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The blood–brain barrier (BBB) is the main obstacle to the effective delivery of therapeutic agents to the brain, compromising treatment efficacy for a variety of neurological disorders. Intra-arterial (IA) injection of hyperosmotic mannitol has been used to permeabilize the BBB and improve parenchymal entry of therapeutic agents following IA delivery in preclinical and clinical studies. However, the reproducibility of IA BBB manipulation is low and therapeutic outcomes are variable. We demonstrated that this variability could be highly reduced or eliminated when the procedure of osmotic BBB opening is performed under the guidance of interventional MRI. Studies have reported the utility and applicability of this technique in several species. Here we describe a protocol to open the BBB by IA injection of hyperosmotic mannitol under the guidance of MRI in mice. The procedures (from preoperative preparation to postoperative care) can be completed within ~1.5 h, and the skill level required is on par with the induction of middle cerebral artery occlusion in small animals. This MRI-guided BBB opening technique in mice can be utilized to study the biology of the BBB and improve the delivery of various therapeutic agents to the brain.

This study aimed to explore the positive experiences of dyadic coping between patients with acute leukemia and their spouses in China, and to highlight the target factors that could promote coping and adaptation.A qualitative descriptive study was employed. This study was conducted at a tertiary hospital in China from September 2021 to February 2022. A purposive sampling method was used to select participants, and 17 patients diagnosed with acute leukemia and their spouses were interviewed. Qualitative data were analyzed using the content analysis method. This study followed the COREQ checklist.This study's data were categorized into five themes and twelve subthemes: (1) adapting to a new role-couples used role adjustments to adapt; (2) commitment to companionship-patients benefit from spousal commitment in word or in deed; (3) active communication-allows couples to get to know each other better; (4) white lies-shield partner from negative information; (5) seeking external support-outside of couple cohesion. In sum, positive dyadic coping experiences between couples follow the marital commitment of "never forsake."This study contributes new knowledge to the understanding of the dyadic coping experiences of patients with acute leukemia and their spouses within the Chinese social-cultural context and contributes to cross-cultural comparisons. The results can be used to design and implement couple-based intervention programs to support couples by enhancing their mutual support to cope with and adjust to acute leukemia effectively.

The blood-brain barrier (BBB) tightly controls entry of molecules and cells into the brain, restricting the delivery of therapeutics. Blood-brain barrier opening (BBBO) utilizes reversible disruption of cell-cell junctions between brain microvascular endothelial cells to enable transient entry into the brain. Development of BBBO techniques has been hindered by a lack of physiological models for in vitro study. Here, we utilize an in vitro tissue-engineered microvessel model to demonstrate that melittin, a membrane active peptide present in bee venom, supports BBBO. From endothelial and neuronal viability studies, we identify the accessible concentration range for BBBO. We then use a tissue-engineered model of the human BBB to optimize dosing and elucidate the mechanism of opening. Melittin and other membrane active variants transiently increase paracellular permeability via disruption of cell-cell junctions. In mice, we demonstrate a minimum clinically effective intra-arterial dose of 3 μM·min melittin, which is reversible within one day and neurologically safe. Melittin-induced BBBO represents a novel platform for delivery of therapeutics into the brain.

Unraveling the pathology of stroke is a prerequisite for designing therapeutic strategies. It was reported that myelin injury exceeded axonal loss in the peri-infarct region of rodent white matter stroke. An in-depth investigation of the post-stroke white matter damage in higher-order species might innovate stroke intervention. In this study, adult male cynomolgus monkeys received surgical middle cerebral artery occlusion (MCAO), and serial magnetic resonance scans to non-invasively assess brain damage. Spontaneous movements were recorded to evaluate post-stroke behavior. The axon and myelin loss, as well as immune cell infiltration were examined using immunohistochemistry. Magnetic resonance imaging revealed cerebral infarcts and white matter injury after MCAO in monkeys, which were confirmed by neurological deficits. Immunostaining of white matter fibers showed substantial demyelination whilst retention of axons in the infarcts 8 days post MCAO, while a progressive loss of myelin and axons was observed after one month. Gliosis, microglia activation, and leukocyte infiltration were identified in the lesions. These results demonstrate that demyelination predates axonal injury in non-human primate ischemic stroke, which provides a time window for stroke intervention focusing on prevention of progressive axonal loss through myelin regeneration.

