and proteolipid protein, and Luxol fast blue histological staining of myelin. Intraperitoneal injection of Evans blue did not result in any differences between the fluorescent signal in the brain of healthy and cuprizone-treated mice (IVIS analysis with subsequent dye extraction). In contrast, intravenous injection of antibody conjugates (anti-GFAP or non-specific IgG) after 4 weeks of a cuprizone diet demonstrated accumulation in the corpus callosum of cuprizone-treated mice both by contrast-enhanced MRI (for gadolinium-labeled antibodies) and by fluorescence microscopy (for Alexa488-labeled antibodies). Our results suggest that the methods with better sensitivity could detect the accumulation of macromolecules (such as fluorescent-labeled or gadolinium-labeled antibody conjugates) in the brain, suggesting a local BBB disruption in the demyelinating area. These findings support previous investigations that questioned BBB integrity in the cuprizone model and demonstrate the possibility of delivering antibody conjugates to the corpus callosum of cuprizone-treated mice.

Analysis of Single Biomacromolecules and Viruses: Is It a Myth or Reality?

The beginning of the twenty-first century witnessed novel breakthrough research directions in the life sciences, such as genomics, transcriptomics, translatomics, proteomics, metabolomics, and bioinformatics. A newly developed single-molecule approach addresses the physical and chemical properties and the functional activity of single (individual) biomacromolecules and viral particles. Within the alternative approach, the combination of "single-molecule approaches" is opposed to "omics approaches". This new approach is fundamentally unique in terms of its research object (a single biomacromolecule). Most studies are currently performed using postgenomic technologies that allow the properties of several hundreds of millions or even billions of biomacromolecules to be analyzed. This paper discusses the relevance and theoretical, methodological, and practical issues related to the development potential of a single-molecule approach using methods based on molecular detectors.

Therapeutic Efficiency of Proteins Secreted by Glial Progenitor Cells in a Rat Model of Traumatic Brain Injury.

Traumatic brain injuries account for 30-50% of all physical traumas and are the most common pathological diseases of the brain. Mechanical damage of brain tissue leads to the disruption of the blood-brain barrier and the massive death of neuronal, glial, and endothelial cells. These events trigger a neuroinflammatory response and neurodegenerative processes locally and in distant parts of the brain and promote cognitive impairment. Effective instruments to restore neural tissue in traumatic brain injury are lacking. Glial cells are the main auxiliary cells of the nervous system, supporting homeostasis and ensuring the protection of neurons through contact and paracrine mechanisms. The glial cells' secretome may be considered as a means to support the regeneration of nervous tissue. Consequently, this study focused on the therapeutic efficiency of composite proteins with a molecular weight of 5-100 kDa secreted by glial progenitor cells in a rat model of traumatic brain injury. The characterization of proteins below 100 kDa secreted by glial progenitor cells was evaluated by proteomic analysis. Therapeutic effects were assessed by neurological outcomes, measurement of the damage volume by MRI, and an evaluation of the neurodegenerative, apoptotic, and inflammation markers in different areas of the brain. Intranasal infusions of the composite protein product facilitated the functional recovery of the experimental animals by decreasing the inflammation and apoptotic processes, preventing neurodegenerative processes by reducing the amounts of phosphorylated Tau isoforms Ser396 and Thr205. Consistently, our findings support the further consideration of glial secretomes for clinical use in TBI, notably in such aspects as dose-dependent effects and standardization.

Alteration of Blood Immune Biomarkers in MCI Patients with Different APOE Genotypes after Cognitive Training: A 1 Year Follow-Up Cohort Study.

