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Methotrexate (MTX), a widely used antimetabolite in paediatric cancer to treatment, has been widely reported to cause bone loss and bone marrow (BM) microvascular (particularly sinusoids) damage. Investigations must now investigate how MTX‐induced bone loss and microvasculature damage can be attenuated/prevented. In the present study, we examined the potency of icariin, an herbal flavonoid, in reducing bone loss and the dilation/damage of BM sinusoids in rats caused by MTX treatment. Groups of young rats were treated with five daily MTX injections (0.75 mg/kg) with and without icariin oral supplementation until Day 9 after the first MTX injection. Histological analyses showed a significant reduction in the bone volume/tissue volume (BV/TV) fraction (%) and trabecular number in the metaphysis trabecular bone of MTX‐treated rats, but no significant changes in trabecular thickness and trabecular spacing. However, the BV/TV (%) and trabecular number were found to be significantly higher in MTX + icariin‐treated rats than those of MTX alone‐treated rats. Gene expression analyses showed that icariin treatment maintained expression of osteogenesis‐related genes but suppressed the induction of adipogenesis‐related genes in bones of MTX‐treated rats. In addition, icariin treatment attenuated MTX‐induced dilation of BM sinusoids and upregulated expression of endothelial cell marker CD31 in the metaphysis bone of icariin + MTX‐treated rats. Furthermore, in vitro studies suggest that icariin treatment can potentially enhance the survival of cultured rat sinusoidal endothelial cells against cytotoxic effect of MTX and promote their migration and tube formation abilities, which is associated with enhanced production of nitric oxide. [ABSTRACT FROM AUTHOR]

Cancer chemotherapy can cause significant damage to the bone marrow (BM) microvascular (sinusoidal) system. Investigations must now address whether and how BM sinusoidal endothelial cells (SECs) can be protected during chemotherapy. Herein we examined the potential protective effects of genistein, a soy‐derived flavonoid, against BM sinusoidal damage caused by treatment with methotrexate (MTX). The groups of young adult rats were gavaged daily with genistein (20 mg/kg) or placebo. After 1 week, rats also received daily injections of MTX (0.75 mg/kg) or saline for 5 days and were killed after a further 4 days. Histological analyses showed that BM sinusoids were markedly dilated (p < 0.001) in the MTX‐alone group but were unaffected or less dilated in the genistein+MTX group. In control rats, genistein significantly enhanced expression of vascular endothelial growth factor (VEGF; p < 0.01), particularly in osteoblasts, and angiogenesis marker CD31 (p < 0.001) in bone. In MTX‐treated rats, genistein suppressed MTX‐induced apoptosis of BM SECs (p < 0.001 vs MTX alone group) and tended to increase expression of CD31 and VEGF (p < 0.05). Our in vitro studies showed that genistein in certain concentrations protected cultured SECs from MTX cytotoxic effects. Genistein enhanced tube formation of cultured SECs, which is associated with its ability to induce expression of endothelial nitric oxide synthase and production of nitric oxide. These data suggest that genistein can protect BM sinusoids during MTX therapy, which is associated, at least partially, with its indirect effect of promoting VEGF expression in osteoblasts and its direct effect of enhancing nitric oxide production in SECs. Flavonoid genistein may have a potency to protect bone marrow sinusoids during methotrexate therapy, which is associated, at least partially, with its indirect effect of promoting angiogenic factor vascular endothelial growth factor expression in osteoblasts and its direct effect of enhancing nitric oxide production in sinusoidal endothelial cells. [ABSTRACT FROM AUTHOR]

Wound healing is a complex but a fine‐tuned biological process in which human skin has the ability to regenerate itself following damage. However, in particular conditions such as deep burn or diabetes the process of wound healing is compromised. Despite investigations on the potency of a wide variety of stem cells for wound healing, adipose‐derived stem cells (ASCs) seem to possess the least limitations for clinical applications, and literature showed that ASCs can improve the process of wound healing very likely by promoting angiogenesis and/or vascularisation, modulating immune response, and inducing epithelialization in the wound. In the present review, advantages and disadvantages of various stem cells which can be used for promoting wound healing are discussed. In addition, potential mechanisms of action by which ASCs may accelerate wound healing are summarised. Finally, clinical studies applying ASCs for wound healing and the associated limitations are reviewed. Despite investigations on the potency of a wide variety of stem cells for wound healing, adipose‐derived stem cells (ASCs) seem to possess the least clinical limitations for clinical applications, and our review showed that ASCs can improve the process of wound healing very likely by promoting angiogenesis and/or vascularisation, modulating immune response, and inducing epithelialization in the wound. [ABSTRACT FROM AUTHOR]

