Bone cancer is a critical health problem on a global scale,and the associated huge clinical and economic burdens are still rising.Although many clinical approaches are currently used for bone cancer treatment,these me...Bone cancer is a critical health problem on a global scale,and the associated huge clinical and economic burdens are still rising.Although many clinical approaches are currently used for bone cancer treatment,these methods usually affect the normal body functions and thus present significant limitations.Meanwhile,advanced materials and additive manufacturing have opened up promising avenues for the development of new strategies targeting both bone cancer treatment and post-treatment bone regeneration.This paper presents a comprehensive review of bone cancer and its current treatment methods,particularly focusing on a number of advanced strategies such as scaffolds based on advanced functional materials,drug-loaded scaffolds,and scaffolds for photothermal/magnetothermal therapy.Finally,the main research challenges and future perspectives are elaborated.展开更多
Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA rece...Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.展开更多
Cancer growth in the bone due to its random shape disables bone strength and thus changes its capacity to support body weight or muscles,which can crucially affect the quality of human life in terms of normal walking ...Cancer growth in the bone due to its random shape disables bone strength and thus changes its capacity to support body weight or muscles,which can crucially affect the quality of human life in terms of normal walking or daily activities.For successful patient recovery,it is necessary to remove the cancer-affected minimal bone area and quickly replace it with a biocompatible metal implant within less than 2 weeks.An electron beam-melted Ti-6Al-4V implant was designed and applied in a patient to preserve the natural knee joint close to the bone tumor.The developed implant fits the bone defect well,and the independent ambulatory function of the natural knee joint was restored in the patient within six weeks after surgery.A delayed fracture occurred six months after the successful replacement of cancer-affected bone with Ti-6Al-4V implant at the proximal meshed junction of the implant because of a minor downward slip.Microstructural,mechanical,and computational analyses were conducted for the fractured area to find the main reason for the delayed fracture.Our findings pertaining to the mechanical and material investigation can help realize the safe implantation of the three-dimensionally printed titanium implant to preserve the natural joints of patients with massive bone defects of the extremities.展开更多
In patients with advanced cancer, cancer-induced bone pain（CIBP） is a severe and common problem that is difficult to manage and explain. As c-Jun N-terminal kinase（JNK） and chemokine（C-X-C motif） ligand 1（CXCL1...In patients with advanced cancer, cancer-induced bone pain（CIBP） is a severe and common problem that is difficult to manage and explain. As c-Jun N-terminal kinase（JNK） and chemokine（C-X-C motif） ligand 1（CXCL1） have been shown to participate in several chronic pain processes, we investigated the role of JNK and CXCL1 in CIBP and the relationship between them. A rat bone cancer pain model was established by intramedullary injection of Walker 256 rat gland mammary carcinoma cells into the left tibia of Sprague-Dawley rats. As a result, intramedullary injection of Walker 256 carcinoma cells induced significant bone destruction and persistent pain. Both phosphorylated JNK1（p JNK1） and p JNK2 showed time-dependent increases in the ipsilateral spinal cord from day 7 to day 18 after tumor injection. Inhibition of JNK activation by intrathecal administration of SP600125, a selective p JNK inhibitor, attenuated mechanical allodynia and heat hyperalgesia caused by tumor inoculation. Tumor cell inoculation also induced robust CXCL1 upregulation in the ipsilateral spinal cord on day 18 after tumor injection. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody showed a stable analgesic effect. Intrathecal administration of SP600125 reduced CXCL1 increase in the spinal cord, whereas inhibition of CXCL1 in the spinal cord showed no influence on JNK activation. Taken together, these results suggested that JNK activation in spinal cord contributed to the maintenance of CIBP, which may act through modulation of CXCL1. Inhibition of the p JNK/CXCL1 pathway may provide a new choice for treatment of CIBP.展开更多
Objective： To observe the effects of p38 mitogen activated protein kinase （MAPK） inhibitor SB203580 by intrathecal injection on the pain behavior and the spinal proinflammatory cytokines in a rat model of bone canc...Objective： To observe the effects of p38 mitogen activated protein kinase （MAPK） inhibitor SB203580 by intrathecal injection on the pain behavior and the spinal proinflammatory cytokines in a rat model of bone cancer pain induced by breast cancer cells. Methods： Eleven rats were used to establish the models of bone cancer pain, six rats were treated by intrathecal SB203580 injection, and the other 5 were as the controls. The paw withdrawal latency （PWL）, histology and the spinal levels of IL-1β and TNF-α were detected. Results： All the 11 rats presented evident bone destruction and thermal hyperalgesia after intra-tibial injection of breast cancer cells. No effect of SB203580 on the bone destruction was observed. However, following intrathecal injection of SB203580, the left PWLs （12.12± 1.26 s at 16 days and 12.99 ± 1.65 s at 19 days） were significant higher than that of controls （9.05 ± 1.08 s at 16 days and 8.55 ± 1.60 s at 19 days）, P 〈 0.05. Meanwhile, inkathecal injection of SB203580 evidently reduced the levels of spinal IL-1β and TNF-α. Conclusion： Intrathecal injection of SB203580 in a rat model of bone cancer pain cannot prevent the tibial destruction but significantly depress the thermalgia sensitivity, which might result from inhibiting inkacellular p38 MAPK signaling transduction, and thereby reducing the release of the proinflammatory cytokines.展开更多
Cancer pain is one of the most common symptoms in patients with advanced cancer.In this study,we aimed to investigate the effects of the Mas-related gene C(MrgC)receptors on bone cancer pain.Mechanical withdrawal thre...Cancer pain is one of the most common symptoms in patients with advanced cancer.In this study,we aimed to investigate the effects of the Mas-related gene C(MrgC)receptors on bone cancer pain.Mechanical withdrawal threshold(MWT)and thermal withdrawal latency(TWL)were measured after the inoculation of Walker 256 mammary gland carcinoma cells into the tibia of adult Sprague-Dawley rats.The effects of MrgC receptor agonist bovine adrenal medulla 8-22(BAM8-22)on nociceptive behaviors were investigated after intrathecal injection on days 16 and 17.Glial fibrillary acidic protein(GFAP)-positive cells in the spinal dorsal cord,and calcitonin gene related peptide(CGRP)-,neuronal nitric oxide synthase(nNOS)-and IL-1β-positive neurons in the dorsal root ganglia(DRG)were examined by immunofluorescence staining.The expression of nNOS and IL-1βproteins in the spinal dorsal horn and the DRG was examined by Western blotting after treatment with(Tyr6)-γ2-MSH-6-12(MSH),which was another MrgC receptor agonist.The results showed that intrathecal injection of BAM8-22(30 nmol)attenuated mechanical allodynia in a rat model of bone cancer pain and the effects could last for about 60 min,and single administration of BAM8-22 for two consecutive days reduced mechanical allodynia by about half on the third day.Moreover,the number of GFAP-positive cells in the spinal dorsal horn,and the number of CGRP-,nNOS-and IL-1β-positive neurons in the DRG were decreased.Similarly,intrathecal administration of MSH(15 nmol)reduced the expression of nNOS and IL-1βin the spinal dorsal horn and the DRG.In conclusion,activation of MrgC receptors suppresses the activation of astrocytes in the spinal dorsal cord and the expression of CGRP,nNOS,and IL-1βin the spinal dorsal cord and/or DRG,which may underlie the inhibition of bone cancer pain.These findings provide a novel strategy for the treatment of bone cancer pain.展开更多
