Molecular mechanisms and clinical management of cancer bone metastasis

As one of the most common metastatic sites of malignancies,bone has a unique microenvironment that allows metastatic tumor cells to grow and flourish.The fenestrated capillaries in the bone,bone matrix,and bone cells,including osteoblasts and osteoclasts,together maintain the homeostasis of the bone microenvironment.In contrast,tumor-derived factors act on bone components,leading to subsequent bone resorption or excessive bone formation.The various pathways involved also provide multiple targets for therapeutic strategies against bone metastases.In this review,we summarize the current understanding of the mechanism of bone metastases.Based on the general process of bone metastases,we specifically highlight the complex crosstalk between tumor cells and the bone microenvironment and the current management of cancer bone metastases.

Colony-stimulating factor-1 receptor inhibition combined with paclitaxel exerts effective antitumor effects in the treatment of ovarian cancer

Ovarian cancer is the tumor with the highest mortality among gynecological malig-nancies.Studies have confirmed that paclitaxel chemoresistance is associated with increased infiltration of tumor-associated macrophages(TAMs)in the microenvironment.Colony-stimu-lating factor 1(CSF-1)receptor(CSF-1R)plays a key role in regulating the number and differ-entiation of macrophages in certain solid tumors.There are few reports on the effects of targeted inhibition of CSF-1R in combination with chemotherapy on ovarian cancer and the tu-mor microenvironment.Here,we explored the antitumor efficacy and possible mechanisms of the CSF-1R inhibitor pexidartinib(PLX3397)when combined with the first-line chemothera-peutic agent paclitaxel in the treatment of ovarian cancer.We found that CSF-1R is highly ex-pressed in ovarian cancer cells and correlates with poor prognosis.Treatment by PLX3397 in combination with paclitaxel significantly inhibited the growth of ovarian cancer both in vitro and in vivo.Blockade of CSF-1R altered the macrophage phenotype and reprogrammed the immunosuppressive cell population in the tumor microenvironment.

Ammonia promotes the proliferation of bone marrow-derived mesenchymal stem cells by regulating the Akt/mTOR/S6k pathway

Ammonia plays an important role in cellular metabolism.However,ammonia is considered a toxic product.In bone marrow-derived mesenchymal stem cells,multipotent stem cells with high expression of glutamine synthetase(GS)in bone marrow,ammonia and glutamate can be converted to glutamine via glutamine synthetase activity to support the proliferation of MSCs.As a major nutritional amino acid for biosynthesis,glutamine can activate the Akt/mTOR/S6k pathway to stimulate cell proliferation.The activation of mTOR can promote cell entry into S phase,thereby enhancing DNA synthesis and cell proliferation.Our studies demonstrated that mesenchymal stem cells can convert the toxic waste product ammonia into nutritional glutamine via GS activity.Then,the Akt/mTOR/S6k pathway is activated to promote bone marrow-derived mesenchymal stem cell proliferation.These results suggest a new therapeutic strategy and potential target for the treatment of diseases involving hyperammonemia.

Targeting RAS-RAF-MEK-ERK signaling pathway in human cancer:Current status in clinical trials

Molecular target inhibitors have been regularly approved by Food and Drug Administration(FDA)for tumor treatment,and most of them intervene in tumor cell proliferation and metabolism.The RAS-RAF-MEK-ERK pathway is a conserved signaling pathway that plays vital roles in cell proliferation,survival,and differentiation.The aberrant activation of the RAS-RAF-MEK-ERK signaling pathway induces tumors.About 33%of tumors harbor RAS mutations,while 8%of tumors are driven by RAF mutations.Great efforts have been dedicated to targeting the signaling pathway for cancer treatment in the past decades.In this review,we summarized the development of inhibitors targeting the RAS-RAF-MEK-ERK pathway with an emphasis on those used in clinical treatment.Moreover,we discussed the potential combinations of inhibitors that target the RAS-RAF-MEK-ERK signaling pathway and other signaling pathways.The inhibitors targeting the RAS-RAF-MEK-ERK pathway have essentially modified the therapeutic strategy against various cancers and deserve more attention in the current cancerresearchandtreatment.

