Targeting Neoantigens in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is currently the third leading cause of cancer-related death in the United States after lung and colon cancer. PDAC is estimated to be the second leading cause of cancer-related death by 2030. The diagnosis at a late stage is the underlying cause for higher mortality and poor prognosis after surgery. Treatment resistance to chemotherapy and immunotherapy results in recurrence after surgery and poor prognosis. Neoantigen burden and CD8+ T-cell infiltration are associated with clinical outcomes in PDAC and paucity of neoantigen-reactive tumor-infiltrating lymphocytes may be the underlying cause for treatment resistance for immunotherapy. This suggests a need to identify additional neoantigens and therapies targeting these neoantigens to improve clinical outcomes in PDAC. In this review, we focus on describing the pathophysiology, current treatment strategies, and treatment resistance in PDAC followed by the need to target neoantigens in PDAC.

Targeting Neoantigens in Cancer: Possibilities and Opportunities in Breast Cancer.

As one of the most prevalent forms of cancer worldwide, breast cancer has garnered significant attention within the clinical research setting. While traditional treatment employs a multidisciplinary approach including a variety of therapies such as chemotherapy, hormone therapy, and even surgery, researchers have since directed their attention to the budding role of neoantigens. Neoantigens are defined as tumor-specific antigens that result from a multitude of genetic alterations, the most prevalent of which is the single nucleotide variant. As a result of their foreign nature, neoantigens elicit immune responses upon presentation by Major Histocompatibility Complexes I and II followed by recognition by T cell receptors. Previously, researchers have been able to utilize these immunogenic properties and manufacture neoantigen-specific T-cells and neoantigen vaccines. Within the context of breast cancer, biomarkers such as tumor protein 53 (TP53), Survivin, Partner and Localizer of BRCA2 (PALB2), and protein tyrosine phosphatase receptor T (PTPRT) display exceeding potential to serve as neoantigens. However, despite their seemingly limitless potential, neoantigens must overcome various obstacles if they are to be fairly distributed to patients. For instance, a prolonged period between the identification of a neoantigen and the dispersal of treatment poses a serious risk within the context of breast cancer. Regardless of these current obstacles, it appears highly promising that future research into neoantigens will make an everlasting impact on the health outcomes within the realm of breast cancer. The purpose of this literature review is to comprehensively discuss the etiology of various forms of breast cancer and current treatment modalities followed by the significance of neoantigens in cancer therapeutics and their application to breast cancer. Further, we have discussed the limitations, future directions, and the role of transcriptomics in neoantigen identification and personalized medicine. The concepts discussed in the original and review articles were included in this review article.

Targeting Oncostatin M Receptor to Attenuate Carotid Artery Plaque Vulnerability in Hypercholesterolemic Microswine.

Atherosclerosis is a chronic inflammatory disease that leads to acute embolism via the formation of atherosclerotic plaques. Plaque formation is first induced by fatty deposition along the arterial intima. Inflammation, bacterial infection, and the released endotoxins can lead to dysfunction and phenotypic changes of vascular smooth muscle cells (VSMCs), advancing the plaque from stable to unstable form and prone to rupture. Stable plaques are characterized by increased VSMCs and less inflammation while vulnerable plaques develop due to chronic inflammation and less VSMCs. Oncostatin M (OSM), an inflammatory cytokine, plays a role in endothelial cells and VSMC proliferation. This effect of OSM could be modulated by p27KIP1, a cyclin-dependent kinase (CDK) inhibitor. However, the role of OSM in plaque vulnerability has not been investigated. To better understand the role of OSM and its downstream signaling including p27KIP1 in plaque vulnerability, we characterized the previously collected carotid arteries from hyperlipidemic Yucatan microswine using hematoxylin and eosin stain, Movat Pentachrome stain, and gene and protein expression of OSM and p27KIP1 using immunostaining and real-time polymerase chain reaction. OSM and p27KIP1 expression in carotid arteries with angioplasty and treatment with either scrambled peptide or LR12, an inhibitor of triggering receptor expressed on myeloid cell (TREM)-1, were compared between the experimental groups and with contralateral carotid artery. The results of this study elucidated the presence of OSM and p27KIP1 in carotid arteries with plaque and their association with arterial plaque and vulnerability. The findings suggest that targeting OSM and p27KIP1 axis regulating VSMC proliferation may have therapeutic significance to stabilize plaque.

