Drosophila and mammalian models along with humans have demonstrated that fruit flies and small mammalian models like rats and mice have many similarities with humans in basic metabolic functions and share many molecular mechanisms which regulate these metabolic processes. In this paper, we describe diet-induced, chemically and genetically induced animal models of the MetS. The advantages and limitations of rodent and Drosophila models of MetS and obesity are also analyzed.Overweight and obesity are health conditions tightly related to a number of metabolic complications collectively called “metabolic syndrome” (MetS). Clinical diagnosis of MetS includes the presence of the increased waist circumference or so-called abdominal obesity, reduced high density lipoprotein level, elevated blood pressure, and increased blood glucose and triacylglyceride levels. Different approaches, including diet-induced and genetically induced animal models, have been developed to study MetS pathogenesis and underlying mechanisms. Studies of metabolic disturbances in the fruit fly  Metabolic syndrome (MetS) is a combination of metabolic abnormalities that increases the risk of cardiovascular diseases, diabetes, stroke, and other pathologies. These abnormalities include central obesity, hypertension, insulin resistance, and atherogenic dyslipidemia . ApproxiThe clustering of several metabolic abnormalities within an individual was first discussed by Dr. Reaven in 1988. This clinical phenotype has been given different names over the years such as “insulin resistance syndrome,” “syndrome X,” “hypertriglyceridemic waist,” and “the deadly quartet.” But now, it is most commonly called “metabolic syndrome”  and is iIn 1999, the WHO published the definition of metabolic syndrome based on the assumption that development of insulin resistance and impaired glucose regulation is among the major factors contributed to MetS. The definition states that to diagnose a patient with MetS, the presence of two additional risk factors should be confirmed from a list that includes hypertension, central obesity, increased levels of blood triacylglycerides (TAG), or low levels of high density lipoproteins (HDL) . Over thDrosophila melanogaster, has become an emerging model to explore metabolic disturbances and obesity-related disorders in a cost-effective and expedient manner [Drosophila and rodent models have shown that flies and small mammal models have many similarities with humans in basic metabolic functions and share many molecular mechanisms regulating these metabolic processes. Here, we also provide information on feasibility of using Drosophila not only for studying mechanisms underlying MetS but also for testing preventive strategies against obesity and MetS.As a multifactorial condition with an endangered rate of spread, MetS requires the development of appropriate experimental models in animals that mimic the disease state to address the difficulty of assessing the pathophysiology of MetS in humans. Rats and mice are the most common models used in the study of MetS , 8. In rt manner , 10. In Different approaches have been developed to study MetS pathogenesis and underlying mechanisms including diet-induced and genetic models of MetS .Feeding with high caloric food rich in fats or carbohydrates or both is a popular and effective approach to induce metabolic abnormalities in laboratory animals .It is not surprising that mammalian models are widely used to study different aspects of MetS since they share many functional and metabolic similarities with humans. Diet-induced obesity rodent models are most popular for studies of human obesity and related complications such as MetS. To induce the obesity phenotype, animals are fed with different types of high caloric diets, the high-fat diet  being the most popular. The development of clinical parameters as observed in human MetS patients such as abnormal lipid concentration in plasma coupled with high blood pressure and insulin resistance has been demonstrated in numerous high-fat diet (HFD) studies with rodents –16. In pMetabolic abnormalities associated with MetS were also registered in studies where rats and mice were fed with high fructose or sucrose diets , 19, 20.Many other studies support the high impact of fructose consumption in MetS development. In rats, the consumption of fructose in drinking water for 12 weeks induced the classic symptoms of the MetS. Rats given the high fructose diet showed a greater significant increase in body mass and had significantly higher levels of blood glucose, serum insulin, total cholesterol, and TAG, as well as higher systolic blood pressure, diastolic blood pressure, and mean arterial pressure compared to the control group that did not receive fructose . In addiIn male Wistar rats, the consumption of 30% sucrose in drinking water resulted in the development of MetS symptoms such as increased body weight, elevated blood pressure, and increased blood levels of insulin, TAG, total cholesterol, and low-density lipoproteins . SimilarCheng et al.  demonstrA modified high-carbohydrate high-fat (HCHF) diet containing 17.5% fructose, 39.5% sweetened condensed milk, 20% ghee, and 15.5% powdered rat food, as well as drinking water supplemented with 25% fructose, led to partial development of components of MetS after 8 weeks of feeding in Wistar rats and fully developed MetS after 12 weeks [Drosophila melanogaster has been used as a model for elucidating the mechanisms that regulate fat metabolism, distribution, and deposition. Obese flies accumulate triacylglycerols mainly in the fat body, an organ similar to mammalian adipose tissue, which specializes in lipid storage and catabolism. Furthermore, obese flies exhibit pathophysiological complications, including hyperglycemia, reduced longevity, and cardiovascular function, similar to those observed in obese humans [Drosophila insulin signaling, despite having eight insulin-like peptides with partially redundant functions, is very similar to the human insulin pathway and has served as a model to study many different aspects of diabetes and the diabetic state [Drosophila mutant combinations affecting different levels of the insulin pathway is that the abnormal metabolic state can be studied from the onset of the life cycle and followed throughout [In recent years, the fruit fly e humans , 10, 40.e humans . Drosophic state , 43. Oneroughout , 45.D. melanogaster, high carbohydrate diets based on sucrose, glucose, or fructose delayed pupation, increased larval mortality, shortened lifespan, and induced an obese-like phenotype in adults [Drosophila that disrupts evolutionarily conserved insulin and glucagon-like signaling [In n adults , 46, 47.n adults . A high-n adults –53. As iignaling .Metabolic syndrome negatively affects healthy longevity but takes years to study in mammalian models, thereby delaying the development of translational applications . Therefoob/ob), leptin receptor-deficient (LepRdb/db), and lethal yellow agouti (Ay/a) mice are the three most commonly used spontaneous mutant obese mouse models. Leptin is a peptide hormone that is secreted by adipocytes and regulates appetite. Leptin and its receptor are key factors in the development of obesity. Leptin resistance is characterized by reduced satiety, overconsumption of nutrients, and increased total body mass [ob/ob mice are homozygous mutants and show obesity, hyperphagia, transient hyperglycemia, glucose intolerance, and elevated plasma insulin [db/db mice manifest morbid obesity, chronic hyperglycemia, and pancreatic beta cell atrophy and become hypoinsulinemic [ob/ob and LepRdb/db mice are commonly used to model diabetes 2 type and obesity [y/a mice have a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. They display insulin resistance and can even develop diabetes depending on the background strain. Leptin signaling is active in Ay/a mice that demonstrate a delayed onset in obesity. However, obesity development can be accelerated by using a high-fat diet, making Ay/a mice a convenient model to study human obesity [The leptin-deficient , and mutations of the MC4R protein are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure [MC4R-deficient mice are another very useful strain for use in human obesity research. These mice have a mutation in the melanocortin-4 receptor gene  are widely used and are among the best genetic rat models for MetS research because these rats display all the conditions of MetS, and several other rat strains were derived from the obese Zucker rats having specific MetS traits , 65. ZDFShort-lived genetically obese DU6 (Titan) mice show increased plasma insulin, leptin, IL-6, and fasting TAG levels. Fat accumulation in pancreas and thymic medullary hyperplasia as well as liver transcriptome and proteome alterations indicates multiple changes in lipid metabolism in Titan mice. Late dietary restriction in these mice demonstrated antiobesity effects including decrease in fat content and improvement of expression of genes involved in lipid synthesis. This supports the use of “Titan” mice as a model of metabolic disorders, systemic inflammation, and early aging .Another mouse model of MetS was developed by crossing aromatase-deficient (ArKO) mice with apolipoprotein E-deficient (ApoE−/−) mice . Double Drosophila models of obesity have also been developed. There are a number of laboratory-generated and naturally occurring genetic variants that make Drosophila an ideal model to test the effects of genes on obesity [Drosophila via TAG quantification. Several conditional in vivo gene expression systems, among which the two-component GAL4-UAS system is the most popular, can induce overexpression or RNAi-mediated transgenic gene knockdown in a spatially or temporarily restricted manner. These genetic manipulations allow for analysis of the consequences of obesity without altering diet or the nutrient-sensing pathways [In addition to mammalian models, genetic  obesity . Geneticpathways , 40. Forpathways –72.Drosophila for study chemically induced MetS, because many drugs have significant toxic effects on Drosophila and flies do not prefer food supplemented with toxicants [Drosophila [Weight gain is a widely observed side effect of many prescribed drugs, and drug-induced increases in body weight make people more susceptible to obesity-related diseases. Antipsychotics, antidepressants, antihyperglycemics, antihypertensives, and corticosteroids  are all medications that are associated with significant weight gain and with a high incidence of MetS , 73 thatoxicants , 78. Heroxicants , 80 and osophila , 82.Drosophila models have contributed to our understanding of the preventative approaches.Animal models are widely used not only for investigation of MetS pathogenesis but also for studying the preventive approaches. For humans, four therapies are actively proposed for body weight reduction: calorie restriction , increased physical activity, behavioral changes, and, in appropriate patients, pharmacologically approved weight-reducing drugs , 84. In Drosophila is mostly used to study dietary interventions including dietary restriction and natural-based drugs. Different approaches are developed to modelling dietary restriction: (i) animals have continuous access to food but the amount of food is restricted , and (ii) intermittent fasting where periods of feeding are alternated with fasting periods [Drosophila, it is easy to manipulate food composition changing both the content and ratio between carbohydrates and proteins in the food. Along with short lifespan, it makes Drosophila a very suitable model to study long-term effects of caloric restriction, in particular on lifespan and transgenerational effects. The convenience of applying genomic and metabolic analysis to Drosophila allowed to identify key signaling pathways underlying CR effects [D. melanogaster possibly due to fast fly metabolism and the doubts about the use of those time frames for food restriction as for mammals and humans. At the same