Indirect three-dimensional (3D) bioprinting refers to a 3D printing technique that can rapidly fabricate scaffolds with controllable internal pores, cavities, and channels through the use of sacrificial molds. It has attracted much attention in recent years owing to its ability to create complex vascular network-like channels through thick tissue constructs while maintaining endothelial cell activity. Biodegradable materials play a crucial role in tissue engineering. Scaffolds made of biodegradable materials act as temporary templates, interact with cells, integrate with native tissues, and affect the results of tissue remodeling. Biodegradable ink selection, especially the choice of scaffold and sacrificial materials in indirect 3D bioprinting, has been the focus of several recent studies. The major objective of this review is to summarize the basic characteristics of biodegradable materials commonly used in indirect 3D bioprinting for vascularization, and to address recent advances in applying this technique to the vascularization of different tissues. Furthermore, the review describes how indirect 3D bioprinting creates blood vessels and vascularized tissue constructs by introducing the methodology and biodegradable ink selection. With the continuous improvement of biodegradable materials in the future, indirect 3D bioprinting will make further contributions to the development of this field.Mature vasculature is important for the survival of bioengineered tissue constructs, both  At present, only a few tissue-engineered products, such as skin  and cartin vivo implantation of engineered tissue constructs any larger in scale than this limit, it is necessary to ensure sufficient vasculature throughout the construct and good integration with the host vascular system  . CompareAlthough technological progress has helped the progress of vascularization in bioengineered constructs, major challenges remain . The firin vitro. To date, no in vivo experiment has shown that, even with good integration with the host, thick tissue constructs remain viable for long or that necrosis will not occur after implantation.The second challenge is the integration of allogeneic and autologous vascular networks. Effective integration with host circulation is the precondition of effective blood perfusion after implantation . Studiesin vivo. Currently, many strategies depend on the ingrowth of host vessels to achieve graft blood perfusion  and fills it with a second material. After selective dissolution, the sacrificial mold or template is removed while the construct (patrix) formed by the second material is preserved . ThroughCurrently, indirect 3D bioprinting has made progress in both hard and soft tissue engineering systems. Some specific tissue constructs such as functional nerve guide conduits, human knee meniscal scaffolds, sized vascular grafts, can be successfully produced in laboratories as proof of concept . At the Generally, indirect 3D bioprinting for blood vessels and vascularized tissue constructs includes two general aspects: channel fabrication and vascularization. Channel fabrication can be further divided into three steps: sacrificial mold fabrication, patrix fabrication, and sacrificial mold removal. Manufacture of the negative mold is designed to simulate the shape and extension direction of the vascular network in a solid columnar form. In patrix fabrication, the patrix is built around the sacrificial mold to form the final scaffold or construct. Afterwards, special steps are performed to remove the sacrificial mold, leaving isometric hollow channels inside the scaffold or construct. The detailed production process and precautions of each step have been described in excellent reviews . Figure 7 mPa s -based and laser-based printing. DLP printing is realized by dynamically projecting an entire computer-generated optical mask into a photosensitive prepolymer solution to induce photopolymerization, while laser-based printing uses a bottom-up approach (drop-by-drop) to build constructs . DLP priAnother technique called embedded extrusion bioprinting involves printing a cell-containing hydrogel in a supporting bath, which serves as a sacrificial printing environment . As atypVascularization is essential for engineered tissue grafts to achieve biological function and can be realized by seeding ECs into hollow scaffold channels . After mAnother elegant vascularization strategy of indirect 3D bioprinting is to encapsulate ECs in the sacrificial ink to realize synchronous distribution of ECs in the process of blood vessel  fabrication. This approach reduces the manufacturing process and can realize precise control of cell distribution . Owing tin vivo , and enzymatic degradation in vivo . Eventuain vivo . Biodegrin vivo . Howeverin vivo, the use of them as sacrificial material helps to skip the processing step of sacrificial mold removal in vitro, thus shortening the manufacturing time. 4) In theory, by regulating and matching the degradation rate of scaffolds and sacrificial materials, the removal of sacrificial channels and channel endothelialization can be completed in vivo before the scaffolds completely degrade, thus realizing the direct in vivo application of constructs.In the field of indirect 3D printing, biodegradable polymers play vital roles in fabricating vascular or vascularized tissue: 1) As scaffold materials, they allow endothelial cells and a variety of angiogenic factors to exist, as well as providing a flexible environment for complex angiogenesis. 2) As sacrificial materials, compared with non-degradable ones, the damage to cell activity when manufacturing or removing the sacrificial molds is much lower. 3) Since the biodegradable materials can degrade In the following section, we mainly enumerate the commonly used biodegradable polymers in indirect 3D bioprinting for blood vessels and vascularized tissue constructs. in vivo is also necessary  is the most commonly used material among gelatin derivatives and composites. GelMA is a photopolymerizable hydrogel made of gelatin derivatized with methacrylamide side groups . It has in vitro .Fibrin scaffolds have a wide range of applications in tissue engineering, especially in bone tissue engineering. Fibrin is a natural biopolymer produced by thrombin cleavage of fibrinogen, and serves as a temporary scaffold for tissue healing in physiologic processes . It also2+ under mild conditions , a silk-derived protein-based material approved by the FDA , has beel-lactide-co-ɛ-caprolactone) (PLCL), and poly(lactic-co-glycolic) acid (PLGA) , hyaluronic acid (HA), PLA, PCL, poly (d (PLGA) . Inorganin vivo or bioactive components, cytotoxicity, biocompatibility, and whether the removal conditions are inconducive are usually considered first.Ideal sacrificial materials should have good fluidity for free molding, rapid solidification to save printing time, a low expansion rate, and appropriate mechanical strength to achieve good shape fidelity. During the process of printing, there should be no adverse reactions with the scaffold material that result in deformation of the scaffold structure. If working in combination with scaffold materials containing cells or other bioactive factors, sacrificial materials should be chosen to ensure non-toxic and non-stimulatory conditions. Also, the conditions for their state transformation and removal should be mild and easy to achieve, preserving the shape and properties of the scaffold. When exposed to living cells Currently the commonly used sacrificial materials that come closest to meeting the conditions described earlier are carbohydrate glass , Pluroniin vivo.As mentioned above, nonbiodegradable materials usually exhibit certain cytotoxicity and their removal is relatively cumbersome. As a result, researchers have investigated biodegradable materials, which show higher biosafety and are expected to achieve direct application . used PVA successfully to make sacrificial templates with characteristic sizes of 100–500 μm in multi-branch structures, which helped to further simulate the complex environment of cell growth, and showed great potential for production of large-sized vascularized scaffolds that would meet clinical needs  was developed to test drug toxicity  embedded in the permeable ECM. After endothelialization and epithelization, the selective reabsorption and vectorial transmission of solute were realized through external circulation devices, which favor the further study of tissue-engineered kidneys  composed of thousands of patient-specific-induced pluripotent stem cell–derived organoids, as shown in There are also some special needs for biomaterials. Highly vascularized tissues usually consist of large amounts of active cells, which require the biomaterials to be sufficiently friendly to cells and cell migration, growth, and proliferation, and should facilitate substance exchange . UsuallyThe 3D printing technique is relatively mature in the field of osteochondral tissue engineering and has been used in the fabrication of long bones, mandibles, cheekbones, human finger bones, and other structures . Biomatein vivo angiogenesis around cartilage models (. constructed a microchanneled cartilage template using sacrificial Pluronic ink. After in vivo cultivation, they found that, compared to solid templates, channeled templates showed better vascularization, more degradation of cartilage precursor hydrogel in the core region, less ectopic bone formation, and better integration with the host tissue, which are all clinically important (For endochondral bone repair, current techniques enable e models , but thee models . Daly etmportant . Howeverin vitro and angiogenesis in vivo (. Another team found that by combining bioactive peptide hydrogels with scaffolds having finger-shaped pores created via indirect 3D bioprinting, more vessels and more collagen I and III formed in the scaffolds (Creating man-made skin grafts for wounds and burn healing is the primary purpose of skin tissue engineering . Tissue- in vivo . Anothercaffolds . Most stcaffolds . It is iin vivo. Many accomplishments have demonstrated the feasibility of indirect 3D bioprinting for manufacturing blood vessels and vascularized tissue constructs, and most experiments show that indirect 3D bioprinting has advantages in channel structure design and construction. On the other hand, the selection of biodegradable inks is an important aspect of indirect 3D bioprinting for successful 3D tissue construct fabrication and in vitro/vivo application. Theoretically, indirect 3D bioprinting allows a wider range of materials to be used, since the use of sacrificial materials lowers the mechanical performance requirements for scaffold materials. However, this introduces new requirements for the sacrificial materials. At present, owing to the lack of satisfactory biodegradable materials, further in vivo applications are limited. A large number of studies are investigating advanced sacrificial/scaffold bioinks, which assists in the assembly of biodegradable, biosafe, bioactive, and more bionic structures at higher resolution. Efforts are now transitioning from theoretical verification to tissue and organ model construction. We expect that with the future continuous development of biodegradable materials, the use of indirect 3D bioprinting will continue to increase and will contribute to the field of tissue engineering.As described in this paper, tissue vascularization has always been a critical issue in tissue engineering and is key to the application and survival of engineered tissue constructs


Since the 1940s, humans have developed new drugs and consumption has increased significantly in the last 15 years. This global phenomenon is now a major public health concern due to Antimicrobial resistance (AMR). AMR is a severe threat to both human and animal health. Indeed, the spread across systems can occur through a number of pathways, both related and unrelated to agriculture, comprising the wastewater, soils, manure applications, direct exchange between humans and animals, and food consumption. Characterizing the presence in the environment  and managing human health risks due to exposure to resistant organisms requires national and international interdisciplinary cooperation. In fact, a holistic approach such as the One Health approach is needed to tackle this public health menace. This Special Issue includes 19 papers (16 articles and 3 reviews) that collectively provide novel information about this topic.E. coli isolates to assess virulence risk, and to evaluate potential transfer of AMR. The study allowed concluding about the presence of multidrug resistance to the last-resort antibiotics that are transferable between bacteria in food-producing animals [Aeromonas veronii (A. veronii) isolates recovered from pigs in KwaZulu-Natal, South Africa were explored by whole genome sequencing on the Illumina MiSeq platform. In this case, phylogenomic and metadata analyses revealed a predilection for water environments and aquatic animals, with more recent reports in humans and food animals across geographies, making A. veronii a potential One Health indicator bacterium [In one of the published studies, a method was developed to detect bacteria resistant to colistin, carbapenems, and β-lactams in commercial poultry farms, characterizing also the phylogenetic and virulence markers of  animals . Also, i animals . In anotacterium . An exteacterium .Another study also published in this special issue addresses how soil disturbance, and the subsequent shift in community composition, will affect the types, abundance, and mobility of antibiotic