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OBJECTIVE: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancy in the United States, and biomarkers of patient outcomes are limited. Data using immunohistochemical (IHC) analysis are mixed regarding whether and which tumor infiltrating lymphocytes (TILs) impact survival, and IHC does not adequately quantify rare cell populations, including CD137+ (4-1BB) tumor-reactive TILs. Our study investigates if a higher percentage of CD3+ CD137+ TILs is associated with improved overall survival (OS) in OC. METHODS: Flow cytometry was performed on viably banked OC digests. Chart review and statistical analysis were performed. Forty-seven patients were included, 40 of whom were diagnosed with high-grade serous ovarian carcinoma (HGSOC), papillary serous carcinoma, or undifferentiated histology. RESULTS: A high percentage of CD3+ CD137+ TILs correlated with improved OS (n = 40, r = 0.48, P = 0.0016). Subjects were divided into CD3+ CD137+ TIL high and low groups by the median. Subjects with high CD3+CD137+ TIL frequencies (>9.6%) had longer OS (Wilcoxon rank-sum test; P = 0.0032) and improved OS (logrank test; P = 0.007). Differences in CD3+ or CD3+ CD8+ TILs did not impact survival. CD3+ CD137+ TILs were predictive of OS regardless of germline mutation or debulking status. Analysis of subgroups including late stage HGSOC and late stage HGSOC with primary optimal cytoreduction indicated CD3+ CD137+ TILs correlated with improved OS after adjusting for age and PARP inhibitor use (P = 0.034 and P = 0.016, respectively). CONCLUSIONS: Prevalence of CD3+ CD137+ TILs in digested OC specimens is associated with improved OS, while general TIL markers are not. CD137 has the potential to be a novel biomarker for survival in OC.
Subject(s)
Lymphocytes, Tumor-Infiltrating , Ovarian Neoplasms , Tumor Necrosis Factor Receptor Superfamily, Member 9 , Humans , Female , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Tumor Necrosis Factor Receptor Superfamily, Member 9/analysis , Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology , Ovarian Neoplasms/immunology , Ovarian Neoplasms/pathology , Ovarian Neoplasms/mortality , Middle Aged , Aged , CD3 Complex/analysis , Adult , Cystadenocarcinoma, Serous/pathology , Cystadenocarcinoma, Serous/immunology , Cystadenocarcinoma, Serous/mortality , Aged, 80 and overABSTRACT
Kawasaki disease (KD) is a systemic vasculitis affecting children younger than 5 years of age. Early period in life is marked by rapid somatic growth with cell proliferation and immaturity of the immunity with dominant innate immune system. Coronary complications in KD are the most common acquired heart disease in children, yet the diagnosis of KD still depends on the clinical diagnostic criteria. Glossy red lips and conjunctival injection are characteristic signs enabling pediatricians to make the initial diagnosis of KD; however, little is known why these are so characteristic. The diagnostic criteria of KD seem to be scattered in seemingly irrelevant body systems such as the eyes, lips, skin, and heart. KD is classified as a connective tissue disease. Recently, red blood cells (RBCs) have emerged as important modulators in innate immune response. RBCs are reported to participate in extracellular matrix remodeling and upregulating matrix metalloproteinase (MMP) expression in dermal fibroblasts. Also, fibroblast growth factors and microRNAs associated with fibrosis are drawing attention in KD. The cardinal signs of KD appear at the border of muco-cutaneous junction. Head and neck regions are abundant in tissues undergoing epithelial-to-mesenchymal transition (EMT). Interstitial carditis and valve insufficiency as well as coronary arterial lesions may complicate KD, and these lesions present in tissues that originated from epicardial progenitor cells by EMT. Having reviewed the recent research on KD, we presume that the signs of KD present at borders between keratinized and non-keratinized stratified squamous epithelium where the EMT is still ongoing for the rapid somatic growth where RBCs are recruited as an innate immune response and to prevent excessive fibrosis in mucosa. KD presents scarcely in adults with somatic growth and immune maturation completed. In this review, we attempted to explain the reasons for the clinical manifestations of KD and to search for a link among the diagnostic clues in the perspective of EMT during the somatic growth and immune system maturation in children with KD.