Transcriptional and Translational Regulation of Differentially Expressed Genes in Yucatan Miniswine Brain Tissues following Traumatic Brain Injury.

Traumatic brain injury (TBI) is a leading cause of morbidity, disability, and mortality worldwide. Motor and cognitive deficits and emotional disturbances are long-term consequences of TBI. A lack of effective treatment for TBI-induced neural damage, functional impairments, and cognitive deficits makes it challenging in the recovery following TBI. One of the reasons may be the lack of knowledge underlying the complex pathophysiology of TBI and the regulatory factors involved in the cellular and molecular mechanisms of inflammation, neural regeneration, and injury repair. These mechanisms involve a change in the expression of various proteins encoded by genes whose expression is regulated by transcription factors (TFs) at the transcriptional level and microRNA (miRs) at the mRNA level. In this pilot study, we performed the RNA sequencing of injured tissues and non-injured tissues from the brain of Yucatan miniswine and analyzed the sequencing data for differentially expressed genes (DEGs) and the TFs and miRs regulating the expression of DEGs using in-silico analysis. We also compared the effect of the electromagnetic field (EMF) applied to the injured miniswine on the expression profile of various DEGs. The results of this pilot study revealed a few DEGs that were significantly upregulated in the injured brain tissue and the EMF stimulation showed effect on their expression profile.

Therapeutic Potential of Targeting p27kip1 in Plaque Vulnerability.

Atherosclerosis, a critical contributor to coronary artery diseases, involves the accumulation of cholesterol, fibrin, and lipids within arterial walls, inciting inflammatory reactions culminating in plaque formation. This multifaceted interplay encompasses excessive fibrosis, fatty plaque development, vascular smooth muscle cell (VSMC) proliferation, and leukocyte migration in response to inflammatory pathways. While stable plaques demonstrate resilience against complications, vulnerable ones, with lipid-rich cores, necrosis, and thin fibrous caps, lead to thrombosis, myocardial infarction, stroke, and acute cerebrovascular accidents. The nuanced phenotypes of VSMCs, modulated by gene regulation and environmental cues, remain pivotal. Essential markers like alpha-SMA, myosin heavy chain, and calponin regulate VSMC migration and contraction, exhibiting diminished expression during VSMC de-differentiation and proliferation. p27kip, a CDK inhibitor, shows promise in regulating VSMC proliferation and appears associated with TNF-α-induced pathways impacting unstable plaques. Oncostatin M (OSM), an IL-6 family cytokine, correlates with MMP upregulation and foam cell formation, influencing plaque development. Efforts targeting mammalian target of rapamycin (mTOR) inhibition, notably using rapamycin and its analogs, demonstrate potential but pose challenges due to associated adverse effects. Exploration of the impact of p27kip impact on plaque macrophages presents promising avenues, yet its complete therapeutic potential remains untapped. Similarly, while OSM has exhibited potential in inducing cell cycle arrest via p27kip, direct links necessitate further investigation. This critical review discusses the role of mTOR, p27kip, and OSM in VSMC proliferation and differentiation followed by the therapeutic potential of targeting these mediators in atherosclerosis to attenuate plaque vulnerability.

Quantitative Assessment of Intracellular Effectors and Cellular Response in RAGE Activation.