Dexamethasone (Dex) is known to cause significant bone growth impairment in childhood. Although previous studies have suggested roles of osteocyte apoptosis in the enhanced osteoclastic recruitment and local bone loss, whether it is so in the growing bone following Dex treatment requires to be established. The current study addressed the potential roles of chemokine CXCL12 in chondroclast/osteoclast recruitment and bone defects following Dex treatment. Significant apoptosis was observed in cultured mature ATDC5 chondrocytes and IDG‐SW3 osteocytes after 48 hours of 10−6 M Dex treatment, and CXCL12 was identified to exhibit the most prominent induction in Dex‐treated cells. Conditioned medium from the treated chondrocytes/osteocytes enhanced migration of RAW264.7 osteoclast precursor cells, which was significantly inhibited by the presence of the anti‐CXCL12 neutralizing antibody. To investigate the roles of the induced CXCL12 in bone defects caused by Dex treatment, young rats were orally gavaged daily with saline or Dex at 1 mg/kg/day for 2 weeks, and received an intraperitoneal injection of anti‐CXCL12 antibody or control IgG (1 mg/kg, three times per week). Aside from oxidative stress induction systemically, Dex treatment caused reductions in growth plate thickness, primary spongiosa height, and metaphysis trabecular bone volume, which are associated with induced chondrocyte/osteocyte apoptosis and enhanced chondroclast/osteoclast recruitment and osteoclastogenic differentiation potential. CXCL12 was induced in apoptotic growth plate chondrocytes and metaphyseal bone osteocytes. Anti‐CXCL12 antibody supplementation considerably attenuated Dex‐induced chondroclast/osteoclast recruitment and loss of growth plate cartilage and trabecular bone. CXCL12 neutralization did not affect bone marrow osteogenic potential, adiposity, and microvasculature. Thus, CXCL12 was identified as a potential molecular linker between Dex‐induced skeletal cell apoptosis and chondroclastic/osteoclastic recruitment, as well as growth plate cartilage/bone loss, revealing a therapeutic potential of CXCL12 functional blockade in preventing bone growth defects during/after Dex treatment. © 2018 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Neurotrophins and their receptors are key molecules that are known to be critical in regulating nervous system development and maintenance and have been recognized to be also involved in regulating tissue formation and healing in skeletal tissues. Studies have shown that neurotrophins and their receptors are widely expressed in skeletal tissues, implicated in chondrogenesis, osteoblastogenesis, and osteoclastogenesis, and are also involved in regulating tissue formation and healing events in skeletal tissue. Increased mRNA expression for neurotrophins NGF, BDNF, NT-3, and NT-4, and their Trk receptors has been observed in injured bone tissues, and NT-3 and its receptor, TrkC, have been identified to have the highest induction at the injury site in a drill-hole injury repair model in both bone and the growth plate. In addition, NT-3 has also recently been shown to be both an osteogenic and angiogenic factor, and this neurotrophin can also enhance expression of the key osteogenic factor, BMP-2, as well as the major angiogenic factor, VEGF, to promote bone formation, vascularization, and healing of the injury site. Further studies, however, are needed to investigate if different neurotrophins have differential roles in skeletal repair, and if NT-3 can be a potential target of intervention for promoting bone fracture healing. [ABSTRACT FROM AUTHOR]