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OBJECTIVE: Prior to the COVID-19 pandemic, telehealth visits and remote clinical trial operations (such as local collection of laboratory tests or imaging studies) were underutilized in gynecologic oncology clinical trials. Current literature on these operational changes provides anecdotal experience and expert opinion with few studies describing patient-level safety data. We aimed to evaluate the safety and feasibility of telehealth and remote clinical trial operations during the COVID-19 Pandemic. METHODS: Gynecologic oncology patients enrolled and actively receiving treatment on a clinical trial at a single, academic institution during the designated pre-Telehealth and Telehealth periods were identified. Patients with at least 1 provider or research coordinator telehealth visit were included. Patient demographics, health system encounters, adverse events, and protocol deviations were collected. Pairwise comparisons were performed between the pre-Telehealth and Telehealth period with each patient serving as their own control. RESULTS: Thirty-one patients met inclusion criteria. Virtual provider visits and off-site laboratory testing increased during the Telehealth period. Delays in provider visits, imaging, and laboratory testing did not differ between time periods. Total and minor protocol deviations increased in incidence during the Telehealth period and were due to documentation of telehealth and deferment of non-therapeutic testing. Major protocol deviations, emergency department visits, admissions, and severe adverse events were of low incidence and did not differ between time periods. CONCLUSIONS: Telehealth and remote clinical trial operations appeared safe and did not compromise clinical trial protocols in a small, single institutional study. Larger scale evaluations of such trial adaptations should be performed to determine continued utility following the Pandemic.
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OBJECTIVE: The goal of this study was to evaluate if addition of adjuvant chemotherapy to radiation therapy improves overall survival in patients with high-intermediate risk stage I endometrial carcinoma with lymphovascular invasion. METHODS: Patients diagnosed between January 2010 and December 2015 with FIGO (International Federation of Gynecology and Obstetrics) stage I endometrioid endometrial carcinoma with lymphovascular invasion who underwent hysterectomy with lymphadenectomy and met the GOG-99 criteria for high-intermediate risk were identified in the National Cancer Database. Patients who received adjuvant radiotherapy with or without adjuvant chemotherapy (administered within 6 months of surgery) and had at least 1 month of follow-up were selected for further analysis. Overall survival was compared with the log-rank test following stratification by type of radiation treatment. A Cox model was constructed to control for a priori selected confounders. RESULTS: A total of 2881 patients who met the inclusion criteria were identified; 2417 (83.9%) patients received radiation therapy alone while 464 (16.1%) received chemoradiation. Rate of adjuvant chemotherapy administration was comparable between patients who received vaginal brachytherapy alone (16.2%), and external beam radiation therapy (with or without vaginal brachytherapy) (15.8%), p=0.78. Rate of chemoradiation was higher for patients with grade 3 (28.8%) tumors compared with those with grade 2 (9.9%) and grade 1 (8.3%) tumors, p<0.001. After controlling for confounders for patients receiving external beam radiation, addition of chemotherapy was not associated with improved overall survival (HR 0.90, 95% CI 0.56 to 1.46). For patients receiving vaginal brachytherapy addition of chemotherapy was associated with better overall survival (HR 0.644, 95% CI 0.45 to 0.92). Benefit was limited to patients with grade 3 tumors, p=0.026; 4-year overall survival rate was 81.1% versus 74.9%. CONCLUSIONS: In patients with high-intermediate risk FIGO stage I endometrioid endometrial carcinoma and lymphovascular invasion, addition of chemotherapy to radiation therapy was associated with a survival benefit for patients with grade 3 tumors receiving vaginal brachytherapy.
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BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on Kawasaki disease (KD) has not yet been established. We investigated changes in the observed number and severity of KD cases and accompanying coronary artery complications during the COVID-19 pandemic in Korea. METHODS: This retrospective observational study included patients aged < 18 years with acute-phase KD diagnosed between March 2018 and February 2021. Data were extracted from the Clinical Data Warehouse that houses data from five affiliated university hospitals in Korea. We analyzed changes in the number of patient admissions and clinical characteristics, including cardiac complications, before and after the onset of the COVID-19 pandemic. RESULTS: A total of 475 admissions were included in the analysis. After March 2020, we observed a significant decrease of 33% in the number of hospitalizations for KD compared with the average number of hospitalizations during the previous 2 years. The number of admissions per month significantly decreased by 7.9 persons/month (95% confidence interval, -13.8 to -2.0; P < 0.05) compared with that before COVID-19. By contrast, the proportion of patients aged < 1 year with KD increased. The proportion of patients with refractory KD and the rate of cardiac complications did not change significantly. CONCLUSION: Since the onset of the COVID-19 pandemic, the total number of hospital admissions for KD has decreased in Korea. Although the proportion of admissions of infants aged < 1 year increased, no changes were observed in clinical courses and complications.