resistance genes (ARGs) that compose the active layer resistome by assessing resistance phenotypes through antibiotic susceptibility testing, and analyzing types, abundance, and mobility of ARGs through whole genome analyses of bacteria isolated from a disturbance-induced thaw gradient in Interior Alaska. This study emphasizes the hypothesis that both phylogeny and ecology shape the resistome and suggest that a shift in community composition as a result of disturbance induced will be reflected in the predominant ARGs comprising the active layer resistome . In a diSalmonella spp. from agricultural settings to nearby water sources, highlighting their antibiotic resistance genes (ARG) and virulence factor (VF) distribution using a combination of both culture-dependent and independent methods, concluding that agricultural environment contamination may have a direct relationship with the presence of antibiotic-producing Salmonella in freshwater streams [Escherichia coli (E. coli) pEK499 and its clinically most important ARG (blaCTX-M-15), after introduction via irrigation water or manure into a lettuce-growing system. This study demonstrated long-term persistence of undesired ARB and ARG after their introduction via both irrigation and amendments adding the need to define critical actions in order to mitigate their transfer to the consumer [E. coli, Enterobacter cloacae, and Citrobacter freundii for their potential to transmit resistance to antibiotic-susceptible E. coli, proving that ESBL-producing E. coli was able to transfer resistance with different efficiency to E. coli-susceptible recipients [Using water as an environmental matrix, one study aimed at characterizing and tracking nonresistant and extended-spectrum β-lactamase–producing (ESBL)- streams . Also, iconsumer . IrrigatE. coli from a One Health approach applied on a beef production system, identifying the municipal sewage as a hot spot for MDR emergence and dissemination [E. coli isolated from clinical, dairy manure, and freshwater ecosystem environments concluding that manure and environmental isolates were significantly different from clinical isolates based on analyzed traits, suggesting more transmission occurs between these two sources in the sampled environment [E. coli isolated from different sources , emphasizing the need of a specific surveillance program of AMR indicators in wastewaters from animal or human origin, in order to apply sanitary measures to reduce the burden of resistant bacteria arriving to risky environments such as WWTPs [One of the published studies aimed to compare antimicrobial resistance (AMR) in extended-spectrum cephalosporin-resistant and generic mination . Also puironment . The samas WWTPs .An additional study published intended to assess settleable dust loading rates and bioburden in Portuguese dwellings by passive sampling onto quartz fiber filters and electrostatic dust cloths (EDCs), including azole-resistance screening reinforcing the importance of applying azole resistance screening to unveil azole resistance detection in fungal species . A similE. coli isolation from non-infectious dogs in a veterinary teaching hospital in Taiwan, finding three major subtypes  of ST131 in fecal carriage [Another published study observed three major subtypes  of ST131 in fecal carriage in dogs in Taiwan by rectal swabs used for carriage .A multicenter retrospective study applied in two different teaching hospitals in Romania was published. This study analyzed urine samples from patients to determine the frequency of incriminating pathogens and their resistance to different antibiotics, concluding that the obtained data are an important tool in managing urinary tract infections .Acinetobacter [The three review papers also published in this special issue focused on three different topics: Mitochondria-mediated azole drug resistance and fungal pathogenicity addressing the opportunities for therapeutic development ; correlatobacter , all preOverall, the papers in this Special Issue reveal different perspectives of antimicrobial resistance: from the presence of resistant organisms in different environmental compartments to human exposure in different settings. Furthermore, descriptions of prevention and intervention actions to tackle this public health menace were also described and can be used in the future.


Several insights from the clinical treatment of breast cancer patients have revealed that only a portion of patients achieve the expected curative effect after traditional targeted therapy, that surgical treatment may promote the development of cancer metastasis, and that the optimal combination of neoadjuvant chemotherapy and traditional treatment is not clear. Therefore, a more precise classification of breast cancer and selection of treatment methods should be undertaken to improve the efficacy of clinical treatment. In the clinical treatment of breast cancer, cell communication molecules are often selected as therapeutic targets. However, various cell communications are not static. Their dynamic changes are related to communicating cells, communicating molecules, and various intertwined internal and external environmental factors. Understanding the dynamic microenvironment can help us improve therapeutic efficacy and provide new ways to more accurately determine the cancer status. Therefore, this review describes multiple types of cellular communication in the breast cancer microenvironment and incorporates internal and external environmental factors as variable signaling factors in cell communication. Using dynamic and developmental concepts, we summarize the functional changes in signaling molecules and cells to aid in the diagnosis and treatment of breast cancer. The breast cancer microenvironment consists of mammary ductal epithelium, many kinds of stromal cells  and the extracellular matrix (ECM). Stromal cells surround the cancerous ductal epithelial cells and contact each other through the ECM , 2. DuriCell communication refers to the process in multi-cellular organisms in which cells send a signal to target cells that interact with receptors to cause specific biological effects in target cells. Through accurate and efficient cell communication, physiological and biochemical reactions in cells are regulated and unified to adapt to the changing external environment . NotablyAccording to whether there is physical contact between communicating cells, cell communication can be divided into direct communication and indirect communication. In the breast cancer microenvironment, these two cell communication modes can occur in the same type of cell or between different types of cells.Direct cell communication in the breast cancer microenvironment mainly consists of gap junctions and contact signaling by plasma-membrane-bound molecules . They exGap junctions, which are composed of connexons, consist of connections between histologically identical or heterogeneously adjacent cells. Gap junctions form channels through the pairing of two connexons located in neighboring cells. Human breast ductal epithelial cells, myoepithelial cells and endothelial cells express multiple subtypes of connexin proteins, among which the most important are Cx26 and Cx43. A previous study showed that the deregulated expression of Cx43 and Cx26 in breast cancer often affects the stability of intercellular gap junctions and deregulates cell proliferation. The import of exogenous Cx26 into MCF-7 breast cancer cells can promote the formation of gap junctions in the microenvironment to inhibit the proliferation and invasiveness of breast cancer cells . Macroph2+, the same types of cadherins can interact with each other to form adhesive belts and desmosomes [In adjacent cells, with the help of Casmosomes . These ssmosomes . E-cadhesmosomes . Studiessmosomes -16. Concsmosomes . Therefosmosomes . Anothersmosomes . Some stsmosomes .+ NKT cells and suppress their immune-killing effects to facilitate immune escape in breast cancer [In addition to adjacent cells, cell communication also occurs between cells that are not adjacent through direct cell-cell contact; for example, CD24 expressed by tumour cell can interact with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10), which is expressed by tumour-associated macrophages to send anti-phagocytic signal . This kit cancer . MHC-I mIndirect cell communication includes soluble chemical signal cell communication and extracellular matrix mediated cell communication. The former can mediate paracrine and autocrine communications, and transmit communication molecules between cells through extracellular vesicles, while the latter mainly forms interaction links through the extracellular matrix between cells.During indirect cell communication, chemical signal communication mediated by autocrine and paracrine mechanisms has been more commonly and thoroughly studied than that mediated by other mechanisms. Traditionally, these chemical molecules include interleukin (IL), interferon (IFN), tumor necrosis factor (TNF), transforming growth factor (TGF), chemokines and growth factors. It has been confirmed that all cells in the breast cancer microenvironment can release various cytokines and act specifically on surrounding cells by binding to the receptors expressed on their membrane surface. Subsequently, they sequentially induce biological behavioral changes in recipient cells and regulate the occurrence and development of breast cancer through the kinase signaling system. The most abundant cell type in the breast cancer microenvironment is the fibroblast. Fibroblasts can become cancer-associated fibroblasts (CAFs) after communicating with cancer cells . In the EVs refer to bilayer membrane vesicular bodies that detach from the cell membrane or are secreted from cell. They comprise mainly microvesicles (MVs) and exosomes (Exs). MVs are small vesicles that detach from the membrane after cell activation, damage or apoptosis. They have a diameter of approximately 100–1000 nm. Exs are formed when multi-vesicular bodies fuse with the plasma membrane and can also be released directly from the plasma membrane. They have a diameter of approximately 40–100 nm . CurrentThe ECM, which plays an important role in mediating cell communication, is composed of macromolecules that are synthesized and secreted by cells and located on the surface of or between cells , 38. TheIn brief, breast cancer is the integrated result of a variety of adaptive responses produced by the body after communicating with internal and external environmental factors. Internal and external environmental factors affect the local tumor microenvironment through various modes of cell communication, and during the process of tumor metastasis, close cell communication also forms between the microenvironment of the primary tumor and the metastatic microenvironment. Therefore, basic research on breast cancer should not only focus on cell communication within the local primary breast cancer microenvironment but also be extended to cell communication between the primary cancer microenvironment and the internal and external environments.With continuous growth of the tumor, tumor cells may be transferred to distant sites to form metastases via the blood, lymph or nerve fibers. The formation and development of secondary tumors is often a major cause of cancer-related death. The lung, bone, liver, and brain are common sites of breast cancer metastasis. This kind of organ selectivity is not only associated with the blood supply but also with cell communication between primary tumors and metastases. For example, researchers have summarized 5 fundamental steps during breast cancer metastasis to the bone: (a) Primary cancer cells secrete soluble factors or microvesicles that cause preliminary metastatic ECM deposition to occur; (b) bone marrow-derived cells (BMDCs) infiltrate the metastatic microenvironment; (c) cancer cells arrive at metastases; (d) micro-metastases develop; (e) metastases form .+/VIM+ lung fibroblasts to facilitate the formation of metastases [+/VEGFR1+ hematopoietic progenitor cells (HPCs) in the lungs to stimulate the development of a pre-metastasis into a colonization site for endothelial progenitor cells (EPCs) and disseminated tumor cells (DTCs) [The metastatic microenvironment, also called the metastatic niche, often depends on the formation of direct communication and indirect cell communications between the primary tumor and metastases. During pulmonary metastasis of breast cancer, the cancer cells can secrete TGF-β3 to promote periostin (POSTN) produced in SMAtastases . During tastases . During tastases . The ECMtastases . Cancer s (DTCs) . TherefoIn addition to cell communications between primary tumors and metastases, cell communication can also occur between cells in the microenvironment and cells within other organizations. In the internal environment, proteins, enzymes, hormones, nutrients and metabolites likely act as signaling molecules in cell communication. During lactation, the nerves distributed in mammary glands must transfer signals to the central nervous system, but this process is mainly regulated by hormones secreted from the ovary and pituitary rather than efferent nerves. Therefore, it is meaningful to recognize cell communication mediated by hormones in breast cancer. In addition, metabolites produced by cells within other organs can be treated as generalized signaling molecules that can spread in the local microenvironment and participate in cell communication.