The central nervous system (CNS) is the most important section of the nervous system as it regulates the function of various organs. Injury to the CNS causes impairment of neurological functions in corresponding sites and further leads to long-term patient disability. CNS regeneration is difficult because of its poor response to treatment and, to date, no effective therapies have been found to rectify CNS injuries. Biomaterial scaffolds have been applied with promising results in regeneration medicine. They also show great potential in CNS regeneration for tissue repair and functional recovery. Biomaterial scaffolds are applied in CNS regeneration predominantly as hydrogels and biodegradable scaffolds. They can act as cellular supportive scaffolds to facilitate cell infiltration and proliferation. They can also be combined with cell therapy to repair CNS injury. This review discusses the categories and progression of the biomaterial scaffolds that are applied in CNS regeneration. The central nervous system (CNS), which comprises the brain and spinal cord, is the most important and complex part of the nervous system. Two of the most common causes of injury to the CNS are trauma  and hemoα) secreted by inflammatory cells can also aggravate local inflammatory reactions [Pathologically, CNS injury can directly result in the death of parenchymal cells in damaged tissue . CNS injeactions , 19. Theeactions , 16. Fureactions , 20, 21.Recovery from CNS injury requires rescuing of the surviving cells and axons, repairing damaged tissue, regeneration of severed axons, reconstruction of the connection between the nervous process and soma, and rehabilitation of the impaired neural functions. In recent years, with developments in stem cell biology, cell therapies have been introduced into CNS regeneration , 23. NumBiomaterial scaffolds have been studied in tissue regeneration for decades. They have been utilized for regeneration of soft tissue, cartilage, bone, and the peripheral nerve system (PNS) with favorable results –32. BiomBiomaterial scaffolds are used in effort to provide specific microenvironmental cues in 3D controlled fashion to enhance cell survival, infiltration, and differentiation. Since the revelation by David and Aguayo  of the sBiomaterial scaffolds that serve as temporary ECM provide a niche for cell infiltration and differentiation. They not only support the surrounding neural tissue but also act as a substrate for cell growth, neurite formation, and axon regeneration. They can also carry bioactive molecules that can create a relatively stable, permeable, and nutritious environment for regeneration –48. MoreBased on required structure and physical and biological properties of prospective tissue construct applied in CNS injury, the biomaterial scaffolds utilized in CNS regeneration can be further classified into hydrogels and biodegradable scaffolds. In this section, we introduce the categories of hydrogels and biodegradable scaffolds utilized in CNS regeneration. in vitro and in vivo [Hydrogels are an attractive scaffold substrata owing to their high water content and porous inner structure, which makes them soft and flexible and minimizes tissue damage –53. Thei in vivo –56.Hydrogels can be classified into polymeric covalently cross-linked hydrogels and self-assembled hydrogels according to the forming mechanism , 51. In Hydrogel forming polymeric materials are classified as either natural materials or synthetic materials . Naturalβ sheet structures when dissolved in water [Ethyleneglycol monomethacrylate (HEMA) and ethylene dimethacrylate (EDMA) are the first materials reportedly used to synthesize polymeric covalently cross-linked hydrogels , 74. Nowin water , 80. Thein water . Subsequin water –85. Thesin water –88. Peptin water , 90. MorBiodegradable scaffolds are biomaterials characterized by biodegradability and 3D inner architecture. Their 3D porous structures are fabricated through methods such as electrospinning, freeze-drying, microfluidic fabrication, water emulsion, thermoforming, and 3D printing –93. The ε-caprolactone (PCL) [co-glycolic acid (PLGA) [ε-caprolactone-co-ethyl ethylene phosphate (PCLEEP) are common copolymers that are utilized in nerve system regeneration [Biodegradable scaffolds can also be synthesized from natural materials or synthetic materials. The natural materials often used for this purpose include collagen , fibroinne (PCL) , poly L-ne (PCL) , 105. Hone (PCL) . To solvd (PLGA)  and polyneration . Synthetneration . For synneration , 94.Both hydrogels and biodegradable scaffold are important biomaterial scaffolds utilized in CNS regeneration. They can serve as temporary ECM to provide a niche for cell infiltration and differentiation. For future study, the choice of suitable materials for scaffold synthesis and techniques for fabricated 3D structure nontoxically should be important issues in scaffold synthesis. Besides in vivo interaction between the ECMs and scaffolds and the mechanisms of degradation still need further study.Spinal cord injury (SCI) is characterized by long-term paralysis and sensory disturbances. SCI patients often lose the ability to work and require lifelong care . Althoug2+ can hamper neurite formation and axon regrowth. To overcome this problem, McKay et al. [2+ composites. The developed hydrogels exhibited excellent ability to regulate astrocyte behavior and prevent Ca2+-related secondary neuron damage during acute SCI.Natural polymer-derived hydrogels were first applied to SCI in 1995, when Joosten et al. used collagen hydrogels in experimental SCI model. They compared two methods of collagen hydrogels preparation, as either a fluid or preformed solid gel, in a rat SCI model. Their results showed that even though both scaffolds can reduce the gliotic response, only fluid collagen gel can induce regeneration of damaged axons . Their sy et al.  developeHydrogels made from natural materials can also deliver specific antibodies or drugs to block receptors that impede regeneration after SCI. Nogo is a myelin-associated inhibitor (MAI) that can limit axon growth and benumb functional neuronal circuits. Wen et al. developed hyaluronic acid (HA) hydrogels that blend with the anti-Nogo receptor antibody (antiNgR). Hydrogels have also been combined with PLGA microspheres containing brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The hydrogels were implanted into the rat SCI model and, after a few weeks, angiogenesis and axons regrowth were observed in hydrogels; the implanted rats also exhibited improved locomotor recovery . These sSimilar to natural hydrogels, hydrogels made from synthetic materials for the treatment of SCI can mimic the extracellular matrix to provide an environment for cell proliferation and adhesion. Further, hydrogel networks can serve as scaffolds that support regeneration until the materials are ultimately absorbed by the host. Hydrogels made from synthetic materials are more adjustable than hydrogels made from natural materials, as their key parameters can be easily controlled through modification. Poly(hydroxyethyl methacrylate) (PHEMA) was one of the earliest biomaterials utilized for tissue engineering scaffolds as they alleviate inflammation and promote axon regeneration after SCI . SubsequHydrogels made from synthetic materials can also act as a carrier to deliver growth factor to lesions and enhance their reparative effect. Chen et al.  incorporAdjunction of functional sequence is also a common method used to modify hydrogels. RGD , IKVAV , and lamSAPs and PAs are important synthetic polymers for producing self-assembling hydrogels. The self-assembling hydrogels are injectable and facilitate clinical application. Gou et al.  were the in vitro and in vivo evidences demonstrate that with specific stimulation macrophages can polarize towards functionally divergent subsets. Historically, polarized macrophages have been classified as classical (M1) macrophages, which promote inflammation, or as alternatively activated (M2) macrophages, which restrict inflammation and foster wound repair. Outside the CNS, M1 macrophages are quite rapidly (after about 1 week) replaced by M2 macrophages that successively infiltrate the lesion, where they largely contribute first to tissue repair and then remodeling via release of anti-inflammatory cytokines, stimulation of proliferation of fibroblasts and endothelial cells (angiogenesis), and production of ECM [Neuroinflammation develops within hours after SCI and TBI and can persist for months to years . Delivern of ECM –134. Hown of ECM . Similarn of ECM , 137. Hyn of ECM  applied n of ECM  also foun of ECM . HoweverIn summary, hydrogels have great potential in the treatment of SCI. They have advantages such as excellent histological and functional recovery and the fact that they can be injected into lesions. The injectability of hydrogels minimizes the risk of secondary injury when hydrogels are administrated in SCI. They can also be modified by functional sequences or delivering growth factors. However, issues such as the need to enhance their mechanical strength, durability, and stability in application and balance between fluidity and mechanical strength need to be investigated in future studies. The exact mechanisms by which hydrogels interact with SCI also require further study.Biodegradable scaffolds are also important biomaterials that are utilized in SCI. They are often surgically implanted into lesions and are synthesized through electrospinning techniques to decrease the use of organic solvent. In the spinal cord, the axons often appear in a longitude arrangement, and the electrospinning technique can fabric materials into any desired pattern and mimic the arrangement of axons. Chitosan, gelatin, PCL, and PLGA are the scaffolds predominantly applied in SCI, as they have an effect on axon regeneration, are anti-inflammatory, and promote tissue repair . The effBiodegradable scaffolds can be incorporated with hydrogels to treat SCI . The goaSurface modification of scaffolds can enhance the effect of regeneration through promotion of cell adhesion to the scaffold. Zamani et al.  developeBiodegradable scaffolds are also utilized in SCI as they have good mechanical strength and tunable inner pattern and are biodegradable. However, the need for surgical implantation narrows their application in some clinical situations. In summary, biodegradable scaffolds as biomaterials that are applied in SCI have considerable potential. In future studies, the application of new materials, relationship of the inner pattern and SCI recovery, exploration of multicomponent scaffolds, and development of a mini-invasive implantation method may be the main problems explored in the development of biodegradable scaffolds.Traumatic brain injury (TBI), brain tumors, and brain hemorrhages are common causes of brain damage. In the USA, at least 5.3 million people suffered from disability after TBI, costing approximately $76.5 billion in lost productivity in 2010 . These dThe brain is protected by the cranial bone, which makes it difficult to inject materials into the brain directly. The materials applied in brain injury scenarios are often surgically implanted. Natural materials, such as hyaluronic acid (HA) , collageSeveral hydrogels made from synthetic materials have also been applied in brain regeneration. In general, such hydrogels are combined with cell therapy in brain injury treatment. Hydrogels made from synthetic materials are easier to chemically modify and have a 3D inner structure and low immune responses. PHPMA-RGD hydrogels containing brain-derived neurotrophic factors have been tested in a rat TBI model, with results showing the occurrence of axon regeneration and cell infiltration . Self-asBiodegradable scaffolds are used to carry cells in brain regeneration. Only a few studies have investigated the effect of bare biodegradable scaffolds in animal TBI models. In this section, we discuss research conducted on the materials associated with brain regeneration.The mechanisms of biodegradable scaffolds in promoting brain regeneration are mainly concentrated on their effects in enhancing support for microenvironments, guiding axon sprouting, and cell migration. PCL based scaffolds are the most studied scaffolds in brain regeneration. Nisbet et al. implanted electrospun PCL scaffolds into the caudate putamen of an adult rat brain and discovered neurite infiltration and growth in the scaffold . They stThe combination of biomaterial scaffolds and cell therapy in CNS regeneration has garnered the attention of researchers in recent years. The combination of these two therapeutic methods makes it possible to achieve both cell regeneration and tissue reconstruction. The basic principle of this modality is combining exogenous cell and scaffolds to form “live” scaffolds. These “live” scaffolds can be implanted into animals through injection or