time, there are several studies which report on effectiveness of time-restricted feeding for combating metabolic dysfunction in Drosophila model of obesity [All mentioned above strategies can be applied to rodent models, whereas  periods . For Dro effects –88. In r effects –91. Inte obesity  and rest obesity .Drosophila [There is strong evidence that regular exercise contributes to body weight and fat loss and reduces the risk of MetS and obesity. Exercise interventions in humans usually focus on chronic diseases, national fitness, and body weight loss; therefore, it is important to use animal models to investigate the molecular mechanisms underlying the health benefits from regular physical activity. Some reports have shown that endurance exercise can be effective for cardiac function and fat metabolism in osophila , 95 althosophila .ob/ob leptin-deficient mice) and germ-free mouse models are indispensable because they allow interventions that cannot be performed in humans to provide evidence of how gut bacteria influences host metabolism [D. melanogaster has become an attractive model for microbiota studies because its gut microbiota has lower diversity, consisting of a small number of species that can be cultivable and easily manipulated [Gut microbiota also play an important role in the development of obesity and MetS. MetS is often accompanied by an imbalance of the gut microbiota that leads to a low-grade inflammatory response following by destruction of the gut barrier and development of insulin resistance through metabolites affecting host metabolism and hormone release. Therefore, gut microbiota may be a potential target for the treatment of MetS . Murine tabolism . In receipulated .Drosophila as an alternative model organism of obesity are currently very limited [Dietary interventions, including natural-based drugs, are proposed to be an important approach for MetS and obesity management , 100. Va limited  but nutrDrosophila model of obesity and MetS. It is reported that glibenclamide and rosiglitazone, known antidiabetic drugs showing effectiveness in rodents, have no any effect on the diet-induced metabolic disruption observed in Drosophila [When the behavioral and dietary approaches are not sufficient, a pharmacologic treatment is recommended. Pharmacological management of obesity has a long history with multiple disappointments. Numerous drugs were approved for the treatment of obesity; however, most of them were withdrawn because of their adverse effects and insufficient efficacy. The cause of failure has been multifactorial and concerns the limited translational value of animal models to predict cardiovascular safety coupled with considerable patient heterogeneity . Herewitosophila .The main rodent models used for the study of obesity and MetS are diet-induced obesity models and genetically modified models, the most common being monogenic animals, that display metabolic disorders as a result of a single mutated gene. Both types of animal models have many advantages for studying MetS and obesity, but there are some limitations that should be taken into account when choosing the most appropriate model.db/db mice are larger/obese when compared to control (heterozygous) littermates, and LepRdb/db mice demonstrate higher fat accumulation in the inguinal and axillary regions. In addition, LepRdb/db mice also develop frank hyperglycemia by 8 weeks of age [ob/ob, LepRdb/db, and Ay/a mice fall short of an ideal model for MetS, and researchers should take this into account before choosing them for MetS studies [Monogenic models have the advantage of developing severe metabolic phenotypes that provide more possibilities for therapeutic interventions since the effects of drugs can be faster and better observed. Monogenic models can also save time because pathology progresses more quickly than in diet-induced obesity models . In parts of age –114. To  studies . In this studies .Another disadvantage of monogenic animals is the high mortality of certain strains due to ketosis, e.g., db/db mice have a mutation of the leptin receptor and yet are widely used as a model of diabetes type 2. Sophisticated care is also needed for these animals, which can make research more expensive . In geneDiet-induced MetS animal models (DIMSM), especially rodent models, are the most commonly used to study the MetS, because of their simplicity and low cost . Rodent To get diet-induced MetS animal models, different types of diets are used such as high-carbohydrate diets, high-fat diets, and high-fat high-carbohydrate diets , 117. A D. melanogaster, not all MetS criteria, especially central obesity and blood pressure, can be applied [D. melanogaster, there are no such clear indicators. Researchers are guided only by the parameters of the control group versus the experimental one. However, it is difficult to establish whether the parameters of an experimental fly group are within the normal distribution or beyond the range of healthy parameters. Drosophila is a fast and suitable model for screening research on obesity-related genes and certain antiobesity approaches, in particular by measuring levels of storage lipids. However, this model does not allow for a fully assess the pathophysiological consequences of such manipulations proceeding in humans, notably due to the open circulatory system and differences in organ structure and behavior traits.A defined cluster of clinical criteria has been established to diagnose human patients and rodent models with MetS. In the case of  applied . For humDrosophila. Rodents, especially diet-induced models, can develop all key features of the human MetS [D. melanogaster does not.In terms of structural, physiological, and genetic proximity to humans, rodents seem to be the preferable models for the study of MetS pathophysiology than man MetS  whereas Drosophila [Drosophila homolog Brummer lipase) [Drosophila genetics, makes the fly a very useful model system to study energy homeostasis and its perturbations [Discovery of leptin, one the main obese genes in mouse  inspiredosophila , 124. Vi lipase) . This lerbations  in a cosDrosophila show advantages in the study of genetics of obesity as compared with mammals, in particular, in identifying of new genes related to obesity. Taking into account that genetic background of obesity is mostly polygenic, a functional relationship between these candidate genes and adiposity remains a significant challenge in which the fruit fly plays an optimistic role. Genome-wide analysis in Drosophila helps to reveal diet-by-gene interactions and uncover diet-responsive genes [Due to easy of genetic manipulations, ve genes .in vivo is needed, where Drosophila is at the forefront [Drosophila perform forward genetic screens related to obesity before assessing whether misregulation of the corresponding mammalian orthologue affects adiposity [Functional screens in cultured cells permit rapid testing of candidate genes, as it was shown in studies of insulin secretion in islet cells for genes associated with type 2 diabetes . Howeverorefront , 130. Modiposity , 130.Drosophila allowed to identify ∼500 candidate obesity genes. More than 60% of candidate genes identified in that screen were conserved between Drosophila and humans, and notably, a large number were previously uncharacterized. In particular, a role for hedgehog signaling was identified as the top-scoring fat-body-specific pathway in Drosophila [in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals [In the study of Pospisilik et al. , genome-osophila  and thenosophila , 131. It mammals .Drosophila obesity and MetS studies complemented each other and permit to identify conserved and distinct mechanisms underlying metabolic disturbances. Advantages and limitations of different animal obesity models are summarized in Thus, rodent and Drosophila emerges recently as a new model to study metabolic disturbances. Diet, genetic, and chemical-based approaches are developed in both mammalian and insect models to induce obesity and related metabolic disturbances. Whereas genetic models allow fast obtaining disease phenotype, diet-induced obesity models seem to be better to disclose molecular mechanisms and to explore preventive strategies due to obesity is a multifactorial disease. Due to easy genetic manipulations, Drosophila seems an attractive model to screening obesity genes. Rodent models have preference in the establishment of pathophysiological complications of MetS. At the same time, the physiological features of both models should be taken into account when extrapolating data to humans.Rats and mice are the most common model of obesity and metabolic syndrome, and


Wound healing is a programmed process of continuous events which is impaired in the case of diabetic patients. This impaired process of healing in diabetics leads to amputation, longer hospitalisation, immobilisation, low self-esteem, and mortality in some patients. This problem has paved the way for several innovative strategies like the use of nanotechnology for the treatment of wounds in diabetic patients. The use of biomaterials, nanomaterials have advanced approaches in tissue engineering by designing multi-functional nanocomposite scaffolds. Stimuli-responsive scaffolds that interact with the wound microenvironment and controlled release of bioactive molecules have helped in overcoming barriers in healing. The use of different types of nanocomposite scaffolds for faster healing of diabetic wounds is constantly being studied. Nanocomposites have helped in addressing specific issues with respect to healing and improving angiogenesis. Method: A literature search was followed to retrieve the articles on strategies for wound healing in diabetes across several databases like PubMed, EMBASE, Scopus and Cochrane database. The search was performed in May 2022 by two researchers independently. They keywords used were “diabetic wounds, nanotechnology, nanocomposites, nanoparticles, chronic diabetic wounds, diabetic foot ulcer, hydrogel”. Exclusion criteria included insulin resistance, burn wound, dressing material. Nanomedicine is one of the fastest-growing fields offering several avenues for therapy, diagnostics, delivery systems and improving efficiency . The supVarious factors, including pH, temperature, blood sugar level, and oxygen saturation, are important in the healing of wounds. Scaffolds have attracted interest recently as a novel dressing and provide an innovative perspective on tissue regeneration , 11. ResWhile researchers are experimenting with effective and scarless wound healing strategies, wound management in diabetes itself is a tedious process for the patients and the healthcare sector. So, several advanced techniques and technology have been employed in the remedial measures for diabetic wounds.S. aureus and E. coli  induces the formation of blood vessels and the migration of endothelial cells by eNOS or MAPk pathways. Zinc oxide is known to induce NO production, hence several scaffolds for wound healing have incorporated ZnO NP’s nanofibers fabricated using poly-caprolactone with ZnO NP’s which exhibited high proliferation of fibroblast cells. A higher rate of vascular regeneration was observed because of the expression of VEGF and FGF . Cerium Poly-N-acetyl-glucosamine based nanofibrous scaffold was prepared to overcome the limitations in treating a diabetic wound. This bioactive scaffold was found to enhance cell metabolism, and migration of endothelial cells with a higher rate of wound closure in a full- thickness diabetic mice model. The gene expression of uPAR, VEGF, Il-1 and MMP responsible for migration, angiogenesis, inflammatory activity, and matrix remodelling was observed . AnotherThe ulcers in diabetic wounds are caused by oxidative stress, so researchers prepared Prussian blue nanoparticles (PBNP’s) to scavenge the free radicals generated at the wound site. This PBNP was encapsulated in a heat-sensitive gel using poly -poly (ethylene glycol)-poly  (PDLLA-PEG-PDLLA) hydrogel (PLEL). It was