Subject(s)
COVID-19 , Mucocutaneous Lymph Node Syndrome , COVID-19/epidemiology , Hospitalization , Humans , Infant , Mucocutaneous Lymph Node Syndrome/complications , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/epidemiology , Pandemics , SARS-CoV-2ABSTRACT
BACKGROUND: Lysophosphatidic acid receptors (LPARs) are G-protein-coupled receptors involved in many physiological functions in the central nervous system. However, the role of the LPARs in multiple sclerosis (MS) has not been clearly defined yet. METHODS: Here, we investigated the roles of LPARs in myelin oligodendrocyte glycoprotein peptides-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. RESULTS: Pre-inhibition with LPAR1-3 antagonist Ki16425 deteriorated motor disability of EAElow. Specifically, LPAR1-3 antagonist (intraperitoneal) deteriorated symptoms of EAElow associated with increased demyelination, chemokine expression, cellular infiltration, and immune cell activation (microglia and macrophage) in spinal cords of mice compared to the sham group. This LPAR1-3 antagonist also increased the infiltration of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells into spinal cords of EAElow mice along with upregulated mRNA expression of IFN-γ and IL-17 and impaired blood-brain barrier (BBB) in the spinal cord. The underlying mechanism for negative effects of LPAR1-3 antagonist was associated with the overproduction of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) 2 and NOX3. Interestingly, LPAR1/2 agonist 1-oleoyl-LPA (LPA 18:1) (intraperitoneal) ameliorated symptoms of EAEhigh and improved representative pathological features of spinal cords of EAEhigh mice. CONCLUSIONS: Our findings strongly suggest that some agents that can stimulate LPARs might have potential therapeutic implications for autoimmune demyelinating diseases such as MS.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/metabolism , Isoxazoles/toxicity , Oxidative Stress/physiology , Propionates/toxicity , Receptors, Lysophosphatidic Acid/metabolism , Animals , Dose-Response Relationship, Drug , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Female , Isoxazoles/pharmacology , Mice , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein/toxicity , Oxidative Stress/drug effects , Peptide Fragments/toxicity , Propionates/pharmacology , Receptors, Lysophosphatidic Acid/antagonists & inhibitorsABSTRACT
Gintonin (GT), a glycolipoprotein fraction isolated from ginseng, exerts neuroprotective effects in models of neurodegenerative diseases such as Alzheimer's disease. However, the in vivo role of GT in multiple sclerosis (MS) has not been clearly resolved. We investigated the effect of GT in myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of MS. GT alleviated behavioral symptoms of EAE associated with reduced demyelination, diminished infiltration and activation of immune cells (microglia and macrophage), and decreased expression of inflammatory mediators in the spinal cord of the EAE group compared to that of the sham group. GT reduced the percentages of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells but increased the population of CD4+/CD25+/Foxp3+ (Treg) cells in the spinal cord, in agreement with altered mRNA expression of IFN-γ, IL-17, and TGF-ß in the spinal cord in concordance with mitigated blood-brain barrier disruption. The underlying mechanism is related to inhibition of the ERK and p38 mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) pathways and the stabilization of nuclear factor erythroid 2-related factor 2 (Nrf2) via increased expression of lysophosphatidic acid receptor (LPAR) 1-3. Impressively, these beneficial effects of GT were completely neutralized by inhibiting LPARs with Ki16425, a LPAR1/3 antagonist. Our results strongly suggest that GT may be able to alleviate EAE due to its anti-inflammatory and antioxidant activities through LPARs. Therefore, GT is a potential therapeutic option for treating autoimmune disorders including MS.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Animals , Cytokines , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Mice , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein , NF-E2-Related Factor 2 , Plant Extracts , Receptors, Lysophosphatidic Acid , Spinal CordABSTRACT
