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Background: Venous thromboembolism (VTE) has a serious impact on the prognosis of patients with spontaneous intracranial hemorrhage (sICH). However, the use of prophylactic heparin remains controversial. Objectives: This study investigated the safety and timing of prophylactic heparin for VTE in patients with sICH. Design: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines. Methods: Two authors systematically searched Web of Science, Cochrane Library, Embase, and PubMed to find all published research before June 2023. The incidence of deep venous thrombosis (DVT) and mortality were set as primary endpoints. Results: This meta-analysis included seven randomized controlled trials (RCTs) and five observational studies involving a total of 4419 sICH patients in the heparin (n = 2808) and control (n = 1183) groups. Among these patients, 205 received early heparin administration, while 223 received late heparin administration. The results suggested that, compared to the control group, patients in the heparin group had a lower incidence of VTE [odds ratio (OR), 0.47; 95% CI, 0.31-0.71; p < 0.001], DVT (OR, 0.53; 95% CI, 0.33-0.85; p = 0.009), pulmonary embolism (OR, 0.31 95% CI, 0.15-0.65; p = 0.002), and mortality (OR, 0.70; 95% CI, 0.54-0.90; p = 0.006), but there were no statistical differences in hematoma enlargement, extracranial hematoma, and major disability (p > 0.05). There was no statistically significant difference in DVT, mortality, hematoma enlargement, and extracranial hemorrhage between the early heparin group (<24-48 h) and the late heparin group (p > 0.05). Conclusion: In patients with sICH, prophylactic use of heparin may be beneficial because it reduces the incidence of VTE and mortality without increasing the risk of additional bleeding. In addition, early prophylactic use of heparin appears to be safe. However, large-scale RCTs are lacking to support this evidence.

Prophylactic use of heparin reduces the incidence of venous thromboembolism and reduces overall mortality in patients with spontaneous bleeding in the brain Why was the study done? Venous thromboembolism has a serious impact on the prognosis of patients with spontaneous bleeding in the brain. However, the use of prophylactic heparin remains controversial. This study investigates the safety and timing of prophylactic heparin for venous thromboembolism in patients with spontaneous bleeding in the brain. What did the researchers find? Our results showed that patients in the heparin group had lower rates of blood clot in a deep vein, death, and pulmonary embolism compared with the control group, and there were no significant differences in hematoma enlargement, extracranial hematoma, and severe disability. There were no significant differences in blood clot in a deep vein, mortality, hematoma enlargement, and extracranial hemorrhage between the early and late heparin groups. What do the findings mean? This study suggests that prophylactic use of heparin may be beneficial in patients with spontaneous bleeding in the brain, and that early prophylactic use of heparin appears to be safe.

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MicroRNA (miR)­125a­5p represses tafazzin phospholipid­lysophospholipid transacylases (TAFAZZIN) expression and inhibits the epithelial­mesenchymal transition (EMT) of ovarian cancer cells. EMT was found to have a crucial role in the acquisition of chemoresistance. Thus, the present study aimed to determine whether miR­125a­5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer. The expression of miR­125a­5p/TAFAZZIN and its association with chemotherapy response were determined in tissue samples from patients with breast cancer. Furthermore, the effects of miR­125a­5p on breast cancer cells were elucidated using cell proliferation and cell apoptosis assays. Then, the regulatory mechanism of miR­125a­5p in breast cancer was investigated by reverse transcription­quantitative PCR, western blotting, dual­luciferase reporter and RNA immunoprecipitation assays. The results demonstrated that miR­125a­5p inhibited the EMT of MCF­7/adriamycin (Adr) breast cancer cells, as well as decreased the proliferation and increased the apoptosis of breast cancer cells treated with Adr/docetaxel. In addition, miR­125a­5p downregulated the expression levels of TAFAZZIN, Transglutaminase 2, phosphorylated­AKT, N­cadherin, vimentin and proliferating cell nuclear antigen, and significantly increased those of E­cadherin, cleaved caspase-3 and Bax in MCF7/Adr cells. Similar results were obtained with small interfering RNA­TAFAZZIN. Moreover, TAFAZZIN was identified as a direct target of miR­125a­5p in MCF7/Adr breast cancer cells. In addition, increased miR­125a­5p expression was observed in breast tumors from patients exhibiting a chemotherapy response, and TAFAZZIN mRNA expression was elevated in patients with no chemotherapy response. Hence, miR­125a­5p expression was negatively correlated with TAFAZZIN mRNA expression in breast cancer tissues. All these data suggested that miR­125a­5p reverses EMT and restores drug sensitivity by negatively regulating TAFAZZIN in breast cancer and, therefore, has potential as a novel therapeutic target for this disease.