confirmed that the nanoparticle was able to protect the cells and mitochondria against reactive oxygen species (ROS). In an animal model, it was found to progress diabetic wound healing at a faster rate, reduce ROS production, and enhance cell survival and growth simultaneously reducing the interleukin and tumor necrosis factor .In vivo studies showed that the exosome released promoted angiogenesis in the full-thickness wound (A pH-responsive scaffold was developed which aided in faster healing with less scar formation. This injectable scaffold was prepared with polysaccharides and exhibited antibacterial activity against multi-drug resistant bacteria. ss wound . A dual ss wound .Silver nanoclusters were conjugated with vancomycin in a gelatin-based hydrogel along with nimesulide that is pH sensitive. This complete biomaterial containing phenylboronic acid and polyvinyl alcohol also contained ROS and exhibited anti-inflammatory action. It was found to be biocompatible, with excellent cell-adhesive behaviour and aided healing in wounds with infection. Because of its sensitive and dual-responsive properties, hydrogel was found to be good for treating chronic diabetic wounds . A thermHydrogels are the most preferred dressing agent for wound healing owing to their capability to retain moisture at the site of wounds, agent because hydrogels are designed to hold moisture at the wound surface, and create the best setting for healing, balancing skin hydration and in the removal of necrotic tissue. They could be prepared with ease providing sustained drug release. Both natural and synthetic polymers could be used in the preparation of hydrogels. These may include, fibrin, hyaluronic acid, cellulose derivatives, copolymers and others .in vivo models demonstrated excellent healing of wounds (in vitro studies on L929 cells demonstrate superior biocompatibility with improved cell proliferation. Further, in vivo studies also demonstrated a faster healing process and suggested that this hydrogel as an ideal candidate suited for wound recovery and healing (Hydrogels are exceptional in providing a humid atmosphere for the healing of wounds and ensure permeable water vapours with microbial entry prevention at the wound site. A heparinised PVA-based hydrogel formulated demonstrated significant antibacterial activity without any cellular toxic effects . Anotherf wounds . Topic nf wounds . A ZnO-bf wounds . Though  healing . Though Diabetes being a chronic disease is yet challenging to cure and the medical requirements are inadequate . The skiin vitro studies. In vivo studies demonstrated restoration of blood vessels through HIF-1α/VEGF and collagen deposition in diabetic wound. It was also suggested to have its application in regenerative medicine (in vivo studies further demonstrated significant wound healing at a faster rate without any infection (In vivo studies on both normal and diabetic wounds were conducted in mice in comparison with commercially available dressings. Histology confirmed significant re-epithelialization and faster healing of diabetic wounds than the commercial products (in vivo studies (Due to vascular impairment, diabetes-related wound healing and skin regrowth remain a major concern. To overcome this, a silica-based nanocomposite hydrogel scaffold that could promote both wound healing and skin regeneration in diabetic conditions was developed by enhancing early angiogenesis with no bioactive factors. This injectable nanocomposite exhibits an excellent healing pattern with superior antibacterial properties. Also, enables viability, growth, and angiogenesis of endothelial progenitor cells through medicine . Severalmedicine . A multinfection . A 2-D nnfection . Anotherproducts . A bioacproducts . A cost- studies . An algi studies . Some exS. aureus. The excellent antibacterial action exhibited by this nanocomposite sponge made it a suitable dressing agent for diabetic foot ulcers with mild toxicity towards mammalian cells (in vivo studies in rats and exhibited wide-spectrum antibacterial action through in vitro studies (in vivo studies in rats demonstrated that the nano-curcumin based nanocomposite showed significant collagen deposition and epidermis re-epithelialization in wounds (The major risk associated with patients affected with diabetes includes delayed wound healing and amputation. This is mainly due to the reduced tissue blood circulation causing hypoxia and the associated risks. A PVA/Chitosan-based nano fibre wound dressing was developed with high antimicrobial activity, improved vapour transmission rate, good odour-absorbing capacity and no cytotoxic effects; and was proved to accelerate the diabetic wound healing when tested in both diabetic and non-diabetic rats . A safe,an cells . A hydro studies . An injen wounds .Although there is a gap in the translation of nanomedicine, the use of computer-aided analysis has become evident in this area. This has led researchers get a clear vision on the behaviour and application of nanoparticle- based therapy in reproductive biology , transpoSeveral impeding factors in healing chronic wounds exist using conventional treatment methods. Novel strategies have been designed to overcome them using nanotechnology has proved to be promising. The advanced biomaterials developed with cellular and acellular scaffolds in conjunction with nanomaterials of suitable nature would prove to be an efficient wound care management in diabetic ulcers. The ability to modulate and control the release of active compounds and drugs has added advantage of controlling infection in these wounds significantly shortening the stay at the hospital for patients. An in-depth analysis of the factors that promote angiogenesis and wound closure at a faster rate by the use of nanocomposite biomaterials would help in translating these products to patients. Production of such tailor-made biomaterial constructs with specific factors and design would be the desired wound treatment strategy specifically in chronic wounds. With the recent advancements in the field of artificial intelligence the design of scaffolds could be customised to evade toxicity and meet the scrupulous needs that exist in regenerative therapy. This would help researchers validate and predict the outcome of their research without the sacrifice of many animals, avoid the strain of extraneous tasks involving the toxicological assessment. So, by means of integrating artificial intelligence and the lab-scale studies will yield effective translation of nanotherapeutics in wound care management.RRR and DV conceptualized the manuscript and performed the literature search and AJ and SY drafted the manuscript. RR, DU and AS reviewed and modified the manuscript. All authors contributed to the article and approved the submitted version.


Several well-defined biological processes, including but not limited to impaired DNA damage repair, increased efflux of drugs, and epithelial-mesenchymal transition (EMT), have been linked to drug resistance in cancer cells. Over the past decade, accumulating evidence has focused on the accumulation of cholesterol in cancer cells as one of the driving mechanisms of drug resistance. This Research Topic explored molecular pathways responsible for cancer drug resistance in a range of cancers, especially narrowing down to pathways impacted by cholesterol while suggesting the role of cholesterol-lowering agents as potential anticancer therapeutics.Cancer was responsible for approximately 10 million deaths in 2020. Despite the notable progress made in anticancer therapy, cancer patients present with Xelwa et al. discussed some of the opportunities and challenges that emanate from targeting growth factors. Some of these challenges arise from the heterogeneity of the tumor and its ability to evade detection and destruction. Subsequently, the authors have highlighted the potential of the combinatorial targeting of the growth factor signaling pathways as an avenue to bypass these challenges, especially to combat drug resistance in PC.Several growth factor signaling pathways  are responsible for pancreatic cancer (PC) initiation and progression. These pathways are critical in various biological processes such as cell differentiation, migration, proliferation, and apoptosis. Their cellular functions provide unique opportunities to target them toward pancreatic ductal adenocarcinoma (PDAC) treatment. In recent years, several attempts have been made to do so, however, with some challenges. Kumar and Mandal argued that cholesterol-lowering drugs such as statins (lovastatin) in combination with selective cholesterol absorption inhibitors (ezetimibe) and citrate lyase inhibitors  have shown anticancer activity in various cancers  by modifying operative signaling pathways such as PTEN/Akt, PI3k/Akt, Akt/NF-κB, Akt/FOXO1, and Akt/mTOR. The authors have substantiated the significance of cholesterol in cancer cells by tabulating the past and present clinical trials involving statins as anticancer therapeutics. The authors have argued in the light of the published literature (see references in the article) that inhibition of Akt using cholesterol-lowering drugs could improve the chemosensitivity of cancer cells, thus mitigating therapy resistance and metastasis.The well-known signaling protein Akt, a serine/threonine kinase has been hailed as a cell survival protein, in its phosphorylated form (phospho-Akt) activates several downstream proteins involved in the process such as cell proliferation, migration, invasion, metabolism, and apoptosis. Thus, targeting dysregulated Akt in cancer cells could be effective in disease prevention and therapy. Abdulla et al. attempted to delineate the complexities governing these two processes and partly addressed the gap in the literature with a specific focus on the influence of hypoxia on cellular cholesterol content and the resulting implications this has on EMT and drug resistance. The role of cholesterol in modulating multidrug-resistant transporters and transcriptional regulation of EMT has been explained in depth. The authors postulated a potential hypothesis that an intricate relationship exists between hypoxia, EMT, and cholesterol and consequently proposed that targeting cellular cholesterol could serve as a novel avenue to combat cancer pathogenesis.Emerging scientific evidence implicates cholesterol dyshomeostasis in cancer progression and drug resistance. Importantly, the tumor cell plasticity program “EMT” plays a crucial role in drug resistance. Laka et al. accumulated evidence that phytochemicals may be used for lowering cholesterol by especially targeting the P53 pathway in cancer cells, where mutant p53 is responsible for regulating cholesterol biosynthesis mevalonate pathway by activating Sterol regulatory element-binding protein 2 (SREBP-2) in cancer cells and wild-type p53 represses SREBP-2 transcriptional activity. Several phytochemicals and their roles in cholesterol-lowering and cancer have been detailed in this article.While the abovementioned articles focused on using synthetic drugs such as statins as an anticancer therapy, it is important to mention that about 30% of the patient population is non-responsive to statin therapy in general. Therefore, alternative cholesterol-lowering agents need to be identified and developed. The articles published in this special topic corroborated the role of cholesterol in cancer and documented the published literature to explore the complex molecular pathways underlying cancer proliferation, drug resistance, and metastasis. There is a need to identify new classes of cholesterol-lowering compounds , and their testing as single agents or in combination with existing anticancer therapies must be done to restore drug sensitivity. Future studies need to focus on delineating the role of cholesterol in influencing the tumor microenvironment. It would be intriguing to recognize the role of cholesterol in T-cell exhaustion induced by the tumor microenvironment to potentially improve immunotherapies.