OBJECTIVES: In patients undergoing surgery for early stage endometrial cancer, we sought to evaluate the effect of lymphadenectomy (LND), as well as surgical route, on the risk of postoperative venous thromboembolism (VTE). METHODS: The Surveillance, Epidemiology, and End Results cancer registries (2000-2013) linked to Medicare claims follow up from 1999 to 2014 was accessed to identify those with stage I-II endometrioid endometrial cancer who underwent hysterectomy. Performance of LND, 90-day incidence of postoperative VTE, open vs minimally invasive surgery (MIS), demographics, comorbidities, grade, and stage were collected. A washout period of 12 months with no prior VTE was required. t-test, Chi square test, univariate and multivariable Poisson regression with robust variance estimator were used. RESULTS: A total of 15,101 patients had hysterectomy for early stage endometrial cancer. LND was performed in 9004 (60%) patients. VTE was found in 486 patients. There were 346 VTEs (3.8%) in the LND group vs 140 (2.3%) in those without LND (RR = 1.67, p < 0.0001). Adjusting for age, stage, grade, comorbidities and surgical approach, LND remained a significant risk for VTE (RR = 1.7, p < 0.001). In those who underwent MIS, LND was associated with a two-fold increase in the risk of VTE (p = 0.0008) (adjusted RR = 1.99, p = 0.0014) and had a statistically comparable rate of VTE when compared to the open surgical approach (p = 0.054). CONCLUSIONS: LND is associated with an increased 90-day risk of postoperative VTE in patients undergoing surgery for early stage endometrial cancer. The need for extended postoperative VTE prophylaxis in patients undergoing LND via MIS needs further exploration.
Subject(s)
Endometrial Neoplasms/surgery , Lymph Node Excision/statistics & numerical data , Postoperative Complications/epidemiology , Venous Thromboembolism/epidemiology , Aged , Endometrial Neoplasms/blood , Endometrial Neoplasms/epidemiology , Endometrial Neoplasms/pathology , Female , Humans , Hysterectomy/adverse effects , Hysterectomy/methods , Hysterectomy/statistics & numerical data , Lymph Node Excision/adverse effects , Minimally Invasive Surgical Procedures/methods , Minimally Invasive Surgical Procedures/statistics & numerical data , Neoplasm Staging , Postoperative Complications/etiology , SEER Program , United States/epidemiology , Venous Thromboembolism/etiologyABSTRACT
OBJECTIVE: Elevated serum phosphate levels have been associated with increased risks of cardiovascular events and death in several patient populations. The effects of serum phosphate on outcomes in patients with critical limb ischemia (CLI) have not been evaluated. In this study, we assessed the effect of abnormal phosphate levels on mortality and major limb events after surgical intervention for CLI. METHODS: A retrospective review was undertaken to identify all patients at a single institution who underwent a first-time open or endovascular intervention for CLI between 2005 and 2014. Patients without recorded postoperative phosphate levels were excluded. Postoperative phosphate levels ≤30 days of the initial operation were recorded, and the mean was calculated. Patients were stratified according to mean phosphate levels (low: <2.5 mg/dL, normal: 2.5-4.5 mg/dL, and high: >4.5 mg/dL). Patient demographics, comorbidities, and operative details were compared in univariate analysis. Multivariable regression and Cox proportional hazard modeling were used to account for patient demographics and comorbid conditions. RESULTS: We identified 941 patients, including 42 (5%) with low phosphate, 768 (82%) with normal phosphate, and 131 (14%) with high phosphate. Patients with elevated phosphate were younger and had higher rates of congestive heart failure, diabetes, and dialysis dependence. Bypass was more common among patients with normal phosphate compared with high or low phosphate levels. There was no difference in the Wound, ischemia, and Foot infection (WiFi) classification or TransAtlantic Inter-Society Consensus classification among the cohorts. There were significant differences in 1-year mortality (low: 19%, normal: 17%, high: 33%; P < .01) and 3-year mortality (low: 38%, normal: 34%, high: 56%; P < .01) between phosphate cohorts. Major amputation (low: 12%, normal: 12%, high: 15%) and restenosis (low: 21%, normal: 24%, high: 28%) tended toward worse outcomes among patients with elevated phosphate levels but did not reach statistical significance. After adjustment for baseline characteristics, mortality was higher (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.3-2.2) and amputation-free survival was lower (HR, 1.5; 95% CI, 1.2-1.9) among patients with elevated compared with normal phosphate levels. A subgroup analysis was then performed to assess dialysis and nondialysis patients separately. Patients with elevated serum phosphate levels maintained a significantly higher risk of mortality in each group (dialysis: HR, 1.8; 95% CI, 1.2-2.6; nondialysis: HR, 1.5; 95% CI, 1.04-2.10). CONCLUSIONS: Elevated phosphate levels are associated with increased mortality and decreased amputation-free survival after interventions for CLI. Future studies evaluating the effects of phosphate reduction in patients with CLI are warranted.