Many studies aim to detect the early phase of dementia. One of the major ways to achieve this is to identify corresponding biomarkers, particularly immune blood biomarkers. The objective of this study was to identify such biomarkers in patients with mild cognitive impairment (MCI) in an experiment that included cognitive training. A group of patients with MCI diagnoses over the age of 65 participated in the study (n = 136). Measurements of cognitive functions (using the Mini-Mental State Examination scale and Montreal Cognitive Assessment) and determination of 27 serum biomarkers were performed twice: on the first visit and on the second visit, one year after the cognitive training. APOE genotypes were also determined. Concentrations of EGF (F = 17; p = 0.00007), Eotaxin (F = 7.17; p = 0.008), GRO (F = 13.42; p = 0.0004), IL-8 (F = 8.16; p = 0.005), MCP-1 (F = 13.46; p = 0.0001) and MDC (F = 5.93; p = 0.016) increased after the cognitive training in MCI patients. All these parameters except IL-8 demonstrated a weak correlation with other immune parameters and were poorly represented in the principal component analysis. Differences in concentrations of IP-10, FGF-2, TGFa and VEGF in patients with MCI were associated with APOE genotype. Therefore, the study identified several immune blood biomarkers that could potentially be associated with changes in cognitive function.

Survival Estimation, Prognostic Factors Evaluation, and Prognostic Prediction Nomogram Construction of Breast Cancer Patients with Bone Metastasis in the Department of Bone and Soft Tissue Tumor: A Single Center Experience of 8 Years in Tianjin, China.

Purpose: Bone metastasis in breast cancer remains globally concerned. Accurate survival estimation would be beneficial for clinical decision-making, especially for the patients with potential indications of surgery. Based on a retrospective cohort from China, the study aimed to construct a prognostic prediction nomogram for breast cancer patients with bone metastasis. Methods: Breast cancer patients with bone metastasis diagnosed between 2009 and 2017 in our department were retrospectively selected. The total cohort was divided into construction and validation cohorts (ratio 7 : 3). A nomogram was constructed to predict the probability of survival, and the performance of model was validated. Results: A total of 343 patients were enrolled with 243 and 100 patients in construction and validation cohorts, respectively. The median overall survival for the total cohort was 63.2 (95% CI: 52.4-74.0) months. Elevated ALP (HR = 1.71, 95% CI: 1.16-2.51; P=0.006), no surgery for breast cancer (HR = 2.19, 95% CI: 1.30-3.70; P=0.003), synchronous bone metastasis (HR = 1.98, 95% CI: 1.22-3.22; P=0.006), and liver metastasis (HR = 1.68, 95% CI: 1.20-2.37; P=0.003) were independent prognostic factors for worse survival. The independent predictors and other five factors (including age at diagnosis, ER status, PR status, Her-2 status, and the performance of bisphosphonate) were incorporated to construct the nomogram. The C-index was 0.714 (95% CI: 0.636-0.792) and 0.705 (95% CI: 0.705) in the construction cohort and validation cohort, respectively. All the calibration curves were close to the 45-degree line, which indicated satisfactory calibration. Conclusion: A retrospective study aiming at prognostic estimation of breast cancer patients with bone metastasis was designed. Four independent prognostic factors were identified and a prognostic nomogram was constructed with satisfactory discrimination and calibration. The model could be used in survival estimation and individualized treatment planning.

Racial disparities in bone metastasis patterns and targeted screening and treatment strategies in newly diagnosed lung cancer patients.

Objective: Race disparities exist in bone metastasis (BM) development and survival in lung cancer (LC) patients. The Surveillance, Epidemiology, and End Results (SEER) database was used to investigate different patterns of BM development and survival in different races.Design: LC patients with BM were identified from the database from 2010 to 2014. Risk factors were investigated by univariable and multivariable logistic regression. Potential factors for prognosis were evaluated by univariable and multivariable Cox regression.Results: Asian and Pacific Islander (API) patients presented the highest prevalence of BM (24.6%), followed by white (20.7%) and black patients (19.9%) (χ2 = 78.74; p < .001). After adjusting for the demographic and clinical factors, API race was independently associated with a high risk of BM development. The median survival times for the API, white and black LC patients with BM were 16 months (95% CI: 15.2-16.8), 11 months (95% CI: 10.9-11.1) and 10 months (95% CI: 9.7-10.3), respectively, with significant differences (p < .001). Multivariable Cox regression showed that API race was positively associated with greater overall survival compared with white and black patients. Male gender, larger tumor size, lymph node involvement, lower tumor differentiated grade, and the presence of lung, liver and brain metastases were independently associated with a high risk of developing BM and worse survival with LC across all races. Age, income, insurance and histological types had different impacts on BM among different races.Conclusion: Homogeneous and heterogeneous associated factors for BM were revealed among different races. Individualized screening and treatment should be performed race-specifically.

