Cholesterol and Immune Microenvironment: Path Towards Tumorigenesis.

PURPOSE OF REVIEW: Since obesity is a major risk factor for many different types of cancer, examining one of the most closely associated comorbidities, such as hypercholesterolemia, is crucial to understanding how obesity causes cancer. Hypercholesterolemia is usually associated with many cardiovascular complications such as hypertension, angina, and atherosclerosis. In addition, cholesterol may be a major factor in increasing cancer risk. Cancer patients who received statins, an anti-hypercholesteremic medicine, demonstrated improved prognosis possibly through its effect on tumor proliferation, apoptosis, and oxidative stress. Cholesterol could also aid in tumor progression through reprogramming tumor immunological architecture and mediators. This review focuses on the immunomodulatory role of cholesterol on cellular and molecular levels, which may explain its oncogenic driving activity. We look at how cholesterol modulates tumor immune cells like dendritic cells, T cells, Tregs, and neutrophils. Further, this study sheds light on the modification of the expression pattern of the common cancer-related immune mediators in the tumor immune microenvironment, such as programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-ß), interleukin 12 (IL-12), IL-23, and forkhead box protein P3 (FOXP3). RECENT FINDINGS: We highlight relevant literature demonstrating cholesterol's immunosuppressive role, leading to a worse cancer prognosis. This review invites further research regarding the pathobiological role of cholesterol in many obesity-related cancers such as uterine fibroids, post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancers. This review suggests that targeting cholesterol synthesis may be a fruitful approach to cancer targeting, in addition to traditional chemotherapeutics.

The Role of Nanomedicine in Benign Gynecologic Disorders.

Nanomedicine has revolutionized drug delivery in the last two decades. Nanoparticles appear to be a promising drug delivery platform in the treatment of various gynecological disorders including uterine leiomyoma, endometriosis, polycystic ovarian syndrome (PCOS), and menopause. Nanoparticles are tiny (mean size < 1000 nm), biodegradable, biocompatible, non-toxic, safe, and relatively inexpensive materials commonly used in imaging and the drug delivery of various therapeutics, such as chemotherapeutics, small molecule inhibitors, immune mediators, protein peptides and non-coding RNA. We performed a literature review of published studies to examine the role of nanoparticles in treating uterine leiomyoma, endometriosis, PCOS, and menopause. In uterine leiomyoma, nanoparticles containing 2-methoxyestradiole and simvastatin, promising uterine fibroid treatments, have been effective in significantly inhibiting tumor growth compared to controls in in vivo mouse models with patient-derived leiomyoma xenografts. Nanoparticles have also shown efficacy in delivering magnetic hyperthermia to ablate endometriotic tissue. Moreover, nanoparticles can be used to deliver hormones and have shown efficacy as a mechanism for transdermal hormone replacement therapy in individuals with menopause. In this review, we aim to summarize research findings and report the efficacy of nanoparticles and nanotherapeutics in the treatment of various benign gynecologic conditions.

Senescence-associated secretory phenotype (SASP) and uterine fibroids: Association with PD-L1 activation and collagen deposition.

Uterine fibroids (or uterine leiomyoma, UFs) are one of the most prevalent benign uterine tumors with high proliferation and collagen synthesis capabilities. UFs are a significant worldwide health issue for women, affecting their physical and financial well-being. Risk factors for UFs include age, racial disparities, obesity, uterine infections, hormonal variation, and lifestyle (i.e., diet, exercise, stress, and smoking). Senescence and its associated secretory phenotypes (SASPs) are among the most salient changes accompanying the aging process. As a result, SASPs are suggested to be one of the major contributors to developing UFs. Interleukin 6 (IL-6), IL-8, IL-1, chemokine ligand 20 (CCL-20), and transforming growth factor-beta (TGF-ß) are the most prominent SASPs associated with aging. In addition, different processes contribute to UFs such as collagen deposition and the changes in the immune microenvironment. Programmed death ligand 1 is a major player in the tumor immune microenvironment, which helps tumor cells evade immune attacks. This review focuses on the correlation of SASPs on two axes of tumor progression: immune suppression and collagen deposition. This review opens the door towards more investigations regarding changes in the UF immune microenvironment and age-UFs correlation and thus, a novel targeting approach for UF treatment.

Immunosuppressive tumor microenvironment and uterine fibroids: Role in collagen synthesis.

Uterine fibroids (UF), also called uterine leiomyoma, is one of the most prevalent uterine tumors. UF represents a serious women's health global problem with a significant physical, emotional, and socioeconomic impact. Risk factors for UF include racial disparities, age, race, hormonal factors, obesity, and lifestyle (diet, physical activity, and stress. There are several biological contributors to UF pathogenesis such as cellular proliferation, angiogenesis, and extracellular matrix (ECM) accumulation. This review addresses tumor immune microenvironment as a novel mediator of ECM deposition. Polarization of immune microenvironment towards the immunosuppressive phenotype has been associated with ECM deposition. Immunosuppressive cells include M2 macrophage, myeloid-derived suppressor cells (MDSCs), and Th17 cells, and their secretomes include interleukin 4 (IL-4), IL-10, IL-13, IL-17, IL-22, arginase 1, and transforming growth factor-beta (TGF-ß1). The change in the immune microenvironment not only increase tumor growth but also aids in collagen synthesis and ECM disposition, which is one of the main hallmarks of UF pathogenesis. This review invites further investigations on the change in the UF immune microenvironment as well as a novel targeting approach instead of the traditional UF hormonal and supportive treatment.