It is widely acknowledged that the climacteric syndrome negatively affects women’s quality of life and leads to cerebral ischemic injury, osteoporosis and cardiovascular disease. One of the main active ingredients in Radix Scutellariae, Baicalin, has been established to possess a wide range of pharmacological effects and is beneficial in enhancing osteogenic differentiation and cardiovascular disease. Baicalin’s profound metabolic impact on various stem cell populations and their fate specification could improve the efficiency of stem cell therapy for climacteric syndrome. However, Baicalin-mediated processes are complex and many of the underlying mechanisms are not fully fathomed yet. This review aims to shed light on the regulatory role of Baicalin on the diverse behaviors of distinct stem cell populations and provide a good cell source for stem cell therapy to broaden the therapeutic landscape for climacteric syndrome patients.  Scutellaria baicalensis Georgi has a long history of therapeutic and commercial value in traditional Chinese medicine . One of Menopause is a physiological condition that naturally develops in women as they age. Climacteric syndrome is a set of symptoms that often occur throughout the perimenopausal and postmenopausal periods . AccompaStem cells are self-renewing cells with multi-lineage differentiation potential , which iAlthough it is well-established that Baicalin has several positive physiological functions, this paper is focused on how Baicalin regulates physiological mechanisms in embryonic stem cells, neural stem cells and other stem cell populations  by demonEmbryonic stem cells (ESCs) have a remarkable capacity for maintaining an undifferentiated condition before differentiating for a long period . Since Eα -myosin heavy chain (α-MHC) is a heart-specific gene , which reduces apoptosis and viability produced by this state, thereby increasing cardiac protection . BaicaliCancer is characterized by aberrant cell development and the potential for metastatic spread and is associated with a high global mortality rate. Reports suggest 19.3 million new cancer diagnoses and 10 million cancer deaths globally in 2020 (Cancer cells are formed partly from the differentiation of cancer stem cells (CSCs), which has become a major research hotspot for treatment in recent decades  are undifferentiated cells that can proliferate, self-renew indefinitely, and differentiate into all types of neurons and glial cells . Adult NAlzheimer’s disease is a degenerative disorder characterized by brain atrophy, loss of neurons, associated with behavioral changes and cognitive decline . As a coJak-STAT is an intracellular signal transduction pathway, including Janus Kinases (JAK) and the signal and activator of transcription (STAT). The JAK-STAT pathway is a highly regulated and efficient system that regulates gene expression . STAT3 iOverwhelming evidence substantiates that activating Erk1/2 can increase neurogenesis in C17.2 NSCs , which iFurthermore, Baicalin has been shown to induce hippocampus regeneration and improve cognitive function following cerebral ischemia injury , providiin vitro modeling of AD (Induced pluripotent stem cells (iPSCs) are pluripotent, which refer to the cells produced after gene reprogram in somatic cells . IPSCs hng of AD .in vitro studies, and future research needs on in vivo studies in order to obtain more exploratory findings.The basic-helix-loop-helix (bHLH) family of transcription factors, such as Hes1, Ascl1 and Oligo2, play a crucial role in the neural development and fate determination of iPSCs . Hes1 caMammary stem cells (MaSCs) have the potential to self-renew and change, developing into luminal progenitors and basal cells, which then differentiate into ducts or alveolar cells . As a revia hormone-like activities, providing a good supply of stem cells for stem cell therapy as well as a novel treatment for breast cancer.Many natural monomer compounds exhibit hormone-like properties and may be used for medical therapy . ResearcAs pluripotent stem cells, bone marrow mesenchymal stem cells (BMSCs) can differentiate into chondrocytes, osteoblast and fat cells . Over thin vitro . Current evidence substantiates that Baicalin can be utilized to treat climacteric sickness and control stem cell proliferation, differentiation and self-renewal.It is widely acknowledged that natural substances like Baicalin have various pharmacological effects, with low toxicity and can cross the blood-brain barrier , which oStem cell therapy has been widely used in recent years and has been clinically used for treating arthritis , brain iin vivo to limit the proliferation of hematopoietic stem cells (HSCs) in a concentration-dependent way (in vivo (in vivo transformation of the two and the combined regulation of stem cells. Furthermore, Baicalin has poor water solubility and a limited bioavailability (Indeed, various shortcomings of Baicalin should be addressed before its implementation for the treatment of climacteric illness. Baicalin, for example, has been demonstrated dent way  After hy(in vivo , baicale(in vivo  and booslability , limitinlability . Therefo


Most persons living with dementia receive home health or hospice aide services during their hospice stay. To equip aides with essential knowledge and skills to effectively communicate with and care for persons living with dementia, we developed a 17-video dementia care expert program for aides, available in both English and Spanish. The objective of this presentation is two-fold: first, describe the development and refinement of the Aliviado aide dementia care expert program, including topic selection, usability testing, and cultural tailoring; and second, discuss aide knowledge improvement, along with special considerations for training aides during COVID-19. The Aliviado dementia care expert program for aides has been completed by 414 aides across 15 hospices as of February 2022; of which, 384 aides (93%) completed a dementia knowledge assessment both before and after the training and demonstrated significant knowledge gains with moderate-to-large effect sizes .