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PURPOSE: This study aimed to investigate the therapeutic potential of tumor suppression and mechanism for different implantation modes of iodine-125 (I-125) seeds irradiation in a mice xenograft model, and its skeletal complications. MATERIALS AND METHODS: A total of 24 mice carrying A549 lung tumor-derived xenografts were randomly assigned to four groups, including non-radioactive (sham) seeds implantation, I-125 seeds fractional implantation, I-125 seeds single implantation and I-125 seeds single implantation combined with anlotinib. Ki67 immunohistochemistry, TUNEL immunofluorescence and CD31 morphometric analysis were used to determine the proliferation index, rate of apoptotic cells and microvessel density, respectively. Additionally, the side effects on the skeletal system in mice treated with I-125 seeds implantation were evaluated by histomorphometric staining with tartrate-resistant acid phosphate (TRAP) and alkaline phosphatase (ALP) expression in femur, tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen type I N-terminal propeptide (PINP) levels in serum were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: The I-125 seeds single and fractionated implantation had similar therapeutic effects and complications when the total number of I-125 seeds was the same. A single implantation of I-125 seeds with or without anlotinib could analogously inhibit the tumor growth in xenografts mice, while the single implantation combined with anlotinib had more effective in tumor inhibition. The results of Ki67, TUNEL and CD31 staining confirmed an evident reduction in tumor cell proliferation and angiogenesis, as well as an increase in apoptosis. A relatively integrated bone metabolism was indicated after I-125 seeds single implantation with or without anlotinib, and the results were similar in I-125 seeds fractional implantation, including a reduction in the number of TRAP-positive cells and an increase in ALP expression level. Additionally, the serum TRACP-5b activity was decreased and the serum PINP concentration was increased following I-125 seeds implantation. CONCLUSIONS: Single and fractionated implantation pattern of I-125 radioactive seeds had similar therapeutic efficacy against tumor growth, while brachytherapy with I-125 seeds implantation may be an effective and safe treatment strategy for its potential protection against cancer treatment-induced bone loss.

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PURPOSE: The aim of the present study was to investigate the duality of irradiation effect on osteoclastogenesis, particularly on the cytoskeleton and expression of lytic enzymes in osteoclast precursors. Therefore, the present study may serve as a useful reference for the prevention and treatment of radiation-induced bone loss in the clinic. MATERIALS AND METHODS: Two typical osteoclast precursors, murine RAW 264.7 macrophage cells and mouse bone marrow-derived macrophages (BMMs), were exposed to radiation in the order of 0.25-8 Gy, and the effects on cell viability, TRAP activity and bone resorption were subsequently investigated. Furthermore, changes in the cytoskeleton, cell apoptosis, and expression of lytic enzymes in osteoclasts were examined to elucidate the molecular mechanism of the duality of irradiation on osteoclastogenesis. RESULTS: Morphological changes and impaired viability were observed in RAW 264.7 cells and BMMs treated with 1-8 Gy irradiation with or without RANKL. However, the cell fusion tendency of osteoclasts was enhanced after 2 Gy irradiation, and an increased number of fused giant osteoclasts and enhanced F-actin ring formation were observed. Consistently, the bone resorption activity and the enzyme expression of TRAP, cathepsin K, matrix metalloproteinase 9, activator protein 1, and Caspase 9 were increased following irradiation with 2 Gy. Furthermore, intracellular ROS production and apoptosis of osteoclast precursors were increased. CONCLUSIONS: Irradiation with 2 Gy inhibited the viability of osteoclast precursors, but increased osteoclastogenesis by enhancing cell fusion and increasing the secretion of lytic enzymes, which may be an important mechanism of radiation-induced bone loss.