The human body has symmetric bones.This paper uses control engineering concepts to design a suitable controller to synchronize two symmetric bones of the human body to control and treat bone cancer.A Nonsingular Termi...The human body has symmetric bones.This paper uses control engineering concepts to design a suitable controller to synchronize two symmetric bones of the human body to control and treat bone cancer.A Nonsingular Terminal Sliding Mode Control(NTSMC)method will be employed to design the proposed control inputs.The control inputs can be the chemical drugs that can be used to treat bone cancer.The dynamical equations of bone cancer will be used to apply the designed control method and test it.For testing the designed controller,Simulink/MATLAB software will be used.The proposed controller is chattering-free,robust against uncertainties and external disturbances,and finite-time stable in the control engineering view.Bone cancer will be treated for almost one year using the proposed control method.展开更多
Objective: In this study, we aimed to estimate the updated incidence and mortality of primary bone cancers based on population-based cancer registration data in 2014, collected by the National Central Cancer Registry ...Objective: In this study, we aimed to estimate the updated incidence and mortality of primary bone cancers based on population-based cancer registration data in 2014, collected by the National Central Cancer Registry of China(NCCRC).Methods: In 2017, 339 registries' data were qualified based on data quality criteria set down by the NCCRC.Cases of primary bone cancers were retrieved from the national database. We estimated numbers of primary bone cancer cases and deaths in China using age-specific rates and corresponding national population stratified by area,sex, age-group(0, 1-4, 5-9, 10-14, …, 85+). Chinese standard population in 2000 and Segi's World population were applied for the calculation of age-standardized incidence and mortality rates.Results: In 2014, 24,000 primary bone cancer cases and 17,200 deaths attributable to primary bone cancers were estimated to have occurred in China. The crude incidence rate of primary bone cancers was 1.76/100,000, with agestandardized incidence rate by Chinese standard population(ASIRC) and by World standard population(ASIRW)being 1.35/100,000 and 1.32/100,000, respectively. The crude mortality rate of primary bone cancers was1.26/100,000, with age-standardized mortality rate by Chinese standard population(ASMRC) and by World standard population(ASMRW) being 0.88/100,000 and 0.86/100,000, respectively. Age-specific incidence curve was bimodally distributed with age, with the first peak occurring in the second decade of the life and the second peak in the elderly. Males had higher crude and age-standardized rates for both incidence and mortality compared with females. Both crude and age-standardized incidence rates were higher in rural areas than in urban areas, so were the crude and age-standardized mortality rates.Conclusions: This population-based study presents the most recently available estimates on primary bone cancers in China, revealing that the males are 1.34 times as much as females suffering from primary bone cancers and the adolescents in puberty and the elderly are predominantly affected groups by these cancers. High-quality cancer registration data are a prerequisite for undertaking further study for gaining insight into the causes and risk factors for primary bone cancers in China.展开更多
Objective: The aim of our study was to assess bone cancer mortality and the related social factors in Inner Mongolia in China. Methods: We obtained data from the Centers for Disease Control in Inner Mongolia from five...Objective: The aim of our study was to assess bone cancer mortality and the related social factors in Inner Mongolia in China. Methods: We obtained data from the Centers for Disease Control in Inner Mongolia from five monitoring points of the Death Registry System in Inner Mongolia from 2008 to 2012. We calculated the crude mortality rate for bone cancer. The χ2 test was used to examine differences in bone cancer mortality rates between sexes and years. Unconditional logistic regressions were applied to analyze the effect of socio-demographic characteristics by sex. Results: Between 2008 and 2012, the crude mortality rate of bone cancer was 1.12/100000 (95% confidence interval = 1.02-1.21). The bone cancer mortality was 2.24 in men and 1.25 in women, resulting in a male-female ratio of 1.8. No between-year difference in the mortality rate was observed between 2008 and 2012 (men: χ2 = 4.65, P = 0.325;women: χ2 = 2.21, P = 0.698). In general, mortality increased with increasing age. People with a lower education level exhibited an increased risk of bone cancer among both men and women. Jobs involving extensive manual labor decreased the likelihood of bone cancer mortality, and the odds ratio was higher for men than women (0.6 vs. 0.45). Unmarried people had a higher risk for bone cancer than married people. Conclusion: The mortality rate of bone cancer was not significantly different between men and women from 2008 to 2012. The risk of bone cancer increased with age among both sexes. Unmarried people and those with a low education status had an elevated risk of bone cancer, whereas employment in a field involving extensive manual labor appeared to be a protective factor against bone cancer.展开更多
Objectives: To report an epidemiology study and prognosis for metastatic bone tumor. Methodology: It was a descriptive, transversal study on records of patients hospitalized in Rheumatology and Oncology-Radiotherapy d...Objectives: To report an epidemiology study and prognosis for metastatic bone tumor. Methodology: It was a descriptive, transversal study on records of patients hospitalized in Rheumatology and Oncology-Radiotherapy departments of the University Teaching Hospital of Brazzaville, Congo from 1 January 2005 to 31 July 2011 (7 years and 6 months). The diagnosis of bone metastasis was made because of the existence of bone pain, or pathological fracture, or bone swelling and a bone-condensing or mixed or osteolytic radiological image. The anatomo-pathological evidence was made after biopsy of the bone lesion or primary cancer. 3687 patients were hospitalized for active cancer, among them 81 had documented bone metastasis. Results: There were 60 men (74.1%) and 21 women (25.9%) with a sex ratio of 2.85. The average age was 53 years, ranging from 3 to 80 years. 75% of patients were more or equal to 50 years old at the discovery of the bone metastasis. Bone pain was the main mode of discovery (67.9% of cases). However, in 6.2% of cases, it was discovered incidentally. The metastasis was bone condensing in 50.7% of cases, osteolytic in 40.7% and mixed in 8.6%. They were unifocal in 25.9% and multifocal in 74.1% of cases. The Primary cancer most frequently found was that of the prostate in 55.6% of cases, breast in 20.7% and rhabdomyosarcoma in 4.9%. In 6.2% of cases, the primary site of cancer was unknown. The average survival was 25 months. Conclusion: The clinical and radiological presentation remains classic. Cancer of the prostate and breast are the main neoplasia responsible for bone metastasis in our series. The discovery of metastasis remains a major evolutionary step of cancer.展开更多