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders.

Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders' pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G).

Neurobiological Highlights of Cognitive Impairment in Psychiatric Disorders.

This review is focused on several psychiatric disorders in which cognitive impairment is a major component of the disease, influencing life quality. There are plenty of data proving that cognitive impairment accompanies and even underlies some psychiatric disorders. In addition, sources provide information on the biological background of cognitive problems associated with mental illness. This scientific review aims to summarize the current knowledge about neurobiological mechanisms of cognitive impairment in people with schizophrenia, depression, mild cognitive impairment and dementia (including Alzheimer's disease).The review provides data about the prevalence of cognitive impairment in people with mental illness and associated biological markers.

Supermagnetic Human Serum Albumin (HSA) Nanoparticles and PLGA-Based Doxorubicin Nanoformulation: A Duet for Selective Nanotherapy.

Predicting the ability of nanoparticles (NP) to access the tumor is key to the success of chemotherapy using nanotherapeutics. In the present study, the ability of the dual NP-based theranostic system to accumulate in the tumor was evaluated in vivo using intravital microscopy (IVM) and MRI. The system consisted of model therapeutic doxorubicin-loaded poly(lactide-co-glycolide) NP (Dox-PLGA NP) and novel hybrid Ce3/4+-doped maghemite NP encapsulated within the HSA matrix (hMNP) as a supermagnetic MRI contrasting agent. Both NP types had similar sizes of ~100 nm and negative surface potentials. The level of the hMNP and PLGA NP co-distribution in the same regions of interest (ROI, ~2500 µm2) was assessed by IVM in mice bearing the 4T1-mScarlet murine mammary carcinoma at different intervals between the NP injections. In all cases, both NP types penetrated into the same tumoral/peritumoral regions by neutrophil-assisted extravasation through vascular micro- and macroleakages. The maximum tumor contrasting in MRI scans was obtained 5 h after hMNP injection/1 h after PLGA NP injection; the co-distribution level at this time reached 78%. Together with high contrasting properties of the hMNP, these data indicate that the hMNP and PLGA NPs are suitable theranostic companions. Thus, analysis of the co-distribution level appears to be a useful tool for evaluation of the dual nanoparticle theranostics, whereas assessment of the leakage areas helps to reveal the tumors potentially responsive to nanotherapeutics.

Synchronous bone metastasis in lung cancer: retrospective study of a single center of 15,716 patients from Tianjin, China.

BACKGROUND: This study aimed to describe the incidence, clinical characteristics, and prognosis of lung cancer patients with synchronous bone metastasis (SBM) and to analyze the prognostic factors of the lung cancer patients with SBM. METHODS: A total of 15,716 lung cancer patients who were diagnosed between 2009 to 2018 in the Tianjin Medical University Cancer Institute and Hospital were retrospectively reviewed. Among them, patients with SBM were checked. Both the demographic and clinical characteristics were included as follows: age, gender, marital status, history of smoking, alcohol consumption, family history of tumor, Karnofsky score, lymph node metastasis, histological type. Besides, laboratory data such as alkaline phosphatase, lactate dehydrogenase, carcinoembryonic antigen, squamous cell carcinoma antigen, cytokeratin-19 fragment, and neuron specific enolase were also included. The log-rank test and multivariate Cox regression analysis were employed to reveal the potential prognostic predictors. A further analysis using the Kaplan-Meier was employed to demonstrate the difference on the prognosis of LC patients between adenocarcinoma and non-adenocarcinoma. RESULTS: Among the included patients, 2738 patients (17.42%) were diagnosed with SBM. A total of 938 patients (34.3%) with SBM were successfully followed and the median survival was 11.53 months (95%CI: 10.57-12.49 months), and the 1-, 2-, and 5-year overall survival rate was 51, 17, and 8%, respectively. Multivariable Cox regression results showed history of smoking and high level of NSE were associated with the poor prognosis, while adenocarcinoma histological type was associated with better survival. CONCLUSION: The prevalence of SBM in lung cancer is relatively high with poor survival. The lung cancer patients with SBM showed diverse prognosis. Among all the pathological types, the division of adenocarcinoma suggested different prognosis of the lung cancer patients with SBM. The present study emphasized the importance of pathological diagnosis on prognostic determinants in lung cancer patients with SBM.