In GDMs, CAT was lower than controls at any time point (p < 0.05), while in GDMs delta(Δ) CAT (prior-to and immediately after exercise) was lower than controls (p = 0.003). In GDMs, UtA PI centiles decreased between prior-to and either immediately or one hour after exercise, while they did not change in controls. In GDMs, pre-conceptional BMI and weight gain predicted negatively ΔTAC (prior-to to one hour after exercise); Conclusions: Moderate intensity exercise bout improves oxidation capacity in GDM and uncomplicated pregnancies, although at a lesser extent in the former. Exercise leads to decreased UtA arteries resistance in women with GDM.Background: Gestational diabetes mellitus (GDM) is associated with aggravated oxidation capacity and utero-placental circulation, while aerobic exercise could improve both. The study aims to assess oxidation capacity and utero-placental circulation before and after a bout of aerobic exercise in GDM and uncomplicated pregnancies.; Methods: In this cross-sectional study, women with GDM (GDMs) and women with uncomplicated pregnancies(controls), underwent 30 min of moderate intensity cycling. Total antioxidant capacity (TAC), catalase activity (CAT), reduced glutathione (GSH), Uterine Arteries (UtA PI) and Umbilical Artery (UmA PI) pulsatility indexes were estimated prior-to, immediately after and one hour after exercise; Results: In each group, 25 pregnant women were included. In both groups, between prior-to and immediately after exercise, TAC and CAT increased, while GSH decreased, ( In uncomplicated pregnancies the body of the mother undergoes numerous physiological changes which contribute to an environment appropriate for the developing fetus . EnhanceGestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during pregnancy. It is accompanied by inadequate pancreatic function, insufficient to overcome the developing pregnancy-related “physiologic” insulin resistance . In GDM,Regular mild to moderate intensity physical exercise during pregnancy is highly recommended, as it is associated with various beneficial effects to the mothers and their fetuses ,12. Off The aim of the present study was to assess anti- oxidation parameters as well as utero-placental circulation before and after a bout of aerobic exercise of moderate intensity in women with GDM as compared to women with uncomplicated pregnancies.In this pilot cross-sectional study women with GDM and women with uncomplicated pregnancies were recruited between February 2020 and February 2021 from pregnant women consulting at the outpatient clinic of the Second Department of Obstetrics and Gynecology of the Aristotle University of Thessaloniki, for the follow-up of their pregnancies.All pregnant women at 24–28 weeks of gestation underwent screening for GDM with a 75 g two-hour oral glucose tolerance Test (OGTT). Gestational diabetes mellitus was diagnosed as per the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria  .The aim of this study was to identify potential defects in oxidation capacity and utero-placental circulation in GDM pregnancies by employing physical exercise as amplifier. To answer the formulated hypotheses GDM women should be compared to women with normal carbohydrate metabolism (controls). To reflect the latter, the control group was formed by uncomplicated pregnancies, because complications  in otherwise normal (regarding GDM) women might affect indirectly or directly the physiology of carbohydrates, oxidation capacity and utero-placental circulation. Therefore, the inclusion criteria were formed as follows: women with positive GDM diagnosis were offered to participate in the study, whereas women with negative GDM diagnosis and uncomplicated pregnancies were offered to participate in the study as controls. Women with GDM were matched with women with uncomplicated pregnancies according to pre-pregnancy BMI, maternal age and gestational age. Exclusion criteria comprised pregnancies with pre-existing diabetes mellitus (type 1 or 2), hypertensive disorders of pregnancy, chromosomally abnormal fetuses with or without structural defects, fetal growth restriction and smoking habitus.All participants signed an informed consent form and they agreed that their anonymized data could be used for research purposes. The protocol of the study was approved by the ethical committee and the institutional review board , in accordance with the Declaration of Helsinki.At the initial visit, maternal and pregnancy characteristics were recorded, including maternal age, gestational age, maternal height, pre-pregnancy weight and BMI, and weight gain . PhysicaTotal antioxidant capacity, catalase, and GSH, were determined in a HITACHI, U-1900 spectrophotometer as previously described . Intra- www.fetalmedicine.com (accessed on 1 June 2022)). Transformation of uterine arteries and of umbilical artery pulsatility indexes to centiles were made using the Gomez et al., and the Arduini et al., reference curves, respectively [For the measurement of the Pulsatility Index of the maternal uterine arteries and umbilical artery, a General Electric Voluson S10  ultrasound machine with convex transducer (RAB6-RS) was used. All ultrasound examinations were performed by examiners certified for doppler assessment sonographers by Fetal Medicine Foundation , if their distribution was normal, or as medians and interquartile range values if the distribution was non-normal. Categorical variables were summarized as percentages. In continuous variables, the differences between prior-to and immediately or one hour after the exercise bout as well as between immediately after and one hour after the exercise bout were reported as delta (Δ). Quantitative variables were compared between the two groups at the different time-points by employing General Linear Models ANOVA (Non-matched) and Bonferroni post-hoc test. Repeated measures ANOVA involved one factor between patients (factor “Group” with two levels) and one factor for the repeated measures within patients (factor “time” with 3 levels). Chi-square or Fisher’s exact test were used for pairwise comparisons of proportions, as appropriate, and odds ratios (ORs) along with their 95% confidence intervals (CIs) were calculated. In all the above tests, a Forward stepwise linear regression analysis was employed in both groups, in order to reveal potential correlations and confounders, including maternal pre-pregnancy BMI, maternal age, maternal weight gain, parity, history of GDM and physical activity as independent variables and ΔTAC, ΔGSH, ΔCAT, ΔUtA and ΔUmA centile as dependent variables.The analyses were performed on open source software R 2.15.1 .In this case, 250 pregnant women visiting consecutively the obstetric outpatient clinic of the Second Department of Obstetrics and Gynecology of Aristotle University of Thessaloniki for a regular follow-up of their pregnancy, were screened for participation in the study. Among them, 32 pregnant women were identified with GDM and were offered to participate in the study; 25 of the 32 agreed to participate in the study. Then 30 women with uncomplicated pregnancies (out of the 250 consecutively examined) were matched to the already recruited 25 GDM pregnancies regarding pre-pregnancy BMI, maternal age and gestational age and were asked to participate in the study. From them 25 agreed finally to participate in the study. Thus, 50 pregnant women agreed to participate in the study (25 with GDM and 25 with uncomplicated pregnancies) .p = 0.043) , weight gain, maternal age, mode of conception, parity, gestational age and physical activity. Presence of GDM in previous pregnancies differed significantly between the studied groups  .p < 0.001), while they did not differ between either prior-to and one hour after the exercise bout or between immediately after and one hour after the exercise bout. Prior to the exercise bout there was a trend towards decreased TAC mean values in women with GDM compared to women with uncomplicated pregnancies (p = 0.066). Between the two groups, TAC mean values did not differ significantly immediately after and one hour after the exercise bout. No significant differences were found regarding any ΔTAC value in the three time points, between the two groups , while they did not differ between either prior-to and one hour after the exercise bout or between immediately after and one hour after the exercise bout. Mean values of catalase activity were significantly lower in women with GDM compared to women with uncomplicated pregnancies, at any time point . Delta catalase activity between prior-to and immediately after the exercise bout was significantly lower in women with GDM compared to women with uncomplicated pregnancies . No significant differences were found regarding Δcatalase activity values between prior-to and one hour after the exercise bout, between the two groups  or one hour after (p < 0.05) the exercise bout, while they did not differ between immediately after and one hour after the exercise bout. At immediately after the exercise bout, there were statistically significant decreased GSH mean values in women with GDM compared to women with uncomplicated pregnancies (p < 0.05). No significant differences were found regarding GSH mean values prior-to and one hour after the exercise bout, between the two groups. No significant differences were found regarding any ΔGSH value in the three time points, between the two groups . Between the two groups, mean UtA PI centiles did not differ significantly prior to the exercise bout. Mean UtA PI centiles were significantly lower in women with GDM compared to women with uncomplicated pregnancies immediately after and one hour after the exercise bout (p < 0.01). The changes of Uta PI centiles (ΔUtA PI) between prior-to and either immediately after or one hour after the exercise bout were significantly greater in women with GDM compared to women with uncomplicated pregnancies . Mean UmA PI centiles did not differ significantly at any time point, between the two groups as well as within each group  of ΔTAC between prior-to and one hour after the exercise bout in the GDM group, while no significant predictors were found in women with uncomplicated pregnancies.When forward stepwise linear regression analysis was employed to reveal potential predictors of either ΔTAC or ΔCAT or ΔGS taken as dependent variables (Δ representing the difference between either prior-to and immediately after the exercise bout or prior-to and one hour after the exercise bout) with maternal age, maternal pre-pregnancy BMI and weigh gain, parity, history of GDM and physical activity taken as independent variables. Pre-conceptional BMI and weight gain were found to be negative predictors  with maternal age, maternal pre-pregnancy BMI and weigh gain, parity, history of GDM and physical activity taken as independent variables, no significant predictors were found in either group.We found that, in pregnant women at the third trimester, a bout of aerobic exercise of moderate intensity (cycling) resulted in increase of TAC and catalase activity measurements in both women with GDM and women with uncomplicated pregnancies. However, in all time points, catalase activity was significantly lower in women with GDM compared to women with uncomplicated pregnancies, while its increase immediately after the bout of exercise was less pronounced in the former compared to the latter. Similarly, a trend for lower TAC measurements prior (baseline) to the bout of exercise of moderate intensity was observed in women with GDM compared to women with uncomplicated pregnancies.To our knowledge, this is the first time that exercise in pregnancy is studied in relation to oxidation status. Previous studies in non-pregnant populations, have shown that a bout of exercise results in marked elevations of biomarkers of pro- and anti- oxidation status at rates of variable magnitude ,24,25. FHyperglycemic environment is associated with enhanced pro-oxidation ,6. In woIn addition, in the present study in women with GDM, pre-conceptional BMI and weight gain were negative predictors of ΔTAC (prior-to to one hour after exercise). In the past, we have shown that pre-pregnancy BMI in normal uncomplicated pregnancies is positively associated with maternal leptin concentrations and insulin resistance indices . The latFurthermore, in the present study, a bout of exercise of moderate intensity resulted in decreased mean UtA PI centiles in women with GDM but not in women with uncomplicated pregnancies. Regarding uncomplicated pregnancies, in the past, similarly to the findings of the present study, a bout of exercise of moderate intensity in pregnant women with uncomplicated pregnancies did not affect UtA PI centiles before and after exercise . In factIn pregnancies with a well-regulated glucose-insulin axis, insulin signaling regulates oxidation status in endothelial cells resulting to relaxation and decreased vascular resistance. However, in GDM, increased insulin resistance leads to reduction of NO bioavailability and therefore, to vascular dysfunction explaining thus, the reported association of the latter with GDM ,40,41. ATo our knowledge, this is the first study assessing the effect of a bout of moderate intensity aerobic exercise on oxidation capacity and UtA resistance (via measurement of UtA PI) in pregnant women with GDM and in women with uncomplicated pregnancies.A limitation of the study is the lack of evaluation of pro-oxidative markers. Evaluation of pro- and anti- oxidation markers would provide a more comprehensive depiction of the redox status changes after moderate exercise in uncomplicated pregnancies and pregnancies with GDM. Evaluation of mVO2max would have been helpful but it is not advised in pregnancy due to possible negative outcomes during the process of its estimation. The relatively small size of the study is also a limitation.In conclusion, it appears that pregnancies complicated with GDM demonstrate a defective anti-oxidation system although they respond positively to the beneficial effect of a bout of aerobic exercise of moderate intensity during pregnancy, whereas pre-conceptional BMI and weight gain emerge as negative predictors of the anti-oxidation response. Of note, this bout of aerobic exercise of moderate intensity is followed by an improvement of resistance in uterine arteries of pregnant women with GDM, a phenomenon not observed in women with uncomplicated pregnancies. Thus, aerobic exercise of moderate intensity among its other proven beneficial effects, emerges as a useful therapeutic tool in pregnancies with GDM regarding the improvement of anti-oxidation capacity as well as UtA resistance. Further studies should investigate in a more detailed way this line of pathophysiology.