+ breast cancer cells stimulated by estrogen and subsequently transmit signaling molecules to influence ER- breast cancer cells. Thus, this is a paracrine-dependent communication mechanism in which estrogen indirectly acts on ER- breast cancer cells [During the process of mammary gland development and lactation, estrogen, progesterone secreted by the ovaries and prolactin secreted by the pituitary gland play important roles in humoral regulation. The occurrence of breast cancer degradation after ovariectomy suggests that circulating levels of humoral factors regulate the development of breast cancer . The incer cells , 58. Theer cells  and adreer cells .During the process of tumor progression, tumor cells can acquire many kinds of nutrients via the blood vessels in the tumor microenvironment. However, a variety of metabolites can also be taken up by tumor cells through circulation of the blood and be signaling molecules between cells to regulate several biological behaviors. The tricarboxylic acid (TCA) cycle is one of the important metabolic mechanisms within cells of the body. As an important intermediate in the TCA cycle, alpha-ketoglutarate (α-KG) is not only involved in metabolism, but also serves as a signaling molecule to affect cell proliferation and migration. Increases in α-KG have been found to up-regulate succinate dehydrogenase (SDH) and fumarate hydratase (FH), reduce the onco-metabolites succinate and fumarate, and further stabilize HIF prolyl hydroxylase 2 (PHD2) and decrease HIF-1α, ultimately suppressing breast cancer metastasis . During The living environment of the individual is the external environment. Although the external environment cannot directly communicate with the tumor microenvironment, by altering the cells and signaling molecules in the internal environment, external environmental factors can also indirectly affect cell communication in the breast cancer microenvironment. Part of the influence of external environment is more acceptable, and some effects of external factors are dynamic. Therefore, analysis of the external environment involved in cell communications can provide more acceptable strategies for breast cancer treatment  Fig. 1)1).Fig. 1Nicotine is an important carcinogen contained in tobacco products. Tobacco smoking causes most of the nicotine to enter the blood circulation through respiration to the lungs. A study showed that as an important component of the breast cancer microenvironment, fibroblasts are influenced by nicotine. Nicotine can interact with nicotinic acetylcholine receptors (nAChRs) on fibroblasts to promote the expression of CTGF and TGF-β and further promote the EMT and metastasis of breast cancer cells . In vivoA study showed that circadian rhythm disorder is a risk factor for breast cancer. In the human body, the circadian rhythm is produced by the endogenous circadian clock. Research has suggested that the biological clock is mainly controlled by the light cycle. One study showed that compared with normal daytime workers, night time workers have an increased incidence of breast cancer by 10%–60% . In 1987Breast tissue is not sterile but contains a diverse population of bacteria . NotablySurgical treatment is an important strategy to cure breast cancer. For patients, surgical treatment not only includes removal of the primary tumor, but it can also alter cell communication between local tissue and distant metastases. Primary tumors in breast cancer can block the angiogenesis of micro-metastatic foci and produce metabolic byproducts to inhibit proliferation. Removal of the primary tumor can eliminate these inhibitions and avoid competition for essential host-derived nutrients that are required for tumor proliferation between the primary tumor and its metastases . High leIn modern society, the quickening pace of life has introduced high-stress work, disordered daily schedules, and social environmental pressures, resulting in a state of long-term psychological stress. Epidemiological studies have shown that compared with women living in the countryside, women living in the faster pace of urban life have a higher incidence of breast cancer. Hongyu Chen found that mice living under a chronic stress state more easily developed lung metastasis of breast cancer. However, using propranolol to block β-adrenergic signaling can observably suppress stress-induced lung metastasis. The underlying β-adrenergic mechanism induces the generation of monocytes and macrophages that metastasize to the lung to promote pulmonary metastasis of breast cancer cells . In summEating habits are often associated with the development of cancer. Lutein is an important component of plant pigments in corn, vegetables, and fruits. As a kind of carotenoid, lutein is present in the leaves of the plant chloroplast, and the body can acquire it through the daily intake of fruits and vegetables. In recent years, lutein has been shown to increase the content of active oxygen to inhibit the proliferation of triple-negative breast cancer cells . In postIt is widely believed that regular exercise habits are beneficial to health. Researchers found that resistance training can decrease inflammatory factors and is associated with prolonged survival for breast cancer patients . A paperThe dynamic changes of cell communication in the breast cancer microenvironment are closely related to the changes in communicating cells and molecules. These changes can be attributed to the changes in communication induced by molecules in the external environment, as well as the internal differences in the composition and heterogeneous functions of communication cells and molecules. Moreover, the stage of occurrence and progression of breast cancer greatly enrich the connotation of this dynamic change. Therefore, the concept of dynamic cell communication should be deeply rooted and implemented in the clinical diagnosis and treatment of breast cancer, to improve the therapeutic effect.+ T cells. In this way, cancer cells are phagocytized or destroyed by innate immune cells. However, chronic inflammatory stimulation can promote T cells to differentiate into Th2 cells, which secrete IL-4, IL-5, IL-6, IL-10 and IL-13. This will induce T-cell anergy and the loss of T-cell-mediated cytotoxicity, thus promoting the progression of cancer [+ B cells, which elicit anti-tumor T cell immunity and improve therapy efficacy, emerged [With the development of research examining the breast cancer microenvironment, the medical community is increasingly focusing on immuno-therapeutic strategies and elucidation of the dynamic changes in immune cells. Moreover, immune cells play important roles in communication between the external environment and the microenvironment. Therefore, tracking the dynamic changes in immune cells is of great significance. In general, the dynamic changes in the immune cells in the breast cancer microenvironment can be classified based on three conditions. A. The same immune cells with different functions during different stages of tumor development. During different inflammatory conditions in the breast cancer microenvironment, the functions of immune cells are significantly different. Acute stimulation of T lymphocytes leads them to differentiate into Th1 cells and secrete INFγ, TNFα and IL-2 to synergistically inhibit cancer development with CD8f cancer . B. The f cancer . The ultf cancer . C. The f cancer . The reaf cancer . Studiesf cancer  and T cef cancer , fully rf cancer . Howeverf cancer . In addi emerged . TherefoThe dynamic changes in the breast cancer microenvironment are closely associated with changes in various communication and signaling molecules. These changes include the structure, content, and location of signaling molecules and the complexes formed with other molecules. Any slight alterations could change or even reverse the existing pattern of cell communication. These molecules such as the adhesion molecules PD-L1 and PD-1, which mediate direct communication between tumor cells and T cells, VEGF and VEGFR, which mediate indirect cell communication in a paracrine and autocrine manner, and estrogen and estrogen receptors, which mediate indirect cell communication similar to hormone and lactic acid metabolite mediation of indirect communication in the local acidic microenvironment, are often considered to be targets in breast cancer treatment. Among these molecules, as the most important molecules in immune therapy, immuno-suppressive molecules have engaged the attention of researchers. In investigations ofimmune escape, researchers have discovered that these immuno-suppressive molecules can change during breast cancer development or in different subtypes of breast cancer.+ and CD4+ mediated anti-tumor response, the modulation of angiogenesis and invasiveness through the inhibition of metalloproteinase, and finally, the enhancement of tumor infiltration by neutrophils and macrophages. In addition to changes in the functions of molecules, the content of molecules also affects their final roles in breast cancer cells. That is particularly important in clinical chemotherapy for breast cancer. It has been found that the maximum-tolerated dose of standard breast cancer chemotherapy drugs  can promote the proliferation of cancer cells by acting on CAFs, and may even reverse the anticancer effects of chemotherapy drugs. Some researchers have suggested that low-dose metronomic therapy could reduce this effect and increase the effect of the drug [Immuno-suppressive molecules refer to molecules that can inhibit the immune response and induce immune evasion. The main immuno-suppressive factors associated with breast cancer include PD-L1, GM-CSF, CTLA4, SDF1, CXCL5, IDO, IL-4, IL-8, IL-10, IL-13, MIF, NOS2, PD1, COX2, VEGF and TGF-β. Most of these immuno-suppressive factors mainly suppress the immune response and promote cancer development in a cell-cell communication manner. In addition, some molecules play different roles during breast cancer development. There are two major sources of TGF-β: mononuclear cells (precursors for macrophages) and low-density polymorphonuclear cells (immature neutrophils) . Takeshithe drug . In addiCell communication and signal transduction are processes that coordinate various communication molecules in vitro, in vivo and in the microenvironment, and finally produce integrated reactions in target cells. Tumors are characterized by the abnormal proliferation and differentiation of target cells and represent an adaptive response to various upstream communication related cell and molecular variations. When we fully realize and enhance the significance of cell communication research, there are still some problems in the research field of dynamic changes of breast cancer cell communication.Tumor size, metastasis to lymph nodes, distant organ metastasis or ER, PR and ERBB2 are usually used as indicators for the clinical classification of breast cancer. These methods cannot satisfy the needs of treatment. Analogous to surgical treatment, the current criteria for the stages of cancer and treatment efficacy cannot explain how the primary cancer promotes the development of metastatic cancer. In the future, these criteria will restrict advancements in the clinical diagnosis and treatment of breast cancer. Taking breast cancer metastasis as an example, current breast cancer staging is heavily dependent on the evaluation of pathology specimens, in which the index of lymph node metastasis or organ metastasis is clearly very uncertain. However, as described earlier, using specific signaling pathways and gene expression profiles may further classify triple negative breast cancer, and Liu Y et al. recently divided the formation of the pre-metastatic niche into 4 stages: priming, licensing, initiation and progression, and enhanced the classification of phenotypes and stages of breast cancer . MoreoveWe are influenced by the external environment in which we always live. Moreover, most of these influences are easy to acquire. Similar to changing the local immune microenvironment, intervening in external environmental factors combined with conventional therapies can undoubtedly produce better effects of cancer therapy. Many external environmental factors can influence the overall physiological state of the body . These The ultimate goal of cell communication is to induce downstream target cells to produce a variety of biological effects in response to changes in external environmental factors. In these biological effects, we often focus on communicating cells with a dominant effect on biology, such as rapidly proliferating cells, dysfunctional cells, and cell communities that exhibit explosive growth during metastasis, but ignore the communication between cells that do not produce obvious pathological changes, termed "recessive cell communication". Two of these cell types and their associated microenvironments are worth mentioning. One type is the temporary dormant cell in a relatively suitable metastatic microenvironment , and another type is the long-term dormant cell in a relatively inappropriate metastatic microenvironment  .Tumor do1. Cell communication in the breast cancer microenvironment includes direct and indirect ways and all the communication patterns are dynamic. Understanding the dynamic changes in the microenvironment of breast cancer is very important for the individualized diagnosis and treatment of breast cancer.2. External environmental factors and internal environmental signaling molecules can communicate with the primary local microenvironment of breast cancer. Guided by interventions involving external environmental factors, a more efficient, economic and acceptable breast cancer prevention and treatment strategy is possible.