The review delves into the methods for the quantitative assessment of intracellular effectors and cellular response of Receptor for Advanced Glycation End products (RAGE), a vital transmembrane receptor involved in a range of physiological and pathological processes. RAGE bind to Advanced Glycation End products (AGEs) and other ligands, which in turn activate diverse downstream signaling pathways that impact cellular responses such as inflammation, oxidative stress, and immune reactions. The review article discusses the intracellular signaling pathways activated by RAGE followed by differential activation of RAGE signaling across various diseases. This will ultimately guide researchers in developing targeted and effective interventions for diseases associated with RAGE activation. Further, we have discussed how PCR, western blotting, and microscopic examination of various molecules involved in downstream signaling can be leveraged to monitor, diagnose, and explore diseases involving proteins with unique post-translational modifications. This review article underscores the pressing need for advancements in molecular approaches for disease detection and management involving RAGE.

Research Note: Bovine lactoferrin in chickens: an investigation into its viability as an antibiotic alternative.

Finding effective antibiotic alternatives is crucial to managing the re-emerging health risk of Clostridium perfringens (CP) type A/G-induced avian necrotic enteritis (NE), a disease that has regained prominence in the wake of governmental restrictions on antibiotic use in poultry. Known for its antimicrobial and immunomodulatory effects, the use of bovine lactoferrin (bLF) in chickens is yet to be fully explored. In this study, we hypothesized that bLF can accumulate in the small intestines of healthy chickens through gavage and intramuscular supplementation and serves as a potential antibiotic alternative. Immunohistochemistry located bLF in various layers of the small intestines and ELISA testing confirmed its accumulation. Surprisingly, sham-treated chickens also showed the presence of bLF, prompting a western blotting analysis that dismissed the notion of cross-reactivity between bLF and the avian protein ovotransferrin. Although the significance of the route of administration remains inconclusive, this study supports the hypothesis that bLF is a promising and safe antibiotic alternative with demonstrated resistance to the degradative environment of the chicken intestines. Further studies are needed to determine its beneficial pharmacological effects in CP-infected chickens.

Transcriptomic Analysis of Gene Expression and Effect of Electromagnetic Field in Brain Tissue after Traumatic Brain Injury.

Traumatic brain injury (TBI) due to a direct blow or penetrating injury to the head damages the brain tissue and affects brain function. Primary and secondary damage to the brain tissue increases disability, morbidity, and mortality and costs millions of dollars in treatment. Injury to the brain tissue results in the activation of various inflammatory and repair pathways involving many cellular and molecular factors. Increased infiltration of immune cells to clear the debris and lesion healing, activation of Schwann cells, myelination, oligodendrocyte formation, and axonal regeneration occur after TBI to regenerate the tissue. However, secondary damage to brain tissue results in behavioral symptoms. Repair and regeneration are regulated by a complex cascade involving various cells, hormones, and proteins. A change in the expression of various proteins due to altered gene expression may be the cause of impaired repair and the sequelae in TBI. In this pilot study, we used a Yucatan miniswine model of TBI with and without electromagnetic field (EMF) stimulation and investigated the differential gene expression between injured and non-injured cortex tissues. We found several differentially expressed genes including INSC, TTR, CFAP126, SEMA3F, CALB1, CDH19, and SERPINE1. These genes are associated with immune cell infiltration, myelination, reactive oxygen species regulation, thyroid hormone transportation, cell proliferation, and cell migration. There was a time-dependent effect of EMF stimulation on the gene and protein expression. The findings support the beneficial effect of EMF stimulation in the repair process following TBI.

Increased Oxidative Stress and Decreased Sirtuin-3 and FOXO3 Expression Following Carotid Artery Intimal Injury in Hyperlipidemic Yucatan Microswine.