Subject(s)
Amputation, Surgical , Endovascular Procedures , Hyperphosphatemia/complications , Ischemia/therapy , Phosphates/blood , Vascular Surgical Procedures , Aged , Aged, 80 and over , Biomarkers/blood , Boston , Critical Illness , Disease-Free Survival , Endovascular Procedures/adverse effects , Endovascular Procedures/mortality , Female , Humans , Hyperphosphatemia/blood , Hyperphosphatemia/diagnosis , Hyperphosphatemia/mortality , Ischemia/complications , Ischemia/diagnostic imaging , Ischemia/mortality , Kaplan-Meier Estimate , Limb Salvage , Male , Middle Aged , Proportional Hazards Models , Recurrence , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Up-Regulation , Vascular Surgical Procedures/adverse effects , Vascular Surgical Procedures/mortalityABSTRACT
A missense mutation in mouse Nek8, which encodes a ciliary kinase, produces the juvenile cystic kidneys (jck) model of polycystic kidney disease, but the functions of Nek8 are incompletely understood. Here, we generated a Nek8-null allele and found that homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts. The requirement for Nek8 in left-right patterning is conserved, as knockdown of the zebrafish ortholog caused randomized heart looping. Ciliogenesis was intact in Nek8-deficient embryos and cells, but we observed misexpression of left-sided marker genes early in development, suggesting that nodal ciliary signaling was perturbed. We also generated jck/Nek8 compound heterozygotes; these mutants developed less severe cystic disease than jck homozygotes and provided genetic evidence that the jck allele may encode a gain-of-function protein. Notably, NEK8 and polycystin-2 (PC2) proteins interact, and we found that Nek8(-/-) and Pkd2(-/-) embryonic phenotypes are strikingly similar. Nek8-deficient embryos and cells did express PC2 normally, which localized properly to the cilia. However, similar to cells lacking PC2, NEK8-depleted inner medullary collecting duct cells exhibited a defective response to fluid shear, suggesting that NEK8 may play a role in mediating PC2-dependent signaling.
Subject(s)
Body Patterning , Cilia/physiology , Polycystic Kidney Diseases/genetics , Protein Serine-Threonine Kinases/genetics , Animals , Biomarkers/metabolism , Disease Models, Animal , Female , Heart Defects, Congenital/embryology , Heterozygote , Homozygote , Male , Mice , Mice, Inbred C57BL , NIMA-Related Kinases , Phenotype , Protein Serine-Threonine Kinases/metabolism , TRPP Cation Channels/metabolism , ZebrafishABSTRACT
IMPORTANCE: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown. OBJECTIVE: To investigate the effect of tesamorelin on visceral and liver fat. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized, placebo-controlled trial conducted among 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation at Massachusetts General Hospital in Boston. The first patient was enrolled on January 10, 2011; for the final patient, the 6-month study visit was completed on September 6, 2013. INTERVENTIONS: Participants were randomized to receive tesamorelin, 2 mg (n=28), or placebo (n=22), subcutaneously daily for 6 months. MAIN OUTCOMES AND MEASURES: Primary end points were changes in visceral adipose tissue and liver fat. Secondary end points included glucose levels and other metabolic end points. RESULTS: Forty-eight patients received treatment with study drug. Tesamorelin significantly reduced visceral adipose tissue (mean change, -34 cm2 [95% CI, -53 to -15 cm2] with tesamorelin vs 8 cm2 [95% CI, -14 to 30 cm2] with placebo; treatment effect, -42 cm2 [95% CI, -71 to -14 cm2]; P = .005) and liver fat (median change in lipid to water percentage, -2.0% [interquartile range {IQR}, -6.4% to 0.1%] with tesamorelin vs 0.9% [IQR, -0.6% to 3.7%] with placebo; P = .003) over 6 months, for a net treatment effect of -2.9% in lipid to water percentage. Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL [95% CI, 5-13 mg/dL] vs 2 mg/dL [95% CI, -3 to 8 mg/dL] in the placebo group; treatment effect, 7 mg/dL [95% CI, 1-14 mg/dL]; P = .03), but changes at 6 months in fasting glucose (mean change, 4 mg/dL [95% CI, -2 to 10 mg/dL] with tesamorelin vs 2 mg/dL [95% CI, -4 to 7 mg/dL] with placebo; treatment effect, 2 mg/dL [95% CI, -6 to 10 mg/dL]; P = .72 overall across time points) and 2-hour glucose (mean change, -1 mg/dL [95% CI, -18 to 15 mg/dL] vs -8 mg/dL [95% CI, -24 to 8 mg/dL], respectively; treatment effect, 7 mg/dL [95% CI, -16 to 29 mg/dL]; P = .53 overall across time points) were not significant. CONCLUSIONS AND RELEVANCE: In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01263717.