Objectives: To determine the epidemiological, clinical and paraclinical profile of bone metastases cancer. Patients and Methods: It was a retrospective study performed on a series of cases, admitted in Rheumatology de...Objectives: To determine the epidemiological, clinical and paraclinical profile of bone metastases cancer. Patients and Methods: It was a retrospective study performed on a series of cases, admitted in Rheumatology department of the University Teaching Hospital of Lomé, Togo from October 1989 to December 2008. The diagnosis of bone metastasis was made because of the existence of inflammatory bone pain, or pathological fracture, or bone swelling and a bone condensing or mixed or osteolytic radiological image. The anatomopathological evidence was made after biopsy of the bone lesion or primary cancer. 2018 patients were hospitalized in rheumatology, and among them 77 had documented bone metastasis. Results: There were 53 men (68.8%) and 24 women (31.2%) with a sex ratio of 2.2. The mean age was 56.6 ± 12.6 years, ranging from 21 to 82 years. The primary cancer most frequently found was that of the prostate, representing 57.1% of bone metastasis and breast in 15.6%. The main manifestations of patients with bone metastases were inflammatory bone pain (76.6%) and alteration of general condition (75.3%). The spine was the main area of pain (64.9%). The metastasis was bone condensing in 48.1% of cases, osteolytic in 40.3% and mixed in 11.6%. The average survival was 22 months. Conclusion: The clinical and radiological presentation remains classic. Cancer of the prostate and breast are the main neoplasia responsible for bone metastasis in our series. The diagnosis of the primary tumor is often made at the stage of metastasis in black Africa.展开更多
Objective:To study the effects of Yishen Qutong granula on pain sensitization and bone destruction of rats with bone cancer pain.Methods:Walker256 cells were passaged in ascites and injected into the tibia of female W...Objective:To study the effects of Yishen Qutong granula on pain sensitization and bone destruction of rats with bone cancer pain.Methods:Walker256 cells were passaged in ascites and injected into the tibia of female Wistar rats to prepare the bone cancer pain model.On the 14th day after model establishment,60 rats were randomly divided into model group,sham-operated group,Yishen Qutong granula low,middle,high dose group and tramadol hydrochloride positive control group.After continuous administration for 14 days,the mechanical pain threshold,thermal threshold and weight-bearing difference of both hind limbs were observed.Results:Compared with the model group,Yishen Qutong groups increased the mechanical pain threshold,thermal pain threshold and reduced the weight difference of both hind limbs(P<0.05).Compared with the positive drug group,there was no significant difference in increasing the mechanical pain threshold and thermal pain threshold of rats in the medium dose group of Yishen Qutong(P>0.05),and Yishen Qutong granula significantly reduced the weight-bearing difference of hind limbs in all groups(P<0.05).Conclusion:Yishen Qutong granula can relieve pain sensitization and alleviate bone damage in rats with bone cancer pain.展开更多
Objectives:Photodynamic therapy(PDT)is a minimally invasive method used in the treatment of various cancers and skin diseases,but it is not widely used in bone cancer,where the current therapy is often not effective a...Objectives:Photodynamic therapy(PDT)is a minimally invasive method used in the treatment of various cancers and skin diseases,but it is not widely used in bone cancer,where the current therapy is often not effective and accompanied by side effects.Alternative and more effective therapies like PDT are needed.In this in-vitro study,the effect of the photosensitizer(PS)chlorin e6(Ce6)on cancerous bone tumor cells using PDT was examined.Methods:A total of 27 tissue specimens from patients with primary bone cancers or bone metastases of different origins were genetically characterized and treated with PDT.Following a 24-h incubation,cell viability was determined,and the effect of PDT on cell migration was analyzed over 48 h.Results:We could demonstrate that the effect on proliferation of PDT in combination with the PS Ce6 was best in cells isolated from primary osteosarcoma and in bone metastases from mammary carcinomas.Besides proliferation,PDT was also effective in inhibiting the migration of these cells.A statistically significant correlation between the PDT effect and CD164 gene expression was detected,indicating that a high expression of this gene could result in a higher effectiveness of the photodynamic treatment.Conclusion:This study analyzes for the first time the effect of PDT in bone cancers and metastases and shows the potential of treating these cancer types with Ce6 PDT.展开更多
Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesi...Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.展开更多
Bone metastasis is the primary cause of mortality in breast cancer(BC)patients.The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1(DEC1)in promoting BC-related...Bone metastasis is the primary cause of mortality in breast cancer(BC)patients.The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1(DEC1)in promoting BC-related bone metastasis.Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues,with elevated levels correlating with increased metastatic potential,suggesting their synergistic involvement in BC progression.Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells.In MDA-MB-231 cells,DEC1 overexpression(OE)upregulated CXCR4 and proliferation/migration-related genes,whereas DEC1 knockdown reversed these effects.Notably,AMD3100,a specific CXCR4 antagonist,partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes.Mechanistically,DEC1 bound to the CXCR4 promoter region(-230 to-326)and activated its transcription,corroborated by ChIP-seq data.Furthermore,pharmacological inhibition of AKT(LY294002)or JAK2(AZD1480),but not ERK(PD98059),attenuated DEC1-mediated CXCR4 upregulation,although all three inhibitors mitigated DEC1-driven migration-related gene expression.Additionally,DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts,amplifying the CXCR4/CXCL12 axis within the bone microenvironment.Collectively,our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression,providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.展开更多
OBJECTIVE:To explore the mechanism of Wenshen Zhuanggu Fang(温肾壮骨方,WSZG)against breast cancer bone metastasis from the perspective of macrophage polarization through bioinformatics and experiments.METHODS:Bioinfor...OBJECTIVE:To explore the mechanism of Wenshen Zhuanggu Fang(温肾壮骨方,WSZG)against breast cancer bone metastasis from the perspective of macrophage polarization through bioinformatics and experiments.METHODS:Bioinformatics study was used to explore the mechanism underlying the effect of WSZG on breast cancer bone metastasis.Cell viability,migration,invasion and apoptosis assays were performed to detect the influence of WSZG on breast cancer cell MDA-MB-231BO promoted by macrophages.The protein expression level and cytokine content were detected by western blot and enzyme-linked immunosorbent assay kit in vitro.Tumor growth in vivo were performed to evaluate the effects of WSZG on breast cancer bone metastasis.M2/M1 ratio and the maker protein expression were detected by flow cytometry analysis,immunohistochemistry and immunofluorescence double staining.RESULTS:M2 macrophages associated with poor prognosis and may lead to secondary bone metastasis in patients with triple-negative breast cancer.WSZG could treat breast cancer bone metastasis through regulating macrophage polarization by signal transducers and transcription signaling activators(STAT)signaling pathway.WSZG downregulated STAT6,CD206 and Arginase-1,while upregulated STAT1 and Inducible Nitric Oxide Synthase,thus inhibited the M2 macrophagepromoted invasion and migration capabilities of MDA-MB-231BO cells.WSZG treatment suppressed the bone metastasis of breast cancer,and the M2/M1 ratio was reduced by regulating STAT expression in bone metastatic tissue.CONCLUSION:WSZG inhibited breast cancer bone metastasis by adjusting the promoting effect of macrophages on MDA-MB-231BO breast cancer cells and decreasing M2 polarization by downregulating STAT signaling.展开更多
The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell d...The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell differentiation and function,and chronic unfolded protein response activation has been identified in bone disease.The unfolded protein response has been found to promote oncogenesis and drug resistance,raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease.Understanding the critical role of unfolded protein response signaling in cancer development and metastasis,as well as its role in bone homeostasis,may lead to novel mechanisms by which to target cancer-associated bone disease.In this review,we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology,and furthermore,review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.展开更多
Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain,which may display sexual dimorphism.Here,we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived i...Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain,which may display sexual dimorphism.Here,we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin(IL)-17A promotes the progression of mouse bone cancer pain without sex differences.Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors.In contrast,chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity,implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain.IL-17A expression predominantly in spinal astro-cytes,whereas its receptor IL-17 receptor A(IL-17RA)was mainly detected in neurons expressing VGLUT2 and PAX2,and a few in astrocytes expressing GFAP.Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain.IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia,which could be rescued by CaMKIIa inhibitor.Moreover,selective knockdown IL-17RA in spinal Vglut2^(+)or Vgat^(+)neurons,but not in astrocytes,significantly blocked the bone cancer-induced hyperalgesia.Together,our findings pro-vide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain.Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKIIa signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.展开更多
Recently,the term theragenerative has been proposed for biomaterials capable of inducing therapeutic approaches followed by repairing/regenerating the tissue/organ.This study is focused on the design of a new theragen...Recently,the term theragenerative has been proposed for biomaterials capable of inducing therapeutic approaches followed by repairing/regenerating the tissue/organ.This study is focused on the design of a new theragenerative nanocomposite composed of an amphiphilic non-ionic surfactant(Pluronic F127),bioactive glass(BG),and black phosphorus(BP).The nanocomposite was prepared through a two-step synthetic strategy,including a microwave treatment that turned BP nanosheets(BPNS)into quantum dots(BPQDs)with 5±2 nm dimensions in situ.The effects of surfactant and microwave treatment were assessed in vitro:the surfactant distributes the ions homogenously throughout the composite and the microwave treatment chemically stabilizes the composite.The presence of BP enhanced bioactivity and promoted calcium phosphate formation in simulated body fluid.The inherent anticancer activity of BP-containing nanocomposites was tested against osteosarcoma cells in vitro,finding that 150μg mL^(-1)was the lowest concentration which prevented the proliferation of SAOS-2 cells,while the counterpart without BP did not affect the cell growth rate.Moreover,the apoptosis pathways were evaluated and a mechanism of action was proposed.NIR irradiation was applied to induce further proliferation suppression on SAOS-2 cells through hyperthermia.The inhibitory effects of bare BP nanomaterials and nanocomposites on the migration and invasion of bone cancer,breast cancer,and prostate cancer cells were assessed in vitro to determine the anticancer potential of nanomaterials against primary and secondary bone cancers.The regenerative behavior of the nanocomposites was tested with healthy osteoblasts and human mesenchymal stem cells;the BPQDs-incorporated nanocomposite significantly promoted the proliferation of osteoblast cells and induced the osteogenic differentiation of stem cells.This study introduces a new multifunctional theragenerative platform with promising potential for simultaneous bone cancer therapy and regeneration.展开更多
Aim:Peripheral cytokines contribute to arthritis and bone cancer pain through sensory nerve actions.However,increased spinal cytokine and glial filament expression,coined neuroinflammation,has also been proposed to pl...Aim:Peripheral cytokines contribute to arthritis and bone cancer pain through sensory nerve actions.However,increased spinal cytokine and glial filament expression,coined neuroinflammation,has also been proposed to play a part in chronic pain.Therefore,spinal cord,dorsal root ganglia and circulating cytokines were compared in murine arthritis and bone cancer models in relationship to behavioral signs of pain.Methods:Exploratory behaviors were studied after intra-articular complete Freund’s adjuvant or bone intramedullary sarcoma cell injection.Nervous tissue and blood cytokine expression were determined by real-time polymerase chain reaction(PCR)and multiplex immunoassays,respectively.Results:PCR analysis did not reveal any hallmark of spinal neuroinflammation in spontaneously-behaving mice with cartilage or bone lesions.However,imposed paw stimulation during joint inflammation increased spinal interleukin-1β(IL-1β)expression.Spontaneous paw guarding during rearing was displayed by animals with joint inflammation and bone destruction and was accompanied by increased circulating IL-6 and monocyte chemoattractant protein-1,respectively.In addition,dorsal root ganglia were found to constitutively express receptors for this chemotactic cytokine.Conclusion:Our findings indicate that spinal neuroinflammation is not a necessary condition for chronic pain and suggest that circulating cytokine action in dorsal root ganglia may contribute to experimental joint inflammation and bone cancer pain.展开更多
基金the Engineering and Physical Sciences Research Council(EPSRC)UK through the Global Challenges Research Fund(No.EP/R015139/1)Rosetrees&Stoneygate Trust Enterprise Fellowship(Ref:A2750/M874)from Rosetrees Trust UK and Stoneygate Trust UK.
文摘Bone cancer is a critical health problem on a global scale,and the associated huge clinical and economic burdens are still rising.Although many clinical approaches are currently used for bone cancer treatment,these methods usually affect the normal body functions and thus present significant limitations.Meanwhile,advanced materials and additive manufacturing have opened up promising avenues for the development of new strategies targeting both bone cancer treatment and post-treatment bone regeneration.This paper presents a comprehensive review of bone cancer and its current treatment methods,particularly focusing on a number of advanced strategies such as scaffolds based on advanced functional materials,drug-loaded scaffolds,and scaffolds for photothermal/magnetothermal therapy.Finally,the main research challenges and future perspectives are elaborated.
基金supported by the National Natural Science Foundation of China (81200854)the Natural Science Foundation of Jiangxi Province, China (20122BAB215027)+1 种基金the Science Foundation of the Educational Committee of Jiangxi Province, China (GJJ12064)the International Postdoctoral Exchange Fellowship Program, China (20150062)
文摘Given that lysophosphatidic acid（LPA） and the tetrodotoxin-resistant sodium channel Na_v1.8 are both involved in bone cancer pain, the present study was designed to investigate whether crosstalk between the LPA receptor LPA_1（also known as EDG2） and Na_v1.8 in the dorsal root ganglion（DRG） contributes to the induction of bone cancer pain. We showed that the EDG2 antagonist Ki16198 blocked the mechanical allodynia induced by intrathecal LPA in na？ve rats and attenuated mechanical allodynia in a rat model of bone cancer. EDG2 and Na_v1.8expression in L_（4-6）DRGs was upregulated following intrathecal or hindpaw injection of LPA. EDG2 and Na_v1.8expression in ipsilateral L_（4-6）DRGs increased with the development of bone cancer. Furthermore, we showed that EDG2 co-localized with Na_v1.8 and LPA remarkably enhanced Na_v1.8 currents in DRG neurons, and this was blocked by either a protein kinase C（PKC） inhibitor or a PKCe inhibitor. Overall, we demonstrated the modulation of Na_v1.8 by LPA in DRG neurons, and that this probably underlies the peripheral mechanism by which bone cancer pain is induced.
基金supported by the National Cancer Center Grant(No.NCC-2110270)the Ulsan National Institute of Science and Technology(No.1.200110.01)+1 种基金the National Research Foundation of Korea(NRF)Grant funded by the Korea government(MSIP)(No.2018R1A5A6075959)the Korea government(MSIT)(No.2021M2D2A1A01050059).