surgical implantation. The parenchyma part of CNS comprises neuron and glial cells that include astrocyte and oligodendrocyte. Neural stem/progenitor cells (NSPCs) are present in the adult CNS and are important in the maintenance and repair of CNS . NSPCs c in vivo. Further, they can carry growth factors or drugs to promote their effects in stem cell therapy. Mothe et al. developed a kind of hyaluronan and methyl cellulose (HAMC) hydrogels. They conjugated HAMC hydrogels with recombinant platelet-derived growth factor-A (rPDGF-A) to promote oligodendrocyte differentiation. The HAMC-rPDGF-A hydrogels were blended with adult brain-derived neural stem/progenitor cells (NSPCs), and the hydrogels were injected into a subacute, clinically relevant model of a rat SCI. They found that rats treated with HAMC-rPDGF-A hydrogels showed reduced lesion size, increased distribution of perilesional host neurons and oligodendrocytes, and better functional recovery [In the field of SCI treatment, both hydrogels and biodegradable scaffolds have been studied in various studies. Hydrogels have been proven to improve both cell proliferation and differentiationrecovery . An interecovery . This rerecovery .Biodegradable scaffolds have advantages in terms of mechanical property and biodegradability. Research on the application of biodegradable scaffolds in the treatment of SCI is concentrated on critical issues such as vitality of imbedded cells and whether they can differentiate into desired cell types. Terraf et al. utilized PCL scaffolds to carry human endometrial stem cells and applied them in a rat hemisected SCI model. According to their result, neurite outgrowth and axon regeneration can be observed and animals also showed functional recovery . The str in vivo through MRI imaging. They encapsulated human neural progenitor cells (iPS-NPCs) into the hydrogels and injected the hydrogels into a mice stroke model. Their results showed that hydrogels can promote survival of iPS-NPCs after transplantation into the stroke core. In addition, the hydrogels can also increase differentiation of transplanted cells [ in vivo [Application of biomaterial scaffolds as cell carriers and tissue supporters has also been investigated in brain injury. Hydrogel use in the brain has been proved to promote proliferation, maturation, and differentiation of stem cells with or without other trophic factors. Because hydrogels are injectable, when damage is located in the deep region of the brain, they can be injected directly into lesions to avoid damage to the superficial cortical tissue. Shi et al. developed RADA16 self-assembling peptide hydrogels that carry brain-derived neurotrophic factor (BDNF). They seeded both MSCs and astrocytes into the scaffold and applied chemokine receptor 4 to promote migration of transplanted cells. Their results indicate that transplantation of scaffolds can aid repair of moderate-sized lesion cavities caused by TBI . With thed cells . Self-as in vivo . With th in vivo . in vivo process of implanted cells in the brain is important for explaining the mechanisms of repair. To achieve this goal, Hwang et al. applied poly-L-lactic acid (PLLA) scaffolds to carry NSCs that express firefly luciferase. Thus, they can monitor the process of cell proliferation in vivo conveniently and noninvasively. Their result showed that the signals from cells in the scaffold are both stronger and more durable than nonencapsulated cells [The application of biodegradable scaffolds and cell therapy in regeneration of the brain is a newly developed field and has been increasingly noticed in recent years. Chitosan scaffolds are one of the most popular scaffolds used in brain injury. Shi et al. developed a kind of BDNF blended chitosan scaffold to carry umbilical cord mesenchymal stem cells (hUC-MSCs) through a freeze-dry technique. They found that the scaffolds can increase the differentiation rate of NSCs and the average neuron perimeter . The in ed cells . The plaed cells .In summary, in the treatment of CNS damage, using both hydrogels and biodegradable stem cell scaffolds can combine advantages of both modalities. The scaffolds can increase the survival rate of stem cells and accelerate the accumulation of ECM. They also give stem cells an isolated environment to differentiate and proliferate. Moreover, stem cells can differentiate into desired cell types to reconstruct the damaged tissue and result in functional recovery. However, many factors can affect the repair effect, such as cell type, topography, category of materials, and physical and chemical properties of materials. Thus, the optimum method of combination of materials and stem cells still needs future study.In this review, we summarized present development in the application of biomaterial scaffolds in central nervous system regeneration. We showed that some materials have great potential in CNS regeneration as well as the combination of materials and cell therapy in this field. Biomaterial scaffolds can reduce inflammation at injury sites and can also change the microenvironment of lesions. In addition, they can carry drugs and neurotrophic factors to enhance the effect of therapy. Moreover, combining biomaterial scaffolds and cell therapy can promote survival and differentiation of stem cells and reduce the side effect of cell therapy. Hence, biomaterial scaffolds-assisted therapy is a promising strategy in CNS regeneration. However, these effects of scaffolds are based on animal experimentation; human CNS injury is more complex and is still a great problem that needs to be solved by the overall medical world. Developing biomaterial scaffolds that are biodegradable, biocompatible, and mechanically flexible is still an important issue in CNS regeneration. Moreover, using hybrid knowledge of cell therapy, pharmaceutical therapy, and clinic technique to enhance the ability of biomaterial scaffolds in CNS regeneration is an important strategy to improve biomaterial scaffolds. Finally, degrading the speed of biomaterial scaffolds should correspond to differentiating the phase of tissue regeneration, so that they can be designed to have different functions in different stages of regeneration. With the development of materials and biology, it is reasonable to surmise that we can achieve perfect CNS regeneration in the near future.


Exosomes, which are one of the smallest extracellular vesicles released from cells, have been shown to carry different nucleic acids, including microRNAs (miRNAs). miRNAs significantly regulate cell growth and metabolism by posttranscriptional inhibition of gene expression. The rapidly changing understanding of exosomes’ formation and function in delivering miRNAs from cell to cell has prompted us to review current knowledge in exosomal miRNA secretion mechanisms as well as possible therapeutic applications for personalized medicine. Our understanding of cell-to-cell communication has been revolutionized by the observation that extracellular vesicles (EVs) derived from cells are not only capable of transferring miRNAs, mRNAs, and proteins in a paracrine (between cells of the same origin) manner, but also in an endocrine (to distant target cells) manner. EVs have been characterized by size into three different classes  ,3. PreviTHM: Extracellular vesicles transport miRNA in a paracrine and endocrine manner. Questions regarding the cellular options of producing either microvesicles or exosomes and their difference in miRNA composition and number are still unknown.Exosomes were discovered during mammalian reticulocyte maturation, shedding from the plasma membrane . They arTHM: Exosomes interact with the cell via their surface proteins in a ligand-receptor manner. Tetraspanins such as CD63 may be used for affinity purification.MicroRNAs (miRNAs) are small, endogenous, non-coding nucleotides, approximately 22 nt long, regulating gene expression post-transcriptionally. Primary miRNAs (pri-miRNAs) are transcribed by RNA polymerase II. Nuclear RNase Drosha processes the pri-miRNAs into a hairpin precursor miRNA (pre-miRNA). Pre-miRNAs are transported into the cytoplasm, where the hairpin is cleaved off, resulting in double-stranded mature miRNA . One strSince the Agonaute proteins are crucial for miRNA function, they have also been considered as a fundamental carrier of miRNA and may also be involved in exosomal loading and miRNA release. However, recent studies have shown that exosomal miRNAs are free of Ago2, and more than 90% of Ago protein–bounded miRNAs are independent of extracellular vesicles ,17. ThisTHM: miRNA composition/loading into exosomes mainly depends on the surface molecules of exosome membranes, the endosomal sorting complex required for transport (ESCRT), and the specific binding motifs of the miRNAs themselves.Exosomes play an essential role in maintaining cell homeostasis during liver damage. It is generally acknowledged that circulating miR-122 is released from hepatocytes regardless of the type of liver injury ,26,27,28Hepatocytes not only secret exosomes for cell survival, but they are also regulated by exosomes from different sources. Currently, exosomes from mesenchymal stem cells (MSCs) have attracted great attention worldwide and have been proposed as one of the most efficient liver cancer therapy options ,43. ReseTHM: The type and degree of (liver) injury determine exosomal miRNA secretion as part of maintaining homeostasis. Released liver miRNAs may modify the reaction pattern of other cells such as hematopoietic or endothelial cells. Progression of chronic diseases such as hepatitis and liver fibrosis will change secretion patterns of miRNAs, exosomal loads, and may lead to changes in therapeutic responses.Recent studies indicate that exosome uptake might not be a random process; rather, it is mediated by endocytosis, micropinocytosis or phagocytosis, which have been extensively described before ,61. AmonTetraspanins  were repIntegrin exists ubiquitously on cell membranes, serving as bridges for extracellular matrix (ECM) and signal transduction to the cells . For focTHM: Exosomes contain miRNA profiles which may allow the determination of the status of the cells and their origin. Its surface molecules may determine the specificity of uptake in the target organ and explain metastatic organotropism.Because exosome proteins control the vesicle contents, in order to maintain their oncogenesis and metastasis, cancer cells tend to sequester antitumor miRNAs in vesicles and load them to exosomes. miR-146 has been proved as a tumor suppressor in prostate, glioma, breast and pancreatic cancers ,79,80,81In addition, the tumor suppressor miRNA let-7 is highly concentrated in the exosomal fraction from highly metastatic gastric cancer cells in comparison with that from less metastatic gastric cancer cells . IntraveBesides carrying tumor suppressor miRNAs, exosome function is also involved in the intercellular transmission of oncogenically acting miRNAs. For example, in many cancer cells, oncogenic miR-21 ,90 expreTHM: Tumor suppressor miRNAs are more preferentially sequestered by vesicles and secreted as exosomal miRNAs, not only inhibiting the growth of cells in the surrounding environment but also targeting cells at a long distance. The miRNA profiles of exosomes may enable us to analyze their targeted cell groups and possible functions.Currently, the diagnostic potential of the analysis of circulating exosomes and their microRNAs has been recognized they are used as biomarkers in a variety of diseases. In particular, in a wide variety of different acute and chronic liver diseases, miRNA and exosomal vesicles are discussed as putative early prognostic indicators ,97,98,99Finally, if exosomes are able to modify the cancer environment or provide a specific niche for metastases, their membrane and miRNA analyses may be helpful in understanding the as yet unexplainable behavior of cancers with identical morphologic appearances. Here exosomal miRNA-based manipulation of signal pathways in the target cell and modification of oncogenic factors could well be responsible for several mysteries: (i) observed early cancer recurrences in spite of complete resection in the immediate vicinity of the original tumor; (ii) metastases via lymphangiosis and hemangiosis due to endothelial cell manipulations; and (iii) the development of early therapeutic resistance not based on genetic mutations.THM: Exosomal miRNA opens a new era of molecular diagnostic tools. It has the therapeutic potential to determine functional aspects, such as organ aging, as being the basis for individual patient tolerance of therapeutic intervention. Furthermore, this tool may determine the influence of physiological and pathological processes in exosome formation. To this end, more details about the interaction between formation and function are necessary in order to apply this knowledge for individualized patient management.