Menstruation in the USA.

Purpose of review: Menstruation touches all spheres of human society, including psychology, education, business, policy, race, and religion. This narrative review aims to describe the relationship menstruation holds with these spaces. Recent findings: First, menstruation plays many roles in psychology - premenstrual syndrome affects psychological wellbeing and in turn, psychological stress impacts menstruation. Functional hypothalamic amenorrhea can result when stress hormones inhibit the Hypothalamus-Pituitary-Ovarian axis. Furthermore, menstruation has many implications for all aged individuals, especially adolescents and those who are menopausal. These implications underscore the importance of proper education surrounding menstruation, which can be achieved via social media, school systems, family, and clinicians. However, menstrual health education is highly variable depending on the state and family that someone is raised in. Additionally, menstruation can pose a financial burden as menstrual products can be expensive and access to these products is limited for those who are homeless, incarcerated, and low-income. Recent public policy measures in various states have aimed to achieve "menstrual equity," by requiring public schools to supply free menstrual products in bathrooms. Furthermore, racial disparities exist with menstrual disorders. Uterine fibroids occur more frequently in Black menstruators compared to White menstruators, and Black women experience worse outcomes overall with fibroids and endometriosis management. Finally, analysis of religion and its relationship to menstruation underscores the immense stigma and "impurity" associated with menstruation. Summary: Overall, this review highlights the universality of menstruation in society. As a "fifth vital sign", there is significant room for improvement in terms of education, research, and cultural acceptance of menstruation. Future research should explore interventions to reduce these gaps.

Refining "Long-COVID" by a Prospective Multimodal Evaluation of Patients with Long-Term Symptoms Attributed to SARS-CoV-2 Infection.

INTRODUCTION: COVID-19 long-haulers, also decribed as having "long-COVID" or post-acute COVID-19 syndrome, represent 10% of COVID-19 patients and remain understudied. METHODS: In this prospective study, we recruited 30 consecutive patients seeking medical help for persistent symptoms (> 30 days) attributed to COVID-19. All reported a viral illness compatible with COVID-19. The patients underwent a multi-modal evaluation, including clinical, psychologic, virologic and specific immunologic assays and were followed longitudinally. A group of 17 convalescent COVID-19 individuals without persistent symptoms were included as a comparison group. RESULTS: The median age was 40 [interquartile range: 35-54] years and 18 (60%) were female. At a median time of 152 [102-164] days after symptom onset, fever, cough and dyspnea were less frequently reported compared with the initial presentation, but paresthesia and burning pain emerged in 18 (60%) and 13 (43%) patients, respectively. The clinical examination was unremarkable in all patients, although the median fatigue and pain visual analog scales were 7 [5-8] and 5 [2-6], respectively. Extensive biologic studies were unremarkable, and multiplex cytokines and ultra-sensitive interferon-α2 measurements were similar between long-haulers and convalescent COVID-19 individuals without persistent symptoms. Using SARS-CoV-2 serology and IFN-γ ELISPOT, we found evidence of a previous SARS-CoV-2 infection in 50% (15/30) of patients, with evidence of a lack of immune response, or a waning immune response, in two patients. Finally, psychiatric evaluation showed that 11 (36.7%), 13 (43.3%) and 9 (30%) patients had a positive screening for anxiety, depression and post-traumatic stress disorder, respectively. CONCLUSIONS: Half of patients seeking medical help for post-acute COVID-19 syndrome lack SARS-CoV-2 immunity. The presence of SARS-CoV-2 immunity, or not, had no consequence on the clinical or biologic characteristics of post-acute COVID-19 syndrome patients, all of whom reported severe fatigue, altered quality of life and psychologic distress.

Mirror-image symmetry and search asymmetry: a comparison of their effects on visual search and a possible unifying explanation.

Visual search may be affected by mirror-image symmetry between target and non-targets and also by switching the roles of target and non-target. Do different attention mechanisms underlie these two phenomena? Can a unifying explanation account for both? We conducted two experiments to decompose processing into component parts, and compared results to competing models' predictions. Mirror-image search was unimpaired after target discrimination had been balanced across search conditions-results were consistent with an unlimited-capacity, decision noise model. Search asymmetry affected higher-level processing, however, resulting in capacity limitations that necessitated serial processing. A unifying explanation can account for these two seemingly unrelated phenomena.

Divided attention and visual search for simple versus complex features.

Under what search conditions does attention affect perceptual processes, resulting in capacity limitations, rather than affecting noisy decision-making processes? Does parallel or serial processing cause the capacity limitations? To address these issues, we varied stimulus complexity, set size, and whether distractors were mirror images of the target. Both target detection and localization produced similar patterns of results. Capacity limitations only occurred for complex stimuli used in within-object conjunction searches. Parallel processing, rather than serial processing, probably caused these capacity limitations. Moreover, although mirror-image symmetry adversely affected early visual processing, it did not place additional demands on attention.