文摘Cancer growth in the bone due to its random shape disables bone strength and thus changes its capacity to support body weight or muscles,which can crucially affect the quality of human life in terms of normal walking or daily activities.For successful patient recovery,it is necessary to remove the cancer-affected minimal bone area and quickly replace it with a biocompatible metal implant within less than 2 weeks.An electron beam-melted Ti-6Al-4V implant was designed and applied in a patient to preserve the natural knee joint close to the bone tumor.The developed implant fits the bone defect well,and the independent ambulatory function of the natural knee joint was restored in the patient within six weeks after surgery.A delayed fracture occurred six months after the successful replacement of cancer-affected bone with Ti-6Al-4V implant at the proximal meshed junction of the implant because of a minor downward slip.Microstructural,mechanical,and computational analyses were conducted for the fractured area to find the main reason for the delayed fracture.Our findings pertaining to the mechanical and material investigation can help realize the safe implantation of the three-dimensionally printed titanium implant to preserve the natural joints of patients with massive bone defects of the extremities.
基金supported by the National Natural Science Foundation of China(No.81172150)
文摘In patients with advanced cancer, cancer-induced bone pain（CIBP） is a severe and common problem that is difficult to manage and explain. As c-Jun N-terminal kinase（JNK） and chemokine（C-X-C motif） ligand 1（CXCL1） have been shown to participate in several chronic pain processes, we investigated the role of JNK and CXCL1 in CIBP and the relationship between them. A rat bone cancer pain model was established by intramedullary injection of Walker 256 rat gland mammary carcinoma cells into the left tibia of Sprague-Dawley rats. As a result, intramedullary injection of Walker 256 carcinoma cells induced significant bone destruction and persistent pain. Both phosphorylated JNK1（p JNK1） and p JNK2 showed time-dependent increases in the ipsilateral spinal cord from day 7 to day 18 after tumor injection. Inhibition of JNK activation by intrathecal administration of SP600125, a selective p JNK inhibitor, attenuated mechanical allodynia and heat hyperalgesia caused by tumor inoculation. Tumor cell inoculation also induced robust CXCL1 upregulation in the ipsilateral spinal cord on day 18 after tumor injection. Inhibition of CXCL1 by intrathecal administration of CXCL1 neutralizing antibody showed a stable analgesic effect. Intrathecal administration of SP600125 reduced CXCL1 increase in the spinal cord, whereas inhibition of CXCL1 in the spinal cord showed no influence on JNK activation. Taken together, these results suggested that JNK activation in spinal cord contributed to the maintenance of CIBP, which may act through modulation of CXCL1. Inhibition of the p JNK/CXCL1 pathway may provide a new choice for treatment of CIBP.
基金a grant from the National Nature Sciences Foundation of China (No. 30672426).
文摘Objective： To observe the effects of p38 mitogen activated protein kinase （MAPK） inhibitor SB203580 by intrathecal injection on the pain behavior and the spinal proinflammatory cytokines in a rat model of bone cancer pain induced by breast cancer cells. Methods： Eleven rats were used to establish the models of bone cancer pain, six rats were treated by intrathecal SB203580 injection, and the other 5 were as the controls. The paw withdrawal latency （PWL）, histology and the spinal levels of IL-1β and TNF-α were detected. Results： All the 11 rats presented evident bone destruction and thermal hyperalgesia after intra-tibial injection of breast cancer cells. No effect of SB203580 on the bone destruction was observed. However, following intrathecal injection of SB203580, the left PWLs （12.12± 1.26 s at 16 days and 12.99 ± 1.65 s at 19 days） were significant higher than that of controls （9.05 ± 1.08 s at 16 days and 8.55 ± 1.60 s at 19 days）, P 〈 0.05. Meanwhile, inkathecal injection of SB203580 evidently reduced the levels of spinal IL-1β and TNF-α. Conclusion： Intrathecal injection of SB203580 in a rat model of bone cancer pain cannot prevent the tibial destruction but significantly depress the thermalgia sensitivity, which might result from inhibiting inkacellular p38 MAPK signaling transduction, and thereby reducing the release of the proinflammatory cytokines.
基金supported by grants from the National Natural Science Foundation of China(No.31371124)the Ministry of Education's Industry-University Cooperation Collaborative Education Project(No.202101099013,201802136084).
文摘Cancer pain is one of the most common symptoms in patients with advanced cancer.In this study,we aimed to investigate the effects of the Mas-related gene C(MrgC)receptors on bone cancer pain.Mechanical withdrawal threshold(MWT)and thermal withdrawal latency(TWL)were measured after the inoculation of Walker 256 mammary gland carcinoma cells into the tibia of adult Sprague-Dawley rats.The effects of MrgC receptor agonist bovine adrenal medulla 8-22(BAM8-22)on nociceptive behaviors were investigated after intrathecal injection on days 16 and 17.Glial fibrillary acidic protein(GFAP)-positive cells in the spinal dorsal cord,and calcitonin gene related peptide(CGRP)-,neuronal nitric oxide synthase(nNOS)-and IL-1β-positive neurons in the dorsal root ganglia(DRG)were examined by immunofluorescence staining.The expression of nNOS and IL-1βproteins in the spinal dorsal horn and the DRG was examined by Western blotting after treatment with(Tyr6)-γ2-MSH-6-12(MSH),which was another MrgC receptor agonist.The results showed that intrathecal injection of BAM8-22(30 nmol)attenuated mechanical allodynia in a rat model of bone cancer pain and the effects could last for about 60 min,and single administration of BAM8-22 for two consecutive days reduced mechanical allodynia by about half on the third day.Moreover,the number of GFAP-positive cells in the spinal dorsal horn,and the number of CGRP-,nNOS-and IL-1β-positive neurons in the DRG were decreased.Similarly,intrathecal administration of MSH(15 nmol)reduced the expression of nNOS and IL-1βin the spinal dorsal horn and the DRG.In conclusion,activation of MrgC receptors suppresses the activation of astrocytes in the spinal dorsal cord and the expression of CGRP,nNOS,and IL-1βin the spinal dorsal cord and/or DRG,which may underlie the inhibition of bone cancer pain.These findings provide a novel strategy for the treatment of bone cancer pain.
基金support from Warsaw University of Technology(WUT),grant No:504440200003.
文摘The human body has symmetric bones.This paper uses control engineering concepts to design a suitable controller to synchronize two symmetric bones of the human body to control and treat bone cancer.A Nonsingular Terminal Sliding Mode Control(NTSMC)method will be employed to design the proposed control inputs.The control inputs can be the chemical drugs that can be used to treat bone cancer.The dynamical equations of bone cancer will be used to apply the designed control method and test it.For testing the designed controller,Simulink/MATLAB software will be used.The proposed controller is chattering-free,robust against uncertainties and external disturbances,and finite-time stable in the control engineering view.Bone cancer will be treated for almost one year using the proposed control method.