Tumor rejection antigens allow tumors sufficiently distinct from normal tissue to activate the immune system and induce an efficient anti-tumor response. Tumor mutated specific antigens  without central tolerance are major tumor rejection antigens. The recent developments of innovative deep sequencing technologies (at an affordable cost) along with advances in bioinformatics have enabled systemic analysis of the mutation load of the tumor as well as identification of the potentially immunogenic neoantigens. T cell reactivity against these predicted neoantigens can then be analyzed , 2. ThisDeep sequencing to assess the mutations present within the protein-encoding regions of the genome (the exome) of an individual tumor will generate a unique set of data for each tumor. Whole exome sequencing data from the tumor sample and non-transformed cells will be used to detect nonsynonymous somatic mutations with the use of mutation calling tools. RNA seq analysis will be used to identify expressed mutations in order to predict potential neoantigens. Epitope prediction algorithms based on published or submitted MHC Class I and II binding data will provide estimates of binding affinity to identify putative T cell neoepitopes. Data resulting from functional assays, including combinatorial encoding of MHC multimer screening flow cytometry assays, or functional read outs such as cytokine production, will provide an indication of T cell reactivity to validate the tumor-specific immunogenic neoepitopes. The analyses of mutations in MHC class I and II genes as well as key molecules affecting antigen processing and presentation are vital to provide a better assessment of their potential impact on cytolytic T cell responses. The genetic landscape, the pool of neoepitopes and functional tumor rejection measures of neoantigen-specific T cells (tumor recognition) could be used to further assess their relevance to clinical outcome, design therapeutic tumor-specific neoantigen (TSNA) vaccination, apply adoptive neoantigen T cell transfer therapy and to guide more effective immuno-oncology combination immunotherapy.+ and CD4+ T cells, respectively [One of the major limitations of this approach is in the early stage computational tools that are used both to identify tumor-specific mutations and to guide epitope prediction. Multiple computational tools, such as EBcall, JointSNVMix, MuTect, SomtaticSniper, Strelka and VarScan 2, are used to compare tumor samples to normal tissue at each variant locus to increase the accuracy of somatic single nucleotide variant (sSNV) calling –7. Becauectively –10. The ectively –14, it iectively . This laAnother potential limitation of this technology is that representative, high-quality tissue samples are needed in order to produce reliable results. Tumor tissue from formalin-fixed, paraffin-embedded (FFPE) samples may be used for whole exome sequencing. However, proper collection and storage of the tumor tissue is essential to ensure high quality DNA for deep sequencing. Because of the heterogeneity of the tumor, it is also essential to collect representative tissue to avoid any bias. In addition, mutational profiles may change due to disease progression or ongoing treatment. Therefore, assessing the tumor sample closest to the intervention is best to eliminate the potential variation and increase accuracy. Moreover, although PBMCs are commonly used as non-transformed cells, the signal from even low frequency circulating tumor cells from whole blood needs to be further validated for potential contribution to data noise.Tissue from the tumor sample and non-transformed cells are needed for whole exome sequencing. However, as mentioned above, proper collection and storage of representative tissue is essential to ensure high-quality samples for deep sequencing. For downstream assessment of T cell reactivity in functional assays, TILs and PBMCs are needed and must be viably preserved as a single-cell suspension.This is a novel technology that is still currently under development. Two pilot preclinical studies in mouse models first demonstrated that whole exome sequencing is efficient to identify neoantigen-specific CD8+ T cells with tumor elimination , 17. Sev


Cardiovascular disease remains the main cause of morbidity and mortality in patients with diabetes. The risk of vascular ischemia is increased in this population and outcome following an event is inferior compared to individuals with normal glucose metabolism. The reasons for the adverse vascular profile in diabetes are related to a combination of more extensive atherosclerotic disease coupled with an enhanced thrombotic environment. Long-term measures to halt the accelerated atherosclerotic process in diabetes have only partially addressed vascular pathology, while long-term antithrombotic management remains largely similar to individuals without diabetes. We address in this review the pathophysiological mechanisms responsible for atherosclerosis with special emphasis on diabetes-related pathways. We also cover the enhanced thrombotic milieu, characterized by increased platelet activation, raised activity of procoagulant proteins together with compromised function of the fibrinolytic system. Potential new therapeutic targets to reduce the risk of atherothrombosis in diabetes are explored, including alternative use of existing therapies. Special emphasis is placed on diabetes-specific therapeutic targets that have the potential to reduce vascular risk while keeping an acceptable clinical side effect profile. It is now generally acknowledged that diabetes is not a single clinical entity but a continuum of various stages of the condition with each having a different vascular risk. Therefore, we propose that future therapies aiming to reduce vascular risk in diabetes require a stratified approach with each group having a “stage-specific” vascular management strategy. This “individualized care” in diabetes may prove to be essential to improve vascular outcome in this high risk population. The prevalence of diabetes continues to increase and is reaching epidemic proportions.Despite advances in therapy, cardiovascular disease (CVD) remains the main cause of morbidity and mortality in diabetes , 6. SimiThis review summarizes the pathophysiological mechanisms responsible for increased atherothrombotic risk in diabetes, addresses current treatment modalities, and explores additional pathways that can be targeted to reduce vascular events in this high-risk population.Both extensive vascular pathology and an enhanced thrombotic environment contribute to premature vascular occlusive events and poor clinical outcome in patients with diabetes.A normal endothelial cell (EC) function is the key to maintain vascular health. EC dysfunction is one of the earliest abnormalities in the atherothrombotic process, which also contributes to the latter stages of the disease. Another central mechanism in vascular pathology is systemic inflammation, which promotes vascular damage. EC dysfunction and an inflammatory milieu are both associated with a prothrombotic and hypofibrinolytic environment, facilitating vascular occlusion and leading to myocardial infarction, stroke, and occlusive peripheral vascular disease, common complications in patients with diabetes.The endothelium plays an important role in maintaining vascular homeostasis by regulating vasodilation and vasoconstriction, thrombosis and fibrinolysis, platelet activation, platelet and leukocyte interaction, and smooth muscle cell function. Under physiological conditions, the endothelium modulates vascular tone by producing and releasing various vasodilator substances, most importantly nitric oxide (NO), and vasoconstrictor substances including endothelin , 11. WheEndothelial cell dysfunction plays a role in all stages of the atherosclerotic process from initiation of atherosclerosis to precipitation of thrombosis , 13, as We will concentrate on diabetes-specific pathways for vascular pathology related to IR and elevated glucose levels.miR-145 has recently been shown to modulate the phenotypic switch of vascular smooth muscle cells from a contractile to a proliferative state in atherosclerosis (Reduced NO bioavailability and elevated levels of reactive oxygen species (ROS) play fundamental roles in vascular disease in diabetes Figure . IR inhiclerosis , 19.in vivo study in diabetic mice has demonstrated that inhibiting NO synthase reduced platelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation and increased fibrinogen-platelet binding and expression of P-selectin as well as CD40 ligand. Diabetic mice also exhibited reduced VASP phosphorylation, increased fibrinogen-platelet binding, and enhanced expression of P-selectin/CD40 ligand, which was rescued by endothelial-specific restoration of NO production -6 and tumor necrosis factor (TNF)-α. Moreover, the stimulation of the toll-like receptor induces the phosphorylation of insulin receptor substrate-1 by c-Jun amino-terminal kinase (JNK) and protein kinase C (PKC) causing downregulation of the PI3-kinase/Akt pathway and the glucose transporter GLUT-4. Suppression of the PI3-kinase/Akt pathway leads to reduced eNOS activity and decreased NO production. Furthermore, the increased oxidative stress and hyperglycemia, stimulate vascular inflammation via several cellular mechanisms, including promoting activation of PKC and NF-κB signaling. Secretion of cytokines IL-1 and TNF-α enhances NF-κB activity and production of adhesion molecules by ECs further aggravating the inflammatory process  is used employing agents that target the thromboxane and P2Y12 pathways. However, inhibitors of the P2Y12 pathway seem to vary in efficacy. In the TRITON trial, DAPT with aspirin and prasugrel following myocardial infarction was superior to aspirin and clopidogrel but at the expense of increased bleeding events, failing to overall improve clinical outcome. A sub-analysis of diabetes patients, however, has shown reduction in further ischemic events without a significant increase in bleeding risk , making A relatively recent development is the implication of reticulated platelets in atherothrombotic events . These aper se, drives the increased production of this antifibrinolytic protein, a concept that was confirmed using in vitro and in vivo studies  darapladip quickly faded with the failure of this agent to reduce coronary vascular events. The clinical findings suggest that this enzyme is a biomarker of vascular pathology rather than a factor having a direct role in pathogenesis. Inadequate dosing and off-target effect(s) have also been blamed for failing to demonstrate a clinical benefit with this agent so far . More stExperimental studies and preclinical models have indicated that IL-1β blockade is effective at preventing coronary artery disease. A recent study involving 10,061 patients with previous myocardial infarction and C-reactive protein levels above 2 mg/l, showed that IL-1 inhibition, using Canakinumab, reduced the composite end point of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death by 15 and 14% using 150 and 300 mg of this agent, respectively (injected once every 3 months). However, there was no difference in all-cause mortality, which may be related to increased fatal infection in the Canakinumab arm of the study.Antioxidants have been repeatedly considered as potential drugs for the prevention and therapy of atherosclerosis given the role of ROS in the pathogenesis of atherosclerosis . HoweverGiven the pivotal role of endothelial dysfunction in vascular pathology, a number of agents that improve EC function are currently in clinical use and others are under development. Angiotensin-converting (ACE) inhibitors, angiotensin II-receptor blockers (ARB), some β blockers, and calcium channel blockers, all modulate EC function. However, not all have the same clinical effects; for example, ACEI convincingly provide protection from future vascular events, whereas the case for ARB is less clear despite targeting a largely similar pathway.Compounds that act directly on guanylate cyclase (sGC), a key enzyme of the NO signaling pathway, have also been investigated in preclinical studies. The therapeutic potential of sGC activators (cinaciguat or ataciguat) and sGC stimulators (riociguat) has been explored in animal models and clinical trials . In a reWhile all these agents can improve endothelial dysfunction by lowering blood pressure, it is clear that additional