Currently, human glioma tumors are mostly modeled in immunodeficient recipients; however, lack of interactions with adaptive immune system is a serious flaw, particularly in the era when immunotherapies dominate treatment strategies. Our group was the first to successfully establish the orthotopic transplantation of human glioblastoma (GBM) in immunocompetent mice by inducing immunological tolerance using a short-term, systemic costimulation blockade strategy (CTLA-4-Ig and MR1). In this study, we further validated the feasibility of this method by modeling pediatric diffuse intrinsic pontine glioma (DIPG) and two types of adult GBM (GBM1, GBM551), in mice with intact immune systems and immunodeficient mice. We found that all three glioma models were successfully established, with distinct difference in tumor growth patterns and morphologies, after orthotopic xenotransplantation in tolerance-induced immunocompetent mice. Long-lasting tolerance that is maintained for up to nearly 200 d in GBM551 confirmed the robustness of this model. Moreover, we found that tumors in immunocompetent mice displayed features more similar to the clinical pathophysiology found in glioma patients, characterized by inflammatory infiltration and strong neovascularization, as compared with tumors in immunodeficient mice. In summary, we have validated the robustness of the costimulatory blockade strategy for tumor modeling and successfully established three human glioma models including the pediatric DIPG whose preclinical study is particularly thwarted by the lack of proper animal models.

Aim of this study is to assess effects of Evi-1 on regulation of c-Jun N-terminal kinase (JNK)/c-Jun pathway on colorectal cancer and the relationship of their expression with clinicopathological characteristics and prognosis.The clinical data of 394 CRC patients and the mRNA expression of Evi-1 were downloaded from The Cancer Genome Atlas (TCGA). Immunohistochemical (IHC) method was used to detect the protein expression of Evi-1, JNK and c-Jun in CRC tissues and adjacent normal tissues.The TCGA dataset demonstrated that Evi-1 mRNA was upregulated in CRC. Evi-1 mRNA expression was significantly correlated with lymphatic metastasis, T stage, distant metastasis and TNM stage. IHC staining showed that Remmele immunoreactive Score (IRS) of Evi-1, JNK and c-Jun were highly expressed in CRC tissues compared with normal tissues adjacent to cancer. Evi-1 in CRC tissues was negatively correlated with JNK and c-Jun. Overexpression of Evi-1, JNK and c-Jun was significantly correlated with the degree of differentiation, T staging, lymphatic metastasis, distant metastasis and TNM classification.The present study shows that Evi-1 expression is negatively correlated with JNK and c-Jun expression, and closely related to some clinical data. Further, Evi-1 combined with JNK and c-Jun can be used for adverse prognosis of CRC.

Radiation therapy is a standard and effective non-surgical treatment for primary brain tumors and metastases. However, this strategy inevitably results in damage of normal brain tissue, causing severe complications, especially the late-delayed cognitive impairment. Due to the multifactorial and complex pathological effects of radiation, there is a lack of effective preventative and restorative treatments for the irradiated brain. Stem-cell therapy has held considerable promise for decades in the treatment of central nervous system (CNS) disorders because of its unique capacity for tissue repair and functional integrity. Currently, there is growing interest in using stem cells as a novel option to attenuate the adverse effects of irradiation. In the present review, we discuss recent studies evaluating stem-cell therapies for the irradiated brain and their therapeutic effects on ameliorating radiation-related brain injury as well as their potential challenges in clinical applications. We discuss these works in context of the pathogenesis of radiation-induced injury to CNS tissue in an attempt to elucidate the potential mechanisms of engrafted stem cells to reverse radiation-induced degenerative processes.