文摘Objective: In this study, we aimed to estimate the updated incidence and mortality of primary bone cancers based on population-based cancer registration data in 2014, collected by the National Central Cancer Registry of China(NCCRC).Methods: In 2017, 339 registries' data were qualified based on data quality criteria set down by the NCCRC.Cases of primary bone cancers were retrieved from the national database. We estimated numbers of primary bone cancer cases and deaths in China using age-specific rates and corresponding national population stratified by area,sex, age-group(0, 1-4, 5-9, 10-14, …, 85+). Chinese standard population in 2000 and Segi's World population were applied for the calculation of age-standardized incidence and mortality rates.Results: In 2014, 24,000 primary bone cancer cases and 17,200 deaths attributable to primary bone cancers were estimated to have occurred in China. The crude incidence rate of primary bone cancers was 1.76/100,000, with agestandardized incidence rate by Chinese standard population(ASIRC) and by World standard population(ASIRW)being 1.35/100,000 and 1.32/100,000, respectively. The crude mortality rate of primary bone cancers was1.26/100,000, with age-standardized mortality rate by Chinese standard population(ASMRC) and by World standard population(ASMRW) being 0.88/100,000 and 0.86/100,000, respectively. Age-specific incidence curve was bimodally distributed with age, with the first peak occurring in the second decade of the life and the second peak in the elderly. Males had higher crude and age-standardized rates for both incidence and mortality compared with females. Both crude and age-standardized incidence rates were higher in rural areas than in urban areas, so were the crude and age-standardized mortality rates.Conclusions: This population-based study presents the most recently available estimates on primary bone cancers in China, revealing that the males are 1.34 times as much as females suffering from primary bone cancers and the adolescents in puberty and the elderly are predominantly affected groups by these cancers. High-quality cancer registration data are a prerequisite for undertaking further study for gaining insight into the causes and risk factors for primary bone cancers in China.
文摘Objective: The aim of our study was to assess bone cancer mortality and the related social factors in Inner Mongolia in China. Methods: We obtained data from the Centers for Disease Control in Inner Mongolia from five monitoring points of the Death Registry System in Inner Mongolia from 2008 to 2012. We calculated the crude mortality rate for bone cancer. The χ2 test was used to examine differences in bone cancer mortality rates between sexes and years. Unconditional logistic regressions were applied to analyze the effect of socio-demographic characteristics by sex. Results: Between 2008 and 2012, the crude mortality rate of bone cancer was 1.12/100000 (95% confidence interval = 1.02-1.21). The bone cancer mortality was 2.24 in men and 1.25 in women, resulting in a male-female ratio of 1.8. No between-year difference in the mortality rate was observed between 2008 and 2012 (men: χ2 = 4.65, P = 0.325;women: χ2 = 2.21, P = 0.698). In general, mortality increased with increasing age. People with a lower education level exhibited an increased risk of bone cancer among both men and women. Jobs involving extensive manual labor decreased the likelihood of bone cancer mortality, and the odds ratio was higher for men than women (0.6 vs. 0.45). Unmarried people had a higher risk for bone cancer than married people. Conclusion: The mortality rate of bone cancer was not significantly different between men and women from 2008 to 2012. The risk of bone cancer increased with age among both sexes. Unmarried people and those with a low education status had an elevated risk of bone cancer, whereas employment in a field involving extensive manual labor appeared to be a protective factor against bone cancer.
文摘Objectives: To report an epidemiology study and prognosis for metastatic bone tumor. Methodology: It was a descriptive, transversal study on records of patients hospitalized in Rheumatology and Oncology-Radiotherapy departments of the University Teaching Hospital of Brazzaville, Congo from 1 January 2005 to 31 July 2011 (7 years and 6 months). The diagnosis of bone metastasis was made because of the existence of bone pain, or pathological fracture, or bone swelling and a bone-condensing or mixed or osteolytic radiological image. The anatomo-pathological evidence was made after biopsy of the bone lesion or primary cancer. 3687 patients were hospitalized for active cancer, among them 81 had documented bone metastasis. Results: There were 60 men (74.1%) and 21 women (25.9%) with a sex ratio of 2.85. The average age was 53 years, ranging from 3 to 80 years. 75% of patients were more or equal to 50 years old at the discovery of the bone metastasis. Bone pain was the main mode of discovery (67.9% of cases). However, in 6.2% of cases, it was discovered incidentally. The metastasis was bone condensing in 50.7% of cases, osteolytic in 40.7% and mixed in 8.6%. They were unifocal in 25.9% and multifocal in 74.1% of cases. The Primary cancer most frequently found was that of the prostate in 55.6% of cases, breast in 20.7% and rhabdomyosarcoma in 4.9%. In 6.2% of cases, the primary site of cancer was unknown. The average survival was 25 months. Conclusion: The clinical and radiological presentation remains classic. Cancer of the prostate and breast are the main neoplasia responsible for bone metastasis in our series. The discovery of metastasis remains a major evolutionary step of cancer.
文摘Objectives: To determine the epidemiological, clinical and paraclinical profile of bone metastases cancer. Patients and Methods: It was a retrospective study performed on a series of cases, admitted in Rheumatology department of the University Teaching Hospital of Lomé, Togo from October 1989 to December 2008. The diagnosis of bone metastasis was made because of the existence of inflammatory bone pain, or pathological fracture, or bone swelling and a bone condensing or mixed or osteolytic radiological image. The anatomopathological evidence was made after biopsy of the bone lesion or primary cancer. 2018 patients were hospitalized in rheumatology, and among them 77 had documented bone metastasis. Results: There were 53 men (68.8%) and 24 women (31.2%) with a sex ratio of 2.2. The mean age was 56.6 ± 12.6 years, ranging from 21 to 82 years. The primary cancer most frequently found was that of the prostate, representing 57.1% of bone metastasis and breast in 15.6%. The main manifestations of patients with bone metastases were inflammatory bone pain (76.6%) and alteration of general condition (75.3%). The spine was the main area of pain (64.9%). The metastasis was bone condensing in 48.1% of cases, osteolytic in 40.3% and mixed in 11.6%. The average survival was 22 months. Conclusion: The clinical and radiological presentation remains classic. Cancer of the prostate and breast are the main neoplasia responsible for bone metastasis in our series. The diagnosis of the primary tumor is often made at the stage of metastasis in black Africa.
基金General Program of National Natural Science Foundation of China(No.81873283)Special Project of"Ten Diseases and Ten Drugs"of Beijing Municipal Commission of Science and Technology(No.z171100001717017)。
文摘Objective:To study the effects of Yishen Qutong granula on pain sensitization and bone destruction of rats with bone cancer pain.Methods:Walker256 cells were passaged in ascites and injected into the tibia of female Wistar rats to prepare the bone cancer pain model.On the 14th day after model establishment,60 rats were randomly divided into model group,sham-operated group,Yishen Qutong granula low,middle,high dose group and tramadol hydrochloride positive control group.After continuous administration for 14 days,the mechanical pain threshold,thermal threshold and weight-bearing difference of both hind limbs were observed.Results:Compared with the model group,Yishen Qutong groups increased the mechanical pain threshold,thermal pain threshold and reduced the weight difference of both hind limbs(P<0.05).Compared with the positive drug group,there was no significant difference in increasing the mechanical pain threshold and thermal pain threshold of rats in the medium dose group of Yishen Qutong(P>0.05),and Yishen Qutong granula significantly reduced the weight-bearing difference of hind limbs in all groups(P<0.05).Conclusion:Yishen Qutong granula can relieve pain sensitization and alleviate bone damage in rats with bone cancer pain.