mechanisms operate to explain the difference in vascular outcome , 70. It Experimental agents to improve EC function include eNOS-transcription enhancer and agents that inhibit phosphodiesterase-5 (PDE-5) and sphingosine-1-phosphate , 76. It Aging and diabetes both cause vascular dysfunction and the existence of both conditions has an additive effect in vascular damage, leading to increased vascular inflammation and cardiovascular risk . So far,It has recently been demonstrated that following a coronary ischemic event, a single dose of reconstituted HDL increased cardiac glucose uptake and reduced infarct size in both metabolically normal and insulin-resistant mice . While tvia modulation of actin cytoskeleton organization in ECs, and it was reported that inhibition of miR-155 can reduce atherosclerotic plaques . However, a recent study demonstrated that treatment with n-3 PUFAs failed to modulate fibrin clot properties, platelet activation, or inflammation in patients with atherosclerosis and type 2 diabetes .Antiplatelet agents remain a cornerstone in the management of the thrombotic environment in diabetes. However, the best treatment regimen at various stages of the vascular pathology is yet to be determined; this can be divided into primary prevention, secondary prevention immediately following an event and long-term secondary prevention. This topic is reviewed extensively elsewhere , 96, 97 2 (TXA2), a prothrombotic and vasoconstrictive eicosanoid. At higher doses, aspirin can also inhibit COX2, leading to the unwanted reduction in production of prostacyclin (PGI2) an antithrombotic and vasodilatory agent (Aspirin irreversibly inhibits cyclo-oxygenase (COX) enzymes, at lower doses exhibiting relative selectivity for COX1, which is responsible for the synthesis of thromboxane Ary agent . In addiry agent .Until relatively recently, aspirin was used for primary prevention in patients with diabetes, although there was no clear evidence supporting such an approach. A number of studies investigating aspirin in primary vascular protection in diabetes failed to show a benefit, including PPP trial, JPAD, and POPADAD studies, and therefore, current guidelines do not advocate the use of this agent for primary prevention –103. It One of the issues that remain unresolved is the optimal dosing regimen of aspirin in diabetes. Given the increased platelet turnover in diabetes and the relatively short half-life of aspirin, this agent may fail to provide 24 h coverage , 104. ThAspirin is used in combination with other antiplatelet agents that target the P2Y12 pathway, following acute coronary syndrome (ACS) in diabetes patients and individuals with no diabetes. Of the three agents that target the P2Y12 pathway, both prasugrel and ticagrelor showed superiority to clopidogrel in improving vascular outcome in patients with diabetes , 106. A Dual antiplatelet therapy is usually continued for a period of 1 year after an ACS to be followed by aspirin only therapy that is continued indefinitely. However, recent evidence indicates that longer-term DAPT therapy with aspirin and ticagrelor offers a survival advantage in diabetes patients, unlike those without diabetes . The safAn inherent difficulty in optimizing antiplatelet therapy in diabetes is related to the heterogeneity of this condition and the variable vascular risk according to duration of diabetes, treatment modalities, and presence of microvascular complications. In order to optimize antiplatelet therapy in diabetes, there are a number of questions that remain unanswered, including: (i) Is an alternative dosing of aspirin required in diabetes? (ii) How long to continue treatment with DAT following ACS? (iii) Are different antiplatelet regimen required in different groups of diabetes patients, particularly for primary prevention? (iv) Are additional antiplatelet agents that target other pathways required? Addressing these questions will require large clinical outcome studies which are both time consuming and expensive. Therefore, using surrogate markers, such as platelet activation tests, may provide provisional data justifying clinical outcome studies. In other words, an integrated bench to bedside approach is perhaps the most cost effective way to investigate newer antithrombotic agents or analyze alternative application of existing agents.Proteins of the contact system have been investigated and considered as therapeutic targets due to their important role in the initiation of thrombosis. TF is expressed by exposed vascular smooth muscle cells at the atherosclerotic plaque rupture sites where it triggers the activation of FVII and the initiation of the coagulation cascade. Activation of FIX and FX by the TF/FVIIa complex then leads to the formation of FXa/FVa complex which converts prothrombin into thrombin .Heparin is an indirect inhibitor of FX and prothrombin and is used in diabetes and non-diabetes subjects with ACS. It is mainly used in unfractionated form or as the low-molecular weight form of heparin, named enoxaparin, which has been suggested to be more effective than the unfractionated form of heparin . AnotherThe recent development of direct oral anticoagulants has further helped by offering a more targeted inhibition of the protein arm of coagulation. Bivalirudin is a direct inhibitor of thrombin which has been reported to be superior to heparin as a therapy for diabetes patients with ACS due to the significant reduction in bleeding complications in some studies , 112. Thin vivo using FeCl3- induced and stenosis-induced models of venous thrombosis . Developing therapies that reduce incorporation of these proteins into diabetes clots will facilitate fibrinolysis, thus limiting thrombus formation while keeping bleeding risk to a minimum. Therefore, rather than full inhibition of one pathway, which compromises normal physiology and increases bleeding risk, what is perhaps required is partial inhibition of multiple pathways with a focus on those that show a diabetes-specific abnormality.Potential treatments and targets to further reduce atherothrombosis risk in diabetes are summarized in Figure Research conducted for the prevention and treatment of atherothrombotic disease has seen major advances over the past few decades, which translated clinically into significant improvement in vascular mortality and morbidity. We now have a number of agents that limit the atherosclerotic process and also control the risk of thrombosis. Despite these advances, however, the risk of vascular disease in patients with diabetes remains unacceptably high with relatively poor prognosis following an ischemic event. Therefore, future work is required to develop more effective therapeutic agents to halt the accelerated atherosclerotic process, typically associated with diabetes. Moreover, work is needed to develop antithrombotic strategies that target diabetes-specific pathways, thereby maximizing benefit and limiting the risk of bleeding. These include alternative use of existing agents and development of novel agents. An example of the former is investigating the efficacy of twice daily aspirin regimen in diabetes, whereas the latter includes development of agents that target the hypofibrinolytic environment, a key abnormality in individuals with deranged glucose metabolism .Finally, we should accept that diabetes is not a single clinical entity but a continuum of different stages of the condition with each having a different vascular risk. Therefore, in order to maximize benefit, future therapies aiming to reduce atherothrombotic risk in diabetes may require stratifying patients into different categories with each group having a “stage-specific” vascular management strategy. Admittedly, this will add to the complexity of clinical therapy, particularly as vascular risk will vary over time in each patient, but this “individualized care” approach is perhaps key to improve long-term outcome in this high-risk population.NP designed the review, undertook the literature search, and wrote the manuscript and RA designed the review and critically reviewed the manuscript. Both authors agreed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Lacrimo-auriculo-dento-digital (LADD) syndrome is an extremely rare disorder which may occur sporadically or inheritably as an autosomal dominant condition. It is characterized by defects in the lacrimal apparatus, ear problems, and dental and digital abnormalities. However, specific symptoms vary greatly among the cases with a high degree of overlap with other similar genetic disorders. Here, we describe a 7-year-old boy with LADD syndrome, clinical and radiological findings, dental treatment undertaken, and its differential diagnosis. Lacrimo-auriculo-dento-digital (LADD) syndrome, also known as Levy-Hollister syndrome, is a rare genetic disorder characterized by anomalies affecting the lacrimal and salivary glands and ducts, ears, dentition, and extremities with a high degree of variation in the signs and symptoms and an overlap of similar findings in other genetic disorders –3. MalfoUnderdevelopment or absence of the salivary glands may result in dry mouth (xerostomia) and vulnerability to severe dental caries. Other oral findings include small teeth (microdontia), enamel hypoplasia, belated eruption, and missing teeth –9. Cup-sA 7-year-old boy reported to the Department of Pedodontics and Preventive Dentistry with a chief complaint of dryness of mouth since birth and decayed teeth. Additional concerns included dryness and itchiness in the eyes. The patient weighed 28 kgs and the measured height was 115.2 cm. He had abundant scalp hair but normal hair density was observed on the body and limbs. His ears appeared to be normally located but were small and cup-shaped. Shape of the head was abnormal in that the parietal aspect appeared prominent although the frontal region was normal . Eyes apPalpation of soft tissues in the submandibular and parotid regions revealed no perceptible enlargement. On intraoral examination, reduced saliva with multiple carious lesions and enamel dysplasia were observed. Several primary teeth were absent as per their chronological age of eruption . A panorDental treatment involved scaling, restorations in relation to primary maxillary canines and second molars, and extraction of root stumps of mandibular canines. Band adaptation was done in relation to permanent molars and alginate impressions were taken for the purpose of fabricating space maintainers. Patient was instructed in oral hygiene measures, prescribed fluoride mouthrinse and salivary substitute, and recalled. During the second visit, a lingual arch space maintainer was given in the lower arch, and topical fluoride varnish and resin-based pit and fissure sealants were applied . PatientIn this case report, we have described a 7-year-old boy with reduced lacrimal secretions, cup-shaped ears, and dental anomalies, characteristic of LADD syndrome. However, the child lacked significant digital malformations. Reduced tears and saliva production were probably as a consequence of aplasia of lacrimal and salivary glands, respectively, as confirmed by imaging methods. The proband demonstrated bilateral cup-shaped ears that were positioned normally and no concomitant hearing loss.A significant finding in the present case was the absence of several primary teeth. Maintenance of arch space in such cases presents a clinical challenge due to increased caries risk and discomfort in wearing appliances because of diminished salivary flow. However, in the present case, prescription of salivary substitute may have played a role in enabling the patient to wear the appliance comfortably due to its lubricating properties which proved to be beneficial in that the patient could wear the appliance for a period sufficient to prevent pathological migration and provided space for eruption of permanent teeth. FGF3 gene [LADD syndrome is an autosomal dominant disorder caused due to mutations in one of at least three genes, the fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), and fibroblast growth factor 10 (FGF10) –13. SeveGF3 gene .LADD syndrome is an extremely rare condition with characteristic oral, lacrimal, and auditory clinical findings. It requires a thorough evaluation to rule out the above-mentioned similar conditions and determine presence of associated systemic manifestations. Multiple missing primary dentition is an unusual association that requires comprehensive dental therapy.