Policies aiming at reducing rates of hospitalisation and death from Covid-19 encouraged older people to reduce their physical contacts. For grandparents in England, this meant that provision of care for grandchildren was allowed only under very limited circumstances. To date, evidence on changes in grandparenting during the pandemic is scarce and little is known about whether and to what extent reduction in grandchild care provision impacted grandparents’ mental health. Using pre-pandemic data from Wave 9 (2018/19) and the second Covid-19 sub-study (November/December 2020) of the English Longitudinal Study of Ageing, we first described changes in grandparenting since the start of the pandemic. Then, using regression models, we investigated associations between changes in grandparenting and mental health  during the pandemic, while controlling for pre-pandemic levels of the outcome variables. Almost a third of grandparents reported that the amount of grandchild care during the pandemic reduced or stopped altogether, whereas 10% provided as much or more care compared to pre-pandemic levels, mostly to help parents while working. Compared to grandparents who provided grandchild care at some point during the pandemic, those who stopped altogether were more likely to report poorer mental health, even taking into account pre-pandemic health. A reduction in grandparenting was only marginally associated with higher depression. Although policies to limit physical contacts and shield older people reduced their risks of getting ill from Covid-19, our study shows the consequences of stopping childcare provision in terms of poorer mental health among grandparents.


Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. This is attributed to the disease already being advanced at presentation and having a particularly aggressive tumor biology. The PDAC tumor microenvironment (TME) is characterized by a dense desmoplastic stroma, dominated by cancer-associated fibroblasts (CAF), extracellular matrix (ECM) and immune cells displaying immunosuppressive phenotypes. Due to the advanced stage at diagnosis, the depletion of immune effector cells and lack of actionable genomic targets, the standard treatment is still apoptosis-inducing regimens such as chemotherapy. Paradoxically, it has emerged that the direct induction of apoptosis of cancer cells may fuel oncogenic processes in the TME, including education of CAF and immune cells towards pro-tumorigenic phenotypes. The direct effect of cytotoxic therapies on CAF may also enhance tumorigenesis. With the awareness that CAF are the predominant cell type in PDAC driving tumorigenesis with various tumor supportive functions, efforts have been made to try to target them. However, efforts to target CAF have, to date, shown disappointing results in clinical trials. With the help of sophisticated single cell analyses it is now appreciated that CAF in PDAC are a heterogenous population with both tumor supportive and tumor suppressive functions. Hence, there remains a debate whether targeting CAF in PDAC is a valid therapeutic strategy. In this review we discuss how cytotoxic therapies and the induction of apoptosis in PDAC fuels oncogenesis by the education of surrounding stromal cells, with a particular focus on the potential pro-tumorigenic outcomes arising from targeting CAF. In addition, we explore therapeutic avenues to potentially avoid the oncogenic effects of apoptosis in PDAC CAF. It is nPDGFRB), alpha smooth muscle actin (α-SMA/ACTA2), fibroblast activating protein (FAP), fibroblast-specific protein 1 (FSP1/S100A4), podoplanin (PDPN) and Meflin (ISLR) [One of the greatest challenges in studying subpopulations of CAF in the PDAC TME is a lack of CAF-specific markers; the CAF population has previously been identified by an absence of markers to define other cell types: EPCAM for epithelial cells, CD45 to mark leukocytes and CD31 to mark endothelial cells. However, several markers have been identified to be expressed on CAF, including platelet-derived growth factor receptor-β (PDGFR-β/n (ISLR) ,22. Howen (ISLR) . A furthn (ISLR)  is also n (ISLR) .The interactions between CAF and their microenvironment are highly complex. As mentioned, evidence is emerging that CAF have different functions in the TME ranging from tumor promoting to tumor suppressing, with some maintaining important homeostatic roles. For instance, there are studies that have demonstrated that the presence of certain sub-types of CAF are associated with more aggressive tumors and shorter survival . InitialMyCAF and iCAF are two examples of the heterogeneous CAF populations present in PDAC. Cancer cells drive this transcriptional heterogeneity by reprogramming CAF of different origins which then respond to the complex signaling in the TME in different manners. The growing interest in understanding the different populations of CAF in the PDAC TME has led to many recent studies carried out at single cell resolution ,28,29,30Despite increasing knowledge about the heterogeneity of CAF and their importance in both normal tissue homeostasis and in tumorigenesis, they have often been neglected when developing and administering anti-cancer therapies. There is limited understanding of how CAF  are affected by conventional anti-cancer therapies, both directly and indirectly. This review will focus on the often-neglected oncogenic processes arising by cell death in the TME and how apoptosis and administration of cytotoxic therapies in PDAC potentially fuel oncogenesis by the education of CAF into tumor-promoting phenotypes. We will then review the potential pro-tumorigenic outcomes arising from the ablation of CAF in PDAC before touching on novel targeting strategies that could avoid the oncogenic effects of direct apoptosis and depletion in PDAC CAF.Under normal physiological conditions, somatic cells undergo mitosis and, after a certain number of divisions, apoptosis. When this balance is disturbed, disease, including cancer can develop, either by an increase in cell proliferation or a decrease in cell death. Apoptosis in cancer cells has largely been associated as a positive phenomenon, with the main goal of cancer treatment being to induce maximal death in cancer cells and minimal damage to healthy cells. However, even though apoptosis is a cell-autonomous event, when put into a complex microenvironment, the effects of apoptosis are not uniformly positive and paradoxically, many of these effects have been seen to fuel oncogenesis. As a matter of fact, many studies in different cancer types have shown that higher levels of apoptosis is correlated with poorer outcomes ,37,38,39Drosophila melanogaster, where caspase-dependent apoptosis in the imaginal disk was shown to activate mitogenic signaling, promoting the proliferation of neighboring cells [2 has shown to be a key mediator in AiP. When caspases are cleaved, calcium-independent phospholipase A2 (iPLA2) is activated, resulting in an increased production of arachidonic acid which is converted, via cyclooxygenase 1 (COX1) or cyclooxygenase 2 (COX2), to PGE2. PGE2 in the context of cancer has been shown to promote stem and progenitor cell proliferation and angiogenesis, inhibit T-cell activation and educate immune cells to tumor-promoting phenotypes [2 being released by tumor cells following conventional cytotoxic treatments has led to efforts in trying to target PGE2, which was shown to be effective by the inhibition of cancer stem cell (CSC) repopulation, reduce incidence and mortality and enhance the effectiveness of chemotherapeutic regimens [It is known that apoptotic cells can promote proliferation in surrounding cells, a process also known as apoptosis-induced proliferation (AiP). This compensatory mechanism was first observed in ng cells ,41,42. Ienotypes ,44. The regimens ,46,47.The modulation of immune cells in the TME by apoptotic cells is often neglected in pre-clinical studies. Anti-cancer therapies have historically been tested using human tumors xenotransplanted into immunocompromised mice ,49 whereApoptotic cells also release extracellular vesicles (EVs) as a way to communicate with proximal and distal sites. EVs released from apoptotic cells are membrane-delimited vesicles that display a broad size heterogeneity ranging from exosomes (30–150 nm) and microvesicles (100–1000 nm) to larger apoptotic blebs/bodies (50 to 5000 nm) . These vRecently, there have been a number of reviews published giving further details about the oncogenic effects of apoptosis in cancer cells ,52,55,66Drosophila, observed compensatory proliferation occurring in imaginal disc compartments neighboring those in which apoptosis was induced [Paradoxically, apoptosis induction in cancer cells can cause undesired effects and even promote tumor progression. Initial studies, performed in  induced . These p induced , and hav induced ; hence, 2 release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs [2 and inducing AiP, in addition to suppressing the immune response in an already immunosuppressive TME.Apoptosis and necrosis are the two major types of tumor therapy-induced cell death . Apoptosry DAMPs . These dDAMPs released by damaged tissue or dying cancer cells have also been shown to activate CAF . For insHMGB1 is the DAMP most associated with cancer and has been shown to play an active role in cancer-associated inflammation and pathogenesis. HMGB1 is a potent TLR activator, and the link between DAMP induced TLR activation, chronic inflammation and carcinogenesis has been demonstrated in previous studies ,76. In PThe increase in reactive oxygen species (ROS) is often observed in the progression of apoptosis or necrosis induced by cytotoxic drugs. The release of ROS and a shift in tumor cell metabolism can endow stromal fibroblasts, especially myofibroblasts, with a tumor-promoting phenotype . For insCancer cells releasing EVs upon apoptosis potentially have tumor-promoting effects. A study in gastric cancer showed that CAF induced apoptosis in the cancer cells, which resulted in the release of apoptotic vesicles from the cancer cells, educating the CAF to facilitate migration of cancer cells. This suggests CAF-mediated cancer cell apoptosis may promote cancer dissemination .These studies are just a few examples of how conventional cytotoxic therapies potentially educate CAF to adopt a phenotype that can drive tumorigenesis . HoweverCytotoxic therapies