Background It is not known what combination of bevacizumab and chemotherapy agents is the best therapeutic regimen. Comparative study results among the efficacies of bevacizumab plus chemotherapy remain controversial in patients with HER2-negative metastatic breast cancer. Methods We searched Pubmed, Embase, and Cochrane Library Central Resister of Controlled Trials through were July 2019 for randomized controlled trials that evaluated the efficacy of bevacizumab plus chemotherapy in HER2-negative metastatic breast cancer. Data on included study characteristics, outcomes, and risk of bias were abstracted by two reviewers. Results A total of 16 RCT studies involving 5689 patients were included. The results showed that bevacizumab (Bev) - taxanes (Tax) - capecitabine (Cap) has highest-ranking and is probably more effective for prolonging progression-free survival (PFS) than Tax, Cap, Bev-Tax and Bev-Cap, which was no convincing differences among Bev-Cap-vinorelbine, Bev-Tax-everolimus, Bev-Tax-trebananib, Bev-exemestane, Bev-Cap-cyclophosphamide in Bev-containing regimens. For overall response rate (ORR), Bev-Tax-Cap is superior to Tax, Cap and Bev-Cap, while Bev-Tax-trebananib is superior to Cap. The cumulative probability ranking showed that Bev-Tax-Cap or Bev-Tax-trebananib may have best pathological response rate in HER2-negative metastatic breast cancer. Conclusion Our results provide moderate quality evidence that bevacizumab-taxanes-capecitabine maybe the most effective bevacizumab plus chemotherapy on PFS and ORR in HER2-negative metastatic breast cancer, however it should be also considered that bevacizumab may add toxicity to chemotherapy and whether improve overall survival (OS) or not.

The role of NCAM in corticogenesis is incompletely understood. The authors demonstrate that NCAM controls NPC proliferation and fate decision through profilin2-dependent regulation of actin polymerization. This finding sheds new light on NCAM’s functions in neurodevelopmental and mental disorders., The development of cerebral cortex requires spatially and temporally orchestrated proliferation, migration, and differentiation of neural progenitor cells (NPCs). The molecular mechanisms underlying cortical development are, however, not fully understood. The neural cell adhesion molecule (NCAM) has been suggested to play a role in corticogenesis. Here we show that NCAM is dynamically expressed in the developing cortex. NCAM expression in NPCs is highest in the neurogenic period and declines during the gliogenic period. In mice bearing an NPC-specific NCAM deletion, proliferation of NPCs is reduced, and production of cortical neurons is delayed, while formation of cortical glia is advanced. Mechanistically, NCAM enhances actin polymerization in NPCs by interacting with actin-associated protein profilin2. NCAM-dependent regulation of NPCs is blocked by mutations in the profilin2 binding site. Thus, NCAM plays an essential role in NPC proliferation and fate decision during cortical development by regulating profilin2-dependent actin polymerization.