While the COVID-19 pandemic has caused major educational disruptions, it has also catalyzed innovation in service-learning as a real-time response to pandemic-related problems. The limited number of qualified providers was primed to restrict SARS-CoV-2 vaccination efforts. Thus, New York State temporarily allowed healthcare professional trainees to vaccinate, enabling medical students to support an overwhelmed healthcare system and contribute to the public health crisis. Here, we describe a service-learning vaccination program directed towards underserved communities. A faculty-led curriculum prepared medical students to communicate with patients about COVID-19 vaccines and to administer intramuscular injections. Qualified students were deployed to public vaccination clinics located in under-served neighborhoods in collaboration with an established community partner. Throughout the program, 128 students worked at 103 local events, helping to administer 26,889 vaccine doses. Analysis of a retrospective survey administered to participants revealed the program taught fundamental clinical skills and was a transformative service-learning experience. As new virus variants emerge and nations battle recurrent waves of infection, the need for effective vaccination plans continues to grow. The program described here offers a novel framework that academic medical centers could adapt to increase vaccine access in their local community and provide students with a uniquely meaningful educational experience. Service learning is an experiential educational approach that combines community engagement with academic coursework and personal reflection ,2. It isThe shortage of qualified healthcare professionals capable of administering vaccinations at the scale required early in the pandemic presented a unique service-learning opportunity to medical students with historic precedent. During the great influenza pandemic of 1918, American medical students assisted with the mass inoculation program . Indeed,Following the executive order enabling students to serve as vaccinators, Weill Cornell Medicine began training students as volunteer vaccinators to staff community vaccination sites organized by the Community Healthcare Network (CHN), a federally qualified health center. Guidelines for student training were set by the NYS Department of Health (DOH) to include completion of at least one year of clinical training, vaccine specific online training modules, an in-person training session, and BCLS certification. The online training modules included specific education about counseling and administration of the Pfizer-BioNTech COVID-19 vaccine (Comirnaty), the Moderna COVID-19 vaccine (Spikevax), and the Johnson and Johnson COVID-19 vaccine consistent with Emergency Use Authorization (EUA) and Centers for Disease Control and Prevention (CDC) guidelines. Students who had completed the full foundational curriculum in addition to at least one clerkship were eligible for training. Student volunteers were required to be fully vaccinated or willing to take both vaccine doses at associated vaccine events. Students who did not meet the clinical curricular requirements and/or were not vaccinated were excluded from training and volunteering.https://www.immunize.org/catg.d/p7010.pdf (accessed on 2 February 2021)). In-person skills training session were held in an Objective Structured Clinical Examination (OSCE) format familiar to medical students under supervision of an anesthesiology resident and/or attending physician. All NYS guidelines for Personal Protective Equipment (PPE) were strictly adhered to and measures were discussed regarding managing adverse outcomes. During the OSCE-style sessions, students were supervised conducting a complete mock COVID-19 vaccination encounter including patient education, vaccine preparation, and immunization administration of a saline intramuscular (IM) injection on a fellow classmate. Upon successful completion of all training components, students were added to the certified roster and became eligible to volunteer at vaccination events.A skills checklist for the in-person skills demonstration was provided by the NYC.GOV website (Vaccination events occurred from February to July 2021. Patient eligibility was in accordance with NYS guidelines A. Each eVaccination events took place throughout NYC at transient (pop-up) and stable -funded) sites. The permanent locations were intentionally established in under-served and under-represented communities: Church of God in Brooklyn, Fort Washington Collegiate Church in Washington Heights, New Jerusalem Worship Center in Jamaica Queens and Convent Avenue Baptist Church in Harlem B–D. TranThe program was evaluated with a retrospective survey. Questions for medical student vaccinators were developed to address the following broad categories: quantify degree of involvement in the vaccination program, safety, skills development (hands-on and communication with patients), areas for improvement, and personal reflections. The survey was administered via RedCap  and inclOur program was unique in its ability to quickly train vaccinators, place students at vaccination sites and collect data regarding this service-learning opportunity, which became a unique curricular experience for Weill Cornell Medicine (WCM) students that may serve as a model for similar service-learning efforts. The ever-changing landscape of State and Federal guidelines temporally guided many program milestones A. For exBased on the inclusion criteria, 324 WCM students were eligible for vaccine training. Of these, 128 completed training and became certified vaccinators (40%). These students were from both MD and MD-PhD programs and tended to be in the later years of training . 80 studStudents helped to inoculate 14,293 individuals with 26,889 vaccine doses . PatientThe effect of the program as a service-learning opportunity for student participants was evaluated through a retrospective survey (Supplementary file). Fifty students  completed the optional post-volunteer survey. A summary of the results as well as representative excerpts are shown in Inspection of qualitative responses indicated that participation in the vaccination program was an opportunity for professional growth. When asked why they volunteered, students indicated desires to work with vulnerable communities, reduce disparity in vaccine access, feeling a sense of civic responsibility to help with pandemic efforts and wanting to help pandemic efforts in a direct way. When describing how volunteering as a vaccinator contributed to their professional development, student responses ranged from improving communication with diverse patient populations to better understanding how large-scale public health efforts are coordinated an executed. Finally, when asked how this experience contributed to their medical education students gave many reasons, including fostering an interest in public health and gaining confidence and experience functioning as an independent provider.Here we discuss the development, implementation, and evaluation of an innovative service-learning COVID-19 vaccination program. While there is growing body of literature about medical student contributions to the COVID-19 response ,28,29,30Our vaccination program met its primary goals, to expand access to the COVID-19 vaccine and to provide a valuable service-learning experience for medical students. Our program evaluation survey results indicate that the training provided was well received. Training notably increased the percent of students feeling comfortable administering IM injections, with all respondents noting that they felt adequately prepared to participate. We also observed a notable increase in students’ comfort counseling patients on the COVID-19 vaccination before and after volunteering. Together these findings demonstrate that this service-learning experience provided educational value and boosted clinical confidence, solidifying both comfort with clinical skills and patient counseling. Qualitative survey responses echoed these findings. In fact, multiple students indicated that this was the most meaningful part of their medical education to date.Crucial to the success of our program were the three key-stakeholder groups—Medical students, community partners and the government—Each of whom made unique contributions to the program. Medical students, eager to volunteer and altruistic with their motives, formed the backbone of the program workforce by increasing the number of eligible vaccinators. They were trained providers whose competency was readily identified by supervising faculty. Once trained, students could help administer vaccine doses at both their home medical institutions’ clinical locations, as well as partner locations throughout their community. Collaborating with established community partners meant efforts to be directed towards delivering care to vulnerable communities in need of vaccination infrastructure without extensive relationship building. Finally, government bodies provided vital support by guaranteeing a reliable supply of vaccines, passing policies which enabled students to become qualified vaccinators and providing key financial support required to sustain a long-term program. While the collaborative approach was overwhelming positive, one limitation was that a third-party managed the digital infrastructure tracking vaccines. As such, we were unable to retrospectively analyze vaccine data based on the provider . Nevertheless, we believe that this three-part model integrating students, community partners and government agencies, can be utilized to enhance community-outreach programs at our institution and can be emulated for future service-based learning programs at medical schools across the country.Given the emergence of new SARS-CoV-2 variants  and evolving nature of the COVID-19 pandemic the need for COVID-19 vaccinations remains high. Inoculations are available to children younger than 18, booster shots are available to most adults, and at least 20% of the American population eligible to receive the vaccine has yet to receive a single dose. As the Public Readiness and Emergency Preparedness (PREP) Act continues to allow medical students to serve as vaccinators, institutions around the country have the potential to help fulfill these needs, which we anticipate will continue to grow. Internationally, there is tremendous need for augmented vaccine distribution. This is particularly the case in developing nations, many of which have immunized less than half their population . NeverthHere, we provide a skills-based, checklist-guided approach to ensure competency amongst medical student that can be easily adapted and implemented by medical schools. While this framework was designed for medical students, we anticipate it could also benefit trainees in other allied healthcare professions, many of whom often participate in vaccine distribution . There iMedical students are uniquely positioned to aid in the distribution of vaccines during a pandemic such as COVID-19. In doing so, students are able to benefit under-resourced communities and increase vaccine availability, while also having the opportunity for service-learning which improves proficiency in IM injections and patient counseling. Collaboration amongst various stakeholders is key to the success of such an initiative. Medical school faculty and residents provide training to volunteer medical students, community partners identify communities in need of assistance, and government bodies provide vaccines and permit students to administer care in this capacity. As the COVID-19 pandemic evolves, and the need for additional vaccination remains ever-present, other academic medical institutions can rapidly adapt this service-learning model which enhances student education and improves community health.