are the standard treatment in advanced PDAC, with the majority of patients not eligible for curative surgical resection. With CAF being the main cellular component, driving tumorigenesis, one could hypothesize that cytotoxic therapies could be used to eradicate CAF together with the tumor cells. Indeed, using standard chemotherapy regimens such as gemcitabine and nab-paclitaxel have resulted in a reduction of α-SMA-positive cells .In comparison to cancer cells, CAF are considered to be relatively genetically stable, However, when fibroblasts are exposed to cytotoxic drugs or radiation-induced DNA damage, genetic mutations can be induced, resulting in CAF expressing a phenotype that contributes to the process of malignant transformation and further tumor progression ,83. TherShh), desert hedgehog (Dhh), and Indian hedgehog (Ihh), all involved in conserved pathways including cell differentiation, proliferation and survival [This idea of chemotherapeutics activating the tumor stroma, resulting in a more aggressive phenotype, has been suggested in several cancer models. Chemotherapy can stimulate HIF1, NFkB, SMAD, STAT3 and JNK/AP1 stress-linked signaling pathways in CAF, leading to a microenvironment which in turn can promote cancer proliferation and educate immune cells to an immunosuppressive phenotype, making cancer more invasive ,87,88. Ssurvival . Deregulsurvival , and strsurvival . In addition to apoptosis, cell senescence can be induced by chemotherapy in those cells sensitive to the cytotoxic agent. Senescence results in proliferation arrest. However, as a consequence of cell transformation it has been observed that clones can emerge that restart proliferation and become more aggressive . In diffStudies have shown that CAF exposed to chemotherapy release EVs that in turn can educate surrounding cells to a pro-oncogenic state and enhance treatment resistance in cancer cells. MSCs under stress increase osteosarcoma migration and apoptosis resistance via the release of EVs containing microRNAs associated with metabolic and metastasis-related genes . CAF expMost cancer patients will under their course of treatment have radiotherapy. Even though the cancer cells are being targeted, ultimately, the surrounding TME, including the CAF will also be irradiated. CAF, however, will undergo senescence and permanent DNA damage rather than die when irradiated. Radiotherapy-treated CAF are activated and educated towards an unfavorable phenotype, leading to an altered secretome of factors associated with driving cancer cells to EMT, increased invasiveness and therapy resistance .Even though PDAC is a relatively radiotherapy resistant cancer, it is a treatment option sometimes used in combination with chemotherapy. Very little is known about the fate of PDAC CAF when exposed to radiotherapy. Recently, it was shown that radiotherapy increased inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) secretion by CAF following radiotherapy which in turn increased iNOS/NO signaling in tumor cells through NFkB. Tumor cells educated by CAF subjected to radiotherapy increased the release of inflammatory cytokines; upon inhibition of iNOS when combined with radiotherapy, PDAC tumor growth was delayed in a mouse model .2, which can also be applied to apoptotic stromal cells. CAF-mediated PGE2 secretion is known to induce cancer cell invasion [2 could have many pro-tumorigenic functions in the TME. For instance, stromal cells undergoing apoptosis reprogramed monocytes/macrophages after phagocytosis to upregulate COX2, IDO, PD-L1, IL-10 and release PGE2, resulting in inhibition of T-cell proliferation [Apoptotic cells are known to release PGEinvasion . Stromalferation .Together, these studies imply that conventional anti-cancer treatments can educate CAF to drive tumorigenesis  and sugg+ cells using diphtheria toxin depletion in a PDAC model reduced tumor growth and re-established tissue homeostasis [+ cells [Based upon the growing body of studies showing the role of CAF in tumor progression, there has been an extensive effort in targeting CAF in the PDAC stroma by selective depletion. Pre-clinical studies carried out in various cancer types including PDAC have shown promising results. For example, the conditional ablation of FAPeostasis . Furthereostasis . Other eeostasis , FAP anteostasis , peptideeostasis  and CAR-[+ cells  have als[+ cells . These d+ CAF and poor clinical outcomes [+ macrophages [Even though some studies have been encouraging with regards to targeting stromal cells, there are also numerous studies attempting to target CAF that have yielded unexpected results reflecting the heterogeneity of CAF and questioning whether CAF only have tumor-promoting functions . Severaloutcomes ,117,118;rophages ,120.SMO), which prevents the induction of GLI transcriptional activity when cancer cells are exposed to Shh ligands. In a study where mice were treated with the SMO inhibitor IPI-926 prior to tumor formation, smaller tumors were seen compared to the controls; however, the tumors were more poorly differentiated than the controls and the mice had severe weight loss and died earlier [Paracrine Hedgehog (Hh) signaling from cancer cells is known to activate CAF and promote stromal desmoplasia. Hence, blocking Hh signaling was hypothesized to lead to reduced fibrosis and desmoplastic formation in PDAC. When Hh-dependent CAF in a PDAC mouse model were genetically depleted, accumulation of an Hh-dependent stroma in all the stages of PDAC development was blocked. The mice with the Hh-depleted stroma developed tumors much faster than controls and their tumors were poorly differentiated with a higher tendency to metastasize . Another earlier , questio earlier .+) expression with either chemotherapy or vismodegib [Even though there are a few preclinical studies with Hh inhibitors in combination with cytotoxic therapies that have shown some encouraging results ,124, usismodegib , highligRecently, it was discovered that Meflin, a membrane-bound glycosylphosphatidylinositol-anchored protein, is a marker for tumor-suppressive CAF in PDAC. Meflin was previously identified on MSCs in their undifferentiated state  and PSCsWe are now starting to document the heterogeneity of CAF, with some being shown to be tumor progressive and some tumor suppressive. As well as cancer cell-CAF crosstalk, with recent publications showing that different CAF populations can communicate with other stromal cells , and potAs discussed, depletion and/or direct cytotoxic targeting of the tumor-supportive stroma in PDAC may enhance tumor progression; hence, there is a need to explore other routes in targeting the tumor-supportive stroma. Induction of quiescence or reprograming (from tumor-promoting to tumor-suppressive phenotypes) may be more promising approaches. There have been studies suggesting that vitamin D analogues or derivatives  have the capability to reprogram activated PSCs to a more quiescent state, sensitize PDAC cells to chemotherapy and inhibit tumor progression in mice ,131,132.Minnelide is a synthetic and water-soluble pro-form of triptolide, a diterpenoid epoxide produced by the thunder god vine. When treated with Minnelide, CAF can be educated into a more quiescent state via TGF-β1 inhibition  which isSSA3) in PDAC has shown to be associated with decreased survival and to be a pro-tumorigenic driver by the interaction of PDGFRα+ CAF and cancer cells [Stromal expression of serum amyloid A3  has been shown to be a driver in PDAC tumorigenesis via its involvement in ECM synthesis, stress-fiber assembly, cell contraction and promotion of unfavorable ECM remodeling via CAF MMP secretion ,144,145.LXA4). LXA4 inhibited TGF-β-mediated transformation in PSCs by blocking pSmad2/3 signaling, restricted crosstalk between CAF and PDAC cells and inhibited tumor growth, attributed to a significant reduction in fibrosis in a PDAC mouse model [Conversion of PDAC CAF to a myoblastic phenotype without inducing apoptosis has also been achieved with the bioactive lipid Lipoxin a4 (se model .Targeting upstream signaling pathways essential to the change from being tumor-restraining fibroblasts to a tumor-supporting phenotype might be another option. Studies using inhibitors alone or in combination with cytotoxic therapies have been carried out. Examples of inhibitors used are the FAK inhibitor defactinib , fibroblAnother approach is attempting to modulate CAF matrix deposition. For instance, PEGPH20, a pegylated hyaluronidase enzyme, has the ability to deplete hyaluronic acid produced by CAF. Hyaluronidase treatment showed promise in animal models and early clinical trials by improving progression-free survival in some PDAC patients ,156. UnfThese studies suggests that there are multiple strategies to explore when considering the targeting of CAF without fueling pro-oncogenic processes via direct apoptosis induction or depletion . This giDespite being the main component of the TME in desmoplastic tumors such as PDAC, CAF were for a long time overlooked, especially when administering anti-cancer therapies. As discussed in this review, we now understand that inducing cell death with cytotoxic therapies can drive CAF-dependent tumor progression either directly or indirectly. Eliminating CAF from the PDAC TME is therefore a viable and evidence-led approach; however, many studies have highlighted the complexity of CAF, indicating that they could have both tumor supportive and suppressive roles. It is likely that future studies will look to target or modulate specific CAF phenotypes to impact pathology in a more controlled manner.To target specific CAF phenotypes in PDAC, there are still many unanswered questions that need to be addressed. First, we need to improve our understanding of the origin of different CAF and identify more CAF-subpopulation markers for differentiating tumor-promoting versus tumor-suppressive CAF phenotypes. We then need a better understanding of how CAF heterogeneity varies in individual patients and cancer subtypes and whether we can stratify PDAC patients based on stromal composition to yield improved therapeutic outcomes.By answering the above questions in addition to gaining better knowledge of how anti-cancer therapies directly and indirectly educate CAF in the TME, hopefully strategies to target PDAC cells and its surrounding tumor-promoting stroma can be optimized, resulting in improved survival for patients.


