Case Report: Identification of a novel LYN::LINC01900 transcript with promyelocytic phenotype and TP53 mutation in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant disease of myeloid hematopoietic stem/progenitor cells characterized by the abnormal proliferation of primitive and naive random cells in the bone marrow and peripheral blood. Acute promyelocytic leukemia (APL) is a type (AML-M3) of AML. Most patients with APL have the characteristic chromosomal translocation t(15; 17)(q22; q12), forming PML::RARA fusion. The occurrence and progression of AML are often accompanied by the emergence of gene fusions such as PML::RARA, CBFß::MYH11, and RUNX1::RUNX1T1, among others. Gene fusions are the main molecular biological abnormalities in acute leukemia, and all fusion genes act as crucial oncogenic factors in leukemia. Herein, we report the first case of LYN::LINC01900 fusion transcript in AML with a promyelocytic phenotype and TP53 mutation. Further studies should address whether new protein products may result from this fusion, as well as the biological function of these new products in disease occurrence and progression.

Tunable Gas-Gas Reactions through Nanobubble Pathway.

Combustible gas-gas reactions usually do not occur spontaneously upon mixing without ignition or other triggers to lower the activation energy barrier. Nanobubbles, however, could provide such a possibility in solution under ambient conditions due to high inner pressure and catalytic radicals within their boundary layers. Herein, a tunable gas-gas reaction strategy via bulk nanobubble pathway is developed by tuning the interface charge of one type of bulk nanobubble and promoting its fusion and reaction with another, where the reaction-accompanied size and number concentration change of the bulk nanobubbles and the corresponding thermal effect clearly confirm the occurrence of the nanobubble-based H2 /O2 combustion. In addition, abundant radicals can be detected during the reaction, which is considered to be critical to ignite the gas reaction during the fusion of nanobubbles in water at room temperature. Therefore, the nanobubble-based gas-gas reactions provide a safe and efficient pathway to produce energy and synthesize new matter inaccessible under mild or ambient conditions.

Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage: roles of microglia/macrophages.

BACKGROUND: Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage (ICH). As a regulator of inflammation and lipid metabolism, Liver X receptor (LXR) has the potential to alter microglia/macrophage (M/M) phenotype, and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes. To support potential clinical translation, the benefits of enhanced LXR signalling are examined in experimental ICH. METHODS: Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle. Behavioural tests were conducted at multiple time points. Lesion and haematoma volume, and other brain parameters were assessed using multimodal MRI with T2-weighted, diffusion tensor imaging and dynamic contrast-enhanced MRI sequences. The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes, M/M phenotype, lipid/cholesterol-laden phagocytes, oligodendrocyte lineage cells and neural stem cells. Western blot and real-time qPCR were also used. CX3CR1CreER: Rosa26iDTR mice were employed for M/M-depletion experiments. RESULTS: GW3965 treatment reduced lesion volume and white matter injury, and promoted haematoma clearance. Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E, and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1ß+ to Arginase1+CD206+ regulatory phenotype. Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice. LXR activation increased the number of Olig2+PDGFRα+ precursors and Olig2+CC1+ mature oligodendrocytes in perihaematomal regions, and elevated SOX2+ or nestin+ neural stem cells in lesion and subventricular zone. MRI results supported better lesion recovery by GW3965, and this was corroborated by return to pre-ICH values of functional rotarod activity. The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1CreER: Rosa26iDTR mice. CONCLUSIONS: LXR agonism using GW3965 reduced brain injury, promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling.

Iron Neurotoxicity and Protection by Deferoxamine in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is a subtype of stroke that is characterized by high morbidity and mortality, for which clinical outcome remains poor. An extensive literature indicates that the release of ferrous iron from ruptured erythrocytes in the hematoma is a key pathogenic factor in ICH-induced brain injury. Deferoxamine is an FDA-approved iron chelator that has the capacity to penetrate the blood-brain barrier after systemic administration and binds to iron. Previous animal studies have shown that deferoxamine attenuates ICH-induced brain edema, neuronal death, and neurological deficits. This review summarizes recent progress of the mechanisms by which deferoxamine may alleviate ICH and discusses further studies on its clinical utility.

Neuroprotection by Ozanimod Following Intracerebral Hemorrhage in Mice.

The destruction of the blood-brain barrier (BBB) after intracerebral hemorrhage (ICH) is associated with poor prognosis. Modulation of sphingosine 1-phosphate receptor (S1PR) may improve outcomes from ICH. Ozanimod (RPC-1063) is a newly developed S1PR regulator which can selectively modulate type 1/5 sphingosine receptors. Here, we studied the impact of Ozanimod on neuroprotection in an experimental mouse model of ICH, induced by injecting collagenase type VII into the basal ganglia. Ozanimod was administered by gavage 2 h after surgery and once a day thereafter until sacrifice. The results demonstrate that Ozanimod treatment improved neurobehavioral deficits in mice and decreased weight loss after ICH. Ozanimod significantly reduced the density of activated microglia and infiltrated neutrophils in the perihematoma region. Furthermore, Ozanimod reduced hematoma volume and water content of the ICH brain. The results of TUNEL staining indicate that Ozanimod mitigated brain cell death. The quantitative data of Evans blue (EB) staining showed that Ozanimod reduced EB dye leakage. Overall, Ozanimod reduces the destruction of the BBB and exert neuroprotective roles following ICH in mice.