文摘Objectives:Photodynamic therapy(PDT)is a minimally invasive method used in the treatment of various cancers and skin diseases,but it is not widely used in bone cancer,where the current therapy is often not effective and accompanied by side effects.Alternative and more effective therapies like PDT are needed.In this in-vitro study,the effect of the photosensitizer(PS)chlorin e6(Ce6)on cancerous bone tumor cells using PDT was examined.Methods:A total of 27 tissue specimens from patients with primary bone cancers or bone metastases of different origins were genetically characterized and treated with PDT.Following a 24-h incubation,cell viability was determined,and the effect of PDT on cell migration was analyzed over 48 h.Results:We could demonstrate that the effect on proliferation of PDT in combination with the PS Ce6 was best in cells isolated from primary osteosarcoma and in bone metastases from mammary carcinomas.Besides proliferation,PDT was also effective in inhibiting the migration of these cells.A statistically significant correlation between the PDT effect and CD164 gene expression was detected,indicating that a high expression of this gene could result in a higher effectiveness of the photodynamic treatment.Conclusion:This study analyzes for the first time the effect of PDT in bone cancers and metastases and shows the potential of treating these cancer types with Ce6 PDT.
基金supported by the National Natural Science Foundation of China(No.82360238,82071245)。
文摘Cancer pain is one of the most prevalent and debilitating symptoms in patients with advanced malignancies,arising from multifactorial mechanisms involving peripheral,central,and systemic pathways.Conventional analgesics,including opioids and nonsteroidal anti-inflammatory drugs,are often limited by their insufficient efficacy,tolerance,and risk of dependence.Traditional Chinese Medicine(TCM),characterized by its multi-component,multi-target,and systemic regulatory properties,has shown promising potential in cancer pain management.This review provides a comprehensive overview of the clinical classification and underlying mechanisms of cancer pain(including nerve infiltration,dysregulation of inflammatory mediators and ion channels,central sensitization,neuro-immune crosstalk,metabolic reprogramming,and gut-brain axis impairment),as well as the analgesic effects of representative TCM agents in cancer pain management.For example,bioactive components such as tetrahydroberberine,levo-tetrahydropalmatine,and piperine exert analgesic effects,thereby improving the quality of life of patients by inhibiting inflammatory cascades,regulating neurotransmitter systems,and preserving neural integrity.Commonly used preclinical models,including bone cancer pain,pancreatic cancer pain,and chemotherapy-induced peripheral neuropathy models,are summarized for their utility in mechanistic studies and efficacy evaluations.This review also discusses the current limitations of clinical evidence,such as small sample sizes,short follow-up periods,and limited translation from animal models,alongside major challenges in standardization,mechanistic elucidation,and clinical trial design.Future directions should focus on precise pain phenotyping,integrated multi-target interventions,rigorous efficacy safety validation,and innovations in drug delivery to facilitate the standardization and global adoption of TCM in cancer pain management.
基金supported by the Natural Science Foundation of China(Grant Nos.82073934,81872937)Office of Jiangsu Provincial Academic Degrees Committee(Grant No.JX10114120).
文摘Bone metastasis is the primary cause of mortality in breast cancer(BC)patients.The present study elucidates the functional role of the differentiated embryonic chondrocyte-expressed gene 1(DEC1)in promoting BC-related bone metastasis.Analysis of patient-derived samples and public databases revealed a significant upregulation of DEC1 and CXCR4 in breast tumors compared with adjacent normal tissues,with elevated levels correlating with increased metastatic potential,suggesting their synergistic involvement in BC progression.Intracardiac injection experiments demonstrated that Dec1-WT 4T1 cells induced more severe osteolysis and larger metastatic lesions than Dec1-KD 4T1 cells.In MDA-MB-231 cells,DEC1 overexpression(OE)upregulated CXCR4 and proliferation/migration-related genes,whereas DEC1 knockdown reversed these effects.Notably,AMD3100,a specific CXCR4 antagonist,partially reversed the DEC1-OE-induced upregulation of CXCR4 and associated pro-metastatic genes.Mechanistically,DEC1 bound to the CXCR4 promoter region(-230 to-326)and activated its transcription,corroborated by ChIP-seq data.Furthermore,pharmacological inhibition of AKT(LY294002)or JAK2(AZD1480),but not ERK(PD98059),attenuated DEC1-mediated CXCR4 upregulation,although all three inhibitors mitigated DEC1-driven migration-related gene expression.Additionally,DEC1 enhanced CXCL12 secretion from mesenchymal stromal cells and osteoblasts,amplifying the CXCR4/CXCL12 axis within the bone microenvironment.Collectively,our findings demonstrate that DEC1 promotes BC bone metastasis by directly transactivating CXCR4 expression,providing a molecular basis for targeting DEC1 to prevent and treat BC bone metastasis.
基金National Natural Science Foundation of China:Study on the Scientific Connotation of Traditional Chinese Medicine"Conghua Theory"by Regulating Metastatic Site-specific Polarization of Macrophages in Breast Cancer Lung and Bone Metastases(No.81774308)National Natural Science Foundation of China:Study on the Pharmacodynamic Substances and Mechanism of Wenshen Zhuanggu Recipe Regulating Exocrine Integrin/Sarcoma/Mitogenactivated protein kinase Signal Axis in Intervention of Bone Metastasis Niche Formation in Breast Cancer(No.82174016)。
文摘OBJECTIVE:To explore the mechanism of Wenshen Zhuanggu Fang(温肾壮骨方,WSZG)against breast cancer bone metastasis from the perspective of macrophage polarization through bioinformatics and experiments.METHODS:Bioinformatics study was used to explore the mechanism underlying the effect of WSZG on breast cancer bone metastasis.Cell viability,migration,invasion and apoptosis assays were performed to detect the influence of WSZG on breast cancer cell MDA-MB-231BO promoted by macrophages.The protein expression level and cytokine content were detected by western blot and enzyme-linked immunosorbent assay kit in vitro.Tumor growth in vivo were performed to evaluate the effects of WSZG on breast cancer bone metastasis.M2/M1 ratio and the maker protein expression were detected by flow cytometry analysis,immunohistochemistry and immunofluorescence double staining.RESULTS:M2 macrophages associated with poor prognosis and may lead to secondary bone metastasis in patients with triple-negative breast cancer.WSZG could treat breast cancer bone metastasis through regulating macrophage polarization by signal transducers and transcription signaling activators(STAT)signaling pathway.WSZG downregulated STAT6,CD206 and Arginase-1,while upregulated STAT1 and Inducible Nitric Oxide Synthase,thus inhibited the M2 macrophagepromoted invasion and migration capabilities of MDA-MB-231BO cells.WSZG treatment suppressed the bone metastasis of breast cancer,and the M2/M1 ratio was reduced by regulating STAT expression in bone metastatic tissue.CONCLUSION:WSZG inhibited breast cancer bone metastasis by adjusting the promoting effect of macrophages on MDA-MB-231BO breast cancer cells and decreasing M2 polarization by downregulating STAT signaling.