Major global crops in high-yielding, temperate cropping regions are facing increasing threats from the impact of climate change, particularly from drought and heat at critical developmental timepoints during the crop lifecycle. Research to address this concern is frequently focused on attempts to identify exotic genetic diversity showing pronounced stress tolerance or avoidance, to elucidate and introgress the responsible genetic factors or to discover underlying genes as a basis for targeted genetic modification. Although such approaches are occasionally successful in imparting a positive effect on performance in specific stress environments, for example through modulation of root depth, major-gene modifications of plant architecture or function tend to be highly context-dependent. In contrast, long-term genetic gain through conventional breeding has incrementally increased yields of modern crops through accumulation of beneficial, small-effect variants which also confer yield stability via stress adaptation. Here we reflect on retrospective breeding progress in major crops and the impact of long-term, conventional breeding on climate adaptation and yield stability under abiotic stress constraints. Looking forward, we outline how new approaches might complement conventional breeding to maintain and accelerate breeding progress, despite the challenges of climate change, as a prerequisite to sustainable future crop productivity. Breeding is a long-term process. Conventional selection procedures consider plant performance in multiple environments over many years and are thus well-suited for adaptation to climate change. However, modern breeding technologies can help to accelerate the incremental accumulation of positive alleles for “invisible” physiological traits underlying climate adaptation.Crop growth and performance are impacted by a complex interplay with a multitude of interacting environmental (E) and management factors (M), with climate variation explaining a considerable proportion of global crop yield variation , but can also be due to diurnal fluctuation of environmental factors, for example a combination of heat with high light intensity, causing an imbalance between rates of root water uptake and canopy transpiration. Therefore, the generic term “drought stress” needs to be understood as a collective of potential drought scenarios ] returned more than 17,500 published articles, of which around 20% referred to the four major global arable crops wheat, rice, maize and soybean. Over half of all these articles were published in just the last five years. However, despite this rapidly growing publication activity, which presumably reflects a simultaneous rise in research activity in the face of expanding climatic challenges for crop production, progress in improving drought tolerance has been no more than incremental in most crops. For example, studies describing individual genes or gene networks purportedly conferring drought resistance in model and crop plants are very frequent  has a major effect on quantitative inheritance of row number per rachis  can increase spikelet fertility  depending on the timing, duration and severity of specific drought events. Rarely are these complex responses governed by single genes and thus amenable to simple selection, marker-assisted breeding, transgenesis or gene editing approaches. Physiologically, a strategy in response to drought, for example an increase in abscisic acid (ABA) production, can trigger several feedbacks in eco-physiological networks. Depending on the genetic and environmental context, this can result in positive or negative effects on short or long-term plant growth patterns  occur in tandem, and they can also be further compounded by stress from high light , likely due to a misconception that these traits are not relevant in high-yielding conditions because yield-suppressing factors are able to be minimised by intensive management. This chain of argumentation is often expressed in popular media sources, but rarely supported by empirical data in peer-reviewed publications. In stark contrast to this hypothesis, however, studies that empirically examined retrospective breeding progress in different crops have actually concluded that the opposite situation appears to be the case  and specific physiological processes contributing to grain yield  are frequently studied in considerable detail in selected plant genotypes. To adequately understand genotype–environment interactions with abiotic stress and their impact on reproductive capacity and grain yield, it becomes necessary to elucidate “hidden” traits and pleiotropic interactions by detailed temporal phenotyping across critical crop growth periods. However, detailed investigations of dynamic temporal phenotypes in representative crop populations or breeding progenies are much more challenging than single time-point phenotyping of simple target traits. Although analyses of dynamic phenotypes in large breeding populations are very rare to date, new advances in digital phenotyping and drone-based remote sensing are beginning to deliver a level of detail that can help uncover hidden genetic variants impacting the complex genetics of yield and stress responses (for examples, see Chen et al. Extensive retrospective datasets documenting breeding progress, like those described in Fig. Long-term yield gains through breeding progress typically correspond with incremental, genome-wide elimination of alleles with small, detrimental effects as a response to selection (Voss-Fels et al. Recently, Mahmoud et al.  presente“Silver bullets” to breed for climate change, in the form of novel or induced genetic variants for beneficial phenological and physiological responses, can certainly play an important role in context-dependent crop stress adaptation, and new tools like gene editing provide breeders with completely new opportunities to accelerate the implementation and stacking of beneficial variants for important target traits. However, the majority of major-effect genes for key adaptation traits are generally rapidly fixed in high-performing modern crop gene pools, and pleiotropic interactions associated with severe changes in plant phenology mean that breeders need to be cautious when promising huge returns from technological breakthroughs on a single-gene level. On the other hand, conventional selection processes in plant breeding, driven by testing and selection in diverse environments over many years, have proven well-suited for gradual adaptation of modern cultivars to changing environmental conditions—just as the same approach was enormously successful in adapting globally successful crops to diverse eco-geographical and climatic conditions that go far beyond the natural habitat range in their centres of origin.Incremental accumulation of beneficial alleles for complex quantitative traits impacting yield and quality has been the fundamental basis of historical breeding progress in all crops, and this process can be expected to also play a major role in crop adaptation to climate change in future. However, retrospective breeding progress for climate adaptation was in most cases simply the positive by-product of long-term, multi-environment selection for high yield and cultivar registration policies that encourage high yield stability (Snowdon et al.


Circular RNAs (circRNAs) are a type of long non-coding RNA with covalently closed loops that are naturally resistant to exoribonuclease. With the rapid development of high-throughput sequencing technologies and bioinformatics, increasing data suggest that circRNAs are abnormally expressed in renal cell carcinoma (RCC) and act as important regulators of RCC carcinogenesis and progression. CircRNAs play important biological roles in modulating cell proliferation, migration, invasion, apoptosis, and gemcitabine chemoresistance in RCC. Most of the circRNAs studied in RCC have been reported to be significantly associated with many clinicopathologic characteristics and survival parameters of RCC. The stability and specificity of circRNAs enable them potential molecular markers for RCC diagnosis and prognosis. Moreover, circRNAs have emerged as targets for developing new therapies, because they can regulate various signaling pathways associated with RCC initiation and progression. In this review, we briefly summarize the biogenesis, degradation, and biological functions of circRNAs as well as the potential clinical applications of these molecules for RCC diagnosis, prognosis, and targeted therapy. Renal cell carcinoma (RCC), the most common kidney neoplasm, originates in renal tubular epithelial cells and affects over 430,000 individuals all over the world per year . The incGene mutation and epigenetic disorder play an important role in the occurrence and development of RCC. It is well known that the von Hippel-Lindau (VHL) gene, one of the most common tumor suppressor mutated genes in RCC, is frequently inactivated in over 80% of ccRCC patients . This leCircRNAs, a novel subclass of non-coding RNAs, are characterized with the covalently closed structure without 5′caps and 3′poly(A) tails. Due to the absence of free ends, circRNAs are naturally resistant to exoribonuclease and more stable than linear RNA both inside cells and in extracellular plasma, including blood, saliva, urine, and exosomes . MoreovePrecursor messenger RNA (pre-mRNA) is canonically spliced into functional linear RNA transcript with 5′ to 3′ polarity via removing introns. However, circRNAs are generally generated by back-splicing of precursor mRNAs(pre-mRNAs), a process of binding between the downstream 5′ splice donor site and upstream 3′ splice acceptor . AccordiEmerging data have identified that circRNAs formation is modulated by cis-regulatory elements and trans-acting factors. Several recent studies have suggested that the processing of circRNAs can be accelerated by either RNA pairing of reversely complementary sequences across their flanking introns  or proteUp to now, the elimination and degradation of circRNAs in cells remain poorly understood. Most of the exon-containing circRNAs are transported from the nucleus to the cytoplasm in a size-dependent manner through ATP-dependent RNA helicase ddx39 . BecauseThe potential functions and biological activities of circRNAs have been extensively studied. The main functions of circRNAs include modulating the parental genes expression, regulating gene transcription, acting as miRNA sponges, translating into proteins or peptides, serving as protein scaffolding and reservoir, forming pseudogenes, and acting as biomarkers .CircRNAs play an important role in regulating parental genes by interacting with proteins and RBPs. On the one hand, certain circRNAs containing introns, both EIciRNAs and ciRNAs, can interact with RBP and affect the mRNA expression of parental genes. For example, EIciRNAs interact with U1 small nuclear ribonucleoprotein (snRNP) to further combine with polymerase II (Pol II) and regulate the promoter region of host gene transcription . AdditioAmong its biological functions, circRNAs mainly exert their function as a miRNAs sponge. By binding to the 3′UTR of mRNAs, miRNAs affect the stability of mRNAs and modulate gene expression in the nucleus and cytoplasm . There iThough circRNAs do not contain a 5′ methylguanosine (m7G) cap structure and a poly (A) tail, several studies have shown that engineered circRNAs can encode proteins when they contain internal ribosome entry sites (IRESs) that can promote direct binding of initiation factors or the ribosome to the translatable circRNAs . MoreoveCircRNAs maybe serve as protein scaffolding to provide