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The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anticancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated ß-galactosidase (SA-ß-gal) staining-positive cells, and upregulated senescence-related genes p53/p21, whereas no changes happened to p16. Additionally, DNA damage γ-H2AX foci, G0/G1 phase of cell cycle arrest, and cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the JAK1/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP9), whereas 0.8 µM JAK1 inhibitor (JAKi) treatment effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, whereas CM with JAKi intervention may effectively improve these deterioration effects. In conclusion, irradiation could provoke BMSC senescence and SASP secretion and further aggravate osteogenic differentiation dysfunction via paracrine signaling, whereas SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.

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A novel class of chiral N,N,N imine-containing ligands derived from TsDPEN (N-(p-tosyl)-1,2-diphenylethylene-1,2-diamine) has been developed and applied to the copper-catalyzed asymmetric Kinugasa reaction. The copper(ii) salt proved to be an efficient catalyst precursor, and it provides an efficient way to synthesize enantioenriched cis-ß-lactam. The pathway is air-tolerant and easily manipulated, and the ligands are easy to synthesize. A working model is proposed in which the stereocontrolling step is the [2 + 2] cycloaddition between ketene and imine to explain the observed stereoselectivities.

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Camellia pingguoensis D. Fang is a shrub which is found on limestone of karst forests in Guangxi, China. In this study, we characterized the whole plastid genome of C. pingguoensis using Illumina paired-end sequencing reads. The plastome is 156,621 bp in length, containing two copies of inverted repeat (IR) regions (26,046 bp), a large-single copy (LSC) region (86,289 bp), and a small-single copy (SSC) region (18,240 bp). A total of 114 unique genes in the genome has 80 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. The phylogenetic result indicates C. pingguoensis is closely related to C. nitidissima C. W. Chi.

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Radiotherapy, one of the clinical treatments of cancer, is accompanied by a high risk of damage to healthy tissues, such as bone loss and increased risk of fractures. The aim of the present study was to establish a rat model of local and systemic bone injury by focal irradiation, in order to study the etiological mechanism and intervention. The proximal metaphyseal region of the left hindlimb of male Sprague­Dawley rats were exposed to a single 2 Gy or three 8 Gy doses delivered on days 1, 3 and 5 using a small animal irradiator, the changes in bone volume and microarchitecture were evaluated, and the mineral apposition rate (MAR) was assessed. Furthermore, bone marrow­derived macrophages (BMMs) were isolated and induced to osteoclasts. It has been demonstrated that a single dose of 2 Gy may result in a significant loss of lumbar bone density at 3 days post­irradiation, however this is restored at 30 days post­irradiation. In the 3x8 Gy irradiation rat model, there was a rapid decrease in the aBMD of lumbar spine at 3 days and at 7 days post­irradiation, and the aBMD decline persisted even at 60 days post­irradiation. In addition, microCT analysis revealed a persistent decline in bone volume and damage in microarchitecture in the 3x8 Gy irradiation model, accompanied by a decrease in MAR, index of the decline in bone­forming ability. In the cellular mechanism, a single 2 Gy local irradiation mainly manifested as an enhancement of the BMMs osteoclastogenesis potential, which was different from the osteoclastogenesis inhibition after high­dose focal irradiation (3x8 Gy). In summary, the irradiation with simulated clinical focal fractionated radiotherapy exerts short­ and long­term systemic injury on bone tissue, characterized by different osteoclastogenesis potential between the high dose mode and a single 2 Gy focal irradiation. Physicians must consider the irreversibility of bone damage in clinical radiotherapy.

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Irradiation-induced bone loss is widely reported, especially in radiotherapy-induced osteoporosis. In addition to the mechanism of osteogenesis inhibition and osteoclastogenesis promotion, the regulation effect of osteocytes, which also send signals to modulate osteoclastogenesis, should be elucidated. In this study, the effect of irradiation on osteocyte and its accommodation to osteoclastogenesis via the release of high mobility group box 1 (HMGB1) was explored. Furthermore, the control response of HMGB1 inhibitor on receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) expression in osteocyte and osteocyte-induced osteoclastogenesis was assessed. It was observed that irradiated osteocyte-like MLO-Y4 cells exhibited polygonal-shaped morphological changes and shortened dendrites, inhibited cell viability and induced cellular apoptosis, along with the reduction in dendritic E11 protein/messenger RNA expression at a doses of 4 Gy. Additionally, the secretion of HMGB1 in supernatants was promoted, accompanied by the decreased OPG and elevated RANKL expression. When the RAW264.7 cells were cocultured with irradiated MLO-Y4 cells or its conditioned medium, enhanced migration and differentiation of osteoclast precursor was observed, and this difference was alleviated with anti-HMGB1 neutralizing antibody. In conclusion, this study demonstrated that irradiation deteriorated osteocytes' potential to promote recruitment and differentiation of osteoclast precursor via stimulating HMGB1 release and subsequent elevation of RANKL/OPG level. This study will assist in designing the intervention programs for irradiation-induced bone loss.