Phodopus sungorus), has been particularly useful in elucidating alternate mechanisms. These animals display elevated levels of aggression during the non-breeding season, in spite of gonadal regression and reduced levels of circulating androgens. Our laboratory has provided considerable evidence that the adrenal hormone precursor dehydroepiandrosterone (DHEA) is important in maintaining aggression in both male and female Siberian hamsters during the non-breeding season, a mechanism that appears to be evolutionarily-conserved in some seasonal rodent and avian species. This review will discuss research on the neuroendocrine mechanisms of aggression in Siberian hamsters, a species that displays robust neural, physiological, and behavioral changes on a seasonal basis. Furthermore, we will address how these findings support a novel neuroendocrine pathway for territorial aggression in seasonal animals, in which adrenal DHEA likely serves as an essential precursor for neural androgen synthesis during the non-breeding season.Aggression is an essential social behavior that promotes survival and reproductive fitness across animal systems. While research on the neuroendocrine mechanisms underlying this complex behavior has traditionally focused on the classic neuroendocrine model, in which circulating gonadal steroids are transported to the brain and directly mediate neural circuits relevant to aggression, recent studies have suggested that this paradigm is oversimplified. Work on seasonal mammals that exhibit territorial aggression outside of the breeding season, such as Siberian hamsters ( Aggression is a well-studied social behavior that is universally exhibited across vertebrates in various social contexts , 2. AmonPhodopus sungorus), which exhibit robust changes in morphology, physiology, and behavior on a seasonal basis. Siberian hamsters breed during the summer months and cease breeding and undergo gonadal regression, a reduction in body mass, and changes in thermoregulation during the winter months  is the primary environmental cue that is used by animals to shape seasonal shifts in reproductive physiology and social behavior [reviewed in the studies by Prendergast et al.  and Walts et al.  and Golds et al. ].via direct actions on neural substrates, such as the hypothalamus and pituitary gland, and via peripheral actions on the adrenal glands and gonads [reviewed in the studies by Haller et al. (1) located on the hypothalamus , via a multi-step conversion in brain regions that express the appropriate steroidogenic enzymes  and estrogen receptors (ERα and ERβ) to regulate social behaviors  levels in male hamsters in regions associated with aggressive behavior, including the medial amygdala (MeA) and the medial prefrontal cortex, or in the hippocampus, an area that shows changes in GR levels across photoperiods in other animals . In cont2 compared to long-day females [Figure In summary, our findings provide compelling evidence that adrenal DHEA serves as a critical precursor of neurally-derived androgens in non-breeding Siberian hamsters Figure . We havePeromyscus sp.) undergo seasonal changes in reproductive physiology and behavior. For example, male beach mice (P. polionotus) and deer mice (P. maniculatus) increase territorial aggression during the non-breeding season, in spite of gonadal regression and low circulating levels of androgens  do not undergo gonadal regression in response to short-day photoperiods, yet still exhibit elevated levels of aggression during the non-breeding season  decrease aggression in response to exogenous DHEA administration  during the non-breeding season. Male song sparrows display elevated circulating DHEA levels during the non-breeding season, which typically match seasonal changes in territorial aggression  elevate plasma DHEA, reduce circulating T, and display similar aggressive behaviors compared to breeding males (Sitta europaea) do not elevate aggressive behaviors following exogenous DHEA administration (Sturnus vulgaris) exhibit lower plasma DHEA levels compared to breeding males (Saxicola torquatus rubicola), suggesting that steroid hormones only regulate territorial aggression in a breeding context , both in the brain and in systemic circulation. It is important that future work addresses this area of research to pinpoint the sex steroid synthesis pathway cascades that are critical in establishing seasonal differences in aggression. Ongoing and future studies in hamsters and other seasonal species will continue to provide important insights into the role of neurally-active steroid hormones in the regulation of aggression.KM and GD drafted the manuscript, with editorial contributions from NR.The authors declare no competing interests, financial, or otherwise.


We additionally analyzed the impact of depressive symptoms and a chronic medical condition (asthma), on STAI and SF-36 trajectory curves. STAI scores remained stable throughout pregnancy. A previous history of anxiety increased the overall STAI scores. Asthma and depressive symptoms scores had no impact on the STAI trajectory. Physical SF-36 scores decreased over the course of pregnancy, whereas mental SF-36 trended towards improvement. Asthma reduced physical SF-36 overall. While high depressive symptoms decreased the overall mental SF-36, they were also significantly associated with mental SF-36 improvements over time. Anxiety symptoms are stable during pregnancy and are not modulated by depressive symptoms or asthma. Physical HRQoL declines in pregnancy. In contrast, mental HRQoL appears to improve, particularly in women with high initial levels of depressive symptoms.Anxiety and health related Quality of Life (HRQoL) have emerged as important mental health measures in obstetric care. Few studies have systematically examined the longitudinal trajectories of anxiety and HRQoL in pregnancy. Using a linear growth modeling strategy, we analyzed the course of State-Trait Anxiety Inventory (STAI)- and Short Form (36) Health Survey (SF-36) scores between the 12 The epidemiology and the impact of affective disorders such as major depressive disorder (MDD) or generalized anxiety Disorder (GAD) in pregnancy have been studied extensively . Less inThe exploration of longitudinal trajectories of psychological and physical symptoms of interest, as opposed to cross-sectional sampling, has proliferated in the biomedical literature over the recent years. There is increasing recognition that the systematic measurement of health parameters over time can reveal novel information about aetiological trajectory drivers , 3, whicAnxiety symptoms during pregnancy have emerged as an independent risk factor for adverse obstetric and developmental outcomes. Anxiety levels are closely linked to maternal cortisol trajectories . ChildreHealth related Quality of Life (HRQoL), a concept of subjectively experienced wellbeing measured by standardized psychological assessment tools, is a health outcome measure that is widely used to evaluate clinical interventions and to guide clinical management . HRQoL mPregnant women with pre-existing and mental- and physical health difficulties are thought to be at increased risk for obstetric complications and poorer birth outcomes. Therefore, prevention and early recognition of adverse mental health outcomes form part of routine care in obstetric practice. Asthma and major depressive disorder (MDD), for example, are common health conditions that are routinely screened for in obstetric settings, with the goal of achieving optimal treatment to minimize their role as recognized risk factors for adverse obstetric outcomes –18. For As far as we are aware, no previous studies have systematically investigated the longitudinal course of anxiety symptoms and HRQoL measures during pregnancy, and little is known about the modulators of their trajectories. In this study, we analysed the longitudinal trajectories of anxiety symptoms and HRQoL scores in a cohort of 355 pregnant women recruited from a socioeconomically disadvantaged area in Adelaide, South Australia. Using a linear growth modeling strategy to examine the pregnancy trajectories of anxiety and HRQoL, we hypothesized that the presence of a chronic medical condition (asthma) and/or high levels of depressive symptoms at an early pregnancy stage would negatively impact on overall anxiety and HRQoL levels (“intercepts”), as well as on their trajectory throughout the pregnancy (“slopes”).Approval for the study was provided by The Queen Elizabeth Hospital, Lyell McEwin Hospital, and Modbury Hospital Human Research Ethics Committee and The University of Adelaide Human Research Ethics Committee. All women gave written informed consent.Participants for this study were recruited in the context of a non-interventional prospective cohort study evaluating the impact maternal asthma on perinatal outcomes. Mental health measures, as specifically analyzed in the current study, were collected as secondary outcomes of this larger cohort. Pregnant women with and without asthma were recruited through the Lyell McEwin Hospital antenatal clinics, a public health service in South Australia, Australia, between May 2009 and May 2012. Women were assessed by a midwife, with additional respiratory training, at 12, 20, 28, and 36 weeks gestation. The midwife utilised a standardised data collection tool to collect demographic data including maternal weight, height, previous obstetric history, medical history. Maternal smoking was assessed by maternal self-report, with women classified according to smoking status during the first antenatal visit. Socioeconomic status for each woman was determined using her residential postcode at the time of delivery. Women were then ranked according to their level of advantage, or relative disadvantage, based on data from the Socio-Economic Indexes for Areas, calculated from the Australian Bureau of Statistics’ 5-yearly Census of Population and Housing. These indexes are widely used measures of relative socioeconomic status. Among women with asthma, additional data were collected related to asthma control, medication use, lung function, which are described in more detail in previous publications , 24. TheData was prospectively collected at each study visit.Symptoms of anxiety and HRQoL were assessed longitudinally at 12, 20, 28, and 36 weeks gestation. Anxiety symptoms were assessed using the State-Trait Anxiety Inventory (STAI). 