Hypercholesterolemia is a major risk factor for atherosclerosis as oxidized-low-density lipoproteins (ox-LDL) contribute to the formation of foam cells and inflammation. Increased immune cell infiltration and oxidative stress induce instability of a plaque. Rupture of the unstable plaque precipitates adverse ischemic events. Since reactive oxygen species (ROS) play a critical role in plaque formation and vulnerability, regulating ROS generation may have therapeutic potential. Sirtuins, specifically sirtuin-3 (SIRT3), are antigenic molecules that can reduce oxidative stress by reducing mitochondrial ROS production through epigenetic modulation. Lack of SIRT3 expression is associated with dysregulation of ROS and endothelial function following high-fat high-cholesterol diet. SIRT3 deacetylates FOXO3a (Forkhead transcription factor O subfamily member 3a) and protects mitochondria against oxidative stress which can lead to even further protective anti-oxidizing properties. This study was designed to investigate the association between hyperlipidemia, intimal injury, chronic inflammation, and the expression of NAD-dependent deacetylase SIRT-3, FOXO3, antioxidant genes, and oxidative stress in carotid arteries of hypercholesterolemic Yucatan microswine. We found that intimal injury in hypercholesterolemic state led to increased expression of oxidative stress, inflammation, neointimal hyperplasia, and plaque size and vulnerability, while decreasing anti-oxidative regulatory genes and mediators. The findings suggest that targeting the SIRT3-FOXO3a-oxidative stress pathway will have therapeutic significance.

Modulation of Inflammatory Response by Electromagnetic Field Stimulation in Traumatic Brain Injury in Yucatan Swine.

Traumatic brain injury is a leading cause of disability and death worldwide and represents a high economic burden for families and national health systems. After mechanical impact to the head, the first stage of the damage comprising edema, physical damage, and cell loss gives rise to a second phase characterized by glial activation, increased oxidative stress and excitotoxicity, mitochondrial damage, and exacerbated neuroinflammatory state, among other molecular calamities. Inflammation strongly influences the molecular events involved in the pathogenesis of TBI. Therefore, several components of the inflammatory cascade have been targeted in experimental therapies. Application of Electromagnetic Field (EMF) stimulation has been found to be effective in some inflammatory conditions. However, its effect in the neuronal recovery after TBI is not known. In this pilot study, Yucatan miniswine were subjected to TBI using controlled cortical impact approach. EMF stimulation via a helmet was applied immediately or two days after mechanical impact. Three weeks later, inflammatory markers were assessed in the brain tissues of injured and contralateral non-injured areas of control and EMF-treated animals by histomorphometry, immunohistochemistry, RT-qPCR, Western blot, and ELISA. Our results revealed that EMF stimulation induced beneficial effect with the preservation of neuronal tissue morphology as well as the reduction of inflammatory markers at the transcriptional and translational levels. Immediate EMF application showed better resolution of inflammation. Although further studies are warranted, our findings contribute to the notion that EMF stimulation could be an effective therapeutic approach in TBI patients.

miRNA profiling of esophageal adenocarcinoma using transcriptome analysis.

Esophageal adenocarcinoma (EAC) occurs following a series of histological changes through epithelial-mesenchymal transition (EMT). A variable expression of normal and aberrant genes in the tissue can contribute to the development of EAC through the activation or inhibition of critical molecular signaling pathways. Gene expression is regulated by various regulatory factors, including transcription factors and microRNAs (miRs). The exact profile of miRs associated with the pathogenesis of EAC is largely unknown, though some candidate miRNAs have been reported in the literature. To identify the unique miR profile associated with EAC, we compared normal esophageal tissue to EAC tissue using bulk RNA sequencing. RNA sequence data was verified using qPCR of 18 selected genes. Fourteen were confirmed as being upregulated, which include CDH11, PCOLCE, SULF1, GJA4, LUM, CDH6, GNA12, F2RL2, CTSZ, TYROBP, and KDELR3 as well as the downregulation of UGT1A1. We then conducted Ingenuity Pathway Analysis (IPA) to analyze for novel miR-gene relationships through Causal Network Analysis and Upstream Regulator Analysis. We identified 46 miRs that were aberrantly expressed in EAC compared to control tissues. In EAC tissues, seven miRs were associated with activated networks, while 39 miRs were associated with inhibited networks. The miR-gene relationships identified provide novel insights into potentially oncogenic molecular pathways and genes associated with carcinogenesis in esophageal tissue. Our results revealed a distinct miR profile associated with dysregulated genes. The miRs and genes identified in this study may be used in the future as biomarkers and serve as potential therapeutic targets in EAC.