Subject(s)
Adiposity/drug effects , Fatty Liver/drug therapy , Growth Hormone-Releasing Hormone/analogs & derivatives , HIV Infections/complications , Intra-Abdominal Fat/drug effects , Abdominal Fat/drug effects , Adult , Double-Blind Method , Fatty Liver/etiology , Female , Growth Hormone-Releasing Hormone/therapeutic use , Humans , Liver/drug effects , Liver/metabolism , Male , Middle AgedABSTRACT
Myocardial infarction (MI) is one of the leading causes of morbidity and mortality world-wide. Whether endogenous repair and regenerative ability could be augmented by drug administration is an important issue for generation of novel therapeutic approach. Recently it was reported that in mice pretreated with thymosin beta 4 (TB4) and subsequently subjected to experimental MI, a subset of epicardial cells differentiated into cardiomyocytes. In clinical settings, epicardial priming with TB4 prior to MI is impractical. Here we tested if TB4 treatment after MI could reprogram epicardium into cardiomyocytes and augment the epicardium's injury response. Using epicardium genetic lineage trace line Wt1(CreERT2/+) and double reporter line Rosa26(mTmG/+), we found post-MI TB4 treatment significantly increased the thickness of epicardium and coronary capillary density. However, epicardium-derived cells did not adopt cardiomyocyte fate, nor did they migrate into myocardium to become coronary endothelial cells. Our result thus indicates that TB4 treatment after MI does not alter epicardial cell fate to include the cardiomyocyte lineage, providing both cautions and insights for the full exploration of the potential benefits of TB4 in the clinical settings. This article is part of a Special Issue entitled 'Possible Editorial'.
Subject(s)
Myocardial Infarction/drug therapy , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Pericardium/cytology , Pericardium/drug effects , Thymosin/pharmacology , Thymosin/therapeutic use , Animals , Cell Differentiation/drug effects , Mice , Myocardial Infarction/metabolismABSTRACT
Myocarditis was previously attributed to an epidemic viral infection. Additional harmful reagents, in addition to viruses, play a role in its etiology. Coronavirus disease 2019 (COVID-19) vaccine-induced myocarditis has recently been described, drawing attention to vaccine-induced myocarditis in children and adolescents. Its pathology is based on a series of complex immune responses, including initial innate immune responses in response to viral entry, adaptive immune responses leading to the development of antigen-specific antibodies, and autoimmune responses to cellular injury caused by cardiomyocyte rupture that releases antigens. Chronic inflammation and fibrosis in the myocardium eventually result in cardiac failure. Recent advancements in molecular biology have remarkably increased our understanding of myocarditis. In particular, microRNAs (miRNAs) are a hot topic in terms of the role of new biomarkers and the pathophysiology of myocarditis. Myocarditis has been linked with microRNA-221/222 (miR-221/222), miR-155, miR-10a*, and miR-590. Despite the lack of clinical trials of miRNA intervention in myocarditis yet, multiple clinical trials of miRNAs in other cardiac diseases have been aggressively conducted to help pave the way for future research, which is bolstered by the success of recently U.S. Food and Drug Administration-approved small-RNA medications. This review presents basic information and recent research that focuses on myocarditis and related miRNAs as a potential novel biomarker and the therapeutics.