20 itemDepressive symptom severity at 12 weeks gestation was assessed using Edinburgh Postnatal Depression Score Questionnaire (EPDS). The EPDAll data were analysed using Stata 12.0. The data were inspected graphically to establish normality prior to analysis. To identify potential confounders, we used chi squares or Student’s t-test for testing the association between demographic, psychiatric or medical characteristics of the sample at baseline and high depressive symptom status as identified by the EPDS.For multivariable analysis, linear growth models of the State-Trait Total score and the SF-36 Mental and Physical subscales were performed against positive screening for depressive symptoms at baseline (as per the EPDS) and asthma, adjusting for a history of anxiety, a history of PND, current antidepressant usage, a history of physical and/or sexual abuse, parity and a family history of psychiatric disorder. Subjects with missing data were included in analyses, as data collection at every time point does not need to be adhered to in growth models.Average STAI scores remained statistically stable over time throughout pregnancy , and the majority of women in the sample reported stable low levels of anxiety symptoms throughout pregnancy , Table 4Linear growth model analysis of of participants’ STAI trajectories  revealedFor the entire sample, scores on the physical subscale significantly decreased over time , indicating a reduction in subjective physical wellbeing , Table 5Linear growth model analysis of the participants’ SF-36 physical trajectories indicated that the asthma group performed significantly worse compared to others on the SF-36 physical health subscale . There were no significant interaction effects between Physical SF-3 and the EPDS and Asthma groups over time .SF-36 mental subscale levels for the entire sample increased during the course of the pregnancy in the entire cohort, but not significantly so  , Table 6Linear growth model analysis revealed that participants with a history of anxiety, a history of stress, a history of emotional problems and issues with accommodation reported significantly lower initial scores on the SF-36 Mental Subscale . There wth and the 36th week of pregnancy. Further, we investigated the impact of asthma and depressive symptoms at baseline on anxiety and HRQoL trajectories. In a cohort of 355 pregnant women, recruited from a socioeconomically disadvantaged area in South Australia, we firstly found that anxiety symptoms are relatively stable throughout pregnancy. A previous history of anxiety was the only factor that increased the overall longitudinal level of anxiety symptoms (intercept). Asthma or depressive symptoms at baseline had no impact on the rate of symptom change over time (slope). Secondly, we found that physical HRQoL significantly decreased over the course of pregnancy, whereas mental HRQoL trended towards improvement. As expected, asthma reduced physical HRQoL overall (intercept), but had no impact on the rate of deceleration over time (slope). Surprisingly, while high EPDS status decreased mental HRQoL overall (intercept), it was also significantly associated with faster mental HRQoL improvements over time compared to the low EPDS group.We carried out linear growth model analyses to describe the longitudinal course of anxiety symptoms and HRQoL between the 12nd trimester followed by increasing symptoms during the 3nd trimester up to childbirth. Such a possible U-shaped pattern was not borne out in our analysis, which suggests overall stable anxiety trajectories in our sample. Our finding that higher levels of anxiety symptoms at the beginning of pregnancy significantly predict higher symptom levels throughout the rest of pregnancy is consistent with previous reports [The course of anxiety symptoms throughout pregnancy has previously been described in a number of cross-sectional studies, albeit not by specific trajectory analysis , 31, 32. reports , 32.The STAI has previously been employed as an assessment tool in pregnancy, and has been used in several studies to measure the impact of psychological treatments delivered to pregnant women (for review see ). ComparContrary to our hypotheses, neither asthma nor high EPDS status altered the intercept or slope of anxiety trajectories in pregnancy. No previous study has applied linear growth modeling to longitudinal symptom courses in pregnant women, to delineate this interaction between anxiety symptoms with mood or physical illness. Our findings highlight that anxiety changes over time could be independent of these factors. This underscores the importance of specifically assessing and treating anxiety in prenatal care . CurrentOur finding on physical HRQoL was consistent with our prior expectations. Similar to previous studies, we found that physical SF-36 scores decreased throughout pregnancy , 38, andMental SF-36 scores trended towards improvement over time, again consistent with previous reports . As expeThis study relied on self-reports for assessment of anxiety, HRQoL, and depressive symptoms. Whilst all assessment tools are evidence-based in terms of their validity, there is ultimately no certainty about reported symptom levels, and it is possible that clinician-rated scales would have led to different conclusions. Further, it is possible that a previous history of specific anxiety disorder such as panic disorder, social phobia, or generalized anxiety disorder (GAD) is associated with unique STAI trajectories in pregnancy. We did not specifically assess participants for these disorders using validated structured clinical interviews, and therefore cannot comment on this issue. Future research should consider pre-existing DSM-defined anxiety disorders when carrying out trajectory analyses of anxiety symptoms.The study was conducted in a socioeconomically disadvantaged area of South Australia, and study participants had lower levels of education, lower employment rates, and higher rates of psychosocial adversity, including a history of abuse, than would be expected in a representative community sample in Australia. Therefore, it is possible that our findings are not generalizable to the entire population. Future research should include ‘control’ populations where the above factors play less of a role.The linear growth model analyses of this study suggest that anxiety symptoms are relatively stable throughout pregnancy, whereas physical HRQoL decreases and mental HRQoL improves. Our findings indicate that chronic health conditions and depressive symptoms in early pregnancy have no impact on the trajectory characteristics of anxiety. In contrast, these factors modulate physical and mental HRQoL. Interestingly, we found that advancing pregnancy may improve subjective mental wellbeing in women who struggle with high levels of depressive symptoms in the first trimester.Given the complex interactions between anxiety, quality of life, depressive symptoms, and physical health, our study highlights the importance of comprehensive assessments of mental health and subjective wellbeing in obstetric practice. These assessments should specifically address anxiety and HRQoL, and specific bio-psycho-social treatments should be offered to women who are reporting difficulties in these areas. Our study suggests that comprehensive perinatal mental healthcare is particularly important in socioeconomically disadvantaged populations.


Bisphosphonates have found application in the treatment of reoccurrence of bone diseases, breast cancer, etc. They have also been found to exhibit antimicrobial, anticancer and antimalarial activities. However, they suffer from pharmacological deficiencies such as toxicity, poor bioavailability and low intestinal adsorption. These shortcomings have resulted in several researchers developing delivery systems that can enhance their overall therapeutic effectiveness. This review provides a detailed overview of the published studies on delivery systems designed for the delivery of bisphosphonates and the corresponding in vitro/in vivo results. Osteoporosis, osteoarthritis and bone cancer are the most commonly diagnosed skeletal disorders , while oIn general, disruption in bone micro-architecture features leads to reduction in bone mineral density relative to normal healthy bone. Osteoporotic bone exhibits reduced collagen, and consequently results in loss of protein which leads to weakening of bone . Thus, oClinically, bisphosphonates are the most widely administered therapeutic agents for treating conditions with increased bone resorption associated with osteoclastic activity, as well as osteoporosis, Paget and metastatic bone diseases ,19. BispBisphosphonates are classified as stable pyrophosphonate analogues . They be2) groups are present as substituents to X, they enhance the bone binding properties of bisphosphonates through tridentate binding to calcium, while the major function of Y is to influence bisphosphonates’ antiresorptive potency  carrier which contains hydroxybisphosphonate targeting moieties plus the model radio therapeutics was dependent on enzymatic stimulus and pH . A. A116]. Liposomes are promptly absorbed by phagocytic cells such as the spleen, liver and the avid reticulo-endothelial system, which is due to their lipid bilayers’ interaction tendency with cellular surfaces . The benN--aminobutane-1-hydroxy-1,1-bisphosphonic acid disodium salt, was prepared by Anada et al., and formulated into liposomes with cholesterol (CH) and distearoylphosphotidylcholine (DSPC). In vitro test results showed that the liposomes decorated with bisphosphonate moieties were observed to exhibit increased attraction for pure HA particles . T. T190]. EG-DSPE) . ExampleWang et al. prepared distearoylphosphoethanolamine-polyethylene glycol conjugate with 2-(3-mercaptopropylsulfanyl)-ethyl-1,1-bisphosphonic acid (thiolBP) which was incorporated into micelles and liposomes. It was prepared by the application of reverse-phase evaporation vesicle techniques and lipid film hydration methods. The designed liposomes were able to entrap the bone morphogenetic protein-2 in a bioactive form, suggesting their ability to deliver bioactive factors in mineralized scaffolds for bone tissue engineering .Ye et al. prepared multifunctional micelles using doxorubicin-poly(ethylene glycol)-alendronate as amphiphilic material. They reported that doxorubicin-loaded micelle retarded tumor growth, reduced bone loss and decreased cardiac toxicity in tumor-bearing mice, suggesting their potential uses for treating bone metastatic tumor .Miller et al conjugated alendronate and paclitaxel with poly(ethylene glycol) forming self-assembled micelles with paclitaxel molecules at the inner core and the alendronate at the outer shell. The in vitro cytotoxic and antiangiogenic activity of the free drugs and micelles were the same. However, the micelles exhibited improved efficacy and safety profiles suggesting their potential use as bone-targeted anticancer and anti-angiogenic therapy for breast cancer bone metastases .Although the aforementioned delivery systems have been reported to be useful for the delivery of bisphosphonates and other bioactive agents, these systems also suffer from some limitations. Nitrogen-containing bisphosphonates such as alendronate contain primary amine groups. The conjugation of the amines to other drugs to form hybrid compounds compromises the therapeutic efficacy of the bisphosphonates. In some reports, conjugation of chemotherapeutic agents with bisphosphonates for enhanced selectivity towards bone metastases tumors resulted in compounds that did not exhibit antitumor effects ,201. In Bisphosphonates are employed for the therapy of diseases associated with the bone and also used in conjunction with anticancer drugs for selected types of cancer therapy. However, bisphosphonates exhibit some pharmacological drawbacks which include poor solubility, low oral bioavailability and toxicity. To overcome these limitations, several delivery systems for the drug have been employed for targeted and controlled delivery of bisphosphonates with enhanced therapeutic effects. These systems are reported to enhance the overall therapeutic effectiveness of bisphosphonates such as improved bioavailability, reduced toxicity and effective delivery of bisphosphonates to the specific target. However most of these systems have only been evaluated in vitro and in vivo and there is a pressing need for these systems to undergo clinical trials to ascertain its effectiveness for cancer therapeutic and other pathologies. Based on the research trends thus far, there is no doubt that some of these systems containing bisphosphonates will in the future reach clinical trials.