Role of sirtuins in attenuating plaque vulnerability in atherosclerosis.

Atherosclerosis is characterized by the development of intimal plaque, thrombosis, and stenosis of the vessel lumen causing decreased blood flow and hypoxia precipitating angina. Chronic inflammation in the stable plaque renders it unstable and rupture of unstable plaques results in the formation of emboli leading to hypoxia/ischemia to the organs by occluding the terminal branches and precipitate myocardial infarction and stroke. Such delibitating events could be controlled by the strategies that prevent plaque development or plaque stabilization. Despite the use of statins to stabilize plaques, there is a need for novel targets due to continuously increasing cases of cardiovascular events. Sirtuins (SIRTs), a family of signaling proteins, are involved in sustaining genome integrity, DNA damage response and repair, modulating oxidative stress, aging, inflammation, and energy metabolism. SIRTs play a critical role in modulating inflammation and involves in the development and progression of atherosclerosis. The role of SIRTs in relation to atherosclerosis and plaque vulnerability is scarcely discussed in the literature. Since SIRTs regulate oxidative stress, inflammation, and aging, they may also regulate plaque progression and vulnerability as these molecular mechanisms underlie the pathogenesis of plaque development, progression, and vulnerability. This review critically discusses the role of SIRTs in plaque progression and vulnerability and the possibility of targeting SIRTs to attenuate plaque rupture, focusing on the highlights in genomics, molecular pathways, and cell types involved in the underlying pathophysiology.

COVID-19 and Kidney: The Importance of Follow-Up and Long-Term Screening.

Renal involvement and kidney injury are common in COVID-19 patients, and the symptoms are more severe if the patient already has renal impairment. Renal involvement in COVID-19 is multifactorial, and the renal tubule is mainly affected, along with podocyte injury during SARS-CoV-2 infection. Inflammation, complement activation, hypercoagulation, and crosstalk between the kidney and lungs, brain, and heart are contributory factors. Kidney injury during the acute phase, termed acute kidney injury (AKI), may proceed to chronic kidney disease if the patient is discharged with renal impairment. Both AKI and chronic kidney disease (CKD) increase mortality in COVID-19 patients. Further, COVID-19 infection in patients suffering from CKD is more severe and increases the mortality rate. Thus, it is important to address both categories of patients, either developing AKI or CKD after COVID-19 or previously having CKD, with proper management and treatment. This review discusses the pathophysiology involved in AKI and CKD in COVID-19 infection, followed by management and treatment of AKI and CKD. This is followed by a discussion of the importance of screening and treatment of CKD patients infected with COVID-19 and future perspectives to improve treatment in such patients.

A Review of Hematological Complications and Treatment in COVID-19.

COVID-19, caused by SARS-CoV-2, and its variants have spread rapidly across the globe in the past few years, resulting in millions of deaths worldwide. Hematological diseases and complications associated with COVID-19 severely impact the mortality and morbidity rates of patients; therefore, there is a need for oversight on what pharmaceutical therapies are prescribed to hematologically at-risk patients. Thrombocytopenia, hemoglobinemia, leukopenia, and leukocytosis are all seen at increased rates in patients infected with COVID-19 and become more prominent in patients with severe COVID-19. Further, COVID-19 therapeutics may be associated with hematological complications, and this became more important in immunocompromised patients with hematological conditions as they are at higher risk of hematological complications after treatment. Thus, it is important to understand and treat COVID-19 patients with underlying hematological conditions with caution. Hematological changes during COVID-19 infection and treatment are important because they may serve as biomarkers as well as to evaluate the treatment response, which will help in changing treatment strategies. In this literature review, we discuss the hematological complications associated with COVID-19, the mechanisms, treatment groups, and adverse effects of commonly used COVID-19 therapies, followed by the hematological adverse events that could arise due to therapeutic agents used in COVID-19.