Aims: To study the different effects of mean HbA1c and HbA1c variability on diabetes-related complications in patients with type 2 diabetes mellitus.Methods: 1869 patients with type 2 diabetes were followed-up for a median of 9.5 years in a Diabetes Shared Care Program. Mean HbA1c (HbA1c-mean) and standard deviation of HbA1c (HbA1c-SD) were calculated during the first 5 years. The clinical outcomes included nephropathy (urine albumin-to-creatinine ratio [UACR] > 300 mg/g and doubling of serum creatinine), retinopathy (any and advanced), and mortality (due to all-causes, and cardiovascular disease [CVD]).Results: HbA1c-mean was independently associated with UACR > 300 mg/g (Hazard ratio [HR] 1.308 [95% confidence interval {CI}, 1.194-1.433]), any retinopathy (HR 1.274 [1.171-1.385]), and advanced retinopathy (HR 1.237 [1.014-1.509]). HbA1c-SD was independently associated with UACR > 300 mg/g (HR 1.478 [1.189-1.837]), doubling of serum creatinine (HR 2.133 [1.470-3.095]), all-cause mortality (HR 1.880 [1.561-2.266]), and CVD mortality (HR 1.431 [1.069-1.915]). Receiver operating characteristic (ROC) curves showed HbA1c-mean was more associated with any retinopathy, whereas HbA1c-SD was more associated with doubling of serum creatinine, all-cause and CVD mortality.Conclusion: Both HbA1c-mean and HbA1c-SD predicted most diabetes-related complications in patients with type 2 diabetes. However, HbA1c-mean was more effective at predicting retinopathy, while HbA1c-SD was more effective at predicting deterioration of renal function and increased mortality. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a pivotal role in bone formation, remodeling, and fracture healing. The regulation of angiogenesis in the bone microenvironment is highly complex and orchestrated by intercellular communication between bone cells and endothelial cells. Here, we report that EGF-like domain 7 (EGFL7), a member of the epidermal growth factor (EGF) repeat protein superfamily is expressed in both the osteoclast and osteoblast lineages, and promotes endothelial cell activities. Addition of exogenous recombinant EGFL7 potentiates SVEC (simian virus 40-transformed mouse microvascular endothelial cell line) cell migration and tube-like structure formation in vitro. Moreover, recombinant EGFL7 promotes angiogenesis featuring web-like structures in ex vivo fetal mouse metatarsal angiogenesis assay. We show that recombinant EGFL7 induces phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3), and focal adhesion kinase (FAK) in SVEC cells. Inhibition of ERK1/2 and STAT3 signaling impairs EGFL7-induced endothelial cell migration, and angiogenesis in fetal mouse metatarsal explants. Bioinformatic analyses indicate that EGFL7 contains a conserved RGD/QGD motif and EGFL7-induced endothelial cell migration is significantly reduced in the presence of RGD peptides. Moreover, EGFL7 gene expression is significantly upregulated during growth plate injury repair. Together, these results demonstrate that EGFL7 expressed by bone cells regulates endothelial cell activities through integrin-mediated signaling. This study highlights the important role that EGFL7, like EGFL6, expressed in bone microenvironment plays in the regulation of angiogenesis in bone. J. Cell. Physiol. 229: 82-94, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Methotrexate (MTX) chemotherapy is known to cause bone loss which lacks specific preventative treatments, although clinically folinic acid is often used to reduce MTX toxicity in soft tissues. This study investigated damaging effects of MTX injections (0.75 mg/kg/day for 5 days) in rats and potential protective benefits of fish oil (0.25, 0.5, or 0.75 ml/100 g/day) in comparison to folinic acid (0.75 mg/kg) in the tibial metaphysis. MTX treatment significantly reduced height of primary spongiosa and volume of trabecular bone while reducing density of osteoblasts. Consistently, MTX reduced osteogenic differentiation but increased adipogenesis of bone marrow stromal cells, accompanied by lower mRNA expression of osteogenic transcription factors Runx2 and Osx, but an up-regulation of adipogenesis-related genes FABP4 and PPAR-γ. MTX also increased osteoclast density, bone marrow osteoclast formation, and mRNA expression of proinflammatory cytokines IL-1, IL-6, TNF-α, and RANKL/OPG ratio in bone. Fish oil (0.5 or 0.75 ml/100 g) or folinic acid supplementation preserved bone volume, osteoblast density, and osteogenic differentiation, and suppressed MTX-induced cytokine expression, osteoclastogenesis, and adipogenesis. Thus, fish oil at 0.5 ml/100 g or above is as effective as folinic acid in counteracting MTX-induced bone damage, conserving bone formation, suppressing resorption and marrow adiposity, suggesting its therapeutic potential in preventing bone loss during MTX chemotherapy. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:587-596, 2014. [ABSTRACT FROM AUTHOR]

Aims: Bruton's tyrosine kinase inhibitors (BTKIs), including first‐generation ibrutinib, second‐generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. Methods: Across all indications of three FDA‐approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). Results: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13‐2.93]), pulmonary oedema (ROR = 2.15 [1.19‐3.88]), ventricular extrasystoles (ROR = 5.18 [2.15‐12.44]), heart rate irregular (ROR = 3.05 [1.53‐6.11]), angina pectoris (ROR = 3.18 [1.71‐5.91]) and cardiotoxicity (ROR = 25.22 [17.14‐37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. Conclusions: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed. [ABSTRACT FROM AUTHOR]