基金supported by the National Institutes of Health(Grants P30 CA036727 and R01 CA258621)and funding from the University of Nebraska Medical Center Graduate Studies Assistantship.
文摘The unfolded protein response pathway is an evolutionarily conserved cytoprotective signaling cascade,essential for cell function and survival.Unfolded protein response signaling is tightly integrated with bone cell differentiation and function,and chronic unfolded protein response activation has been identified in bone disease.The unfolded protein response has been found to promote oncogenesis and drug resistance,raising the possibility that unfolded protein response modulators may have activity as anti-cancer agents.Cancer-associated bone disease remains a major cause of morbidity for patients with multiple myeloma or bone-metastatic disease.Understanding the critical role of unfolded protein response signaling in cancer development and metastasis,as well as its role in bone homeostasis,may lead to novel mechanisms by which to target cancer-associated bone disease.In this review,we summarize the current research delineating the roles of the unfolded protein response in bone biology and pathophysiology,and furthermore,review unfolded protein response modulating agents in the contexts of cancer and cancer-associated bone disease.
基金supported by National Natural Science Foundation of China(31930042 and 82021002)STI 2030-Major Projects(2021ZD0203200-5,China)and by funds from the innovative research team of high-level local universities in Shanghai,Shanghai Municipal Science and Technology Major Project(No.2018SHZDZX01,China),ZJLab and Shanghai Center for Brain Science and Brain-Inspired Technology.
文摘Spinal microglia and astrocytes are both involved in neuropathic and inflammatory pain,which may display sexual dimorphism.Here,we demonstrate that the sustained activation of spinal astrocytes and astrocyte-derived interleukin(IL)-17A promotes the progression of mouse bone cancer pain without sex differences.Chemogenetic or pharmacological inhibition of spinal astrocytes effectively ameliorates bone cancer-induced pain-like behaviors.In contrast,chemogenetic or optogenetic activation of spinal astrocytes triggers pain hypersensitivity,implying that bone cancer-induced astrocytic activation is involved in the development of bone cancer pain.IL-17A expression predominantly in spinal astro-cytes,whereas its receptor IL-17 receptor A(IL-17RA)was mainly detected in neurons expressing VGLUT2 and PAX2,and a few in astrocytes expressing GFAP.Specific knockdown of IL-17A in spinal astrocytes blocked and delayed the development of bone cancer pain.IL-17A overexpression in spinal astrocytes directly induced thermal hyperalgesia and mechanical allodynia,which could be rescued by CaMKIIa inhibitor.Moreover,selective knockdown IL-17RA in spinal Vglut2^(+)or Vgat^(+)neurons,but not in astrocytes,significantly blocked the bone cancer-induced hyperalgesia.Together,our findings pro-vide evidence for the crucial role of sex-independent astrocytic signaling in bone cancer pain.Targeting spinal astrocytes and IL-17A/IL-17RA-CaMKIIa signaling may offer new gender-inclusive therapeutic strategies for managing bone cancer pain.
基金support from Progetto MIUR PRIN2017-ACTION,Grant No.2017SZ5WZB and POR Campania FESR 2014-2020(Campania imaging Infrastructure for Research in Oncology-C.I.R.O)The authors also thank Maria Rosaria Bonetti for lab technical support,Cristina Del Barone for facilitating microscopy analysis,Dr.Antonio Pennetta for ICP analysis and Dr.Roberta Marzella for support to project management.CISUP(Centre for Instrument Sharing-University of Pisa)and the EUroBioImaging(EUBI)Facility at CNR(Naples)are acknowledged for the use of the Bruker Avance NEO 500 Solid State NMR spectrometer and of AxioVision microscope(Carl Zeiss Micro Imaging GmbH),respectively.
文摘Recently,the term theragenerative has been proposed for biomaterials capable of inducing therapeutic approaches followed by repairing/regenerating the tissue/organ.This study is focused on the design of a new theragenerative nanocomposite composed of an amphiphilic non-ionic surfactant(Pluronic F127),bioactive glass(BG),and black phosphorus(BP).The nanocomposite was prepared through a two-step synthetic strategy,including a microwave treatment that turned BP nanosheets(BPNS)into quantum dots(BPQDs)with 5±2 nm dimensions in situ.The effects of surfactant and microwave treatment were assessed in vitro:the surfactant distributes the ions homogenously throughout the composite and the microwave treatment chemically stabilizes the composite.The presence of BP enhanced bioactivity and promoted calcium phosphate formation in simulated body fluid.The inherent anticancer activity of BP-containing nanocomposites was tested against osteosarcoma cells in vitro,finding that 150μg mL^(-1)was the lowest concentration which prevented the proliferation of SAOS-2 cells,while the counterpart without BP did not affect the cell growth rate.Moreover,the apoptosis pathways were evaluated and a mechanism of action was proposed.NIR irradiation was applied to induce further proliferation suppression on SAOS-2 cells through hyperthermia.The inhibitory effects of bare BP nanomaterials and nanocomposites on the migration and invasion of bone cancer,breast cancer,and prostate cancer cells were assessed in vitro to determine the anticancer potential of nanomaterials against primary and secondary bone cancers.The regenerative behavior of the nanocomposites was tested with healthy osteoblasts and human mesenchymal stem cells;the BPQDs-incorporated nanocomposite significantly promoted the proliferation of osteoblast cells and induced the osteogenic differentiation of stem cells.This study introduces a new multifunctional theragenerative platform with promising potential for simultaneous bone cancer therapy and regeneration.
文摘Aim:Peripheral cytokines contribute to arthritis and bone cancer pain through sensory nerve actions.However,increased spinal cytokine and glial filament expression,coined neuroinflammation,has also been proposed to play a part in chronic pain.Therefore,spinal cord,dorsal root ganglia and circulating cytokines were compared in murine arthritis and bone cancer models in relationship to behavioral signs of pain.Methods:Exploratory behaviors were studied after intra-articular complete Freund’s adjuvant or bone intramedullary sarcoma cell injection.Nervous tissue and blood cytokine expression were determined by real-time polymerase chain reaction(PCR)and multiplex immunoassays,respectively.Results:PCR analysis did not reveal any hallmark of spinal neuroinflammation in spontaneously-behaving mice with cartilage or bone lesions.However,imposed paw stimulation during joint inflammation increased spinal interleukin-1β(IL-1β)expression.Spontaneous paw guarding during rearing was displayed by animals with joint inflammation and bone destruction and was accompanied by increased circulating IL-6 and monocyte chemoattractant protein-1,respectively.In addition,dorsal root ganglia were found to constitutively express receptors for this chemotactic cytokine.Conclusion:Our findings indicate that spinal neuroinflammation is not a necessary condition for chronic pain and suggest that circulating cytokine action in dorsal root ganglia may contribute to experimental joint inflammation and bone cancer pain.