binding sites for the assembly of multiple proteins, such as enzymes and their substrates, thus forming large protein complexes . For exaA pseudogene is defined as any genomic sequence that contains a defective copy of a gene, which is similar to another gene and has no capacity for coding protein due to the accumulation of mutations . In 2016More and more studies have shown that circRNAs play pivotal roles in the occurrence and development of cancer and might function as cancer biomarkers and novel therapeutic targets . A resulEarly detection of circRNAs was rare and limited because of the stable circular structure. With the development of detecting techniques and bioinformatics tools, investigations on circRNAs have been significantly increased and substantial progress has been made in the identification of differential expression of circRNAs in RCC. Genome-wide detection plays an essential role in circRNAs detection, and RNA sequencing (RNA-seq) was the first technology used for the detection of circRNAs genomes. A few years ago, a study using circRNAs microarrays found that 542 circRNAs were abnormally expressed in ccRCC, of which 324 circRNAs were significantly down-regulated, while 218 circRNAs were up-regulated in ccRCC tumors . In 2019The aberrant circRNAs commonly exist in RCC , regulatin vitro and reduced tumor growth in vivo, which offered a potential therapeutic target for RCC treatment. Another study revealed that CircPUM1 upregulated FABP7 expression by competitively binding to miR-340-5p, and then activated the MEK/ERK pathway, thus promoting ccRCC progression , number of tumors, distant metastasis and recurrence. For instance, circPTCH1 is upregulated in RCC cell lines and tumor samples, and higher levels of circPTCH1 are significantly correlated with advanced Fuhrman grade and greater risk of metastases . AccordiSince circRNAs are very stable and conserved molecules, along with their cell-type-specific and tissue-specific expression patterns, reflecting their potentials as novel biomarkers. Early diagnosis and accurate evaluation of the prognosis of RCC are vital for improving treatment efficacy and reducing the mortality of patients with RCC. Therefore, specific biomarkers are urgently needed for the early diagnosis of primary patients and early identification of the local recurrence or distant metastasis after surgical resection in RCC.Increasing studies identified that the expression of circRNAs shows disease specificity and clinical relevance. For instance, the area under the receiver operating characteristic curve (AUC-ROC) of hsa_circ_0001451 was 0.704 for ccRCC diagnosis, with sensitivity and specificity of 0.755 and 0.608, respectively . AdditioAdditionally, some circRNAs play an important role as a prognostic biomarker, such as overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). A study indicated that high circPRRC2A expression was an independent risk factor of worse OS and poorer metastasis-free survival . StudiesThe above examples demonstrated that some circRNAs could be promising biomarkers for the diagnosis and prognosis of RCC. However, the differential expression of these circRNAs in tissues cannot be shown in plasma or serum. Therefore, the clinical application of circRNAs as biomarkers still needs further research.As mentioned above, aberrant circRNAs are related to the occurrence and development of tumors by modulating various signaling pathways, which are potential targets for novel drugs in RCC. Overexpression or knockdown of related circRNAs might be an effective intervention strategy for RCC progression. Considering that the PI3K/Akt/mTOR signaling pathway is an important regulator of cell survival and proliferation, targeting circRNAs to inhibit PI3K/Akt/mTOR pathway may be an effective way to treat renal cell carcinoma. Studies have shown that overexpression of hsa-circ-0072309  and circAt present, drug resistance is a tremendous obstacle to cancer treatment, which needs to be solved urgently. According to the research, high expression of hsa-circ_0035483 was associated with gemcitabine resistance in RCC . Gemcitain vitro and in vivo. A study reported that overexpression of circ-FNDC3B may weaken the effects of curcumin on inhibiting proliferation and promoting apoptosis of RCC cell through regulating the miR-138-5p/IGF2 axis, which provides a new perspective for the treatment of renal cell carcinoma (In addition, circRNAs have an impact on the efficacy of some drugs, such as curcumin. Curcumin could suppress renal carcinoma tumorigenesis arcinoma .As circRNAs’ regulatory roles in cancer are gradually being unveiled, circRNAs might be developed as novel effective therapeutic targets. The real clinical application of circRNAs as drugs or targets needs more details. In general, the research on circRNAs as potential therapeutic targets will be a hot spot in the field of oncology.In the past decade, the role of circRNAs in carcinogenesis has been widely investigated by researchers. As outlined in this review, a large amount of data indicates that circRNAs are strongly associated with tumorigenesis and progression of RCC. We summarized the differentially expressed circRNAs in RCC and their regulatory pathways on cancer-related biological behaviours. The regulatory role of circRNAs in RCC carcinogenesis and progression reflects their potential therapeutic targets for RCC. CircRNAs are significantly associated with many clinicopathologic characteristics and survival parameters in RCC patients which along with their acceptable diagnostic values render them potential diagnostic and prognostic biomarkers for RCC.It is worth noting that there are limitations of current research and many challenges remain to be overcome in this field. CircRNAs have a variety of important biological functions, but almost all reported circRNAs in RCC focused on their function as miRNAs sponges. However, it is unclear whether other functions of circRNAs are involved in regulation at the same time, such as regulating gene transcription, functioning as protein decoys, and translating into proteins or peptides, which are worth further research. In addition, circRNAs’ roles in serving as protein decoys and translating into peptide may be promising, which may be involved in the pathogenesis of RCC by regulating the expression of disease-related proteins. CRISPR-Cas13 technique, which can knock out circRNAs without affecting homologous mRNAs , may bec


Metabolic related diseases such as cancer, diabetes mellitus and atherosclerosis are major challenges for human health and safety worldwide due to their associations with high morbidity and mortality. It is of great significance to develop the effective active pharmaceutical ingredient (API) delivery systems for treatment of metabolic diseases. With their unique merits like easy preparation, high adjustability, low toxicity, low cost, satisfactory stability and biodegradation, deep eutectic solvents (DESs) are unarguably green and sustainable API delivery systems that have been developed to improve drug solubility and treat metabolic related diseases including cancer, diabetes mellitus and atherosclerosis. Many reports about DESs as API delivery systems in the therapy of cancer, diabetes mellitus and atherosclerosis exist but no systematic overview of these results is available, which motivated the current work. Metabolic related diseases are diseases caused by obstacles in the process of anabolism and catabolism in human body . Cancer,Drug delivery systems, such as liposomes, hydrogels, nanomaterials and ionic liquids, are significant alternatives to improve the solubility of poorly water-soluble active pharmaceutical ingredients (APIs) . NotablySekiguchi and Obi introduced the earliest eutectic mixture (sulfathiazole:urea based DES) into biomedical field in 1964 . The DESPreviously, DESs have been successfully used in the therapy of metabolic related diseases. However, there was no systematic review on these studies. Herein, we summarized the applications of DESs as API delivery systems in the treatment of metabolic diseases including cancer, diabetes mellitus and atherosclerosis.d-limonene, l-menthone, 1,8-cineole, thymol and cymene were selected to be mixed with ibuprofen to prepare the DES system , proline:urea  and proline:malic acid:lactic acid:water   was used to explore the potential of DES as a solubilizing agent for polyphenol administration  can be used to increase the solubility of ethambutol.The amino acid based DESs have good solubility to some specific compounds  Figure , Table 20.3:0.5) . The resstration . Take ruIt has been reported that a borneol:menthol  based DES delivery system can promote the intestinal absorption of daidzein  Table 2Table 2. Considering the great mass and energy exchange for cell survival, cancer cells exhibit discernible differences in metabolic level compared to normal cells. They autonomously reprogram their metabolism level and adapt to the tumor microenvironment to meet the vigorous bioenergetic and biosynthetic demand . At the Many anti-cancer drugs that target metabolic pathways have been synthesized by the researchers but it remains unsettled to find an economical-friendly and highly soluble solvent for the anti-cancer drugs administration. DESs were applied to the treatment of cancer through their anti-cancer activity or the capacity for dissolving anti-cancer drugs. A limonene based DES  could also effectively inhibit the proliferation of human colon cancer cell line HT29 without affecting the viability of healthy cells, indicating that therapeutic DESs have extensive anti-cancer potential  Table 3Table 3. N,N-diethylammonium chloride (DAC) based and choline chloride based DES were evaluated by investigating the interaction of DESs and cancer cell lines  with the conductor-like screening model for real solvents  significantly reduced blood glucose levels within 4 hours in a time-dependent manner. In brief, DESs can be used as a promising insulin carrier in the treatment of endocrine diabetes, which is administered through the skin, nasal mucosa or oral mucosa.Transdermal administration of choline:geranic acid based DESs can also increase API delivery efficiency for insulin and increase the skin permeability of the drug  Table 3Table 3. Atherosclerosis, one of the most common cardiovascular disorders is highly associated with the disorders of lipid and lipoprotein metabolism . Curcumiin vivo, and explore their effectiveness in metabolic-related diseases. Moreover, substantial work should be done in the clinical treatment of metabolic diseases using DES-based API delivery systems.As green, economical and biodegradable solvents, DESs are becoming increasingly important because of their abundant precursor components, accessible synthesis methodologies and potential to improve drug solubility and bioavailability. DESs have been effectively employed as API delivery systems in the treatment of metabolic related diseases. However, it is difficult to achieve long-term sustained release using most DESs carriers. Additional efforts should be done to develop the sustained DESs delivery systems, assess their safety