Growth plate cartilage injuries often result in bony repair at the injury site and premature mineralisation at the uninjured region causing bone growth defects, for which underlying mechanisms are unclear. With the prior microarray study showing upregulated bone morphogenetic protein (BMP) signalling during the injury site bony repair and with the known roles of BMP signalling in bone healing and growth plate endochondral ossification, this study used a rat tibial growth plate drill-hole injury model with or without systemic infusion of BMP antagonist noggin to investigate roles of BMP signalling in injury repair responses within the injury site and in the adjacent "uninjured" cartilage. At days 8, 14 and 35 post-injury, increased expression of BMP members and receptors and enhanced BMP signalling (increased levels of phosphorylated (p)-Smad1/5/8) were found during injury site bony repair. After noggin treatment, injury site bony repair at days 8 and 14 was reduced as shown by micro-CT and histological analyses and lower mRNA expression of osteogenesis-related genes Runx2 and osteocalcin (by RT-PCR). At the adjacent uninjured cartilage, the injury caused increases in the hypertrophic zone/proliferative zone height ratio and in mRNA expression of hypertrophy marker collagen-10, but a decrease in chondrogenesis marker Sox9 at days 14 and/or 35, which were accompanied by increased BMP signalling (increased levels of pSmad1/5/8 protein and BMP7, BMPR1a and target gene Dlx5 mRNA). Noggin treatment reduced the hypertrophic zone/proliferative zone height ratio and collagen-10 mRNA expression, but increased collagen-2 mRNA levels at the adjacent growth plate. This study has identified critical roles of BMP signalling in the injury site bony repair and in the hypertrophic degeneration of the adjacent growth plate in a growth plate drill-hole repair model. Moreover, suppressing BMP signalling can potentially attenuate the undesirable bony repair at injury site and suppress the premature hypertrophy but potentially rescue chondrogenesis at the adjacent growth plate. • Trauma injury often leads to dysrepair at the injured growth plate cartilage, for which molecular mechanisms are unclear. • BMP signalling was shown upregulated in a prior microarray study, but its function in growth plate repair is unclear. • Systemic treatment with BMP inhibitor noggin suppressed the bony repair at the growth plate injury site in rats. • Systemic BMP inhibitor noggin treatment attenuated premature hypertrophy at the adjacent uninjured growth plate cartilage. • Enhanced BMP signalling promotes injury site bony repair and premature hypertrophy at the uninjured growth plate cartilage. [ABSTRACT FROM AUTHOR]

The commercial application of high power impulse magnetron sputtering (HiPIMS) is hindered by its low deposition rate in thin film and coating industries. This study proposes an effective method to enhance the deposition rate of TiN films by superimposing middle-frequency (MF) pulses during the off-time of HiPIMS pulsing. The impact of Ti target poisoning ratios (ranging from 30 % to 70 %) controlled by the plasma emission monitoring (PEM) feedback control system and MF/HiPIMS pulse on-time ratios (ranging from 1.5 to 24) on the structural, morphological, and mechanical properties of thin films was investigated. Increasing the target poisoning ratio and the ratio of MF/HiPIMS on-time pulses up to 6 resulted in increased peak current and peak power density of HiPIMS for the superimposed TiN films. Compared to TiN films grown solely using HiPIMS, all the superimposed TiN films exhibited improved deposition rates ranging from 3.89 to 6.36 nm/kW·min. Analysis of crystallographic and chemical composition confirmed the formation of single-phase stoichiometric TiN films with a smooth columnar microstructure. The TiN film grown at a 60 % target poisoning ratio and an MF/HiPIMS pulse on-time ratio of 1.5 displayed the highest hardness of 34.4 GPa and elastic modulus of 485 GPa, surpassing the values obtained for pure HiPIMS-grown, MF-grown, and DC-grown films. Moreover, TiN film deposited at target poisoning ratios of 50 % and a 6 times MF/HiPIMS pulse on-time ratio exhibited a high hardness of 30.3 GPa and a high deposition rate of 5.94 nm/min/kW, which was 2.15 times higher than that of pure HiPIMS. Additionally, the formation of stoichiometric TiN films led to relatively lower electrical resistivity. Overall, the superimposition of HiPIMS and MF pulses presents a promising approach to overcome the limitations of HiPIMS and enhance the deposition rate of TiN films. The findings of this study highlight the potential of TiN films grown by the superimposed HiPIMS-MF and PEM feedback control technique for various industrial applications. • The deposition rate of TiN film decreases with increasing target poisoning ratio. • HiPIMS-MF at 50 % target poisoning rate grows stoichiometric single-phase TiN film. • Increasing MF/HiPIMS pulse on-time ratio can increase the TiN deposition rate. • TiN film has a hardness of 30.3 GPa and a high deposition rate of 5.94 nm/kW/min. [ABSTRACT FROM AUTHOR]