Intra-arterial (IA) infusion of mannitol induces osmotic blood-brain barrier opening (OBBBO) and that method has been used for decades to improve drug delivery to the brain. However, high variability of outcomes prevented vast clinical adoption. Studies on dynamic multi-scale imaging of OBBBO as well as extravasation of IA injected therapeutic agents are essential to develop strategies assuring precision and reproducibility of drug delivery. Intravital microscopy is increasingly used to capture the dynamics of biological processes at the molecular level in convenient mouse models. However, until now OBBBO has been achieved safely in subcortical structures, which prevented direct insight into the process of extravasation through the skull window. Here, we used our previously developed real-time MRI to adjust the procedure to achieve robust cortical OBBBO. We found that catheter-mediated delivery to the cortex from the ipsilateral carotid artery can be improved by temporarily occluding the contralateral carotid artery. The reproducibility and safety of the method were validated by MRI and histology. This experimental platform was further exploited for studying with intravital microscopy the extravasation of 0.58 kDa rhodamine and 153 kDa anti-VEGF monoclonal antibody (bevacizumab) upon IA injection. Dynamic imaging during IA infusion captured the spatiotemporal dynamic of infiltration for each molecule into the brain parenchyma upon OBBBO. Small-sized rhodamine exhibited faster and higher penetration than the antibody. Histological analysis showed some uptake of the monoclonal antibody after IA delivery, and OBBBO significantly amplified the extent of its uptake. For quantitative assessment of cortical uptake, bevacizumab was radiolabeled with zirconium-89 and infused intraarterially. As expected, OBBBO potentiated brain accumulation, providing 33.90 ± 9.06% of injected dose per gram of brain tissue (%ID/g) in the cortex and 17.09 ± 7.22%ID/g in subcortical structures. In contrast IA infusion with an intact BBB resulted in 3.56 ± 1.06%ID/g and 3.57 ± 0.59%ID/g in the same brain regions, respectively. This study established reproducible cortical OBBBO in mice, which enabled multi-photon microscopy studies on OBBBO and drug targeting. This approach helped demonstrate in a dynamic fashion extravasation of fluorescently-tagged antibodies and their effective delivery into the brain across an osmotically opened BBB.

The blood-brain barrier (BBB) tightly controls entry of molecules and cells into the brain, restricting the delivery of therapeutics. Blood-brain barrier opening (BBBO) utilizes reversible disruption of cell-cell junctions between brain microvascular endothelial cells to enable transient entry into the brain. Here, we demonstrate that melittin , a membrane active peptide present in bee venom, supports transient BBBO. From endothelial and neuronal viability studies, we first identify the accessible concentration range for BBBO. We then use a tissue-engineered model of the human BBB to optimize dosing and elucidate the mechanism of opening. Melittin and other membrane active variants transiently increase paracellular permeability via disruption of cell-cell junctions that result in transient focal leaks. To validate the results from the tissue-engineered model, we then demonstrate that transient BBBO can be reproduced in a mouse model. We identify a minimum clinically effective intra-arterial dose of 3 μM min melittin, which is reversible within one day and neurologically safe. Melittin-induced BBBO represents a novel technology for delivery of therapeutics into the brain.

To prevent thromboembolic events associated with heparin-induced thrombocytopenia (HIT), patients usually are treated with argatroban, lepirudin, and bivalirudin. Here, we conducted a meta-analysis of studies to comparing the treatment of HIT with the following direct thrombin inhibitor: argatroban versus lepirudin and argatroban versus bivalirudin. We systematically searched PubMed, Embase, and Cochrane Library database for relevant studies. The clinical outcomes were thromboembolic complication and bleeding. A total of 589 articles were found and 9 of which were finally included in this meta-analysis. There were no significantly differences of thromboembolic complication between argatroban and hirudin analogues (lepirudin and bivalirudin) in the treatment of HIT (lepirudin: RR = 0.773, 95% CI = 0.449-1.331, P = 0.353; bivalirudin: RR = 0.768, 95% CI = 0.386-1.527, P = 0.452). Moreover, the incidence of clinical bleeding of argatroban was similar to hirudin analogues (lepirudin: RR = 0.755, 95% CI = 0.531-1.073, P = 0.117; bivalirudin: RR = 0.995, 95% CI = 0.673-1.472, P = 0.981). Current evidences show that argatroban has the similar effectiveness and safety with lepirudin and bivalirudin for defending against HIT.

Ischemic stroke is a major cause of disability and mortality worldwide, but effective restorative treatments are very limited at present. Regenerative medicine research revealed that stem cells are promising therapeutic options. Dental pulp stem cells (DPSCs) are autologously applicable cells that origin from the neural crest and exhibit neuro-ectodermal features next to multilineage differentiation potentials. DPSCs are of increasing interest since they are relatively easy to obtain, exhibit a strong proliferation ability, and can be cryopreserved for a long time without losing their multi-directional differentiation capacity. Besides, use of DPSCs can avoid fundamental problems such as immune rejection, ethical controversy, and teratogenicity. Therefore, DPSCs provide a tempting prospect for stroke treatment.