A total of 8 contributions which includes two mini-reviews, two reviews and four original research articles are summarized here:The native extracellular matrix (ECM) is an active material which engages in multi-faceted and complex interactions with cells. Directed cell to ECM communications are known to be essential for functional tissue regeneration such that stem cells, whether native or therapeutically introduced, require an ECM for sensical structural development. Current technologies available for therapeutic interventions in cardiovascular disease have relied largely on mechanical products, xenografts, or some form of composite structure (Bioprosthetics). These products unlike native, biologically living tissues such as heart valves and blood vessels have a shortened life span because of a lack of self-repair and immune mediated destruction. These materials also do not grow with younger patients. Extracellular matrix as a medical therapeutic product involves decellularization of a tissue such that all that remains is the ECM framework, devoid of cellular structures or biological markers. Such scaffolds have enormous potential as a therapeutic option. A breakthrough in regenerative medicine would revolutionize the field of cardiovascular medicine and surgery, where a large sub-set of patients currently face limited treatment options. The advent of regenerative therapies could yield needed, life-saving treatment of congenital cardiovascular defects  by supporting somatic growth in the young patient, aid in induction of neovascularization at sites of cardiac damage, and provide hemodynamically resilient, living vascular grafts to replace large arteries that have limited patency due to disease. This Research Topic, aptly named, “Extracellular Matrix for Cardiovascular Reconstruction,” is being presented at this specific time because of the recent explosion of exciting Delfín et al. remind us of the critical roles that selected ECM proteins play in both cardiovascular homeostasis and in pathologies. Specifically, they focus on a recently identified protein, ABI3BP, that is present in the cardiovascular tissues and whose concentrations are decreased in diseased conditions such as dilated cardiomyopathy. The article further emphasizes the multi-faceted and complex role that a single ECM protein, i.e., ABI3BP, has in both augmenting and reducing cardiac repair/regeneration. The other mini-review by Ramaswamy et al. sheds light on several matricellular proteins such as Decorin, Fibulin-1 and Lumican in the context of vascular tissue engineering. The article describes matricellular protein activity that could positively influence important properties in functional de novo blood vessels, such as mechanical integrity, anti-thrombogenicity, endothelialization, and measured recruitment of vascular smooth muscle cells.In a mini-review article, O'Rourke et al. provide a comprehensive review of not only traditional understanding of macrophages in cardiovascular tissues but infuse the article with a report of contemporary findings regarding the restriction of inflammatory responses by macrophages that lead to abnormal ECM remodeling and subsequent heart failure following myocardial infarction. Meanwhile, the other review article by Pattar et al. also targets the critical problem of poor ECM remodeling following myocardial infarction, and discusses the surgical repair of the disease-induced, damaged cardiac muscle, using decellularized ECM bioscaffolds. Of primary interest is the bio-active molecules that are contained within these bioscaffold materials and that can enhance healthy, cardiac regenerative processes while minimizing abnormal tissue remodeling.Hostile vs. healing macrophage responses in tissue remodeling has long been an aggressively pursued area among cardiovascular researchers. Bax et al.; Gonzalez et al.; Bibevski et al.; Allen et al. round-up the list of contributions in this Research Topic, with all four having a materials and/or mechanobiological framework but in different settings. Following in vivo observations, Bax et al. developed an in vitro engineered tissue model system to study the individual and combined effects of TGFβ growth factor and cyclic strain on human epicardium-derived cells. Through TGFβ/ALK5-dependent signaling, these cells promoted remodeling of the cardiac ECM via the production of type I collagen. Gonzalez et al. utilized a bioreactor platform to identify how physiologically-relevant, fluid-induced oscillatory shear stresses can differentiate human bone-marrow derived mesenchymal stem cells seeded on a 3-dimensional substrate. The experiments led to ECM formation that exhibited a healthy valve phenotype, which could potentially accelerate heart valve regeneration in vivo. Such an approach may serve useful for a heart valve replacement strategy that supports somatic tissue growth in the treatment of critical congenital valve diseases in the young. In the case report with histologic study, Bibevski et al. showed that ECM implanted in the pulmonary artery to fill a defect remodels to mimic the surrounding tissue and the intended biologic function. Clinical reports such as this give us guidance as to what works with bare ECM and what doesn't. Equally relevant is the insightful article by Allen et al. that follows the clinical remodeling of small intestine submucosa (SIS)-ECM after endarterectomy, thereby demonstrating the utility of biological materials in cardiovascular repair procedures.Finally, four original research articles by In summary, understanding the cellular mechanisms of pathological and healthy cardiovascular ECM remodeling under biochemical and/or biomechanical environments of pertinence, as well as the advancement of ECM-mimicking biomaterials for use in cardiovascular surgical repair hold promise for a breakthrough in overcoming current treatment limitations. The 8 articles presented herein have addressed this subject matter, with an appreciation of the state-of-the-field and the current challenges that await us. The topic editors are sincerely appreciative to the 47 authors who contributed to these 8 articles, which will help orient the research community on the ECM, to its properties/responses, and with the overall goal of improving existing treatments for cardiovascular disease. For now, the holy grail of replacing cardiovascular structures with ECM scaffold guided, biologically remodeling tissues that can grow with the patient although within sight, remains elusive.SB, SR, and JH topic editors for this Research Topic, entitled “Extracellular Matrix for Cardiovascular Reconstruction” were responsible for the writing of this editorial. All authors contributed to the article and approved the submitted version.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.


Idiopathic pulmonary fibrosis is an age-dependent progressive and fatal lung disease of unknown etiology, which is characterized by the excessive accumulation of extracellular matrix inside the interstitial layer of the lung parenchyma that leads to abnormal scar architecture and compromised lung function capacity. Recent genetic studies have attributed the pathological genes or genetic mutations associated with familial idiopathic pulmonary fibrosis (IPF) and sporadic IPF to telomere-related components, suggesting that telomere dysfunction is an important determinant of this disease. In this study, we summarized recent advances in our understanding of how telomere dysfunction drives IPF genesis. We highlighted the key role of alveolar stem cell dysfunction caused by telomere shortening or telomere uncapping, which bridged the gap between telomere abnormalities and fibrotic lung pathology. We emphasized that senescence-associated secretory phenotypes, innate immune cell infiltration, and/or inflammation downstream of lung stem cell dysfunction influenced the native microenvironment and local cell signals, including increased transforming growth factor-beta (TGF-β) signaling in the lung, to induce pro-fibrotic conditions. In addition, the failed regeneration of new alveoli due to alveolar stem cell dysfunction might expose lung cells to elevated mechanical tension, which could activate the TGF-β signaling loop to promote the fibrotic process, especially in a periphery-to-center pattern as seen in IPF patients. Understanding the telomere-related molecular and pathophysiological mechanisms of IPF would provide new insights into IPF etiology and therapeutic strategies for this fatal disease. Idiopathic pulmonary fibrosis is a progressive and fatal lung disease of unknown etiology. The pathological manifestation of this disease is the deposition of excessive extracellular matrix filaments in the interstitial space and gradual loss of alveolar epithelial cells in the lung parenchyma , 2. Oncet-loop lariat structure with telomeric double-stranded repeats  and their binding proteins. Telomeres protect genome integrity and prevent degradation and chromosomal end-to-end fusion . Telomer repeats . This st repeats , 5 .–43.23–43Accumulating evidence has implicated telomere dysfunction in the pathogenesis of IPF. However, the underlying molecular mechanisms remain unclear. Available data suggest that cellular senescence or death of alveolar stem cells induced by telomere dysfunction is implicated in pulmonary fibrosis by altering cell signaling and the microenvironment in the lung.TERT mutations in two IPF families  had heterozygous mutations in TERT or TERC .–43.TERT TERT or TERC mutations. This fact suggests the importance of telomere dysfunction in IPF pathogenesis, but the question of how telomere dysfunction drives the genesis of pulmonary fibrosis remains. The capacity to regenerate lung tissue was determined to be significantly decreased in generation (G) 4 TERC KO mice after partial pneumonectomy, indicating that adult lung stem cells are significantly affected by telomere shortening -induced pulmonary fibrosis, suggesting that telomere shortening promotes the genesis of pulmonary fibrosis , and increased lung cellular senescence and apoptosis were observed. Thus, these findings suggest the important role of alveolar stem cell AEC2s in the pathogenesis of pulmonary fibrosis  cells  fluids  were found to be upregulated in monocyte-derived macrophages in experimental pulmonary fibrosis, as well as in resident alveolar macrophages in IPF patients  cells , 57. TRF) fluids , 59. Simammation . These dammation . Severalpatients . Moreovepatients . Whetherpatients .In summary, we propose a model to demonstrate how telomere dysfunction drives the pathogenesis of IPF . TelomerThe available data from human IPF cases and animal model studies have established a connection between telomere dysfunction and pulmonary fibrosis mediated by alveolar stem cell AEC2s. However, it is still unclear how these cells promote the development of pulmonary fibrosis. Although some animal model studies support the idea that cellular senescence of AEC2s drives the development of pulmonary fibrosis , 59, 61,Although it is now well-recognized that telomere dysfunction preferably affects lung AEC2 function and is a major driver of pulmonary fibrosis, other stem cells such as club cells and basal cells might also be affected by telomere dysfunction, thereby exerting their respective effects. Notably, 40% of familial IPF and 25% of sporadic IPF cases have significantly short telomeres, in which genetic alterations in telomere-related genes have been identified, suggesting the important role of telomere dysfunction in the pathogenesis of pulmonary fibrosis. Furthermore, it has been reported that some telomere-unrelated genes are also implicated in the genesis of pulmonary fibrosis, suggesting complex mechanisms of IPF at different pathophysiological levels , 72.TERT or TERC mutations and telomere shortening do not develop pulmonary fibrosis, suggesting that aging and environmental factors are also involved in disease pathogenesis , Hangzhou Science and Technology Bureau (20182014B01), and Hangzhou Human Resources and Social Security Bureau (4125F5061700502).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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