Head and neck cancers are a type of life-threatening cancers characterized by an immunosuppressive tumor microenvironment. Only less than 20% of the patients respond to immune checkpoint blockade therapy, indicating the need for a strategy to increase the efficacy of immunotherapy for this type of cancers. Previously, we identified a type B CpG-oligodeoxynucleotide (CpG-ODN) called CpG-2722, which has the universal activity of eliciting an immune response in grouper, mouse, and human cells. In this study, we further characterized and compared its cytokine-inducing profiles with different types of CpG-ODNs. The antitumor effect of CpG-2722 was further investigated alone and in combination with an immune checkpoint inhibitor in a newly developed syngeneic orthotopic head and neck cancer animal model. Along with other inflammatory cytokines, CpG-2722 induces the gene expressions of interleukin-12 and different types of interferons, which are critical for the antitumor response. Both CpG-2722 and anti-programmed death (PD)-1 alone suppressed tumor growth. Their tumor suppression efficacies were further enhanced when CpG-2722 and anti-PD-1 were used in combination. Mechanistically, CpG-2722 shaped a tumor microenvironment that is favorable for the action of anti-PD-1, which included promoting the expression of different cytokines such as IL-12, IFN-β, and IFN-γ, and increasing the presence of plasmacytoid dendritic cells, M1 macrophages, and CD8 positive T cells. Overall, CpG-2722 provided a priming effect for CD8 positive T cells by sharpening the tumor microenvironment, whereas anti-PD-1 released the brake for their tumor-killing effect, resulting in an enhanced efficacy of the combined CpG-2722 and anti-PD-1. [ABSTRACT FROM AUTHOR]

• PD-L1 expression (CPS ≥ 1) was found in 94.3% of R/M HNSCC patients. • PD-L1 expression rates do not differ in those with or without betel nut exposure. • Prior lines of systemic therapy did not influence PD-L1 expression rates. This study explored the relationship between betel-nut chewing and programmed death-ligand 1 (PD-L1) expression in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients in Taiwan. A total 280 R/M HNSCC patients, predominantly male, were evaluated; 75.4 % of whom chewed betel-nut. The prevalence of PD-L1 expression (combined positive score ≥1) was 94.3 % with similar PD-L1 expression rates between betel-nut-exposed and non-exposed groups. PD-L1 prevalence did not differ in those who received prior first-or second-line systemic therapy. In summary, betel-nut exposure did not notably affect PD-L1 expression rates in R/M HNSCC patients in Taiwan. [ABSTRACT FROM AUTHOR]

Graphical abstract Bone marrow sinusoidal endothelial cells constitutively provide adhesion molecules such as E-selectin, P-selectin, ICAM-1, and VCAM-1 to the cells within the bone marrow which have corresponding ligands by which the egress of cells from bone marrow into the circulation might be facilitated/regulated. Apart from expressing adhesion molecules, bone marrow sinusoidal endothelial cells regulate egress of bone marrow residing cells by providing chemokines including CXCL1, CXCL2, and CXCL12, and also by providing ECM proteins including collagen IV, laminin, fibronectin, hemonectin, hyaluronic acid, thrombospondin, and tenascin to the egressing cells. Abstract Despite more attention to cell migration from circulation into the bone marrow (BM), particularly homing of haematopoietic stem/progenitor cells, the process and mechanisms of cell mobilisation from the BM into the circulation remain largely underexplored. The process of cell mobilisation or transcellular cell migration from BM into the circulation (cell egress) is a crucial biological process in mammals as it is important to maintain homeostasis of various physiological functions including, but not limited to, the immune system, erythropoiesis, platelet release, and stem cell migration. The BM microvascular system composes of a monolayer of specialized endothelial cells, called sinusoidal endothelial cells (SECs). While it is very well evident that the process of cell egress occurs exclusively through BM SECs, there is a lack of systematic analyses addressing the extent of contribution of BM SECs to the process of cell egress from the BM. Therefore, this review aims to address the potential ability of BM SECs in regulating and/or facilitating the process of cell egress from BM. In this review, we address, firstly, the unique ultra-/structural and molecular features of BM SECs and discuss the possible biological interactions between BM SECs and various egressing cells in physiological conditions. Secondly, we propose the potential role of BM SECs in egress of leukemic cells from BM into the circulation. Finally, we discuss the potential role of BM SECs in homing of haematopoietic stem cells. Collectively, the current review suggests that the BM SECs may not be merely a neutral gatekeeper for cell intravasation and extravasation, but rather is a dynamic trafficking surveillance system, thereby the process of BM cell egress/mobilisation can be regulated. [ABSTRACT FROM AUTHOR]