Nomogram for predicting overall survival in colorectal cancer with distant metastasis.

BACKGROUND: Colorectal cancer (CRC) is a major cancer burden, and prognosis is determined by many demographic and clinicopathologic factors. The present study aimed to construct a prognostic nomogram for colorectal cancer patients with distant metastasis. METHODS: Colorectal cancer patients with distant metastasis diagnosed between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results database. Cox proportional hazards regression was used to identify independent prognostic factors. A nomogram was constructed to predict survival, and validation was performed. RESULTS: A total of 7099 stage IV colorectal cancer patients were enrolled in the construction cohort. The median overall survival was 20.0 (95% CI 19.3-20.7) months. Age at diagnosis, marital status, race, primary tumour site, tumour grade, CEA level, T stage, N stage, presence of bone, brain, liver and lung metastasis, surgery for primary site and performance of chemotherapy were independent prognostic factors. The nomogram was constructed and the calibration curve showed satisfactory agreement. The C-index was 0.742 (95% CI 0.726-0.758). In the validation cohort (7098 patients), the nomogram showed satisfactory discrimination and calibration with a C-index of 0.746 (95% CI 0.730-0.762). CONCLUSION: A series of factors associated with the survival of CRC patients with distant metastasis were found. Based on the identified factors, a nomogram was generated to predict the survival of stage IV colorectal cancer patients. The predictive model showed satisfactory discrimination and calibration, which can provide a reference for survival estimation and individualized treatment decisions.

Incidence and prognosis of distant metastasis in malignant peripheral nerve sheath tumors.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcomas (STS) with recurrence and metastatic potential. We aimed to investigate the risk factors for developing distant metastases (DM) and to identify the prognostic factors in patients with DM. METHODS: Based on the Surveillance, Epidemiology, and End Result (SEER) database, MPNST patients diagnosed between 2010 and 2016 were extracted in our study. The logistic regression model was performed for predicting DM development while the Cox proportional hazard regression model was conducted for revealing the prognostic factors. RESULTS: Eventually, 764 patients diagnosed with MPNSTs were included with 109 cases presenting with metastases at initial diagnosis. Larger tumor size and lymph node metastases were independent risk factors for developing DM. The median overall survival (OS) for patients with metastases was 8.0 (95% CI: 6.1-9.9) months. Multiple metastatic sites and no surgical treatment were prognostic factors for worse survival. Tumors located in non-head and neck region were related with better survival. CONCLUSIONS: The incidence of DM was 14.3% with a dismal median OS of 8.0 months for metastatic MPNSTs. More evaluation should be applied for patients with large tumor size and lymph metastases. Tumors located in head and neck region and the presence of multiple metastases predicted worse survival outcome. Surgical treatment can significantly improve the survival of MPNST patients with distant metastasis.

Brain Metabolic Profile after Intranasal vs. Intraperitoneal Clomipramine Treatment in Rats with Ultrasound Model of Depression.