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BACKGROUND: Childhood hypertension is associated with hypertension and metabolic syndrome in adulthood. Since the definition of childhood hypertension is based on the distribution of normative blood pressure (BP), a reference range is essential to create hypertension guidelines for children. We aimed to investigate the compatibility of the new Korean BP reference with the United States (US) BP reference based on the 2017 Clinical Practice Guideline. METHODS: We compared the new Korean reference BP values for children and adolescents aged 10 to 17 years with those in the 2017 Clinical Practice Guidelines. We also analyzed the differences in the prevalence of hypertension in Korean children and adolescents when reference value was applied. Considering Korean and US BP references together, linear trend lines were sought. RESULTS: Systolic BP (SBP) and diastolic BP (DBP) values in 95th percentiles showed no significant differences between the two BP references. Applying the two reference values, there was no significant difference in the prevalence of elevated BP and a combination of elevated BP and hypertension. Combining the Korean and US BP values and plotting them against age, approximate lines for the 90th and 95th SBP and DBP percentiles were observed. CONCLUSIONS: The BP values of the new Korean BP reference were similar to those of the US BP reference; they were reliable and interchangeable.
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RESEARCH QUESTION: Are preconception ovarian reserve markers, such as Anti-Mullerian hormone and antral follicle count, associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation? DESIGN: This is a secondary analysis of women with unexplained infertility who had a singleton live birth after enrollment in the Analysis of Multiple Intrauterine Gestations after Ovarian Stimulation (AMIGOS) trial that randomized couples to superovulation with letrozole, clomiphene, or gonadotropins with insemination for up to 4 cycles. RESULTS: Compared to controls (N = 156), women who developed preeclampsia (N = 17) had lower Anti-Mullerian hormone levels (2.24 ± 1.20 vs. 2.89 ± 2.32, p = 0.07) and lower antral follicle count (18 ± 7.67 vs. 21 ± 11.43, p = 0.16); though these differences were not statistically significant. There was no relationship between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.76-1.25) or antral follicle count (OR: 0.98, 95% CI 0.93-1.04) with preeclampsia and between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.83-1.17) and antral follicle count (OR: 1.00, 95% CI: 0.97-1.04) with placenta medicated pregnancy complications after adjusting for age, BMI and race. CONCLUSIONS: Preconception ovarian reserve markers are not associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation with insemination.
Subject(s)
Ovarian Follicle/metabolism , Ovarian Reserve , Placenta/metabolism , Pre-Eclampsia/diagnosis , Adult , Anti-Mullerian Hormone/blood , Female , Humans , Infant, Newborn , Infertility, Female/therapy , Live Birth , PregnancyABSTRACT
Hypertrophic cardiomyopathy (HCM) is characterized by ventricular wall hypertrophy with diastolic dysfunction. Pediatric HCM is distinguished from the adult in many aspects. Most children with HCM do not present clinically until the adolescent period, even when they are born with genetic mutations. Some infants with early-onset HCM present with massive progressive myocardial hypertrophy in the first few months of life, which is often fatal. The mortality of pediatric HCM peaks during the infantile and adolescent periods. These periods roughly correlate with children's growth spurt. Non-sarcomeric causes of HCM are more frequent in pediatric HCM, while sarcomeric causes are more common in adults. From the perspective of cardiac development, the fetal heart has immature cardiomyocytes, which are characterized by proliferation and exit their cell cycles with a decreased regenerative property after birth. In the perinatal period, there is a dynamic change in maturation of cardiomyocytes from immature to mature cells. Infants who are treated with steroids or born to mothers with diabetes or hyperthyroidism often show phenotypes of HCM, which gradually resolve. With remarkable advancement of molecular biology, understanding on maturation of cardiomyocytes has increased. Neonates undergo abrupt environmental changes during the transitional circulation, which is affected by oxygen, metabolic and hormonal fluctuations. Derangement in physiological transition to the normal postnatal environment may influence maturation of proliferative immature cardiomyocytes during early infancy. This article reviews updates of infantile HCM and recent molecular studies related to maturation of cardiomyocytes from the clinical point of view of identifying distinct characteristics of infantile HCM.