Biomarkers to monitor the prognosis, disease severity, and treatment efficacy in coronary artery disease.

INTRODUCTION: Coronary Artery Disease (CAD) is a prevalent condition characterized by the presence of atherosclerotic plaques in the coronary arteries of the heart. The global burden of CAD has increased significantly over the years, resulting in millions of deaths annually and making it the leading health-care expenditure and cause of mortality in developed countries. The lack of cost-effective strategies for monitoring the prognosis of CAD warrants a pressing need for accurate and efficient markers to assess disease severity and progression for both reducing health-care costs and improving patient outcomes. AREA COVERED: To effectively monitor CAD, prognostic biomarkers and imaging techniques play a vital role in risk-stratified patients during acute treatment and over time. However, with over 1,000 potential markers of interest, it is crucial to identify the key markers with substantial utility in monitoring CAD progression and evaluating therapeutic interventions. This review focuses on identifying and highlighting the most relevant markers for monitoring CAD prognosis and disease severity. We searched for relevant literature using PubMed and Google Scholar. EXPERT OPINION: By utilizing the markers discussed, health-care providers can improve patient care, optimize treatment plans, and ultimately reduce health-care costs associated with CAD management.

Coronary artery disease is a narrowing or blockage of coronary arteries due to the formation of plaque. The main risk factors are inflammation, aging, high cholesterol, shear stress, obesity, and smoking. Narrowing of the arteries results in decreased blood supply (nutrient and oxygen) to the tissue precipitating ischemia presented as angina or myocardial infarction. During ischemic events, there occurs a change in the expression of various molecular and cellular components and increased expressions of many of these factors have been used as biomarkers to diagnose the pathology. Myoglobin, fatty acid-binding proteins, and glycogen phosphorylase isoenzyme BB are early biomarkers, troponin-T and troponin-I are late biomarkers, while creatine kinase-myocardial band is a biomarker in the first 10­12 h for the diagnosis of AMI. However, there is a need for a panel of biomarkers that can help in the prediction, prognosis, and diagnosis of disease progression (atherosclerosis), pre-ischemic and ischemic events, and post-MI periods to design the treatment strategies in a specific and sensitive manner. There is a need for cost-effective sensitive biomarkers that can prevent progression, risk stratify, predict, diagnose, and prevent MI in a timely manner. In this comprehensive review, we discuss the key markers of substantial utility for monitoring coronary artery disease progression and the efficacy of therapeutic intervention among various markers of interest.

Oncostatin M, Serpins, and Oxidative Stress in Extracellular Matrix Remodeling and Arteriovenous Fistula Maturation.

End-stage renal disease is a crippling diagnosis that generally requires dialysis to prolong life. To facilitate filtration of patient's blood in dialysis, surgical formation of an arteriovenous fistula (AVF) is commonly performed. Maturation of the AVF is required to allow for successful dialysis. However, AVFs commonly fail to mature, leading to the fistula closure, the necessity for another fistula site, and markedly increased morbidity and mortality. The current literature concerning molecular mechanisms associated with AVF maturation failure supports the role of inflammatory mediators involving immune cells and inflammatory cytokines. However, the role of oncostatin M (OSM), an inflammatory cytokine, and its downstream targets are not well investigated. Through inflammation, oxidative stress, and hypoxic conditions, the vascular tissue surrounding the AVF undergoes fibrosis, stenosis, and wall thickening, leading to complete occlusion and nonfunctional. In this report, first we critically review the existing literature on the role of OSM in the most common causes of early AVF failure - vascular inflammation, thrombosis, and stenosis. We next consider the potential of using OSM as a therapeutic target, and finally discuss therapeutic agents targeting inflammatory mediators involved in OSM signaling to potentiate successful maturation of the AVF.

Role of Transcription Factors and MicroRNAs in Regulating Fibroblast Reprogramming in Wound Healing.