Tumor microenvironment-responsive BSA nanocarriers for combined chemo/chemodynamic cancer therapy.

Tumor microenvironment (TME), characterized by high glutathione (GSH), high hydrogen peroxide (H2O2) and acidic pH levels, is favorable for the growth, invasion and metastasis of cancer cells. Taking advantage of the specific characteristics of tumors, TME-responsive GCBD NPs are designed to deliver nanoscale coordination polymers (NCPs, GA-Cu) and chemotherapy drugs (doxorubicin, DOX) based on bovine serum albumin (BSA) nanocarriers into cancer cells for combined chemodynamic therapy (CDT) and chemotherapy. In an acidic environment, GCBD NPs could release approximately 90% copper ions, which can not only consume overexpressed GSH to modulate the TME but can also react with endogenous H2O2 in a Fenton-like reaction to achieve the CDT effect. Meanwhile, the released DOX could enter the nucleus of tumor cells and affect their proliferation to achieve efficient chemotherapy. Both in vitro and in vivo experiments showed that GCBD NPs had good biosafety and could effectively inhibit the growth of cancer cells. GCBD NPs are promising as a biocompatible nanoplatform to exploit TME characteristics for combined chemo and chemodynamic therapy, providing a novel strategy to eradicate tumors with high efficiency and specificity.

Neuroprotection of minocycline by inhibition of extracellular matrix metalloproteinase inducer expression following intracerebral hemorrhage in mice.

Intracerebral hemorrhage (ICH) is a severe neurological dysfunction and a medical emergency with a high mortality rate. Minocycline ameliorates deficits in rodent models of acute and chronic neurological diseases. However, the role of minocycline in ICH remains unclear. The extracellular matrix metalloproteinase inducer (EMMPRIN) is a key inflammatory mediator in some neurological diseases, triggering matrix metalloproteinases (MMPs) production. In this study, we aimed to use minocycline to inhibit EMMPRIN and thus the activity of MMPs. Male adult C57BL/6 mice were injected with collagenase type VII or saline into the right basal ganglia and euthanized at different time points. The minocycline was intraperitoneally injected once every 12 h for three days to block the expression of EMMPRIN from two hours after ICH. We found that breakdown of the BBB was most severe 3 days after ICH. The minocycline treatment significantly decreased EMMPRIN and MMP-9 expression, reduced zonula occludens-1 and occludin, and alleviated BBB disruption. Moreover, minocycline treatment displayed a lower brain water content, lesser neurological dysfunction, and smaller injury volume on day 3 than those of the vehicle-treated group. Minocycline also inhibited the activation of microglia/macrophages, infiltration of neutrophils, and production of inflammatory mediators, including tumor necrosis factor alpha and interleukin-1beta. The current study shows that minocycline exhibits protective roles in ICH by decreasing EMMPRIN and MMP-9 expression, alleviating BBB disruption, inhibiting neuroinflammation, areducing neuronal degeneration and death.

Lin28B regulates the fate of grafted mesenchymal stem cells and enhances their protective effects against Alzheimer's disease by upregulating IGF-2.

Mesenchymal stem cells (MSCs) transplantation has emerged as a potential therapeutic approach for Alzheimer's disease (AD). However, the poor proliferation capacity and low survival rate of engrafted MSCs in the hostile microenvironment of AD limit their therapeutic efficiency. Lin28B is a conserved RNA-binding protein associated with cell self-renewal and survival. The purpose of the present study was to explore whether lin28B might influence the functions of implanted MSCs and strengthen their neuroprotective potential in AD. A gain-of-function assay was used to upregulate lin28B expression in MSCs by lentiviral transfection. Our in vitro results indicated that lin28B promoted MSCs proliferation and migration, and protected MSCs against Aß1-42-induced cell death by upregulating insulin-like growth factor-2 (IGF-2). Blockage of IGF-2 partially abrogated the above effects of lin28B. After intracerebroventricular injection into amyloid precursor protein/presenilin 1 mice, implanted MSCs were monitored using bioluminescence imaging. We observed that administration of MSCs transfected with lin28B significantly stimulated their proliferation and prolonged cell retention after delivery. Moreover, administration of the transfected MSCs markedly mitigated cognitive deficits, promoted amyloid plaque clearance, decreased the activation of microglia, and reduced neuronal cell death. The data above confirmed our hypothesis that lin28B is a crucial modulator determining the fate of transplanted MSCs by regulating IGF-2-associated pathways and thereby enhancing their protective effects against AD.