BACKGROUND: Molecular mechanisms of depression remain unclear. The brain metabolome after antidepressant therapy is poorly understood and had not been performed for different routes of drug administration before the present study. Rats were exposed to chronic ultrasound stress and treated with intranasal and intraperitoneal clomipramine. We then analyzed 28 metabolites in the frontal cortex and hippocampus. METHODS: Rats' behavior was identified in such tests: social interaction, sucrose preference, forced swim, and Morris water maze. Metabolic analysis was performed with liquid chromatography. RESULTS: After ultrasound stress pronounced depressive-like behavior, clomipramine had an equally antidepressant effect after intranasal and intraperitoneal administration on behavior. Ultrasound stress contributed to changes of the metabolomic pathways associated with pathophysiology of depression. Clomipramine affected global metabolome in frontal cortex and hippocampus in a different way that depended on the route of administration. Intranasal route was associated with more significant changes of metabolites composition in the frontal cortex compared to the control and ultrasound groups while the intraperitoneal route corresponded with more profound changes in hippocampal metabolome compared to other groups. Since far metabolic processes in the brain can change in many ways depending on different routes of administration, the antidepressant therapy should also be evaluated from this point of view.

Therapeutic Effects of hiPSC-Derived Glial and Neuronal Progenitor Cells-Conditioned Medium in Experimental Ischemic Stroke in Rats.

Transplantation of various types of stem cells as a possible therapy for stroke has been tested for years, and the results are promising. Recent investigations have shown that the administration of the conditioned media obtained after stem cell cultivation can also be effective in the therapy of the central nervous system pathology (hypothesis of their paracrine action). The aim of this study was to evaluate the therapeutic effects of the conditioned medium of hiPSC-derived glial and neuronal progenitor cells in the rat middle cerebral artery occlusion model of the ischemic stroke. Secretory activity of the cultured neuronal and glial progenitor cells was evaluated by proteomic and immunosorbent-based approaches. Therapeutic effects were assessed by overall survival, neurologic deficit and infarct volume dynamics, as well as by the end-point values of the apoptosis- and inflammation-related gene expression levels, the extent of microglia/macrophage infiltration and the numbers of formed blood vessels in the affected area of the brain. As a result, 31% of the protein species discovered in glial progenitor cells-conditioned medium and 45% in neuronal progenitor cells-conditioned medium were cell type specific. The glial progenitor cell-conditioned media showed a higher content of neurotrophins (BDNF, GDNF, CNTF and NGF). We showed that intra-arterial administration of glial progenitor cells-conditioned medium promoted a faster decrease in neurological deficit compared to the control group, reduced microglia/macrophage infiltration, reduced expression of pro-apoptotic gene Bax and pro-inflammatory cytokine gene Tnf, increased expression of anti-inflammatory cytokine genes (Il4, Il10, Il13) and promoted the formation of blood vessels within the damaged area. None of these effects were exerted by the neuronal progenitor cell-conditioned media. The results indicate pronounced cytoprotective, anti-inflammatory and angiogenic properties of soluble factors secreted by glial progenitor cells.

A Novel Phenylpyrrolidine Derivative: Synthesis and Effect on Cognitive Functions in Rats with Experimental Ishemic Stroke.

We performed an in silico, in vitro, and in vivo assessment of a potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (compound 1) as a potential prodrug for cognitive function improvement in ischemic brain injury. Using in silico methods, we predicted the pharmacological efficacy and possible safety in rat models. In addition, in silico data showed neuroprotective features of compound 1, which were further supported by in vitro experiments in a glutamate excitotoxicity-induced model in newborn rat cortical neuron cultures. Next, we checked whether compound 1 is capable of crossing the blood-brain barrier in intact and ischemic animals. Compound 1 improved animal behavior both in intact and ischemic rats and, even though the concentration in intact brains was low, we still observed a significant anxiety reduction and activity escalation. We used molecular docking and molecular dynamics to support our hypothesis that compound 1 could affect the AMPA receptor function. In a rat model of acute focal cerebral ischemia, we studied the effects of compound 1 on the behavior and neurological deficit. An in vivo experiment demonstrated that compound 1 significantly reduced the neurological deficit and improved neurological symptom regression, exploratory behavior, and anxiety. Thus, here, for the first time, we show that compound 1 can be considered as an agent for restoring cognitive functions.