Phosphocreatine (PCr) is an exogenous energy substance, which provides phosphate groups for adenosine triphosphate (ATP) cycle and promotes energy metabolism in cells. However, it is still unclear whether PCr has influenced on mitochondrial energy metabolism as well as oxidative phosphorylation (OXPHO) in previous studies. Therefore, the aim of the present study was to investigate the regulation of PCr on lipopolsaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs) and mitochondrial OXPHO pathway. PCr protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c (Cyt C), Ca(2+), reactive oxygen species and subsequent activation of caspases, and increasing Bcl2 expression, while suppressing Bax expression. More importantly, PCr significantly improved mitochondrial swelling and membrane potential, enhanced the activities of ATP synthase and mitochondrial creatine kinase (CKmt) in creatine shuttle, influenced on respiratory chain enzymes, respiratory control ratio, phosphorus/oxygen ratio and ATP production of OXPHO. Above PCr-mediated mitochondrial events were effectively more favorable to reduced form of flavin adenine dinucleotide (FADH2) pathway than reduced form of nicotinamide-adenine dinucleotid pathway in the mitochondrial respiratory chain. Our results revealed that PCr protects against LPS-induced HUVECs apoptosis, which probably related to stabilization of intracellular energy metabolism, especially for FADH2 pathway in mitochondrial respiratory chain, ATP synthase and CKmt. Our findings suggest that PCr may play a certain role in the treatment of atherosclerosis via protecting endothelial cell function.

The neural cell adhesion molecule (NCAM) plays a pivotal role in the development and maintenance of the nervous system via homophilic (NCAM-NCAM) and heterophilic (NCAM-other molecules) interactions. Many synthetic peptides have been engineered to mimic these interactions and induce NCAM-downstream signaling pathways. Such NCAM mimetics have displayed neuritogenic and neuroprotective properties, as well as synaptic modulation in vitro and in vivo. Furthermore, they have been used successfully in preclinical studies to treat neurological disorders including stroke, traumatic brain injury and Alzheimer's disease. This review focuses on recent progress in the development of NCAM mimetic peptides, in particular, on establishing C3, plannexin, and FGL as therapeutic candidates for neurological disorders.

Concrete materials' damage and destruction under cyclic loading are known as concrete fatigue. Based on the domestic and foreign literature, this paper analyzes and explores the progress and development trend of the fatigue mechanism of concrete on the aspects of experimental study of concrete fatigue, fracture mechanics and damage mechanics research.

This paper exploited a novel method of single solvent recycling plus enzymatic pretreatment. Petroleum ether (60-90 degrees C) was an ideal solvent to extract Eucommia gum at high temperature (approximately 80 degrees C) and to precipitate the gum (flocculent) as the temperature of the solution fell to below 40 degrees C. The gutta percha was almost completely precipitated from solution as the temperature cooled down to below 0 degree C. After filtration and recovery of the precipitated gum, the filtrate, petroleum ether, was applied to an activated carbon column to remove dissolved impurities and reused for next gutta percha extraction. Because impurities were kept in solution, the precipitated gutta percha was highly pure. In an experiment of enzyme hydrolyzing the plant cell wall, cuticle layers on the surfaces of leaves prevented cellulase from approaching to and hydrolyzing the cellulose of the cell wall. NaOH (1%) at 70 degrees C efficiently degraded the cuticle layer, which greatly improved the enzymatic hydrolysis of cellulose within eucommia leaves. Gutta percha that was extracted from the alkali- and cellulase-treated leaves had a degree of polymerization as high as in the leaves, and the yield increased from 2.5% of milled leaves up to over 3.2%. The tensile strength of obtained gutta percha increased from 0.02 MPa of milled Eucommia leaves to 60.5 MPa, the breakage extensibility ranged from about 0 to 24%, and the tearing strength ranged from 0.5 to 36 kN/m.