Nanovaccines for cancer immunotherapy:Current knowledge and future perspectives

Cancer immunotherapy harnesses the immune system to attack tumors and has received extensive attention in recent years.Cancer vaccines as an important branch of immunotherapy are designed for delivering tumor antigens to antigen-presenting cells(APCs)to stimulate a strong immune response to against tumors,representing a potentially therapeutic and prophylactic effect with the long-term anticancer benefits.Nevertheless,the disappointing outcomes of their clinical use might be attributed to dilemma in antigen selection,immunogenicity,lymph nodes(LNs)targeting ability,lysosomal escape ability,immune evasion,etc.Nanotechnology,aiming to overcome these barriers,has been utilized in cancer vaccine development for decades.Numerous preclinical and clinical studies demonstrate positive results in nanomaterials-based cancer vaccines with considerable improvement in the vaccine efficacy.In this review,we systematically introduced the characteristics of nanovaccines and highlighted the different types of nanomaterials used for cancer vaccine design.In addition,the opportunities and challenges of the emerging nanotechnology-based cancer vaccines were discussed.

Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials

Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,notably cancer.With the development of various drugs targeting epigenetic regulators,epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials.In this review,we summarize the aberrant functions of enzymes in DNA methylation,histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.

Biomaterial-assisted biotherapy:A brief review of biomaterials used in drug delivery,vaccine development,gene therapy,and stem cell therapy

Biotherapy has recently become a hotspot research topic with encouraging prospects in various fields due to a wide range of treatments applications,as demonstrated in preclinical and clinical studies.However,the broad applications of biotherapy have been limited by critical challenges,including the lack of safe and efficient de-livery systems and serious side effects.Due to the unique potentials of biomaterials,such as good biocompati-bility and bioactive properties,biomaterial-assisted biotherapy has been demonstrated to be an attractive strategy.The biomaterial-based delivery systems possess sufficient packaging capacity and versatile functions,enabling a sustained and localized release of drugs at the target sites.Furthermore,the biomaterials can provide a niche with specific extracellular conditions for the proliferation,differentiation,attachment,and migration of stem cells,leading to tissue regeneration.In this review,the state-of-the-art studies on the applications of bio-materials in biotherapy,including drug delivery,vaccine development,gene therapy,and stem cell therapy,have been summarized.The challenges and an outlook of biomaterial-assisted biotherapies have also been discussed.

Applications of genome editing technology in the targeted therapy of human diseases:mechanisms,advances and prospects

Based on engineered or bacterial nucleases,the development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all eukaryotic cells.Genome editing has extended our ability to elucidate the contribution of genetics to disease by promoting the creation of more accurate cellular and animal models of pathological processes and has begun to show extraordinary potential in a variety of fields,ranging from basic research to applied biotechnology and biomedical research.Recent progress in developing programmable nucleases,such as zinc-finger nucleases(ZFNs),transcription activator-like effector nucleases(TALENs)and clustered regularly interspaced short palindromic repeat(CRISPR)–Cas-associated nucleases,has greatly expedited the progress of gene editing from concept to clinical practice.Here,we review recent advances of the three major genome editing technologies(ZFNs,TALENs,and CRISPR/Cas9)and discuss the applications of their derivative reagents as gene editing tools in various human diseases and potential future therapies,focusing on eukaryotic cells and animal models.Finally,we provide an overview of the clinical trials applying genome editing platforms for disease treatment and some of the challenges in the implementation of this technology.