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Food insecurity is a major social determinant of health affecting more than 10% of Americans. Social determinants of health are increasingly recognized as a driving force of health inequities. It is well established that food insecurity leads to adverse health outcomes outside of pregnancy, such as obesity, hypertension, diabetes mellitus, and mental health problems. However, limited data exist about the impact of food insecurity during pregnancy on maternal and neonatal outcomes. Food insecurity and other social determinants of health are rarely addressed as part of routine obstetrical care. The COVID-19 pandemic has only exacerbated the crisis of food insecurity across the country, disproportionally affecting women and racial and ethnic minorities. Women's health providers should implement universal screening for maternal food insecurity and offer resources to women struggling to feed themselves and their families. Reducing maternal health inequities in the United States involves recognizing and addressing food insecurity, along with other social determinants of health, and advocating for public policies that support and protect all women's right to healthy food during pregnancy.
Subject(s)
COVID-19 , Pandemics , Female , Food Insecurity , Humans , Infant, Newborn , Pregnancy , Pregnant Women , SARS-CoV-2 , United States/epidemiologyABSTRACT
BACKGROUND: Multiple sclerosis (MS) and its animal model, the experimental autoimmune encephalomyelitis (EAE), are primarily characterized as dysfunction of the blood-brain barrier (BBB). Ginsenoside-Rg3-enriched Korean Red Ginseng extract (Rg3-KRGE) is known to exert neuroprotective, anti-inflammatory, and anti-oxidative effects on neurological disorders. However, effects of Rg3-KRGE in EAE remain unclear. METHODS: Here, we investigated whether Rg3-KRGE may improve the symptoms and pathological features of myelin oligodendroglial glycoprotein (MOG)35-55 peptide - induced chronic EAE mice through improving the integrity of the BBB. RESULTS: Rg3-KRGE decreased EAE score and spinal demyelination. Rg3-KRGE inhibited Evan's blue dye leakage in spinal cord, suppressed increases of adhesion molecule platelet endothelial cell adhesion molecule-1, extracellular matrix proteins fibronection, and matrix metallopeptidase-9, and prevented decreases of tight junction proteins zonula occludens-1, claudin-3, and claudin-5 in spinal cord following EAE induction. Rg3-KRGE repressed increases of proinflammatory transcripts cyclooxygenase-2, inducible nitric oxide synthase, interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha, but enhanced expression levels of anti-inflammatory transcripts arginase-1 and IL-10 in the spinal cord following EAE induction. Rg3-KRGE inhibited the expression of oxidative stress markers (MitoSOX and 4-hydroxynonenal), the enhancement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and NOX4, and NADPH activity in the spinal cord of chronic EAE mice. Furthermore, apocynin, a NOX inhibitor, mimicked beneficial effects of Rg3-KRGE in chronic EAE mice. CONCLUSION: Our findings suggest that Rg3-KRGE might alleviate behavioral symptoms and pathological features of MS by improving BBB integrity through modulation of NOX2/4 expression.
ABSTRACT
It has been previously indicated that gintonin, which is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand, restores memory dysfunctions in an APPswe/PSEN-1 double-transgenic mouse model of Alzheimer's disease (AD Tg mice) by attenuating ß-amyloid plaque deposition, recovering cholinergic dysfunctions and upregulating hippocampal neurogenesis in the cortex and hippocampus. Although ß-amyloid plaque depositions in AD is accompanied with disruptions of brain microvessels, including the brain-blood barrier (BBB), it is unknown whether gintonin exerts protective effects on brain microvascular dysfunctions in AD Tg mice. In the present study, the effects of gintonin-enriched fraction (GEF) on the changes in ß-amyloid plaque depositions, brain permeability of Evans blue, and microvascular junctional proteins were investigated in AD Tg mice. Long-term oral administration of GEF reduced ß-amyloid plaque depositions in the cortex and hippocampus of AD Tg mice. GEF treatment also reduced the permeability of Evans blue through BBB and decreased immunoreactivity of platelet endothelial cell adhesion molecule-1 (a marker of BBB disruption) in the cortex and hippocampus of AD Tg mice in a dose-dependent manner. However, GEF elevated the protein expression of occludin, claudin-5 and zonula occludens-1, which are tight-junction proteins. The present results demonstrated that long-term oral GEF treatment not only attenuates ß-amyloid plaque depositions in the brain but also exhibits protective effects against microvascular disruptions in AD Tg mice. Finally, GEF exhibits anti-AD effects through attenuation of ß-amyloid plaque depositions and protection against brain microvascular damage in an AD animal model.