Non-healing diabetic foot ulcer, a chronic inflammatory disease, is a sizable clinical and economic burden to healthcare systems around the world. Chronic inflammation plays a critical role in the nonhealing pattern due to the arrest of the cellular response during wound healing in the inflammatory phase without progressing to the proliferative and remodeling phase. Fibroblasts play a critical role in all three phases of wound healing. Activation of fibroblasts in the presence of cytokines results in the formation of myofibroblast that contributes to extracellular matrix formation. Additionally, few studies documented the presence of inflammatory, angiogenic, and angiostatic fibroblast subpopulation during wound healing. Various studies have discussed the role of transcription factors and microRNA in regulating the transdifferentiation of fibroblast to myofibroblast, however, what factors regulate the reprogramming of fibroblast to inflammatory, angiogenic, and angiostatic phenotypes have not been clearly addressed in the literature. This critical review article addresses the role of transcription factors and microRNAs in regulating fibroblast to myofibroblast transdifferentiation followed by the prediction of transcription factors and microRNAs, based on the bioinformatics analysis, in regulating transdifferentiation of fibroblasts to inflammatory, angiogenic, and angiostatic subtypes. The results of in-silico networking revealed multiple new transcription factors and microRNAs and their interaction with specific markers on other fibroblasts suggesting their role in the regulation of fibroblast reprogramming.

Novel mediators regulating angiogenesis in diabetic foot ulcer healing.

A non-healing diabetic foot ulcer (DFU) is a debilitating clinical problem amounting to socioeconomic and psychosocial burdens. DFUs increase morbidity due to prolonged treatment and mortality in the case of non-treatable ulcers resulting in gangrene and septicemia. The overall amputation rate of the lower extremity with DFU ranges from 3.34% to 42.83%. Wound debridement, antibiotics, applying growth factors, negative pressure wound therapy, hyperbaric oxygen therapy, topical oxygen, and skin grafts are common therapies for DFU. However, recurrence and nonhealing ulcers are still major issues. Chronicity of inflammation, hypoxic environment, poor angiogenesis, and decreased formation of the extracellular matrix (ECM) are common impediments leading to nonhealing patterns of DFUs. Angiogenesis is crucial for wound healing since proper vessel formation facilitates nutrients, oxygen, and immune cells to the ulcer tissue to help in clearing out debris and facilitate healing. However, poor angiogenesis due to decreased expression of angiogenic mediators and matrix formation results in nonhealing and ultimately amputation. Multiple proangiogenic mediators and vascular endothelial growth factor (VEGF) therapy exist to enhance angiogenesis, but the results are not satisfactory. Thus, there is a need to investigate novel pro-angiogenic mediators that can either alone or in combination enhance the angiogenesis and healing of DFUs. In this article, we critically reviewed the existing pro-angiogenic mediators followed by potentially novel factors that might play a regulatory role in promoting angiogenesis and wound healing in DFUs.

Cholesterol: An Important Determinant of Muscle Atrophy in Astronauts.

Since cholesterol is not routinely measured in astronauts before and after their return from space, there is no data on the role of blood cholesterol level in muscle atrophy and microgravity. Since the first moon landing, aerospace medicine became outdated and has not pushed boundaries like its rocket engineering counterpart. Since the 2019 astronaut twin study, there has yet to be another scientific breakthrough for aerospace medicine. Microgravity-induced muscle atrophy is the most known consequence of spaceflight. Yet, so far, there is no therapeutic solution to prevent it or any real efforts in understanding it on a cellular or molecular level. The most obvious reason to this unprecedented level of research is due to the small cohort of astronauts. With the establishment of private space industries and exponential recruitment of astronauts, there is more reason to push forward spaceflight-related health guidelines and ensure the safety of the brave humans who risk their lives for the progression of mankind. Spaceflight is considered the most challenging job and the failure to prevent injury or harm should be considered reckless negligence by the institutions that actively prevented sophistication of aerospace medicine. In this critical review, role of cholesterol is analyzed across the NASA-established parameters of microgravity-induced muscle atrophy with a focus on potential therapeutic targets for research.