The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis

Necrosis,a type of unwanted and passive cell demise,usually occurs under the excessive external stress and is considered to be unregulated.However,under some special conditions such as caspase inhibition,necrosis is regulable in a well-orchestrated way.The term'regulated necrosis'has been proposed to describe such programed necrosis.Recently,several forms of necrosis,including necroptosis,pyroptosis,ferroptosis,parthanatos,oxytosis,NETosis,and Na^(+)/K^(+)ATPasimediated necrosis,have been identified,and some crucial regulators governing regulated necrosis have also been discovered.Mixed lineage kinase domain-like pseudokinase(MLKL),a core regulator in necroptosis,acts as an executioner in response to ligands of death receptor family.Its activation requires the receptor-interacting protein kinases,RIP1 and RIP3.However,MLKL is only involved in necroptosis,i.e.MLKL is dispensable for necrosis.Therefore,this review is aimed at summarizing the molecular mechanisms of MLKLdependent and MLKL-independent necrosis.

A new and promising application of gene editing: CRISPR-controlled smart materials for tissue engineering,bioelectronics, and diagnostics

A recent study published in the journal Science by Collins et al.proposed a programmable clustered regularly interspaced short palindromic repeats(CRISPR)-responsive smart material containing the CRISPR-associated nuclease,Casl2a,and hydrogels containing DNA to deliver biological information via changes in material properties(English et al.,2019).

Neurological complications and infection mechanism of SARS-CoV-2

Currently,SARS-CoV-2 has caused a global pandemic and threatened many lives.Although SARS-CoV-2 mainly causes respiratory diseases,growing data indicate that SARS-CoV-2 can also invade the central nervous system(CNS)and peripheral nervous system(PNS)causing multiple neurological diseases,such as encephalitis,encephalopathy,Guillain-Barrésyndrome,meningitis,and skeletal muscular symptoms.Despite the increasing incidences of clinical neurological complications of SARS-CoV-2,the precise neuroinvasion mechanisms of SARS-CoV-2 have not been fully established.In this review,we primarily describe the clinical neurological complications associated with SARS-CoV-2 and discuss the potential mechanisms through which SARS-CoV-2 invades the brain based on the current evidence.Finally,we summarize the experimental models were used to study SARS-CoV-2 neuroinvasion.These data form the basis for studies on the significance of SARS-CoV-2 infection in the brain.

Targeting folate receptorβpositive tumor-associated macrophages in lung cancer with a folate-modified liposomal complex

Tumor-associated macrophages(TAMs)facilitate cancer progression by promoting tumor invasion,angiogenesis,metastasis,inflammatory responses,and immunosuppression.Folate receptorβ(FRβ)is overexpressed in TAMs.However,the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood.In this study,we verified that FRβoverexpression in lung cancer TAMs was associated with poor prognosis.We utilized a folate-modified lipoplex comprising a folatemodified liposome(F-PLP)delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment.Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis.Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth.Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis,reducing tumor proliferation,and inhibiting tumor angiogenesis.In addition,a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously.This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.

Oxidized mitochondrial DNA sensing by STING signaling promotes the antitumor effect of an irradiated immunogenic cancer cell vaccine

Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Cell deaths:Involvement in the pathogenesis and intervention therapy of COVID-19

The current pandemic of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2)infection has dramatically influenced various aspects of the world.It is urgent to thoroughly study pathology and underlying mechanisms for developing effective strategies to prevent and treat this threatening disease.It is universally acknowledged that cell death and cell autophagy are essential and crucial to maintaining host homeostasis and participating in disease pathogenesis.At present,more than twenty different types of cell death have been discovered,some parts of which have been fully understood,whereas some of which need more investigation.Increasing studies have indicated that cell death and cell autophagy caused by coronavirus might play an important role in virus infection and pathogenicity.However,the knowledge of the interactions and related mechanisms of SARS-CoV-2 between cell death and cell autophagy lacks systematic elucidation.Therefore,in this review,we comprehensively delineate how SARS-CoV-2 manipulates diverse cell death(including apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis)and cell autophagy for itself benefits,which is simultaneously involved in the occurrence and progression of COVID-19,aiming to provide a reasonable basis for the existing interventions and further development of novel therapies.