The mechanistic adaptations that allow the cell walls of succulent plants to fold provide insights into cellular water storage and the reversible responses to drought and rehydration. Succulent plants represent a large functional group of drought-resistant plants that store water in specialized tissues. Several co-adaptive traits accompany this water-storage capacity to constitute the succulent syndrome. A widely reported anatomical adaptation of cell walls in succulent tissues allows them to fold in a regular fashion during extended drought, thus preventing irreversible damage and permitting reversible volume changes. Although ongoing research on crop and model species continuously reports the importance of cell walls and their dynamics in drought resistance, the cell walls of succulent plants have received relatively little attention to date, despite the potential of succulents as natural capital to mitigate the effects of climate change. In this review, we summarize current knowledge of cell walls in drought-avoiding succulents and their effects on tissue biomechanics, water relations, and photosynthesis. We also highlight the existing knowledge gaps and propose a hypothetical model for regulated cell wall folding in succulent tissues upon dehydration. Future perspectives of methodological development in succulent cell wall characterization, including the latest technological advances in molecular and imaging techniques, are also presented. Aloe, Asphodelaceae; With their peculiar appearance and their capacity to thrive under extreme conditions, succulent plants have long captivated botanists and plant enthusiasts . DroughtDrought can lead to different degrees of water stress in plants, defined as ‘situations in which plant water potential and turgor are reduced enough to interfere with normal functioning’, although the ‘exact cell water potential at which this occurs depends on the kind of plant’ . Many drDespite being traditionally associated with arid and hyper-arid deserts  are apoplastic polysaccharides associated with the cell wall that can be repurposed for energy storage and other functions . They co2 diffusion and water movement in photosynthetic organs, thus influencing the interplay of factors linked to limitation of photosynthesis , changes in pectin are likely crucial to drought-induced cell wall remodelling . The natPectin gel properties are also determined by rhamnogalacturonan I (RG-I), whose side chains influence cell wall hydration and elasticity  , which sAloe and closely related genera lack support tissues and are also primarily supported by hydrostatic pressure on a reinforced epidermis , many species exhibit secondary cell wall bands in the hydrenchyma (b). Similarly, wide-band tracheids occur in the vascular tissues of succulent organs in many genera of succulent families of the Caryophyllales, namely Cactaceae, Aizoaceae, Anacampserotaceae, and Didiereaceae; these tracheids have annular or helical secondary wall thickenings that extend deeply into the lumen  even during extended drought . Ψ can bP is the pressure potential, hydrostatic potential, or turgor pressure, and ΨS is the solute or osmotic potential (see C) and low values of volumetric modulus of elasticity (ε) in succulent organs, which is related to highly elastic cell walls  has generally been interpreted as an indicator of drought tolerance (i.e. tolerating low Ψ) among non-succulent plants  between hydrenchyma and chlorenchyma –1; see KOX) expected to be particularly limiting due to long outside-xylem hydraulic pathways  and, thus, on photosynthesis, in addition to the limitation they impose on KOX. Several interrelated cell wall properties, such as thickness, ε, and effective porosity, have been postulated as some of the strongest determinants of gi  and Asclepiadoideae  and Pyrrosia  Burm.f. and its relatives in Asphodelaceae due to their widespread medicinal uses has fostered one of the most detailed cell wall characterizations in succulent tissues. In the leaf hydrenchyma of A. vera, besides structural cell wall polysaccharides, cell contents are rich in storage polysaccharides and free sugars, including the prized acetylated glucomannans, which have putative medicinal properties  has confirmed the existence of a tightly regulated cell wall folding process during dehydration  mannans are mobilized from the pseudobulb and subsequently degraded and converted to starch, which temporarily accumulates before further catabolic reactions (Aloe.Another study on two species of ow-DM HG  that is ow-DM HG . GranulaWSPs see  by provin starch , whereasSansevieria the collapsible walls in the hydrenchyma exhibit bands of secondary thickening (From different studies, it seems clear that collapsible cell walls in succulents maintain their high elasticity or even increase it further during drought through elastic adjustment, a process that is likely driven by cell wall remodelling (ickening a, 1988b,ickening , 2021. TArabidopsis, and those of Aloe, is presented in A hypothetical model, based on the observations of Aloe, for instance, it has recently been postulated that HGs and mannans are involved in the folding process (The cell wall is a central aspect of drought resistance in plants, yet much remains to be determined about the molecular and physiological mechanisms of cell wall folding processes in drought-avoiding succulents. Cell wall folding in resurrection plants, which has received special attention over the past decades, relies on different mechanisms in different lineages, most of which involve arabinose-rich polymers acting as cell wall plasticizers (Aloe species and relatives and to provide a deeper insight into cell wall dynamics under drought (As studies of separate cell wall components tend to overlook the complexity of the cell wall and the interactions between different components, holistic approaches should be favoured for cell wall characterization in succulents. Advancing cell wall analytical methods provide promising prospects, with a growing demand for high-throughput methods for rapid screening and profiling of cell wall components ( drought b. HoweveWhile omics studies have shed light on cell wall-related genes and their respective products (


Genome instability and immune evasion are both defining hallmarks of cancer. Tumorigenesis is frequently initiated when there is DNA damage to a proto-oncogene or tumor suppressor gene and DNA repair mechanisms are lost or insufficient to correct the damage; immune evasion then prevents the host immune system from recognizing these transformed cells. Therapies targeting genomic instability and immune evasion have been effectively used to treat cancer. Genotoxic therapies such as chemoradiation have been employed in cancer treatments for several decades, while immunotherapy is a relatively new class of cancer therapy that has led to disease regression even in patients with advanced cancer. Several recent studies have shown synergy between both classes of therapy targeting these two defining hallmarks of cancer, and different mechanisms are proposed to be involved. Here, we review the different classes of DNA damage, their links to cancer, and their contribution to immunotherapy responses, as well as the different models that are currently being used to study tumor–immune interactions. One of the major hallmarks of cancer is genome instability resulting from DNA damage caused by external insults and malfunctions in the cell’s DNA damage response (DDR) mechanisms ,2. Both BRCA1 and BRCA2 cause HR deficiency, replication fork instability, increased mutations, and genomic instability [Malfunctions in the DDR can either be caused by mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes. For example, BRCA1, which is involved in HR, has been found to be mutated at both germline and somatic levels, or epigenetically silenced in cancer . The lostability ,12. Howetability ,14,15.Another promising class of cancer therapeutics that work well in cancers with certain classes of DDR defects are immune checkpoint inhibitors (ICIs) ,18,19,20Genotoxic cancer treatments also synergize well with ICIs. One commonly employed genotoxic treatment is radiation therapy (RT), which induces cancer cell death through ionizing radiation. A large clinical trial, the PACIFIC trial, found that patients with non-small-cell lung cancer had significantly longer progression-free survival when treated with a combination of chemoradiation and a PD-(L)1 inhibitor . Indeed,Chemotherapy, another common form of genotoxic treatment, uses a class of pharmaceutical agents that cause DNA damage through several different mechanisms, such as DNA alkylation and crosslinking, anti-metabolites that inhibit RNA or DNA synthesis, and topoisomerase inhibition . ChemothIn this review, we will discuss the different types of DNA damage and repair pathways, the association between genomic instability and tumorigenesis, the link between DNA damage and immunotherapy response, and the various models that are being employed to study these tumor–immune interactions.Double-stranded breaks (DSBs) are a deleterious form of DNA damage that results in cell cycle arrest, apoptosis, cellular senescence, or carcinogenesis ,40. ATM HR has the highest fidelity . DamagedNHEJ is relatively accurate and activated by the direct ligation of the broken strands of DNA via the end-binding proteins Ku70-Ku80 and 53BP1. RIF1 prevents DNA from being resected, while recruiting DNA-PKcs for end processing. XRCC4 and DNA ligase IV are also recruited to the DSB to ligate the DNA ends and fill in any gaps in the sequence . GermlinMMEJ, also known as Alt-EJ, is less accurate than NHEJ, giving rise to a large number of chromosomal translocations . It is iSSA is a less well-studied form of DSB repair that involves Rad50, Rad52, and RPA, and is a relatively low-fidelity pathway, resulting in deletions of repetitive sequences . The inhSingle-stranded breaks (SSBs), base damages, and DNA mismatches are repaired by nucleotide excision repair (NER), base excision repair (BER), or DNA mismatch repair (MMR) ,68,69. WBulky lesions such as pyrimidine dimers are repaired via global genomic NER (GG-NER) or transcription-coupled NER (TC-NER). GG-NER repairs damage detected by XPC-Rad23B or DDB1-DDB2 . TC-NER Base damages caused by oxidation, deamination, and alkylation are repaired via short-patch (SP)-BER or long-patch (LP)-BER ,75. AP eDNA mismatch repair (MMR) repairs base–base mismatches and insertion–deletion mutations that occur during DNA replication and recombination ,83. MSH2Fanconi anemia (FA) pathway repairs DNA interstrand crosslinks (ICL) [Fanconi anemia, associated with leukemias, ovarian, breast and other cancers [The ks (ICL) . ICLs afks (ICL) ,92,93. Fks (ICL) ,95,96. MR-loops