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A pre-prepared Ni-PyBisulidine complex has been developed for the catalytic asymmetric Henry reaction of α-keto esters, 2-acylpyridines and 2-acylpyridine N-oxides. The corresponding ß-nitro-α-hydroxy esters were obtained in good to excellent yields (up to 99%) with a high enantiomeric excess (ee) (up to 94%) with a catalyst loading of 1-2 mol%. The desired products of 2-acylpyridines and 2-acylpyridine N-oxides, which were simple methyl ketones, were obtained in medium to excellent yields (up to 94%) with medium to good ee (up to 86%) by using 2 mol% of catalyst.

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Ionizing radiation-induced bone loss is a potential health concern in radiotherapy, occupational exposure, and astronauts. Although impaired bone vasculature and reduced proliferation of bone-forming osteoblasts has been implicated in this process, it has not been clearly characterized that whether radiation affects the growth of bone-resorbing osteoclasts. The molecular crosstalk between different cell populations in the skeletal system has not yet been elucidated in detail, especially between the increased bone resorption at early stage of post-irradiation and bone marrow-derived endothelial progenitor cells (BM-EPCs). In order to further understand the mechanisms involved in radiation-induced bone loss at the cellular level, we assessed the effects of irradiation on angiogenesis of BM-EPCs and osteoclastogenesis of receptor activator for nuclear factor-κB ligand (RANKL)-stimulated RAW 264.7 cells and crosstalk between these cell populations. We herein found significantly dysfunction of BM-EPCs in response to irradiation at a dose of 2 Gy, including inhibited proliferation, migration, tube-forming abilities, and downregulated expression of pro-angiogenesis vascular endothelial growth factors A (VEGF A). Meanwhile, we observed that irradiation promoted osteoclastogenesis of RANKL-stimulated RAW 264.7 cells directly or indirectly. These results provide quantitative evidences of irradiation induced osteoclastogenesis at a cellular level, and strongly suggest the involvement of osteoclastogenesis, angiogenesis and crosstalk between bone marrow cells in the radiation-induced bone loss. This study may provide new insights for the early diagnosis and intervention of bone loss post-irradiation.

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Rabies remains a major public health concern in many developing countries. The precise neuropathogenesis of rabies is unknown, though it is hypothesized to be due to neuronal death or dysfunction. Mice that received intranasal inoculation of an attenuated rabies virus (RABV) strain HEP-Flury exhibited subtle clinical signs, and eventually recovered, which is different from the fatal encephalitis caused by the virulent RABV strain CVS-11. To understand the neuropathogenesis of rabies and the mechanisms of viral clearance, we applied RNA sequencing (RNA-Seq) to compare the brain transcriptomes of normal mice vs. HEP-Flury or CVS-11 intranasally inoculated mice. Our results revealed that both RABV strains altered positively and negatively the expression levels of many host genes, including genes associated with innate and adaptive immunity, inflammation and cell death. It is found that HEP-Flury infection can activate the innate immunity earlier through the RIG-I/MDA-5 signaling, and the innate immunity pre-activated by HEP-Flury or Newcastle disease virus (NDV) infection can effectively prevent the CVS-11 to invade central nervous system (CNS), but fails to clear the CVS-11 after its entry into the CNS. In addition, following CVS-11 infection, genes implicated in cell adhesion, blood vessel morphogenesis and coagulation were mainly up-regulated, while the genes involved in synaptic transmission and ion transport were significantly down-regulated. On the other hand, several genes involved in the MHC class II-mediated antigen presentation pathway were activated to a greater extent after the HEP-Flury infection as compared with the CVS-11 infection suggesting that the collaboration of CD4(+) T cells and MHC class II-mediated antigen presentation is critical for the clearance of attenuated RABV from the CNS. The differentially regulated genes reported here are likely to include potential therapeutic targets for expanding the post-exposure treatment window for RABV infection.