Bone Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote Recovery Following Spinal Cord Injury via Improvement of the Integrity of the Blood-Spinal Cord Barrier.

Mesenchymal stem cell (MSC) transplantation has been shown to represent a potential treatment for traumatic spinal cord injury (SCI). However, there are several obstacles that need to be overcome before MSCs can be considered for clinical application, such as failure of MSCs to reach the spinal cord lesion core and possible tumor formation. Recent studies have suggested that MSC treatment is beneficial owing to paracrine-secreted factors. Extracellular vesicles are considered to be some of the most valuable paracrine molecules. However, the therapeutic mechanism of extracellular vesicles on spinal cord injury has not been studied clearly. Therefore, our study investigated the effect of systemic administration of extracellular vesicles on the loss of motor function after SCI and examined the potential mechanisms underlying their effects. Disruption of the blood-spinal cord barrier (BSCB) is a crucial factor that can be detrimental to motor function recovery. Pericytes are an important component of the neurovascular unit, and play a pivotal role in maintaining the structural integrity of the BSCB. Our study demonstrated that administration of bone mesenchymal stem cell-derived extracellular vesicles (BMSC-EV) reduced brain cell death, enhanced neuronal survival and regeneration, and improved motor function compared with the administration of BMSC-EV free culture media (EV-free CM). Besides, the BSCB was attenuated and pericyte coverage was significantly decreased in vivo. Furthermore, we found that exosomes reduced pericyte migration via downregulation of NF-κB p65 signaling, with a consequent decrease in the permeability of the BSCB. In summary, we identified that extracellular vesicles treatment suppressed the migration of pericytes and further improved the integrity of the BSCB via NF-κB p65 signaling in pericytes. Our data suggest that extracellular vesicles may serve as a promising treatment strategy for SCI.

p16/Ki67 dual staining improves the detection specificity of high-grade cervical lesions.

AIM: The goal of this study was to analyze the specificity of p16/Ki67 dual staining in the detection of high-grade cervical lesions. METHODS: A total of 223 patients with an average age of 39 years old were enrolled in this study. All samples were analyzed by p16/Ki67 immunocytochemical dual staining, liquid-based cytology and high-risk human papillomavirus (HR-HPV) test. Diagnosis of each patient was verified by histopathological test. RESULTS: The specificity of p16/Ki67 dual staining was 68.33%, which was significantly higher than that of cytology (38.33%) and HR-HPV test (21.67%) (P < 0.05) for CIN2+ detection. p16/Ki67 dual staining had similar sensitivity with HR-HPV test for CIN2+ detection (90.18% vs 93.87%, P = 0.286). In atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cases, the specificity of p16/Ki67 dual staining was significantly higher than that of HPV test (66.67% vs 3.70%, P < 0.05) and its sensitivity was similar to that of HPV test for CIN2+ detection. The sensitivity and specificity of dual staining for CIN2+ detection in HR-HPV positive women were 90.85% and 70.21%, respectively, which were higher than those of cytology (83.01% and 42.55%) and HPV16/18 test (70.59% and 44.68%). CONCLUSIONS: p16/Ki67 dual staining could improve the specificity of high-grade cervical lesions detection and have similar sensitivity to HPV test for CIN2+ detection. When triaging women with ASC-US or LSIL liquid-based cytology, compared with positive HR-HPV, the specificity of CIN2+ lesion detection was increased by p16/Ki67 dual staining. p16/Ki67 dual staining could reduce colposcopy referrals and avoid excessive diagnosis and treatment.

MicroRNA Let-7f-5p Promotes Bone Marrow Mesenchymal Stem Cells Survival by Targeting Caspase-3 in Alzheimer Disease Model.

Widespread death of transplanted mesenchymal stem cells (MSCs) hampers the development of stem cell therapy for Alzheimer disease (AD). Cell pre-conditioning might help cope with this challenge. We tested whether let-7f-5p-modified MSCs could prolong the survival of MSCs after transplantation. When exposed to Aß25-35in vitro, MSCs showed significant early apoptosis with decrease in the let-7f-5p levels and increased caspase-3 expression. Upregulating microRNA let-7f-5p in MSCs alleviated Aß25-35-induced apoptosis by decreasing the caspase-3 levels. After computerized analysis and the luciferase reporter assay, we identified that caspases-3 was the target gene of let-7f-5p. In vivo, hematoxylin and eosin staining confirmed the success of MSCs transplantation into the lateral ventricles, and the let-7f-5p upregulation group showed the lowest apoptotic rate of MSCs detected by TUNEL immunohistochemistry analysis and immunofluorescence. Similarly, bioluminescent imaging showed that let-7f-5p upregulation moderately prolonged the retention of MSCs in brain. In summary, we identified the anti-apoptotic role of let-7f-5p in Aß25-35-induced cytotoxicity, as well as the protective effect of let-7f-5p on survival of grafted MSCs by targeting caspase-3 in AD models. These findings show a promising approach of microRNA-modified MSCs transplantation as a therapy for neurodegenerative diseases.