form when an RNA strand displaces the non-template DNA strand behind RNA polymerase during transcription, creating a triple-stranded nucleic acid structure ,98,99. PThe translesion DNA synthesis (TLS) pathway gets activated when bulky DNA lesions block replicative DNA polymerase progression. PCNA gets monoubiquitinated and switches to bind a TLS polymerase which fills in the gap with low fidelity . This paWhile mutations in the R-loop processing and TLS pathway components have not been specifically linked to cancer predisposition, both contribute to replication stress and genomic instability and thus are likely to contribute to tumorigenesis. A summary of the different types of DNA damage, modes of DNA repair, examples of genes involved, and examples of related cancers are given in Cancer immunotherapy is a promising new class of therapy that harnesses the patient’s immune system to kill cancer cells . Immune While cancer immunotherapy can result in tumor remission in some patients with advanced disease, the proportion of treated patients that respond is small . It is tWhile one might expect mutations in DNA repair genes to predict an increase in tumor mutational burden, this is not always true if the mutation occurs in a region that is not functionally important. A scoring system such as the HRD score, which combines information about mutations in DNA repair genes and genomic scars that suggests a HR defect, might therefore be important to determine the loss of DNA repair capacity . The usaThe cellular role of PD-L1 outside of immunity has been under-studied. It was recently reported that PD-L1 binds to the transcripts of several DNA repair proteins, playing an important role in regulating DNA repair . This noWhile deficiencies in HR and MMR pathways have both been demonstrated to lead to improved response with cancer immunotherapy, deficiencies in several other key DNA repair pathways, including TLS, FA, R-loop processing pathways, and ATM mutations in tumors, have all been under-studied in the context of cancer immunotherapy response. Since a high TMB is frequently observed in cancers that have DDR defects and high TMB is a good prognostic marker for immunotherapy response, it is very likely that these other DDR-deficient cancers also respond well to immune checkpoint blockade and should be explored further in future studies.Altered RNA metabolism and processing frequently lead to the accumulation of R-loops, increased DNA damage, and tumorigenesis ,130,131.The RNA-editing enzyme ADAR1 has also been found to be important in response to cancer immunotherapy. Ablation of ADAR1 in tumor cells inflamed tumors and sensitized tumors to immune checkpoint blockade due to the increased innate immune response recognition of dsRNA upon decreased A-to-I RNA editing . InteresBesides DDR deficiencies, genotoxic treatments can also improve response to immune checkpoint blockade in cancer. Both chemotherapy and radiotherapy have been shown to synergize with immune checkpoint blockade, and several clinical trials are ongoing for the co-treatment of tumors with PARP inhibitors and immune checkpoint inhibitors ,138,139.Radiotherapy in particular exhibits remarkable synergy with the host immune response. The abscopal effect, a rare but interesting phenomenon where the radiation treatment of one tumor site leads to the regression of tumors at distant metastatic sites in the same patient, provided early evidence that tumor irradiation synergizes with host immunity to achieve systemic anti-tumor effects . In miceOne potential mechanism that might explain this synergy is the increase in neoantigens in tumors after treatment with genotoxic therapies. In support of this mechanism, a pivotal study in lung cancer demonstrated that increased sensitivity to anti-CTLA4 immunotherapy in irradiated tumors can be directly attributed to the resulting upregulation of neoantigen presentation. Using both whole exome sequencing and RNA sequencing to detect somatic mutations in tumors from a patient with complete response to a combination of radiation and anti-CTLA4 therapy, the authors demonstrated that irradiation induced a rapid expansion of T cells that targets a neoantigen which was upregulated post-radiation .Another mechanism of synergy between genotoxic cancer therapies and immunotherapy is activation of the cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Upon genotoxic treatment of cancer cells, nuclear integrity is often compromised, leading to the leakage of DNA into the cytosol ,145,146.One of the best-studied classes of STING activators is cyclic dinucleotides (CDN) which is formed by the catalysis of ATP and GTP . cGAMP iENPP1 is a type II transmembrane glycoprotein that degrades the STING ligand . A recenBesides ENPP1, TREX1 is an exonuclease that also acts to antagonize the cGAS-STING pathway in cells, likely through the degradation of cytosolic DNA ,168,169.Several pre-clinical and clinical genotoxic therapies have also been shown to upregulate the cGAS-STING pathway and potentiate cancer immunotherapy in animal models. ATM inhibition, ATR inhibition, Chk1 inhibition, PARP inhibition, and WEE1 inhibition have all been shown to lead to cGAS-STING pathway activation and potentiation of cancer immunotherapy ,180,181.In order to study tumor immunology, we need reliable models that faithfully recapitulate the interaction between cells from the immune system and tumor cells. Current commonly used models include in vitro cell line co-culture models, genetically engineered mouse models (GEMM), and syngeneic or humanized animal models. Cell line co-culture models involve co-culturing T cells (either donor-derived or T-cell lines) with cancer cells. The T cells are typically artificially activated before the co-culture and might first be primed with an artificial antigen such as ovalbumin that is also expressed on co-cultured cancer cells. However, this model consists only of two different cell types and does not take into account other microenvironmental factors .Syngeneic mouse models involve implanting tumor cell lines obtained from commonly used strains of mice into other mice of the same strain . This moHumanized mice models overcome this problem by engineering human proteins to be expressed by mice or replacing the immune-compromised mice hematopoietic system with human hematopoietic stem cells (HSCs) or peripheral blood mononuclear cells (PBMCs). Using such a model, it is possible to construct mice “avatars” of a patient to study immunotherapy response by using cells from the patient’s tumor to inoculate NSG mice and transplanting CD34+ HSCs from the same patient into the mice ,186. TheGEMMs are mice models of cancers that have either oncogenic or tumor suppressor mutations engineered into their genomes to increase their chances of developing cancers ,190. TheTumor-on-chip models are a form of indirect co-culture system that cultures tumor cells in the form of 3D tissue spheroids or fragments on a chip in a controlled environment . The chiPatient-derived organoid tumor models are 3D ex vivo models derived from tumor tissues that better recapitulate intra-tumoral heterogeneity and cell–cell interactions in vivo ,193. OneCancer is a disease that is defined by genomic instability and immune evasion. The advent of cancer immunotherapy has improved outcomes even for cancer patients with advanced disease. However, due to low rates of response and response heterogeneity, methods of enhancing cancer immunotherapy and improved biomarkers of response are urgently needed. In this review, we have discussed the various DNA repair processes that are frequently disrupted in cancer, giving rise to this genomic instability. We have also discussed how these DNA repair defects could contribute to sensitivity to traditional genotoxic therapies or cancer immunotherapy. We summarized the findings of publications that described how genotoxic treatments enhance cancer immunotherapy and DNA-repair-related biomarkers of response and also discussed the different model systems that are being used in immunotherapy studies. Going forward, one of the key areas that remains to be addressed includes the contribution of tumor heterogeneity to cancer immunotherapy response and how these might interact with genotoxic therapies. The intrinsic heterogeneity of tumors, with different cell populations consisting of different mixtures of mutations and microenvironmental changes, affect therapeutic responses in different ways. For example, hypoxic regions of the tumor are known to be resistant to radiation treatment. Resistance to radiation in hypoxic regions might thus inhibit synergy with cancer immunotherapy, leading to the survival and outgrowth of therapy-resistant populations of cells and tumor recurrence. Other microenvironmental and mutational heterogeneity might also influence the synergy between genotoxic therapies and immunotherapy; this is therefore an area that warrants further investigation.The cellular DDR machinery is necessarily complex in order to coordinate and repair the wide-ranging forms of genotoxic insults that affect genomic DNA. Two of the major DDR pathways that remain to be explored comprehensively in the context of cancer immunotherapy co-treatment include the Fanconi anemia pathway and the R-loop resolution pathway. Targeted inhibitors to these pathways might enhance response to cancer immunotherapy in certain contexts, and tumors deficient in these pathways might also benefit significantly from immunotherapy treatments.New and more targeted forms of radiation therapies such as proton therapy and carbon ion therapy allow higher doses of radiation to be used with fewer side effects in cancer. These are primarily used for tumors in deep-seated locations or locations that are difficult to target with conventional photon-based radiation due to their proximity to important organs. Whether this higher precision and dose translates to enhanced synergy with cancer immunotherapy also warrants further investigation. The fields of traditional genotoxic therapies and promising new cancer immunotherapy are merging due to their ability to synergize and enhance patients’ response to treatment. Here, we have provided a snapshot of the various DNA repair pathways that have been shown to synergize with or have the potential to synergize with cancer immunotherapy. While some mechanistic aspects of this synergy have been elucidated, much work remains to be done to expand this increased efficacy to a larger patient population. Since genomic instability is an inherent characteristic of cancer, we believe that identifying the appropriate targetable DDR pathway in each tumor, when performed in conjunction with immunotherapy, has the potential to benefit almost all cancer patients.