Failure of brainstem supranuclear centers for saccadic eye movements results in the clinical presence of a brainstem-mediated supranuclear saccadic gaze palsy (SGP), which is manifested as slowing of saccades with or without range of motion limitation of eye movements and as loss of quick phases of optokinetic nystagmus. Limitation in the range of motion of eye movements is typically worse with saccades than with smooth pursuit and is overcome with vestibular–ocular reflexive eye movements. The differential diagnosis of SGPs is broad, although acute-onset SGP is most often from brainstem infarction and chronic vertical SGP is most commonly caused by the neurodegenerative condition progressive supranuclear palsy. In this review, we discuss the brainstem anatomy and physiology of the brainstem saccade-generating network; we discuss the clinical features of SGPs, with an emphasis on insights from quantitative ocular motor recordings; and we consider the broad differential diagnosis of SGPs. The goal of the ocular motor system is achievement of single, clear vision via maintenance of an object of visual interest on the fovea, the specialized retinal region with the greatest photoreceptor density. To achieve this, several functional classes of eye movements exist, including saccades, smooth pursuit, optokinetic nystagmus (OKN), vestibular reflexes, and vergence—each served by distinct cortical, brainstem, and cerebellar supranuclear networks. Failure of brainstem supranuclear saccade centers results in a brainstem-mediated supranuclear gaze palsy, which we refer to as a saccadic gaze palsy (SGP). We review the anatomy and physiology of brainstem immediate premotor saccade-initiating neurons and discuss SGP clinical features and its differential diagnosis. Comprehensive coverage of networks involved in saccade generation and termination is beyond the scope of this article but can be reviewed elsewhere .Saccades are rapid eye movements with which gaze is shifted to direct the fovea to objects of visual interest and explore the visual world , 3. SaccExecution of a saccade requires an initial burst of neuronal discharge, called the pulse, by excitatory burst neurons (EBNs) in the brainstem reticular formation to agonist ocular motoneurons Figure C 7, 8)., 8.7, 8)Excitatory burst neurons for horizontal saccades are located in the paramedian pontine reticular formation (PPRF) in the pons just rostral to the abducens nucleus and, for vertical and torsional saccades, in the rostral interstitial medial longitudinal fasciculus (RIMLF) rostral to the oculomotor nucleus in the mesencephalic reticular formation, although a few are also located in the INC just caudal to the RIMLF Figure B 14–16)–1614–16)Exam detection of SGP requires assessment not only of the static range of ocular motility, but also of dynamic eye movements in three planes. Saccades, smooth pursuit, vestibular–ocular reflexes, and OKN should be assessed horizontally and vertically  with or without range limitations. Saccade slowing in isolation is evidence of SGP, even with full eye movement range. It is important to note that isolated mildly impaired eye elevation is not sufficient to diagnose SGP, as this may be seen in healthy elderly individuals as a result mechanical orbital changes . Some paPathology affecting PPRF causes horizontal SGP , although some patients do exhibit SGP –64. In aVertical SGP  is a key feature of Niemann–Pick type C (NPC), present in 65% , 67. NPCGaucher disease is an autosomal-recessive sphingolipidosis caused by mutations in the GBA gene which decrease glucocerebrosidase activity . GaucherSpinocerebellar ataxias (SCA) are due to genetic CAG-repeat expansions resulting in protein polyglutamine extension. There is substantial phenotypic overlap between mutations and mild SGP has been reported with many; however horizontal SGP with early, severe slowing of horizontal saccades is characteristic of spinocerebellar ataxia type 2 –77, in wTumors affecting the pineal gland, including pineal germinoma or teratoma, pineocytoma, pineoblastoma, glioma, or metastasis, can lead to the dorsal midbrain syndrome via compression of the midbrain tectal plate. Rarely, pineal lesions in the elderly mimic PSP , 79.Ma1 and Ma2 are intracellular proteins expressed in the testes and brain . A studyAnti-glutamic acid decarboxylase (GAD) antibody is associated with many eye movement disorders, including downbeat and periodic alternating nystagmus, ocular flutter and opsoclonus, and ophthalmoplegia with or without stiff person syndrome (SPS) or cerebellar dysfunction –87. EarlAnti-IgLON5 antibodies are associated with a novel category of neurological disease, cell surface antibody-associated neurodegeneration, at the border between autoimmune and neurodegenerative disease . In an aSaccadic gaze palsy is rare in demyelinating disease, but may occur as an initial demyelinating event or as an exacerbation in multiple sclerosis , 101.Creutzfeldt–Jakob disease (CJD) can cause vertical SGP as an early or late feature and in familial or sporadic cases –107. SGPTropheryma whipplei. It may mimic PSP, with vertical SGP that may progress to complete ophthalmoplegia. Oculomasticatory myorhythmia is the pathognomonic, although not consistently present, finding consisting of pendular vergence oscillations and concurrent masticatory muscle contractions. Systemic features include gastrointestinal symptoms, weight loss, fever and polyarthralgia. Neurologic involvement includes cerebellar ataxia, tremor, postural instability, dystonia, myoclonus, cognitive deficits, delirium, and seizures.Whipple disease is a chronic infection by gram-positive bacillus Pathophysiologic understanding of brainstem mechanisms that may result in SGP is the first step in accurate identification and localization of this eye movement deficit. Chronic progressive vertical SGP is a core feature of PSP; however the differential diagnosis of SGP is broad and careful consideration must be given to the temporal course and accompanying features to ensure accurate diagnosis.All authors  participated in conception and organization of review, literature search, and all stages of writing—from initial draft to final product.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The ‘junk DNA’ that has haunted human genetics for a long time now turns out to hold enormous hidden treasures. As species had their genomes and transcriptomes sequenced, there are an overwhelming number of lncRNA transcripts being reported, however, less than 100 of them have been functionally characterized. DNA damage is recognized and quickly repaired by the cell, with increased expression of numerous genes involved in DNA repair. Most of the time the studies have focused only on proteins involved in these signaling pathways. However, recent studies have implied that lncRNAs can be broadly induced by DNA damage and regulate DNA repair processes by various mechanisms. In this paper, we focus on recent advances in the identification and functional characterization of novel lncRNAs participating in DNA double strand break repair. Our genome integrity is under attack every day by a variety of exogenous and endogenous sources . MultiplDNA double strand breaks are among the most detrimental damages which can lead to severe genome rearrangements. The two main repair pathways triggered by DSBs are homologous recombination and nonhomologous end joining repair . It has When the homologous template is unavailable, the break ends are directly ligated through nonhomologous end joining repair. The initial step in NHEJ repair is the recognition and binding of the Ku70/80 heterodimer to the DSB . SubsequDNA double-strand break repair pathways have a multifaceted function in tumorigenesis and in the response to therapeutic modalities. Firstly, erroneous or deregulated DNA repair results in chromosomal abnormalities, genomic instability, and higher mutation rates, which can predispose the cells to cancer and make them vulnerable to certain kinds of genotoxic stresses . On the Radiation therapy which causes a variety of DNA lesions including DSBs damage continues to be a mainstay in the treatment of an assortment of malignancies . HoweverBesides DSB repair proteins, mutations in long non-coding RNAs (lncRNAs) are associated with tumorigenesis. Large scale screening has provided novel p53 interactors, including lncRNAs, which can be potential therapeutic targets –43. ReseDino is either intact or inactivated. Both lines of Dino knockout mice exhibit impaired response to doxorubicin, suggesting that in mouse Dino acts in trans similarly to human DINO . Pr. Pr58]. in-vitro synthesized and also endogenous RNA, the authors demonstrated that LINP1 transcript physically interacted with Ku80-DNA-PKcs complex. Therefore, LINP1 knockdown in TNBC cells led to reduced DSB repair, and conversely, overexpression of LINP1 in ER-positive cells increased NHEJ activity [The discovery of lncRNAs has dramatically changed the understanding of the biology of human diseases, especially when genomic studies of tough-to-treat cancers have mainly focused on protein-coding genes and provided no effective targeted therapies. Many TNBC (triple negative breast cancer) patients poorly respond to chemotherapy and radiotherapy due to EGFR  gene amplification and TP53 mutations , 61. Mosactivity . The autUltraviolet light can damage DNA, triggering a general transient shutdown of gene transcription . This reThe simplest definition for lncRNAs is RNA genes larger than 200 base-pairs that do not appear to have coding potential. However, the characteristics of lncRNAs are far more complex than were originally imagined, as they are involved in numerous biological processes across many aspects of life rather than just results of transcriptional noise. In normal proliferating cells, lncRNAs are expressed, on average, at much lower levels than coding genes , 68. DurLncRNAs can have pro-survival or pro-apoptotic functions in response to DNA damage that can be utilized for future translational research. Given that expressions and functions of lncRNAs are highly cell type specific, cancer treatments may benefit from targeting lncRNAs crucial to cancer cell function, whereas having little effect on nearby normal cells that do not require these lncRNAs. The connection between DSB repair and ionizing radiation has been solidly established and work to date proposes that targeting the DSB repair pathways still has extensive potential for expanding radio- and chemosensitization in the clinic . Althoug