Vaccine adjuvants:mechanisms and platforms

Adjuvants are indispensable components of vaccines.Despite being widely used in vaccines,their action mechanisms are not yet clear.With a greater understanding of the mechanisms by which the innate immune response controls the antigen-specific response,the adjuvants’action mechanisms are beginning to be elucidated.Adjuvants can be categorized as immunostimulants and delivery systems.Immunostimulants are danger signal molecules that lead to the maturation and activation of antigenpresenting cells(APCs)by targeting Toll-like receptors(TLRs)and other pattern recognition receptors(PRRs)to promote the production of antigen signals and co-stimulatory signals,which in turn enhance the adaptive immune responses.On the other hand,delivery systems are carrier materials that facilitate antigen presentation by prolonging the bioavailability of the loaded antigens,as well as targeting antigens to lymph nodes or APCs.The adjuvants’action mechanisms are systematically summarized at the beginning of this review.This is followed by an introduction of the mechanisms,properties,and progress of classical vaccine adjuvants.Furthermore,since some of the adjuvants under investigation exhibit greater immune activation potency than classical adjuvants,which could compensate for the deficiencies of classical adjuvants,a summary of the adjuvant platforms under investigation is subsequently presented.Notably,we highlight the different action mechanisms and immunological properties of these adjuvant platforms,which will provide a wide range of options for the rational design of different vaccines.On this basis,this review points out the development prospects of vaccine adjuvants and the problems that should be paid attention to in the future.

SARS-CoV-2 variants,immune escape,COVID-19 vaccine,and therapeutic strategies

The global pandemic of coronavirus disease 2019(COVID-19) caused by severe acute respiratory syndrome coronavirus2(SARS-CoV-2) has brought considerable challenges to worldwide public health and the economy. Over 535 million confirmed cases and 6.3 million deaths of COVID-19 were reported as of June 17, 2022(https://covid19.who.int/).

Low levels of neutralizing antibodies against XBB Omicron subvariants after BA.5 infection

The COVID-19 response strategies in Chinese mainland were recently adjusted due to the reduced pathogenicity and enhanced infectivity of Omicron subvariants.In Chengdu,China,an infection wave was predominantly induced by the BA.5 subvariant.It is crucial to determine whether the hybrid anti-SARS-CoV-2 immunity following BA.5 infection.

CCL5/CCR5 axis in human diseases and related treatments

To defense harmful stimuli or maintain the immune homeostasis, the body produces and recruits a superfamily of cytokines such as interleukins, interferons, chemokines etc. Among them, chemokines act as crucial regulators in defense systems. CCL5/CCR5 combination is known for facilitating inflammatory responses, as well as inducing the adhesion and migration of different T cell subsets in immune responses. In addition, recent studies have shown that the interaction between CCL5 and CCR5 is involved in various pathological processes including inflammation, chronic diseases, cancers as well as the infection of COVID-19. This review focuses on how CCL5/CCR5 axis participates in the pathological processes of different diseases and their relevant signaling pathways for the regulation of the axis. Moreover, we highlighted the gene therapy and chemotherapy studies for treating CCR5-related diseases, including the ongoing clinical trials. The barriers and perspectives for future application and translational research were also summarized.

Epigenetic regulation of macrophages: from homeostasis maintenance to host defense

Macrophages are crucial members of the innate immune response and important regulators.The differentiation and activation of macrophages require the timely regulation of gene expression,which depends on the interaction of a variety of factors,including transcription factors and epigenetic modifications.Epigenetic changes also give macrophages the ability to switch rapidly between cellular programs,indicating the ability of epigenetic mechanisms to affect phenotype plasticity.In this review,we focus on key epigenetic events associated with macrophage fate,highlighting events related to the maintenance of tissue homeostasis,responses to different stimuli and the formation of innate immune memory.Further understanding of the epigenetic regulation of macrophages will be helpful for maintaining tissue integrity,preventing chronic inflammatory diseases and developing therapies to enhance host defense.