RNA interference (RNAi), a newly developed method in which RNA molecules inhibit gene expression, has recently received considerable research attention. In the development of RNAi-based therapies, nanoparticles, which have distinctive size effects along with facile modification strategies and are capable of mediating effective RNAi with targeting potential, are attracting extensive interest.This review presents an overview of the mechanisms of RNAi molecules in gene therapy and the different nanoparticles used to deliver RNAi molecules; briefly describes the current uses of RNAi in cancer therapy along with the nano-based delivery of RNA molecules in previous studies; and highlights some other carriers that have been applied in clinical settings. Finally, we discuss the nano-based delivery of RNAi therapeutics in preclinical development, including the current status and limitations of anti-cancer treatment.With the growing number of RNAi therapeutics entering the clinical phase, various nanocarriers are expected to play important roles in the delivery of RNAi molecules for cancer therapeutics. Cancer is a major public health problem around the world , and theDuring the last decade, remarkable advances have been made in genome research, revolutionizing the entire field. As a consequence, information may no longer be a bottleneck in understanding and tackling complex genetic diseases such as cancer , and genAlthough RNAi is thought to be more effective in treating disease compared to other methods , severalIn this review, we primarily discuss the delivery of RNAi molecules by nanoparticles in cancer therapy. We hope that this review provides useful information to help translate this novel therapy to clinical application.The different types of RNAi molecules are microRNA (miRNA), siRNA and short hairpin RNA (shRNA). In RNAi, RNAi molecules delivered into cells initiate the degradation of complementary messenger RNA (mRNA) molecules via the cells’ internal machinery. This halts the production of the proteins encoded by the mRNAs, resulting in reduced gene expression Fig.  8].Fig..Fig.8].FsiRNAs show great potential for use in nucleic acid therapeutics because of their potent and specific RNAi-triggering activity . siRNA imiRNAs are endogenous non-coding RNAs involved in the post-transcriptional regulation of gene expression . They arIn addition to siRNA and miRNA, shRNA can also be cloned into an expression vector and express siRNA. This makes it possible to structure an RNAi carrier to silence intracellular gene expression in mammals. shRNAi can use RNA polymerase III-dependent promoters  to realize RNAi. The transformation of shRNA can cause long-time gene silence in mammals. Ohno et al. developed a 30-nucleotide, single-strand RNA termed guide hairpin RNA (ghRNA) that has a similar physiological function similar to miRNA and siRNA and causes no innate cytokine response in vitro or in vivo .siRNA, miRNA and shRNA are all RNA molecules that rely on the Dicer enzyme; they can mediate RNAi and lead to the cleavage of mRNA. miRNA is single-stranded RNA, whereas siRNA and shRNA are double-stranded RNAs. The fundamental difference between siRNA and miRNA is that miRNA is endogenous , whereas siRNA is artificially synthesized and transfected into the human body, where it operates within the RNAi pathway. miRNA primarily acts on the 3′-untranslated region of the target gene, while siRNA can act on any part of mRNA . miRNA iThe activation of proto-oncogenes such as chromosomal rearrangements, insertion mutations, point mutations, and gene amplification  can tip There is a certain relationship between the role of the gene expression and apoptosis genes. RNAi knockout technology plays a role in the inhibition of the occurrence and development of a variety of tumors. Cioca et al. reported that a specific combination of Bcl-2 and c-raf of the siRNA gene can induce apoptosis in HL-60, U937 and THP-1 leukemia cell lines and enhance their sensitivity to etoposide and daunorubicin . This inIn addition, nanocarriers can be further functionalized with targeting moieties based on the target organ using polyethylene glycol (PEG) and/or other ligands . Wang etGene-knockout technology plays a role in cancer cell growth, proliferation, metastasis, and multi-drug resistance. Recent studies have identified several cancer-related genes as potential targets for RNAi-based therapy.Since the expression and functionality of siRNAs and miRNAs are significantly reduced in cancer cells, RNAi is an attractive target for the development of innovative therapeutics. However, the main obstacle to achieving gene silencing in vivo using RNAi techniques is the delivery of therapeutic RNAi molecules . Thus, tRecently, nanoparticles have received considerable attention as vectors for gene delivery . NanoparOrganic nanoparticles include cationic polymer nanoparticles, lipid-based systems and so on. Drugs can be incorporated into organic nanoparticles via chemical bonding or physical embedding . Among tVarious lipid-based systems have been reported, including liposomes, micelles, emulsions, and solid lipid nanoparticles (SLNs). Generally, cationic lipids have been used as siRNA delivery carriers because they associate easily with negatively charged nucleic acids . The phyMore and more inorganic substances, such as mesoporous silica nanoparticles (MSNs), carbon nanotubes, quantum dots and metal nanoparticles, are being reported as carriers for RNAi deliver. Inorganic nanomaterials are synthesized by inorganic particles and biodegradable polycation. They always play a role in gene therapy by a novel nanosize drug carrier . Among iGold nanoparticles (AuNPs) have received great interest in biomedical applications. For siRNA loading, AuNP can be directly conjugated to siRNA via gold-thiol chemistry. Conde et al.  functionIn a recent study, exosome-mimetic nanovesicles showed high production yield and the ability to deliver anti-cancer chemotherapeutics into cells . LunavatThe nanoparticle-based delivery of RNAi molecules can produce multiple advantages. Many studies Table  have ideWu et al. concluded that PEI-PEG may be a promising non-viral carrier for altering gene expression in the treatment of gastric cancer due to several advantages including relatively high gene transfection efficiency and low cytotoxicity; their previous research demonstrated that PEI-PEG can efficiently deliver RNAi to SGC7901 gastric carcinoma cells and suppress CD44v6 expression .Huschka et al. quantitatively demonstrated the remotely controlled, light-triggered release of antisense ssDNA from poly-L-lysine nanoshell vectors . This poMohammadi et al. developed a novel nanoparticle based on single-walled carbon nanotubes conjugated to piperazine–PEI derivatives for breast cancer gene therapy. This nanoparticle targets epithelial cell adhesion molecules, which are frequently overexpressed in solid tumors and were recently identified as a cancer stem cell marker . The vecIn addition to siRNA, many studies have been carried out on the roles of miRNA and shRNA in cancer therapy. Human cancer was recently associated with changes in miRNA profile , drawing1,N11-bisethylnorspermine and selectively disassembled in the cytoplasm, where it released miRNA [A biodegradable polycationic prodrug named DSS-BEN was synthesized from the polyamine analog Ned miRNA . Xie et ed miRNA .An experiment was carried out to observe the inhibition of human multiple myeloma cells based on conjugation of gold nanoparticles with miRNAs . The resEbrahimian et al. fabricated a novel nanoparticle formulation based on poly lactic-coglycolic acid (PLGA) for the simultaneous delivery of small amounts of DOX and bcl-xl shRNA . In vitrRNAi has great potential for therapeutic treatments. Although siRNA has been researched for a long time, miRNA has only recently generated significant attention, and many gaps in knowledge remain. In clinical settings, there are many obstacles to the targeted delivery of siRNA in vivo, including the specificity and stability of the RNAi reagents . In receViral vectors are optimal vehicles for gene transfer because of their ability to efficiently infect host cells . At presLipids are promising and versatile carriers because they can be custom designed to have functional properties that allow for the protection of siRNA, steric stabilization, targeting, membrane destabilization and triggered drug release . HoweverPeptides can replace liposomes for the delivery of siRNA to some cells; histidine-lysine (HK) polymers have been reported to be more effective than liposomes in the delivery of siRNA to targeted cells. Lysine in HK polymers can combine with the phosphate backbone of siRNA, while histidine increases the release of siRNA in vivo by acting as a proton pump; these two peptides cooperate with each other to accomplish the delivery of RNAi. Additionally, polymers can connect to the adapter body and deliver siRNA to targeted cells. With their biodegradability and diversity of permutations, peptides have significant potential as carriers of nucleic acids. However, their low transfection efficiencies mean that peptides must be modified by PEI , which cBacterial colonization in tumors has been recognized to have a beneficial effect in cancer cells ; these mMany studies have been carried out in recent years to discuss the specific roles of miRNA in health and disease , 75. NevRNAi is an economic, fast, and efficient method of cancer therapy. Many studies have shown that siRNA has a significant therapeutic effect on cultured tumor cells; however, few in vivo studies have been reported because siRNA is easily degraded in vivo, the transfection efficiency and targeting are low. Nanoparticles have been successfully demonstrated as efficient carriers for the delivery of RNAi molecules due to their unique characteristics. The addition of active targeting molecules to nanoparticles can enhance the tumor-targeting efficacy or the transfection efficiency to tumor cells. However, nanoparticle carriers still possess disadvantages that limit their application, including immunogenicity and toxicity. Furthermore, the detailed mechanism of RNAi is not completely clear, and the identification of RNAi molecules’ targets and the signaling pathways involved in the regulation of RNAi molecule expression in tumor formation remains a challenge. Although RNAi molecules are effective in silencing oncogenes, it is critical to identify the RNAi regulatory network rather than just a few isolated targets. Thus, more studies on the delivery of RNAi molecules by nanoparticles in cancer therapy are needed to establish a new method of treating cancer.